|
1
|
Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [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: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
Collapse
MESH Headings
- Humans
- Liver Cirrhosis/genetics
- Liver Cirrhosis/pathology
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/virology
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Epigenesis, Genetic
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/pathology
- Hepatitis B virus/genetics
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- Animals
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- RNA, Circular/genetics
- RNA, Circular/metabolism
Collapse
Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
| |
Collapse
|
|
2
|
Sotoudeheian M. Value of Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) in Assessing Liver Fibrosis in Metabolic Dysfunction-Associated Liver Disease: A Comprehensive Review of its Serum Biomarker Role. Curr Protein Pept Sci 2025; 26:6-21. [PMID: 38982921 DOI: 10.2174/0113892037315931240618085529] [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: 03/11/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 07/11/2024]
Abstract
Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a broad condition characterized by lipid accumulation in the liver tissue, which can progress to fibrosis and cirrhosis if left untreated. Traditionally, liver biopsy is the gold standard for evaluating fibrosis. However, non-invasive biomarkers of liver fibrosis are developed to assess the fibrosis without the risk of biopsy complications. Novel serum biomarkers have emerged as a promising tool for non-invasive assessment of liver fibrosis in MAFLD patients. Several studies have shown that elevated levels of Mac-2 binding protein glycosylation isomer (M2BPGi) are associated with increased liver fibrosis severity in MAFLD patients. This suggests that M2BPGi could serve as a reliable marker for identifying individuals at higher risk of disease progression. Furthermore, the use of M2BPGi offers a non-invasive alternative to liver biopsy, which is invasive and prone to sampling errors. Overall, the usage of M2BPGi in assessing liver fibrosis in MAFLD holds great promise for improving risk stratification and monitoring disease progression in affected individuals. Further research is needed to validate its utility in clinical practice and establish standardized protocols for its implementation.
Collapse
|
|
3
|
Yan Q, Zhang J, Chen R, Zhang J, Zhou R. Percutaneous Transhepatic Cholangioscopy in Hepatolithiasis Associated With Decompensated Cirrhosis: A Retrospective Cohort Study. J Evid Based Med 2024; 17:843-850. [PMID: 39722153 DOI: 10.1111/jebm.12673] [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: 10/29/2024] [Revised: 11/25/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Multiple and complicated hepatolithiasis can be associated with decompensated cirrhosis. Endoscopic retrograde cholangiopancreatography is unavailable for multiple and complicated hepatolithiasis, and the mainstay for decompensated cirrhosis is liver transplantation. However, due to the ethical factors and the complexity of operation, liver transplantation cannot be widely operated. This study aimed to evaluate percutaneous transhepatic cholangioscopy in the extraction of stones and the recompensation of cirrhosis in patients with hepatolithiasis associated with decompensated cirrhosis. METHODS Between January 2021 and February 2024, we retrospectively reviewed the clinical data of 21 patients with multiple and complicated hepatolithiasis associated with decompensated cirrhosis. Before PTCS, the 21 patients were all assessed by the Model for End-stage Liver Disease as having indications for liver transplantation. One-step PTCS (n = 19) and two-step PTCS (n = 2) were used to remove the stones. RESULTS The technical success rate was 100%, and most stones were cleared 90.48% (19/21). After 3 months of PTCS, MELD score of the patients had significantly decreased (10.81 ± 3.31 vs. 17.24 ± 3.40, p < 0.05), and it was lowest at 6 months after the operation (9.94 ± 4.31). After a median follow-up period of 18 months (up to 40 months), the stone recurrence rate was 28.57% (6/21), 13 patients survived without liver transplantation, three patients underwent liver transplantation and survived, and five patients died of liver failure or cancer (mortality rate 23.81%). CONCLUSIONS PTCS can significantly improve patients' liver function in hepatolithiasis associated with decompensated cirrhosis.
Collapse
Affiliation(s)
- Qianyu Yan
- Research Center of Biliary Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Zhang
- Research Center of Biliary Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Chen
- Research Center of Biliary Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Jingyi Zhang
- Department of Ultrasonography, West China Hospital, Sichuan University, Chengdu, China
| | - Rongxing Zhou
- Research Center of Biliary Disease, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
4
|
Kutaiba N, Tran A, Ashraf S, Con D, Lokan J, Goodwin M, Testro A, Egan G, Lim R. Computed Tomography-Derived Extracellular Volume Fraction and Splenic Size for Liver Fibrosis Staging. J Comput Assist Tomogr 2024; 48:837-843. [PMID: 38858799 DOI: 10.1097/rct.0000000000001631] [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: 06/12/2024]
Abstract
OBJECTIVE Extracellular volume fraction (fECV) and liver and spleen size have been correlated with liver fibrosis stages and cirrhosis. The purpose of the current study was to determine the predictive value of fECV alone and in conjunction with measurement of liver and spleen size for severity of liver fibrosis. METHODS This was a retrospective study of 95 subjects (65 with liver biopsy and 30 controls). Spearman rank correlation coefficient was used to assess correlation between radiological markers and fibrosis stage. Receiver operating characteristic analysis was performed to assess the discriminative ability of radiological markers for significant (F2+) and advanced (F3+) fibrosis and cirrhosis (F4), by reporting the area under the curve (AUC). RESULTS The cohort had a mean age of 51.4 ± 14.4 years, and 52 were female (55%). There were 36, 5, 6, 9, and 39 in fibrosis stages F0, F1, F2, F3, and F4, respectively. Spleen volume alone showed the highest correlation ( r = 0.552, P < 0.001) and AUCs of 0.823, 0.807, and 0.785 for identification of significant and advanced fibrosis and cirrhosis, respectively. Adding fECV to spleen length improved AUCs (0.764, 0.745, and 0.717 to 0.812, 0.781, and 0.738, respectively) compared with splenic length alone. However, adding fECV to spleen volume did not improve the AUCs for significant or advanced fibrosis or cirrhosis. CONCLUSIONS Spleen size (measured in length or volume) showed better correlation with liver fibrosis stages compared with fECV. The combination of fECV and spleen length had higher accuracy compared with fECV alone or spleen length alone.
Collapse
Affiliation(s)
| | - Anthony Tran
- From the Department of Radiology, Austin Health, Heidelberg, Victoria
| | - Saad Ashraf
- From the Department of Radiology, Austin Health, Heidelberg, Victoria
| | | | - Julie Lokan
- Anatomical Pathology, Austin Health, Heidelberg
| | | | | | - Gary Egan
- Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia
| | | |
Collapse
|
|
5
|
Tillakeratne S, Pearson SA, Alavi M, Hajarizadeh B, Martinello M, Law M, George J, Amin J, Matthews G, Grebely J, Dore GJ, Valerio H. Trends in viral hepatitis liver-related morbidity and mortality in New South Wales, Australia. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2024; 51:101185. [PMID: 39282135 PMCID: PMC11402402 DOI: 10.1016/j.lanwpc.2024.101185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/13/2024] [Accepted: 08/15/2024] [Indexed: 09/18/2024]
Abstract
Background Monitoring hepatitis B virus (HBV) and hepatitis C virus (HCV) liver-related morbidity and mortality is key to evaluate progress towards elimination targets. Methods HBV and HCV notifications in NSW, Australia (1995-2022) were linked to hospital and mortality records. Temporal trends in decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and mortality were evaluated among people notified for HBV and HCV. Segmented Poisson regression models were used to assess the impact of the viral hepatitis elimination era (1 January 2015-31 December 2022) on advanced liver disease and mortality. Findings During 1995-2022, there were 64,865 people with an HBV notification and 112,277 people with an HCV notification in NSW. Between 2002 and 2022, there were significant reductions in age-adjusted HBV- and HCV-related DC, HCC, and liver-related mortality. Among those with HBV, age-standardised incidence per 1000 person-years (py) in 2002, 2015, and 2022 was 3.08, 1.47, and 1.16 for DC (p < 0.001); 2.97, 1.45, and 0.75 for HCC (p < 0.001); and 2.84, 1.93, and 1.40 for liver-related mortality (p < 0.001). Among those with HCV, age-standardised incidence per 1000 py in 2002, 2015, and 2022, was 5.53, 4.57, and 2.31 for DC (p < 0.001); 2.22, 2.59, and 1.87 for HCC (p < 0.001); and 3.89, 4.73, and 3.16 for liver-related mortality (p < 0.001). In 2022, absolute liver-related mortality per 100,000 population was 0.95 for HBV and 3.56 for HCV. In adjusted analyses, older age, comorbidity, and a history of alcohol use disorder were associated with increased liver-related mortality among those with HBV and HCV. Interpretation This population-level study demonstrated declining risks of DC, HCC, and mortality, with HBV-related declines commencing well before elimination era while HCV-related declines were mostly during elimination era. Population liver mortality indicates elimination target achieved for combined viral hepatitis and HBV, but not HCV. Funding The Kirby Institute, UNSW Sydney, and New South Wales Ministry of Health, Australia.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Janaki Amin
- The Kirby Institute, UNSW Sydney, Australia
- Department of Health Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | | | | | | | | |
Collapse
|
|
6
|
Kumar D, Prasad MK, Kumar S, Aziz T, Prasad ML, Sinha R, Guria RT, Kumar A, Vidyapati, Kumar S, Kumar P. Serum zinc level in liver cirrhosis with hepatic encephalopathy and its correlation with different stages of hepatic encephalopathy. J Family Med Prim Care 2024; 13:3979-3987. [PMID: 39464910 PMCID: PMC11504758 DOI: 10.4103/jfmpc.jfmpc_537_24] [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: 04/01/2024] [Revised: 05/12/2024] [Accepted: 05/16/2024] [Indexed: 10/29/2024] Open
Abstract
Background Hepatic encephalopathy (HE) severe complication of liver cirrhosis with high mortality. Few studies have found zinc deficiency in liver cirrhosis and HE patients and found it as a precipitating factor for the development of HE. This study was done to measure the serum zinc level in patients with liver cirrhosis with HE and a correlation was obtained between serum zinc level with grades of HE. Material and Methods A cross-sectional observational study was done on 150 patients with liver cirrhosis with HE at a tertiary care center in Jharkhand. All cases were evaluated by history taking, clinical examination, and a questionnaire and classified into different WHC grades of HE and CPC classes of cirrhosis. Routine blood investigations, imaging studies, and morning serum zinc levels were done for all patients. Results Majority of patients with liver cirrhosis with HE had zinc deficiency. There was a statistically highly significant (P < .00001) association between low serum zinc levels and WHC grades of HE. The serum zinc levels in different classes of cirrhosis showed highly significant differences (P < .00001). The mean serum zinc level was significantly low in patients who died (35.56 ± 11.65 vs 48.36 ± 10.91, P < .0001). The study revealed a strong positive correlation (r = .88, P = .048) between serum zinc and serum albumin levels. Conclusion Serum zinc is deficient in patients with liver cirrhosis and HE. Zinc deficiency is significantly associated with higher severity of cirrhosis and higher grades of HE. All patients with liver cirrhosis with HE and hypoalbuminemia should be evaluated for zinc deficiency.
Collapse
Affiliation(s)
- Divakar Kumar
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Manoj Kumar Prasad
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Sandeep Kumar
- Department of Medicine, Anugrah Narayan Magadh Medical College and Hospital, Gaya, Bihar, India
| | - Tarique Aziz
- Department of Biochemistry, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Manohar Lal Prasad
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Rashmi Sinha
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Rishi T. Guria
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Abhay Kumar
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Vidyapati
- Department of Medicine, Rajendra Institute of Medical Sciences Ranchi, Ranchi, Jharkhand, India
| | - Sameer Kumar
- Department of Medicine, Anugrah Narayan Magadh Medical College and Hospital, Gaya, Bihar, India
| | - Pramod Kumar
- Department of Biochemistry, Hi-Tech Medical College, Rourkela, Odisha, India
| |
Collapse
|
|
7
|
Che T, Yang X, Zhang Y, Zheng Y, Zhang Y, Zhang X, Wu Z. Mitochondria-Regulated Information Processing Nanosystem Promoting Immune Cell Communication for Liver Fibrosis Regression. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2400413. [PMID: 38721946 DOI: 10.1002/smll.202400413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/23/2024] [Indexed: 10/04/2024]
Abstract
Liver fibrosis is a coordinated response to tissue injury that is mediated by immune cell interactions. A mitochondria-regulated information-processing (MIP) nanosystem that promotes immune cell communication and interactions to inhibit liver fibrosis is designed. The MIP nanosystem mimics the alkaline amino acid domain of mitochondrial precursor proteins, providing precise targeting of the mitochondria. The MIP nanosystem is driven by light to modulate the mitochondria of hepatic stellate cells, resulting in the release of mitochondrial DNA into the fibrotic microenvironment, as detected by macrophages. By activating the STING signaling pathway, the developed nanosystem-induced macrophage phenotype switches to a reparative subtype (Ly6Clow) and downstream immunostimulatory transcriptional activity, fully restoring the fibrotic liver to its normal tissue state. The MIP nanosystem serves as an advanced information transfer system, allowing precise regulation of trained immunity, and offers a promising approach for effective liver fibrosis immunotherapy with the potential for clinical translation.
