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Zarandi PK, Ghiasi M, Heiat M. The role and function of lncRNA in ageing-associated liver diseases. RNA Biol 2025; 22:1-8. [PMID: 39697114 PMCID: PMC11660375 DOI: 10.1080/15476286.2024.2440678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 10/09/2024] [Accepted: 12/04/2024] [Indexed: 12/20/2024] Open
Abstract
Liver diseases are a significant global health issue, characterized by elevated levels of disorder and death. The substantial impact of ageing on liver diseases and their prognosis is evident. Multiple processes are involved in the ageing process, which ultimately leads to functional deterioration of this organ. The process of liver ageing not only renders the liver more susceptible to diseases but also compromises the integrity of other organs due to the liver's critical function in metabolism regulation. A growing body of research suggests that long non-coding RNAs (lncRNAs) play a significant role in the majority of pathophysiological pathways. They regulate gene expression through a variety of interactions with microRNAs (miRNAs), messenger RNAs (mRNAs), DNA, or proteins. LncRNAs exert a major influence on the progression of age-related liver diseases through the regulation of cell proliferation, necrosis, apoptosis, senescence, and metabolic reprogramming. A concise overview of the current understanding of lncRNAs and their potential impact on the development of age-related liver diseases will be provided in this mini-review.
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Affiliation(s)
- Peyman Kheirandish Zarandi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
- Cancer Biology Signaling Pathway Interest Group (CBSPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohsen Ghiasi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
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2
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Shah N, Faridi M, Bhave S, Ghosh A, Balasubramanian S, Arankalle V, Shah R, Chitkara AJ, Wadhwa A, Chaudhry J, Srinivasan R, Surendranath M, Sapru A, Mitra M. Expert consensus and recommendations on the live attenuated hepatitis A vaccine and immunization practices in India. Hum Vaccin Immunother 2025; 21:2447643. [PMID: 39819191 PMCID: PMC11740680 DOI: 10.1080/21645515.2024.2447643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025] Open
Abstract
While Hepatitis A Virus (HAV) vaccination in global immunization programs has shown a virtual elimination of the disease within few years of the vaccination program, changing epidemiological landscape in India underscores the need for evidence-based, updated guidance on immunization practices. In May 2024, a panel of 15 distinguished opinion leaders and an organizing committee convened for an intensive, face-to-face advisory board meeting on high burden of HAV infection among adults, increased mortality rate in adolescents, symptomatic presentation in children, and evolving landscape globally and within India. Extensive comparable deliberations on long-term follow-up data from India and data from country of origin advocated immunogenicity, tolerability, and long-term protective effects of single-dose live attenuated HAV vaccine in children. Finally, a consensus was achieved on recognition of increased global attention toward HAV prevention through vaccination coverage. The need for a single dose of live attenuated HAV vaccine was an important outcome of this meeting.
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Affiliation(s)
- Nitin Shah
- Department of Paediatrics, P. D. Hinduja Hospital & Medical Research Centre, Mumbai, India
| | - M.M.A. Faridi
- Department of Paediatrics and Neonatology, Era’s Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Sheila Bhave
- Department of Paediatrics, KEM Hospital Research Centre, Pune, India
| | - Apurba Ghosh
- Department of Paediatrics, Institute of Child Health, Kolkata, India
| | - S. Balasubramanian
- Department of Pediatrics, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India
| | - Vidya Arankalle
- Department of Communicable Diseases, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Raju Shah
- Department of Pediatrics, Ankur Children Hospital, Ahmedabad, Gujarat, India
| | | | - Arun Wadhwa
- Department of Pediatrics, Dr. Wadhwa’s Clinic, New Delhi, India
| | - Jaydeep Chaudhry
- Department of Paediatrics, Institute of Child Health, Kolkata, India
| | | | - M. Surendranath
- Department of Pediatrics, Vijay Marie Hospital, Hyderabad, India
| | - Amita Sapru
- Department of Paediatrics, KEM Hospital Research Centre, Pune, India
| | - Monjori Mitra
- Department of Paediatrics, Institute of Child Health, Kolkata, India
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3
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Chen Q, Ma J, Wu R, Wang Y, Ma X, Zheng X, Jin H. Factors influencing hepatitis B vaccination intention and behavior among college students in Tibet: Insights from the expanded theory of planned behavior. Hum Vaccin Immunother 2025; 21:2452026. [PMID: 39817760 PMCID: PMC11740673 DOI: 10.1080/21645515.2025.2452026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025] Open
Abstract
Hepatitis B (Hep B) remains a critical public health issue globally, particularly in Tibet, where vaccination rates and influencing factors among college students are yet understudied. This study applies a cross-sectional design to investigate the Hep B vaccination rate among 1,126 college students in Tibet and utilizes the expanded theory of planned behavior (ETPB) to identify vaccination behavior intention (BI) and vaccination behavior (VB). Stratified cluster sampling across three universities was used to assess behavioral attitudes (BA), subjective norms (SN), perceived behavioral control (PBC), past vaccination history (PVH) and vaccination knowledge (VK), and used structural equation modeling (SEM) for model validation and multi-group comparison. Results indicated that 16.3% of students had received the Hep B vaccine. VK notably improved BA toward vaccination (β = 0.518, p < .001). BA (β = 0.232, p < .001), PBC (β = 0.239, p < .001), SN (β = 0.385, p < .001) positively influenced BI. However, PVH failed to predict BI. BI (β = 0.448, p < .001) and PVH (β = 0.127, p < .001) were significant predictors of VB. Significant ethnic variations were noted. The positive effect of PVH on VB (β = 0.151, p < .001) and the mediating role of PBC in VB (β = 0.076, p < .05) were significant among Tibetan students. The effect of VK on BA was stronger among Tibetans (β = 0.503, p < .05),while the impact of attitude on BI was more pronounced among Han students (β = 0.366, p < .05). The vaccination rate for Hep B among college students in Tibet is relatively low, and the ETPB model effectively explains their vaccination intentions and behaviors. Tailored intervention strategies for Tibetan and Han students are recommended to boost vaccination rates effectively.
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Affiliation(s)
- Qi Chen
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, PR China
- Department of Prevention and Health Care, Affiliated Hospital of Xizang Minzu University, Xianyang, PR China
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, P.R. China
| | - Jun Ma
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, PR China
| | - Ruipeng Wu
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, P.R. China
| | - Yingting Wang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, P.R. China
| | - Xiaoxin Ma
- Department of General Practice, Chengguan Liangdao Subdistrict Community Health Service Center, Lhasa, PR China
| | - Xiaolei Zheng
- Department of General Practice, Chengguan Liangdao Subdistrict Community Health Service Center, Lhasa, PR China
| | - Hui Jin
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, PR China
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4
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Huang PH, Nowalk MP, Zimmerman RK, Olson SM, Talbot HK, Zhu Y, Gaglani M, Murthy K, Monto AS, Martin ET, Silveira FP, Balasubramani G. Vaccine effectiveness against influenza-associated hospitalizations in adults with liver disease, 2015-2020: US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN). Hum Vaccin Immunother 2025; 21:2457205. [PMID: 39875316 PMCID: PMC11776484 DOI: 10.1080/21645515.2025.2457205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/07/2025] [Accepted: 01/20/2025] [Indexed: 01/30/2025] Open
Abstract
Influenza causes 100,000-710,000 hospitalizations annually in the U.S. Patients with liver disease are at higher risk of severe outcomes following influenza infection. This study evaluated influenza vaccine effectiveness (VE) against influenza-associated hospitalization among adults with liver disease. Data from the U.S. Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN), a test-negative case-control study, from 2015 to 2020 were used to estimate VE among adults ≥18 years admitted for acute respiratory illness. VE was calculated as (1-adjusted odds ratio)*100%, comparing the odds of vaccine receipt between laboratory-confirmed influenza cases and test-negative controls using multiple logistic regression with inverse probability of treatment weighting (IPTW). In total, 1,622 (12.8%) of 12,704 adults had ≥1 liver disease(s). Compared with those without liver disease, adults with liver disease were more likely to be admitted to the intensive care unit (15.7% vs 12.8%, p = .001) or to die in hospital (3.0% vs 1.4%, p < .001). The IPTW-adjusted VE against influenza-associated hospitalization was 27% (95% confidence interval [CI], 22-32%) among patients without liver disease, but the VE of 11% (95% CI, -8-26%) was not significant among those with liver disease. Significant effect modification of VE by the presence of liver disease was found (p < .05 for interaction term). While influenza vaccination significantly reduced the risk of influenza-associated hospitalization among adults without liver disease, the protective effect was not significant among those with liver disease. Further studies are warranted to evaluate influenza VE in patients with different types of liver disease and with specific vaccine formulations.
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Affiliation(s)
- Po-Han Huang
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | | | | | - Samantha M. Olson
- Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - H. Keipp Talbot
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yuwei Zhu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Manjusha Gaglani
- Department of Research Analytics and Development, Baylor Scott & White Health, Temple, TX, USA
- Department of Pediatrics, Baylor College of Medicine, Temple, TX, USA
| | - Kempapura Murthy
- Department of Research Analytics and Development, Baylor Scott & White Health, Temple, TX, USA
| | - Arnold S. Monto
- Center for Respiratory Virus Research and Response, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Emily T. Martin
- Center for Respiratory Virus Research and Response, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Fernanda P. Silveira
- Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, PA, USA
| | - G.K. Balasubramani
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
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5
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Pu R, Wang Z, Shang X, Lu J, Xu J, Xing Y. Chronic hepatitis B infection and pre-eclampsia/eclampsia: a Mendelian randomisation study. J OBSTET GYNAECOL 2025; 45:2500972. [PMID: 40372048 DOI: 10.1080/01443615.2025.2500972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 04/26/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND This study aimed to investigate the potential causal association between chronic hepatitis B (CHB) infection and the risk of pre-eclampsia/eclampsia using a Mendelian randomisation (MR) design. METHODS We conducted a two-sample MR analysis using genome-wide association study (GWAS) summary statistics from three large-scale datasets. For CHB infection, we used data from 351,885 individuals UK Biobank. For pre‑eclampsia/eclampsia, we analysed two FinnGen datasets with sample sizes of 118,291 and 126,760 individuals, respectively. Genetic variants strongly associated with CHB infection (p < 5 × 10-8) were selected as instrumental variables. The inverse-variance weighted (IVW) method was employed as the primary analysis. Sensitivity analyses included MR-Egger regression, weighted median, weighted mode and MR-PRESSO. Cochran's Q test and MR-Egger intercept tests were performed to assess heterogeneity and horizontal pleiotropy, respectively. RESULTS MR analysis revealed significant positive genetic associations between CHB infection and increased risk of pre-eclampsia (OR = 1.154, 95%CI = 1.014-1.313, p = .029) and eclampsia (OR = 1.561, 95%CI = 1.030-2.366, p = .035). Findings were robust across sensitivity analyses for both outcomes. CONCLUSIONS Our study provides genetic evidence that CHB infection increases the risk of both pre-eclampsia and eclampsia. These findings suggest that considering CHB status as a risk factor and implementing targeted HBV screening programmes may be beneficial for pregnant women.
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Affiliation(s)
- Rui Pu
- School of Stomatology, Stomatology Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Zhen Wang
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
| | - Xiaopeng Shang
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
| | - Jiexia Lu
- School of Stomatology, Stomatology Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Jiling Xu
- School of Stomatology, Stomatology Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Yuhang Xing
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
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6
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Comertpay B, Gov E. Multiomics Analysis and Machine Learning-based Identification of Molecular Signatures for Diagnostic Classification in Liver Disease Types Along the Microbiota-gut-liver Axis. J Clin Exp Hepatol 2025; 15:102552. [PMID: 40292334 PMCID: PMC12019836 DOI: 10.1016/j.jceh.2025.102552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/17/2025] [Indexed: 04/30/2025] Open
Abstract
Background Liver disease, responsible for around two million deaths annually, remains a pressing global health challenge. Microbial interactions within the microbiota-gut-liver axis play a substantial role in the pathogenesis of various liver conditions, including early chronic liver disease (eCLD), chronic liver disease (CLD), acute liver failure (ALF), acute-on-chronic liver failure (ACLF), non-alcoholic fatty liver disease (NAFLD), steatohepatitis, and cirrhosis. This study aimed to identify key molecular signatures involved in liver disease progression by analyzing transcriptomic and gut microbiome data, and to evaluate their diagnostic utility using machine learning models. Methods Transcriptomic analysis identified differentially expressed genes (DEGs) that, when integrated with regulatory elements microRNAs, transcription factors, receptors, and the gut microbiome highlight disease-specific molecular interactions. To assess the diagnostic potential of these molecular signatures, a two-step analysis involving principal component analysis (PCA) and Random Forest classification was conducted, achieving accuracies of 75% for ALF and 89% for NAFLD. Additionally, machine learning algorithms, including K-neighbors, multi-layer perceptron (MLP), decision tree, Random Forest, logistic regression, gradient boosting, CatBoost, Extreme Gradient Boosting (XGB), and Light Gradient Boosting Machine (LGBM), were applied to gene expression data for ALF and NAFLD. Results Key genes including CLDN14, EGFR, GSK3B, MYC, and TJP2, alongside regulatory miRNAs let-7a-5p, miR-124-3p, and miR-195-5p and transcription factors NFKB1 and SP1 may be suggested as critical to liver disease progression. Additionally, gut microbiota members, Dictyostelium discoideum and Eikenella might be novel candidates associated with liver disease, highlighting the importance of the gut-liver axis. The Random Forest model reached 75% accuracy and 83% area under the curve for ALF, while NAFLD classification achieved 100% accuracy, precision, recall, and area under the curve underscoring robust diagnostic potential. Conclusion This study establishes a solid foundation for further research and therapeutic advancement by identifying key biomolecules and pathways critical to liver disease. Additional experimental validation is needed to confirm clinical applicability.
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Affiliation(s)
- Betul Comertpay
- Department of Bioengineering, Faculty of Engineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
| | - Esra Gov
- Department of Bioengineering, Faculty of Engineering, Adana Alparslan Türkeş Science and Technology University, Adana, Turkey
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Chen L, Chen Z, Shi D, Ke H, Mao C, Wan M. Sulfur dioxide-releasing nanomotors improve the therapeutic effect of liver fibrosis by restoring the fenestrae of sinusoids. J Colloid Interface Sci 2025; 692:137557. [PMID: 40233557 DOI: 10.1016/j.jcis.2025.137557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/17/2025]
Abstract
The dual barriers formed by the capillarized liver sinusoids and excessive deposited extracellular matrix (ECM) significantly impede the retention of therapeutic agents in the fibrotic liver. Currently, there are limited reports on strategies capable of simultaneously overcoming these barriers. Here, we propose sulfur dioxide (SO2)-releasing nanomotors based on endogenous in vivo reactions to restore the fenestrae of sinusoids and degrade ECM by activating the endogenous signaling pathway to improve the retention of therapeutic agents in the damaged liver. These nanomotors leverage the specific enzyme concentration gradient in damaged liver tissue as a chemoattractant signal, guiding their targeted delivery. The nanomotors incorporate an l-cysteine-based substrate that, upon enzymatic catalysis, generates SO2. The released SO2 can upregulate the cyclic guanosine monophosphate expression to restore the fenestrated phenotype of liver sinusoidal endothelial cells. Concurrently, SO2 can stimulate the endogenous nitric oxide production to induce matrix metalloproteinase-1 activation to facilitate the collagen degradation. The animal experimental model also demonstrates the effective retention of nanomotors in damaged liver tissue and reversal of liver fibrosis.
