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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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Souza M, Amaral MJM, Lima LCV, Villela-Nogueira CA. Meta-Analysis of Placebo-Treated Patients: Dropout Rates From Treatment in MASH Randomised Controlled Trials. Aliment Pharmacol Ther 2025; 61:776-786. [PMID: 39807647 DOI: 10.1111/apt.18498] [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: 08/06/2024] [Revised: 08/22/2024] [Accepted: 01/04/2025] [Indexed: 01/16/2025]
Abstract
BACKGROUND Dropout is common and affects the statistical power and randomization balance of randomised controlled trials (RCTs). AIMS To estimate the dropout rate in RCTs of metabolic dysfunction-associated steatohepatitis (MASH) and to examine factors associated with dropout in placebo-treated participants. METHODS PubMed and Cochrane databases were searched for phase 2-4 MASH RCTs with placebo arms through November 24, 2024. Dropout was defined as the attrition of patients included in the intention-to-treat analysis but did not complete treatment. RCTs were qualitatively reviewed to assess the expected and observed dropouts. Generalised linear mixed model was used to estimate pooled dropout rates. RESULTS Sixty RCTs with 3230 placebo-treated participants with MASH were analysed. Thirty-three RCTs reported the dropout rate used to estimate the effect size. Of these, 60.6%, 36.4%, and 3.0% had an expected dropout rate that was higher, lower, and similar, respectively, than the observed dropout rate in the placebo arm. Overall, the dropout rate was 11.06% (95% confidence interval [CI] 9.07 to 13.42), with a higher rate in phase 3-4 trials than in phase 2 trials. The corresponding rates due to adverse events, loss to follow-up and patient choice were 2.41% (95% CI 1.67 to 3.48), 1.79% (95% CI 1.06 to 2.99) and 4.06% (95% CI 2.97 to 5.53), respectively. Meta-regression determined that the dropout rate increased with longer treatment duration. CONCLUSION Placebo dropout in MASH RCTs is significant, mainly due to patient choice. Factors such as trial phase and treatment duration should be considered when calculating sample size in future clinical trials.
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Affiliation(s)
- Matheus Souza
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcio J M Amaral
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luan C V Lima
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Shi R, Chai K, Wang H, Zhou J, Yang S, Li J, Qiao C, Sheng X, Zhang X, Wu J. Clinical Assessment of Common Medications for Nonalcoholic Fatty Liver Disease: A Systematic Review and Bayesian Network Meta-Analysis. J Evid Based Med 2025; 18:e70002. [PMID: 39963857 PMCID: PMC11833758 DOI: 10.1111/jebm.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 02/02/2025] [Accepted: 02/10/2025] [Indexed: 02/20/2025]
Abstract
OBJECTIVE With a steadily rising prevalence, nonalcoholic fatty liver disease (NAFLD) was a leading global cause of liver-related health problems. In the clinical management of NAFLD, various western pharmaceuticals were widely utilized. This network meta-analysis aimed to evaluate the effectiveness of common western medications for NAFLD patients. METHODS We systematically reviewed and screened articles based on predesigned criterion about western medications for NAFLD, which were from Embase, Cochrane Library, PubMed, CNKI, WanFang, and China Science and Technology Journal Database until August 1, 2024. Eligible studies included randomized controlled trials of patients aged 18 or older with NAFLD, comparing Western medicines to placebos or other Western medicine treatments. The risk of bias assessment tool 2.0 from the Cochrane system was used to assess the quality of the included articles. A Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 with a random-effects model and Markov Chain Monte Carlo methods. Treatment rankings were based on Surface Under the Cumulative Ranking Curve (SUCRA) values, and heterogeneity was assessed with I2 and Q statistics. The outcomes were analyzed in WinBUGS and visualized using Stata 14.0, generating network plots and cumulative probability rankings to compare treatment effects. The systematic review was registered in PROSPERO (CRD42024509176). RESULTS Based on 37 included articles involving 7673 patients, pioglitazone demonstrated the most significant effects in resolving nonalcoholic steatohepatitis without worsening fibrosis, increasing high-density lipoprotein cholesterol levels, and achieving a ≥ 2-point reduction in NAFLD activity scores (odds ratio [OR] = 0.09, 95% confidence interval [CI]: 0.01 to 0.81), with a SUCRA probability of 91.4%. Aldafermin showed remarkable effects in improving liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase, with cumulative probabilities of 90% for ALT and 69.8% for AST. Cluster analysis revealed that Resmetirom and Aldafermin were superior options for enhancing liver function, while pioglitazone emerged as the best treatment for the comprehensive improvement of NAFLD. CONCLUSIONS Pioglitazone outperformed other western medicines in terms of overall efficacy when treating NAFLD, but Aldafermin and Resmetirom showed superior improvement in liver function. This study provided a certain level of support for the use of specific clinical medications.
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Affiliation(s)
- Rui Shi
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Keyan Chai
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Haojia Wang
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Jiying Zhou
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Siyun Yang
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Jiaqi Li
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Chuanqi Qiao
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Xiaoguang Sheng
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Xiaomeng Zhang
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
| | - Jiarui Wu
- Department of Clinical Chinese PharmacySchool of Chinese MateriaBeijing University of Chinese MedicineBeijingChina
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Geng W, Liao W, Cao X, Yang Y. Therapeutic Targets and Approaches to Manage Inflammation of NAFLD. Biomedicines 2025; 13:393. [PMID: 40002806 PMCID: PMC11853636 DOI: 10.3390/biomedicines13020393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.
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Affiliation(s)
- Wanying Geng
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China;
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Wanying Liao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Xinyuan Cao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Yingyun Yang
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
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Kelly MP, Nikolaev VO, Gobejishvili L, Lugnier C, Hesslinger C, Nickolaus P, Kass DA, Pereira de Vasconcelos W, Fischmeister R, Brocke S, Epstein PM, Piazza GA, Keeton AB, Zhou G, Abdel-Halim M, Abadi AH, Baillie GS, Giembycz MA, Bolger G, Snyder G, Tasken K, Saidu NEB, Schmidt M, Zaccolo M, Schermuly RT, Ke H, Cote RH, Mohammadi Jouabadi S, Roks AJM. Cyclic nucleotide phosphodiesterases as drug targets. Pharmacol Rev 2025; 77:100042. [PMID: 40081105 DOI: 10.1016/j.pharmr.2025.100042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 01/13/2025] [Indexed: 03/15/2025] Open
Abstract
Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.
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Affiliation(s)
- Michy P Kelly
- Department of Neurobiology, Center for Research on Aging, University of Maryland School of Medicine, Baltimore, Maryland
| | - Viacheslav O Nikolaev
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Leila Gobejishvili
- Department of Physiology, School of Medicine, University of Louisville, Kentucky, Louisville
| | - Claire Lugnier
- Translational CardioVascular Medicine, CRBS, UR 3074, Strasbourg, France
| | | | - Peter Nickolaus
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - David A Kass
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Rodolphe Fischmeister
- Université Paris-Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S 1180, Orsay, France
| | - Stefan Brocke
- Department of Immunology, UConn Health, Farmington, Connecticut
| | - Paul M Epstein
- Department of Cell Biology, UConn Health, Farmington, Connecticut
| | - Gary A Piazza
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Adam B Keeton
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Gang Zhou
- Georgia Cancer Center, Augusta University, Augusta, Georgia
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Ashraf H Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - George S Baillie
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Mark A Giembycz
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Gretchen Snyder
- Molecular Neuropharmacology, Intra-Cellular Therapies Inc (ITI), New York, New York
| | - Kjetil Tasken
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Nathaniel E B Saidu
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Martina Schmidt
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Manuela Zaccolo
- Department of Physiology, Anatomy and Genetics and National Institute for Health and Care Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Ralph T Schermuly
- Department of internal Medicine, Justus Liebig University of Giessen, Giessen, Germany
| | - Hengming Ke
- Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, North Carolina
| | - Rick H Cote
- Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire
| | - Soroush Mohammadi Jouabadi
- Section of Vascular and Metabolic Disease, Department of Internal Medicine, Erasmus MC University Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Anton J M Roks
- Section of Vascular and Metabolic Disease, Department of Internal Medicine, Erasmus MC University Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands.
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Amorim R, Soares P, Chavarria D, Benfeito S, Cagide F, Teixeira J, Oliveira PJ, Borges F. Decreasing the burden of non-alcoholic fatty liver disease: From therapeutic targets to drug discovery opportunities. Eur J Med Chem 2024; 277:116723. [PMID: 39163775 DOI: 10.1016/j.ejmech.2024.116723] [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: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/22/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.
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Affiliation(s)
- Ricardo Amorim
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Pedro Soares
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Sofia Benfeito
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Fernando Cagide
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - José Teixeira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal.
| | - Fernanda Borges
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
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Hu Y, Sun C, Chen Y, Liu YD, Fan JG. Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease. J Clin Transl Hepatol 2024; 12:802-814. [PMID: 39280073 PMCID: PMC11393841 DOI: 10.14218/jcth.2024.00123] [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: 04/17/2024] [Revised: 06/27/2024] [Accepted: 07/09/2024] [Indexed: 09/18/2024] Open
Abstract
Given the global prevalence and rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), the absence of licensed medications is striking. A deeper understanding of the heterogeneous nature of MASLD has recently contributed to the discovery of novel groups of agents and the potential repurposing of currently available medications. MASLD therapies center on four major pathways. Considering the close relationship between MASLD and type 2 diabetes, the first approach involves antidiabetic medications, including incretins, thiazolidinedione insulin sensitizers, and sodium-glucose cotransporter 2 inhibitors. The second approach targets hepatic lipid accumulation and the resultant metabolic stress. Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs. The third approach focuses on targeting oxidative stress, inflammation, and fibrosis. Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications.