Collapse
Affiliation(s)
- Tingting Che
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Xiaopeng Yang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Yuanyuan Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Yin Zheng
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong, 250012, China
| | - Yufei Zhang
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of functional polymer materials, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Xinge Zhang
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of functional polymer materials, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Zhongming Wu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong, 250012, China
| |
Collapse
|
|
8
|
Wei T, Jin Q. Research trends and hotspots in exercise interventions for liver cirrhosis: A bibliometric analysis via CiteSpace. Medicine (Baltimore) 2024; 103:e38831. [PMID: 38996156 PMCID: PMC11245219 DOI: 10.1097/md.0000000000038831] [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: 12/13/2023] [Accepted: 06/14/2024] [Indexed: 07/14/2024] Open
Abstract
Cirrhosis is a chronic liver disease with severe consequences for a patient's health and survival. Exercise is an essential therapeutic strategy for both cirrhosis prevention and treatment. On the other hand, information regarding the present status of exercise-related research in cirrhosis is limited. Therefore, this study seeks to close the information gap in the scientific literature by using bibliometric techniques to analyze the trends, focal points, and cutting-edge research areas on exercise and cirrhosis. On September 22, 2023, research articles and reviews on exercise intervention for cirrhosis were obtained and downloaded from the Web of Science Core Collection (WoSCC). Subsequently, we employed CiteSpace (version 6.1.R6) to conduct bibliometric and knowledge graph analyses. 588 papers in 301 scholarly journals were written by 673 authors from 460 institutions spread over 63 countries and regions. The most productive nation among them is the United States. Not only is Zobair M. Younossi 1 of the most prolific writers, but he also receives the most co-citations. Most articles were published by the University of Michigan in the US, with the University of Alberta in Canada coming in second. Meanwhile, the WORLD JOURNAL OF GASTROENTEROLOGY has the most published articles, whereas HEPATOLOGY has the greatest number of co-citations. Apart from the theme words, the most frequently utilized keywords were "quality of life," "insulin resistance," and "mortality." Future research may concentrate on "obesity," "sarcopenia," and "Mediterranean diet," according to the analysis of keyword emergence. CiteSpace is used in this work to visually represent the topic of exercise intervention in cirrhosis, offering valuable information to researchers regarding the field's current status and possible future direction.
Collapse
Affiliation(s)
- Tao Wei
- Department of Physical Education, Yangzhou University, Yangzhou, Jiangsu, China
| | - Qiguan Jin
- Department of Physical Education, Yangzhou University, Yangzhou, Jiangsu, China
| |
Collapse
|
|
9
|
Chu R, Wang Y, Kong J, Pan T, Yang Y, He J. Lipid nanoparticles as the drug carrier for targeted therapy of hepatic disorders. J Mater Chem B 2024; 12:4759-4784. [PMID: 38682294 DOI: 10.1039/d3tb02766j] [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: 05/01/2024]
Abstract
The liver, a complex and vital organ in the human body, is susceptible to various diseases, including metabolic disorders, acute hepatitis, cirrhosis, and hepatocellular carcinoma. In recent decades, these diseases have significantly contributed to global morbidity and mortality. Currently, liver transplantation remains the most effective treatment for hepatic disorders. Nucleic acid therapeutics offer a selective approach to disease treatment through diverse mechanisms, enabling the regulation of relevant genes and providing a novel therapeutic avenue for hepatic disorders. It is expected that nucleic acid drugs will emerge as the third generation of pharmaceuticals, succeeding small molecule drugs and antibody drugs. Lipid nanoparticles (LNPs) represent a crucial technology in the field of drug delivery and constitute a significant advancement in gene therapies. Nucleic acids encapsulated in LNPs are shielded from the degradation of enzymes and effectively delivered to cells, where they are released and regulate specific genes. This paper provides a comprehensive review of the structure, composition, and applications of LNPs in the treatment of hepatic disorders and offers insights into prospects and challenges in the future development of LNPs.
Collapse
Affiliation(s)
- Runxuan Chu
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
| | - Yi Wang
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tung, Hong Kong SAR, P. R. China.
| | - Jianglong Kong
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tung, Hong Kong SAR, P. R. China.
| | - Ting Pan
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
- Department of Pharmaceutics School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China
| | - Yani Yang
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
| | - Jun He
- National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, P. R. China.
| |
Collapse
|
|
10
|
Song QW, Yuan YP, Sun QS, Zhan XD, Jiang YX, Tang XN. Effects of Bulleyaconitine A on Extracellular Matrix Secretion and Expression of Related Proteins in Acetaldehyde-Activated Hepatic Stellate Cells. Bull Exp Biol Med 2024; 177:74-78. [PMID: 38955854 DOI: 10.1007/s10517-024-06134-8] [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: 08/22/2022] [Indexed: 07/04/2024]
Abstract
Activated hepatic stellate cells differentiate into myofibroblasts, which synthesize and secrete extracellular matrix (ECM) leading to liver fibrosis. It was previously demonstrated that bulleyaconitine A (BLA), an alkaloid from Aconitum bulleyanum, inhibits proliferation and promotes apoptosis of human hepatic Lieming Xu-2 (LX-2) cells. In this study, we analyzed the effect of BLA on the production of ECM and related proteins by LX-2 cells activated with acetaldehyde (AA). The cells were randomized into the control group, AA group (cells activated with 400 μM AA), and BLA+AA group (cells cultured in the presence of 400 μM AA and 18.75 μg/ml BLA). In the BLA+AA group, the contents of collagens I and III and the expression of α-smooth muscle actin and transforming growth factor-β1 (TGF-β1) were statistically significantly higher than in the control, but lower than in the AA group. Expression of MMP-1 in the BLA+AA group was also significantly higher than in the AA group, but lower than in the control. Expression of TIMP-1 in the BLA+AA group was significantly higher than in the control, but lower than in the AA group. Thus, BLA suppressed activation and proliferation of LX-2 cells by inhibiting TGF-β1 signaling pathway and decreasing the content of collagens I and III by reducing the MMP-1/TIMP-1 ratio.
Collapse
Affiliation(s)
- Q W Song
- Department of Medical Parasitology, Wannan Medical College, Anhui, China
| | - Y P Yuan
- Department of Medical Parasitology, Wannan Medical College, Anhui, China
| | - Q S Sun
- Department of Medical Parasitology, Wannan Medical College, Anhui, China
| | - X D Zhan
- Department of Medical Parasitology, Wannan Medical College, Anhui, China
| | - Y X Jiang
- Department of Pathogenic Biology and Immunology, Jiaxing University College of Medicine, Zhejiang, China
| | - X N Tang
- Department of Medical Parasitology, Wannan Medical College, Anhui, China.
- Anhui Province Key Laboratory of Biological Macromolecules Research, Wannan Medical College, Anhui, China.
| |
Collapse
|
|
11
|
Hu J, Teng J, Hui S, Liang L. SGLT-2 inhibitors as novel treatments of multiple organ fibrosis. Heliyon 2024; 10:e29486. [PMID: 38644817 PMCID: PMC11031788 DOI: 10.1016/j.heliyon.2024.e29486] [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: 12/26/2023] [Revised: 04/08/2024] [Accepted: 04/08/2024] [Indexed: 04/23/2024] Open
Abstract
Fibrosis, a significant health issue linked to chronic inflammatory diseases, affects various organs and can lead to serious damage and loss of function. Despite the availability of some treatments, their limitations necessitate the development of new therapeutic options. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), known for their glucose-lowering ability, have shown promise in offering protective effects against fibrosis in multiple organs through glucose-independent mechanisms. This review explores the anti-fibrotic potential of SGLT2i across different tissues, providing insights into their underlying mechanisms and highlighting recent research advancements. The evidence positions SGLT2i as a potential future treatments for fibrotic diseases.
Collapse
Affiliation(s)
- Junpei Hu
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
| | - Jianhui Teng
- Department of Geriatrics, Hunan Provincial People's Hospital, China
| | - Shan Hui
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
| | - Lihui Liang
- Department of Geriatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, China
| |
Collapse
|
|
12
|
Habibi P, Falamarzi K, Ebrahimi ND, Zarei M, Malekpour M, Azarpira N. GDF11: An emerging therapeutic target for liver diseases and fibrosis. J Cell Mol Med 2024; 28:e18140. [PMID: 38494851 PMCID: PMC10945076 DOI: 10.1111/jcmm.18140] [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: 09/17/2023] [Revised: 01/07/2024] [Accepted: 01/16/2024] [Indexed: 03/19/2024] Open
Abstract
Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.
Collapse
Affiliation(s)
- Pardis Habibi
- Student Research CommitteeShiraz University of Medical SciencesShirazIran
- Transplant Research CenterShiraz University of Medical SciencesShirazIran
| | - Kimia Falamarzi
- Student Research CommitteeShiraz University of Medical SciencesShirazIran
- Transplant Research CenterShiraz University of Medical SciencesShirazIran
| | | | - Mohammad Zarei
- Renal Division, Brigham & Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
- John B. Little Center for Radiation SciencesHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
| | - Mahdi Malekpour
- Student Research CommitteeShiraz University of Medical SciencesShirazIran
- Transplant Research CenterShiraz University of Medical SciencesShirazIran
| | - Negar Azarpira
- Transplant Research CenterShiraz University of Medical SciencesShirazIran
| |
Collapse
|
|
13
|
Schattenberg JM, Balp MM, Reinhart B, Porwal S, Tietz A, Pedrosa MC, Docherty M. Identification of Fast Progressors Among Patients With Nonalcoholic Steatohepatitis Using Machine Learning. GASTRO HEP ADVANCES 2023; 3:101-108. [PMID: 39132186 PMCID: PMC11307632 DOI: 10.1016/j.gastha.2023.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 09/07/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims There is a high unmet need to develop noninvasive tools to identify nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) patients at risk of fast progression to end-stage liver disease (ESLD). This study describes the development of a machine learning (ML) model using data around the first clinical evidence of NAFLD/NASH to identify patients at risk of future fast progression. Methods Adult patients with ESLD (cirrhosis or hepatocellular carcinoma) due to NAFLD/NASH were identified in Optum electronic health records (2007-2018 period). Patients were stratified into fast (0.5 and 3 years) and standard progressor (6-10 years) cohorts based on retrospectively established progression time between ESLD and the earliest observable disease, and characteristics were reported using descriptive statistics. Two ML models predicting fast progression were created, performance was compared, and top predictive features from the final model were compared between cohorts. Results Among a total of 4013 NAFLD patients with cirrhosis or hepatocellular carcinoma (mean age 58.6 ± 12.5; 65% female), 24% were fast (n = 951) and 25% standard (n = 992) progressors that were used for modeling. The cohorts were comparable for gender, body mass index, type 2 diabetes, and arterial hypertension, but differed significantly for obesity, hyperlipidemia, and age at index. The final model (NASH FASTmap) is a 44 feature light gradient boosting model which performed better (area under the curve [0.77], F1-score [0.74], accuracy [0.71], and precision [0.71]) than eXtreme gradient boosting model to predict fast progression. Conclusion Future fast progression to ESLD in NAFLD/NASH patients can be predicted from clinical data using ML. Electronic health record implementation of NASH FASTmap could support clinical assessment for risk stratification and potentially improve disease management.
Collapse
Affiliation(s)
- Jörn M. Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center, Mainz, Germany
| | | | | | | | | | | | | |
Collapse
|
|
14
|
Wang L, Li D, Zhu Z, Liao Y, Wu J, Liu Y, Yang R, Dai H, Wu Z, Sun X. Knockout of Sema4D alleviates liver fibrosis by suppressing AOX1 expression. Pharmacol Res 2023; 195:106886. [PMID: 37591326 DOI: 10.1016/j.phrs.2023.106886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/30/2023] [Accepted: 08/08/2023] [Indexed: 08/19/2023]
Abstract
Liver fibrosis can occur in many chronic liver diseases, and no effective treatments are available due to the poorly characterized molecular pathogenesis. Semaphorin 4D (Sema4D) has immune functions and serves important roles in T cell priming. Here, we found that Sema4D was highly expressed in fibrotic liver, and the expression of Sema4D increased with hepatic stellate cells (HSCs) activation. Knockout of Sema4D alleviated liver fibrosis. Mechanistically, knockout of Sema4D alleviated liver fibrosis by suppressing the expression of AOX1 in retinol metabolism. Further investigation demonstrated that retinoic acid receptor α (RARA), an important nuclear receptor of retinoic acid, was reduced by Sema4D knockout during liver fibrogenesis. Sema4D knockout-mediated suppression of liver fibrosis was partly mediated by regulating the balance of Th1, Th2, Th17, and T-bet+Treg cells via inhibiting AOX1/RARA. Thus, targeting Sema4D may hold promise as a potential therapeutic approach for treating liver fibrosis.
