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Castanho Martins M, Dixon ED, Lupo G, Claudel T, Trauner M, Rombouts K. Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk. Liver Int 2025; 45:e16117. [PMID: 39394864 DOI: 10.1111/liv.16117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
AIMS Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. METHODS We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. RESULTS Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. CONCLUSIONS The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
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Affiliation(s)
- Maria Castanho Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Giulia Lupo
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
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Gao F, Guan C, Cheng N, Liu Y, Wu Y, Shi B, Huang J, Li S, Tong Y, Gao Y, Liu J, Wang C, Zhang C. Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on open-ring steroid scaffold. Eur J Med Chem 2025; 286:117250. [PMID: 39827488 DOI: 10.1016/j.ejmech.2025.117250] [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: 11/04/2024] [Revised: 01/05/2025] [Accepted: 01/05/2025] [Indexed: 01/22/2025]
Abstract
Vitamin D receptor (VDR) has emerged as a crucial target for the treatment of hepatic fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) components leading to impaired liver function. Activation of VDR has been shown to inhibit the transformation of hepatic stellate cells (HSCs), which play a key role in the development of liver fibrosis, thus reducing ECM production. In this study, a series of 37 non-steroidal VDR agonists with novel scaffold were designed and synthesized utilizing the scaffold hopping strategy. Over one-third of these compounds demonstrated significant VDR affinity and agonistic activity. Among them, compound E15 exhibited the highest VDR agonistic activity, showing promising results in vitro by effectively inhibiting HSC activation. Further in vivo assessments of E15 in a carbon tetrachloride-induced murine model of liver fibrosis demonstrated significant anti-fibrotic activity. Histological analyses revealed a reduction in lesions, inflammatory cell infiltration, and collagen deposition. Concurrently, blood biochemical assays indicated decreased hepatic fibrosis markers and improved serum liver function indices. Notably, E15 achieved these therapeutic effects without inducing hypercalcemia, a common adverse effect associated with VDR agonists such as calcipotriol. These findings underscore the potential of E15 as a potent and safe therapeutic agent for the treatment of liver fibrosis.
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Affiliation(s)
- Fei Gao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Chun Guan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Nuo Cheng
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yichen Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yue Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Bingyue Shi
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Jiayi Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Sitong Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yu Tong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yi Gao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Jiayi Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Cong Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China.
| | - Can Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China.
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Sun Y, Yuan X, Hu Z, Li Y. Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution. Biochem Pharmacol 2025; 232:116730. [PMID: 39710274 DOI: 10.1016/j.bcp.2024.116730] [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: 06/10/2024] [Revised: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.
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Affiliation(s)
- Yaxin Sun
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyan Yuan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhenhua Hu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; Department of Health and Nursing, Nanfang College of Sun Yat-sen University, Guangzhou, China.
| | - Yuanyuan Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China.
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4
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Chung SI, Liang L, Han H, Park KH, Lee JH, Park JW. Vitamin D Attenuates Non-Alcoholic Fatty Liver Disease in High-Fat Diet-Induced Obesity Murine Model. Yonsei Med J 2025; 66:75-86. [PMID: 39894040 PMCID: PMC11790407 DOI: 10.3349/ymj.2024.0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 07/15/2024] [Accepted: 08/09/2024] [Indexed: 02/04/2025] Open
Abstract
PURPOSE Obesity and metabolic syndrome are acknowledged as key factors contributing to the development of non-alcoholic fatty liver disease (NAFLD). Vitamin D (VitD) is a multifaceted secosteroid hormone known for its anti-fibrotic and anti-inflammatory properties, with its deficiency often linked to obesity. Our study aimed to investigate whether VitD supplementation could mitigate the liver pathology associated with NAFLD. MATERIALS AND METHODS The NAFLD model was developed by subjecting male C57BL/6 mice to a high-fat diet (HFD) for 14 weeks. These mice were supplemented with VitD through intraperitoneal injection at a dosage of 7 µg/kg, administered three times per week for 7 weeks. RESULTS HFD resulted in VitD deficiency, insulin resistance, and increased liver weight. It elevated serum levels of liver aminotransferases and triglyceride, ultimately leading to steatohepatitis with fibrosis. This model exhibited increased levels of transforming growth factor (TGF)-β1, pro-inflammatory cytokines, HNF4α transcription factors, reactive oxygen species (ROS), renin-angiotensin system activity, and epithelial-mesenchymal transitions (EMT) within the liver. Supplementation with VitD resulted in the recovery of liver weight, improvement in histologic features associated with steatohepatitis, and reduction in alanine aminotransferases and triglyceride levels induced by the HFD. Additionally, it mitigated the HFD-induced over-expressions of TGF-β1 and fibrosis-related genes, along with pro-inflammatory cytokines and ROS. Notably, no adverse effect was found due to VitD supplementation in this model. CONCLUSION VitD ameliorates steatohepatitis within obesity-induced NAFLD through its multifaceted pathways. VitD supplementation emerges as a potentially safe, cost-effective, and direct treatment approach for NAFLD patients dealing with obesity or metabolic dysfunction.
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Affiliation(s)
- Sook In Chung
- Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Lin Liang
- Graduate School of Medicine, Yonsei University, Seoul, Korea
| | - Heejae Han
- Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Hee Park
- Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Hyun Lee
- Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Jung-Won Park
- Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
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Zhao Y, Fan J, Wang J, Wan J, Ma H, Sha X, Wang H. 1α,25(OH)2D3 Regulates the TGF-β1/Samd Signaling Pathway Inhibition of Hepatic Stellate Cell Activation. Drug Res (Stuttg) 2025. [PMID: 39814037 DOI: 10.1055/a-2463-5530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
To investigate the effect of 1α,25(OH)2D3 on hepatic stellate cells and the mechanism of the TGF-β1/Smad signaling pathway.LX2 cells were treated with TGF-β1 and different concentrations of 1α,25(OH)2D3. Cell proliferation was assessed using the CCK8 assay to determine the optimal concentration of 1α,25(OH)2D3 activity. The cell cycle and apoptotic rates were evaluated using flow cytometry. The expressions of Samd2, Samd3, Samd4, and Samd7 was assessed by western blotting, whereas the expression of MMP1, MMP13, and TIMP-1 was detected by qPCR.Compared with the control group, the 1α,25(OH)2D3 group had a higher apoptotic rate of LX2 cells, the cell cycle was blocked from the G1 stage to the S stage, the expressions of Samd2, Samd7, MMP1, and MMP13 increased, while the expressions of Samd3, Samd4, and TIMP-1 decreased.1α,25(OH)2D3 inhibits hepatic stellate cell activation and exerts anti-hepatic fibrosis effects by downregulating the expression of Samd3, Samd4, TIMP-1 and upregulating the expression of Samd2, Samd4, MMP1, and MMP13.
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Affiliation(s)
- Yihan Zhao
- Xi'an Eighth Hospital, Xi'an, China
- Second Clinical College, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
| | | | - Jia Wang
- Xi'an Eighth Hospital, Xi'an, China
| | - Jie Wan
- Xi'an Eighth Hospital, Xi'an, China
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Marginean CM, Pirscoveanu D, Cazacu SM, Popescu MS, Marginean IC, Iacob GA, Popescu M. Non-Alcoholic Fatty Liver Disease, Awareness of a Diagnostic Challenge—A Clinician’s Perspective. GASTROENTEROLOGY INSIGHTS 2024; 15:1028-1053. [DOI: 10.3390/gastroent15040071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease globally. NAFLD is a complex pathology, considered to be the hepatic expression of metabolic syndrome (MetS). It is supposed to become the main indication for liver transplantation in the coming years and is estimated to affect 57.5–74.0% of obese people, 22.5% of children and 52.8% of obese children, with 50% of individuals with type 2 diabetes being diagnosed with NAFLD. Recent research has proved that an increase in adipose tissue insulin resistance index is an important marker of liver injury in patients with NAFLD. Despite being the main underlying cause of incidental liver damage and a growing worldwide health problem, NAFLD is mostly under-appreciated. Currently, NAFLD is considered a multifactorial disease, with various factors contributing to its pathogenesis, associated with insulin resistance and diabetes mellitus, but also with cardiovascular, kidney and endocrine disorders (polycystic ovary syndrome, hypothyroidism, growth hormone deficiency). Hepatitis B and hepatitis C, sleep apnea, inflammatory bowel diseases, cystic fibrosis, viral infections, autoimmune liver diseases and malnutrition are some other conditions in which NAFLD can be found. The aim of this review is to emphasize that, from the clinician’s perspective, NAFLD is an actual and valuable key diagnosis factor for multiple conditions; thus, efforts need to be made in order to increase recognition of the disease and its consequences. Although there is no global consensus, physicians should consider screening people who are at risk of NAFLD. A large dissemination of current concepts on NAFLD and an extensive collaboration between physicians, such as gastroenterologists, internists, cardiologists, diabetologists, nutritionists and endocrinologists, is equally needed to ensure we have the knowledge and resources to address this public health challenge.
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Affiliation(s)
- Cristina Maria Marginean
- Internal Medicine Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Denisa Pirscoveanu
- Neurology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Sergiu Marian Cazacu
- Research Center of Gastroenterology and Hepatology, Gastroenterology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marian Sorin Popescu
- Internal Medicine Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Endocrinology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Wang P, Li J, Ji M, Pan J, Cao Y, Kong Y, Zhu L, Li J, Li B, Chang L, Zhang Z. Vitamin D receptor attenuates carbon tetrachloride-induced liver fibrosis via downregulation of YAP. JOURNAL OF HAZARDOUS MATERIALS 2024; 478:135480. [PMID: 39146589 DOI: 10.1016/j.jhazmat.2024.135480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/02/2024] [Accepted: 08/08/2024] [Indexed: 08/17/2024]
Abstract
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl₄) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl4-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl4-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl4-induced hepatic fibrosis.
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Affiliation(s)
- Ping Wang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Jie Li
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Mintao Ji
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity. The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Jinjing Pan
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Yanmei Cao
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007, China
| | - Yulin Kong
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215007, China
| | - Jiafu Li
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Bingyan Li
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China.
| | - Lei Chang
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity. The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou 215123, China; Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200433, China.
| | - Zengli Zhang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China.
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Yang X, Lin H, Wang M, Huang X, Li K, Xia W, Zhang Y, Wang S, Chen W, Zheng C. Identification of key genes and pathways in duck fatty liver syndrome using gene set enrichment analysis. Poult Sci 2024; 103:104015. [PMID: 39003797 PMCID: PMC11298935 DOI: 10.1016/j.psj.2024.104015] [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: 04/25/2024] [Revised: 06/05/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024] Open
Abstract
High-laying ducks are often fed high-energy, nutritious feeds to maintain high productivity, which predisposes them to lipid metabolism disorders and the development of fatty liver syndrome (FLS), which seriously affects production performance and has a substantial economic impact on the poultry industry. Therefore, it is necessary to elucidate the mechanisms underlying the development of fatty liver syndrome. In this study, seven Shan Partridge ducks, each with fatty liver syndrome and normal laying ducks, were selected, and Hematoxylin Eosin staining (HE staining), Masson staining, and transcriptome sequencing were performed on liver tissue. In addition to exploring key genes and pathways using conventional analysis methods, we constructed the first Kyoto Encyclopedia of Genes and Genomes (KEGG) database-based predefined gene set containing 12,764 pathways and 16,836 genes and further performed gene set enrichment analysis (GSEA) on the liver transcriptome data. Finally, key nodes and biological processes were identified via the protein-protein interaction (PPI) network. The results showed that the liver in the FL group exhibited steatosis and fibrosis, and a total of 3,663 genes with upregulated expression versus 2,296 downregulated genes were screened by conventional analysis. GSEA analysis and PPI network analysis revealed that the liver in the FL group exhibited disruption of the mitochondrial electron transport chain, leading to decreased oxidative phosphorylation and the secretion of excessive proinflammatory factors amid the continuous accumulation of lipids. Under continuous chronic inflammation, cell cycle arrest triggers apoptosis, while fibrosis becomes more severe, and procarcinogenic genes are activated, leading to the continuous development and deterioration of the liver. In conclusion, the predefined gene set constructed in this study can be used for GSEA, and the identified hub genes provide useful reference data and a solid foundation for the study of the genetic regulatory mechanism of fatty liver syndrome in ducks.