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Affiliation(s)
- Ye Hu
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Sun
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Chen
- Department of Geriatrics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu-Dong Liu
- Department of Gastroenterology, Changxing branch of Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Li QZ, He MH, Zeng R, Lei YY, Yu ZY, Jiang M, Zhang X, Li JL. Molecular Editing of Ketones through N-Heterocyclic Carbene and Photo Dual Catalysis. J Am Chem Soc 2024; 146:22829-22839. [PMID: 39086019 DOI: 10.1021/jacs.4c08163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024]
Abstract
The molecular editing of ketones represents an appealing strategy due to its ability to maximize the structural diversity of ketone compounds in a straightforward manner. However, developing efficient methods for the arbitrary modification of ketonic molecules, particularly those integrated within complex skeletons, remains a significant challenge. Herein, we present a unique strategy for ketone recasting that involves radical acylation of pre-functionalized ketones facilitated by N-heterocyclic carbene and photo dual catalysis. This protocol features excellent substrate tolerance and can be applied to the convergent synthesis and late-stage functionalization of structurally complex bioactive ketones. Mechanistic investigations, including experimental studies and density functional theory (DFT) calculations, shed light on the reaction mechanism and elucidate the basis of the regioselectivity.
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Affiliation(s)
- Qing-Zhu Li
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Mei-Hao He
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Rong Zeng
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Yuan-Yuan Lei
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Zhao-Yuan Yu
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Min Jiang
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Xiang Zhang
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Jun-Long Li
- Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China
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Alfawaz S, Burzangi A, Esmat A. Mechanisms of Non-alcoholic Fatty Liver Disease and Beneficial Effects of Semaglutide: A Review. Cureus 2024; 16:e67080. [PMID: 39286709 PMCID: PMC11404706 DOI: 10.7759/cureus.67080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2024] [Indexed: 09/19/2024] Open
Abstract
Non-alcoholic fatty liver disease stands as the predominant cause of chronic liver disease, with its prevalence and morbidity expected to escalate significantly, leading to substantial healthcare costs and diminished health-related quality of life. It comprises a range of disease manifestations that commence with basic steatosis, involving the accumulation of lipids in hepatocytes, a distinctive histological feature. If left untreated, it often advances to non-alcoholic steatohepatitis, marked by inflammatory and/or fibrotic hepatic changes, leading to the eventual development of non-alcoholic fatty liver disease-related cirrhosis and hepatocellular carcinoma. Because of the liver's vital role in body metabolism, non-alcoholic fatty liver disease is considered both a consequence and a contributor to the metabolic abnormalities observed in the metabolic syndrome. As of date, there are no authorized pharmacological agents for non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. Semaglutide, with its glycemic and weight loss advantages, could potentially offer benefits for individuals with non-alcoholic fatty liver disease. This review aims to investigate the impact of semaglutide on non-alcoholic fatty liver disease.
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Affiliation(s)
- Sultan Alfawaz
- Department of Clinical Pharmacology, King Abdulaziz University, Faculty of Medicine, Jeddah, SAU
| | - Abdulhadi Burzangi
- Department of Clinical Pharmacology, King Abdulaziz University, Faculty of Medicine, Jeddah, SAU
| | - Ahmed Esmat
- Department of Clinical Pharmacology, King Abdulaziz University, Faculty of Medicine, Jeddah, SAU
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10
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Li S, Xiong F, Zhang S, Liu J, Gao G, Xie J, Wang Y. Oligonucleotide therapies for nonalcoholic steatohepatitis. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102184. [PMID: 38665220 PMCID: PMC11044058 DOI: 10.1016/j.omtn.2024.102184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.
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Affiliation(s)
- Sixu Li
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
| | - Feng Xiong
- Department of Cardiology, The Third People’s Hospital of Chengdu, Chengdu 610031, China
| | - Songbo Zhang
- Department of Breast Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Jinghua Liu
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Jun Xie
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
- Viral Vector Core, University of Massachusetts Chan Medical, School, Worcester, MA 01605, USA
| | - Yi Wang
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610066, China
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Nendouvhada LP, Sibuyi NRS, Fadaka AO, Meyer S, Madiehe AM, Meyer M, Gabuza KB. Phytonanotherapy for the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease. Int J Mol Sci 2024; 25:5571. [PMID: 38891759 PMCID: PMC11171778 DOI: 10.3390/ijms25115571] [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: 04/20/2024] [Revised: 04/27/2024] [Accepted: 04/27/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, is a steatotic liver disease associated with metabolic syndrome (MetS), especially obesity, hypertension, diabetes, hyperlipidemia, and hypertriglyceridemia. MASLD in 43-44% of patients can progress to metabolic dysfunction-associated steatohepatitis (MASH), and 7-30% of these cases will progress to liver scarring (cirrhosis). To date, the mechanism of MASLD and its progression is not completely understood and there were no therapeutic strategies specifically tailored for MASLD/MASH until March 2024. The conventional antiobesity and antidiabetic pharmacological approaches used to reduce the progression of MASLD demonstrated favorable peripheral outcomes but insignificant effects on liver histology. Alternatively, phyto-synthesized metal-based nanoparticles (MNPs) are now being explored in the treatment of various liver diseases due to their unique bioactivities and reduced bystander effects. Although phytonanotherapy has not been explored in the clinical treatment of MASLD/MASH, MNPs such as gold NPs (AuNPs) and silver NPs (AgNPs) have been reported to improve metabolic processes by reducing blood glucose levels, body fat, and inflammation. Therefore, these actions suggest that MNPs can potentially be used in the treatment of MASLD/MASH and related metabolic diseases. Further studies are warranted to investigate the feasibility and efficacy of phytonanomedicine before clinical application.
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Affiliation(s)
- Livhuwani P. Nendouvhada
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Bellville 7535, South Africa (A.O.F.); (M.M.)
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Nicole R. S. Sibuyi
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Bellville 7535, South Africa (A.O.F.); (M.M.)
- Health Platform, Advanced Materials Division, Mintek, Randburg 2194, South Africa
| | - Adewale O. Fadaka
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Bellville 7535, South Africa (A.O.F.); (M.M.)
| | - Samantha Meyer
- Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville 7535, South Africa;
| | - Abram M. Madiehe
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Bellville 7535, South Africa (A.O.F.); (M.M.)
| | - Mervin Meyer
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Bellville 7535, South Africa (A.O.F.); (M.M.)
| | - Kwazikwakhe B. Gabuza
- Department of Science and Innovation/Mintek Nanotechnology Innovation Centre, Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Bellville 7535, South Africa (A.O.F.); (M.M.)
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
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12
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Kokkorakis M, Muzurović E, Volčanšek Š, Chakhtoura M, Hill MA, Mikhailidis DP, Mantzoros CS. Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies. Pharmacol Rev 2024; 76:454-499. [PMID: 38697855 DOI: 10.1124/pharmrev.123.001087] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/22/2023] [Accepted: 01/25/2024] [Indexed: 05/05/2024] Open
Abstract
Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.
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Affiliation(s)
- Michail Kokkorakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Emir Muzurović
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Špela Volčanšek
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Marlene Chakhtoura
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Michael A Hill
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Dimitri P Mikhailidis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (M.K., C.S.M.); Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands (M.K.); Endocrinology Section, Department of Internal Medicine, Clinical Center of Montenegro, Podgorica, Montenegro (E.M.); Faculty of Medicine, University of Montenegro, Podgorica, Montenegro (E.M.); Department of Endocrinology, Diabetes, and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia (Š.V.); Medical Faculty Ljubljana, Ljubljana, Slovenia (Š.V.); Division of Endocrinology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (M.C.); Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri (M.A.H.); Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri (M.A.H.); Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom (D.P.M.); Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates (D.P.M.); and Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts (C.S.M.)
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13
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Mandal B, Das R, Mondal S. Anthocyanins: Potential phytochemical candidates for the amelioration of non-alcoholic fatty liver disease. ANNALES PHARMACEUTIQUES FRANÇAISES 2024; 82:373-391. [PMID: 38354975 DOI: 10.1016/j.pharma.2024.02.005] [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: 11/28/2023] [Revised: 01/30/2024] [Accepted: 02/08/2024] [Indexed: 02/16/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is described by too much hepatic fat deposition causing steatosis, which further develops into nonalcoholic steatohepatitis (NASH), defined by necroinflammation and fibrosis, progressing further to hepatic cirrhosis, hepatocellular carcinoma, and liver failure. NAFLD is linked to different aspects of the metabolic syndrome like obesity, insulin resistance, hypertension, and dyslipidemia, and its pathogenesis involves several elements including diet, obesity, disruption of lipid homeostasis, and a high buildup of triglycerides and other lipids in liver cells. It is therefore linked to an increase in the susceptibility to developing diabetes mellitus and cardiovascular diseases. Several interventions exist regarding its management, but the availability of natural sources through diet will be a benefit in dealing with the disorder due to the immensely growing dependence of the population worldwide on natural sources owing to their ability to treat the root cause of the disease. Anthocyanins (ACNs) are naturally occurring polyphenolic pigments that exist in the form of glycosides, which are the glucosides of anthocyanidins and are produced from flavonoids via the phenyl propanoid pathway. To understand their mode of action in NAFLD and their therapeutic potential, the literature on in vitro, in vivo, and clinical trials on naturally occurring ACN-rich sources was exhaustively reviewed. It was concluded that ACNs show their potential in the treatment of NAFLD through their antioxidant properties and their efficacy to control lipid metabolism, glucose homeostasis, transcription factors, and inflammation. This led to the conclusion that ACNs possess efficacy in the amelioration of NAFLD and the various features associated with it. However, additional clinical trials are required to justify the potential of ACNs in NAFLD.