Collapse
Affiliation(s)
- Lifu Wang
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Dinghao Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China
| | - Zifeng Zhu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China
| | - Yao Liao
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Ji Wu
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Yuheng Liu
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Ruibing Yang
- Guangzhou KingMed Diagnostic Laboratory Group Co Ltd, Guangzhou 510310, China
| | - Hanqiao Dai
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Zhongdao Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China.
| | - Xi Sun
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China.
| |
Collapse
|
|
15
|
Chen X, Zhu S, Li HD, Wang JN, Sun LJ, Xu JJ, Hui YR, Li XF, Li LY, Zhao YX, Suo XG, Xu CH, Ji ML, Sun YY, Huang C, Meng XM, Zhang L, Lv XW, Ye DQ, Li J. N 6-methyladenosine-modified circIRF2, identified by YTHDF2, suppresses liver fibrosis via facilitating FOXO3 nuclear translocation. Int J Biol Macromol 2023; 248:125811. [PMID: 37467831 DOI: 10.1016/j.ijbiomac.2023.125811] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/17/2023] [Accepted: 06/28/2023] [Indexed: 07/21/2023]
Abstract
Circular RNA (circRNA) has been implicated in liver fibrosis and modulated by multiple elusive molecular mechanisms, while the effects of N6-methyladenosine (m6A) modification on circRNA are still elusive. Herein, we identify circIRF2 from our circRNA sequencing data, which decreased in liver fibrogenesis stage and restored in resolution stage, indicating that dysregulated circIRF2 may be closely associated with liver fibrosis. Gain/loss-of-function analysis was performed to evaluate the effects of circIRF2 on liver fibrosis at both the fibrogenesis and resolution in vivo. Ectopic expression of circIRF2 attenuated liver fibrogenesis and HSCs activation at the fibrogenesis stage, whereas downregulation of circIRF2 impaired mouse liver injury repair and inflammation resolution. Mechanistically, YTHDF2 recognized m6A-modified circIRF2 and diminished circIRF2 stability, partly accounting for the decreased circIRF2 in liver fibrosis. Microarray was applied to investigate miRNAs regulated by circIRF2, our data elucidate cytoplasmic circIRF2 may directly harbor miR-29b-1-5p and competitively relieve its inhibitory effect on FOXO3, inducing FOXO3 nuclear translocation and accumulation. Clinically, circIRF2 downregulation was prevalent in liver fibrosis patients compared with healthy individuals. In summary, our findings offer a novel insight into m6A modification-mediated regulation of circRNA and suggest that circIRF2 may be an exploitable prognostic marker and/or therapeutic target for liver fibrosis.
Collapse
Affiliation(s)
- Xin Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China; Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Hai-Di Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Jia-Nan Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Li-Jiao Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Jin-Jin Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ya-Ru Hui
- Department of Graduate Student Affairs, Anhui Medical University, Hefei 230032, China
| | - Xiao-Feng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Liang-Yun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Yu-Xin Zhao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Xiao-Guo Suo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Chuan-Hui Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ming-Lu Ji
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Ying-Yin Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China
| | - Lei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei 230032, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
| |
Collapse
|
|
16
|
Lee YS, Seki E. In Vivo and In Vitro Models to Study Liver Fibrosis: Mechanisms and Limitations. Cell Mol Gastroenterol Hepatol 2023; 16:355-367. [PMID: 37270060 PMCID: PMC10444957 DOI: 10.1016/j.jcmgh.2023.05.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/05/2023]
Abstract
Liver fibrosis is a common result of liver injury owing to various kinds of chronic liver diseases. A deeper understanding of the pathophysiology of liver fibrosis and identifying potential therapeutic targets of liver fibrosis is important because liver fibrosis may progress to advanced liver diseases, such as cirrhosis and hepatocellular carcinoma. Despite numerous studies, the underlying mechanisms of liver fibrosis remain unclear. Mechanisms of the development and progression of liver fibrosis differ according to etiologies. Therefore, appropriate liver fibrosis models should be selected according to the purpose of the study and the type of underlying disease. Many in vivo animal and in vitro models have been developed to study liver fibrosis. However, there are no perfect preclinical models for liver fibrosis. In this review, we summarize the current in vivo and in vitro models for studying liver fibrosis and highlight emerging in vitro models, including organoids and liver-on-a-chip models. In addition, we discuss the mechanisms and limitations of each model.
Collapse
Affiliation(s)
- Young-Sun Lee
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
| |
Collapse
|
|
17
|
Wei Y, Gao C, Wang H, Zhang Y, Gu J, Zhang X, Gong X, Hao Z. Mori fructus aqueous extracts attenuates liver injury by inhibiting ferroptosis via the Nrf2 pathway. J Anim Sci Biotechnol 2023; 14:56. [PMID: 37032323 PMCID: PMC10084661 DOI: 10.1186/s40104-023-00845-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 01/31/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND Liver fibrosis and hepatocellular carcinogenesis secondary to liver fibrosis are serious liver diseases with no effective treatments. Mori fructus aqueous extracts (MFAEs) have served as successful treatments for many types of liver injury including fibrosis although the molecular mechanisms are unknown at present. PURPOSE To investigate the effect of MFAEs in alleviating acute and chronic liver injury and tried to decipher the underlying mechanism. METHODS AND RESULTS Mice were divided into 5 groups (n = 8) for acute (groups: control, 0.3% CCl4, bifendate (BD), 100 and 200 mg/kg MFAEs, 7 d) and chronic (groups: control, 10% CCl4, BD, 100 and 200 mg/kg MFAEs, 4 weeks) liver injury study. Each mouse was injected intraperitoneally with 10 µL/g corn oil containing CCl4 expect the control group. HepG2 cells were used in vitro study. Eighteen communal components were identified by UPLC-LTQ-Orbitrap-MS. We utilized a mouse model for acute and chronic liver injury using CCl4 and MFAEs administration effectively blocked fibrosis and significantly inhibited inflammation in the liver. MFAEs activated the nuclear factor erythroid derived 2 like 2/heme oxygenase 1 (Nrf2/HO-1) pathway and promoted the synthesis of the antioxidants glutathione (GSH), superoxidedismutase (SOD) and glutathione peroxidase (GSH-Px) that resulted in reduced levels of CCl4-induced oxidative stress molecules including reactive oxygen species. These extracts administered to mice also inhibited ferroptosis in the liver by regulating the expression of Acyl-CoA synthetase long chain family member 4 (ACSL4), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thus reducing the occurrence of liver fibrosis. Both in vivo and in vitro tests indicated that the mechanism of MFAEs protection against liver fibrosis was linked to activation of Nrf2 signaling. These effects were blocked in vitro by the addition of a specific Nrf2 inhibitor. CONCLUSION MFAEs inhibited oxidative stress, ferroptosis and inflammation of the liver by activating Nrf2 signal pathway and provided a significant protective effect against CCl4-induced liver fibrosis.
Collapse
Affiliation(s)
- Yuanyuan Wei
- Innovation Centre of Chinese veterinary medicine, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China
- National Center of Technology Innovation for Medicinal function of Food, National Food and Strategic Reserves Administration, Beijing, China
| | - Chen Gao
- Innovation Centre of Chinese veterinary medicine, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China
- National Center of Technology Innovation for Medicinal function of Food, National Food and Strategic Reserves Administration, Beijing, China
| | - Huiru Wang
- Innovation Centre of Chinese veterinary medicine, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China
- National Center of Technology Innovation for Medicinal function of Food, National Food and Strategic Reserves Administration, Beijing, China
| | - Yannan Zhang
- Innovation Centre of Chinese veterinary medicine, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China
- National Center of Technology Innovation for Medicinal function of Food, National Food and Strategic Reserves Administration, Beijing, China
| | - Jinhua Gu
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China
- China Institute of Veterinary Drug Control, Beijing, 100081, China
| | - Xiuying Zhang
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China
- China Institute of Veterinary Drug Control, Beijing, 100081, China
| | - Xuhao Gong
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China
- China Institute of Veterinary Drug Control, Beijing, 100081, China
| | - Zhihui Hao
- Innovation Centre of Chinese veterinary medicine, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing, 100193, China.
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing, 100193, P. R. China.
- National Center of Technology Innovation for Medicinal function of Food, National Food and Strategic Reserves Administration, Beijing, China.
| |
Collapse
|
|
18
|
Meng Q, Luo L, Lei M, Chen Z, Sun Y, Chen X, Zhai Z, Zhang Y, Cao J, Su Z, Li F, Li J, Hong A, Chen X. Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis. Pharmaceuticals (Basel) 2023; 16:ph16040548. [PMID: 37111305 PMCID: PMC10145669 DOI: 10.3390/ph16040548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/16/2023] [Accepted: 03/24/2023] [Indexed: 04/09/2023] Open
Abstract
Liver fibrosis represents a significant health hazard with a high morbidity rate and an increased risk of liver cancer. Targeting overactivated Fibroblast growth factor receptor 2 (FGFR2) is a promising strategy to counteract collagen accumulation during liver fibrosis. However, there is a shortage of drugs to specifically block the activation of FGFR2 in liver fibrosis patients. Data mining, cell validation, and animal studies showed a positive correlation between FGFR2 overexpression and liver fibrosis development. Novel FGFR2 inhibitors were screened using a microarray-based high-throughput binding analysis. The effectiveness of each candidate was validated through simulated docking, binding affinity verification, single-point mutation validation, and in vitro kinase inhibition measurements to demonstrate the ability of each inhibitor to block the catalytic pocket and reverse FGFR2 overactivation. A specific FGFR2 inhibitor, cynaroside (CYN, also known as luteoloside), was screened based on the finding that FGFR2 promotes hepatic stellate cell (HSC) activation and collagen secretion in hepatocytes. The results from cellular assays showed that CYN can inhibit FGFR2 hyperactivation resulting from its overexpression and excessive basic fibroblast growth factor (bFGF), reducing HSC activation and collagen secretion in hepatocytes. Animal experiments on a carbon tetrachloride (CCl4) mouse model and a nonalcoholic steatohepatitis mouse model indicate that CYN treatment reduces liver fibrosis during fibrosis formation. These findings suggest that CYN prevents liver fibrosis formation at the cell level and in mouse models.
Collapse
Affiliation(s)
- Qilin Meng
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Lin Luo
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Minghua Lei
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Zhiqi Chen
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Yuanmeng Sun
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Xue Chen
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Zhaodong Zhai
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Yibo Zhang
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Jieqiong Cao
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Zijian Su
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Fu Li
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Jingsheng Li
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - An Hong
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| | - Xiaojia Chen
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou 510632, China
| |
Collapse
|
|
19
|
Guo Y, Tian G, Chen X, Hou Y, Zhang X, Xue X, Zhao L, Wu Y. GL-V9 ameliorates liver fibrosis by inhibiting TGF-β/smad pathway. Exp Cell Res 2023; 425:113521. [PMID: 36841325 DOI: 10.1016/j.yexcr.2023.113521] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 02/27/2023]
Abstract
Liver fibrosis is a wound-healing response that arises from various aetiologies. Flavonoid compounds have been proved of their anti-liver fibrosis effects. This study aimed to elucidate the protective effect and mechanism of flavonoid compound GL-V9 on CCl4-induced and DDC-induced liver fibrosis. Treatment with GL-V9 alleviated hepatic injury and exhibited a dramatic protection effect of liver fibrosis. Further experiments found that GL-V9 treatment inhibited extracellular matrix (ECM) expression. Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. GL-V9 could inhibit the activation of HSCs through directly binding to TGFβRI, subsequently inhibit TGF-β/Smad pathway. In conclusion, this study proved that GL-V9 executed a protective effect on liver fibrosis by inhibiting TGF-β/Smad pathway.