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Affiliation(s)
- Lin Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Zhengwei Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Di Shi
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Haifeng Ke
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
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Yu Z, Luo J, An W, Wei H, Song A, Mao Y, Li M, He L, Xiao F, Gao Q, Wei H. EOGT knockdown promotes ferroptosis and inhibits hepatocellular carcinoma proliferation by regulating SLC7A11 via HEY1. Cell Signal 2025; 132:111772. [PMID: 40154588 DOI: 10.1016/j.cellsig.2025.111772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 03/19/2025] [Accepted: 03/25/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by a complex molecular landscape. EGF Domain Specific O-linked β-N-acetylglucosamine transferase (EOGT) functions as an O-GlcNAc transferase with specific activity towards proteins containing epidermal growth factor (EGF) repeats. Although it is known to potentially play an oncogenic role in HCC, the exact mechanisms remain unclear. Induction of ferroptosis is a primary mechanism by which anticancer drugs such as sorafenib treat HCC. This study aimed to elucidate the expression profile of EOGT in HCC and its relationship with ferroptosis, as well as to investigate the underlying molecular mechanisms. METHODS Utilizing bioinformatics resources, we explored the potential role of EOGT in HCC. The effects of EOGT on HCC cell behavior were examined using cell models and subcutaneous xenograft models in nude mice. Further insights into the molecular mechanisms were obtained through RNA-seq in cell models, hydrodynamic modeling in mice, Western blotting, chromatin immunoprecipitation (ChIP) sequencing, and dual-luciferase reporter assays to analyze the interaction between HEY1 and SLC7A11. Multiple validation steps were employed to thoroughly investigate the roles of these factors in the regulation of ferroptosis in HCC. RESULTS Our findings revealed that EOGT is upregulated in HCC and correlates with poor prognosis and drug resistance. Knockdown of EOGT inhibited HCC cell proliferation and enhanced sensitivity to ferroptosis by downregulating SLC7A11, a process mediated by HEY1. These results were confirmed by cell viability assays, quantitative real-time PCR (qPCR), Western blotting, and dual-luciferase reporter gene assays. CONCLUSIONS EOGT promotes HCC proliferation and inhibits ferroptosis by modulating the HEY1-SLC7A11 axis, suggesting a potential therapeutic target for HCC treatment.
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Affiliation(s)
- Zhe Yu
- Department of Gastroenterology, Peking University Ditan Teaching Hospital, Beijing 100015, China
| | - Jing Luo
- Department of Gastroenterology, Peking University Ditan Teaching Hospital, Beijing 100015, China
| | - Wen An
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Herui Wei
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Aqian Song
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yuanpeng Mao
- Department of Gastroenterology, Peking University Ditan Teaching Hospital, Beijing 100015, China
| | - Mengqi Li
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Lingling He
- Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Fan Xiao
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Qi Gao
- Beijing Youngen Technology Co., Ltd., Beijing 102629, China.
| | - Hongshan Wei
- Department of Gastroenterology, Peking University Ditan Teaching Hospital, Beijing 100015, China; Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
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Rong G, Liu J, Yang Y, Wang S, Cao W. Skullcapflavone II induces G2/M phase arrest in hepatic stellate cells and suppresses hepatic fibrosis. Eur J Pharmacol 2025; 998:177522. [PMID: 40113067 DOI: 10.1016/j.ejphar.2025.177522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 03/14/2025] [Accepted: 03/14/2025] [Indexed: 03/22/2025]
Abstract
RESEARCH PURPOSE This investigation explored the therapeutic effects and mechanisms of Skullcapflavone II in hepatic fibrosis (HF). MATERIALS AND METHODS The optimal concentration of Skullcapflavone II for LX2 hepatic stellate cells was determined using the CCK8 assay. EdU staining and flow cytometry were utilised to assess cell proliferation and G2/M phase arrest. Mice with carbon tetrachloride-triggered HF were administered Skullcapflavone II at low (15 mg/day), medium (30 mg/day), and high (60 mg/day) doses. Subsequently, hepatic damage and fibrosis were assessed via body weight, liver index, biochemical markers, and histopathological staining. Immunohistochemistry for Collagen I and α-SMA were utilised to examine hepatic stellate cell (HSC) activation. RNA sequencing was utilised to ascertain differentially expressed genes. Molecular docking simulated interactions among Skullcapflavone II and target proteins as well as outcomes were validated by implementing western blotting, immunohistochemistry, and RT-qPCR. RESULTS Skullcapflavone II inhibited LX2 cell proliferation and triggered G2/M phase arrest. Its optimal intervention concentration was 160 μM. In vivo, it ameliorated hepatic function, diminished serum indicators of fibrosis, and suppressed HSC activation. Diminished collagen sediment was validated utilising histopathological examination, whereas immunohistochemistry indicated decreased expression of Collagen I and α-SMA. Additionally, molecular docking showed strong binding of Skullcapflavone II to DNA replication-related proteins. Western blotting and RT-qPCR implied that Skullcapflavone II disrupted DNA replication, which triggered G2/M arrest and hindered HSCs activation and proliferation. CONCLUSION The abovementioned mechanisms of action of Skullcapflavone II substantiate its prospective clinical application against HF.
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Affiliation(s)
- Guoyi Rong
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401331, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Jun Liu
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China; Department of Rehabilitation Medicine of Jiangbei Campus, The First Affiliated Hospital of Army Medical University, Chongqing, 401151, China
| | - Yunheng Yang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401331, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Shang Wang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401331, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Wenfu Cao
- Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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10
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Martínez-Sánchez FD, Corredor-Nassar MJ, Feria-Agudelo SM, Paz-Zarza VM, Martinez-Perez C, Diaz-Jarquin A, Manzo-Santana F, Sánchez-Gómez VA, Rosales-Padron A, Baca-García M, Mejía-Ramírez J, García-Juárez I, Higuera-de la Tijera F, Pérez-Hernandez JL, Barranco-Fragoso B, Méndez-Sánchez N, Córdova-Gallardo J. Factors Associated With Advanced Liver Fibrosis in a Population With Type 2 Diabetes: A Multicentric Study in Mexico City. J Clin Exp Hepatol 2025; 15:102536. [PMID: 40226389 PMCID: PMC11982025 DOI: 10.1016/j.jceh.2025.102536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 02/23/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease, primarily due to insulin resistance and type 2 diabetes (T2D). Despite the strong link between T2D and MASLD, identifying and treating liver fibrosis in T2D patients is still poor. This study aimed to identify the factors related to advanced liver fibrosis in T2D patients. METHODS This retrospective observational study used medical records from four centers in Mexico City from 2018 to 2023. The study included 2000 patients with T2D. Liver fibrosis was evaluated using the Fibrosis-4 (FIB-4) index, and insulin resistance was assessed using the estimated glucose disposal rate (eGDR). RESULTS The mean age of the patients was 58.9 years, with 63.7% being women. The median duration of T2D was 7 years, and the mean HbA1c was 7.63%. Overall, 20.4% had advanced liver fibrosis. The multivariate logistic regression analysis showed that diabetes duration >10 years {odds ratio (OR) = 2.105 (95% confidence interval [CI] 1.321-3.355)}, fasting glucose >126 mg/dL (OR = 1.568 [95% CI 1.085-2.265]), and microalbuminuria >300 mg/24 h (OR = 2.007 [95% CI 1.134-3.552]) were associated with advanced liver fibrosis. Conversely, the eGDR (OR = 0.805 [95% CI 0.703-0.888]), statins (OR = 0.111 [95% CI 0.073-0.168]), and pioglitazone (OR = 0.082 [95% CI 0.010-0.672]) were inversely associated. CONCLUSION Longer diabetes duration, insulin resistance, and microalbuminuria are independently linked to advanced liver fibrosis in T2D patients. Statins and pioglitazone may protect against liver fibrosis. Enhanced screening and management strategies targeting these factors could slow fibrosis progression and reduce the global burden of MASLD.
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Affiliation(s)
- Froylan D. Martínez-Sánchez
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Escolar 411A, Copilco Universidad, Coyoacán, 04360 Ciudad de México, Mexico
- Department of Internal Medicine, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
- Department of Hepatology, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Maria J. Corredor-Nassar
- Department of Internal Medicine, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Sandra M. Feria-Agudelo
- Department of Internal Medicine, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Victor M. Paz-Zarza
- Department of Internal Medicine, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Carolina Martinez-Perez
- Department of Hepatology, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Alejandra Diaz-Jarquin
- Department of Internal Medicine, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Fátima Manzo-Santana
- Department of Gastroneterology, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran”, Vasco de Quiroga 15, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Victor A. Sánchez-Gómez
- Department of Gastroneterology, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran”, Vasco de Quiroga 15, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Alondra Rosales-Padron
- Department of Gastroneterology, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran”, Vasco de Quiroga 15, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Mónica Baca-García
- Department of Gastroneterology and Hepatology, Hospital General de Mexico “Dr. Eduardo Liceaga”, Dr. Balmis 148, Doctores, Cuauhtémoc, 06720 Ciudad de México, Mexico
| | - Jessica Mejía-Ramírez
- Department of Gastroneterology and Hepatology, Hospital General de Mexico “Dr. Eduardo Liceaga”, Dr. Balmis 148, Doctores, Cuauhtémoc, 06720 Ciudad de México, Mexico
| | - Ignacio García-Juárez
- Department of Gastroneterology, Instituto Nacional de Ciencias Medicas y Nutricion “Salvador Zubiran”, Vasco de Quiroga 15, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
| | - Fatima Higuera-de la Tijera
- Department of Gastroneterology and Hepatology, Hospital General de Mexico “Dr. Eduardo Liceaga”, Dr. Balmis 148, Doctores, Cuauhtémoc, 06720 Ciudad de México, Mexico
| | - Jose L. Pérez-Hernandez
- Department of Gastroneterology and Hepatology, Hospital General de Mexico “Dr. Eduardo Liceaga”, Dr. Balmis 148, Doctores, Cuauhtémoc, 06720 Ciudad de México, Mexico
| | - Beatriz Barranco-Fragoso
- Department of Gastroneterology, Centro Medico Nacional 20 de Noviembre, ISSSTE, Félix Cuevas 540, Col del Valle Sur, Benito Juárez, 03104 Ciudad de México, Mexico
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Tlalpan, 14050, Ciudad de México, Mexico
| | - Jacqueline Córdova-Gallardo
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Escolar 411A, Copilco Universidad, Coyoacán, 04360 Ciudad de México, Mexico
- Department of Hepatology, Hospital General “Dr. Manuel Gea González”, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan, 14080 Ciudad de México, Mexico
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11
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Gruevska A, Leslie J, Perpiñán E, Maude H, Collins AL, Johnson S, Evangelista L, Sabey E, French J, White S, Moir J, Robinson SM, Alrawashdeh W, Thakkar R, Forlano R, Manousou P, Goldin R, Carling D, Hoare M, Thursz M, Mann DA, Cebola I, Posma JM, Safinia N, Oakley F, Hall Z. Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver. Metabolism 2025; 168:156237. [PMID: 40127860 DOI: 10.1016/j.metabol.2025.156237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/26/2025]
Abstract
BACKGROUND AND AIMS Steatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development. METHODS We analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs). RESULTS Bulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected >40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs. CONCLUSIONS Our spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.
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Affiliation(s)
- Aleksandra Gruevska
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Elena Perpiñán
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, United Kingdom
| | - Hannah Maude
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Amy L Collins
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Sophia Johnson
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Laila Evangelista
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Eleanor Sabey
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Steven White
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - John Moir
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Stuart M Robinson
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Wasfi Alrawashdeh
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Rohan Thakkar
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Roberta Forlano
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Pinelopi Manousou
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Robert Goldin
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - David Carling
- MRC Laboratory of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Matthew Hoare
- Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom
| | - Mark Thursz
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Inês Cebola
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Joram M Posma
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Niloufar Safinia
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, United Kingdom
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom; FibroFind, Unit 26/27, Baker's Yard, Christon Road, Newcastle upon Tyne, United Kingdom
| | - Zoe Hall
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
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12
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Wang Z, Li Y, Wang X, Zhang W, Chen Y, Lu X, Jin C, Tu L, Jiang T, Yang Y, Ma X, Zeng J, Wen Y, Efferth T. Precision Strike Strategy for Liver Diseases Trilogy with Xiao-Chai-Hu Decoction: A Meta-Analysis with Machine Learning. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156796. [PMID: 40347886 DOI: 10.1016/j.phymed.2025.156796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/30/2025] [Accepted: 04/20/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND AND PURPOSE The progression from hepatitis to liver fibrosis (LF) and ultimately to hepatic carcinoma (HCC) represents the advanced stages of various liver diseases. Currently, no universal treatment effectively addresses all three conditions. The Traditional Chinese Medicine formula Xiao-Chai-Hu decoction (XCHD) has shown promise in treating hepatitis, inhibiting LF, and serving as an adjunct therapy for HCC. This study evaluates the efficacy and optimal treatment durations of XCHD in managing these liver diseases using meta-analysis and machine learning techniques. METHODS Registered in the PROSPERO database (CRD42024534445), this meta-analysis systematically searched seven databases, including 54 studies with a total of 5,710 patients. Statistical analysis was performed using Stata 17.0. Five machine learning models-Random Forest (RF), XGBoost, Lasso, Multilayer Perceptron (MLP), and a stacking model combining these algorithms-were employed to analyze the data and predict the time-effect relationships. The optimal durations of XCHD treatment for the liver disease trilogy were subsequently projected. RESULTS XCHD significantly improved the primary outcome indicators for hepatitis, liver fibrosis, and HCC. Additionally, XCHD demonstrated a beneficial effect on liver dysfunction caused by these diseases. Machine learning predicted the optimal treatment durations of XCHD as 12 weeks for hepatitis, 20.31 weeks for liver fibrosis, and 12 weeks for HCC. CONCLUSION XCHD is effective in treating the liver disease trilogy, with optimal treatment durations of 12 weeks for hepatitis and HCC, and 20.31 weeks for liver fibrosis. These findings support the potential of XCHD in developing precise clinical strategies for managing liver diseases. This study innovatively integrates meta-analysis with machine learning to determine the optimal treatment durations, providing a novel approach for evidence-based precision medicine in Traditional Chinese Medicine.
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Affiliation(s)
- Zexin Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaobao Wang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaohua Lu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Chunmei Jin
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Lang Tu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Tao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiqin Yang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
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13
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Gou Y, Li A, Dong X, Hao A, Li J, Xiang H, Rahaman S, He TC, Fan J. Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease. Genes Dis 2025; 12:101554. [PMID: 40330148 PMCID: PMC12052676 DOI: 10.1016/j.gendis.2025.101554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 05/08/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) patients have multiple metabolic disturbances, with markedly elevated levels of lactate. Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications. Monocarboxylate transporter 4 (MCT4) is highly expressed in hepatocytes and responsible for transporting intracellular lactate out of the cell. To explore whether elevated MCT4 levels played any role in NAFLD development, we overexpressed and silenced MCT4 in hepatocytes and performed a comprehensive in vitro and in vivo analysis. Our results revealed that MCT4 overexpression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism. Conversely, silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites, resulting in hepatic steatosis. In a mouse model of NAFLD, we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis. Mechanistically, MCT4 alleviated hepatic steatosis by regulating a group of hub genes such as Arg2, Olr1, Cd74, Mmp8, Irf7, Spp1, and Apoe, which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response, such as PPAR, HIF-1, TNF, IL-17, PI3K-AKT, Wnt, and JAK-STAT. Collectively, our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.