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Affiliation(s)
- Xue Yang
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China
| | - Hao Lin
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China; College of Animal Science, Anhui Science and Technology University, Anhui 233100, P.R. China
| | - Mengpan Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China; College of Animal Science & Veterinary Medicine, Tianjin Agricultural University, Tianjin, 300391, P.R. China
| | - Xuebing Huang
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China
| | - Kaichao Li
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China
| | - Weiguang Xia
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China
| | - Yanan Zhang
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China
| | - Shuang Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China
| | - Wei Chen
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China
| | - Chuntian Zheng
- State Key Laboratory of Swine and Poultry Breeding Industry, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Key Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Provincial Key Laboratory of Animal Breeding and Nutrition, Guangzhou 510640, P.R. China.
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9
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Wang P, Pan J, Gong S, Zhang Z, Li B. Yes-associated protein inhibition ameliorates carbon tetrachloride-induced acute liver injury in mice by reducing VDR. Chem Biol Interact 2024; 399:111139. [PMID: 38992766 DOI: 10.1016/j.cbi.2024.111139] [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: 05/23/2024] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 07/13/2024]
Abstract
Carbon tetrachloride (CCl4) has a wide range of toxic effects, especially causing acute liver injury (ALI), in which rapid compensation for hepatocyte loss ensures liver survival, but proliferation of surviving hepatocytes (known as endoreplication) may imply impaired residual function. Yes-associated protein (YAP) drives hepatocytes to undergo endoreplication and ploidy, the underlying mechanisms of which remain a mystery. In the present study, we uncover during CCl4-mediated ALI accompanied by increased hepatocytes proliferation and YAP activation. Notably, bioinformatics analyses elucidate that hepatic-specific deletion of YAP substantially ameliorated CCl4-induced hepatic proliferation, effectively decreased the vitamin D receptor (VDR) expression. Additionally, a mouse model of acute liver injury substantiated that inhibition of YAP could suppress hepatocytes proliferation via VDR. Furthermore, we also disclosed that the VDR agonist nullifies CCl4-induced ALI alleviated by the YAP inhibitor in vivo. Importantly, hepatocytes were isolated from mice, and it was spotlighted that the anti-proliferative impact of the YAP inhibitor was abolished by the activation of VDR within these hepatocytes. Similarly, primary hepatic stellate cells (HSCs) were isolated and it was manifested that YAP inhibitor suppressed HSC activation via VDR during acute liver injury. Our findings further elucidate the YAP's role in ALI and may provide new avenues for protection against CCl4-drived acute liver injury.
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Affiliation(s)
- Ping Wang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China
| | - Jinjing Pan
- Department of Clinical Nutrition, Sheyang County People's Hospital, Yancheng, 224300, China
| | - Shiyi Gong
- Deparment of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China
| | - Zengli Zhang
- Department of Occupational and Environmental Health, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
| | - Bingyan Li
- Deparment of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
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10
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Wang D, He R, Song Q, Diao H, Jin Y, Zhang A. Calcitriol Inhibits NaAsO 2 Triggered Hepatic Stellate Cells Activation and Extracellular Matrix Oversecretion by Activating Nrf2 Signaling Pathway Through Vitamin D Receptor. Biol Trace Elem Res 2024; 202:3601-3613. [PMID: 37968493 DOI: 10.1007/s12011-023-03957-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
Previous studies, including our own, have demonstrated that arsenic exposure can induce liver fibrosis, while the underlying mechanism remains unclear and there is currently no effective pharmacological intervention available. Recent research has demonstrated that vitamin D supplementation can ameliorate liver fibrosis caused by various etiologies, potentially through modulation of the Nrf2 signaling pathways. However, it remains unclear whether vitamin D intervention can mitigate arsenic-caused liver fibrosis. As is known hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition are pivotal in the pathogenesis of liver fibrosis. In this study, we investigated the intervention effect of calcitriol (a form of active vitamin D) on arsenite-triggered Lx-2 cells (a human hepatic stellate cell line) activation and ECM oversecretion. Additionally, we also elucidated the role and mechanism of Nrf2 antioxidant signaling pathway. Our results demonstrated that calcitriol intervention significantly inhibits Lx-2 cell activation and ECM oversecretion induced by arsenite exposure. Additionally, calcitriol activates Nrf2 and its downstream antioxidant enzyme expression in Lx-2 cells, thereby reducing ROS overproduction caused by arsenite exposure. Further investigation reveals that calcitriol activates the Nrf2 signaling pathway and inhibits arsenite-triggered Lx-2 cell activation and ECM oversecretion by targeting vitamin D receptor (VDR). In conclusion, this study has demonstrated that vitamin D intervention can effectively inhibit HSC activation and ECM oversecretion triggered by arsenite exposure through its antioxidant activity. This provides a novel strategy for targeted nutritional intervention in the treatment of arsenic-induced liver fibrosis.
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Affiliation(s)
- Dapeng Wang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
- Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-Constructed By the Province and Ministry, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
| | - Rui He
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Qian Song
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Heng Diao
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Ying Jin
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Aihua Zhang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
- Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-Constructed By the Province and Ministry, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
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11
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Bouguéon M, Legagneux V, Hazard O, Bomo J, Siegel A, Feret J, Théret N. A rule-based multiscale model of hepatic stellate cell plasticity: Critical role of the inactivation loop in fibrosis progression. PLoS Comput Biol 2024; 20:e1011858. [PMID: 39074160 PMCID: PMC11309422 DOI: 10.1371/journal.pcbi.1011858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 08/08/2024] [Accepted: 07/05/2024] [Indexed: 07/31/2024] Open
Abstract
Hepatic stellate cells (HSC) are the source of extracellular matrix (ECM) whose overproduction leads to fibrosis, a condition that impairs liver functions in chronic liver diseases. Understanding the dynamics of HSCs will provide insights needed to develop new therapeutic approaches. Few models of hepatic fibrosis have been proposed, and none of them include the heterogeneity of HSC phenotypes recently highlighted by single-cell RNA sequencing analyses. Here, we developed rule-based models to study HSC dynamics during fibrosis progression and reversion. We used the Kappa graph rewriting language, for which we used tokens and counters to overcome temporal explosion. HSCs are modeled as agents that present seven physiological cellular states and that interact with (TGFβ1) molecules which regulate HSC activation and the secretion of type I collagen, the main component of the ECM. Simulation studies revealed the critical role of the HSC inactivation process during fibrosis progression and reversion. While inactivation allows elimination of activated HSCs during reversion steps, reactivation loops of inactivated HSCs (iHSCs) are required to sustain fibrosis. Furthermore, we demonstrated the model's sensitivity to (TGFβ1) parameters, suggesting its adaptability to a variety of pathophysiological conditions for which levels of (TGFβ1) production associated with the inflammatory response differ. Using new experimental data from a mouse model of CCl4-induced liver fibrosis, we validated the predicted ECM dynamics. Our model also predicts the accumulation of iHSCs during chronic liver disease. By analyzing RNA sequencing data from patients with non-alcoholic steatohepatitis (NASH) associated with liver fibrosis, we confirmed this accumulation, identifying iHSCs as novel markers of fibrosis progression. Overall, our study provides the first model of HSC dynamics in chronic liver disease that can be used to explore the regulatory role of iHSCs in liver homeostasis. Moreover, our model can also be generalized to fibroblasts during repair and fibrosis in other tissues.
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Affiliation(s)
- Matthieu Bouguéon
- Univ Rennes, Inria, CNRS, IRISA, UMR 6074, Rennes, France
- Univ Rennes, Inserm, EHESP, Irset, UMR S1085, Rennes, France
| | | | - Octave Hazard
- École Polytechnique, Palaiseau, France
- DI-ENS (Inria, ÉNS, CNRS, PSL University), École normale supérieure, Paris, France
| | - Jérémy Bomo
- Univ Rennes, Inria, CNRS, IRISA, UMR 6074, Rennes, France
- Univ Rennes, Inserm, EHESP, Irset, UMR S1085, Rennes, France
| | - Anne Siegel
- Univ Rennes, Inria, CNRS, IRISA, UMR 6074, Rennes, France
| | - Jérôme Feret
- DI-ENS (Inria, ÉNS, CNRS, PSL University), École normale supérieure, Paris, France
- Team Antique, Inria, Paris, France
| | - Nathalie Théret
- Univ Rennes, Inria, CNRS, IRISA, UMR 6074, Rennes, France
- Univ Rennes, Inserm, EHESP, Irset, UMR S1085, Rennes, France
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12
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Guo E, Yuan H, Li R, Yang J, Liu S, Liu A, Jiang X. Calcitriol ameliorates the progression of hepatic fibrosis through autophagy-related gene 16-like 1-mediated autophagy. Am J Med Sci 2024; 367:382-396. [PMID: 38431191 DOI: 10.1016/j.amjms.2024.02.010] [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: 11/29/2022] [Revised: 10/23/2023] [Accepted: 02/21/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Calcitriol has the potential to counteract fibrotic diseases beyond its classical action of maintaining calcium and bone metabolism; however, its functional mechanism remains unknown. Autophagy-related gene 16-like 1 (Atg16l1) is one of the genes related to autophagy and is involved in protecting against fibrotic diseases. The present study aimed to explore the contribution of autophagy to the inhibition of calcitriol-induced hepatic fibrosis, as well as its potential molecular mechanism. METHODS Carbon tetrachloride (Ccl4)-treated mice were established as hepatic fibrosis models and received calcitriol treatment for 6 weeks. Quantification of Sirius red staining and measurement of key fibrotic markers (collagen-1 and α-SMA) was performed to detect hepatic fibrosis. Chloroquine (CQ) treatment was used to observe autophagic flux, and 3-methyladenine (3-MA) was used to inhibit autophagy. Furthermore, the effects of calcitriol on transforming growth factor β1 (TGFβ1)-stimulated primary hepatic stellate cells (HSCs) were detected. Downregulation of Atg16l1 or vitamin D receptor (VDR) in LX-2 cells was used to explore the mechanism of action of calcitriol in fibrosis and autophagy. Additionally, the electrophoretic mobility shift assay (EMSA) was used to investigate the interactions between VDR and ATG16L1. RESULTS Calcitriol increased the expression of VDR and ATG16L1, enhanced autophagy and attenuated hepatic fibrosis. 3-MA treatment and VDR silencing abolished the protective effects of calcitriol against fibrosis. Calcitriol-induced anti-fibrosis effects were blocked by ATG16L1 suppression. Furthermore, VDR bound to the ATG16L1 promoter and downregulation of VDR decreased the expression of ATG16L1 in LX-2 cells. CONCLUSION Calcitriol mitigates hepatic fibrosis partly through ATG16L1-mediated autophagy.
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Affiliation(s)
- Enshuang Guo
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Infectious Diseases, General Hospital of Central Theater Command of PLA, Wuhan 430070, China; Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Huixing Yuan
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Renlong Li
- Department of Infectious Diseases, General Hospital of Central Theater Command of PLA, Wuhan 430070, China; Southern Medical University, Guangzhou 510515, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shenpei Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Anding Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Xiaojing Jiang
- Department of Infectious Diseases, General Hospital of Central Theater Command of PLA, Wuhan 430070, China; Southern Medical University, Guangzhou 510515, China
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13
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Aggeletopoulou I, Tsounis EP, Triantos C. Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights. Int J Mol Sci 2024; 25:4901. [PMID: 38732118 PMCID: PMC11084591 DOI: 10.3390/ijms25094901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.
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Affiliation(s)
| | | | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
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14
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Lin G, Li W, Hong W, Zhu D, Hu H, Fu J, Gao Y, Chen S, Chai D, Zeng JZ. Spinosin inhibits activated hepatic stellate cell to attenuate liver fibrosis by targeting Nur77/ASK1/p38 MAPK signaling pathway. Eur J Pharmacol 2024; 966:176270. [PMID: 38096970 DOI: 10.1016/j.ejphar.2023.176270] [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: 10/04/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 02/06/2024]
Abstract
AIM Liver fibrosis remains a great challenge in the world. Spinosin (SPI), a natural flavonoid-C-glycoside, possesses various pharmacological activities including anti-inflammatory and anti-myocardial fibrosis effects. In this study, we investigate whether SPI can be a potential lead for the treatment of liver fibrosis and explore whether the orphan nuclear receptor Nur77, a negative regulator of liver fibrosis development, plays a critical role in SPI's action. METHODS A dual luciferase reporter system of α-SMA was established to evaluate the effect of SPI on hepatic stellate cell (HSC) activation in LX2 and HSC-T6 cells. A mouse model of CCl4-induced liver fibrosis was used to test the efficacy of SPI against liver fibrosis. The expression levels of Nur77, inflammatory cytokines and collagen were determined by Western blotting and qPCR. Potential kinase pathways involved were also analyzed. The affinity of Nur77 with SPI was documented by fluorescence titration. RESULTS SPI can strongly suppress TGF-β1-mediated activation of both LX2 and HSC-T6 cells in a dose-dependent manner. SPI increases the expression of Nur77 and reduces TGF-β1-mediated phosphorylation levels of ASK1 and p38 MAPK, which can be reversed by knocking out of Nur77. SPI strongly inhibits collagen deposition (COLA1) and reduces inflammatory cytokines (IL-6 and IL-1β), which is followed by improved liver function in the CCl4-induced mouse model. SPI can directly bind to R515 and R563 in the Nur77-LBD pocket with a Kd of 2.14 μM. CONCLUSION Spinosin is the major pharmacological active component of Ziziphus jujuba Mill. var. spinosa which has been frequently prescribed in traditional Chinese medicine. We demonstrate here for the first time that spinosin is a new therapeutic lead for treatment of liver fibrosis by targeting Nur77 and blocking the ASK1/p38 MAPK signaling pathway.