Collapse
Affiliation(s)
- Yabing Guo
- Pharmaceutical Animal Experimental Center of China Pharmaceutical University, Nanjing, 211198, China
| | - Geng Tian
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Chen
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Yingjian Hou
- Center of Cellular and Molecular Biology, China Pharmaceutical University, Nanjing, 211198, China
| | - Xinyu Zhang
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Xue
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li Zhao
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
| | - Yun Wu
- Yancheng Third People's Hospital, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng, 224001, China.
| |
Collapse
|
|
20
|
Kim H, Park SY, Lee SY, Kwon JH, Byun S, Kim MJ, Yu S, Yoo JY, Yoon HG. Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis. BMB Rep 2023; 56:114-119. [PMID: 36593107 PMCID: PMC9978366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Indexed: 01/04/2023] Open
Abstract
Liver fibrosis is caused by chronic liver damage and results in the aberrant accumulation of extracellular matrix during disease progression. Despite the identification of the HAT enzyme p300 as a major factor for liver fibrosis, the development of therapeutic agents targeting the regulation of p300 has not been reported. We validated a novel p300 inhibitor (A6) on the improvement of liver fibrosis using two mouse models, mice on a choline-deficient high-fat diet and thioacetamide-treated mice. We demonstrated that pathological hall-marks of liver fibrosis were significantly diminished by A6 treatment through Masson's trichrome and Sirius red staining on liver tissue and found that A6 treatment reduced the expression of matricellular protein genes. We further showed that A6 treatment improved liver fibrosis by reducing the stability of p300 protein via disruption of p300 binding to AKT. Our findings suggest that targeting p300 through the specific inhibitor A6 has potential as a major therapeutic avenue for treating liver fibrosis. [BMB Reports 2023; 56(2): 114-119].
Collapse
Affiliation(s)
- Hyunsik Kim
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soo-Yeon Park
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soo Yeon Lee
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jae-Hwan Kwon
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Seunghee Byun
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Mi Jeong Kim
- Department of Food and Biotechnology, College of Science and Technology Institute of Natural Sciences Korea University, Sejong 30019, Korea
| | - Sungryul Yu
- Department of Clinical Laboratory Science, Semyung University, Jecheon 27136, Korea
| | - Jung-Yoon Yoo
- Department of Biomedical Laboratory Science, Yonsei University MIRAE Campus, Wonju 26493, Korea,Corresponding authors. Jung-Yoon Yoo, Tel: +82-33-760-2861; Fax: +82-33-760-2861; E-mail: ; Ho-Geun Yoon, Tel: +82-2-2228-0835; Fax: +82-2-312-5041; E-mail:
| | - Ho-Geun Yoon
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea,Corresponding authors. Jung-Yoon Yoo, Tel: +82-33-760-2861; Fax: +82-33-760-2861; E-mail: ; Ho-Geun Yoon, Tel: +82-2-2228-0835; Fax: +82-2-312-5041; E-mail:
| |
Collapse
|
|
21
|
Kim H, Park SY, Lee SY, Kwon JH, Byun S, Kim MJ, Yu S, Yoo JY, Yoon HG. Therapeutic effects of selective p300 histone acetyl-transferase inhibitor on liver fibrosis. BMB Rep 2023; 56:114-119. [PMID: 36593107 PMCID: PMC9978366 DOI: 10.5483/bmbrep.2022-0188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/01/2022] [Accepted: 12/27/2022] [Indexed: 08/13/2023] Open
Abstract
Liver fibrosis is caused by chronic liver damage and results in the aberrant accumulation of extracellular matrix during disease progression. Despite the identification of the HAT enzyme p300 as a major factor for liver fibrosis, the development of therapeutic agents targeting the regulation of p300 has not been reported. We validated a novel p300 inhibitor (A6) on the improvement of liver fibrosis using two mouse models, mice on a choline-deficient high-fat diet and thioacetamide-treated mice. We demonstrated that pathological hall-marks of liver fibrosis were significantly diminished by A6 treatment through Masson's trichrome and Sirius red staining on liver tissue and found that A6 treatment reduced the expression of matricellular protein genes. We further showed that A6 treatment improved liver fibrosis by reducing the stability of p300 protein via disruption of p300 binding to AKT. Our findings suggest that targeting p300 through the specific inhibitor A6 has potential as a major therapeutic avenue for treating liver fibrosis. [BMB Reports 2023; 56(2): 114-119].
Collapse
Affiliation(s)
- Hyunsik Kim
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soo-Yeon Park
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soo Yeon Lee
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jae-Hwan Kwon
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Seunghee Byun
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Mi Jeong Kim
- Department of Food and Biotechnology, College of Science and Technology Institute of Natural Sciences Korea University, Sejong 30019, Korea
| | - Sungryul Yu
- Department of Clinical Laboratory Science, Semyung University, Jecheon 27136, Korea
| | - Jung-Yoon Yoo
- Department of Biomedical Laboratory Science, Yonsei University MIRAE Campus, Wonju 26493, Korea
| | - Ho-Geun Yoon
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| |
Collapse
|
|
22
|
Han X, Gong N, Xue L, Billingsley MM, El-Mayta R, Shepherd SJ, Alameh MG, Weissman D, Mitchell MJ. Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis. Nat Commun 2023; 14:75. [PMID: 36650129 PMCID: PMC9845313 DOI: 10.1038/s41467-022-35637-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/14/2022] [Indexed: 01/19/2023] Open
Abstract
Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted delivery of RNA therapeutics to activated liver-resident fibroblasts for liver fibrosis treatment remains challenging. Here, we develop a combinatorial library of anisamide ligand-tethered lipidoids (AA-lipidoids) using a one-pot, two-step modular synthetic method and adopt a two-round screening strategy to identify AA-lipidoids with both high potency and selectivity to deliver RNA payloads to activated fibroblasts. The lead AA-lipidoid AA-T3A-C12 mediates greater RNA delivery and transfection of activated fibroblasts than its analog without anisamide and the FDA-approved MC3 ionizable lipid. In a preclinical model of liver fibrosis, AA-T3A-C12 enables ~65% silencing of heat shock protein 47, a therapeutic target primarily expressed by activated fibroblasts, which is 2-fold more potent than MC3, leading to significantly reduced collagen deposition and liver fibrosis. These results demonstrate the potential of AA-lipidoids for targeted RNA delivery to activated fibroblasts. Furthermore, these synthetic methods and screening strategies open a new avenue to develop and discover potent lipidoids with targeting properties, which can potentially enable RNA delivery to a range of cell and tissue types that are challenging to access using traditional lipid nanoparticle formulations.
Collapse
Affiliation(s)
- Xuexiang Han
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Ningqiang Gong
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Lulu Xue
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | | | - Rakan El-Mayta
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sarah J Shepherd
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Mohamad-Gabriel Alameh
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.,Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Drew Weissman
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.,Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA. .,Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. .,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. .,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. .,Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. .,Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| |
Collapse
|
|
23
|
Zhang L, Wu F, Fan C, Huang S, Ma Y, Chen S, Zhang J, Jiang H. Quantitative phosphoproteomic analysis of mice with liver fibrosis by DIA mass spectrometry analysis with PRM verification. J Proteomics 2023; 271:104768. [PMID: 36336261 DOI: 10.1016/j.jprot.2022.104768] [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: 08/03/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
Abstract
Liver fibrosis (LF), commonly associated with chronic liver diseases, is a major public health problem worldwide. Protein phosphorylation is not only an important form of protein modification in organisms but also the most important mechanism to regulate and control the activity and function of proteins, affecting the occurrence and development of many diseases. However, comprehensive phosphoproteomic profiling in LF has not been fully elucidated. In this study, data-independent acquisition (DIA) was used to analyse the phosphoproteomics of mice with LF. A total of 553 phosphopeptides (representing 440 phosphoproteins) had significant phosphorylation levels. Among these phosphoproteins, 49 were upregulated and 401 were downregulated, and 5 phosphoserine (P-Ser) motifs and 2 phosphothreonine (P-Thr) motifs were conserved in LF. GO and KEGG pathway enrichment analyses identified 769 significant GO terms and 49 significant KEGG pathways. Four phosphorylated proteins were selected for parallel reaction monitoring (PRM) verification, and the results were consistent with DIA data. Together, there were significantly different phosphoproteomic profiles in LF, suggesting that protein phosphorylation was related to the occurrence and progression of LF, which could pave the way for further investigation into the related regulatory mechanisms. SIGNIFICANCE: LF is a necessary stage in the development of chronic liver disease to liver cirrhosis and has attracted wide attention. To the best of our knowledge, there are few reports on the phosphorylated proteomics of LF. In this study, DIA and PRM techniques were used to study the liver tissue of mice induced by CCl4. The results showed that phosphorylation had a significant effect on the activity and function of proteins, and the PRM results were consistent with the trend observed in DIA analysis. This study will help to better reveal the relationship of phosphorylated proteins in LF and lay a foundation for further study of related regulatory mechanisms.
Collapse
Affiliation(s)
- Lili Zhang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Furong Wu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
| | - Chang Fan
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Shaopeng Huang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Yanzhen Ma
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Sen Chen
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| | - Jiafu Zhang
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
| | - Hui Jiang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
| |
Collapse
|
|
24
|
Dasgupta T, Manickam V. Fibrosis in Liver and Pancreas: a Review on Pathogenic Significance, Diagnostic Options, and Current Management Strategies. Inflammation 2023; 46:824-834. [PMID: 36595108 DOI: 10.1007/s10753-022-01776-0] [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: 11/13/2022] [Revised: 12/15/2022] [Accepted: 12/16/2022] [Indexed: 01/04/2023]
Abstract
Inflammation is one of the most natural ways of the body's biological response against invading foreign pathogens or injured cells which eventually can lead to a chronic or acute productive response. Fibrosis is an end-stage event associated with an inflammatory response addressed with tissue hardening, discoloration, and most importantly overgrowth of associated tissue. Various organs at different diseased conditions are affected by fibrosis including the liver, pancreas, brain, kidney, and lung. Etiological factors including internal like inflammatory cytokines, growth factors, and oxidative stress and external like alcohol and viruses contribute to the development of fibrosis in both the liver and pancreas. More frequently, these organs are associated with pathogenic progression towards fibrosis from acute and chronic conditions and eventually fail in their functions. The pathogenesis of the organ-fibrotic events mainly depends on the activation of residential stellate cells; these cells help to accumulate collagen in respective organs. Various diagnostic options have been developed recently, and various therapeutic options are in trial to tackle fibrosis. In this review, an overview on fibrosis, the pathogenesis of fibrosis in the liver and pancreas, various diagnostic options developed in recent years, and possible present therapeutic measures to overcome options of fibrosis in the liver and pancreas; thus, restoring the functional status of organs is discussed.
Collapse
Affiliation(s)
- Tiasha Dasgupta
- Department of Bio Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India
| | - Venkatraman Manickam
- Department of Bio Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
| |
Collapse
|
|
25
|
Kim HJ, Baek EB, Hwang JH, Lim M, Jung WH, Bae MA, Son HY, Cho JW. Application of convolutional neural network for analyzing hepatic fibrosis in mice. J Toxicol Pathol 2023; 36:21-30. [PMID: 36683726 PMCID: PMC9837472 DOI: 10.1293/tox.2022-0066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/07/2022] [Indexed: 11/06/2022] Open
Abstract
Recently, with the development of computer vision using artificial intelligence (AI), clinical research on diagnosis and prediction using medical image data has increased. In this study, we applied AI methods to analyze hepatic fibrosis in mice to determine whether an AI algorithm can be used to analyze lesions. Whole slide image (WSI) Sirius Red staining was used to examine hepatic fibrosis. The Xception network, an AI algorithm, was used to train normal and fibrotic lesion identification. We compared the results from two analyses, that is, pathologists' grades and researchers' annotations, to observe whether the automated algorithm can support toxicological pathologists efficiently as a new apparatus. The accuracies of the trained model computed from the training and validation datasets were greater than 99%, and that obtained by testing the model was 100%. In the comparison between analyses, all analyses showed significant differences in the results for each group. Furthermore, both normalized fibrosis grades inferred from the trained model annotated the fibrosis area, and the grades assigned by the pathologists showed significant correlations. Notably, the deep learning algorithm derived the highest correlation with the pathologists' average grade. Owing to the correlation outcomes, we conclude that the trained model might produce results comparable to those of the pathologists' grading of the Sirius Red-stained WSI fibrosis. This study illustrates that the deep learning algorithm can potentially be used for analyzing fibrotic lesions in combination with Sirius Red-stained WSIs as a second opinion tool in non-clinical research.