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Affiliation(s)
- Yannian Gou
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- Western Institute of Digital-Intelligent Medicine, Chongqing 401329, China
| | - Aohua Li
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xiangyu Dong
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Ailing Hao
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Jiajia Li
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Han Xiang
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Saidur Rahaman
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, School of Clinical Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- Western Institute of Digital-Intelligent Medicine, Chongqing 401329, China
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14
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Bing Y, Zou X, Yang X, Yang X, Sheng J, Qu Z. Mechanism elucidation and biochemometric-based screening of substances in Schisandra chinensis leaves for alcoholic liver injury. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156757. [PMID: 40250032 DOI: 10.1016/j.phymed.2025.156757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 04/07/2025] [Accepted: 04/10/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND Alcoholic liver injury (ALI) represents a major international public health concern with no targeted pharmacological intervention and a dearth of clinical trial-approved medications for its management. The dried leaves of Schisandra chinensis (SCL) are rich in flavonoids, lignans, polysaccharides, and other active ingredients with anti-inflammatory, antioxidant, and antitumour activities and are commonly applied in the treatment of osteoarthritis, diabetes, and neurodegenerative diseases. The crude lignans of SCL have been reported to treat CCl4-induced acute liver injury, and SCL tea has also been reported to have hepatoprotective effects. The components of SCL are currently the focus of investigation; however, conclusive pharmacological studies on SCL in the treatment of ethanol-induced ALI are rare. PURPOSE This study aimed to identify the bioactive components and elucidate the mechanism of action of SCL against ALI. METHODS The optimal month for harvesting SCL was first determined using a cellular ALI model. Immediately afterwards, the efficacy of SCL was evaluated based on cellular ALI model and ALI mice model. The expression levels of NLRP3 inflammasome-associated proteins were examined via Western blotting. To identify the bioactive components of SCL, the common components in 10 batches of SCL were identified by UPLC‒Q-TOF‒MS/MS. Subsequent analysis via correlation identified common elements' pharmacological impacts, filtering for substances with notable contributions to effectiveness. Finally, potential bioactive components were further identified through molecular docking and verified in ALIcell models. RESULTS SCL has the best efficacy in early August, and by improving hepatic aminotransferase activity, regulating lipid metabolism, alleviating oxidative stress, reducing the release of inflammatory mediators, and inhibiting the expression of NLRP3-related pyroptosis proteins, it plays a role in alleviating ALI. A total of 32 common components were identified in 10 batches of SCL. Through correlation analysis, 10 functional components, including Schisandrin B, Angeloylgomisin Q, Chlorogenic acid, Rutin, Schisandrin C, p-Hydroxycinnamic acid, Schisandrin A, Schisandrol A, Gomisin J, and Schisantherin B, were screened. Further screening using molecular docking identified 4 key functional components, Rutin, Chlorogenic acid, Schisandrin C, and Schisantherin B, which were verified to mitigate ethanol-induced liver damage. CONCLUSION The present study demonstrated that SCL prevented ALI, with the main contributing components being rutin, chlorogenic acid, pentosidine C and pentosidine B. Hence, our latest study offers significant experimental proof indicating SCL as a promising prospect for ALI prevention.
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Affiliation(s)
- Yifan Bing
- School of Pharmacy, Harbin University of Commerce, Harbin 150076, China.
| | - Xiang Zou
- Engineering Research Center on Natural Antineoplastic Drugs, Ministry of Education, Harbin University of Commerce, Harbin 150076, China.
| | - Xiaolong Yang
- School of Pharmacy, Harbin University of Commerce, Harbin 150076, China.
| | - Xuejing Yang
- School of Pharmacy, Harbin University of Commerce, Harbin 150076, China.
| | - Jiejing Sheng
- School of Pharmacy, Harbin University of Commerce, Harbin 150076, China.
| | - Zhongyuan Qu
- School of Pharmacy, Harbin University of Commerce, Harbin 150076, China.
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Ai R, Tian M, Sun J, He S, Cui Z, Yang Y, Hou X, Zhao Y, Dou T, Chen X, Wang J. Mogroside V prevents ethanol-induced hangover and liver damage by reducing oxidative stress, steatosis and inflammation. Biochem Biophys Res Commun 2025; 766:151912. [PMID: 40306161 DOI: 10.1016/j.bbrc.2025.151912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/04/2025] [Accepted: 04/25/2025] [Indexed: 05/02/2025]
Abstract
Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD). Previous studies presented Mogroside V (MV) have protective effects on against nonalcoholic fatty liver disease. however, the effects of MV on ethanol-induced hangover and liver damage remains to be elucidated. Herein, we investigated the potential effects of MV in relieving hangover and mitigating liver injury induced by ethanol. MV significantly reduced blood ethanol, liver histological alterations and serum ALT, AST、TG levels in ethanol-treated mice. Moreover, MV accelerates alcohol metabolism by inhibiting the upregulation of CYP2E1 induced by ethanol, while enhancing the activity of ADH and ALDH, as well as upregulating the expression of ADH1 and ALDH2. MV mitigates oxidative stress by decreased hepatic malondialdehyde (MDA) levels, restored glutathione (GSH)、superoxide dismutase (SOD) and catalase (CAT) content in ethanol-induced mice. Mechanistically, MV activated the p-AMPK/SREBP-1/FASN pathway to decreased hepatic lipid accumulation and alleviated steatosis. Additionally, MV promoted nuclear translocation of Nrf-2 to attenuates oxidative stress and suppressed TLR4/MyD88/NF-κB signaling pathway to reduce Inflammatory responses triggered by ethanol in mice. In summary, this study highlights mogroside V's hangover relieving effect and its protective effects against ethanol-related liver damage through its lipid metabolism regulation, antioxidative action and anti-inflammatory properties. These results suggest that mogroside V could be developed as a potential therapeutic agent against ethanol-induced liver damage.
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Affiliation(s)
- Rui Ai
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China; School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Muzhao Tian
- Faculty of Basic Medicine, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Jiawang Sun
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China; School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Shuying He
- Faculty of Clinical Medicine, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Zhi Cui
- Faculty of Basic Medicine, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Yizhuang Yang
- School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Xinyue Hou
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Yue Zhao
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China
| | - Tong Dou
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China; School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Macau, Taipa, 999078, China
| | - Xu Chen
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China; School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China.
| | - Juan Wang
- Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China; School of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541199, China; Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, 541001, China.
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Wang Y, Zhu E, Zhu X, Li X, He M, Zhai R, Wu X, Hu D, Han X. Exposure to polycyclic aromatic hydrocarbons and risk of abnormal liver function: The mediating role of C-reactive protein. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 298:118283. [PMID: 40347725 DOI: 10.1016/j.ecoenv.2025.118283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 04/18/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Polycyclic aromatic hydrocarbons (PAHs) exposure has been suggested to be linked to abnormal liver function (ALF). However, the conclusions are inconsistent, and the underlying mechanism is still unclear. In this study, a cross-sectional design including 4935 adults from the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2010 was conducted to quantify the PAHs-ALF associations, and to investigate the possible mediation role of systemic inflammation. Capillary gas chromatography coupled with tandem mass spectrometry (GC-MS/MS) was utilized to detect nine urinary levels of PAH metabolites (OH-PAHs). Plasma levels of systemic inflammation biomarker, C-reactive protein (CRP), were measured by enhanced turbidimetry. ALF was diagnosed on the basis of any abnormities in albumin (ALB), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), and alanine aminotransferase (ALT). Logistic regression model and the least absolute shrinkage and selection operator (LASSO) regression models indicated positive associations between urinary 1-hydroxypyrene (1-OH-PYR), 2-hydroxyphenanthrene (2-OH-PHE), and ALF risk. Significant synergistic effect of 1-OH-PYR and 2-OH-PHE on ALF was observed via additive interaction analysis. The weighted quantile sum (WQS) analysis and the quantile-based g computation (qgcomp) were employed to investigate the mixed effect of PAHs but no significant results were found. However, these two analyses consistently showed that 2-OH-PHE and 1-OH-PYR had top dominant weights in the positive association with ALF. Furthermore, mediation analysis indicated that plasma CRP mediated 13.4 % of the association between 1-OH-PYR and ALF risk. These results enhanced our comprehension of the health effects of PAHs exposure on liver function as well as the underlying mechanism.
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Affiliation(s)
- Yating Wang
- School of Public Health, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Enwei Zhu
- School of Public Health, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Xiaoyan Zhu
- Suzhou Center for Disease Prevention and Control, Suzhou, Jiangsu 215000, China
| | - Xiaoliang Li
- The Third People's Hospital of Zhuhai, Zhuhai, Guangdong 519060, China
| | - Mei'an He
- Department of Occupational and Environmental Health and Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Rihong Zhai
- School of Public Health, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Xuli Wu
- School of Public Health, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Dongsheng Hu
- School of Public Health, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Xu Han
- School of Public Health, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China; Department of Occupational and Environmental Health and Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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17
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Sui Q, Zhu C, Shi S, Xu J, Zhang J, Wang A, Chen P, Liang G, Zhang Y. Ganoderic acid A: an in-depth review of pharmacological effects and molecular docking analysis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 349:119868. [PMID: 40316150 DOI: 10.1016/j.jep.2025.119868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/24/2025] [Accepted: 04/22/2025] [Indexed: 05/04/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ganoderic acid A (GAA, C30H44O7) is one of the most abundant and active components of Ganoderic acids (GAs). GAs are highly oxidized tetracyclic triterpenoid compounds mainly derived from Ganoderma lucidum (Curtis) P. Karst (Chinese: ). GAA is primarily isolated from the fruiting body of Ganoderma lucidum. Modern pharmacological investigations have established the broad pharmacological effects of GAA, highlighting its notable influence on managing various conditions, including inflammatory diseases, neurodegenerative diseases, and cancer. This review provides a comprehensive summary of GAA's pharmacological activities. MATERIAL AND METHODS The literature in this review were searched in PubMed and China National Knowledge Infrastructure (CNKI) using the keywords "Ganoderic acid A″, "Pharmacology" and "Pharmacokinetics". The literature cited in this review dates from 2000 to 2024. RESULTS According to the data, GAA exerts anti-inflammatory, antioxidant, antitumor, neuropsychopharmacological, hepatoprotective, cardiovascular, renoprotective, and lung protective effects by regulating a variety of signal transduction pathways, such as nuclear factor kappa-B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), Toll-like receptor 4 (TLR4), nuclear factor erythroid 2-related factor-2 (Nrf2), phosphoinositide-3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and Notch. Given its promising pharmacological activity, GAA holds excellent potential for treating human diseases. The pharmacokinetic properties of GAA have also been reviewed, revealing low bioavailability but high absorption and elimination rates. In addition, network pharmacology and molecular docking analyses verified that GAA plays a role in multiple diseases through MAPK3, tumor necrosis factor (TNF), caspase-3 (CASP3), peroxisome proliferator-activated receptor gamma (PPARG), and β-catenin (CTNNB1) signaling pathways. CONCLUSION GAA plays a pivotal role in various pathological and physiological processes, boasting broad application prospects. Furthermore, the network pharmacological results reveal the mechanisms of GAA in the treatment of multiple diseases. In the future, it is necessary to conduct further experiments to elucidate its specific mechanism of action, thus laying the foundation for the scientific utilization of GAA.
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Affiliation(s)
- Qi Sui
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Chengkai Zhu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Sha Shi
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Jiaqi Xu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Jingnan Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Ao Wang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Department of Pharmacy, School of Medicine, Hangzhou City University, 50 Huzhou Rd, Hangzhou, Zhejiang, 310015, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Peng Chen
- Department of Pharmacy, School of Medicine, Hangzhou City University, 50 Huzhou Rd, Hangzhou, Zhejiang, 310015, China.
| | - Guang Liang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Yi Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China; Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China.
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18
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Lantzberg B, Zeyn Y, Forster R, Jian L, Schauenburg D, Hieber C, Nuhn L, Zhou T, Silva MJSA, Koynov K, Jiang HL, Kuan SL, Bros M, Opatz T, Weil T. Glycogen-inspired trimannosylated serum albumin nanocarriers for targeted delivery of toll-like receptor 7/8 agonists to immune cells and liver. J Control Release 2025; 382:113705. [PMID: 40199455 DOI: 10.1016/j.jconrel.2025.113705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 03/20/2025] [Accepted: 04/04/2025] [Indexed: 04/10/2025]
Abstract
Nanocarriers can improve the therapeutic efficiency of small molecule immunomodulators or inhibitors, which is important for immunotherapy of liver diseases or cancer. Macromolecular protein carriers, such as human serum albumin (HSA), could provide better penetration compared to large nanoparticles (>50 nm) but are hampered by systemic biodistribution. To overcome these limitations, inspired by the natural glycogen structure, we have designed the HSA nanocarrier (<40 nm) consisting of multiple trimannose (TM) ligands attached to the protein surface, to target mannose or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptors in immune cells or immunological organs such as the liver. Capitalizing on the chemical reactivity of different amino acids present in HSA, we have incorporated multiple copies of a cargo relevant for immunotherapy, i.e. the toll-like receptor (TLR) 7/8 agonist. The resulting TM-HSA conjugates exhibit excellent and specific uptake ex vivo in various immune cells and liver-specific uptake in vivo, opening access to protein nanocarriers with rapid and efficient in vivo targeting with great potential for immune-related diseases.
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Affiliation(s)
- Bellinda Lantzberg
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
| | - Yanira Zeyn
- Department of Dermatology, University Medical Center of Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 63, 55131 Mainz, Germany
| | - Robert Forster
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
| | - Lin Jian
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
| | - Dominik Schauenburg
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
| | - Christoph Hieber
- Department of Dermatology, University Medical Center of Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 63, 55131 Mainz, Germany
| | - Lutz Nuhn
- Faculty for Chemistry and Pharmaceutics, Julius-Maximilians-University Würzburg, Röntgenring 11, 97070 Würzburg, Germany
| | - Tianjiao Zhou
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China
| | - Maria J S A Silva
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
| | - Kaloian Koynov
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China
| | - Seah Ling Kuan
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
| | - Matthias Bros
- Department of Dermatology, University Medical Center of Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 63, 55131 Mainz, Germany.
| | - Till Opatz
- Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.
| | - Tanja Weil
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
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Shin H, Hur MH, Song BG, Park SY, Kim GA, Choi G, Nam JY, Kim MA, Park Y, Ko Y, Park J, Lee HA, Chung SW, Choi NR, Park MK, Lee YB, Sinn DH, Kim SU, Kim HY, Kim JM, Park SJ, Lee HC, Lee DH, Chung JW, Kim YJ, Yoon JH, Lee JH. AI model using CT-based imaging biomarkers to predict hepatocellular carcinoma in patients with chronic hepatitis B. J Hepatol 2025; 82:1080-1088. [PMID: 39710148 DOI: 10.1016/j.jhep.2024.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 11/12/2024] [Accepted: 12/07/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND & AIMS Various hepatocellular carcinoma (HCC) prediction models have been proposed for patients with chronic hepatitis B (CHB) using clinical variables. We aimed to develop an artificial intelligence (AI)-based HCC prediction model by incorporating imaging biomarkers derived from abdominal computed tomography (CT) images along with clinical variables. METHODS An AI prediction model employing a gradient-boosting machine algorithm was developed utilizing imaging biomarkers extracted by DeepFore, a deep learning-based CT auto-segmentation software. The derivation cohort (n = 5,585) was randomly divided into the training and internal validation sets at a 3:1 ratio. The external validation cohort included 2,883 patients. Six imaging biomarkers (i.e. abdominal visceral fat-total fat volume ratio, total fat-trunk volume ratio, spleen volume, liver volume, liver-spleen Hounsfield unit ratio, and muscle Hounsfield unit) and eight clinical variables were selected as the main variables of our model, PLAN-B-DF. RESULTS In the internal validation set (median follow-up duration = 7.4 years), PLAN-B-DF demonstrated an excellent predictive performance with a c-index of 0.91 and good calibration function (p = 0.78 by the Hosmer-Lemeshow test). In the external validation cohort (median follow-up duration = 4.6 years), PLAN-B-DF showed a significantly better discrimination function compared to previous models, including PLAN-B, PAGE-B, modified PAGE-B, and CU-HCC (c-index, 0.89 vs. 0.65-0.78; all p <0.001), and maintained a good calibration function (p = 0.42 by the Hosmer-Lemeshow test). When patients were classified into four groups according to the risk probability calculated by PLAN-B-DF, the 10-year cumulative HCC incidence was 0.0%, 0.4%, 16.0%, and 46.2% in the minimal-, low-, intermediate-, and high-risk groups, respectively. CONCLUSION This AI prediction model, integrating deep learning-based auto-segmentation of CT images, offers improved performance in predicting HCC risk among patients with CHB compared to previous models. IMPACT AND IMPLICATIONS The novel predictive model PLAN-B-DF, employing an automated computed tomography segmentation algorithm, significantly improves predictive accuracy and risk stratification for hepatocellular carcinoma in patients with chronic hepatitis B (CHB). Using a gradient-boosting algorithm and computed tomography metrics, such as visceral fat volume and myosteatosis, PLAN-B-DF outperforms previous models based solely on clinical and demographic data. This model not only shows a higher c-index compared to previous models, but also effectively classifies patients with CHB into different risk groups. This model uses machine learning to analyze the complex relationships among various risk factors contributing to hepatocellular carcinoma occurrence, thereby enabling more personalized surveillance for patients with CHB.