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Affiliation(s)
- Bitasta Mandal
- School of Pharmaceutical Technology, School of Health and Medical Sciences, Adamas University, Kolkata 700126, India.
| | - Rakesh Das
- School of Pharmaceutical Technology, School of Health and Medical Sciences, Adamas University, Kolkata 700126, India.
| | - Sandip Mondal
- School of Pharmaceutical Technology, School of Health and Medical Sciences, Adamas University, Kolkata 700126, India.
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14
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Savari F, Mard SA. Nonalcoholic steatohepatitis: A comprehensive updated review of risk factors, symptoms, and treatment. Heliyon 2024; 10:e28468. [PMID: 38689985 PMCID: PMC11059522 DOI: 10.1016/j.heliyon.2024.e28468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 05/02/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease and a progressive and chronic liver disorder with a significant risk for the development of liver-related morbidity and mortality. The complex and multifaceted pathophysiology of NASH makes its management challenging. Early identification of symptoms and management of patients through lifestyle modification is essential to prevent the development of advanced liver disease. Despite the increasing prevalence of NASH, there is no FDA-approved treatment for this disease. Currently, medications targeting metabolic disease risk factors and some antifibrotic medications are used for NASH patients but are not sufficiently effective. The beneficial effects of different drugs and phytochemicals represent new avenues for the development of safer and more effective treatments for NASH. In this review, different risk factors, clinical symptoms, diagnostic methods of NASH, and current treatment strategies for the management of patients with NASH are reviewed.
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Affiliation(s)
- Feryal Savari
- Department of Medical Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran
| | - Seyed Ali Mard
- Clinical Sciences Research Institute, Alimentary Tract Research Center, Department of Physiology, The School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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15
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Mladenić K, Lenartić M, Marinović S, Polić B, Wensveen FM. The "Domino effect" in MASLD: The inflammatory cascade of steatohepatitis. Eur J Immunol 2024; 54:e2149641. [PMID: 38314819 DOI: 10.1002/eji.202149641] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter of the global adult population. A key event in the pathophysiology of MASLD is the development of metabolic-associated steatohepatitis (MASH), which greatly increases the chances of developing cirrhosis and hepatocellular carcinoma. The underlying cause of MASH is multifactorial, but accumulating evidence indicates that the inflammatory process in the hepatic microenvironment typically follows a pattern that can be roughly divided into three stages: (1) Detection of hepatocyte stress by tissue-resident immune cells including γδ T cells and CD4-CD8- double-negative T cells, followed by their secretion of pro-inflammatory mediators, most notably IL-17A. (2) Recruitment of pro-inflammatory cells, mostly of the myeloid lineage, and initiation of inflammation through secretion of effector-type cytokines such as TNF, TGF-β, and IL-1β. (3) Escalation of the inflammatory response by recruitment of lymphocytes including Th17, CD8 T, and B cells leading to chronic inflammation, hepatic stellate cell activation, and fibrosis. Here we will discuss these three stages and how they are consecutively linked like falling domino tiles to the pathophysiology of MASH. Moreover, we will highlight the clinical potential of inflammation as a biomarker and therapeutic target for the treatment of MASLD.
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Affiliation(s)
- Karlo Mladenić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Maja Lenartić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Sonja Marinović
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Division of Molecular Medicine, Laboratory for Personalized Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Bojan Polić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Felix M Wensveen
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
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16
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Shin S, Kim J, Lee JY, Kim J, Oh CM. Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). J Obes Metab Syndr 2023; 32:289-302. [PMID: 38049180 PMCID: PMC10786205 DOI: 10.7570/jomes23054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/27/2023] [Accepted: 09/30/2023] [Indexed: 12/06/2023] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is characterized by hepatic steatosis and metabolic dysfunction and is often associated with obesity and insulin resistance. Recent research indicates a rapid escalation in MASLD cases, with projections suggesting a doubling in the United States by 2030. This review focuses on the central role of mitochondria in the pathogenesis of MASLD and explores potential therapeutic interventions. Mitochondria are dynamic organelles that orchestrate hepatic energy production and metabolism and are critically involved in MASLD. Dysfunctional mitochondria contribute to lipid accumulation, inflammation, and liver fibrosis. Genetic associations further underscore the relationship between mitochondrial dynamics and MASLD susceptibility. Although U.S. Food and Drug Administration-approved treatments for MASLD remain elusive, ongoing clinical trials have highlighted promising strategies that target mitochondrial dysfunction, including vitamin E, metformin, and glucagon-like peptide-1 receptor agonists. In preclinical studies, novel therapeutics, including nicotinamide adenine dinucleotide+ precursors, urolithin A, spermidine, and mitoquinone, have shown beneficial effects, such as improving mitochondrial quality control, reducing oxidative stress, and ameliorating hepatic steatosis and inflammation. In conclusion, mitochondrial dysfunction is central to MASLD pathogenesis. The innovative mitochondria-targeted approaches discussed in this review offer a promising avenue for reducing the burden of MASLD and improving global quality of life.
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Affiliation(s)
- Soyeon Shin
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Jaeyoung Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Ju Yeon Lee
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Jun Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
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Knöchel J, Bergenholm L, Ibrahim E, Kechagias S, Hansson S, Liljeblad M, Nasr P, Carlsson B, Ekstedt M, Ueckert S. A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts. CPT Pharmacometrics Syst Pharmacol 2023; 12:2038-2049. [PMID: 37750001 PMCID: PMC10725269 DOI: 10.1002/psp4.13052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/28/2023] [Accepted: 09/06/2023] [Indexed: 09/27/2023] Open
Abstract
Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0-1) compared to fibrosis stage 2 and 3 (F2-3). A twofold increase in FPR was observed for T2D. A two-point steatosis worsening increased the FPR 11-fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well-defined lifestyle advise for reducing variability in NASH progression during clinical trials.
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Affiliation(s)
- Jane Knöchel
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology & Safety Sciences, R&D, AstraZenecaGothenburgSweden
| | - Linnéa Bergenholm
- DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaGothenburgSweden
| | - Eman Ibrahim
- Department of PharmacyUppsala UniversityUppsalaSweden
| | - Stergios Kechagias
- Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Sara Hansson
- Translational Science and Experimental Medicine, Research and Early DevelopmentCardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaGothenburgSweden
| | - Mathias Liljeblad
- Translational Science and Experimental Medicine, Research and Early DevelopmentCardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaGothenburgSweden
| | - Patrik Nasr
- Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Björn Carlsson
- Translational Science and Experimental Medicine, Research and Early DevelopmentCardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaGothenburgSweden
| | - Mattias Ekstedt
- Department of Health, Medicine, and Caring SciencesLinköping UniversityLinköpingSweden
| | - Sebastian Ueckert
- Clinical Pharmacology and Quantitative PharmacologyClinical Pharmacology & Safety Sciences, R&D, AstraZenecaGothenburgSweden
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Ziamanesh F, Mohammadi M, Ebrahimpour S, Tabatabaei-Malazy O, Mosallanejad A, Larijani B. Unraveling the link between insulin resistance and Non-alcoholic fatty liver disease (or metabolic dysfunction-associated steatotic liver disease): A Narrative Review. J Diabetes Metab Disord 2023; 22:1083-1094. [PMID: 37975107 PMCID: PMC10638269 DOI: 10.1007/s40200-023-01293-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 08/24/2023] [Indexed: 11/19/2023]
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a significant global health concern, representing the leading cause of chronic liver disease and posing a substantial public health challenge. NAFLD is associated with higher insulin resistance (IR) levels, a key pathophysiological mechanism contributing to its development and progression. To counter this growing trend, it is crucial to raise awareness about NAFLD and promote healthy lifestyles to mitigate the impact of this disease. Methods Relevant studies regarding IR and NAFLD published until May 30, 2023, were extracted from Google PubMed, Scopus, and Web Of Science web databases. The following keywords were used: IR, diabetes mellitus, Non-alcoholic fatty liver disease, and metabolic syndrome. Results IR leads to an accumulation of fatty acids within liver cells, resulting from increased glycolysis and decreased apolipoprotein B-100. Furthermore, the manifestations of NAFLD extend beyond liver-related morbidity and mortality, affecting multiple organs and giving rise to various non-communicable disorders such as diabetes mellitus, metabolic syndrome, polycystic ovary syndrome, obstructive sleep apnea, and cardiovascular disease. Although lifestyle modification remains the primary treatment approach for NAFLD, alternative therapies, including pharmacological, herbal, and surgical interventions, may be considered. By implementing early and simple measures, cirrhosis, end-stage liver disease, and hepatocellular carcinoma can be prevented. Conclusions There is a clear association between NAFLD and elevated levels of IR. Several metabolic conditions, such as obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome, are closely interrelated with NAFLD and IR. Raising awareness about NAFLD and promoting a healthy lifestyle are crucial steps to reverse the impact of this disease.