Collapse
Affiliation(s)
- Hyun-Ji Kim
- Toxicological Pathology Research Group, Department of
Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu,
Daejeon 34114, Republic of Korea,College of Veterinary Medicine, Chungnam National
University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea,†These authors contributed equally to this work
| | - Eun Bok Baek
- College of Veterinary Medicine, Chungnam National
University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea
| | - Ji-Hee Hwang
- Toxicological Pathology Research Group, Department of
Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu,
Daejeon 34114, Republic of Korea
| | - Minyoung Lim
- Toxicological Pathology Research Group, Department of
Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu,
Daejeon 34114, Republic of Korea
| | - Won Hoon Jung
- Therapeutics & Biotechnology Division, Korea Research
Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of
Korea
| | - Myung Ae Bae
- Therapeutics & Biotechnology Division, Korea Research
Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of
Korea
| | - Hwa-Young Son
- College of Veterinary Medicine, Chungnam National
University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea,*Corresponding authors: JW Cho (e-mail: ); HY Son (e-mail: )
| | - Jae-Woo Cho
- Toxicological Pathology Research Group, Department of
Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu,
Daejeon 34114, Republic of Korea,*Corresponding authors: JW Cho (e-mail: ); HY Son (e-mail: )
| |
Collapse
|
|
26
|
Jang YS, Joo HJ, Park YS, Park EC, Jang SI. Association between smoking cessation and non-alcoholic fatty liver disease using NAFLD liver fat score. Front Public Health 2023; 11:1015919. [PMID: 36875368 PMCID: PMC9982128 DOI: 10.3389/fpubh.2023.1015919] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/27/2023] [Indexed: 02/19/2023] Open
Abstract
Background Smoking is well known to be associated with a higher prevalence and incidence of liver diseases such as advanced fibrosis. However, the impact of smoking on developing nonalcoholic fatty liver disease remains controversial, and clinical data on this is limited. Therefore, this study aimed to investigate the association between smoking history and nonalcoholic fatty liver disease (NAFLD). Methods Data from the Korea National Health and Nutrition Examination Survey 2019-2020 were used for the analysis. NAFLD was diagnosed according to an NAFLD liver fat score of >-0.640. Smoking status was classified as into nonsmokers, ex-smokers, and current smokers. Multiple logistic regression analysis was conducted to examine the association between smoking history and NAFLD in the South Korean population. Results In total, 9,603 participants were enrolled in this study. The odds ratio (OR) for having NAFLD in ex-smokers and current smokers in males was 1.12 (95% confidence interval [CI]: 0.90-1.41) and 1.38 (95% CI: 1.08-1.76) compared to that in nonsmokers, respectively. The OR increased in magnitude with smoking status. Ex-smokers who ceased smoking for <10 years (OR: 1.33, 95% CI: 1.00-1.77) were more likely to have a strong correlation with NAFLD. Furthermore, NAFLD had a dose-dependent positive effect on pack-years, which was 10 to 20 (OR: 1.39, 95% CI: 1.04-1.86) and over 20 (OR: 1.51, 95% CI: 1.14-2.00). Conclusion This study found that smoking may contribute to NAFLD. Our study suggests cessation of smoking may help management of NAFLD.
Collapse
Affiliation(s)
- Yun Seo Jang
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea.,Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea
| | - Hye Jin Joo
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea.,Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea
| | - Yu Shin Park
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea.,Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea
| | - Eun-Cheol Park
- Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea.,Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung-In Jang
- Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea.,Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
27
|
Wu X, Liu XQ, Liu ZN, Xia GQ, Zhu H, Zhang MD, Wu BM, Lv XW. CD73 aggravates alcohol-related liver fibrosis by promoting autophagy mediated activation of hepatic stellate cells through AMPK/AKT/mTOR signaling pathway. Int Immunopharmacol 2022; 113:109229. [DOI: 10.1016/j.intimp.2022.109229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/05/2022]
|
|
28
|
Lin Y, Dong M, Liu Z, Xu M, Huang Z, Liu H, Gao Y, Zhou W. A strategy of vascular-targeted therapy for liver fibrosis. Hepatology 2022; 76:660-675. [PMID: 34940991 PMCID: PMC9543235 DOI: 10.1002/hep.32299] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling. APPROACH AND RESULTS The CCl4 -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects. CONCLUSIONS Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.
Collapse
Affiliation(s)
- Yuan Lin
- Department of PathologyShunde HospitalSouthern Medical University (The First People’s Hospital of Shunde Foshan)FoshanChina,State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Meng‐Qi Dong
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Zhi‐Min Liu
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Meng Xu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal TumorNanfang HospitalFirst Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina
| | - Zhi‐Hao Huang
- State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Hong‐Juan Liu
- Department of BioinformationSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yi Gao
- General Surgery CenterDepartment of Hepatobiliary Surgery IIGuangdong ProvincialResearch Center for Artificial Organ and Tissue EngineeringGuangzhou Clinical Research and Transformation Center for Artificial LiverInstitute of Regenerative MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Wei‐Jie Zhou
- Department of PathologyShunde HospitalSouthern Medical University (The First People’s Hospital of Shunde Foshan)FoshanChina,State Key Laboratory of Organ Failure ResearchDepartment of PathologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina,Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal TumorNanfang HospitalFirst Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina,General Surgery CenterDepartment of Hepatobiliary Surgery IIGuangdong ProvincialResearch Center for Artificial Organ and Tissue EngineeringGuangzhou Clinical Research and Transformation Center for Artificial LiverInstitute of Regenerative MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina,Microbiome Medicine CenterZhujiang HospitalSouthern Medical UniversityGuangzhouChina,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| |
Collapse
|
|
29
|
Wei M, Zhang Y, Zhang H, Huang Z, Miao H, Zhang T, Lu B, Ji L. HMGB1 induced endothelial to mesenchymal transition in liver fibrosis: The key regulation of early growth response factor 1. Biochim Biophys Acta Gen Subj 2022; 1866:130202. [PMID: 35820641 DOI: 10.1016/j.bbagen.2022.130202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/29/2022] [Accepted: 07/06/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Liver fibrosis has been the focus and difficulty of medical research in the world and its concrete pathogenesis remains unclear. This study aims to observe the high-mobility group box 1 (HMGB1)-induced hepatic endothelial to mesenchymal transition (EndoMT) during the development of hepatic fibrosis, and further to explore the crucial involvement of Egr1 in this process. METHODS Carbon tetrachloride (CCl4), diosbulbin B (DB), N-acetyl-p-aminophenol (APAP) and bile duct ligation (BDL) were used to induce liver fibrosis in mice. Serum HMGB1 content, the occurrence of EndoMT and the production of extracellular matrix (ECM) in vitro and in vivo were detected by Western-blot. RESULTS The elevated serum HMGB1 content, the occurrence of EndoMT, the production of ECM and the activation of Egr1 were observed in mice with liver fibrosis induced by CCl4, DB, APAP or BDL. HMGB1 induced EndoMT and ECM production in human hepatic sinusoidal endothelial cells (HHSECs), and then HHSECs lost the ability to inhibit the activation of hepatic stellate cells (HSCs). The hepatic deposition of collagen, the increased serum HMGB1 content and hepatic EndoMT were further aggravated in Egr1 knockout mice. Natural compound silymarin attenuated liver fibrosis in mice induced by CCl4 via increasing Egr1 nuclear accumulation, decreasing serum HMGB1 content and inhibiting hepatic EndoMT. CONCLUSION Egr1 regulated the expression of HMGB1 that induced hepatic EndoMT, which plays an important role in the development of liver fibrosis. GENERAL SIGNIFICANCE This study provides a novel therapeutic strategy for the treatment of liver fibrosis in clinic.
Collapse
Affiliation(s)
- Mengjuan Wei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Miao
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tianyu Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| |
Collapse
|
|
30
|
Li J, Xian L, Zheng R, Wang Y, Wan X, Liu Y. Canthaxanthin shows anti-liver aging and anti-liver fibrosis effects by down-regulating inflammation and oxidative stress in vivo and in vitro. Int Immunopharmacol 2022; 110:108942. [PMID: 35810489 DOI: 10.1016/j.intimp.2022.108942] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 11/18/2022]
Abstract
The elderly population is growing rapidly all over the world. The aging population has brought great medical pressure to the society. It is found that aging is one of the pathogenic factors of liver fibrosis and liver cancer. Therefore, it is very important to explore functional foods with anti-aging, anti-fibrosis and anti-liver cancer effect. Therefore, in this work, we studied the potential effects of Canthaxanthin on liver aging, liver fibrosis and liver cancer. Firstly, we established the aging modelof liver cells by using H2O2. On this basis, the anti-aging effect of Canthaxanthin was analyzed, and the results showed that Canthaxanthin could significantly alleviate the aging of liver cells through Sa-β-Gal staining and analysis of the expression of aging related markers. In vivo, aged mice wereused as the animal model for studying the effect of anti-aging of Canthaxanthin. The results showed that Canthaxanthin could significantly alleviate the aging of liver in vivo. Further study show that Canthaxanthin may alleviatethe aging of liver cells by regulating SIRT6; Secondly, we evaluated the effect of Canthaxanthin on liver fibrosis. A model of liver fibrosis was established by CCl4. Masson and Sirius red staining showed that Canthaxanthin could significantly reduce the fibrosis area. Additionally, the level of liver inflammation was also reduced; Thirdly, the effect of Canthaxanthin on hepatoma cells has also been investigated. The resultsshowed that Canthaxanthin could promote the apoptosis of hepatoma cells in vivo and in vitro. To sum up, these results show that canthaxanthin can significantly alleviate liver aging and fibrosis, and Canthaxanthin can also promote the apoptosis of liver cancer cells, indicating that Canthaxanthin can be used as a potential drug or health food for the treatment of liveraging related diseases.
Collapse
Affiliation(s)
- Jiarui Li
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin 130000, China
| | - Lei Xian
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin 130000, China
| | - Ruipeng Zheng
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin 130000, China
| | - Yue Wang
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin 130000, China
| | - Xiaoqiang Wan
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin 130000, China
| | - Ying Liu
- Clinical Laboratory, The First Hospital of Jilin University, Changchun 130000, China.
| |
Collapse
|
|
31
|
Gadhoumi H, Hayouni ELA, Martinez-Rojas E, Yeddes W, Tounsi MS. Biochemical composition, antimicrobial and antifungal activities assessment of the fermented medicinal plants extract using lactic acid bacteria. Arch Microbiol 2022; 204:374. [PMID: 35674987 DOI: 10.1007/s00203-022-02985-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 11/25/2022]
Abstract
To prevent foodborne diseases and extend shelf life, antimicrobial agents may be used in food to inhibit the growth of undesired microorganisms. The present study was aimed to determine the antimicrobial and antifungal activities of the fermented medicinal plants extract using Lactobacillus acidophilus ATCC 4356. The fermentation kinetic parameters, biochemical composition and the volatile compounds of the fermented plant extract were assessed. The results showed that, the fermented plants extract exhibited high content in polyphenols, flavonoids, and tannins (152.7 mg AGE/L; 93.6 mg RE/L; and 62.1 mg CE/L, respectively) comparing to non-fermented the extract. The GC-MS headspace analyses showed the presence of 24 interesting volatile compounds. The richness of the fermented plants extracts in polyphenols and bioactive compound, such as Eucalyptol, Camphene, α-Phellandrene, α-Terpinene, improves their biological activity. In addition, the fermented plants extract exhibited a high antimicrobial potential against pathogenic bacteria and fungi determined by different methods. The maximum inhibition showed in the fermented plants extract against Escherichia coli 25922/3, Pseudomonas aeruginosa 27853 ATCC, Staphylococcus aureus 29213 ATCC, Enterococcus aerogenes 13048 ATCC, Phytophthora infestans P3 4/91 R + , P. infestans P4 20/01 R, P. infestans (GL-1). The obtained results support the hypothesis of using lactic fermentation as a functional ingredient to improve food preservation. The bioprocesses of fermentation technology enhance antimicrobial and antifungal activities which could be used in different industrial applications.
Collapse
Affiliation(s)
- Hamza Gadhoumi
- Faculty of Sciences of Tunis, University of Tunis El Manar, El Manar, 2092, Tunis, Tunisia.
- Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology of Borj-Cédria, BP-901, 2050, Hammam-Lif, Tunisia.
| | - E L Akrem Hayouni
- Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology of Borj-Cédria, BP-901, 2050, Hammam-Lif, Tunisia
| | - Enriqueta Martinez-Rojas
- Department of Agriculture and Food Sciences, Neubrandenburg University of Applied Sciences, Neubrandenburg, Germany
| | - Walid Yeddes
- Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology of Borj-Cédria, BP-901, 2050, Hammam-Lif, Tunisia
| | - Moufida Saidani Tounsi
- Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology of Borj-Cédria, BP-901, 2050, Hammam-Lif, Tunisia
| |
Collapse
|
|
32
|
Green Synthesis of Silymarin-Chitosan Nanoparticles as a New Nano Formulation with Enhanced Anti-Fibrotic Effects against Liver Fibrosis. Int J Mol Sci 2022; 23:ijms23105420. [PMID: 35628233 PMCID: PMC9141191 DOI: 10.3390/ijms23105420] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/03/2022] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
Background: Silymarin (SIL) has long been utilized to treat a variety of liver illnesses, but due to its poor water solubility and low membrane permeability, it has a low oral bioavailability, limiting its therapeutic potential. Aim: Design and evaluate hepatic-targeted delivery of safe biocompatible formulated SIL-loaded chitosan nanoparticles (SCNPs) to enhance SIL’s anti-fibrotic effectiveness in rats with CCl4-induced liver fibrosis. Methods: The SCNPs and chitosan nanoparticles (CNPs) were prepared by ionotropic gelation technique and are characterized by physicochemical parameters such as particle size, morphology, zeta potential, and in vitro release studies. The therapeutic efficacy of successfully formulated SCNPs and CNPs were subjected to in vivo evaluation studies. Rats were daily administered SIL, SCNPs, and CNPs orally for 30 days. Results: The in vivo study revealed that the synthesized SCNPs demonstrated a significant antifibrotic therapeutic action against CCl4-induced hepatic injury in rats when compared to treated groups of SIL and CNPs. SCNP-treated rats had a healthy body weight, with normal values for liver weight and liver index, as well as significant improvements in liver functions, inflammatory indicators, antioxidant pathway activation, and lipid peroxidation reduction. The antifibrotic activities of SCNPs were mediated by suppressing the expression of the main fibrosis mediators TGFβR1, COL3A1, and TGFβR2 by boosting the hepatic expression of protective miRNAs; miR-22, miR-29c, and miR-219a, respectively. The anti-fibrotic effects of SCNPs were supported by histopathology and immunohistochemistry (IHC) study. Conclusions: According to the above results, SCNPs might be the best suitable carrier to target liver cells in the treatment of liver fibrosis.
Collapse
|
|
33
|
Luo P, Liu D, Zhang Q, Yang F, Wong YK, Xia F, Zhang J, Chen J, Tian Y, Yang C, Dai L, Shen HM, Wang J. Celastrol induces ferroptosis in activated HSCs to ameliorate hepatic fibrosis via targeting peroxiredoxins and HO-1. Acta Pharm Sin B 2022; 12:2300-2314. [PMID: 35646542 PMCID: PMC9136576 DOI: 10.1016/j.apsb.2021.12.007] [Citation(s) in RCA: 165] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/28/2021] [Accepted: 11/10/2021] [Indexed: 12/14/2022] Open
Abstract
Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron- and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species (ROS) and inducing ferroptosis in activated hepatic stellate cells (HSCs). By using activity-based protein profiling (ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay (CETSA), we show that celastrol directly binds to peroxiredoxins (PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6, through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1 (HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2, PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.
Collapse
Key Words
- ABPP
- ABPP, activity-based protein profiling
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Anti-oxidant
- CCl4, carbon tetrachloride
- CETSA, cellular thermal shift assay
- COL1A1, collagen type I alpha-1
- COX-2, cyclooxygenase 2
- Cel-P, celastrol-probe
- Celastrol
- ECM, extracellular matrix
- Ferroptosis
- GPX4, glutathione peroxidase 4
- HCC, hepatocellular carcinoma
- HMGB1, high mobility group protein B1
- HO-1
- HO-1, heme oxygenase 1
- HSCs, hepatic stellate cells
- Hepatic fibrosis
- LPO, lipid peroxidation
- PPARγ, peroxisome proliferators-activated receptor γ
- PRDXs, peroxiredoxins
- Peroxiredoxin
- ROS, reactive oxygen species
- Reactive oxygen species
- VDACs, voltage-dependent anion channels
- VIM, vimentin
- α-SMA, alpha smooth muscle actin
Collapse
Affiliation(s)
- Piao Luo
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Central People's Hospital of Zhanjiang, Zhanjiang 524037, China
| | - Dandan Liu
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qian Zhang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Fan Yang
- Department of Urology, the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China
| | - Yin-Kwan Wong
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Fei Xia
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Junzhe Zhang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jiayun Chen
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ya Tian
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Chuanbin Yang
- Department of Urology, the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China
| | - Lingyun Dai
- Department of Urology, the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China
| | - Han-Ming Shen
- Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
| | - Jigang Wang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Central People's Hospital of Zhanjiang, Zhanjiang 524037, China
- Department of Urology, the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| |
Collapse
|
|
34
|
Zhu T, Zhang L, Li C, Tan X, Liu J, Huiqin Li, Fan Q, Zhang Z, Zhan M, Fu L, Luo J, Geng J, Wu Y, Zou X, Liang B. The S100 calcium binding protein A11 promotes liver fibrogenesis by targeting TGF-β signaling. J Genet Genomics 2022; 49:338-349. [PMID: 35240304 DOI: 10.1016/j.jgg.2022.02.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/22/2022] [Accepted: 02/22/2022] [Indexed: 12/16/2022]
Abstract
Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases. However, the pathogenesis of liver fibrosis still remains elusive. Here, we report that the calcium binding protein A11 (S100A11) is consistently upregulated in the integrated data from GSE liver fibrosis and tree shrew liver proteomics. S100A11 is also experimentally activated in liver fibrosis in mouse, rat, tree shrew, and human with liver fibrosis. While overexpression of S100A11 in vivo and in vitro exacerbates liver fibrosis, the inhibition of S100A11 improves liver fibrosis. Mechanistically, S100A11 activates hepatic stellate cells (HSCs) and the fibrogenesis process via the regulation of the deacetylation of Smad3 in the TGF-β signaling pathway. S100A11 physically interacts with SIRT6, a deacetylase of Smad2/3, which may competitively inhibit the interaction between SIRT6 and Smad2/3. The subsequent release and activation of Smad2/3 promote the activation of HSCs and fibrogenesis. Additionally, a significant elevation of S100A11 in serum is observed in clinical patients. Our study uncovers S100A11 as a novel profibrogenic factor in liver fibrosis, which may represent both a potential biomarker and a promising therapy target for treating liver fibrosis and fibrosis-related liver diseases.
Collapse
Affiliation(s)
- Tingting Zhu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
| | - Linqiang Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Chengbin Li
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China
| | - Xiaoqiong Tan
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
| | - Jing Liu
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China
| | - Huiqin Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
| | - Qijing Fan
- School of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, China
| | - Zhiguo Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Mingfeng Zhan
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China
| | - Lin Fu
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China
| | - Jinbo Luo
- Infectious Diseases Department and Hepatic Diseases Department, the First People's Hospital of Yunnan Province, Kunming, Yunnan 650034, China; Infectious Diseases Department and Hepatic Diseases Department, the Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China
| | - Jiawei Geng
- Infectious Diseases Department and Hepatic Diseases Department, the First People's Hospital of Yunnan Province, Kunming, Yunnan 650034, China; Infectious Diseases Department and Hepatic Diseases Department, the Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China.
| | - Yingjie Wu
- School of Laboratory Animal & Shandong Laboratory Animal Center, Science and Technology Innovation Center,Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250021, China; Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Provence Key Lab of Genome Engineered Animal Models Dalian Medical University, Dalian, Liaoning 116044, China.
| | - Xiaoju Zou
- School of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, China.
| | - Bin Liang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China.
| |
Collapse
|
|
35
|
van Lingen E, Tushuizen ME, Steenhuis MEJ, van Deynen T, Martens J, Morales DDI, van der Meulen-de Jong AE, Molendijk I, van der Marel S, Maljaars PWJ. Disease activity in inflammatory bowel disease patients is associated with increased liver fat content and liver fibrosis during follow-up. Int J Colorectal Dis 2022; 37:349-356. [PMID: 34791524 DOI: 10.1007/s00384-021-04065-8] [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] [Accepted: 11/05/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE Liver steatosis is a frequently reported condition in patients with inflammatory bowel disease (IBD). Different factors, both metabolic and IBD-associated, are believed to contribute to the pathogenesis. The aim of our study was to calculate the prevalence of liver steatosis and fibrosis in IBD patients and to evaluate which factors influence changes in steatosis and fibrosis during follow-up. METHODS From June 2017 to February 2018, demographic and biochemical data was collected at baseline and after 6-12 months. Measured by transient elastography (FibroScan), liver steatosis was defined as Controlled Attenuation Parameter (CAP) ≥248 and fibrosis as liver stiffness value (Emed) ≥7.3 kPa. IBD disease activity was defined as C-reactive protein (CRP) ≥10 mg/l and/or fecal calprotectin (FCP) ≥150 μg/g. Univariate and multivariate regression analysis was performed; a p-value of ≤0.05 was considered significant. RESULTS Eighty-two out of 112 patients were seen for follow-up; 56% were male. The mean age was 43 ± 16.0 years, and mean BMI was 25.1 ± 4.7 kg/m2. The prevalence of liver steatosis was 40% and of fibrosis was 20%. At baseline, 26 patients (32%) had an active episode of IBD. Using a multivariate analysis, disease activity at baseline was associated with an increase in liver steatosis (B = 37, 95% CI 4.31-69.35, p = 0.027) and liver fibrosis (B = 1.2, 95% CI 0.27-2.14, p = 0.016) during follow-up. CONCLUSIONS This study confirms the relatively high prevalence of liver steatosis and fibrosis in IBD patients. We demonstrate that active IBD at baseline is associated with both an increase in liver steatosis and fibrosis during follow-up.
Collapse
Affiliation(s)
- E van Lingen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
| | - M E Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - M E J Steenhuis
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - T van Deynen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - J Martens
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - D Diaz-Infante Morales
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - A E van der Meulen-de Jong
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - I Molendijk
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - S van der Marel
- Department of Gastroenterology and Hepatology, Haaglanden Medical Center (HMC), The Hague, The Netherlands
| | - P W J Maljaars
- Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| |
Collapse
|
|
36
|
Abstract
BACKGROUND Cirrhosis is the outcome of chronic liver disease of any etiology due to progressive liver injury and fibrosis. Consequently, cirrhosis leads to portal hypertension and liver dysfunction, progressing to complications like ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, cirrhotic cardiomyopathy, sarcopenia, hepatocellular carcinoma, and coagulation disorders. End-stage liver disease leads to an impaired quality of life, loss of social and economic productivity, and reduced survival. METHODS This narrative review explains the pathophysiology of complications of cirrhosis, the diagnostic approach and innovative management, with focus on data from India. A comprehensive literature search of the published data was performed in regard with the spectrum, diagnosis, and management of cirrhosis and its complications. RESULTS There is a change in the epidemiology of metabolic syndrome, lifestyle diseases, alcohol consumption and the spectrum of etiological diagnosis in patients with cirrhosis. With the advent of universal vaccination and efficacious long-term viral suppression agents for chronic hepatitis B, availability of direct-acting antiviral agents for chronic hepatitis C, and a booming liver transplantation programme across the country, the management of complications is essential. There are several updates in the standard of care in the management of complications of cirrhosis, such as hepatorenal syndrome, hepatocellular carcinoma, and hepatic encephalopathy, and new therapies that address supportive and palliative care in advanced cirrhosis. CONCLUSION Prevention, early diagnosis, appropriate management of complications, timely transplantation are cornerstones in the management protocol of cirrhosis and portal hypertension. India needs improved access to care, outreach of public health programmes for viral hepatitis care, health infrastructure, and disease registries for improved healthcare outcomes. Low-cost initiatives like immunization, alcohol cessation, awareness about liver diseases, viral hepatitis elimination, and patient focused decision-making algorithms are essential to manage liver disease in India.
Collapse
Key Words
- AIH, autoimmune hepatitis
- ALP, alkaline phosphatase
- AVB, acute variceal bleeding
- BMI, body mass index
- CLD, chronic liver disease
- CSPH, clinically significant portal hypertension
- CTP, Child Turcotte Pugh Score
- DAAs, direct-acting antiviral agents
- GGT, gamma glutamyl transpeptidase
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HE, hepatic encephalopathy
- HR, hazard ratio
- HRQoL, health-related quality of life
- HVPG, hepatic vein pressure gradient
- MELD, Model for End Stage Liver disease
- MetS, metabolic syndrome
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NSBB, Non-selective beta blockers
- NVHCP, National Viral Hepatitis Control programme
- SAAG, Serum-ascites albumin gradient
- SBP, spontaneous bacterial peritonitis
- WHO, World Health Organization
- cirrhosis, ascites
- hepatic encephalopathy
- hepatocellular carcinoma
- portal hypertension
Collapse
|
|
37
|
Ahmed T, Misumida N, Grigorian A, Tarantini G, Messerli AW. Transcatheter interventions for valvular heart diseases in liver cirrhosis patients. Trends Cardiovasc Med 2021; 33:242-249. [PMID: 34974163 DOI: 10.1016/j.tcm.2021.12.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/27/2021] [Accepted: 12/27/2021] [Indexed: 10/19/2022]
Abstract
There is an increasing prevalence of patients who have both liver cirrhosis (LC) and severe valvular heart disease. This combination typically poses prohibitive risk for liver transplantation. LC related malnourishment, hypoalbuminemia and hyperdynamic circulation places patients with severe LC at higher rates for significant bleeding and/or thrombosis, as well as infectious and renal complications, after either surgical or transcatheter valvular interventions. Although there remains scarce comparative evidence, the preponderance of data suggest that percutaneous strategies are preferred over surgical ones. A multidisciplinary team is ideal for identifying those patients with LC who would benefit from transcatheter valvular heart interventions.