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Affiliation(s)
- Hyunjae Shin
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Gyeonggi-do, Korea
| | - Moon Haeng Hur
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Byeong Geun Song
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Gi-Ae Kim
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Gwanghyeon Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, Korea
| | | | - Minseok Albert Kim
- Department of Internal Medicine, ABC Hospital, Hwaseong, Gyeonggi-do, Korea
| | - Youngsu Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yunmi Ko
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeayeon Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Sung Won Chung
- Division of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Na Ryung Choi
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Min Kyung Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | | | - Sang Joon Park
- AI Center, MedicalIP. Co. Ltd., Seoul, Korea; Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung-Chul Lee
- Department of Anesthesiology, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Ho Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Wook Chung
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; Inocras Inc., San Diego, CA, USA.
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Teixeira CD, Barbosa PO, Lima WG, Breguez GS, Fagundes MMDA, Costa DC, Magalhães CLDB, Amaral JF, de Souza MO. Preventive treatment with guarana powder ( Paullinia cupana) mitigates acute paracetamol-induced hepatotoxicity by modulating oxidative stress. Toxicol Rep 2025; 14:101946. [PMID: 39989980 PMCID: PMC11847530 DOI: 10.1016/j.toxrep.2025.101946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/21/2025] [Accepted: 01/31/2025] [Indexed: 02/25/2025] Open
Abstract
Liver damage caused by high doses of paracetamol is a global public health concern. Consequently, therapeutic strategies are being explored to prevent this damage. The bioactive compounds present in fruits have shown promise in protecting against disorders associated with paracetamol-induced liver damage. This study assessed the preventive effects of guarana powder on redox status in a rat model of acute hepatotoxicity induced by a toxic dose of paracetamol. Male Wistar rats were divided into four groups: control (C), guarana (G), paracetamol (P), and guarana + paracetamol (GP). Animals in groups G and GP received 300 mg/kg guarana powder daily for seven days. Hepatotoxicity was induced in the P and GP groups by a single dose of 3 g/kg paracetamol on the last day. Paracetamol effectively induced liver damage and oxidative stress in group P animals. Preventive treatment with guarana significantly mitigated this damage and prevented the serum elevation of ALT, AST, and ALP by 44 %, 29 %, and 24 %, respectively. It also prevented a 133 % increase in the necrotic liver area in GP animals compared to the P. Guarana treatment, which prevented reductions in glutathione levels, modulated antioxidant enzyme (SOD and CAT) expression and activity, and protein carbonylation, while enhancing the total antioxidant capacity. Our results suggest that preventive treatment with guarana can attenuate oxidative damage, modulate antioxidant defense gene expression, and protect against paracetamol-induced hepatotoxicity in rats, highlighting guarana powder as a potential therapeutic agent to prevent liver damage induced by high doses of paracetamol.
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Affiliation(s)
- Clécia Dias Teixeira
- Post-Graduate Program in Health and Nutrition (PPGSN), Nutrition School, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Priscila Oliveira Barbosa
- Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, São Paulo, Brazil
| | - Wanderson Geraldo Lima
- Department of Biological Sciences (DECBI), Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Minas Gerais, Brazil
| | - Gustavo Silveira Breguez
- Post-Graduate Program in Health and Nutrition (PPGSN), Nutrition School, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | | | - Daniela Caldeira Costa
- Department of Biological Sciences (DECBI), Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Minas Gerais, Brazil
| | - Cintia Lopes de Brito Magalhães
- Department of Biological Sciences (DECBI), Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Minas Gerais, Brazil
| | - Joana Ferreira Amaral
- Post-Graduate Program in Health and Nutrition (PPGSN), Nutrition School, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Melina Oliveira de Souza
- Post-Graduate Program in Health and Nutrition (PPGSN), Nutrition School, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
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Desai AP, Orman ES, Aridi TG, Stump T, Nephew L, Ghabril MS, Fallon M, Chalasani N, Monahan P. Meaningful differences in patient-reported outcome measurement scores in liver disease. Hepatol Commun 2025; 9:e0727. [PMID: 40434652 PMCID: PMC12122172 DOI: 10.1097/hc9.0000000000000727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/11/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Patient-reported outcome measures (PROMs) are being used more often in chronic liver disease (CLD) clinical care and research. Their interpretability can be greatly enhanced by establishing the smallest meaningful score difference (MSD). We report scores of commonly used PROMs and their MSDs in patients at different stages of liver disease. METHODS Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Profile, Chronic Liver Disease Questionnaire (CLDQ), and Short Form-36 (SF-36) v1.0 scores were aggregated from 2442 adults with CLD at 4 different stages: inpatients with decompensated cirrhosis (n=1146) and outpatients with cirrhosis (n=677) or CLD (n=128) or recipients of liver transplant (LT, n=490) between June 2014 and April 2023 from 3 academic centers. MSDs were estimated using distribution and anchor-based methods. RESULTS The study sample's median age was 60.0 (IQR: 51.0-66.0); 55% were male, 17% Hispanic, 84% White, and 49% college educated. The etiology of CLD was alcohol in 36%, metabolic dysfunction-associated steatohepatitis (MASH) in 31%, and viral hepatitis B/C in 26%. Median PROMIS domain scores were generally lowest in inpatients and highest after transplant. For PROMIS, distribution-based and anchor-based MSDs ranged from 3 to 4 for individual domains and 4 to 6 for summary scores. Distribution-based MSDs were 1 for CLDQ and ranged from 7 to 11 for individual SF-36 domains, except role limitations domains, which ranged from 15 to 18, and component scores, which were 3. When compared across stages of liver disease, PROMIS MSDs were generally similar, although they tended to be 0.5-1.0 points smaller in the decompensated population compared to the stable populations. CONCLUSIONS This study provides data-driven recommendations for MSDs, enhancing the interpretability of commonly used PROMs in liver disease and facilitating the integration of PROMs in various clinical and research settings.
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Affiliation(s)
- Archita P. Desai
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Eric S. Orman
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Tarek G. Aridi
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Timothy Stump
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Lauren Nephew
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Marwan S. Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Michael Fallon
- Division of Gastroenterology and Hepatology, University of Arizona College of Medicine— Phoenix, Phoenix, Arizona, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Patrick Monahan
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
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22
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Tang Y, Zhou H, Pan X, Zhong Z, Liu H, Guo Y. Arrestin domain containing 3 promotes alcohol-induced liver steatosis by reducing stearoyl-CoA desaturase-1 ubiquitinated degradation. Metabolism 2025; 167:156175. [PMID: 40049370 DOI: 10.1016/j.metabol.2025.156175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/18/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND AND AIMS Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide with no approved therapy. The development of ALD is strongly associated with hepatic lipid accumulation. Arrestin domain containing 3 (ARRDC3), a member of the α-arrestin family, is involved in obesity, inflammation, and cancer. However, its role in ALD remains largely unexplored. METHODS Both the NIAAA and traditional Lieber-De Carli mouse models of ALD were employed. ARRDC3 expression was evaluated in liver specimens from ALD patients, mouse hepatic tissues, and hepatocytes. Hepatocyte-targeted Arrdc3 knockdown was achieved through intrahepatic delivery of adeno-associated virus 8 (AAV8) carrying shRNA under a hepatocyte-specific promoter. Mass spectrometry analysis, immunofluorescence, co-immunoprecipitation (co-IP) assays, and molecular docking were used to identify the interaction between ARRDC3 and stearoyl-CoA desaturase 1 (SCD1). RESULTS ARRDC3 levels were significantly elevated in the livers of both ALD patients and mouse models. Knockdown of Arrdc3 using AAV8 alleviated alcohol-induced liver steatosis in both the NIAAA and traditional Lieber-De Carli mouse models. We demonstrated that ARRDC3 promoted the progression of ALD by inducing lipid accumulation in hepatocytes. Mechanistically, ARRDC3 directly binds to SCD1 and inhibits its ubiquitin-proteasome degradation. Inhibition of SCD1 blocked ARRDC3-induced lipid deposition in hepatocytes. We also observed a correlation between ARRDC3 and SCD1 in liver samples from ALD patients. CONCLUSIONS Our findings reveal that ARRDC3 promotes hepatic steatosis in ALD by reducing the ubiquitin-dependent degradation of SCD1. ARRDC3 may serve as a potential therapeutic target for ALD.
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Affiliation(s)
- Ying Tang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Alcohol-related Liver Disease Center, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Haoxiong Zhou
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Alcohol-related Liver Disease Center, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Xuemei Pan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Alcohol-related Liver Disease Center, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Zhenwei Zhong
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Alcohol-related Liver Disease Center, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Alcohol-related Liver Disease Center, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Yunwei Guo
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Alcohol-related Liver Disease Center, 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
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Chen J, Zhang S, Cao X, Daer D, Lin B. Current Situation and Prospects of Digital Therapeutics in the Field of Liver Diseases in China. Adv Ther 2025; 42:2639-2658. [PMID: 40249521 PMCID: PMC12085313 DOI: 10.1007/s12325-024-03086-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/05/2024] [Indexed: 04/19/2025]
Abstract
Digital therapeutics have developed rapidly in recent years, providing a new method for disease management. The burden of liver diseases in China is heavy, and there are obvious problems in disease management. This paper expounds on the definition and classification of digital therapeutics, introduces their application in liver disease treatment and management in detail, and analyzes their development prospects in the field of liver diseases and future challenges.Graphical abstract available for this article.
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Affiliation(s)
- Junfeng Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China
| | - Shaoquan Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China
| | - Xian Cao
- Medical Affairs, Takeda (China) Holdings Co., Ltd, Shanghai, 200126, China
| | - Dili Daer
- Medical Affairs, Takeda (China) Holdings Co., Ltd, Shanghai, 200126, China
| | - Bingliang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China.
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24
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Puhakka E, Ahmed H, Haikonen R, Leclercq S, Hanhineva K, Maccioni L, Amadieu C, Lehtonen M, Männistö V, Rysä J, Stärkel P, Kärkkäinen O. Serum Metabolite Profile in Progressive Versus Nonprogressive Alcohol-Related Liver Disease: A Cross-Sectional Metabolomics Study. Liver Int 2025; 45:e70128. [PMID: 40358071 PMCID: PMC12070861 DOI: 10.1111/liv.70128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 04/22/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND AND AIMS Alcohol-related liver disease (ALD) is a major cause of mortality and disability-adjusted life years. It is not fully understood why a small proportion of patients develop progressive forms of ALD (e.g., fibrosis and cirrhosis). Differences in the metabolic processes could be behind the individual progression of ALD. Our aim was to examine differences in serum metabolome between patients with nonprogressive ALD and patients with an early form of progressive ALD. METHODS The study had three study groups: progressive ALD (alcohol-related steatohepatitis or early-stage fibrosis, n = 50), nonprogressive ALD (simple steatosis, n = 50) and healthy controls (n = 32). Both ALD groups took part in a voluntary alcohol rehabilitation programme. A nontargeted metabolomics analysis and targeted analysis of short-chain fatty acids were done to the serum samples taken on the day of admission. RESULTS We found 111 significantly (p < 0.0005) altered identified metabolites between the study groups. Our main finding was that levels of glycine-conjugated bile acids (Cohen's d = 0.90-0.91), glutamic acid (d = 1.01), 7-methylguanine (d = 0.77) and several phosphatidylcholines (d = 0.61-0.85) were elevated in the progressive ALD group in comparison to the nonprogressive ALD group. Glycine-conjugated bile acids, glutamic acid and 7-methylguanine also positively correlated with increased levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, cell death biomarker M65 and liver stiffness. CONCLUSIONS Our results indicate that the enterohepatic cycle of glycine-conjugated bile acids, as well as lipid and energy metabolism, is altered in early forms of progressive ALD. These metabolic processes could be a target for preventing the progression of ALD.
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Affiliation(s)
- Eemeli Puhakka
- School of PharmacyUniversity of Eastern FinlandKuopioFinland
| | - Hany Ahmed
- Food Sciences Unit, Department of Life TechnologiesUniversity of TurkuTurkuFinland
| | - Retu Haikonen
- Institute of Public Health and Clinical NutritionUniversity of Eastern FinlandKuopioFinland
| | - Sophie Leclercq
- Laboratory of Nutritional Psychiatry, Institute of Neuroscience, UCLouvainUniversité Catholique de LouvainBrusselsBelgium
| | - Kati Hanhineva
- Food Sciences Unit, Department of Life TechnologiesUniversity of TurkuTurkuFinland
- Institute of Public Health and Clinical NutritionUniversity of Eastern FinlandKuopioFinland
| | - Luca Maccioni
- National Institute of Alcohol Abuse and AlcoholismBethesdaMarylandUSA
| | | | - Marko Lehtonen
- School of PharmacyUniversity of Eastern FinlandKuopioFinland
| | - Ville Männistö
- Institute of Clinical MedicineUniversity of Eastern FinlandKuopioFinland
- Department of MedicineKuopio University HospitalKuopioFinland
| | - Jaana Rysä
- School of PharmacyUniversity of Eastern FinlandKuopioFinland
| | - Peter Stärkel
- Department of Hepato‐Gastro‐EnterologyCliniques Universitaires Saint LucBrusselsBelgium
- Laboratory of Hepato‐Gastroenterology, Institute de Recherche Expérimentale et CliniqueUniversité Catholique de LouvainBrusselsBelgium
| | - Olli Kärkkäinen
- School of PharmacyUniversity of Eastern FinlandKuopioFinland
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Jain A, Mishra AK, Hurkat P, Shilpi S, Mody N, Jain SK. Navigating liver cancer: Precision targeting for enhanced treatment outcomes. Drug Deliv Transl Res 2025; 15:1935-1961. [PMID: 39847205 DOI: 10.1007/s13346-024-01780-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/24/2025]
Abstract
Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.