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Affiliation(s)
- Gang Lin
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Weibin Li
- Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China; Department of Ultrasonic Medicine Affiliated Hospital, Xizang Minzu University, Xianyang, China
| | - Wenbin Hong
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Desheng Zhu
- Department of Urology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Hongyu Hu
- Xingzhi College, Zhejiang Normal University, Lanxi, 321004, China
| | - Jiqiang Fu
- Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, China
| | - Yanfang Gao
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Shuaijie Chen
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Dajun Chai
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Jin-Zhang Zeng
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
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15
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Zhou C, Zhang Y, Ye Z, He P, Zhang Y, Gan X, Yang S, Liu M, Wu Q, Qin X. Relationship among serum 25-hydroxyvitamin D, fibrosis stage, genetic susceptibility, and risk of severe liver disease. Nutrition 2024; 119:112320. [PMID: 38185094 DOI: 10.1016/j.nut.2023.112320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 01/09/2024]
Abstract
OBJECTIVES The prospective association between vitamin D and new-onset severe liver disease is still uncertain. The aim of this study was to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with new-onset severe liver disease and to evaluate whether fibrosis stage, as assessed by the fibrosis- 4 (FIB-4) scores and genetic risk for liver cirrhosis may modify this association. METHODS The study included 439 807 participants without liver diseases at baseline from the UK Biobank. Serum 25(OH)D concentrations were measured using the chemiluminescent immunoassay method. The primary outcome was new-onset severe liver disease, a composite definition of compensated or decompensated liver cirrhosis, liver failure, hepatocellular carcinoma, and liver-related death. RESULTS During a median follow-up of 12 y, 4510 participants developed new-onset severe liver disease. Overall, there was an inverse association of serum 25(OH)D with new-onset severe liver disease (per SD increment, adjusted hazard ratio [HR], 0.87; 95% confidence interval, 0.84-0.91). Similarly, serum 25(OH)D (per SD increment) was significantly and inversely associated with new-onset compensated cirrhosis, decompensated cirrhosis, liver failure, and liver-related death, respectively, with HRs ranging from 0.75 to 0.87. No significant association was found for hepatocellular carcinoma. Furthermore, there was a stronger inverse association between serum 25(OH)D and severe liver disease among those with a higher FIB-4 score (≥2.67, 1.3 to <2.67, and <1.3; Pinteraction < 0.001). However, the genetic risks for liver cirrhosis, calculated using 12 related single nucleotide polymorphisms, did not significantly modify the association between serum 25(OH)D and severe liver disease (Pinteraction = 0.216). CONCLUSIONS Lower serum 25(OH)D concentrations were significantly associated with a greater risk for new-onset severe liver disease, especially in participants with higher FIB-4 scores.
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Affiliation(s)
- Chun Zhou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Yanjun Zhang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Ziliang Ye
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Panpan He
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Yuanyuan Zhang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Xiaoqin Gan
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Sisi Yang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Mengyi Liu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Qimeng Wu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Xianhui Qin
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; National Clinical Research Center for Kidney Disease, Guangzhou, China; State Key Laboratory of Organ Failure Research, Guangzhou, China; Guangdong Provincial Institute of Nephrology, Guangzhou, China; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China.
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16
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Jain GK, Raina V, Grover R, Sharma J, Warsi MH, Aggarwal G, Kesharwani P. Revisiting the significance of nano-vitamin D for food fortification and therapeutic application. Drug Dev Ind Pharm 2024; 50:89-101. [PMID: 38175566 DOI: 10.1080/03639045.2023.2301478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 12/29/2023] [Indexed: 01/05/2024]
Abstract
OBJECTIVE Vitamin D (a prohormone) is an important micronutrient required by the body for skeletal homeostasis and a range of non-skeletal actions. Calcitriol, the active form of vitamin D, regulates a variety of cellular and metabolic processes through both genomic and nongenomic pathways. Often prescribed for treating rickets and osteoporosis, vitamin D deficiency can exacerbate various other medical conditions. SIGNIFICANCE, METHODS, AND RESULTS Despite its multifunctional uses, the sensitivity of vitamin D makes formulating an efficient drug delivery system a challenging task, which is further complicated by its poor aqueous solubility. Enhancing the oral absorption of vitamin D is vital in utilizing its full efficacy. Recent developments in encapsulation and nanotechnology have shown promising results in overcoming these constraints. CONCLUSION This review thus offers an insight to adequately comprehend the mechanistic pharmacology of vitamin D, its pathophysiological role, and justification of its medical indications, along with the benefits of utilizing nanotechnology for vitamin D delivery.
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Affiliation(s)
- Gaurav K Jain
- Center for Advanced Formulation Technology (CAFT), Delhi Pharmaceutical Science and Research University (DPSRU), New Delhi, India
| | - Vidya Raina
- Center for Advanced Formulation Technology (CAFT), Delhi Pharmaceutical Science and Research University (DPSRU), New Delhi, India
| | - Rakshita Grover
- Center for Advanced Formulation Technology (CAFT), Delhi Pharmaceutical Science and Research University (DPSRU), New Delhi, India
| | - Jagriti Sharma
- Center for Advanced Formulation Technology (CAFT), Delhi Pharmaceutical Science and Research University (DPSRU), New Delhi, India
| | - Musarrat Husain Warsi
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Geeta Aggarwal
- Center for Advanced Formulation Technology (CAFT), Delhi Pharmaceutical Science and Research University (DPSRU), New Delhi, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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17
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Wang Y, Jiao L, Qiang C, Chen C, Shen Z, Ding F, Lv L, Zhu T, Lu Y, Cui X. The role of matrix metalloproteinase 9 in fibrosis diseases and its molecular mechanisms. Biomed Pharmacother 2024; 171:116116. [PMID: 38181715 DOI: 10.1016/j.biopha.2023.116116] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/25/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024] Open
Abstract
Fibrosis is a process of tissue repair that results in the slow creation of scar tissue to replace healthy tissue and can affect any tissue or organ. Its primary feature is the massive deposition of extracellular matrix (mainly collagen), eventually leading to tissue dysfunction and organ failure. The progression of fibrotic diseases has put a significant strain on global health and the economy, and as a result, there is an urgent need to find some new therapies. Previous studies have identified that inflammation, oxidative stress, some cytokines, and remodeling play a crucial role in fibrotic diseases and are essential avenues for treating fibrotic diseases. Among them, matrix metalloproteinases (MMPs) are considered the main targets for the treatment of fibrotic diseases since they are the primary driver involved in ECM degradation, and tissue inhibitors of metalloproteinases (TIMPs) are natural endogenous inhibitors of MMPs. Through previous studies, we found that MMP-9 is an essential target for treating fibrotic diseases. However, it is worth noting that MMP-9 plays a bidirectional regulatory role in different fibrotic diseases or different stages of the same fibrotic disease. Previously identified MMP-9 inhibitors, such as pirfenidone and nintedanib, suffer from some rather pronounced side effects, and therefore, there is an urgent need to investigate new drugs. In this review, we explore the mechanism of action and signaling pathways of MMP-9 in different tissues and organs, hoping to provide some ideas for developing safer and more effective biologics.
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Affiliation(s)
- Yuling Wang
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Linke Jiao
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Caoxia Qiang
- Department of Traditional Chinese Medicine, Tumor Hospital Affiliated to Nantong University, Jiangsu, China
| | - Chen Chen
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zihuan Shen
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Fan Ding
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Lifei Lv
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tingting Zhu
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingdong Lu
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangning Cui
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Emam RF, Soliman AF, Darweesh SK, AbdElmagid RA, Ibrahim OM, Mohamed DM. Steatosis regression assessed by cap after Vitamin 'D' supplementation in NAFLD patients with Vitamin 'D' deficiency. Eur J Gastroenterol Hepatol 2024; 36:101-106. [PMID: 37942743 DOI: 10.1097/meg.0000000000002653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and previous studies suggested a relationship between vitamin D deficiency and NAFLD. It is suggested that vitamin D supplementation may have significant beneficial effect on liver biochemistry and histology. OBJECTIVE This study aims to assess the degree of possible steatosis regression using controlled attenuation parameter (CAP) in NAFLD patients with vitamin D deficiency after vitamin D supplementation and evaluating its effect on lipid profile and transaminases. PATIENTS AND METHODS This study was conducted on 100 NAFLD patients with vitamin D deficiency. They received 10000 IU/week of vitamin D orally for 3 months. CAP was used to assess hepatic steatosis and fibrosis before/after intervention. Transaminases, lipid profile, and vitamin D levels were evaluated before/after treatment. RESULTS Serum AST, ALT, cholesterol, TG, LDL and HDL showed a significant reduction posttreatment in patients with both normal and elevated baseline levels ( P < 0.001). The posttreatment mean CAP showed a significant reduction (300.44 ± 37.56 vs. 265 ± 36.19 dB/ml) ( P < 0.001), and there was a significant improvement in the mean fibrosis values by LSM (5.32 ± 1.53 vs. 4.86 ± 1.28 KPa) ( P = 0.001). After supplementation, serum vitamin D level was raised significantly in the majority of patients ( P < 0.001); however, only 13% of them reached sufficient levels (>30 ng/ml), insufficient levels (20-29 ng/ml) was reached in 83% and 5% showed vitamin D deficiency (<20 ng/ml). CONCLUSION A significant improvement was detected in hepatic steatosis (by CAP); mean values of LSM, transaminases and lipid profile after three months of oral vitamin D supplementation.
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Affiliation(s)
- Rabab Fouad Emam
- Hepato-gastroenterology and Endemic Medicine Department, Faculty of Medicine, Cairo University
| | - Ahmed Fouad Soliman
- Hepato-gastroenterology and Endemic Medicine Department, Faculty of Medicine, Cairo University
| | - Samar Kamal Darweesh
- Hepato-gastroenterology and Endemic Medicine Department, Faculty of Medicine, Cairo University
| | | | - Ola Mohamed Ibrahim
- Clinical and Chemical pathology Department, Student's Hospital, Cairo University
| | - Dina Mahmoud Mohamed
- Hepato-gastroenterology and Endemic Medicine Department, Student's Hospital, Cairo University, Cairo, Egypt
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Tong C, Halengbieke A, Ni X, Han Y, Tao L, Zheng D, Li Q, Yang X. Bidirectional relationship between nonalcoholic fatty liver disease and serum creatinine-to-body weight ratio as a proxy for skeletal muscle mass index. J Gastroenterol Hepatol 2023; 38:2061-2069. [PMID: 37642537 DOI: 10.1111/jgh.16333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 06/17/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND AND AIM Although an association between skeletal muscle mass index and nonalcoholic fatty liver disease (NAFLD) has previously been demonstrated, the causal direction remains unclear. Herein, we investigated the directional association between NAFLD and the serum creatinine-to-body weight ratio (sCr/bw), a surrogate marker of the muscle mass index, using longitudinal data. METHODS We recruited 9662 participants in 2017 and performed follow-up over 4 years. We evaluated whether sCr/bw was related to NAFLD development (Analysis I) and whether NAFLD was associated with a low sCr/bw incidence (Analysis II) using logistic regression models. Furthermore, a random intercept cross-lagged panel model was applied to evaluate the bidirectional association between sCr/bw ratio and NAFLD (Analysis III). RESULTS Analysis I demonstrated an association between sCr/bw and incident NAFLD (odds ratio [OR] = 0.160, 95% confidence interval [CI]:0.107-0.232). Analysis II indicated a relationship between NAFLD and subsequent low sCr/bw ratio (OR = 1.524, 95% CI: 1.258-1.846). Analysis III indicated that the standard regression coefficient from sCr/bw to subsequent hepatic steatosis (HS) was -0.053 for βsCr/bw2017 → HS2019 and -0.060 for βsCr/bw2019 → HS2021 and the coefficient from HS to subsequent sCr/bw was -0.093 for βHS2017 → sCr/bw2019 and -0.112 for βHS2019 → sCr/bw2021 (all P < 0.05). CONCLUSIONS This study indicated mutual causality between sCr/bw and NAFLD. Considering that sCr/bw is a surrogate marker of muscle mass index, the findings emphasize that NAFLD and low muscle mass form a vicious cycle, which should be taken seriously in clinical practice.