Collapse
Affiliation(s)
- Taha Ahmed
- Department of Internal Medicine, University of Kentucky, Lexington, KY, USA
| | - Naoki Misumida
- Department of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, USA
| | - Alla Grigorian
- Department of Hepatology, University of Kentucky, Lexington, KY, USA
| | - Giuseppe Tarantini
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, Padua, Italy
| | - Adrian W Messerli
- Department of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, USA.
| |
Collapse
|
|
38
|
Bai R, An R, Han K, Xue M, Zhang S, Shen X, Zheng S. Prognosis of liver transplantation: Does postoperative ileus matter? BMC Gastroenterol 2021; 21:444. [PMID: 34823485 PMCID: PMC8620943 DOI: 10.1186/s12876-021-02026-7] [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: 11/17/2020] [Accepted: 11/15/2021] [Indexed: 11/20/2022] Open
Abstract
Background Nowadays, liver transplantation has become a main therapy for end-stage liver disease. However, studies show that there are high mortality and severe complications after liver transplantation. Although gastrointestinal dysfunction is a common and major complication after liver transplantation, there was rarely relative research. This study aims to elucidate the factors about ileus after liver transplantation and patients’ survival. Methods We collected and analyzed the data (n = 318, 2016–2019) from the First Affiliated Hospital of Xi’an Jiaotong University. After excluding cases, a total of 293 patients were included for this study. The subjects were divided into a non-ileus group and an ileus group. We reviewed 38 variables (including preoperative, operative and postoperative relative factors). Additionally, other complications after liver transplantation and survival data were compared between two groups. Results Of the 293 patients, 23.2% (n = 68) experienced postoperative ileus. Ileus patients were not different with non-ileus patients in preoperative, operative and postoperative factors. HBV-positive patients with ileus had a lower MELD score (P = 0.025), and lower postoperative total bilirubin was correlated with ileus (P = 0.049). Besides, Child–Pugh score of HCC patients with ileus was low (P = 0.029). The complications after liver transplantation were not different between two groups. Compared with the patients without ileus, the patients with ileus had a higher mortality rate. Conclusion According to our research, ileus-patients had a lower 1-year survival rates. The preoperative MELD score and postoperative total bilirubin of HBV-positive patients with ileus were lower, and Child–Pugh score of HCC patients with ileus was also lower.
Collapse
Affiliation(s)
- Ruiping Bai
- Department of Anaesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Rui An
- Department of Anaesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Kunyu Han
- Department of Anaesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Mengwen Xue
- Department of Anaesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Simei Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xin Shen
- Department of Anaesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China
| | - Shaohua Zheng
- Department of Anaesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an, China.
| |
Collapse
|
|
39
|
Naringenin: A Promising Therapeutic Agent against Organ Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1210675. [PMID: 34804359 PMCID: PMC8601819 DOI: 10.1155/2021/1210675] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023]
Abstract
Fibrosis is the final common pathology of most chronic diseases as seen in the heart, liver, lung, kidney, and skin and contributes to nearly half of death in the developed countries. Fibrosis, or scarring, is mainly characterized by the transdifferentiation of fibroblasts into myofibroblasts and the excessive accumulation of extracellular matrix (ECM) secreted by myofibroblasts. Despite immense efforts made in the field of organ fibrosis over the past decades and considerable understanding of the occurrence and development of fibrosis gained, there is still lack of an effective treatment for fibrotic diseases. Therefore, identifying a new therapeutic strategy against organ fibrosis is an unmet clinical need. Naringenin, a flavonoid that occurs naturally in citrus fruits, has been found to confer a wide range of pharmacological effects including antioxidant, anti-inflammatory, and anticancer benefits and thus potentially exerting preventive and curative effects on numerous diseases. In addition, emerging evidence has revealed that naringenin can prevent the pathogenesis of fibrosis in vivo and in vitro via the regulation of various pathways that involved signaling molecules such as transforming growth factor-β1/small mother against decapentaplegic protein 3 (TGF-β1/Smad3), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), sirtuin1 (SIRT1), nuclear factor-kappa B (NF-κB), or reactive oxygen species (ROS). Targeting these profibrotic pathways by naringenin could potentially become a novel therapeutic approach for the management of fibrotic disorders. In this review, we present a comprehensive summary of the antifibrotic roles of naringenin in vivo and in vitro and their underlying mechanisms of action. As a food derived compound, naringenin may serve as a promising drug candidate for the treatment of fibrotic disorders.
Collapse
|
|
40
|
Hamade B, Murugan R, Lovelace E, Saul M, Huang DT, Al-Khafaji A. Shock Index, Modified Shock Index and MELD as Predictors of Mortality for Critically Ill Patients With Liver Disease. J Intensive Care Med 2021; 37:1037-1042. [PMID: 34812069 DOI: 10.1177/08850666211049749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Bachar Hamade
- 2569Center for Emergency Medicine - Emergency Services Institute, Department of Intensive Care and Resuscitation - Anesthesia Institute, Cleveland Clinic Foundation, Cleveland, OH
| | - Raghavan Murugan
- Department of CriticalCare Medicine, 20096University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Elijah Lovelace
- Veterans Affairs Pittsburgh Healthcare Systems - Center for HealthEquity Research and Promotion (CHERP), Pittsburgh, PA
| | - Melissa Saul
- 12317Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - David T Huang
- 6595Departments of Critical Care Medicine, Emergency Medicine, and Clinical and Translational Science, University of Pittsburgh MedicalCenter, Pittsburgh, PA
| | - Ali Al-Khafaji
- Departments of Critical Care Medicine and Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| |
Collapse
|
|
41
|
Badawi R, Abu Rahma MZ, Ramadan HK, Soliman S, Mohareb DA, Hawash N, Elkafoury R, Abd-Elsalam S. Lipid Profiles as Markers for the Severity of Liver Diseases in Cirrhotic Patients. THE OPEN BIOMARKERS JOURNAL 2021; 11:93-98. [DOI: 10.2174/1875318302111010093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 07/26/2021] [Accepted: 08/23/2021] [Indexed: 09/01/2023]
Abstract
Background
Liver cirrhosis is a diffuse process in which the anatomical structure and function of the liver are disturbed. Lipid metabolism occurs mainly in the hepatocytes. In liver cirrhosis, it is expected to detect abnormal lipid profile and abnormal neutrophil to lymphocyte ratio due to necro-inflammation and hepatocyte dysfunction. This study aimed to estimate the lipid profile in patients with liver cirrhosis and to assess its relation to the severity of the liver disease based on Child-Pugh Turcotte score and Neutrophil to Lymphocyte Ratio (NLR).
Methods:
This study included 500 cirrhotic patients. All patients are subjected to history taking, clinical examination, liver and renal function tests, lipid profile, and also abdomino-pelvic ultrasound. Child -Pugh score, fibrosis-4 score (FIB4), and neutrophil and platelet lymphocyte ratio were calculated.
Results:
A total of 500 patients were enrolled in this study; 12 patients were excluded (two patients were on the immunosuppressive drug, three patients had body mass index (BMI) >30, and seven patients took lipid-lowering drugs). Cholesterol level was significantly higher in patients with Child- Score A than B and C. Cholesterol, Low-Density Lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol were significantly higher in Child B than C. A significant negative correlation was found between cholesterol level and each of FIB4 and NLR ratios.
Conclusion:
There was a significant negative correlation between the severity of liver cirrhosis and lipid profiles (except triglyceride), FIB4 and NLR ratio.
Collapse
|
|
42
|
Hsu PK, Wu LS, Su WW, Su PY, Chen YY, Hsu YC, Yen HH, Wu CL. Comparing the controlled attenuation parameter using FibroScan and attenuation imaging with ultrasound as a novel measurement for liver steatosis. PLoS One 2021; 16:e0254892. [PMID: 34653177 PMCID: PMC8519468 DOI: 10.1371/journal.pone.0254892] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 07/06/2021] [Indexed: 12/19/2022] Open
Abstract
Background/Aims In a recent study, attenuation imaging (ATI) with ultrasound was used as a new approach for detecting liver steatosis. However, although there are many studies on ATI and controlled attenuation parameter (CAP) that prove their practicability, there are few studies comparing these two methods. As such, this study compared CAP and ATI for the detection and evaluation of liver steatosis. Methods A prospective analysis of 28 chronic liver disease patients who underwent liver biopsy, FibroScan® imaging, and ATI with ultrasound was conducted. The presence and degree of steatosis, as measured with the FibroScan® device and ATI, were compared with the pathological results obtained using liver biopsy. Results The areas under the receiver operating characteristic curve (AUROC) of ATI and CAP for differentiating between normal and hepatic steatosis were 0.97 (95% confidence interval [CI] 0.83–1.00) and 0.96 (95% CI 0.81–0.99), respectively. ATI has a higher AUROC than CAP does in liver steatosis, at 0.99 (95% CI, 0.86–1.00) versus 0.91 (95% CI, 0.74–0.98) in grade ≥ 2 and 0.97 (95% CI, 0.82–1.00) versus 0.88 (95% CI, 0.70–0.97) in grade = 3, respectively. Conclusion The ATI and CAP results showed good consistency and accuracy for the steatosis grading when compared with the liver biopsy results. Moreover, ATI is even better than CAP in patients with moderate or severe steatosis. Therefore, ATI represents a non-invasive and novel diagnostic tool with which to support the diagnosis of liver steatosis in clinical practice.
Collapse
Affiliation(s)
- Po-Ke Hsu
- Department of Gastroenterology, Changhua Christian Hospital, Changhua County, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Li-Sha Wu
- Department of Ultrasound, Changhua Christian Hospital, Changhua County, Taiwan
| | - Wei-Wen Su
- Department of Gastroenterology, Changhua Christian Hospital, Changhua County, Taiwan
| | - Pei-Yuan Su
- Department of Gastroenterology, Changhua Christian Hospital, Changhua County, Taiwan
| | - Yang-Yuan Chen
- Department of Gastroenterology, Changhua Christian Hospital, Changhua County, Taiwan
| | - Yu-Chun Hsu
- Department of Gastroenterology, Changhua Christian Hospital, Changhua County, Taiwan
| | - Hsu-Heng Yen
- Department of Gastroenterology, Changhua Christian Hospital, Changhua County, Taiwan
| | - Chia-Lin Wu
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Nephrology, Changhua Christian Hospital, Changhua County, Taiwan
- * E-mail:
| |
Collapse
|
|
43
|
Jiao W, Bai M, Yin H, Liu J, Sun J, Su X, Zeng H, Wen J. Therapeutic Effects of an Inhibitor of Thioredoxin Reductase on Liver Fibrosis by Inhibiting the Transforming Growth Factor-β1/Smads Pathway. Front Mol Biosci 2021; 8:690170. [PMID: 34540892 PMCID: PMC8440796 DOI: 10.3389/fmolb.2021.690170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/21/2021] [Indexed: 12/24/2022] Open
Abstract
Liver fibrosis is an important stage in the progression of liver injury into cirrhosis or even liver cancer. Hepatic stellate cells (HSCs) are induced by transforming growth factor-β1 (TGF-β1) to produce α-smooth muscle actin (α-SMA) and collagens in liver fibrosis. Butaselen (BS), which was previously synthesized by our group, is an organic selenium compound that exerts antioxidant and tumor cell apoptosis–promoting effects by inhibiting the thioredoxin (Trx)/thioredoxin reductase (TrxR) system. The aim of this study was to investigate the potential effects of BS on liver fibrosis and explore the underlying molecular mechanisms of its action. Liver fibrosis models were established using male BALB/c mice through intraperitoneal injection of CCl4. BS was administered orally once daily at a dose of 36, 90, or 180 mg/kg. Silymarin (Si), which is a drug used for patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, was administered at a dose of 30 mg/kg per day as a control. The action mechanisms of BS against liver fibrosis progression were examined in HSCs. The study revealed that the activity and expression levels of TrxR were elevated in the mouse liver and serum after CCl4-induced liver fibrosis. Oral administration of BS relieved the pathological state of mice with liver fibrosis, showing significant therapeutic effects against liver fibrosis. Moreover, BS not only induced HSC apoptosis but also inhibited the production of α-SMA and collagens by HSCs by downregulating the TGF-β1 expression and blocking the TGF-β1/Smads pathway. The results of the study indicated that BS inhibited liver fibrosis by regulating the TGF-β1/Smads pathway.