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Affiliation(s)
- Ankit Jain
- Department of Pharmacy, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
| | - Ashwini Kumar Mishra
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra, 425405, India
- Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, 284003, India
| | - Pooja Hurkat
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
| | - Satish Shilpi
- School of Pharmaceuticals and Population Health Informatics, FOP, DIT University, Dehradun, Uttarakahnad, India
| | - Nishi Mody
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
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26
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Choudhuri S, Garg NJ. Hepatocyte Nuclear Factor 4 Alpha: A Key Regulator of Liver Disease Pathology and Haemostatic Disorders. Liver Int 2025; 45:e16245. [PMID: 40387433 DOI: 10.1111/liv.16245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/19/2024] [Accepted: 01/03/2025] [Indexed: 05/20/2025]
Abstract
OBJECTIVE Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte differentiation in fetal and adult liver and exerts its transcriptional role in determining physiological functions of the liver. The objective of this review is to address the current knowledge of molecular mechanisms involved in HNF4α regulation in multiple aspects of liver disease pathogenesis. METHODS Based on available literature, this review summarises the current state of knowledge onthe mechanism of HNF4α dysregulation, and the role of HNF4α activity inregulating early to advanced stages of various liver diseases. RESULTS Patients with deranged HNF4α expression are at higher risk for the development of liver diseases such as viral hepatitis, alcoholic/nonalcoholic fatty liver disease, hepatocellular carcinoma, and haematological disorders such as coagulopathy and bleeding disorders. DISCUSSION HNF4α interactions with nuclear receptors and target genes promote liver disease pathology by regulating various metabolic pathways. The strong correlation between deranged HNF4α expression and the severity of liver diseases suggests that targeting HNF4α expression can offer potential therapeutic strategy in the prevention of liver disease pathology and haemostatic disorders.
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Affiliation(s)
- Subhadip Choudhuri
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
| | - Nisha Jain Garg
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
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Birn-Rydder R, Herting EC, Malcolm FL, Humes D, Aagaard NK, Jepsen P. Surgical procedures in patients with alcohol-related cirrhosis: a Danish nationwide register-based cohort study. Scand J Gastroenterol 2025; 60:588-596. [PMID: 40275703 DOI: 10.1080/00365521.2025.2496500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/05/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND & AIMS Alcohol-related cirrhosis (ALD cirrhosis) is a chronic liver disease caused by excessive alcohol consumption. Patients with ALD cirrhosis have increased risk of conditions that may require surgery for example gallstones, gastrointestinal cancers, and hernias, but surgeons may prefer to avoid surgery due to patients' increased risk of complications. We compared the incidence of surgery between patients with ALD cirrhosis and matched comparators. METHODS We used nationwide healthcare registries to include all Danish citizens diagnosed with ALD cirrhosis in 1996-2018. Follow-up began at the time of cirrhosis diagnosis and ended at death or 10 years after diagnosis. We compared their incidence rates and cumulative risks of surgery (excluding biopsies, punctures, drainages, injections, and diagnostic endoscopies) with those for a gender- and age-matched comparator cohort from the general Danish population. RESULTS We included 23,050 patients with ALD cirrhosis and 113,412 matched comparators. The incidence rate ratio (IRR) for surgery overall was 3.38 [95% Confidence Interval (CI): 3.34-3.41] for patients vs. comparators. The 1-year risk of surgery was 42.6% [95% CI: 42.4-42.9] for patients vs. 13.4% [95% CI: 13.3-13.6] for comparators. Abdominal procedures were the most frequent surgical category for the patients with an IRR of 6.55 [95% CI: 6.41-6.69] for patients vs. comparators. CONCLUSIONS We found an increased risk of surgery for patients with ALD cirrhosis compared with the general Danish population. Given the frequency of surgery in these high-risk patients, further research should focus on perioperative management to optimize outcomes.
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Affiliation(s)
- Rasmine Birn-Rydder
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Emma Celia Herting
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Francesca Ligori Malcolm
- National Institute for Health Research(NIHR) Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, School of Medicine, Queen's Medical Centre, Nottingham, United Kingdom
| | - David Humes
- National Institute for Health Research(NIHR) Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, School of Medicine, Queen's Medical Centre, Nottingham, United Kingdom
| | - Niels Kristian Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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Zhao Y, Bo Y, Zu J, Xing Z, Yang Z, Zhang Y, Deng Y, Liu Y, Zhang L, Yuan X, Wang Y, Henry L, Ji F, Nguyen MH. Global Burden of Chronic Liver Disease and Temporal Trends: A Population-Based Analysis From 1990 to 2021 With Projections to 2050. Liver Int 2025; 45:e70155. [PMID: 40421876 DOI: 10.1111/liv.70155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 04/30/2025] [Accepted: 05/19/2025] [Indexed: 05/28/2025]
Abstract
BACKGROUND AND AIMS Globally, the aetiology and epidemiology of chronic liver disease (CLD) are undergoing significant changes. We aimed to investigate the updated global burden of CLD, evaluate the cross-country inequalities, and provide 2050 predictions. METHODS Using the Global Burden of Disease Study (GBD) 2021 data resources, we analysed and forecasted CLD prevalence, incidence, and related death from 1990-2021 to 2050, respectively. We calculated average annual percent change (AAPC) by joinpoint regression model and quantified inequalities according to World Health Organisation-recommended health equity standards. RESULTS In 2021, the number of prevalent, incident CLD and related deaths globally were 1.7 billion (95% uncertainty interval (UI): 1.6-1.8), 58.4 million (95% UI: 54.2-62.8) and 1.4 million (95% UI: 1.3-1.5), respectively. During 1990-2021, the age-standardised incidence rate (ASIR) increased, especially in those aged 15-49 (AAPC: 0.49%; 95% confidence interval [CI]: 0.45%-0.53%), in Europe (AAPC: 0.41%; 95% CI: 0.41%-0.42%) and the Americas (AAPC: 0.41%; 95% CI: 0.39%-0.42%), whereas the age-standardised death rate (ASDR) decreased globally (AAPC: -1.26%; 95% CI: -1.35% [-1.17%]) and across subgroups. During 1990-2021, the ASIR of metabolic dysfunction-associated steatotic liver disease (MASLD) increased the most in those aged 15-49 (AAPC: 0.72%; 95% CI: 0.67%-0.77%) and in the Western Pacific region (AAPC: 0.73%; 95% CI: 0.59%-0.86%). Socio-demographic index (SDI)-related inequalities decreased for the age-standardised prevalence rate (ASPR) and ASIR of CLD but increased for ASDR, placing a disproportionately heavier burden on low-SDI countries. From 2022 to 2050, the ASIR of CLD is projected to increase (AAPC: 0.20%; 95% CI: 0.19%-0.20%), but the ASDR is projected to decline (AAPC: -1.91%; 95% CI: -1.96% [-1.85%]). CONCLUSIONS This study's findings highlight targeted interventions for CLD disparities, focusing on MASLD management, the younger population (15-49 years), and socio-demographic inequalities.
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Affiliation(s)
- Yunyu Zhao
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yajing Bo
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jian Zu
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, China
| | - Zixuan Xing
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhanpeng Yang
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, China
| | - Yue Zhang
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, China
| | - Yujiao Deng
- Division of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Liu
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lanting Zhang
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiao Yuan
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuan Wang
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Linda Henry
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Fanpu Ji
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi, China
- Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi, China
- Global Health Institute, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Shaanxi Provincial Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
- Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA
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Xie J, Xiong S, Yu J, Ma X, Xiang F, Chen Y, Xia B, Li Y, Zhang Z, Liao D, Lin L. Prunella vulgaris polyphenols alleviate liver injury-uveitis comorbidity by regulating acylcarnitine via the S100A9-PP2A-AMPK pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156675. [PMID: 40215815 DOI: 10.1016/j.phymed.2025.156675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/14/2025] [Accepted: 03/19/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Liver injury and uveitis pose severe threats to human health. Owing to the close relationship of physiology and pathology between the liver and the eyes, cases in which both conditions occur simultaneously are not uncommon in clinical settings, significantly complicating treatment. However, no suitable comorbid animal model has been reported, and research on the pathological mechanisms of this comorbidity is lacking. Prunella vulgaris L., a well-known traditional Chinese medicine renowned for its liver-clearing and eye-brightening properties. Prunella vulgaris polyphenols (PVPs) hold promise for improving liver injury and uveitis. However, research exploring their dual therapeutic effects within a single organism remains lacking, leaving the key active components and mechanisms of action largely uninvestigated. PURPOSE This exploratory study aimed to establish a rat model of liver injury combined with uveitis and investigated its pathological mechanisms, evaluating the therapeutic efficacy of PVPs in alleviating liver injury combined with uveitis in rats. Additionally, it explored the mechanism of action and identified key active ingredients of PVPs, offering potential new directions for the development of clinical therapeutic drugs. METHODS A rat model of liver injury with uveitis was established through intraperitoneal d-GalN/LPS injection. Metabolomics and proteomics were applied to investigate pathological mechanisms, followed by validation using acylcarnitine and S100A9 inhibitors. PVPs were administered to evaluate therapeutic effects and explore mechanisms involved in alleviating liver injury and uveitis. Network pharmacology combined with molecular docking identified critical active components in PVPs. Subsequent animal experiments verified the efficacy of the representative component in improving liver injury and uveitis. RESULTS d-GalN/LPS (150 mg/kg : 1 mg/kg) induced significant liver injury and uveitis in rats. Metabolomics analysis pointed to acylcarnitine as a key metabolite, and its inhibition reduced inflammation. Proteomics analysis implicated S100A9 in inflammation and immunity. Then, we intervened with S100A9 inhibitors in the model rats. The results suggested that the pathological mechanism of liver injury and uveitis caused by d-GalN/LPS involved the upregulation of S100A9 expression, an increase in PP2A activity, the inhibition of AMPK phosphorylation, and the downregulation of CPT1A, leading to the accumulation of acylcarnitine and promoting the inflammatory response in the liver and retina. Further, experiments involving PVPs demonstrated dose-dependent improvements in liver injury and uveitis caused by d-GalN/LPS. The underlying mechanism of action involved suppression of S100A9 expression, reduction of PP2A activity, activation of AMPK, upregulation of CPT1A, and subsequent reduction in acylcarnitine accumulation in both the liver and retina. This mechanism effectively alleviated the inflammatory effects induced by d-GalN/LPS. Network pharmacology and molecular docking analyses pinpointed several key active components of PVPs-namely, rosmarinic acid, salviaflaside, esculetin, 2-hydroxycinnamic acid, 3,4-dihydroxybenzaldehyde, and 7,8-dihydroxycoumarin-that play significant roles in mitigating liver injury and uveitis. Follow-up experiments using the representative active component rosmarinic acid in rats confirmed its efficacy in improving symptoms of d-GalN/LPS-induced liver injury and uveitis, further validating the therapeutic potential of these key active components. CONCLUSIONS This study successfully established a rat model of liver injury combined with uveitis and confirmed the efficacy of PVPs in alleviating this condition. Furthermore, it determined that the underlying mechanism involves regulation of the S100A9-PP2A-AMPK pathway, with rosmarinic acid identified as a key active compound. These findings provide a basis for clinical studies on liver-eye comorbidities and offer critical evidence for further research and drug development of PVPs in liver-clearing and eye-brightening.
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Affiliation(s)
- Jingchen Xie
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Suhui Xiong
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Jiahui Yu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Xinyi Ma
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Feng Xiang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Yang Chen
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Bohou Xia
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Yamei Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Zhimin Zhang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China
| | - Duanfang Liao
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Limei Lin
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
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Hassan NH, Kamel GM, Fayed HM, Korany RMS, Ramadan A. Dapagliflozin alleviates thioacetamide induced-liver fibrosis in rats via controlling the Nrf2/HO-1 and TLR4/TGF-β1/PI3K signaling pathways. Immunopharmacol Immunotoxicol 2025; 47:392-405. [PMID: 40296648 DOI: 10.1080/08923973.2025.2496661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 04/17/2025] [Indexed: 04/30/2025]
Abstract
OBJECTIVES Because liver fibrosis causes several insults that can result in death, it is regarded as an epidemic health issue. As "an inhibitor of the sodium-glucose cotransporter-2 (SGLT2)," Dapagliflozin (Dapa) is one of the newest anti-diabetic drugs used to treat type 2 diabetes mellitus. Dapa's antioxidant, anti-inflammatory, and antifibrotic properties produced positive impacts in numerous human and animal models. Due to Dapa's previously documented properties, we planned this investigation to elucidate the protective function of Dapa in male rat liver fibrosis caused by thioacetamide (TAA) as well as the expected pathways. METHODS There were four groups of 24 rats: a control group, a TAA group that received (100 mg/kg b.wt intraperitoneally twice a week for 6 weeks), "TAA + Dapa" groups that given oral Dapa at (1 and 2 mg/kg b.wt. for 4 weeks in addition to TAA injections). RESULTS It was shown that TAA injections increased toll-like receptor 4 (TLR4) (509.6%), tumor necrosis factor (TNF-α) (298.8%), alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), interleukin-6 (IL-6) (330.9%), phosphotidylinositol-3-kinase (PI3K) (428.9% %), and transforming growth factor-beta (TGF-β1) (416.6%) levels. All of these markers were considerably reduced by Dapa treatment. In addition, reduced glutathione (GSH), nuclear factor erythroid 2-related factor 2 (Nrf2) (79%), albumin, Heme-oxygenase 1 (HO-1) (69%), and superoxide dismutase (SOD) were all decreased after TAA injection; however, they were restored by Dapa administration. The Dapa-treated groups had higher Nrf2 and HO-1 gene expressions, based on the results of PCR. Biochemical outcomes were validated by histopathological results. Immunohistopathological study revealed that DAPA treatment decreased caspase-3 and alpha-smooth Muscle Actin (αSMA) expression. CONCLUSION Due to its interactions with the Nrf2/HO-1 and TLR4 pathways, our research showed that Dapa had antioxidant and anti-inflammatory qualities against TAA-induced liver fibrosis.
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Affiliation(s)
- Nourhan Hussien Hassan
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Gehan M Kamel
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Hany M Fayed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Reda M S Korany
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Amer Ramadan
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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Qu XH, Liu XJ. Neferine alleviates alcohol-induced liver injury in mice by inhibiting oxidative stress and inflammation. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2025; 33:389-396. [DOI: 10.11569/wcjd.v33.i5.389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2025]
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Zhang H, Hao E, Xia D, Ma M, Wu J, Liu T, Gao M, Wu X. Estimating liver cirrhosis severity with extracellular volume fraction by spectral CT. Sci Rep 2025; 15:18343. [PMID: 40419616 PMCID: PMC12106838 DOI: 10.1038/s41598-025-03717-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 05/22/2025] [Indexed: 05/28/2025] Open
Abstract
To investigate the diagnostic value of spectral CT in calculating extracellular volume fraction (ECV) for assessing the severity of liver cirrhosis. This retrospective study enrolled 172 participants, including 127 patients diagnosed with liver cirrhosis and 45 matched controls, all of whom underwent spectral CT hepatic enhancement imaging. Disease severity stratification was performed using the Child-Pugh classification system. ECV values were derived from the iodine density map during the delayed phase. These ECV values were then compared across the control group and subclassified cirrhosis groups (Child-Pugh classes A-C). Furthermore, a correlation analysis was performed to assess the relationship between ECV values and Child-Pugh scores in liver cirrhosis. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance of ECV values and MELD-Na in the Child-Pugh classification of liver cirrhosis. The ECV values were 25.49 ± 3.15, 29.73 ± 3.20, 35.64 ± 3.15, and 45.30 ± 5.16 for the control, Child-Pugh A, Child-Pugh B, and Child-Pugh C group, respectively, demonstrating significant intergroup differences (F = 184.67 P < 0.001). A strong positive correlation was observed between ECV and Child-Pugh liver function classification (r = 0.791, P < 0.001). The diagnostic performance of ECV for differentiating between Child-Pugh classes A and B (AUC: 0.901), B and C (AUC: 0.966) was higher compared to the MELD-Na score (AUC: 0.772 and 0.868) (P < 0.05, respectively). Multivariate analyses showed that ECV was an independent factor for cirrhosis (OR 1.610, P < 0.001). ECV values measured using spectral CT can serve as a noninvasive biomarker for assessing the severity of liver cirrhosis.