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Affiliation(s)
- Fateme Ziamanesh
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mohammadi
- Department of Clinical Pharmacy, School of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Sholeh Ebrahimpour
- Department of Clinical Pharmacy, School of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Zhao Q, Wu J, Ding Y, Pang Y, Jiang C. Gut microbiota, immunity, and bile acid metabolism: decoding metabolic disease interactions. LIFE METABOLISM 2023; 2:load032. [PMID: 39872860 PMCID: PMC11749371 DOI: 10.1093/lifemeta/load032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 07/14/2023] [Accepted: 07/21/2023] [Indexed: 01/03/2025]
Abstract
In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.
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Affiliation(s)
- Qixiang Zhao
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Jiayu Wu
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yong Ding
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yanli Pang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Changtao Jiang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
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20
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Humbert A, Lefebvre R, Nawrot M, Caussy C, Rieusset J. Calcium signalling in hepatic metabolism: Health and diseases. Cell Calcium 2023; 114:102780. [PMID: 37506596 DOI: 10.1016/j.ceca.2023.102780] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
The flexibility between the wide array of hepatic functions relies on calcium (Ca2+) signalling. Indeed, Ca2+ is implicated in the control of many intracellular functions as well as intercellular communication. Thus, hepatocytes adapt their Ca2+ signalling depending on their nutritional and hormonal environment, leading to opposite cellular functions, such as glucose storage or synthesis. Interestingly, hepatic metabolic diseases, such as obesity, type 2 diabetes and non-alcoholic fatty liver diseases, are associated with impaired Ca2+ signalling. Here, we present the hepatocytes' toolkit for Ca2+ signalling, complete with regulation systems and signalling pathways activated by nutrients and hormones. We further discuss the current knowledge on the molecular mechanisms leading to alterations of Ca2+ signalling in hepatic metabolic diseases, and review the literature on the clinical impact of Ca2+-targeting therapeutics.
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Affiliation(s)
- Alexandre Humbert
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| | - Rémy Lefebvre
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| | - Margaux Nawrot
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| | - Cyrielle Caussy
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France; Département Endocrinologie, Diabète et Nutrition, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Jennifer Rieusset
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France.
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21
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Le P, Payne JY, Zhang L, Deshpande A, Rothberg MB, Alkhouri N, Herman W, Hernandez AV, Schleicher M, Ye W, Dasarathy S. Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies. Clin Gastroenterol Hepatol 2023; 21:1154-1168. [PMID: 35933075 PMCID: PMC9898457 DOI: 10.1016/j.cgh.2022.07.033] [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: 03/23/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS We conducted a meta-analysis to summarize the rates of progression to and regression of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). METHODS We searched PubMed/Medline and 4 other databases from 1985 through 2020. We included observational studies and randomized controlled trials in any language that used liver biopsy or imaging to diagnose NAFLD in adults with a follow-up period ≥48 weeks. Rates were calculated as incident cases per 100 person-years and pooled using the random-effects Poisson distribution model. Heterogeneity was assessed using the I2 statistic. RESULTS We screened 9744 articles and included 54 studies involving 26,738 patients. Among observational studies, 20% of healthy adults developed NAFL (incidence rate, 4.8/100 person-years) while 21% of people with fatty liver had resolution of NAFL (incidence rate, 2.4/100 person-years) after a median of approximately 4.5 years. In addition, 31% of patients developed NASH after 4.7 years (incidence rate, 7.4/100 person-years), whereas in 29% of those with NASH, resolution occurred after a median of 3.5 years (incidence rate, 5.1/100 person-years). Time to progress by 1 fibrosis stage was 9.9, 10.3, 13.3, and 22.2 years for F0, F1, F2, and F3, respectively. Time to regress by 1 stage was 21.3, 12.5, 20.4, and 40.0 years for F4, F3, F2, and F1, respectively. Rates estimated from randomized controlled trials were higher than those from observational studies. CONCLUSIONS In our meta-analysis, progression to NASH was more common than regression from NASH. Rates of fibrosis progression were similar across baseline stage, but patients with advanced fibrosis were more likely to regress than those with mild fibrosis.
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Affiliation(s)
- Phuc Le
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio.
| | - Julia Yang Payne
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio; Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Lu Zhang
- Department of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Abhishek Deshpande
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio
| | - Michael B Rothberg
- Center for Value-Based Care Research, Cleveland Clinic Community Care, Cleveland Clinic, Cleveland, Ohio
| | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Tucson, Arizona
| | - William Herman
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
| | - Adrian V Hernandez
- Health Outcomes, Policy, and Evidence Synthesis Group, University of Connecticut School of Pharmacy, Storrs, Connecticut; Unidad de Revisiones Sistemáticas y Meta-Análisis, Universidad San Ignacio de Loyola, Lima, Peru
| | - Mary Schleicher
- The Floyd D. Loop Alumni Library, Cleveland Clinic, Cleveland, Ohio
| | - Wen Ye
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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Torosian K, Lal E, Kavanaugh A, Loomba R, Ajmera V, Guma M. Psoriatic disease and non-alcoholic fatty liver disease shared pathogenesis review. Semin Arthritis Rheum 2023; 59:152165. [PMID: 36716599 PMCID: PMC9992353 DOI: 10.1016/j.semarthrit.2023.152165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/03/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023]
Abstract
Psoriatic disease (PD) and non-alcoholic fatty liver disease (NAFLD) potentially share disease pathways given the numerous inflammatory pathways involved in both diseases and a higher prevalence of NAFLD in PD patients. Metabolic syndrome and obesity are a key link between the two diseases, but even when controlling for this, associations between both diseases are still seen. Therapeutics that impact metabolic or inflammatory pathways may be impactful in both PD and NAFLD. In this review, we describe common inflammatory pathways contributing to both PD and NAFLD and critically review the potential impact of treatments for and on both diseases.
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Affiliation(s)
- Kelly Torosian
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Esha Lal
- Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Arthur Kavanaugh
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA; Division of Epidemiology, Department of Family and Preventative Medicine, University of California at San Diego, La Jolla, USA
| | - Veeral Ajmera
- Division of Gastroenterology and Hepatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, USA.
| | - Monica Guma
- Department of Rheumatology, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain; San Diego VA Healthcare Service, San Diego, CA, 92161, USA.
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23
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Tay PWL, Ng CH, Lin SY, Chin YH, Xiao J, Lim WH, Lim SY, Fu CE, Chan KE, Quek J, Tan DJH, Chew N, Syn N, Keitoku T, Tamaki N, Siddiqui MS, Noureddin M, Muthiah M, Huang DQ, Loomba R. Placebo Adverse Events in Non-alcoholic Steatohepatitis Clinical Trials: A Pooled Analysis of 2,944 Participants. Am J Gastroenterol 2023; 118:645-653. [PMID: 36191268 PMCID: PMC10792533 DOI: 10.14309/ajg.0000000000002042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/17/2022] [Indexed: 11/05/2022]
Abstract
INTRODUCTION In the absence of an effective treatment for non-alcoholic steatohepatitis (NASH), a randomized, placebo-controlled trial (RCT) remains the current gold standard study design in NASH. As NASH is a largely asymptomatic disease, the side effects of potential therapies require careful evaluation, therefore a pooled rate of the adverse events (AEs) in placebo-treated patients serves as a useful comparator for safety. Therefore, we performed a systematic review and meta-analysis to estimate the rate of AEs among participants in the placebo arm of NASH RCTs. METHODS Medline, Embase and Cochrane Central Register of Controlled Trials were searched to include clinical trials in phase 2-4 NASH RCTs with placebo treatment arms. A pooled proportions of AEs were analyzed using a generalized linear mixed model with Clopper-Pearson intervals. RESULTS A total of 41 RCTs (2,944 participants on placebo) were included in this meta-analysis. A total of 68% (confidence interval [CI] 55%-77%) of participants on placebo experienced an AE, 7.8% (5.7%-10%) experienced serious AEs and 3.1% (CI: 1.9%-5.1%) experienced AEs leading to discontinuation. A significantly higher proportion of participants experienced serious AEs in phase 3 studies compared to in phase 2 studies ( P < 0.01) and in pharmaceutical funded studies as compared to studies which were federal-funded studies ( P < 0.01). An analysis of clinical trials evaluating bile acid modulating agents determined that 10% (CI: 5.5%-18%) of participants receiving placebo developed pruritus. DISCUSSION The present study summarizes the AEs with NASH placebo. Among participants in the placebo arm in NASH, two-third experienced an AE, and nearly 10% experienced a serious AE.
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Affiliation(s)
- Phoebe Wen Lin Tay
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Snow Yunni Lin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Sze Yinn Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Clarissa Elysia Fu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kai En Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jingxuan Quek
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nicholas Chew
- Department of Cardiology, National University Heart Centre, National University Hospital, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Taisei Keitoku
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Mazen Noureddin
- Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Centre, Los Angeles, California, USA
| | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Daniel Q. Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, California, USA
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Singh S, Sharma N, Shukla S, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Bungau SG, Brisc C. Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics. Molecules 2023; 28:molecules28062811. [PMID: 36985782 PMCID: PMC10057127 DOI: 10.3390/molecules28062811] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Saurabh Shukla
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Sumeet Gupta
- Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Md Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Cristina Brisc
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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25
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The Interlink Between Metabolic-Associated Fatty Liver Disease and Polycystic Ovary Syndrome. Endocrinol Metab Clin North Am 2023. [PMID: 37495343 DOI: 10.1016/j.ecl.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Polycystic ovary syndrome (PCOS) affects around 10% of women in the reproductive age group and is characterized by ovulatory dysfunction, hyperandrogenism, and/or polycystic ovarian morphology. PCOS is highly associated with metabolic-associated fatty liver disease (MAFLD) as both diseases share common risk factors. At the time of diagnosis of PCOS, screening for MAFLD is necessary because most patients with MAFLD are asymptomatic. The importance of early detection of MAFLD in patients with PCOS is that a timely intervention in patients with steatosis or steatohepatitis can reduce the probability of liver disease progression.