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Affiliation(s)
- Chao Tong
- School of Public Health, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Aheyeerke Halengbieke
- School of Public Health, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Xuetong Ni
- School of Public Health, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Yumei Han
- Science and Education Section, Beijing Physical Examination Center, Beijing, China
| | - Lixin Tao
- School of Public Health, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Deqiang Zheng
- School of Public Health, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Qiang Li
- Science and Education Section, Beijing Physical Examination Center, Beijing, China
| | - Xinghua Yang
- School of Public Health, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
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Farías C, Cisternas C, Gana JC, Alberti G, Echeverría F, Videla LA, Mercado L, Muñoz Y, Valenzuela R. Dietary and Nutritional Interventions in Nonalcoholic Fatty Liver Disease in Pediatrics. Nutrients 2023; 15:4829. [PMID: 38004223 PMCID: PMC10674812 DOI: 10.3390/nu15224829] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/06/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is pediatrics' most common chronic liver disease. The incidence is high in children and adolescents with obesity, which is associated with an increased risk of disease progression. Currently, there is no effective drug therapy in pediatrics; therefore, lifestyle interventions remain the first line of treatment. This review aims to present an updated compilation of the scientific evidence for treating this pathology, including lifestyle modifications, such as exercise and dietary changes, highlighting specific nutritional strategies. The bibliographic review was carried out in different databases, including studies within the pediatric population where dietary and/or nutritional interventions were used to treat NAFLD. Main interventions include diets low in carbohydrates, free sugars, fructose, and lipids, in addition to healthy eating patterns and possible nutritional interventions with n-3 polyunsaturated fatty acids (EPA and DHA), amino acids (cysteine, L-carnitine), cysteamine, vitamins, and probiotics (one strain or multi-strain). Lifestyle changes remain the main recommendation for children with NAFLD. Nevertheless, more studies are required to elucidate the effectiveness of specific nutrients and bioactive compounds in this population.
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Affiliation(s)
- Camila Farías
- Department of Nutrition, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Camila Cisternas
- Department of Nutrition, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Juan Cristobal Gana
- Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile
| | - Gigliola Alberti
- Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile
| | - Francisca Echeverría
- Nutrition and Dietetic School, Department of Health Sciences, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Luis A Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380000, Chile
| | - Lorena Mercado
- Department of Nutrition, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Yasna Muñoz
- Department of Nutrition, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
- Escuela de Nutrición y Dietética, Facultad de Farmacia, Universidad de Valparaíso, Valparaíso 2360134, Chile
| | - Rodrigo Valenzuela
- Department of Pediatric Gastroenterology and Nutrition, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile
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Kumar R, Kumar S, Prakash SS. Compensated liver cirrhosis: Natural course and disease-modifying strategies. World J Methodol 2023; 13:179-193. [PMID: 37771878 PMCID: PMC10523240 DOI: 10.5662/wjm.v13.i4.179] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/05/2023] [Accepted: 06/27/2023] [Indexed: 09/20/2023] Open
Abstract
Compensated liver cirrhosis (CLC) is defined as cirrhosis with one or more decompensating events, such as ascites, variceal haemorrhage, or hepatic encephalopathy. Patients with CLC are largely asymptomatic with preserved hepatic function. The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors. The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis, as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years. Furthermore, early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition. With the advent of effective non-invasive tools for detecting hepatic fibrosis, more and more patients with CLC are currently being recognised. This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or, at the very least, prevent its progression. There are numerous emerging approaches for preventing or delaying decompensation in CLC patients. A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression, and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension. Additionally, addressing various cofactors (such as obesity, diabetes, dyslipidaemia, and alcoholism) and precipitating factors (such as infection, viral hepatitis, and hepatotoxic drugs) that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC. However, high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these disease-modifying techniques for CLC patients. This article discussed the natural history of CLC, risk factors for its progression, and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sudhir Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sabbu Surya Prakash
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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22
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Srikuea R, Hirunsai M. TGF-β1 stimulation and VDR-dependent activation modulate calcitriol action on skeletal muscle fibroblasts and Smad signalling-associated fibrogenesis. Sci Rep 2023; 13:13811. [PMID: 37612333 PMCID: PMC10447566 DOI: 10.1038/s41598-023-40978-w] [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: 05/09/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023] Open
Abstract
Fibroblasts play a pivotal role in fibrogenesis after skeletal muscle injury. Excess fibrous formation can disrupt contractile functions and delay functional recovery. Although vitamin D receptor (VDR) is expressed explicitly in regenerating muscle compared with uninjured muscle, how calcitriol [1α,25(OH)2D3] directly regulates skeletal muscle primary fibroblast proliferation, the transition to myofibroblasts, and Smad signalling-associated fibrogenesis is currently unknown. Herein, the effects of calcitriol on cultured skeletal muscle primary fibroblasts of male C57BL/6 mice (aged 1 month old) were investigated. The percentage of BrdU+ nuclei in primary fibroblasts was significantly decreased after calcitriol treatment; however, the antiproliferative effect of calcitriol was diminished after TGF-β1 stimulation to induce fibroblast to myofibroblast transition. This suppressive effect was associated with significantly decreased VDR expression in TGF-β1-treated cells. In addition, Vdr siRNA transfection abolished the effects of calcitriol on the suppression of α-SMA expression and Smad2/3 signalling in myofibroblasts, supporting that its antifibrogenic effect requires VDR activation. Compared with calcitriol, the antifibrotic agent suramin could inhibit fibroblast/myofibroblast proliferation and suppress the expression of TCF-4, which regulates fibrogenic determination. Collectively, these findings suggest that profibrotic stimulation and VDR-dependent activation could modulate the effects of calcitriol on skeletal muscle fibroblast proliferation and fibrogenesis processes. Therefore, TGF-β1 and VDR expression levels are crucial determinants for the antifibrogenic effect of calcitriol on skeletal muscle after injury.
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Affiliation(s)
- Ratchakrit Srikuea
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
| | - Muthita Hirunsai
- Department of Biopharmacy, Faculty of Pharmacy, Srinakharinwirot University, Ongkharak, Nakhon Nayok, 26120, Thailand
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23
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Rastegar-Moghaddam SH, Akbarian M, Rajabian A, Alipour F, Ebrahimzadeh bideskan A, Hosseini M. Vitamin D alleviates hypothyroidism associated liver dysfunction: Histological and biochemical evidence. Heliyon 2023; 9:e18860. [PMID: 37593614 PMCID: PMC10428045 DOI: 10.1016/j.heliyon.2023.e18860] [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: 05/25/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 08/19/2023] Open
Abstract
There is a complex correlation between thyroid hormones (THs) and liver function. Hypothyroidism as a failure of the thyroid gland to produce adequate thyroid hormones to fulfill the metabolic requirements of the body, may perturb liver structure and function. Emerging evidence suggests the protective effects of vitamin D against liver damage. Herein, this study aimed to investigate the role of vitamin D in hypothyroidism-associated liver injury. Forty male Wistar rats were classified into 4 groups: control, hypothyroid (Hypo) group received 0.05% PTU, Hypo- Vitamin D groups were given 100 and 500 IU/kg vitamin D orally via gavage for 6 weeks. Serum level of liver function including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured. Malondialdehyde (MDA) level, superoxide dismutase (SOD) enzyme activity, and total thiol content were measured as oxidative stress indicators in the liver tissue. Furthermore, to estimate liver tissue fibrosis, Masson's trichrome staining was done. Our findings showed that hypothyroidism-induced liver fibrosis was associated with increased levels of ALT, AST and ALP. Though, vitamin D administration could significantly reduce the ALT, AST and ALP in the serum and suppress the accumulation of collagen fibers. Moreover, the activity of SOD and total thiol content was notably reduced, while the MDA content was significantly increased in the PTU- induced hypothyroid rats compared to the control group. Nonetheless, treatment with vitamin D improved mentioned oxidative stress markers in the Hypo-vitamin D groups. In conclusion, vitamin D due to its potential antioxidant and anti-fibrotic properties could be effective in the decrease of hypothyroidism-associated liver injury.
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Affiliation(s)
- Seyed Hamidreza Rastegar-Moghaddam
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Anatomy and Cell Biology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahsan Akbarian
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arezoo Rajabian
- Department of Internal Medicine, Faculty of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Alipour
- Department of Anatomy and Cell Biology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Ebrahimzadeh bideskan
- Department of Anatomy and Cell Biology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Hosseini
- Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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24
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Liu J, Song Y, Wang Y, Hong H. Vitamin D/vitamin D receptor pathway in non-alcoholic fatty liver disease. Expert Opin Ther Targets 2023; 27:1145-1157. [PMID: 37861098 DOI: 10.1080/14728222.2023.2274099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 10/18/2023] [Indexed: 10/21/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, but underlying mechanisms are not fully understood. In recent years, a growing body of evidence has emphasized the therapeutic role of vitamin D in NAFLD, but the specific mechanism remains to be investigated. AREAS COVERED This review summarized the roles of vitamin D/VDR (vitamin D receptor) pathway in different types of liver cells (such as hepatocytes, hepatic stellate cells, liver macrophages, T lymphocytes, and other hepatic immune cells) in case of NAFLD. Meanwhile, the effects of pathways in the gut-liver axis, adipose tissue-liver axis, and skeletal muscle-liver axis on the development of NAFLD were further reviewed. Relevant literature was searched on PubMed for the writing of this review. EXPERT OPINION The precise regulation of regional vitamin D/VDR signaling pathway based on cell-specific or tissue-specific function will help clarify the potential mechanism of vitamin D in NAFLD, which may provide new therapeutic targets to improve the safety and efficacy of vitamin D based drugs.
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Affiliation(s)
- Jingqi Liu
- Fujian Key Laboratory of Vascular Aging, Department of Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Xiamen Institute of Geriatric Rehabilitation, Department of Geriatrics, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian, China
| | - Yang Song
- Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian, China
| | - Ye Wang
- Xiamen Institute of Geriatric Rehabilitation, Department of Geriatrics, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian, China
| | - Huashan Hong
- Fujian Key Laboratory of Vascular Aging, Department of Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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25
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Zheng Y, Li JH, Liao SY, Fu YM, Zhang YJ, Lin JL, Chen XB, Sha WH, Dai SX, Ma WJ. Joint Detection of Serum Vitamin D, Body Mass Index, and Tumor Necrosis Factor Alpha for the Diagnosis of Crohn's Disease. Curr Med Sci 2023:10.1007/s11596-023-2741-6. [PMID: 37249734 DOI: 10.1007/s11596-023-2741-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/16/2022] [Indexed: 05/31/2023]
Abstract
OBJECTIVE Vitamin D (VD) deficiency was reported to contribute to the progression of Crohn's disease (CD) and affect the prognosis of CD patients. This study investigated the role of serum VD, body mass index (BMI), and tumor necrosis factor alpha (TNF-α) in the diagnosis of Crohn's disease. METHODS CD patients (n=76) and healthy subjects (n=76) were enrolled between May 2019 and December 2020. The serum 25-hydroxyvitamin D [25(OH)D] levels, BMI, and TNF-α levels, together with other biochemical parameters, were assessed before treatment. The diagnostic efficacy of the single and joint detection of serum 25(OH)D, BMI, and TNF-α was determined using receiver operating characteristic (ROC) curves. RESULTS The levels of 25(OH) D, BMI, and nutritional indicators, including hemoglobin, total protein, albumin, and high-density lipoprotein cholesterol, were much lower, and the TNF-α levels were much higher in the CD patients than in the healthy subjects (P<0.05 for all). The areas under the ROC curve for the single detection of 25(OH)D, BMI, and TNF-α were 0.887, 0.896, and 0.838, respectively, with the optimal cutoff values being 20.64 ng/mL, 19.77 kg/m2, and 6.85 fmol/mL, respectively. The diagnostic efficacy of the joint detection of 25(OH)D, BMI, and TNF-α was the highest, with an area under the ROC curve of 0.988 (95%CI: 0.968-1.000). CONCLUSION The joint detection of 25(OH)D, TNF-α, and BMI showed high sensitivity, specificity, and accuracy in CD diagnosis; thus, it would be effective for the diagnosis of CD in clinical practice.