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Affiliation(s)
- Hong Zhang
- Department of Radiology, Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, No. 161, Xiwu Road, Xincheng District, Xi'an, 710003, Shaanxi, China
| | - Ee Hao
- Department of Sixth Outpatient, Xijing 986 Hospital, Xi'an, 710054, China
| | - Dongqin Xia
- Department of Ultrasound, Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, 710003, China
| | - Mingyue Ma
- Department of Radiology, Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, No. 161, Xiwu Road, Xincheng District, Xi'an, 710003, Shaanxi, China
| | - Jiayu Wu
- Department of Radiology, Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, No. 161, Xiwu Road, Xincheng District, Xi'an, 710003, Shaanxi, China
| | - Tongchi Liu
- Department of Radiology, Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, No. 161, Xiwu Road, Xincheng District, Xi'an, 710003, Shaanxi, China
| | - Ming Gao
- Department of Radiology, Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, No. 161, Xiwu Road, Xincheng District, Xi'an, 710003, Shaanxi, China
| | - Xiaoping Wu
- Department of Radiology, Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, No. 161, Xiwu Road, Xincheng District, Xi'an, 710003, Shaanxi, China.
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Oyeyemi IT, Ajayi IT, Nabofa EEW. Jatropha tanjorensis J.L.Ellis & Saroja inhibited carbon tetrachloride-induced fibrogenesis in Wistar rats. Nat Prod Res 2025:1-8. [PMID: 40411811 DOI: 10.1080/14786419.2025.2509137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 04/30/2025] [Accepted: 05/17/2025] [Indexed: 05/26/2025]
Abstract
Jatropha tanjorensis has been employed to treat various diseases. This study aimed to investigate the mode of action of J. tanjorensis against liver fibrogenesis induced by carbon tetrachloride (CCl4). Liver fibrosis was induced in male Wistar rats by exposing them to CCl4 for nine weeks. From weeks 7 to 9, J. tanjorensis extract was administered. The study evaluated the activities of antioxidant enzymes and lipid peroxidation (LPO) levels, expression of TGFβ1 and fibrosis-associated proteins, and liver histology. J. tanjorensis significantly increased the depleted antioxidant activities induced by CCl4 while significantly reducing the elevated LPO levels caused by CCl4. Furthermore, it downregulated the upregulation of TGFβ1 and fibrosis-associated proteins induced by CCl4 and mitigated the liver lesions and collagen deposits resulting from CCl4 exposure. Overall, J. tanjorensis alleviated liver injury and fibrogenesis by exerting its antioxidant effect and inhibition of TGFβ1.
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Affiliation(s)
- Ifeoluwa T Oyeyemi
- Department of Biosciences and Biotechnology, University of Medical Sciences, Ondo City, Nigeria
| | - Ifeoluwa T Ajayi
- Department of Medical Laboratory Sciences, University College Hospital, Ibadan, Nigeria
- Department of Biomedical Sciences, University of Wolverhampton, UK
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Yazdian FA, Samak MM, Larijani A, Ashoobi MT, Kharaqani M, Ghezel MA, Barabadi Z, Vojoudi E. From Cells to Exosomes: a Review of Non-Surgical Biotherapeutic-Based Strategies for Liver Regeneration in the Face of End-Stage Diseases. Stem Cell Rev Rep 2025:10.1007/s12015-025-10872-1. [PMID: 40411652 DOI: 10.1007/s12015-025-10872-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 05/26/2025]
Abstract
Liver diseases, such as hepatitis, cirrhosis, and liver cancer, pose significant public health challenges, ranking as the twelfth leading cause of death globally. Given the liver's critical functions in metabolism, detoxification, and biosynthesis, its impairment can lead to severe consequences, often resulting in end-stage liver failure. Although liver transplantation is regarded as the definitive intervention for advanced liver disease, factors such as a shortage of donors and potential surgical complications necessitate the investigation of non-surgical regenerative medicine alternatives. This manuscript provides a comprehensive review of innovative non-surgical therapies aimed at liver regeneration, with an emphasis on both cell-based and cell-free approaches. It examines the contributions of various stem cell populations, including mesenchymal stem cells, hematopoietic stem cells, and induced pluripotent stem cells, in facilitating liver repair through mechanisms of differentiation and paracrine signaling. Furthermore, it explores the therapeutic potential of exosomes and conditioned media derived from stem cells as biotherapeutic agents in the context of regenerative medicine. By elucidating the mechanisms that underpin liver regeneration, this study aspires to inform the development of effective therapeutic strategies to address liver diseases and slow their progression. By elucidating the underlying mechanisms of liver regeneration, this study aims to contribute to the development of effective therapeutic strategies to address liver diseases and slow their progression.
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Affiliation(s)
| | - Matin Mojaveri Samak
- Department of Internal Medicine, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Amirhossein Larijani
- Student Research Committee, School of Medicine, Guilan University of Medical Science, Rasht, Iran
- Regenerative Medicine, Organ Procurement and Transplantation Multi-Disciplinary Centre, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Taghi Ashoobi
- Department of General Surgery, School of Medicine Road Trauma Research Centre, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | | | | | - Zahra Barabadi
- Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran.
- School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran.
| | - Elham Vojoudi
- Regenerative Medicine, Organ Procurement and Transplantation Multi-Disciplinary Centre, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.
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Zhou L, Shi Z, Yang X, Zeng J, You Z, Zhang Y, Zhu Z, Liu Z, Niu Y, Yu H, He J, Long Y, Wu Z, Zhang Y, Lyu C, Deng L, Wang Y, Wu C, Du Y. Tension-induced directional migration of hepatic stellate cells potentially coordinates liver fibrosis progression. Nat Biomed Eng 2025:10.1038/s41551-025-01381-0. [PMID: 40410557 DOI: 10.1038/s41551-025-01381-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 03/25/2025] [Indexed: 05/25/2025]
Abstract
Liver fibrosis is an over-reacted wound healing that becomes lethal in its late stage, when hepatic stellate cells (HSCs) trigger fibrotic response, proliferation of connective tissue and build-up of directional fibrous tissue bands (septa). Current in vitro models of liver fibrosis cannot reproduce liver lobule structure and the dynamic formation of septa at the same time, and the known biochemical cues underlying the progression of liver fibrosis cannot explain directional formation of fibrotic tissue. Here we report a microfabricated in vitro model that reproduces both the hexagonal liver lobule structure and the dynamic directionality of septa formation. By using collagen and primary mouse HSCs or human HSC lines, we found that tension was necessary to coordinate the cell migration that contributes to the band-like cell distribution and that HSCs sensed directional biophysical cues through liquid-liquid phase separation. This system allows the study of the biophysical interaction of HSCs and collagen during the formation of septa structures, and could be used to deepen our understanding of liver fibrosis progression.
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Affiliation(s)
- Lyu Zhou
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Ziao Shi
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Xuesi Yang
- School of Aerospace Engineering, Tsinghua University, Beijing, China
| | - Jia'nan Zeng
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Zhifeng You
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Yuying Zhang
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Zhiyue Zhu
- Department of Mechanical and Industrial Engineering, Ted Rogers Centre For Heart Research, University of Toronto, Toronto, Ontario, Canada
| | - Zhiqiang Liu
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Yudi Niu
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Hongsheng Yu
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Jinliang He
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Yi Long
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Zhaozhao Wu
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Yan Zhang
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Cheng Lyu
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Liping Deng
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Yuan Wang
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems Biology, Beijing, China
| | - Congying Wu
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems Biology, Beijing, China
| | - Yanan Du
- School of Biomedical Engineering, Tsinghua Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
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Xiao Z, Gao S, Li S, Yang F, Zhang D, Niu Z, Zhang Y, Duan Z, Qi S, Ma S. Taohong Siwu Decoction Modulates Glutathione Metabolism to Suppress Hepatocyte Ferroptosis and Demonstrates Anti-Fibrotic Effects in the Liver. JOURNAL OF ETHNOPHARMACOLOGY 2025:120025. [PMID: 40414577 DOI: 10.1016/j.jep.2025.120025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 05/17/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The ameliorative effect of traditional Chinese medicine (TCM) on hepatic fibrosis has been widely recognized and researched, but studies on the mechanism of action have been hampered by its complex composition, which requires more in-depth studies to elucidate why and how TCM works. The theory of TCM believes that the liver is closely related to blood circulation, and hepatic fibrosis is caused by blood stagnation. Taohong Siwu Decoction (THSW) is a classic formula for nourishing and invigorating blood and has been used clinically for centuries. Current evidence has demonstrated its ameliorative effect on hepatic fibrosis, but the exact mechanism of action remains unclear. AIM OF THE STUDY Exploring the possible mechanism of the anti-hepatic fibrosis effect of THSW by proteomics and validating with in vivo and in vitro studies. MATERIALS AND METHODS The carbon tetrachloride (CCl4)-induced fibrosis model was conducted in mice and treated with THSW in vivo with colchicine as the positive control. Then serum biomarker alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathological analysis were evaluated to examine the effects of THSW. And hepatic fibrosis indicators alpha-smooth muscle actin (α-SMA) and Collagen Ⅰ (Col-Ⅰ) were detected by western blotting, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Additionally, the 4D Label-free quantitative proteomic analysis of liver samples was applied. In vitro, erastin-induced BRL-3A cells, a rat hepatocyte line, were performed as a hepatocyte ferroptosis model and treated with or without drug-containing serum of THSW. Finally, molecular docking was used to verify the binding ability of the main components of THSW to potential targets. RESULTS THSW treatment significantly ameliorated serum ALT, AST, hydroxyproline (Hyp) content, α-SMA and Col-Ⅰ mRNA expression in fibrosis mice. Further results showed that THSW decreased the malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE) content and increased the glutathione (GSH) content of liver tissue. Notably, proteomic analyses have identified 294 differentially expressed proteins in the THSW-treated group compared to the model group, with 97 proteins up-regulated and 197 down-regulated. Functional analysis of these differential proteins highlights the significant roles of inflammation and oxidative stress. Further validation in vivo and in vitro, THSW significantly improved the protein expression of glutathione S-transferase M1 (GSTM1), down-regulate the expression of transferrin receptor (TFRC), and kelch-like ECH-associated protein 1(Keap1) proteins, and promote the metabolism of GSH. Especially it reduced serum iron levels, increased total iron binding capacity, and up-regulated recombinant solute carrier family 7, member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4) protein expression, suggesting the inhibition of hepatocyte ferroptosis. In addition, the molecular docking results showed that its main components, amygdalin, hydroxysafflor yellow A, paeoniflorin, and albiflorin, possessed good binding ability with Keap1. CONCLUSIONS THSW represents a novel therapeutic effect on hepatic fibrosis in mice, accompanied by inhibiting hepatocyte ferroptosis. Mechanically, THSW may regulate the glutathione metabolic pathway and TFRC expression through its main ingredients, such as amygdalin, hydroxysafflor yellow A, paeoniflorin, and albiflorin, thereby inhibiting hepatocyte ferroptosis.
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Affiliation(s)
- Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China.
| | - Siqi Gao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
| | - Shengsheng Li
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou 450000, China.
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China.
| | - Dingqi Zhang
- School of Pharmaceutical Sciences, School of TCM Research, Tsinghua University, Beijing 100084, China.
| | - Zhenyi Niu
- Department of Pathology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China.
| | - Yu Zhang
- Department of Pathology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China.
| | - Zhongping Duan
- Beijing Institute of Hepatology, Beijing Youan Hospital Capital Medical University, Beijing 100069, China.
| | - Shenglan Qi
- Institute of Chinese Materia Medica, Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Shanghai Municipal Key Laboratory for Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China.
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Cheng W, Zheng Y, Tang Q, Qi L, Shi Z, Yu Q, Li M, Wei X, Zhou Y, Jiang X. Discovery of Novel Cyclic Peptides as SMAD2-SMAD4 Interaction Inhibitors for the Treatment of Hepatic Fibrosis. J Med Chem 2025; 68:9958-9972. [PMID: 40320643 DOI: 10.1021/acs.jmedchem.4c02938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
Hepatic fibrosis, characterized by the excessive deposition of the extracellular matrix, represents a common consequence of various chronic liver disorders. However, no specific drugs are available for antifibrotic therapy to date. SMAD2 is phosphorylated by transforming growth factor-β and subsequently binds to SMAD4 to generate a heteromeric complex, which then translocates into the nucleus and aggravates liver fibrosis. Herein, based on molecular docking simulation and structure-activity relationship study, we report the discovery of a novel cyclic peptide CMF9 that targets SMAD2 and potently interferes with the SMAD2-SMAD4 interaction. The subsequent in vivo and in vitro pharmacological studies demonstrated that CMF9 dramatically suppressed hepatic stellate cells activation and collagen synthesis, alleviating CCl4-induced hepatic inflammation and fibrosis. Overall, we first demonstrated that the novel cyclic peptide CMF9 could efficiently block the SMAD2-SMAD4 interaction via selectively inhibiting SMAD2 phosphorylation, providing a promising therapeutic strategy for targeting SMAD2 and an alternative candidate for the treatment of liver fibrosis.
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Affiliation(s)
- Wei Cheng
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yawen Zheng
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Qinglin Tang
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Liang Qi
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Zihan Shi
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Qihong Yu
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Mingmin Li
- College of Life Science, China Jiliang University, Hangzhou, Zhejiang 310018, China
| | - Xianzhi Wei
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yifeng Zhou
- College of Life Science, China Jiliang University, Hangzhou, Zhejiang 310018, China
| | - Xianxing Jiang
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
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Zhao YM, Jiang Y, Wang JZ, Cao S, Zhu H, Wang WK, Yu J, Liu J, Hui J. GPATCH4 functions as a regulator of nucleolar R-loops in hepatocellular carcinoma cells. Nucleic Acids Res 2025; 53:gkaf438. [PMID: 40401559 PMCID: PMC12096074 DOI: 10.1093/nar/gkaf438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 04/03/2025] [Accepted: 05/15/2025] [Indexed: 05/23/2025] Open
Abstract
Emerging evidence suggests that dysregulated RNA-binding proteins (RBPs) are associated with a wide variety of cancers. However, the exact roles and pathways of RBPs in the tumorigenesis of hepatocellular carcinoma (HCC), the most common subtype of liver cancer, remain largely unknown. Here, we systematically searched for altered RBP candidates in HCC through multi-omics data integrative analyses and identified that GPATCH4 gene is amplified in >70% HCC patients and its high expression predicts poor prognosis. We mapped the in vivo RNA binding sites of GPATCH4 by iCLIP-seq and characterized that GPATCH4 primarily bound ribosomal RNA (rRNAs). GPATCH4 promoted HCC cell proliferation and transformation both in vitro and in vivo through increasing rRNA transcription and global protein synthesis. GPATCH4 is mainly localized in the nucleolus and helps to unwind RNA loops formed at the rDNA through interacting with DDX21 via its C-terminal intrinsically disordered region. Removal of accumulated R-loops induced by GPATCH4 depletion rescued decreased rRNA transcription and cell proliferation. Taken together, we characterized the understudied GPATCH4 as an RBP with oncogenic function in HCC and revealed a new mechanism by which GPATCH4 functions as a regulator of nucleolar R-loops to control rRNA transcription through interacting with DDX21.