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26
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Cernea S, Onișor D. Screening and interventions to prevent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:286-309. [PMID: 36687124 PMCID: PMC9846941 DOI: 10.3748/wjg.v29.i2.286] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/06/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Liver cancer is the sixth most commonly diagnosed cancer worldwide, with hepatocellular carcinoma (HCC) comprising most cases. Besides hepatitis B and C viral infections, heavy alcohol use, and nonalcoholic steatohepatitis (NASH)-associated advanced fibrosis/cirrhosis, several other risk factors for HCC have been identified (i.e. old age, obesity, insulin resistance, type 2 diabetes). These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection. HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease (NAFLD) patients, and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment. Patients with NASH-cirrhosis should undergo systematic HCC surveillance, while this might be considered in patients with advanced fibrosis based on individual risk assessment. In this context, interventions that potentially prevent NAFLD/ NASH-associated HCC are needed. This paper provided an overview of evidence related to lifestyle changes (i.e. weight loss, physical exercise, adherence to healthy dietary patterns, intake of certain dietary components, etc.) and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms. However, well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.
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Affiliation(s)
- Simona Cernea
- Department M3/Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureş 540139, Romania
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş 540136, Romania
| | - Danusia Onișor
- Department ME2/Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş 540139, Romania
- Gastroenterology Department, Mureș County Clinical Hospital, Târgu Mureș 540072, Romania
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Side effect profile of pharmacologic therapies for liver fibrosis in nonalcoholic fatty liver disease: a systematic review and network meta-analysis. Eur J Gastroenterol Hepatol 2023; 35:1-14. [PMID: 36468565 DOI: 10.1097/meg.0000000000002471] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Several studies have found that antifibrosis treatment for nonalcoholic fatty liver disease (NAFLD) can cause a variety of side effects. No network meta-analysis (NMA) analyzes the adverse events of antifibrotic drugs for NAFLD. This NMA aimed to systematically compare the drug-related side effects when using different pharmacological agents for the treatment of liver fibrosis in NAFLD. PubMed, EMBASE, Web of Science and Cochrane Library were systematically searched to select related studies published in English from the database inception until 30 June 2022. We conducted Bayesian fixed-effects NMA using data from randomized controlled trials (RCTs) to derive relative risks (RRs). The surface under the cumulative ranking (SUCRA) probabilities was used to assess ranking. A total of 26 RCTs with 19 interventions met the inclusion criteria. SUCRA analysis suggested that the lanifibranor group had the highest risk of diarrhea (SUCRA, 94), whereas the liraglutide group had the highest risk of constipation (SUCRA, 92.9). The semaglutide group showed the highest incidence of nausea (SUCRA, 81.2) and abdominal pain (SUCRA, 90.5), respectively. The cenicriviroc group showed the highest risk in the incidence of fatigue (SUCRA, 82.4). The MSDC-0602K group had the highest risk of headache (SUCRA, 76.4), whereas the obeticholic acid group had the highest risk of pruritus (SUCRA, 80.1). The risk of side effects significantly varied among different pharmacologic regimens, and evidence showed that lanifibranor, liraglutide, semaglutide, cenicriviroc, MSDC-0602K and obeticholic acid were the pharmacological interventions with the highest risk in patients with NAFLD. This study may guide clinicians and support further research.
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Wiering L, Tacke F. Treating inflammation to combat non-alcoholic fatty liver disease. J Endocrinol 2023; 256:JOE-22-0194. [PMID: 36259984 DOI: 10.1530/joe-22-0194] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) with its more progressive form non-alcoholic steatohepatitis (NASH) has become the most common chronic liver disease, thereby representing a great burden for patients and healthcare systems. Specific pharmacological therapies for NAFLD are still missing. Inflammation is an important driver in the pathogenesis of NASH, and the mechanisms underlying inflammation in NAFLD represent possible therapeutic targets. In NASH, various intra- and extrahepatic triggers involved in the metabolic injury typically lead to the activation of different immune cells. This includes hepatic Kupffer cells, i.e. liver-resident macrophages, which can adopt an inflammatory phenotype and activate other immune cells by releasing inflammatory cytokines. As inflammation progresses, Kupffer cells are increasingly replaced by monocyte-derived macrophages with a distinct lipid-associated and scar-associated phenotype. Many other immune cells, including neutrophils, T lymphocytes - such as auto-aggressive cytotoxic as well as regulatory T cells - and innate lymphoid cells balance the progression and regression of inflammation and subsequent fibrosis. The detailed understanding of inflammatory cell subsets and their activation pathways prompted preclinical and clinical exploration of potential targets in NAFLD/NASH. These approaches to target inflammation in NASH include inhibition of immune cell recruitment via chemokine receptors (e.g. cenicriviroc), neutralization of CD44 or galectin-3 as well as agonism to nuclear factors like peroxisome proliferator-activated receptors and farnesoid X receptor that interfere with the activation of immune cells. As some of these approaches did not demonstrate convincing efficacy as monotherapies, a rational and personalized combination of therapeutic interventions may be needed for the near future.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
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Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
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Elhini SH, Wahsh EA, Elberry AA, El Ameen NF, Abdelfadil Saedii A, Refaie SM, Elsayed AA, Rabea HM. The Impact of an SGLT2 Inhibitor versus Ursodeoxycholic Acid on Liver Steatosis in Diabetic Patients. Pharmaceuticals (Basel) 2022; 15:ph15121516. [PMID: 36558967 PMCID: PMC9786599 DOI: 10.3390/ph15121516] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/23/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is related to metabolic syndrome via insulin resistance, where preventing disease progression is crucial in the management process. The study included 240 NAFLD patients with type 2 diabetes who were randomly allocated into empagliflozin 25 mg (EMPA group), ursodeoxycholic acid 250 mg (UDCA group), or the control group (placebo). The study outcomes included: changes in liver fat content (LFC; %) (utilizing the Dixon-based MRI-PDFF approach), liver enzymes, lipid and glycemic profiles, FIB-4 index, and non-alcoholic fatty liver score (NFS). All endpoints were assessed at baseline and after 6 months. EMPA outperformed UDCA and placebo in decreasing LFC (−8.73% vs. −5.71% vs. −1.99%; p < 0.0001). In post-treatment ultrasound images and MRI-PDFF calculations, more patients had normal fatty liver grade (no steatosis or LFC < 6.5%) with EMPA compared to UDCA. EMPA and UDCA showed significant regression in the FIB-4 index (−0.34 vs. −0.55; p = 0.011) and NFS scores (−1.00 vs. −1.11; p = 0.392), respectively. UDCA achieved higher reductions in insulin resistance than EMPA (p = 0.03); however, only EMPA significantly increased beta-cell function (54.20; p = 0.03). When exploring the differences between the two drugs, EMPA was better in decreasing LFC (%), while UDCA achieved higher reductions in liver fibrosis scores. Both showed a similar safety profile in managing liver steatosis.
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Affiliation(s)
- Sahar H. Elhini
- Diabetes and Endocrinology Unit, Internal Medicine Department, Faculty of Medicine, Minia University, Minia 61111, Egypt
| | - Engy A. Wahsh
- Clinical Pharmacy Department, Faculty of Pharmacy, October 6 University, Giza 12525, Egypt
| | - Ahmed A. Elberry
- Clinical Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62551, Egypt
- Department of Pharmacy Practice, Pharmacy Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
| | - Nadia F. El Ameen
- Radiology Department, Faculty of Medicine, Minia University, Minia 61111, Egypt
| | | | - Shereen Mahmoud Refaie
- Department of Biomedical Sciences, College of Medicine, King Faisal University, Hofuf 31982, Saudi Arabia
| | - Asmaa A. Elsayed
- Clinical Pharmacy Department, Faculty of Pharmacy, Sohag University, Sohag 82511, Egypt
- Correspondence:
| | - Hoda M. Rabea
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62551, Egypt
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Shedding light on non-alcoholic fatty liver disease: Pathogenesis, molecular mechanisms, models, and emerging therapeutics. Life Sci 2022; 312:121185. [PMID: 36375569 DOI: 10.1016/j.lfs.2022.121185] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder globally impacting an estimated 25% of the population associated with severe consequences such as cirrhosis, hepatocellular carcinoma (HCC), and overall mortality. Fatty liver disease is triggered through multiple pathways, but the most prominent cause is either diabetes or obesity, or a combination of both. Therefore, hepatic glucose, insulin and fatty acid signaling becomes a dire need to understand which is well elaborated in this review. This review summarizes the popular two-hit pathogenesis of NAFLD, the molecular mechanisms underlying hepatic insulin resistance. As fatty liver disease gets advanced, it requires in-vitro as well as in-vivo models closer to disease progression in humans for better understanding the pathological state and identifying a novel therapeutic target. This review summarizes in-vitro (2D cell-culture/co-culture, 3D spheroid/organoid/liver-on-a-chip) models as well as in-vivo (genetically/dietary/chemically induced fatty liver disease) research models. Fatty liver disease research has gathered lots of attention recently since there is no FDA approved therapy available so far. However, there have been numerous promising targets to treat fatty liver disease including potential therapeutic targets under clinical trials are listed in this review.