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Affiliation(s)
- Ying Zheng
- Department of Nutrition, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China
| | - Jing-Hong Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, China
| | - Shan-Ying Liao
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China
| | - Yi-Ming Fu
- The First School of Clinical Medicine & Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Yan-Jun Zhang
- Department of Nutrition, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China
| | - Jun-Long Lin
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, China
| | - Xin-Bin Chen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, China
| | - Wei-Hong Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China.
| | - Shi-Xue Dai
- Department of Gastroenterology, Guangdong Provincial Geriatrics Institute, National Key Clinical Specialty, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China.
| | - Wen-Jun Ma
- Department of Nutrition, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China.
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Tourkochristou E, Mouzaki A, Triantos C. Gene Polymorphisms and Biological Effects of Vitamin D Receptor on Nonalcoholic Fatty Liver Disease Development and Progression. Int J Mol Sci 2023; 24:ijms24098288. [PMID: 37175993 PMCID: PMC10179740 DOI: 10.3390/ijms24098288] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/28/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with increasing prevalence worldwide. The genetic and molecular background of NAFLD pathogenesis is not yet clear. The vitamin D/vitamin D receptor (VDR) axis is significantly associated with the development and progression of NAFLD. Gene polymorphisms may influence the regulation of the VDR gene, although their biological significance remains to be elucidated. VDR gene polymorphisms are associated with the presence and severity of NAFLD, as they may influence the regulation of adipose tissue activity, fibrosis, and hepatocellular carcinoma (HCC) development. Vitamin D binds to the hepatic VDR to exert its biological functions, either by activating VDR transcriptional activity to regulate gene expression associated with inflammation and fibrosis or by inducing intracellular signal transduction through VDR-mediated activation of Ca2+ channels. VDR activity has protective and detrimental effects on hepatic steatosis, a characteristic feature of NAFLD. Vitamin D-VDR signaling may control the progression of NAFLD by regulating immune responses, lipotoxicity, and fibrogenesis. Elucidation of the genetic and molecular background of VDR in the pathophysiology of NAFLD will provide new therapeutic targets for this disease through the development of VDR agonists, which already showed promising results in vivo.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Rion, 26504 Patras, Greece
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Rion, 26504 Patras, Greece
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Munteanu C, Schwartz B. The Effect of Bioactive Aliment Compounds and Micronutrients on Non-Alcoholic Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12040903. [PMID: 37107278 PMCID: PMC10136128 DOI: 10.3390/antiox12040903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 03/28/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
In the current review, we focused on identifying aliment compounds and micronutrients, as well as addressed promising bioactive nutrients that may interfere with NAFLD advance and ultimately affect this disease progress. In this regard, we targeted: 1. Potential bioactive nutrients that may interfere with NAFLD, specifically dark chocolate, cocoa butter, and peanut butter which may be involved in decreasing cholesterol concentrations. 2. The role of sweeteners used in coffee and other frequent beverages; in this sense, stevia has proven to be adequate for improving carbohydrate metabolism, liver steatosis, and liver fibrosis. 3. Additional compounds were shown to exert a beneficial action on NAFLD, namely glutathione, soy lecithin, silymarin, Aquamin, and cannabinoids which were shown to lower the serum concentration of triglycerides. 4. The effects of micronutrients, especially vitamins, on NAFLD. Even if most studies demonstrate the beneficial role of vitamins in this pathology, there are exceptions. 5. We provide information regarding the modulation of the activity of some enzymes related to NAFLD and their effect on this disease. We conclude that NAFLD can be prevented or improved by different factors through their involvement in the signaling, genetic, and biochemical pathways that underlie NAFLD. Therefore, exposing this vast knowledge to the public is particularly important.
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Affiliation(s)
- Camelia Munteanu
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
| | - Betty Schwartz
- The Institute of Biochemistry, Food Science and Nutrition, The School of Nutritional Sciences, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Abouzeed HS, Bahey Eldin L, El Masry SM, Naguib GG, Nagy MA, Toaima NN, Abdel-Ghaffar TY. Stoss therapy versus weekly regimen of vitamin D in children with chronic liver disease: a randomized pilot study. EGYPTIAN LIVER JOURNAL 2023. [DOI: 10.1186/s43066-023-00249-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023] Open
Abstract
Abstract
Background
Vitamin D, a hormone involved in the regulation of mineral homeostasis, protects skeletal integrity and modulates cell growth and differentiation. Recently, its potential antifibrotic effects have also been identified. Children with chronic liver disease mostly suffer from vitamin D deficiency. However, little knowledge is known regarding the optimum regimen that can be utilized effectively and safely to correct vitamin D deficiency in these patients and whether it could be effective in reversal or at least halting the progressive process of liver fibrosis. This study is conducted to answer these questions.
Results
Twenty-four children with chronic liver disease (13 boys and 11 girls) were included in the study. Their age ranged from 4.5 to 11.5 years with median age of 8 years. The aetiology of liver disease was heterogenous with autoimmune hepatitis, glycogen storage disease, or chronic hepatitis, and hepatitis C affects the majority. The patients were divided into two matched groups: group A (n:12) that received stoss parenteral intramuscular vitamin D3 (cholecalciferol) therapy (200,000 IU) once followed by 600 IU/day orally for 6 months (this is equivalent to the RDA as maintenance therapy) and group B (n:12) that received 50,000 IU/week oral vitamin D3 (cholecalciferol) therapy in divided daily doses adding on the maintenance dose 600 IU/day for the first 4 weeks followed by only 600 IU/day orally for the rest of the 6 months (5 months). Following vitamin D3 supplementation, in group A (vitamin D stoss therapy group) and group B (vitamin D oral therapy group), there were statistically significant improvement of Ca, alkaline phosphatase, and vitamin D levels, though there was no difference in between both groups. No significant correlation could be found between vitamin D changes and fibroscan changes in either group.
Conclusion
Vitamin D therapy using stoss dose followed by oral therapy or oral vitamin D therapy from the start was equally safe and effective in improving the clinical and laboratory metabolic bone profile abnormalities. Vitamin D effect on liver fibrosis progression or reversion in children is still not understood, and further studies are needed in this field taking in consideration the various causes of liver disease in children.
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1,25-Dihydroxycholecalciferol down-regulates 3-mercaptopyruvate sulfur transferase and caspase-3 in rat model of non-alcoholic fatty liver disease. J Mol Histol 2023; 54:119-134. [PMID: 36930413 DOI: 10.1007/s10735-023-10118-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of liver morbidity and mortality and has multiple unclear pathogenic mechanisms. Vitamin D deficiency was associated with increased incidence and severity of NAFLD. Increased hepatic expression of 3-mercaptopyruvate sulfur transferase (MPST) and dysregulated hepatocyte apoptosis were involved in NAFLD pathogenesis. We aimed to explore the protective effect of 1,25-Dihydroxycholecalciferol (1,25-(OH)2 D3) against development of NAFLD and the possible underlying mechanisms, regarding hepatic MPST and caspase-3 expression. 60 male adult rats were divided into 4 and 12 week fed groups; each was subdivided into control, high-fat diet (HFD), and HFD + VD. Serum levels of lipid profile parameters, liver enzymes, insulin, glucose, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and hepatic levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and reactive oxygen species (ROS) were measured. BMI and HOMA-IR were calculated, and liver tissues were processed for histopathological and immunohistochemical studies. The present study found that 1,25-(OH)2 D3 significantly decreased BMI, HOMA-IR, serum levels of glucose, insulin, liver enzymes, lipid profile parameters, CRP, TNF-α, hepatic levels of MDA, ROS, hepatic expression of MPST, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and caspase-3; and significantly increased hepatic TAC in both HFD-fed groups. In conclusion: Administration of 1,25-(OH)2 D3 with HFD abolished the NAFLD changes associated with HFD in 4-week group, and markedly attenuated the changes in 12-week group. The anti-apoptotic effect via decrement of caspase-3 and MPST expression are novel mechanisms suggested to be implicated in the protective effect of 1,25-(OH)2 D3.
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Mohamed AA, Halim AA, Mohamed S, Mahmoud SM, Bahgat Eldemiry EM, Mohamed RS, Shaheen MM, Naguib GG, Muharram NM, Khalil MG, Saed S, Ibrahim R, Salah Seif A, Kamal N, Nasraldin K, Abdelrahman AE, El Borolossy R. The effect of high oral loading dose of cholecalciferol in non-alcoholic fatty liver disease patients. A randomized placebo controlled trial. Front Pharmacol 2023; 14:1149967. [PMID: 36998617 PMCID: PMC10043211 DOI: 10.3389/fphar.2023.1149967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 03/02/2023] [Indexed: 03/15/2023] Open
Abstract
Background and Aim: Non-alcoholic fatty liver (NAFLD) is one of the most common progressive metabolic disorders worldwide. There are increasing scientific interests nowadays for the association between vitamin D status and Non-alcoholic fatty liver. Earlier studies have revealed that vitamin D deficiency is highly prevalent in Non-alcoholic fatty liver patients that contributes to poor outcomes. Hence, the present study aimed to assess the efficacy and safety of oral cholecalciferol on Non-alcoholic fatty liver patients.Subjects and Methods: This study was conducted on 140 patients that were randomized either to group 1 that received the standard conventional therapy in addition to placebo or group 2 that received the standard conventional therapy in addition to cholecalciferol during the 4 months study period.Results: At the end of the study group 2 revealed significant decrease (p < 0.05) in the mean serum level of TG, LDL-C, TC, hsCRP as compared to their baseline results and group 1 results. Additionally, a significant improvement in the serum levels of ALT (p = 0.001) was seen in group 2 at the end of the study when compared to group 1. Whereas group 1 did not show any change in these parameters when compared to group 2 and their baseline results.Conclusion: Cholecalciferol was shown to have beneficial effects on serum ALT levels, hsCRP levels and lipid profile of NAFLD patients.Clinical Trial Registration:https://prsinfo.clinicaltrials.gov/prs-users-guide.html, identifier NCT05613192
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Affiliation(s)
- Amal Ahmed Mohamed
- Department of Biochemistry and Molecular Biology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Ahmed Abdel Halim
- Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Sahar Mohamed
- Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | | | | | - Rasha Sobh Mohamed
- Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Gina G. Naguib
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nashwa M. Muharram
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Mona G. Khalil
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Salma Saed
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Randa Ibrahim
- Clinical and Chemical Pathology Department, Nutrition Institute, Cairo, Egypt
| | - Ahmed Salah Seif
- Tropical Medicine Hepatology and Gastroenterology Department, Shebeen El-Kom Teaching Hospital, Menoufia, Egypt
| | - Noha Kamal
- Clinical Pathology Department, Theodor Bilharz Research Institute (TBRI), Ministry of Scientific Research and Higher Education, Gulf Medical University (GMU), Cairo, Egypt
| | - Karima Nasraldin
- Faculty of Biotechnology, Modern Science and Arts University, Cairo, Egypt
| | - Ali Elsaid Abdelrahman
- Diagnostic and Intervention Radiology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Radwa El Borolossy
- Department of Clinical Pharmacy, Faculty of Pharmacy Ain Shams University, Cairo, Egypt
- *Correspondence: Radwa El Borolossy,
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Autoimmune Hepatitis and Fibrosis. J Clin Med 2023; 12:jcm12051979. [PMID: 36902767 PMCID: PMC10004701 DOI: 10.3390/jcm12051979] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/16/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic immune-inflammatory disease of the liver, generally considered a rare condition. The clinical manifestation is extremely varied and can range from paucisymptomatic forms to severe hepatitis. Chronic liver damage causes activation of hepatic and inflammatory cells leading to inflammation and oxidative stress through the production of mediators. This results in increased collagen production and extracellular matrix deposition leading to fibrosis and even cirrhosis. The gold standard for the diagnosis of fibrosis is liver biopsy; however, there are serum biomarkers, scoring systems, and radiological methods useful for diagnosis and staging. The goal of AIH treatment is to suppress fibrotic and inflammatory activities in the liver to prevent disease progression and achieve complete remission. Therapy involves the use of classic steroidal anti-inflammatory drugs and immunosuppressants, but in recent years scientific research has focused on several new alternative drugs for AIH that will be discussed in the review.