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Affiliation(s)
- Yi-Ming Zhao
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yan Jiang
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Jin-Zhu Wang
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Shang Cao
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Hong Zhu
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Wei-Kang Wang
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Jian Yu
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Jiaquan Liu
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Jingyi Hui
- Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
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Liu K, Dong H, Zhang K, Yan W, Wu H, Fan J, Ye W. IL-15-Activated CD38 +HLA-DR +CD8 + T cells induce liver injury in cirrhosis via JAK/STAT5 and PI3K/mTOR pathways. Sci Rep 2025; 15:17612. [PMID: 40399368 PMCID: PMC12095495 DOI: 10.1038/s41598-025-02693-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 05/15/2025] [Indexed: 05/23/2025] Open
Abstract
The development and progression of liver cirrhosis are considerably influenced by immune processes, with CD8 + T cells playing a key role. Notably, cytokines can activate bystander CD38 + HLA-DR + CD8 + T cells without the need for T cell receptor (TCR) stimulation. However, their role in liver fibrosis remains controversial. This study aimed to investigate the pathological role of CD38 + HLA-DR + CD8 + T cells in cirrhosis progression and explore the mechanisms that regulate their functions. Peripheral blood mononuclear cells (PBMCs) were extracted from patients with cirrhosis and healthy donors, and the ratio of CD38+HLA-DR+CD8+ T cells was assessed through flow cytometry. The relationship between the prevalence of these cells and certain clinical indicators was investigated. Additionally, CD8+ T cells from healthy donors were used to examine the impact of cytokine IL-15 on CD38+HLA-DR+CD8+ T cells, utilizing flow cytometry and in vitro cytotoxicity assays. Finally, the signaling pathways involved in IL-15 activation of CD38+HLA-DR+CD8+ T cells were examined in vitro. The proportion of CD38+HLA-DR+CD8+ T cells was significantly increased in patients with cirrhosis compared to healthy donors and exhibited a strong correlation with disease severity, hepatic damage, and inflammation in cirrhosis. IL-15-stimulated CD38+HLA-DR+CD8+ T cells from healthy donors demonstrated proliferation and overexpression of cytotoxic molecules, exhibiting NKG2D- and FasL-dependent innate-like cytotoxicity without TCR activation. Notably, IL-15 did not alter the mitochondrial function of these cells. The JAK/STAT5 and PI3K/mTOR pathways were found to play a critical role in IL-15-induced innate-like cytotoxicity. These findings suggested that CD38+HLA-DR+CD8+ T cells from patients with cirrhosis contribute to immune-mediated liver injury. Furthermore, the JAK/STAT5 and PI3K/mTOR pathways were essential for IL-15-induced activation of CD38+HLA-DR+CD8+ T cells, which expressed NKG2D and FasL, demonstrating innate cytotoxicity independent of TCR engagement.
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Affiliation(s)
- Ke Liu
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongliang Dong
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Kaiyue Zhang
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Wanping Yan
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Huanyu Wu
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Jing Fan
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
- The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, 210003, Jiangsu, PR China.
| | - Wei Ye
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
- The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, 210003, Jiangsu, PR China.
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Song J, Zhang H, Zhang X, Liu M, Peng D, Ren Y, Sun Y, Li Y. Galactose-modified erythrocyte membrane fusion liposomes enable the targeted delivery of drug nanoparticles to the liver. RSC Adv 2025; 15:17781-17794. [PMID: 40443690 PMCID: PMC12120831 DOI: 10.1039/d4ra07489k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 04/11/2025] [Indexed: 06/02/2025] Open
Abstract
The safe and efficient delivery of chemicals and biologics remains crucial for liver disease therapy. In this study, we developed a targeted drug delivery system utilizing a galactose-modified erythrocyte membrane coating technique and drug liposome nanoparticles, which were further optimized using orthogonal experiments and response surface analysis. The specificity, precision, accuracy, and stability exhibited satisfactory performance in bioanalytical analysis. Specifically, targeting ligands (Gal-DSPE-PEG3400) were efficiently inserted into red blood cell (RBC) membranes using a facile insertion method. When Gal-DSPE-PEG3400-RBC was fused with fenofibrate liposome nanoparticles (FNB-Lip) by co-extrusion, the resulting galactose-modified erythrocyte membrane fusion liposome nanoparticles (Gal-RBC-FNB-Lip) showed long-term stability, excellent biocompatibility, prolonged retention time, and superior liver accumulation and therapeutic efficacy. These qualities make it suitable for effective drug delivery. The findings of this study will provide a fundamental basis for research and development of liver-targeted drugs and offer novel insights into the treatment of clinical liver diseases.
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Affiliation(s)
- Jiayu Song
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
- College of Medical Technology, Luohe Medical College Luohe 462000 P. R. China
| | - Huanhuan Zhang
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Xiaohui Zhang
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Meiying Liu
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Dan Peng
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Yuan Ren
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Yan Sun
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Yunlan Li
- School of Public Health, Shaanxi University of Chinese Medicine Xi'an 712046 P. R. China
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
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Zhao J, Gao J, Liu W, Sun J. Dynamic conditional survival nomogram for primary hepatocellular carcinoma: a population-based analysis. Discov Oncol 2025; 16:854. [PMID: 40399541 PMCID: PMC12095709 DOI: 10.1007/s12672-025-02642-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Accepted: 05/09/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND AND PURPOSE Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. While 5-year overall survival (OS) is a common prognostic metric, it does not reflect the evolving prognosis of long-term survivors. The study aimed to evaluate dynamic changes in real-time survival among HCC patients over time using conditional survival (CS) analysis and to develop an individualized, time-updated prognostic model. METHODS A total of 11,926 patients with primary HCC were included and randomly assigned to training (70%) and validation (30%) cohorts. CS was defined as the probability of surviving additional years given time already survived [CS(t1|t0) = OS(t1 + t0)/OS(t0), where OS(t0) represents the survival probability at t0-years from diagnosis, and OS(t0 + t1) represents survival at (t0 + t1)-years]. Univariable and multivariable Cox regressions were used to identify independent prognostic factors and construct a CS-nomogram. Model performance was assessed using area under the curve (AUC), calibration curves, and decision curve analysis. RESULTS CS analysis showed that real-time survival rate increased significantly with each additional year survived, with 5-year CS rising from 35.1% at diagnosis to 52.9%, 66.7%, 79.2%, and 90.2% after 1-4 years of survival. Eleven prognostic factors were included in the final model (all p < 0.05). The CS-nomogram demonstrated strong discrimination (5-year AUC > 0.84 in both cohorts) and good calibration. An interactive web-based tool was developed to facilitate clinical application. CONCLUSION CS analysis offers more accurate and dynamic prognostic information for HCC patients. The CS-nomogram provides personalized, time-adjusted survival estimates, supporting more informed decision-making and survivorship care.
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Affiliation(s)
- Junling Zhao
- Department of Oncology, Changle People's Hospital Affiliated to Shandong Second Medical University, Weifang, China
| | - Jing Gao
- Department of Oncology, Changle People's Hospital Affiliated to Shandong Second Medical University, Weifang, China
| | - Wei Liu
- Department of Oncology, Changle People's Hospital Affiliated to Shandong Second Medical University, Weifang, China
| | - Jianye Sun
- Department of Oncology, Changle People's Hospital Affiliated to Shandong Second Medical University, Weifang, China.
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Zhang X, Fu C, Yang Z, Tan Y, Li H, Zhang X, Chen M, Peng F, Li N. Bioinformatics-Guided Experimental Validation Identifies NQO1 as a Senescence-Ferroptosis Hub in Liver Fibrosis. Biomedicines 2025; 13:1249. [PMID: 40427075 PMCID: PMC12108982 DOI: 10.3390/biomedicines13051249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 04/27/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Background: As a pivotal point for the development of liver diseases, liver fibrosis (LF) is closely associated with cellular senescence and ferroptosis. However, there is a lack of effective markers that accurately predict LF status. This study aims to identify key genes involved in LF through bioinformatics analysis and experimental validation. Methods: We used bioinformatics analysis of Gene Expression Omnibus (GEO) data to investigate the gene functions, prognostic value, and immune associations of characteristic genes in LF. Functional enrichment analysis of DEGs was performed using GO and KEGG. Immune cell types and their proportions were estimated with CIBERSORTx. In addition, we analyzed the role of NQO1 in LF using IHC, WB, PCR, and flow cytometry. Results: Bioinformatics analysis identified 10 hub genes, including AR, CDKN1A, GJA1, CTSB, HIF1A, HMGB1, NQO1, PARP1, PTEN, and TXN. Among them, NQO1 was strongly correlated with immune cell activity. Experimental validation confirmed that NQO1 is upregulated and promotes αSMA and COL1A1 expression in hepatic stellate cells (HSCs). Knockdown of NQO1 significantly affected the proliferation of HSCs. Conclusions: NQO1 plays a critical role in HSC senescence and ferroptosis, promoting HSC activation and contributing to LF progression. Our findings suggest that NQO1 may serve as a potential biomarker for LF.
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Affiliation(s)
- Xinying Zhang
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha 410008, China; (X.Z.)
- Clinical Transfusion Research Centre, Xiangya Hospital, Central South University, Changsha 410008, China
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China;
| | - Chunmeng Fu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China;
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ziyue Yang
- Department of Hepatobiliary Surgery, Liver Transplantation Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yue Tan
- Department of Pharmacology & Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Huan Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha 410008, China; (X.Z.)
- Clinical Transfusion Research Centre, Xiangya Hospital, Central South University, Changsha 410008, China
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiangqian Zhang
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha 410008, China; (X.Z.)
- Clinical Transfusion Research Centre, Xiangya Hospital, Central South University, Changsha 410008, China
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Mengru Chen
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Fang Peng
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha 410008, China; (X.Z.)
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Thoufeeq JM, Prakasarao A, Ganesan S, Rajasekar JS, Rammohan A, Rela M. Excited state kinetics of tryptophan and NAD(P)H in blood plasma of normal and abnormal liver conditions: A tool to understand the metabolic changes and classification. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 333:125867. [PMID: 39946856 DOI: 10.1016/j.saa.2025.125867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/07/2025] [Accepted: 02/05/2025] [Indexed: 03/05/2025]
Abstract
Early diagnosis at the metabolomic level is crucial for the treatment of liver cirrhosis and hepatocellular carcinoma (HCC). In this study, attempts were made to investigate the excited-state kinetics of intrinsic fluorophores, tryptophan and nicotinamide adenine dinucleotide (NADH) to understand the metabolic changes associated with the transformation of normal liver into cirrhosis and HCC. Significant variations were observed in the values of average fluorescence lifetimes for 350 nm (τavg_350) and 450 nm (τavg_450) emissions for cirrhosis and HCC with respect to normal samples. The classification results of hierarchical cluster analysis (HCA) and receiver operator characteristics (ROC) based on the values of τavg_350 discriminates normal from liver diseased group (cirrhosis and HCC) with 86.95 % sensitivity and 96.43 % specificity. In the case of τavg_450 values, 95.65 % sensitivity is obtained for both HCA and ROC analyses. However, specificity of 100 % and 92.86 % was obtained in ROC and HCA analysis, respectively. The changes in the values of τavg_350, τavg_450 and NADHfree/NADHbound in cirrhosis cases after surgery are shifting towards the respective values of normal group. Among the decay kinetics of two emissions, the emission at 450 nm provides better discrimination than 350 nm emission.
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Affiliation(s)
- Jamal Mohamed Thoufeeq
- Department of Medical Physics, College of Engineering, Anna University, Sardar Patel Road, Chennai 600 025, India
| | - Aruna Prakasarao
- Department of Medical Physics, College of Engineering, Anna University, Sardar Patel Road, Chennai 600 025, India.
| | - Singaravelu Ganesan
- Department of Medical Physics, College of Engineering, Anna University, Sardar Patel Road, Chennai 600 025, India
| | - Jasper Sandeep Rajasekar
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute and Medical Centre, Chennai 600 044, India
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute and Medical Centre, Chennai 600 044, India
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute and Medical Centre, Chennai 600 044, India
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Chen N, Li Y, Li X. Dynamic role of long noncoding RNA in liver diseases: pathogenesis and diagnostic aspects. Clin Exp Med 2025; 25:160. [PMID: 40369230 PMCID: PMC12078412 DOI: 10.1007/s10238-025-01678-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Accepted: 04/09/2025] [Indexed: 05/16/2025]
Abstract
Liver disease (LD) is complex pathological condition that has emerged as a major threat to human health and the quality of life. Nonetheless, the molecular mechanisms underlying the pathogenesis of LD have not yet been fully elucidated. Recently, a large amount of evidence has shown that long noncoding RNAs (lncRNAs) play important roles in diverse biological processes in the liver. The dysregulation of lncRNAs in the liver, for example, can affect tumor proliferation, migration, and invasion, contribute to hepatic metabolism disorder of lipid and glucose, and shape of hepatic tumoral microenvironment. Thus, a comprehensive understanding of the functional roles of lncRNAs in LD pathogenesis may provide new perspectives for the development of novel diagnostic and therapeutic tools. In the present review, we summarize the current findings on the relationship between lncRNAs and LD, including the modes of action of lncRNAs, the biological significance of lncRNAs in the pathogenesis of LD, especially in hepatocellular carcinoma (HCC) as well as in some non-neoplastic disorders, and the potential use of lncRNAs as diagnostic biomarkers and therapeutic targets for LD.
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Affiliation(s)
- Ningning Chen
- Department of Neonatology, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), No. 23976, Jingshi Road, Jinan, 250022, Shandong, China
- School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yunxia Li
- Department of Neonatology, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), No. 23976, Jingshi Road, Jinan, 250022, Shandong, China
| | - Xiaoying Li
- Department of Neonatology, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), No. 23976, Jingshi Road, Jinan, 250022, Shandong, China.
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Oldroyd C, Avades T, Martin GP, Notley C, Allison MED. Motivation, self-efficacy, and identity-double-edged swords for relapse prevention in patients with alcohol related cirrhosis. Alcohol Alcohol 2025; 60:agaf027. [PMID: 40401542 PMCID: PMC12096075 DOI: 10.1093/alcalc/agaf027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/23/2025] [Accepted: 04/25/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND AND AIMS Despite the critical importance of alcohol abstinence for patients with advanced liver disease, rates of returning to alcohol remain high and engagement with relapse prevention interventions is low. This study explores the potential barriers to relapse prevention in these patients. METHODS Semi-structured interviews were conducted with patients who had alcohol-related cirrhosis or alcohol-associated hepatitis. Interviews took place during a hospital admission. The study methodology was informed by a constructivist grounded theory approach. RESULTS Thirty-three participants were recruited from two sites. Participants had a mean age of 52 (range 30-60) and there were 10 female participants (30%). Most participants were actively drinking alcohol at time of admission (n = 26) and 16 participants were interviewed during their index admission with alcohol-related liver disease.A renewed understanding of the health risk posed by future alcohol made participants confident that they would not return to alcohol use and participants felt that the most important factor in relapse prevention was their own motivation and willpower. However, many rejected the identity label of 'alcoholic' and drew a distinction between themselves and 'bad drinkers'. These factors combined to create a barrier to relapse prevention therapies, since participants felt these were neither appropriate nor necessary for them. CONCLUSIONS Enhanced self-efficacy, a belief in the importance of willpower, and a rejection of the alcoholic identity can together act to reduce engagement in relapse prevention in patients with advanced liver disease. Relapse prevention interventions should be reframed or redesigned to address these barriers.