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Yan M, Man S, Ma L, Gao W. Comprehensive molecular mechanisms and clinical therapy in nonalcoholic steatohepatitis: An overview and current perspectives. Metabolism 2022; 134:155264. [PMID: 35810782 DOI: 10.1016/j.metabol.2022.155264] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/28/2022] [Accepted: 07/04/2022] [Indexed: 10/17/2022]
Abstract
Our understanding of nonalcoholic steatohepatitis (NASH) pathophysiology continues to advance rapidly. Given the complexity of the pathogenesis of NASH, the field has moved from describing the single pathogenesis of NASH to deeply phenotyping with a description of the multi-mechanism and multi-target pathogenesis that includes glucose, lipid and cholesterol metabolism, fibrotic progression, inflammation, immune reaction and apoptosis. To make the picture more complex, the pathogenesis of NASH involves pathological connections between the liver and several organs such as the adipose, pancreas, kidney and gut. Numerous pharmacologic candidates have been tested in clinical trials and have generated some positive results. Importantly, PPAR as triglyceride synthesis inhibitor and FXR as bile acids synthesis inhibitor have displayed beneficial effects on candidates for lipid and cholesterol metabolism. Although the efficacy of these drugs has been affirmed, serious side effects hinder their further development. It is a particularly important task to carry out the in-depth long-term research. Additionally, drug combination increases response rate and reduces side effects of a single drug. Mastering the advantages and limitations of clinical candidate drugs and continuous improvement and innovation are necessary to formulate a new strategy for the future treatment of NASH.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin 300072, China.
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Sato S, Kamata Y, Kessoku T, Shimizu T, Kobayashi T, Kurihashi T, Takashiba S, Hatanaka K, Hamada N, Kodama T, Higurashi T, Taguri M, Yoneda M, Usuda H, Wada K, Nakajima A, Morozumi T, Minabe M. A cross-sectional study assessing the relationship between non-alcoholic fatty liver disease and periodontal disease. Sci Rep 2022; 12:13621. [PMID: 35948584 PMCID: PMC9365789 DOI: 10.1038/s41598-022-17917-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/02/2022] [Indexed: 11/09/2022] Open
Abstract
The risk factors for non-alcoholic fatty liver disease (NAFLD) progression are not completely known. Porphyromonas gingivalis infection is a risk factor for systemic diseases. We investigated the association of P. gingivalis infection with the risk of non-alcoholic steatohepatitis progression. Here, hematological tests, periodontal examination, and saliva collection were performed for 164 patients with NAFLD. P. gingivalis was identified in saliva using polymerase chain reaction. Hepatic steatosis and stiffness were evaluated using vibration-controlled transient elastography (VCTE) and magnetic resonance imaging. In patients with NAFLD, P. gingivalis positivity (P. gingivalis ratio ≥ 0.01%) in saliva correlated with liver stiffness determined using magnetic resonance elastography (MRE; p < 0.0001). A P. gingivalis ratio of 0.01% corresponds to 100,000 cells/mL and indicates the proportion of P. gingivalis in the total number of bacteria in the oral cavity. Patients with NAFLD and advanced fibrosis on MRE showed significantly elevated endotoxin activity; those who had > 10 periodontal pockets with depths ≥ 4 mm had significantly increased hepatic stiffness on both VCTE and MRE.
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Affiliation(s)
- Satsuki Sato
- Department of Highly Advanced Oral Stomatology, Yokohama Clinic, Kanagawa Dental University, 3-31-6 Tsuruya-cho, Kanagawa, Yokohama, Kanagawa, 221-0835, Japan
| | - Yohei Kamata
- Department of Highly Advanced Oral Stomatology, Yokohama Clinic, Kanagawa Dental University, 3-31-6 Tsuruya-cho, Kanagawa, Yokohama, Kanagawa, 221-0835, Japan.
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Tomoko Shimizu
- Department of Highly Advanced Oral Stomatology, Yokohama Clinic, Kanagawa Dental University, 3-31-6 Tsuruya-cho, Kanagawa, Yokohama, Kanagawa, 221-0835, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Takeo Kurihashi
- Department of Internal Medicine, Yokohama Clinic, Kanagawa Dental University, 3-31-6 Tsuruya-cho, Kanagawa, Yokohama, Kanagawa, 221-0835, Japan
| | - Shogo Takashiba
- Department of Pathophysiology-Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Kazu Hatanaka
- Department of Pathophysiology-Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Nobushiro Hamada
- Division of Microbiology, Department of Oral Science Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa, 238-8580, Japan
| | - Toshiro Kodama
- Department of Implantology and Periodontology, Graduate School of Dentistry, Kanagawa Dental University, 3-31-6 Tsuruya-cho, Kanagawa, Yokohama, Kanagawa, 221-0835, Japan
| | - Takuma Higurashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Masataka Taguri
- Department of Biostatistics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Haruki Usuda
- Department of Pharmacology, Shimane University School of Medicine, 89-1 Enya-cho Izumo, Shimane, 693-0581, Japan
| | - Koichiro Wada
- Department of Pharmacology, Shimane University School of Medicine, 89-1 Enya-cho Izumo, Shimane, 693-0581, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Toshiya Morozumi
- Division of Periodontology, Department of Oral Interdisciplinary Medicine, Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa, 238-8580, Japan
| | - Masato Minabe
- Division of Periodontology, Department of Oral Interdisciplinary Medicine, Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, Kanagawa, 238-8580, Japan
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Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, Cohen DE, Horton JD, Pressman GS, Toth PP. Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2022; 42:e168-e185. [PMID: 35418240 DOI: 10.1161/atv.0000000000000153] [Citation(s) in RCA: 317] [Impact Index Per Article: 105.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is believed to affect >25% of adults worldwide. Unless specific testing is done to identify NAFLD, the condition is typically silent until advanced and potentially irreversible liver impairment occurs. For this reason, the majority of patients with NAFLD are unaware of having this serious condition. Hepatic complications from NAFLD include nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. In addition to these serious complications, NAFLD is a risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. Accordingly, the purpose of this scientific statement is to review the underlying risk factors and pathophysiology of NAFLD, the associations with atherosclerotic cardiovascular disease, diagnostic and screening strategies, and potential interventions.
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Ng CH, Xiao J, Lim WH, Chin YH, Yong JN, Tan DJH, Tay P, Syn N, Foo R, Chan M, Chew N, Tan EX, Huang DQ, Dan YY, Tamaki N, Siddiqui MS, Sanyal AJ, Loomba R, Noureddin M, Muthiah MD. Placebo effect on progression and regression in NASH: Evidence from a meta-analysis. Hepatology 2022; 75:1647-1661. [PMID: 34990037 DOI: 10.1002/hep.32315] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/26/2021] [Accepted: 01/03/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH. METHODS A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. RESULTS This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients. CONCLUSIONS Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.
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Affiliation(s)
- Cheng Han Ng
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Jieling Xiao
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Wen Hui Lim
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Yip Han Chin
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Jie Ning Yong
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Phoebe Tay
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Nicholas Syn
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
| | - Roger Foo
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of CardiologyNational University Heart CentreNational University HospitalSingapore
| | - Mark Chan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of CardiologyNational University Heart CentreNational University HospitalSingapore
| | - Nicholas Chew
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of CardiologyNational University Heart CentreNational University HospitalSingapore
| | - Eunice Xx Tan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
| | - Daniel Q Huang
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
| | - Yock Young Dan
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
| | - Nobuharu Tamaki
- NAFLD Research CenterDivision of Gastroenterology and HepatologyDepartment of MedicineUniversity of California at San DiegoSan DiegoCaliforniaUSA
| | - Mohammad Shadab Siddiqui
- Cedars-Sinai Fatty Liver ProgramDivision of Digestive and Liver DiseasesDepartment of MedicineComprehensive Transplant CenterCedars-Sinai Medical CentreLos AngelesCaliforniaUSA
| | - Arun J Sanyal
- Department of Internal MedicineDivision of Gastroenterology, Hepatology and NutritionVirginia Commonwealth UniversityRichmondVirginiaUSA
- Division of Gastroenterology, Hepatology and NutritionDepartment of Internal MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Rohit Loomba
- NAFLD Research CenterDivision of Gastroenterology and HepatologyDepartment of MedicineUniversity of California at San DiegoSan DiegoCaliforniaUSA
| | - Mazen Noureddin
- Cedars-Sinai Fatty Liver ProgramDivision of Digestive and Liver DiseasesDepartment of MedicineComprehensive Transplant CenterCedars-Sinai Medical CentreLos AngelesCaliforniaUSA
| | - Mark D Muthiah
- Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and HepatologyDepartment of MedicineNational University HospitalSingaporeSingapore
- National University Center for Organ TransplantationNational University Health SystemSingapore
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A Molecular Insight into the Role of Antioxidants in Nonalcoholic Fatty Liver Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9233650. [PMID: 35602098 PMCID: PMC9117022 DOI: 10.1155/2022/9233650] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines fat accumulation in the liver, and it is commonly associated with metabolic syndromes like diabetes and obesity. Progressive NAFLD leads to nonalcoholic steatohepatitis (NASH) and ultimately causes cirrhosis and hepatocellular carcinoma, and NASH is currently a frequent cause of liver transplantation. Oxidative stress is often contributed to the progression of NAFLD, and hence, antioxidants such as silymarin, silybin, or silibinin, pentoxifylline, resveratrol, and vitamins A, C, and E are used in clinical trials against NAFLD. Silymarin induces the peroxisome proliferator-activated receptor α (PPARα), a fatty acid sensor, which promotes the transcription of genes that are required for the enzymes involved in lipid oxidation in hepatocytes. Silybin inhibits sterol regulatory element-binding protein 1 and carbohydrate response element-binding protein to downregulate the expression of genes responsible for de novo lipogenesis by activating AMP-activated protein kinase phosphorylation. Pentoxifylline inhibits TNF-α expression and endoplasmic reticulum stress-mediated inflammatory nuclear factor kappa B (NF-κB) activation. Thus, it prevents NAFLD to NASH progression. Resveratrol inhibits methylation at Nrf-2 promoters and NF-κB activity via SIRT1 activation in NAFLD conditions. However, clinically, resveratrol has not shown promising beneficial effects. Vitamin C is beneficial in NAFLD patients. Vitamin E is not effectively regressing hepatic fibrosis. Hence, its combination with antifibrotic agents is used as an adjuvant to produce a synergistic antifibrotic effect. However, to date, none of these antioxidants have been used as a definite therapeutic agent in NAFLD patients. Further, these antioxidants should be studied in NAFLD patients with larger populations and multiple endpoints in the future.