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Rizzo M, Colletti A, Penson PE, Katsiki N, Mikhailidis DP, Toth PP, Gouni-Berthold I, Mancini J, Marais D, Moriarty P, Ruscica M, Sahebkar A, Vinereanu D, Cicero AFG, Banach M, Al-Khnifsawi M, Alnouri F, Amar F, Atanasov AG, Bajraktari G, Banach M, Gouni-Berthold I, Bhaskar S, Bielecka-Dąbrowa A, Bjelakovic B, Bruckert E, Bytyçi I, Cafferata A, Ceska R, Cicero AF, Chlebus K, Collet X, Daccord M, Descamps O, Djuric D, Durst R, Ezhov MV, Fras Z, Gaita D, Gouni-Berthold I, Hernandez AV, Jones SR, Jozwiak J, Kakauridze N, Kallel A, Katsiki N, Khera A, Kostner K, Kubilius R, Latkovskis G, John Mancini G, David Marais A, Martin SS, Martinez JA, Mazidi M, Mikhailidis DP, Mirrakhimov E, Miserez AR, Mitchenko O, Mitkovskaya NP, Moriarty PM, Mohammad Nabavi S, Nair D, Panagiotakos DB, Paragh G, Pella D, Penson PE, Petrulioniene Z, Pirro M, Postadzhiyan A, Puri R, Reda A, Reiner Ž, Radenkovic D, Rakowski M, Riadh J, Richter D, Rizzo M, Ruscica M, Sahebkar A, Serban MC, Shehab AM, Shek AB, Sirtori CR, Stefanutti C, Tomasik T, Toth PP, Viigimaa M, Valdivielso P, Vinereanu D, Vohnout B, von Haehling S, Vrablik M, Wong ND, Yeh HI, Zhisheng J, Zirlik A. Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP). Pharmacol Res 2023; 189:106679. [PMID: 36764041 DOI: 10.1016/j.phrs.2023.106679] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.
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Affiliation(s)
- Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Via del Vespro 141, 90127 Palermo, Italy.
| | - Alessandro Colletti
- Department of Science and Drug Technology, University of Turin, Turin, Italy
| | - Peter E Penson
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK; Liverpool Centre for Cardiovascular Science, Liverpool, UK
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, Medical School, University College London (UCL), London, UK
| | - Peter P Toth
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA; Preventive Cardiology, CGH Medical Center, Sterling, IL, USA
| | - Ioanna Gouni-Berthold
- Department of Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Germany
| | - John Mancini
- Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - David Marais
- Chemical Pathology Division of the Department of Pathology, University of Cape Town Health Science Faculty, Cape Town, South Africa
| | - Patrick Moriarty
- Division of Clinical Pharmacology, Division of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dragos Vinereanu
- Cardiology Department, University and Emergency Hospital, Bucharest, Romania, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Arrigo Francesco Giuseppe Cicero
- Hypertension and Cardiovascular disease risk research center, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy; IRCCS Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.
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Jiang M, Huang C, Wu Q, Su Y, Wang X, Xuan Z, Wang Y, Xu F, Ge C. Sini San ameliorates CCl4-induced liver fibrosis in mice by inhibiting AKT-mediated hepatocyte apoptosis. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:115965. [PMID: 36460296 DOI: 10.1016/j.jep.2022.115965] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/12/2022] [Accepted: 11/21/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sini San (SNS) is recorded in Zhang Zhongjing's "Treatise on Typhoids" and is used in the treatment of non-alcoholic fatty liver disease, hepatitis, and other liver diseases, with good efficacy in liver fibrosis. However, its anti-liver fibrosis mechanism remains unclear. AIM OF THE STUDY This study aimed to evaluate the ameliorative effect of SNS on carbon tetrachloride (CCl4)-induced liver fibrosis in mice and the underlying mechanisms. MATERIALS AND METHODS The active ingredients in the water extract of SNS were determined using high-performance liquid chromatography (HPLC). CCl4-induced liver fibrosis mice were subsequently treated with different doses of SNS for 3 weeks, and AST, ALT, and T-BIL were detected in the serum. The pathological characteristics of the liver were observed using hematoxylin and eosin (H&E) and Masson's staining. Hepatocyte apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The proteins expression of PI3K, p-PI3K, AKT, p-AKT, FXR, caspase-8, Bax, and Bcl-2 was analyzed using western blotting and immunofluorescence. FXR mRNA expression was measured using quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR). Using network pharmacology and bioinformatics to search for active ingredients that regulate PI3K/AKT signaling in the SNS. The material basis for regulating PI3K/AKT signaling in SNS was searched using network pharmacology and bioinformatics. Based on the network pharmacology results, isorhamnetin or SNS-containing serum was added to HepG2 cells stimulated with TNF-α. The Cell Counting Kit (CCK)-8 assay was used to analyze cell viability and apoptosis of HepG2 cells was detected using flow cytometry. RESULTS SNS reduced serum levels of AST, ALT and T-BIL, down-regulated caspase-8 protein expression and the ratio of Bcl-2/Bax protein expression, and improved apoptosis in liver fibrosis mice. In addition, SNS downregulated the ratio of p-PI3K/PI3K and p-AKT/AKT protein expression and increased FXR expression. Network pharmacology studies showed that quercetin, kaempferol and isorhamnetin in SNS can bind to AKT. In vitro experiments showed that isorhamnetin inhibited HepG2 cell apoptosis, upregulated FXR expression and suppressed AKT activity, whereas AKT inhibitors blocked the effects of isorhamnetin. The effect of the SNS-containing serum was similar to that of isorhamnetin. CONCLUSION SNS ameliorated the progression of fibrosis and improved hepatocyte apoptosis in liver fibrosis mice. The anti-apoptotic mechanism was related to the inhibition of AKT-mediated down-regulation of FXR expression by its active ingredient, isorhamnetin.
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Affiliation(s)
- Meijie Jiang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, PR China
| | - Chunmei Huang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China
| | - Qiong Wu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China
| | - Yong Su
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China
| | - Xinming Wang
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China
| | - Zihua Xuan
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, PR China
| | - Yunlai Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, PR China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, PR China
| | - Fan Xu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, PR China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, PR China.
| | - Chaoliang Ge
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China.
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Megahed A, Gadalla H, Abdelhamid FM, Almehmadi SJ, Khan AA, Albukhari TA, Risha EF. Vitamin D Ameliorates the Hepatic Oxidative Damage and Fibrotic Effect Caused by Thioacetamide in Rats. Biomedicines 2023; 11:biomedicines11020424. [PMID: 36830960 PMCID: PMC9953330 DOI: 10.3390/biomedicines11020424] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/26/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
Vitamin D3 (VD3) is a sunshine hormone that regulates cellular proliferation, differentiation, apoptosis, and angiogenesis related to liver parenchyma. We used a thioacetamide (TAA)-induced hepatic fibrosis rat model in our study to investigate the beneficial roles of VD3 to overcome extensive liver fibrosis. Randomly, four equal groups (eight rats per group) underwent therapy for eight successive weeks: a control group, a group treated with TAA 100 mg/kg BW IP every other day, a group treated with VD3 1000 IU/kg BW IM every day, and a TAA+VD group treated with both therapies. Treatment with VD3 after TAA-induced hepatic fibrosis was found to alleviate elevated liver function measures by decreasing ALT, AST, and ALP activity; decreasing total bilirubin, direct bilirubin, cholesterol, and triglyceride levels; and increasing glucose and 25[OH]D3. Rats treated with VD3 showed marked decreases in MDA and increased SOD, CAT, and GSH levels. In addition, CD34 and FGF23 gene expressions were reduced after dual therapy. Liver sections from the TAA+VD group showed markedly decreased hepatic lesions, and Masson's trichrome stain showed a marked decrease in dense bluish-stained fibrous tissue. The immunohistochemical expression of TGF-β and α-SMA showed markedly decreased positive brown cytoplasmic expression in a few hepatocytes, clarifying the antifibrotic effect of VD3 in hepatic fibrosis. In conclusion, VD3 alleviates hepatotoxicity and fibrosis caused by TAA.
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Affiliation(s)
- Aya Megahed
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansour 35516, Egypt
| | - Hossam Gadalla
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansour 35516, Egypt
| | - Fatma M. Abdelhamid
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansour 35516, Egypt
| | - Samah J. Almehmadi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah P.O. Box 7607, Saudi Arabia
| | - Anmar A. Khan
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, Makkah P.O. Box 7607, Saudi Arabia
| | - Talat A. Albukhari
- Department of Immunology and Hematology, Faculty of Medicine, Umm Al-Qura University, Makkah P.O. Box 7607, Saudi Arabia
| | - Engy F. Risha
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansour 35516, Egypt
- Correspondence: ; Tel.: +20-120-534-8354
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Jiao S, Reinach PS, Huang C, Yu L, Zhuang H, Ran H, Zhao F, Srinivasalu N, Qu J, Zhou X. Calcipotriol Attenuates Form Deprivation Myopia Through a Signaling Pathway Parallel to TGF-β2-Induced Increases in Collagen Expression. Invest Ophthalmol Vis Sci 2023; 64:2. [PMID: 36723926 PMCID: PMC9904334 DOI: 10.1167/iovs.64.2.2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Purpose To determine the role of calcipotriol, a vitamin D3 analogue, in myopia development and altering the expression of scleral α1 chain of type I collagen (Col1α1) in mice. We also aimed to identify if the signaling pathway mediating the above changes is different from the one involved in transforming growth factor β2 (TGF-β2)-mediated increases of COL1A1 in cultured human scleral fibroblasts (HSFs). Methods C57BL/6J mice were either intraperitoneally injected with calcipotriol and subjected to form deprivation (FD) or exposed to normal refractive development for 4 weeks. Scleral vitamin D receptor (Vdr) expression was knocked down using a Sub-Tenon's capsule injection of an adeno-associated virus-packaged short hairpin RNA (AAV8-shRNA). Refraction and biometric measurements evaluated myopia development. A combination of knockdown and induction strategies determined the relative contributions of the vitamin D3 and the TGF-β2 signaling pathways in modulating COL1A1 expression in HSFs. Results Calcipotriol injections suppressed FD-induced myopia (FDM), but it had no significant effect on normal refractive development. AAV8-shRNA injection reduced Vdr mRNA expression by 42% and shifted the refraction toward myopia (-3.15 ± 0.99D, means ± SEM) in normal eyes. In HSFs, VDR knockdown reduced calcipotriol-induced rises in COL1A1 expression, but it did not alter TGF-β2-induced increases in COL1A1 expression. Additionally, TGF-β2 augmented calcipotriol-induced rises in COL1A1 expression. TGF-β receptor (TGFBRI/II) knockdown blunted TGF-β2-induced increases in COL1A1 expression, whereas calcipotriol-induced increases in VDR and COL1A1 expression levels were unaltered. Conclusions Scleral vitamin D3 inhibits myopia development in mice, potentially by activating a VDR-dependent signaling pathway and increasing scleral COL1A1 expression levels.
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Affiliation(s)
- Shiming Jiao
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Peter Sol Reinach
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chengjie Huang
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lan Yu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huiman Zhuang
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hongli Ran
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fei Zhao
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,Research Unit of Myopia Basic Research and Clinical Prevention and Control, Chinese Academy of Medical Sciences, Wenzhou, Zhejiang, China,Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China,National Clinical Research Center for Ocular Diseases, Wenzhou, Zhejiang, China
| | - Nethrajeith Srinivasalu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jia Qu
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China,National Clinical Research Center for Ocular Diseases, Wenzhou, Zhejiang, China
| | - Xiangtian Zhou
- School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,Research Unit of Myopia Basic Research and Clinical Prevention and Control, Chinese Academy of Medical Sciences, Wenzhou, Zhejiang, China,Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang, China,National Clinical Research Center for Ocular Diseases, Wenzhou, Zhejiang, China
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Zang G, Sun X, Sun Y, Zhao Y, Dong Y, Pang K, Cheng P, Wang M, Zheng Y. Chronic liver diseases and erectile dysfunction. Front Public Health 2023; 10:1092353. [PMID: 36684968 PMCID: PMC9853559 DOI: 10.3389/fpubh.2022.1092353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023] Open
Abstract
Chronic liver diseases (CLDs) are characterized by progressive necrosis of hepatocytes, which leads to liver fibrosis and cirrhosis, and ultimately liver dysfunction. The statistics of 2020 shows that the number of patients with CLDs, including chronic hepatitis, fatty liver, and cirrhosis, may exceed 447 million in China. The liver is a crucial organ for the metabolism of various substances, including sex hormones and lipids. CLDs frequently result in abnormalities in the metabolism of sex hormones, glucose, and lipids, as well as mental and psychological illnesses, all of which are significant risk factors for erectile dysfunction (ED). It has been reported that the prevalence of ED in male patients with CLDs ranges from 24.6 to 85.0%. According to a survey of Caucasians, liver transplantation may improve the erectile function of CLDs patients with ED. This finding supports the link between CLDs and ED. In addition, ED is often a precursor to a variety of chronic diseases. Given this correlation and the significant prevalence of CLDs, it is important to evaluate the epidemiology, risk factors, etiology, and treatment outcomes of ED in male patients with CLDs, expecting to attract widespread attention.