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Affiliation(s)
- Christopher Oldroyd
- University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Cambridge Liver Unit, Addenbrooke’s Hospital, Hills Rd, Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom
| | - Tamar Avades
- Hepatology Research Group, University of Plymouth, Plymouth, Devon PL4 8AA, United Kingdom
| | - Graham P Martin
- The Healthcare Improvement Studies Institute, University of Cambridge, Strangeways Research Laboratory, 2 Worts’ Causeway, Cambridge, Cambridgeshire, CB1 8RN, United Kingdom
| | - Caitlin Notley
- Addiction Research Group, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ
| | - Michael E D Allison
- Cambridge University Hospitals NHS Foundation Trust, Cambridge Liver Unit, Addenbrooke’s Hospital, Hills Rd, Cambridge, Cambridgeshire CB2 0QQ, United Kingdom
- Cambridge NIHR Biomedical Research Centre, Hills Rd, Cambridge, Cambridgeshire, United Kingdom
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Mittal G, A P, Dhali A, Prasad R, S Y, Nurani KM, Găman MA. Plant extracts with antioxidant and hepatoprotective benefits for liver health: A bibliometric analysis of drug delivery systems. World J Gastroenterol 2025; 31:105836. [DOI: 10.3748/wjg.v31.i18.105836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/07/2025] [Accepted: 04/21/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND The rising global burden of liver diseases, such as non-alcoholic fatty liver disease and liver fibrosis, has necessitated innovative therapeutic approaches. Plant-based therapies, recognized for their anti-inflammatory and antioxidant properties, have shown promising effects. However, poor bioavailability limits their clinical application.
AIM To map global research trends, key contributors, and emerging themes in plant-based therapies combined with advanced drug delivery systems for liver health.
METHODS Using the Scopus database, 645 documents were retrieved and analyzed using bibliometric tools Biblioshiny and VOSviewer. Analysis focused on publication trends, geographical contributions, and advancements in drug delivery technologies, including nanoparticles, liposomes, and polymeric micelles. Metrics such as publication growth rate, authorship collaboration, and thematic clustering were assessed.
RESULTS The dataset spans 43 years (1981-2024), with an annual growth rate of 11.09% in the number of publications. Research output is dominated by China (33%), followed by the United States (24%) and India (18%). Collaborative studies accounted for 24.34% of publications, with an average of 5.81 co-authors per document. Key innovations include nanoparticle encapsulation of curcumin and silymarin, improving bioavailability by up to 85%. Highly cited studies demonstrated the antioxidant, anti-inflammatory, and anti-fibrotic properties of these compounds. For instance, curcumin nanoparticles showed a 70% improvement in solubility, and silymarin liposomal formulations enhanced therapeutic efficiency by 62%. Thematic analysis revealed a transition from basic clinical observations to molecular and pharmacokinetic research, with a focus on oxidative stress mitigation and hepatoprotection.
CONCLUSION This study highlights the growing synergy between plant-based therapies and advanced drug delivery systems, with significant contributions from Asian and Western countries. Future efforts should prioritize clinical trials, standardization of plant extract formulations, and interdisciplinary approaches to maximize therapeutic outcomes. The findings provide a foundation for integrating plant-derived compounds into evidence-based hepatological therapies, addressing critical challenges in bioavailability and safety.
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Affiliation(s)
- Gaurav Mittal
- MBBS Final Year StudentMahatma Gandhi Institute of Medical Sciences, Maharashtra 442102, India
| | - Prashanth A
- Department of Physiology, Mahatma Gandhi Institute of Medical Sciences, Maharashtra 442102, India
| | - Arkadeep Dhali
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S5 7AU, United Kingdom
| | - Roshan Prasad
- Department of Medicine, Datta Meghe Institute of Higher Education and Research, Sawangi 442107, India
| | - Yogesh S
- Department of Medicine, Madras Medical College, Chennai 600003, India
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Hematology, Centre of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest 022328, Romania
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest 010001, Romania
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Xue H, Wang L, Sun D, Wu Y, Yu C, Huang Y, Chan SO, Ling W, Lv J, Li L, Chen X, Pang Y, Yu C. Associations of Alcohol Consumption and Genetic Predisposition to Hepatic Steatosis With Liver-Related Events: Results From Large Population-Based Cohort Studies. Gastroenterology 2025:S0016-5085(25)00712-7. [PMID: 40379147 DOI: 10.1053/j.gastro.2025.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/30/2025] [Accepted: 04/10/2025] [Indexed: 05/19/2025]
Abstract
BACKGROUND & AIMS The new classification for steatotic liver disease identifies 3 phenotypes based on alcohol consumption. The aim of this study was to evaluate the associations between alcohol intake and liver-related events (LREs) across different drinking categories and whether genetic predisposition influences these associations. METHODS Data from 301,673 UK Biobank participants were analyzed. Alcohol consumption was self-reported and categorized by weekly intake as mild (< 140 g for females and < 210 g for males), moderate (140-350 g for females and 210-420 g for males), and heavy (> 350 g in females and > 420 g for males). A polygenic risk score based on 5 well-known single nucleotide polymorphisms associated with hepatic steatosis was calculated. Hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazard models. The analysis was validated in 47,252 participants from China Kadoorie Biobank. RESULTS During a median follow-up of 12.8 years, 1742 incident cases of LREs were documented. The multivariable-adjusted HRs per SD increment in alcohol intake for LREs were 0.95 (95% CI, 0.89-1.02) among mild drinkers, 1.23 (95% CI, 1.10-1.37) among moderate drinkers, and 1.18 (95% CI, 1.14-1.22) among heavy drinkers. The associations appeared stronger in those with high genetic risk. Compared with adults with low genetic risk and mild alcohol consumption, those with high genetic risk and heavy alcohol consumption had higher risks of LREs (HR, 6.50; 95% CI, 5.26-8.04; P for interaction < .001). Similar findings were observed in China Kadoorie Biobank. CONCLUSIONS Associations between alcohol intake and LREs vary across different drinking categories. Individuals with a higher genetic risk for steatotic liver disease appear more susceptible to alcohol.
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Affiliation(s)
- Hongliang Xue
- Department of Nutrition, School of Public Health, Guangzhou Medical University, Guangzhou, China; The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Liqing Wang
- Department of Neurology, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dianjianyi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China
| | - Yuankai Wu
- Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Canqing Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China
| | - Yating Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Sun On Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Wenhua Ling
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Jun Lv
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China
| | - Xu Chen
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China; Research Institute for Future Food, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
| | - Yuanjie Pang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing, China.
| | - Chao Yu
- Medical Examination Center, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Sah AK, Afzal M, Elshaikh RH, Abbas AM, Shalabi MG, Prabhakar PK, Babker AMA, Khalimova FT, Sabrievna VA, Choudhary RK. Innovative Strategies in the Diagnosis and Treatment of Liver Cirrhosis and Associated Syndromes. Life (Basel) 2025; 15:779. [PMID: 40430206 PMCID: PMC12112768 DOI: 10.3390/life15050779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/27/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Liver cirrhosis continues to be a major global health issue, contributing to high morbidity and mortality due to its progressive nature and associated complications. This review explores recent advancements in the diagnosis and treatment of liver cirrhosis and its related syndromes. Non-invasive diagnostic tools, such as elastography and serum biomarkers, have significantly improved early detection, reducing the need for liver biopsies. Advanced imaging techniques, including MRI and CT, further enhance diagnostic accuracy. In parallel, molecular and genomic research is providing new insights into the pathogenesis of the disease, paving the way for precision medicine. On the treatment front, pharmacological innovations, such as antifibrotic agents and targeted therapies, show promise in slowing disease progression. Endoscopic interventions like variceal banding are improving the management of complications, while advancements in liver transplantation and artificial liver support systems offer life-saving alternatives. Regenerative medicine, particularly stem cell therapy and tissue engineering, is emerging as a promising strategy for liver repair. Managing cirrhosis-related syndromes, including portal hypertension, ascites, hepatic encephalopathy, and hepatorenal syndrome, now involves evolving therapeutic approaches such as transjugular intrahepatic portosystemic shunt (TIPS) and novel pharmacotherapies. Prognostic scoring systems like the MELD and Child-Pugh are being refined with new biomarkers for better risk stratification. The future of cirrhosis care will likely involve the integration of artificial intelligence and machine learning for early diagnosis and personalized treatments, alongside emerging therapies currently under investigation. Despite these advancements, challenges such as costs, accessibility, and healthcare disparities remain barriers to widespread adoption. This review highlights the importance of incorporating innovative diagnostic and therapeutic strategies into clinical practice to improve the outcomes for patients with liver cirrhosis and its complications.
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Affiliation(s)
- Ashok Kumar Sah
- Department of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, Oman;
| | - Mohd Afzal
- Department of Medical Laboratory Technology, Arogyam Institute of Paramedical & Allied Sciences (Affiliated to H.N.B. Uttarakhand Medical Education University), Roorkee 247661, India;
| | - Rabab H. Elshaikh
- Department of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, Oman;
| | - Anass M. Abbas
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (A.M.A.); (M.G.S.)
| | - Manar G. Shalabi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (A.M.A.); (M.G.S.)
| | - Pranav Kumar Prabhakar
- Department of Biotechnology, School of Engineering and Technology, Nagaland University, Meriema, Kohima 797004, India;
| | - Asaad M. A. Babker
- Department of Medical Laboratory Sciences, College of Health Sciences, Gulf Medical University, Ajman 4184, United Arab Emirates;
| | | | - Velilyaeva Aliya Sabrievna
- Department of Psychiatry, Medical Psychology, and Narcology, Samarkand State Medical University, Samarkand 140158, Uzbekistan
| | - Ranjay Kumar Choudhary
- Department of Medical Laboratory Technology, University Institute of Allied Health Sciences, Chandigarh University, Chandigarh 140413, India
- School of Paramedics and Allied Health Sciences, Centurion University of Technology and Management, Sitapur 761211, India
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Zheng C, Liu T, Wang AQ, Chen XA, Zhang RZ, Wang XC, Lv CY, Pan RL, Wang OC, Lu XC. Protein tyrosine phosphatase receptor type kappa (PTPRK) revisited: evolving insights into structure, function, and pathology. J Transl Med 2025; 23:534. [PMID: 40355891 PMCID: PMC12067748 DOI: 10.1186/s12967-025-06496-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/13/2025] [Indexed: 05/15/2025] Open
Abstract
Protein Tyrosine Phosphatase Receptor Type Kappa (PTPRK) is a membrane-bound tyrosine phosphatase encoded by the frequently deleted region of chromosome 6q, which plays a crucial role in regulating cell signaling, adhesion, and immune response. Structurally, PTPRK comprises with an extracellular domain involved in cell-cell adhesion, a transmembrane region, and two intracellular catalytic domains responsible for its phosphatase activity. Notably, PTPRK undergoes proteolytic cleavage by Furin and ADAM10, resulting in the generation of an extracellular E-subunit and a P-subunit. Further processing by γ-secretase releases the intracellular PIC, which plays a pivotal role in regulating β-catenin signaling within the nucleus. PTPRK is widely recognized for its tumor-suppressive properties across various cancers, including colorectal, lung, ovarian, and melanoma. Despite its function as a tumor suppressor, the expression and activity of PTPRK exhibit considerable variability across different cancer types and stages. It exerts its effects by dephosphorylating key signaling molecules such as EGFR, STAT3, CD133 and β-catenin, thereby inhibiting cancer cell proliferation, survival, and metastasis. Beyond its role in cancer, PTPRK is also involved in immune regulation, particularly in the development of CD4 + T cells, and has been implicated in autoimmune diseases such as multiple sclerosis. In the nervous system, PTPRK is linked to neurite outgrowth and synaptic transmission, with genetic polymorphisms in PTPRK associated with an increased risk of neurodegenerative diseases like Alzheimer's disease. Given its extensive involvement in cancer biology, immune regulation, and neurodevelopment, PTPRK presents a promising therapeutic target. Strategies aimed at restoring its activity or targeting PTPRK might offer new approaches for current cancer therapies and overcome drug resistance. In this review, we elucidate the structural characteristics and functional roles of PTPRK in cellular signaling and disease pathogenesis. The variability of PTPRK suggests that the regulatory mechanisms governing its activity are intricate and worth further comprehensive investigation.
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Affiliation(s)
- Chen Zheng
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ting Liu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - An Qi Wang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Xing An Chen
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Rong Zhe Zhang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Xuan Chao Wang
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Chao Yue Lv
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ru Lu Pan
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ou Chen Wang
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xin-Cheng Lu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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50
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Jarosz ŁS, Socała K, Michalak K, Bulak K, Ciszewski A, Marek A, Grądzki Z, Wlaź P, Kowalczuk-Vasilev E, Rysiak A. Subacute exposure to apigenin induces changes in protein synthesis in the liver of Swiss mice. Front Physiol 2025; 16:1576310. [PMID: 40415790 PMCID: PMC12100293 DOI: 10.3389/fphys.2025.1576310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/16/2025] [Indexed: 05/27/2025] Open
Abstract
Apigenin is a natural flavonoid with various pharmacological properties. Available data indicate that it affects the metabolic processes and protein profile of cells, including hepatocytes. However, there is speculation that the use of apigenin may have a hepatotoxic effect. The aim of the experiment was to assess the effect of apigenin administered intraperitoneally to mice on the concentrations of pro- and anti-inflammatory cytokines in the liver tissue and to analyse liver weight and morphological changes in the liver parenchyma. A proteomic analysis was also performed to examine differences in genes expression for specific proteins in liver cells. Adult male albino Swiss mice were divided into two groups and treated with either apigenin (50 mg/kg BW) - APG, or a vehicle (1% DMSO) - CONT, every 24 h for 14 days. The material for the study consisted of liver samples. Slight hepatocyte degeneration microscopically were demonstrated in most mice exposed to apigenin. No significant differences were observed in the absolute and relative weight of the liver or the concentrations of pro- and anti-inflammatory cytokines between the control and experimental group. The mass spectrometry results indicate significantly higher synthesis of the proteins MAP2K19, CEP69, GNMT, BPIFA3, SYT17, ANKRD1, GRHPR, CLEC1A and EF2 in the livers of mice from the APG group in comparison to CONT group. Exposure of mice to apigenin induces functional changes in the liver. In conjunction with the microscopical and proteomic analyses, this study may indicate that inflammatory changes developing in the liver could be self-limiting and subject to regenerative processes.
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Affiliation(s)
- Łukasz S. Jarosz
- Department of Epizootiology and Clinic of Infectious Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Katarzyna Socała
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie–Skłodowska University, Lublin, Poland
| | - Katarzyna Michalak
- Department of Epizootiology and Clinic of Infectious Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Kamila Bulak
- Department of Pathomorphology and Forensic Veterinary Medicine, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Artur Ciszewski
- Department of Epizootiology and Clinic of Infectious Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Agnieszka Marek
- Department of Preventive Veterinary and Avian Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Zbigniew Grądzki
- Department of Epizootiology and Clinic of Infectious Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, Poland
| | - Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie–Skłodowska University, Lublin, Poland
| | - Edyta Kowalczuk-Vasilev
- Institute of Animal Nutrition and Bromatology, Faculty of Animal Science and Bioeconomy, University of Life Sciences in Lublin, Lublin, Poland
| | - Anna Rysiak
- Department of Botany, Mycology, and Ecology, Maria Curie-Skłodowska University, Lublin, Poland
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