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Shi YW, Fan JG. Current status and challenges in the drug treatment for fibrotic nonalcoholic steatohepatitis. Acta Pharmacol Sin 2022; 43:1191-1199. [PMID: 34907360 PMCID: PMC9061812 DOI: 10.1038/s41401-021-00822-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022]
Abstract
Currently, nonalcoholic steatohepatitis (NASH) is one of the most common forms of chronic hepatitis, increasing the burden of health care worldwide. In patients with NASH, the fibrosis stage is the most predictive factor of long-term events. However, there are still no drugs approved by the Food and Drug Administration of the United States for treating biopsy-proven NASH with fibrosis or cirrhosis. Although some novel drugs have shown promise in preclinical studies and led to improvement in terms of hepatic fat content and steatohepatitis, a considerable proportion of them have failed to achieve histological endpoints of fibrosis improvement. Due to the large number of NASH patients and adverse clinical outcomes, the search for novel drugs is necessary. In this review, we discuss current definitions for the evaluation of treatment efficacy in fibrosis improvement for NASH patients, and we summarize novel agents in the pipeline from different mechanisms and phases of trial. We also critically review the challenges we face in the development of novel agents for fibrotic NASH and NASH cirrhosis.
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Affiliation(s)
- Yi-Wen Shi
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China.
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Li F, Jiang M, Ma M, Chen X, Zhang Y, Zhang Y, Yu Y, Cui Y, Chen J, Zhao H, Sun Z, Dong D. Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice. Acta Pharm Sin B 2022; 12:1322-1338. [PMID: 35530137 PMCID: PMC9069401 DOI: 10.1016/j.apsb.2021.09.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/16/2021] [Accepted: 08/27/2021] [Indexed: 01/16/2023] Open
Abstract
Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis. It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis. Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile. We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in HepG2 cells. Gavage administration of nitazoxanide inhibited high-fat diet (HFD)-induced increases of liver weight, blood and liver lipids, and ameliorated HFD-induced renal lipid accumulation in hamsters. Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers. In the hamsters with pre-existing hyperlipidemia and hepatic steatosis, nitazoxanide also showed therapeutic effect. Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet (WD)-induced hepatic steatosis in Apoe -/- mice. The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.
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Affiliation(s)
- Fengfeng Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Man Jiang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Minghui Ma
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Xuyang Chen
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Yidan Zhang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Yixin Zhang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Yuanyuan Yu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Yunfeng Cui
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Jiahui Chen
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Hui Zhao
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
| | - Zhijie Sun
- Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China
| | - Deli Dong
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China
- Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China
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A Network Pharmacology Study on the Active Components and Targets of the Radix Ginseng and Radix Bupleuri Herb Pair for Treating Nonalcoholic Fatty Liver Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1638740. [PMID: 35178098 PMCID: PMC8846978 DOI: 10.1155/2022/1638740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To explore the potential active components and corresponding target herb pairs of Radix Ginseng (Renshen) and Radix Bupleuri (Chaihu) in the treatment of nonalcoholic fatty liver disease (NAFLD) through network pharmacology and in vitro experiments. METHODS The active components and potential targets of the herb pair of Renshen and Chaihu were screened through a network database system, and Venn analysis was performed with the obtained NAFLD targets. The intersecting targets were analysed for gene ontology (GO) functions and Kyoto Encyclopedia of Genes and Genome (KEGG) pathways, and a protein-protein interaction (PPI) network was generated. Cytoscape software was used to construct active component-target networks of the Renshen and Chaihu herb pair. Free fatty acids were added to the HepG2 cell line to create high-fat models that were treated with different concentrations of stigmasterol. The effect of stigmasterol on the lipid metabolism in HepG2 cells and PPARγ-knockdown cells was determined by oil red O staining, Nile red staining, and TG level. PPARγ and UCP-1 mRNA, and protein expression levels were detected by qRT-PCR and Western blot analyses, respectively. RESULTS Twenty active components obtained from the Renshen and Chaihu herb pair were identified. The herb pair active component-target network showed that both Renshen and Chaihu contained stigmasterol and kaempferol as active components. The PPI network comprised 63 protein nodes. GO enrichment analysis and KEGG pathway enrichment analysis showed that the targets were mainly involved in lipid metabolism. Eight core targets were identified: AKT1, PPARG, MAPK3, TNF, TP53, SIRT1, STAT3, and PPARA. In vitro experiments demonstrated that stigmasterol reduced lipid accumulation and TG levels in HepG2 cells, and the mechanism may have been related to the activation of the PPARγ-UCP-1 signalling pathway. CONCLUSION This study preliminarily illustrated the potential components and corresponding core targets of the Renshen and Chaihu herb pair in treating NAFLD. The effect of stigmasterol on the PPARγ-UCP-1 signalling pathway in enhancing lipid metabolism may represent one of the mechanisms of the Renshen and Chaihu herb pair in the treatment of NAFLD. The results provide new evidence and research insights to reveal the roles of Renshen and Chaihu in the management of NAFLD.
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Xu Y, Chen J, Jiang W, Zhao Y, Yang C, Wu Y, Li Q, Zhu C. Multiplexing Nanodrug Ameliorates Liver Fibrosis via ROS Elimination and Inflammation Suppression. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2102848. [PMID: 34758098 DOI: 10.1002/smll.202102848] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/31/2021] [Indexed: 06/13/2023]
Abstract
Liver fibrosis is the leading risk factor for hepatocellular carcinoma. Both oxidative stress and inflammation promote the progression of liver fibrosis, but existing therapeutic strategies tend to focus solely on one issue. Additionally, targeting of pathological microstructures is often neglected. Herein, an esterase-responsive carbon quantum dot-dexamethasone (CD-Dex) is developed for liver fibrosis therapy to simultaneously target pathological microstructures, scavenge reactive oxygen species (ROS), and suppress inflammation. Hepatocyte-targeting CD-Dex can efficiently eliminate the intrahepatic ROS, thereby inhibiting the activation of Kupffer cells, preventing further inflammation progression. Moreover, released dexamethasone (Dex) also suppresses inflammatory response by inhibiting the infiltration of inflammatory cells. Antifibrotic experiments demonstrate that CD-Dex significantly alleviates liver injury and collagen deposition, consequently preventing the progression of liver fibrosis. Taken together, these findings suggest that via ROS elimination and inflammation suppression, the newly developed multiplexing nanodrug exhibits great potential in liver fibrosis therapy.
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Affiliation(s)
- Youcui Xu
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, Intelligent Nanomedicine Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, P. R. China
| | - Jing Chen
- School of Life Sciences, Hefei Normal University, Hefei, 230601, P. R. China
| | - Wei Jiang
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, P. R. China
| | - Yangyang Zhao
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, P. R. China
| | - Chen Yang
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, P. R. China
| | - Yi Wu
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, Intelligent Nanomedicine Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, P. R. China
| | - Qianming Li
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, Intelligent Nanomedicine Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, P. R. China
| | - Chen Zhu
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China, Intelligent Nanomedicine Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, P. R. China
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Lee D, Trinh TA, Shin MS, Kang KS. Adipose tissue. RECENT ADVANCEMENTS IN MICROBIAL DIVERSITY 2022:209-228. [DOI: 10.1016/b978-0-12-822368-0.00009-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yang H, Yue GGL, Leung PC, Wong CK, Lau CBS. A review on the molecular mechanisms, the therapeutic treatment including the potential of herbs and natural products, and target prediction of obesity-associated colorectal cancer. Pharmacol Res 2021; 175:106031. [PMID: 34896542 DOI: 10.1016/j.phrs.2021.106031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. Obesity has been proven to be closely related to colorectal carcinogenesis. This review summarized the potential underlying mechanisms linking obesity to CRC in different aspects, including energy metabolism, inflammation, activities of adipokines and hormones. Furthermore, the potential therapeutic targets of obesity-associated CRC were predicted using network-based target analysis, with total predicted pathways not only containing previously reported pathways, but also putative signaling pathways pending for investigation. In addition, the current conventional therapeutic treatment options, plus the potential use of herbs and natural products in the management of obesity-associated CRC were also discussed. Taken together, the aim of this review article is to provide strong theoretical basis for future drug development, particularly herbs and natural products, in obesity-associated CRC.