Collapse
Affiliation(s)
- Wenxuan Jiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Man Bai
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.,Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hanwei Yin
- Shanghai Yuanxi Medicine Corp, Shanghai, China
| | - Jiayi Liu
- Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jing Sun
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Xiaoxia Su
- Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Huihui Zeng
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Jinhua Wen
- Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| |
Collapse
|
|
44
|
Momen-Heravi F, Catalano D, Talis A, Szabo G, Bala S. Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 25:155-167. [PMID: 34458001 PMCID: PMC8368790 DOI: 10.1016/j.omtn.2021.05.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.
Collapse
Affiliation(s)
- Fatemeh Momen-Heravi
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Austin Talis
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
- KASA BIO, 10405 Old Alabama Road Connector, Suite 201, Alpharetta, GA 30022, USA
| |
Collapse
|
|
45
|
Haep N, Florentino RM, Squires JE, Bell A, Soto-Gutierrez A. The Inside-Out of End-Stage Liver Disease: Hepatocytes are the Keystone. Semin Liver Dis 2021; 41:213-224. [PMID: 33992030 PMCID: PMC8996333 DOI: 10.1055/s-0041-1725023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Chronic liver injury results in cirrhosis and end-stage liver disease (ESLD) which represents a leading cause of death worldwide, affecting people in their most productive years of life. Medical therapy can extend life, but the only definitive treatment is liver transplantation (LT). However, LT remains limited by access to quality donor organs and suboptimal long-term outcomes. The degeneration from healthy-functioning livers to cirrhosis and ESLD involves a dynamic process of hepatocyte damage, diminished hepatic function, and adaptation. However, the mechanisms responsible for deterioration of hepatocyte function and ultimately hepatic failure in man are poorly understood. We review the current understanding of cirrhosis and ESLD as a dynamic process and outline the current mechanisms associated with the development of hepatic failure from the clinical manifestations to energy adaptations, regeneration, and regulation of nuclear transcription factors. A new generation of therapeutics could target stabilization of hepatocyte differentiation and function to avoid the need for transplantation in patients with cirrhosis and ESLD.
Collapse
Affiliation(s)
- Nils Haep
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - James E. Squires
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Aaron Bell
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| |
Collapse
|
|
46
|
Widhiantara IG, Jawi IM. Phytochemical composition and health properties of Sembung plant ( Blumea balsamifera): A review. Vet World 2021; 14:1185-1196. [PMID: 34220120 PMCID: PMC8243688 DOI: 10.14202/vetworld.2021.1185-1196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/25/2021] [Indexed: 11/16/2022] Open
Abstract
Indonesia's mindset has been focusing on the use of natural medicines, food, and healing practices widely recognized by the nation's culture. Traditional medicines and herbs used in traditional medicine can often lead to the discovery of drugs against certain diseases. The aim of this review was to study evidence-based data on the importance of Sembung plant, Blumea balsamifera, as a potential traditional medicine. The distribution, ethnopharmacology, secondary metabolites, and bioactivity against several diseases are focused in this review. Information and research related to Sembung plant were searched using the terms "B. balsamifera," "phytochemicals," and "pharmacological activity" on ResearchGate, Google Scholar, Science Direct, PubMed, and scientific information-based databases up to 2020. Several ethnomedical articles recommend B. balsamifera for the treatment of sinusitis, colic pain, cough, kidney stones, flu, or as a diuretic. This knowledge has already been applied in several countries in Southeast Asia. B. balsamifera has been reported to contain several phytochemicals both volatile (terpenoids, fatty acids, phenols, alcohol, aldehydes, ethers, ketones, pyridines, furans, and alkanes) and non-volatile (flavonoids, flavanones, and chalcones). Extracts and phytochemicals of B. balsamifera contain several biological capacities such as antioxidant, antimicrobial, antifungal, anti-inflammatory, hypolipidemic, anti-infertility, hepatoprotective activity, antidiabetic, gastroprotective, antitumor, anticancer, and immunomodulatory agent against Coronavirus disease-19 infection. This review provides essential data for the potential application of B. balsamifera as a nutraceutical or in future medicinal preparations.
Collapse
Affiliation(s)
- I. Gede Widhiantara
- Medical Science Study Program, Faculty of Medicine, Udayana University, Jalan P.B. Sudirman, Denpasar City, Bali Province 80234, Indonesia
- Study Program of Biology, Faculty of Health, Science, and Technology, Dhyana Pura University, Jalan Raya Padang Luwih, Dalung, North Kuta, Badung, Bali Province 80361, Indonesia
| | - I. Made Jawi
- Department of Pharmacology, Faculty of Medicine, Udayana University, Jalan P.B. Sudirman, Denpasar City, Bali Province 80234, Indonesia
| |
Collapse
|
|
47
|
Borgonovo A, Baldin C, Maggi DC, Victor L, Bansho ETO, Piedade J, Wildner LM, Guimarães L, Bazzo ML, Rocha T, Dantas-Corrêa EB, Alcântara C, Fernandes F, Narciso-Schiavon JL, Pereira GHS, Schiavon LL. Systemic Inflammatory Response Syndrome in Patients Hospitalized for Acute Decompensation of Cirrhosis. Can J Gastroenterol Hepatol 2021; 2021:5581587. [PMID: 33987144 PMCID: PMC8093053 DOI: 10.1155/2021/5581587] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/09/2021] [Accepted: 04/13/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Although recently challenged, systemic inflammatory response syndrome (SIRS) criteria are still commonly used in daily practice to define sepsis. However, several factors in liver cirrhosis may negatively impact its prognostic ability. Goals. To investigate the factors associated with the presence of SIRS, the characteristics of SIRS related to infection, and its prognostic value among patients hospitalized for acute decompensation of cirrhosis. Study. In this cohort study from two tertiary hospitals, 543 patients were followed up, up to 90 days. Data collection, including the prognostic models, was within 48 hours of admission. RESULTS SIRS was present in 42.7% of the sample and was independently associated with upper gastrointestinal bleeding (UGB), ACLF, infection, and negatively related to beta-blockers. SIRS was associated with mortality in univariate analysis, but not in multiple Cox regression analysis. The Kaplan-Meier survival probability of patients without SIRS was 73.0% and for those with SIRS was 64.7%. The presence of SIRS was not significantly associated with mortality when considering patients with or without infection, separately. Infection in SIRS patients was independently associated with Child-Pugh C and inversely related to UGB. Among subjects with SIRS, mortality was independently related to the presence of infection, ACLF, and Child-Pugh C. CONCLUSIONS SIRS was common in hospitalized patients with cirrhosis and was of no prognostic value, even in the presence of infection.
Collapse
Affiliation(s)
- Ariane Borgonovo
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Caroline Baldin
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Dariana C. Maggi
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Livia Victor
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Emilia T. O. Bansho
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Juliana Piedade
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Letícia M. Wildner
- Department of Clinical Analysis, Federal University of Santa Catarina Clinical Analysis Laboratory, University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Lívia Guimarães
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Maria L. Bazzo
- Department of Clinical Analysis, Federal University of Santa Catarina Clinical Analysis Laboratory, University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Tamires Rocha
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Esther B. Dantas-Corrêa
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Camila Alcântara
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Flávia Fernandes
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Janaina L. Narciso-Schiavon
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Gustavo H. S. Pereira
- Department of Gastroenterology and Hepatology, Bonsucesso Federal Hospital, Rio de Janeiro, Brazil
| | - Leonardo L. Schiavon
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| |
Collapse
|
|
48
|
Iron depletion attenuates steatosis in a mouse model of non-alcoholic fatty liver disease: Role of iron-dependent pathways. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166142. [PMID: 33839281 DOI: 10.1016/j.bbadis.2021.166142] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/23/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Iron has been proposed as influencing the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). We have previously shown that, in the Hfe-/- mouse model of hemochromatosis, feeding of a high-calorie diet (HCD) leads to increased liver injury. In this study we investigated whether the feeding of an iron deficient/HCD to Hfe-/- mice influenced the development of NAFLD. METHODS Liver histology was assessed in Hfe-/- mice fed a standard iron-containing or iron-deficient diet plus or minus a HCD. Hepatic iron concentration, serum transferrin saturation and free fatty acid were measured. Expression of genes implicated in iron regulation and fatty liver disease was determined by quantitative real-time PCR (qRT-PCR). RESULTS Standard iron/HCD-fed mice developed severe steatosis whereas NAS score was reduced in mice fed iron-deficient HCD. Mice fed iron-deficient HCD had lower liver weights, lower transferrin saturation and decreased ferroportin and hepcidin gene expression than HCD-fed mice. Serum non-esterified fatty acids were increased in iron-deficient HCD-fed mice compared with standard iron HCD. Expression analysis indicated that genes involved in fatty-acid binding and mTOR pathways were regulated by iron depletion. CONCLUSIONS Our results indicate that decreasing iron intake attenuates the development of steatosis resulting from a high calorie diet. These results also suggest that human studies of agents that modify iron balance in patients with NAFLD should be revisited.
Collapse
|
|
49
|
Jain D, Torres R, Celli R, Koelmel J, Charkoftaki G, Vasiliou V. Evolution of the liver biopsy and its future. Transl Gastroenterol Hepatol 2021; 6:20. [PMID: 33824924 PMCID: PMC7829074 DOI: 10.21037/tgh.2020.04.01] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 03/19/2020] [Indexed: 12/12/2022] Open
Abstract
Liver biopsies are commonly used to evaluate a wide variety of medical disorders, including neoplasms and post-transplant complications. However, its use is being impacted by improved clinical diagnosis of disorders, and non-invasive methods for evaluating liver tissue and as a result the indications of a liver biopsy have undergone major changes in the last decade. The evolution of highly effective treatments for some of the common indications for liver biopsy in the last decade (e.g., viral hepatitis B and C) has led to a decline in the number of liver biopsies in recent years. At the same time, the emergence of better technologies for histologic evaluation, tissue content analysis and genomics are among the many new and exciting developments in the field that hold great promise for the future and are going to shape the indications for a liver biopsy in the future. Recent advances in slide scanners now allow creation of "digital/virtual" slides that have image of the entire tissue section present in a slide [whole slide imaging (WSI)]. WSI can now be done very rapidly and at very high resolution, allowing its use in routine clinical practice. In addition, a variety of technologies have been developed in recent years that use different light sources and/or microscopes allowing visualization of tissues in a completely different way. One such technique that is applicable to liver specimens combines multiphoton microscopy (MPM) with advanced clearing and fluorescent stains known as Clearing Histology with MultiPhoton Microscopy (CHiMP). Although it has not yet been extensively validated, the technique has the potential to decrease inefficiency, reduce artifacts, and increase data while being readily integrable into clinical workflows. Another technology that can provide rapid and in-depth characterization of thousands of molecules in a tissue sample, including liver tissues, is matrix assisted laser desorption/ionization (MALDI) mass spectrometry. MALDI has already been applied in a clinical research setting with promising diagnostic and prognostic capabilities, as well as being able to elucidate mechanisms of liver diseases that may be targeted for the development of new therapies. The logical next step in huge data sets obtained from such advanced analysis of liver tissues is the application of machine learning (ML) algorithms and application of artificial intelligence (AI), for automated generation of diagnoses and prognoses. This review discusses the evolving role of liver biopsies in clinical practice over the decades, and describes newer technologies that are likely to have a significant impact on how they will be used in the future.
Collapse
Affiliation(s)
- Dhanpat Jain
- Department of Anatomic Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Richard Torres
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Romulo Celli
- Department of Anatomic Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Jeremy Koelmel
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Georgia Charkoftaki
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
| |
Collapse
|
|
50
|
Geervliet E, Moreno S, Baiamonte L, Booijink R, Boye S, Wang P, Voit B, Lederer A, Appelhans D, Bansal R. Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis. J Control Release 2021; 332:594-607. [PMID: 33737203 DOI: 10.1016/j.jconrel.2021.03.016] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
Liver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl4)-induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating liver fibrosis.
Collapse
Affiliation(s)
- Eline Geervliet
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7522 NB Enschede, the Netherlands
| | - Silvia Moreno
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany
| | - Luca Baiamonte
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany
| | - Richell Booijink
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7522 NB Enschede, the Netherlands
| | - Susanne Boye
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany
| | - Peng Wang
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany; Technische Universität Dresden, Organic Chemistry of Polymers, 01062 Dresden, Germany
| | - Brigitte Voit
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany; Technische Universität Dresden, Organic Chemistry of Polymers, 01062 Dresden, Germany
| | - Albena Lederer
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany; Department of Chemistry and Polymer Science, Stellenbosch University, Matieland 7602, South Africa.
| | - Dietmar Appelhans
- Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Straße 6, 01069 Dresden, Germany.
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Drienerlolaan 5, 7522 NB Enschede, the Netherlands.
| |
Collapse
|