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Affiliation(s)
- Guanghui Zang
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Xv Sun
- Graduate School, Bengbu Medical College, Bengbu, Anhui, China
| | - Yufeng Sun
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yan Zhao
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yang Dong
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Kun Pang
- Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Ping Cheng
- Graduate School, Bengbu Medical College, Bengbu, Anhui, China
| | - Meng Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Yuli Zheng
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
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Chang MS, Hartman RI, Trepanowski N, Giovannucci EL, Nan H, Li X. Cumulative Erythemal Ultraviolet Radiation and Risk of Cancer in 3 Large US Prospective Cohorts. Am J Epidemiol 2022; 191:1742-1752. [PMID: 35671977 PMCID: PMC9991893 DOI: 10.1093/aje/kwac101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 05/20/2022] [Accepted: 06/01/2022] [Indexed: 01/29/2023] Open
Abstract
Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity = 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR = 1.17, 95% CI: 1.04, 1.31; P for heterogeneity = 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers.
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Affiliation(s)
| | | | | | | | | | - Xin Li
- Correspondence to Dr. Xin Li, Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Health Sciences Building, RG 5114, 1050 Wishard Boulevard., Indianapolis, IN 46202 (e-mail: )
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Vitamin D Status and Steatohepatitis in Obese Diabetic and Non-Diabetic Patients. J Clin Med 2022; 11:jcm11185482. [PMID: 36143129 PMCID: PMC9503920 DOI: 10.3390/jcm11185482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/08/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND AND AIMS The presence of steatohepatitis in obese patients can be multifactorial. The current study tries to determine the differences between diabetic and non-diabetic patients regarding the presence of steatohepatitis. We evaluated sequential liver samples and collected the times of bariatric surgery to assess the presence of NASH in patients with obesity, in the circuit of bariatric surgery. METHODS We performed a retrospective study of 49 patients presenting high-grade obesity in the circuit of bariatric surgery, with liver biopsy. The patients underwent bariatric surgery at a single center in France and were followed for 2 years. The liver biopsies were performed intraoperatively on all 49 patients before the bariatric surgery. The primary endpoint of the study was to evaluate the relationships between steatohepatitis/liver fibrosis and the presence of diabetes and to evaluate the current relationships between the biochemical work-ups. Special importance was accorded to the correlations between vitamin D levels and the presence of hepatic steatosis, due to the antifibrogenic pattern in the liver, as shown in many important papers in the field. RESULTS Significant correlations were found between the presence of liver fibrosis and the presence of diabetes (p = 0.022), but not regarding the antidiabetic treatment. An important correlation was found between the vitamin D levels and the presence of liver fibrosis, as well as with the levels of A1C hemoglobin and LDL cholesterol levels. CONCLUSIONS Vitamin D deficiency presents a strong correlation with hepatic steatosis in individuals with morbid obesity. Correcting vitamin D deficiency may present a beneficial role in treating hepatic steatosis, diabetes, and cardiovascular risk in patients with morbid obesity.
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Pop TL, Sîrbe C, Benţa G, Mititelu A, Grama A. The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases. Int J Mol Sci 2022; 23:ijms231810705. [PMID: 36142636 PMCID: PMC9503777 DOI: 10.3390/ijms231810705] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/09/2022] [Accepted: 09/12/2022] [Indexed: 11/24/2022] Open
Abstract
Vitamin D (calciferol) is a fat-soluble vitamin that has a significant role in phospho-calcium metabolism, maintaining normal calcium levels and bone health development. The most important compounds of vitamin D are cholecalciferol (vitamin D3, or VD3) and ergocalciferol (vitamin D2, or VD2). Besides its major role in maintaining an adequate level of calcium and phosphate concentrations, vitamin D is involved in cell growth and differentiation and immune function. Recently, the association between vitamin D deficiency and the progression of fibrosis in chronic liver disease (CLD) was confirmed, given the hepatic activation process and high prevalence of vitamin D deficiency in these diseases. There are reports of vitamin D deficiency in CLD regardless of the etiology (chronic viral hepatitis, alcoholic cirrhosis, non-alcoholic fatty liver disease, primary biliary cirrhosis, or autoimmune hepatitis). Vitamin D binding protein (VDBP) is synthesized by the liver and has the role of binding and transporting vitamin D and its metabolites to the target organs. VDBP also plays an important role in inflammatory response secondary to tissue damage, being involved in the degradation of actin. As intense research during the last decades revealed the possible role of vitamin D in liver diseases, a deeper understanding of the vitamin D, vitamin D receptors (VDRs), and VDBP involvement in liver inflammation and fibrogenesis could represent the basis for the development of new strategies for diagnosis, prognosis, and treatment of liver diseases. This narrative review presents an overview of the evidence of the role of vitamin D and VDBP in CLD, both at the experimental and clinical levels.
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Affiliation(s)
- Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Claudia Sîrbe
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence:
| | - Gabriel Benţa
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Alexandra Mititelu
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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An Update on the Effects of Vitamin D on the Immune System and Autoimmune Diseases. Int J Mol Sci 2022; 23:ijms23179784. [PMID: 36077185 PMCID: PMC9456003 DOI: 10.3390/ijms23179784] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 12/16/2022] Open
Abstract
Vitamin D intervenes in calcium and phosphate metabolism and bone homeostasis. Experimental studies have shown that 1,25-dihydroxyvitamin D (calcitriol) generates immunologic activities on the innate and adaptive immune system and endothelial membrane stability. Low levels of serum 25-hydroxyvitamin D (25(OH)D) are associated with an increased risk of developing immune-related diseases such as psoriasis, type 1 diabetes, multiple sclerosis, and autoimmune diseases. Various clinical trials describe the efficacy of supplementation of vitamin D and its metabolites for treating these diseases that result in variable outcomes. Different disease outcomes are observed in treatment with vitamin D as high inter-individual difference is present with complex gene expression in human peripheral blood mononuclear cells. However, it is still not fully known what level of serum 25(OH)D is needed. The current recommendation is to increase vitamin D intake and have enough sunlight exposure to have serum 25(OH)D at a level of 30 ng/mL (75 nmol/L) and better at 40–60 ng/mL (100–150 nmol/L) to obtain the optimal health benefits of vitamin D.
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Aggeletopoulou I, Thomopoulos K, Mouzaki A, Triantos C. Vitamin D–VDR Novel Anti-Inflammatory Molecules—New Insights into Their Effects on Liver Diseases. Int J Mol Sci 2022; 23:ijms23158465. [PMID: 35955597 PMCID: PMC9369388 DOI: 10.3390/ijms23158465] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 02/05/2023] Open
Abstract
There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D–VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D–VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
- Correspondence:
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, GR-26504 Patras, Greece;
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, GR-26504 Patras, Greece; (I.A.); (C.T.)
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Czaja AJ. Epigenetic Aspects and Prospects in Autoimmune Hepatitis. Front Immunol 2022; 13:921765. [PMID: 35844554 PMCID: PMC9281562 DOI: 10.3389/fimmu.2022.921765] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.
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Affiliation(s)
- Albert J. Czaja
- *Correspondence: Albert J. Czaja, ; orcid.org/0000-0002-5024-3065
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Association of serum 25-hydroxyvitamin D 3 levels and insulin resistance with viral load and degree of liver fibrosis in Egyptian chronic HBV patients: a case-control study. Clin Exp Hepatol 2022; 8:14-20. [PMID: 35415253 PMCID: PMC8984796 DOI: 10.5114/ceh.2022.114139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/05/2022] [Indexed: 12/04/2022] Open
Abstract
Aim of the study To assess serum 25-hydroxyvitamin D3 level and insulin resistance (IR) in hepatitis B virus (HBV) patients compared with controls and to evaluate the correlation with HBV viral load, severity of liver disease and degree of liver fibrosis. Material and methods A case-control study. Sixty HBV patients and 60 controls were enrolled. Chemiluminescence was used to determine 25-hydroxyvitamin D3 levels. Insulin resistance was evaluated using the homeostasis model assessment method. Polymerase chain reaction was used to quantify HBV viral loads. Severity of liver disease was assessed by Child-Pugh scores. Transient elastography was used to evaluate the degree of liver fibrosis. Results 25-Hydroxyvitamin D3 deficiency is more prevalent among HBV patients compared to controls. 25-Hydroxyvitamin D3 levels declined considerably as viral load rose (p < 0.001). 25-Hydroxyvitamin D3 level declined as liver fibrosis progressed (34.0 ±0.0 ng/ml in F1 vs. 12.67 ±8.0 ng/ml in F4) and the severity of the disease increased (22.75 ±6.36 ng/ml in Child A vs. 5.50 ±0.58 ng/ml in Child C). Insulin resistance is more prevalent among HBV patients compared to controls and it appeared to deteriorate progressively with boosting of the viral load, degree of fibrosis and severity of liver disease (p < 0.001). Conclusions HBV patients had significantly lower 25-hydroxyvitamin D3 levels compared to healthy individuals and HBV infection is associated with IR. 25-Hydroxyvitamin D3 deficiency and IR were associated with HBV viral loads, severity of liver disease, and degree of liver fibrosis.
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Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients 2022; 14:1448. [PMID: 35406059 PMCID: PMC9003337 DOI: 10.3390/nu14071448] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 02/07/2023] Open
Abstract
This is a narrative review of the evidence supporting vitamin D's anticancer actions. The first section reviews the findings from ecological studies of cancer with respect to indices of solar radiation, which found a reduced risk of incidence and mortality for approximately 23 types of cancer. Meta-analyses of observational studies reported the inverse correlations of serum 25-hydroxyvitamin D [25(OH)D] with the incidence of 12 types of cancer. Case-control studies with a 25(OH)D concentration measured near the time of cancer diagnosis are stronger than nested case-control and cohort studies as long follow-up times reduce the correlations due to changes in 25(OH)D with time. There is no evidence that undiagnosed cancer reduces 25(OH)D concentrations unless the cancer is at a very advanced stage. Meta-analyses of cancer incidence with respect to dietary intake have had limited success due to the low amount of vitamin D in most diets. An analysis of 25(OH)D-cancer incidence rates suggests that achieving 80 ng/mL vs. 10 ng/mL would reduce cancer incidence rates by 70 ± 10%. Clinical trials have provided limited support for the UVB-vitamin D-cancer hypothesis due to poor design and execution. In recent decades, many experimental studies in cultured cells and animal models have described a wide range of anticancer effects of vitamin D compounds. This paper will review studies showing the inhibition of tumor cell proliferation, dedifferentiation, and invasion together with the sensitization to proapoptotic agents. Moreover, 1,25-(OH)2D3 and other vitamin D receptor agonists modulate the biology of several types of stromal cells such as fibroblasts, endothelial and immune cells in a way that interferes the apparition of metastases. In sum, the available mechanistic data support the global protective action of vitamin D against several important types of cancer.
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Affiliation(s)
- Alberto Muñoz
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, CIBERONC and IdiPAZ, 28029 Madrid, Spain;
| | - William B. Grant
- Sunlight, Nutrition and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
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Von-Hafe M, Borges-Canha M, Vale C, Leite AR, Sérgio Neves J, Carvalho D, Leite-Moreira A. Nonalcoholic Fatty Liver Disease and Endocrine Axes-A Scoping Review. Metabolites 2022; 12:298. [PMID: 35448486 PMCID: PMC9026925 DOI: 10.3390/metabo12040298] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/20/2022] [Accepted: 03/27/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD often occurs associated with endocrinopathies. Evidence suggests that endocrine dysfunction may play an important role in NAFLD development, progression, and severity. Our work aimed to explore and summarize the crosstalk between the liver and different endocrine organs, their hormones, and dysfunctions. For instance, our results show that hyperprolactinemia, hypercortisolemia, and polycystic ovary syndrome seem to worsen NAFLD's pathway. Hypothyroidism and low growth hormone levels also may contribute to NAFLD's progression, and a bidirectional association between hypercortisolism and hypogonadism and the NAFLD pathway looks likely, given the current evidence. Therefore, we concluded that it appears likely that there is a link between several endocrine disorders and NAFLD other than the typically known type 2 diabetes mellitus and metabolic syndrome (MS). Nevertheless, there is controversial and insufficient evidence in this area of knowledge.