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Affiliation(s)
- Huihai Yang
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Grace Gar Lee Yue
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Ping Chung Leung
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chun Kwok Wong
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Clara Bik San Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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The New Therapeutic Approaches in the Treatment of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:ijms222413219. [PMID: 34948020 PMCID: PMC8704688 DOI: 10.3390/ijms222413219] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/25/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease which is characterized by extremely complex pathogenetic mechanisms and multifactorial etiology. Some of the many pathophysiological mechanisms involved in the development of NAFLD include oxidative stress, impaired mitochondrial metabolism, inflammation, gut microbiota, and interaction between the brain-liver-axis and the regulation of hepatic lipid metabolism. The new therapeutic approaches in the treatment of NAFLD are targeting some of these milestones along the pathophysiological pathway and include drugs like agonists of peroxisome proliferator-activated receptors (PPARs), glucagon-like peptide-1 (GLP-1) agonists, sodium/glucose transport protein 2 (SGLT2) inhibitors, farnesoid X receptor (FXR) agonists, probiotics, and symbiotics. Further efforts in biomedical sciences should focus on the investigation of the relationship between the microbiome, liver metabolism, and response to inflammation, systemic consequences of metabolic syndrome.
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Febbraio MA, Karin M. "Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab 2021; 33:2316-2328. [PMID: 34619076 PMCID: PMC8665123 DOI: 10.1016/j.cmet.2021.09.004] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/30/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023]
Abstract
Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.
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Affiliation(s)
- Mark A Febbraio
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
| | - Michael Karin
- Department of Pharmacology, School of Medicine, University of California, San Diego, San Diego, CA, USA.
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Khanam A, Kottilil S. Acute-on-Chronic Liver Failure: Pathophysiological Mechanisms and Management. Front Med (Lausanne) 2021; 8:752875. [PMID: 34820395 PMCID: PMC8606418 DOI: 10.3389/fmed.2021.752875] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/07/2021] [Indexed: 12/21/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a multifaceted condition with poor treatment options and high short-term mortality. ACLF can develop in patients with or without liver cirrhosis, where patients with decompensated cirrhosis display a higher risk of short-term mortality. Pathophysiological mechanisms include systemic inflammation due to bacterial and fungal infections and acute hepatic insult with drug, alcohol, and viral hepatitis. Cryptogenic factors also contribute to the development of ACLF. The clinical outcome of patients with ACLF gets further complicated by the occurrence of variceal hemorrhage, hepatorenal syndrome, hepatic encephalopathy, and systemic immune dysfunction. Regardless of the better understanding of pathophysiological mechanisms, no specific and definitive treatment is available except for liver transplantation. The recent approach of regenerative medicine using mesenchymal stem cells (MSCs) could be advantageous for the treatment of ACLF as these cells can downregulate inflammatory response by inducing antiinflammatory events and prevent hepatic damage and fibrosis by inhibiting hepatic stellate cell activation and collagen synthesis. Moreover, MSCs are involved in tissue repair by the process of liver regeneration. Considering the broad therapeutic potential of MSCs, it can serve as an alternative treatment to liver transplant in the near future, if promising results are achieved.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
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Lin W, Jin Y, Hu X, Huang E, Zhu Q. AMPK/PGC-1α/GLUT4-Mediated Effect of Icariin on Hyperlipidemia-Induced Non-Alcoholic Fatty Liver Disease and Lipid Metabolism Disorder in Mice. BIOCHEMISTRY. BIOKHIMIIA 2021; 86:1407-1417. [PMID: 34906049 DOI: 10.1134/s0006297921110055] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 07/21/2021] [Accepted: 10/22/2021] [Indexed: 06/14/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Therapeutic activity of icariin, a major bioactive component of Epimedii Herba, in NAFLD is still unknown. Herein, the C57BL/6J mice were fed with a high-fat diet for 16 weeks to establish a NAFLD model. Mice were assigned to five groups: control group, NAFLD group, and icariin treatment groups. Effects of icariin on blood indices, glucose tolerance, insulin sensitivity, histopathological morphology, cell apoptosis, lipid accumulation, and AMPK signaling were analyzed. In addition, another cohort of mice were assigned to five groups: control group, NAFLD group, dorsomorphin treatment group, icariin treatment group, and dorsomorphin + icariin treatment group. Expression of proteins in liver tissues associated with AMPK signaling, and levels of ALT and AST were evaluated. Icariin attenuated the NAFLD-induced increase of the TG, TC, LDL-C, ALT, AST levels. HDL-C levels were affected neither by NAFLD nor by icariin. Furthermore, icariin treatment (100-200 mg/kg) counteracted the NAFLD-reduced glucose tolerance and insulin sensitivity and modulated histopathological changes, cell apoptosis, and lipid accumulation in liver tissues. Additionally, icariin mitigated the NAFLD-induced up-regulation of the cleaved caspase 3/9, SREBP-1c, and DGAT-2 levels, and enhanced the expression level of CPT-1, p-ACC/ACC, AMPKα1, PGC-1α, and GLUT4. Effects of icariin on the AMPK signaling and levels of AST and ALT could be reversed by AMPK inhibitor, dorsomorphin. This paper investigates the glucose-reducing and lipid-lowering effects of icariin in NAFLD. Moreover, icariin might function through activating the AMPKα1/PGC-1α/GLTU4 pathway.
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Affiliation(s)
- Wei Lin
- Department of General Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Yin Jin
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Xiang Hu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Erjiong Huang
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Qihan Zhu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Lu S, Wang Y, Liu J. TNF-α signaling in non-alcoholic steatohepatitis and targeted therapies. J Genet Genomics 2021; 49:269-278. [PMID: 34757037 DOI: 10.1016/j.jgg.2021.09.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/07/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), is featured by significantly elevated levels of various pro-inflammatory cytokines. Among numerous pro-inflammatory factors that contribute to NASH pathogenesis, the secreted protein, tumor necrosis factor-alpha (TNF-α) plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target. In this review, we will first systematically describe the preclinical studies on the biochemical function of TNF-α and its intracellular downstream signaling mechanisms through its receptors. Moreover, we extensively discuss its functions in regulating inflammation, cell death, and fibrosis of liver cells in the pathogenesis of NASH, and the molecular mechanism that TNF-α expression was regulated by NF-κB and other upstream master regulators during NASH progression. As TNF-α is one of the causal factors that remarkably contributes to NASH progression, combination of therapeutic modalities, including TNF-α-based therapies may lead to resolution of NASH via multiple pathways and thus generate clinical benefits. For translational studies, we summarize recent advances in strategies targeting TNF-α and its signaling pathway, which paves the way for potential therapeutic treatments for NASH in future.
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Affiliation(s)
- Sijia Lu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yibing Wang
- School of Kinesiology, Shanghai University of Sports, Shanghai 200438, China.
| | - Junli Liu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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Majzoub AM, Nayfeh T, Barnard A, Munaganuru N, Dave S, Singh S, Murad MH, Loomba R. Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. Aliment Pharmacol Ther 2021; 54:880-889. [PMID: 34435378 PMCID: PMC8711247 DOI: 10.1111/apt.16583] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/02/2021] [Accepted: 08/14/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. There is a major need to understand the efficacy of different pharmacological agents for the treatment of NASH. AIM To assess the relative rank-order of different pharmacological interventions in fibrosis improvement and NASH resolution. METHODS A comprehensive search of several databases was conducted by an experienced librarian. We included randomised controlled-trials (RCTs) comparing pharmacological interventions in patients with biopsy-proven NASH. The primary outcome was ≥1 stage improvement in fibrosis. The secondary outcome was NASH resolution. RESULTS A total of 26 RCTs with 23 interventions met the eligibility criteria. Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively. For NASH resolution, semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively. Lanifibranor, obeticholic acid, pioglitazone and vitamin E were significantly better than placebo in achieving ≥1 stage of fibrosis improvement. Conversely, semaglutide, liraglutide, vitamine E plus pioglitazone, pioglitazone, lanifibranor and obeticholic acid were significantly better than placebo in achieving NASH resolution. CONCLUSION These data provide relative rank-order efficacy of various NASH therapies in terms of their improvements in liver fibrosis and NASH resolution. Therapies that have been shown to improve NASH resolution may be combined with therapies that have an antifibrotic effect to further boost treatment response rate in future.
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Affiliation(s)
- Abdul M. Majzoub
- Division of Internal Medicine, Conemaugh Memorial Medical Center, Johnstown, Pennsylvania, US
| | - Tarek Nayfeh
- Evidence-Based Practice Center, Mayo Clinic, Rochester, Minnesota, US
| | - Abbey Barnard
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, California, US
| | - Nagambika Munaganuru
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, California, US
| | - Shravan Dave
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, California, US
| | - Siddharth Singh
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, California, US
| | - M. Hassan Murad
- Evidence-Based Practice Center, Mayo Clinic, Rochester, Minnesota, US
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, California, US
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Kumar V, Xin X, Ma J, Tan C, Osna N, Mahato RI. Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis. Adv Drug Deliv Rev 2021; 176:113888. [PMID: 34314787 PMCID: PMC8440458 DOI: 10.1016/j.addr.2021.113888] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/12/2021] [Accepted: 07/18/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress. Free fatty acid (FFA) accumulation in the liver exerts oxidative and endoplasmic reticulum (ER) stresses. Hepatocyte injury induces release of inflammatory cytokines from Kupffer cells (KCs), which are responsible for activating hepatic stellate cells (HSCs). In this review, we will discuss various molecular targets for treating chronic liver diseases, including homeostasis of FFA, lipid metabolism, and decrease in hepatocyte apoptosis, role of growth factors, and regulation of epithelial-to-mesenchymal transition (EMT) and HSC activation. This review will also critically assess different strategies to enhance drug delivery to different cell types. Targeting nanocarriers to specific liver cell types have the potential to increase efficacy and suppress off-target effects.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jingyi Ma
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
| | - Natalia Osna
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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