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Affiliation(s)
- Madalena Von-Hafe
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
| | - Marta Borges-Canha
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
- Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
| | - Catarina Vale
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
| | - Ana Rita Leite
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
| | - João Sérgio Neves
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
- Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
| | - Davide Carvalho
- Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
- Investigação e Inovação em Saúde (i3s), Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal
| | - Adelino Leite-Moreira
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
- Serviço de Cirurgia Cardiotorácica do Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
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Sergi CM. Vitamin D supplementation for autoimmune hepatitis: A need for further investigation. World J Hepatol 2022; 14:295-299. [PMID: 35126856 PMCID: PMC8790399 DOI: 10.4254/wjh.v14.i1.295] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/25/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a chronic liver disease harboring an autoimmune basis and progressive character. Despite still obscurity in etiology and pathogenesis, some evidence supports the importance of sustaining the immune system. Vitamin D is a lipo-soluble vitamin, which has been identified as decreased in our body. It is often due to the daily habit change and decrease of individual sun exposure due to the increase of the ultraviolet-induced potential melanocytic transformation. Here, we emphasize the importance of vitamin D supplementation in patients affected with liver disease.
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Affiliation(s)
- Consolato M Sergi
- Anatomic Pathology Division, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, Ottawa K1H 8L1, ON, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton T6G 2B7, AB, Canada
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Gong J, Gong H, Liu Y, Tao X, Zhang H. Calcipotriol attenuates liver fibrosis through the inhibition of vitamin D receptor-mediated NF-κB signaling pathway. Bioengineered 2022; 13:2658-2672. [PMID: 35043727 PMCID: PMC8973618 DOI: 10.1080/21655979.2021.2024385] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Liver fibrosis is an inevitable stage in the development of chronic liver disease to cirrhosis. Nonetheless, the interventional treatment and achieving control over the disease at this stage can substantially reduce the incidence of liver cirrhosis. To demonstrate these aspects, liver pathological sections of 18 patients with chronic liver disease are collected for research according to the degree of fibrosis. Further, the expressions of related proteins in each group are studied by the Western blot method. The cell proliferation and apoptosis are detected by CKK-8 and flow cytometry analyses. Further, a rat model with carbon tetrachloride (CCl4)-induced liver fibrosis is employed to verify the effect and mechanism of VDR on the process of liver fibrosis in vivo. The expression of VDR in liver tissues of patients with liver fibrosis is negatively correlated with α-smooth muscle actin (α-SMA), Col-1, and liver fibrosis stages. Moreover, the tumor necrosis factor (TNF)-α stimulation could increase the proliferation of LX-2, up-regulate the expression of α-SMA, Col-1, NF-κB, p-IκBα, p-IKKβ, p-p65m, and some fibrosis factors, as well as down-regulate the expressions of VDR and matrix metalloproteinase-1 (MMP-1). Considering the protective actions of VDR, calcipotriol, a VDR agonist, effectively reduced the degree of liver fibrosis in a rat model of liver fibrosis by inhibiting the deposition of extracellular (ECM) and activation of hepatic stellate cells (HSCs), which is negatively correlated with the degree of liver fibrosis. Together, these shreds of evidence demonstrated that the calcipotriol showed great potential in effectively attenuating liver fibrosis.
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Affiliation(s)
- Jian Gong
- Department of Infectious Diseases, The Third Xiangya Hospital of Central South University, Changsha, P. R. China
| | - HuanYu Gong
- Department of Infectious Diseases, The Third Xiangya Hospital of Central South University, Changsha, P. R. China
| | - Yang Liu
- Department of Pathology, The Third Xiangya Hospital of Central South University, Changsha, P. R. China
| | - XinLan Tao
- Department of Pathology, The Third Xiangya Hospital of Central South University, Changsha, P. R. China
| | - Hao Zhang
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha, P. R. China
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Kumar A, Saraswat V, Pande G, Kumar R. Does Treatment of Erectile Dysfunction With PDE 5 Inhibitor Tadalafil Improve Quality of Life in Male Patients With Compensated Chronic Liver Disease? A Prospective Pilot Study. J Clin Exp Hepatol 2022; 12:1083-1090. [PMID: 35814506 PMCID: PMC9257884 DOI: 10.1016/j.jceh.2022.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 01/19/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS Erectile dysfunction (ED) is common in patients with compensated cirrhosis but its impact on the quality of life (QOL) is usually overlooked. This study aimed at determining the frequency of ED in male patients with compensated chronic liver disease (CLD), assessing their QOL and the response to treatment with tadalafil. A secondary aim was to assess the effect of the tadalafil therapy on liver fibrosis, if any. METHODS Consecutive patients with compensated CLD and advanced liver fibrosis were screened at the baseline with the International Index of Erectile Function-5 (IIEF-5), QOL questionnaire (WHOQOL-BREF), liver stiffness measurements (LSM) made with Fibroscan™ (Echosens, France), and fibrosis index based on 4 factors (FIB-4) scores. Patients with ED meeting eligibility criteria were prescribed PDE5 inhibitor tadalafil 20 mg on alternate days. During the follow-up, IIEF-5, LSM, and FIB-4 were monitored after 3 and 6 months while the WHOQOL-BREF questionnaire was administered at the baseline and at 6 months. RESULTS Among 89 patients with CLD and advanced liver fibrosis, ED was present in 43 (48%) and tadalafil was prescribed to 34 patients (38%) meeting exclusion and inclusion criteria. At 3 months follow-up, the mean IIEF 5 score increased from 15.57 ± 4 to 20.78 ± 3.6, (P = 0.0001) and the improvement persisted at 6 months (IIEF-5 score 21.87 ± 2.2; P = 0.12). The physical, social relationships, and environment domains in the WHOQOL-BREF questionnaire showed significant improvement at six months (P < 0.05) but not the psychological domain (P = ns). From a baseline value of 12.69 ± 3.1 kPa, the mean LSM decreased to 11.37 ± 3.9 kPa, (P = 0.02) after 3 months on tadalafil. After 6 months, the LSM further decreased from 11 ± 0.9 to 8.2 ± 3.2 kPa (P = 0.034). FIB-4 values showed a decline from the baseline at 3 months, from 1.52 ± 0.58 to 1.32 ± 0.55, P < 0.05 and at 6 months, from 1.25 ± 0.53 to 0.97 ± 0.36, P > 0.05. The CAP values did not show any significant change. There was an insignificant decline in the SGOT and SGPT levels (P > 0.05) with no significant change in CTP or MELD scores. CONCLUSIONS In the short term, tadalafil improves ED and QOL in patients with CLD and advanced liver fibrosis. It may also reduce liver fibrosis in them. Further studies that include liver histology are needed to confirm this preliminary observation of a possible antifibrotic effect.
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Key Words
- ALD, alcoholic liver disease
- CLD, chronic liver disease
- ED, Erectile dysfunction
- FIB-4
- FIB-4, fibrosis index based on 4 factors
- HRQOL, health-related quality of life
- IIEF-5
- IIEF-5, the International Index of Erectile Function-5
- LC, liver cirrhosis
- LSM, liver stiffness measurement
- MAP, mean arterial pressure
- PDE-5 I
- PDE5-I, phosphodiesterase inhibitors
- PDEs, phosphodiesterases
- PPH, porto-pulmonary hypertension
- QOL, quality of life
- SMT, standard medical therapy
- TAA, thioacetamide
- TE, transient elastography
- WHOQOL-BREF
- cAMP, cyclic adenosine monophosphate
- cGMP, cyclic guanosine monophosphate
- erectile dysfunction
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Affiliation(s)
- Alok Kumar
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
| | - Vivek Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India,Address for correspondence: Vivek A. Saraswat, Head, Department of Hepatology, Pancreatobiliary Sciences and Liver Transplantation Mahatma Gandhi Medical College and Hospital, Jaipur, 302022, Rajasthan, India
| | - Gaurav Pande
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India
| | - Rajesh Kumar
- Department of Community Medicine, Rajendra Institute of Medical Sciences, Ranchi, JH, India
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Goto RL, Tablas MB, Prata GB, Espírito Santo SG, Fernandes AAH, Cogliati B, Barbisan LF, Romualdo GR. Vitamin D 3 supplementation alleviates chemically-induced cirrhosis-associated hepatocarcinogenesis. J Steroid Biochem Mol Biol 2022; 215:106022. [PMID: 34774723 DOI: 10.1016/j.jsbmb.2021.106022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 10/05/2021] [Accepted: 11/07/2021] [Indexed: 11/19/2022]
Abstract
Vitamin D3 (VD3) deficiency has been associated with increased risk for cirrhosis and hepatocellular carcinoma, a highly incident malignant neoplasia worldwide. On the other hand, VD3 supplementation has shown some beneficial effects in clinical studies and rodent models of chronic liver disease. However, preventive effects of dietary VD3 supplementation in cirrhosis-associated hepatocarcinogenesis is still unknow. To investigate this purpose, male Wistar rats submitted to a combined diethylnitrosamine- and thioacetamide-induced model were concomitantly supplemented with VD3 (5,000 and 10,000 IU/kg diet) for 25 weeks. Liver samples were collected for histological, biochemical and molecular analysis. Serum samples were used to measure 25-hydroxyvitamin D [25(OH)D] and alanine aminotransferase levels. Both VD3 interventions decreased hepatic collagen deposition and pro-inflammatory p65 protein levels, while increased hepatic antioxidant catalase and glutathione peroxidase activities and serum 25(OH)D, without a clear dose-response effect. Nonetheless, only the highest concentration of VD3 increased hepatic protein levels of VD receptor, while decreased the number of large preneoplastic glutathione-S-transferase- (>0.5 mm²) and keratin 8/18-positive lesions, as well the multiplicity of hepatocellular adenomas. Moreover, this intervention increased hepatic antioxidant Nrf2 protein levels and glutathione-S-transferase activity. In summary, dietary VD3 supplementation - in special the highest intervention - showed antifibrotic and antineoplastic properties in chemically-induced cirrhosis-associated hepatocarcinogenesis. The positive modulation of Nrf2 antioxidant axis may be mechanistically involved with these beneficial effects, and may guide future clinical studies.
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MESH Headings
- Adenoma, Liver Cell/chemically induced
- Adenoma, Liver Cell/metabolism
- Adenoma, Liver Cell/pathology
- Adenoma, Liver Cell/prevention & control
- Alanine Transaminase/blood
- Alanine Transaminase/genetics
- Animals
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/prevention & control
- Catalase/blood
- Catalase/genetics
- Chemoprevention/methods
- Collagen/genetics
- Collagen/metabolism
- Dietary Supplements
- Diethylnitrosamine/toxicity
- Gene Expression Regulation/drug effects
- Glutathione Peroxidase/blood
- Glutathione Peroxidase/genetics
- Glutathione Transferase/genetics
- Glutathione Transferase/metabolism
- Keratins/genetics
- Keratins/metabolism
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis/chemically induced
- Liver Cirrhosis/drug therapy
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/pathology
- Liver Neoplasms/chemically induced
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/prevention & control
- Male
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Nucleocytoplasmic Transport Proteins/genetics
- Nucleocytoplasmic Transport Proteins/metabolism
- Rats
- Rats, Wistar
- Receptors, Calcitriol/genetics
- Receptors, Calcitriol/metabolism
- Thioacetamide/toxicity
- Vitamin D/administration & dosage
- Vitamin D/analogs & derivatives
- Vitamin D/blood
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Affiliation(s)
- Renata L Goto
- São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil
| | - Mariana B Tablas
- São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil
| | - Gabriel B Prata
- São Paulo State University (UNESP), Medical School, Department of Pathology, Botucatu, SP, Brazil
| | - Sara G Espírito Santo
- São Paulo State University (UNESP), Medical School, Department of Pathology, Botucatu, SP, Brazil
| | - Ana Angélica H Fernandes
- São Paulo State University (UNESP), Biosciences Institute, Department of Chemical and Biological Sciences, Botucatu, SP, Brazil
| | - Bruno Cogliati
- University of São Paulo (USP), School of Veterinary Medicine and Animal Science, Department of Pathology, São Paulo, SP, Brazil
| | - Luis F Barbisan
- São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil
| | - Guilherme R Romualdo
- São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil; São Paulo State University (UNESP), Medical School, Department of Pathology, Botucatu, SP, Brazil.
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