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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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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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3
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Megahed A, Gadalla H, Filimban WA, Albukhari TA, Sembawa H, Bagadood RM, Sindi G, Abdelhamid FM, El-Boshy ME, Risha EF. Hesperidin ameliorates thioacetamide-induced liver fibrosis via antioxidative and anti-inflammatory mechanisms targeting TGF-β/α-SMA pathways in rats. Int J Immunopathol Pharmacol 2024; 38:3946320241309004. [PMID: 39707862 DOI: 10.1177/03946320241309004] [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] [Indexed: 12/23/2024] Open
Abstract
Our study intended to explore Hesp antioxidant and anti-inflammatory effects against TAA hepatic fibrosis in rats. Hesperidin (Hesp), is a pharmacologically active flavonoid, found abundantly in citrus species. Our present research attempts to inspect the potential hepatoprotective role of Hesp against thioacetamide (TAA)-induced hepatic fibrosis. Thirty-two male albino rats were split up into four equal groups, each with eight rats: Cont group was treated with ip saline. Every other day, the TAA group was injected 100 mg/kg BW ip TAA, Hesp group received every day oral Hesp 200 mg/kg BW as well as TAA + Hesp group received both therapies (TAA, Hesp) for eight successive weeks. Hesp in TAA treated group reduces ALT, AST, and ALP activities, total, direct bilirubin, total cholesterol, and triglycerides, meanwhile TP, Alb, globulin, A/G ratio levels were insignificantly differed. The antioxidant capacity of Hesp was pronounced by a marked reduction in MDA level. While the antioxidant markers (SOD, CAT, GSH) were insignificantly changed after Hesp treatment. A strong significant correlation in treated rats between fibrosis score and CD34 and FGF23 gene expression. Liver sections from dual-treated rats showed a moderately decreased hepatic lesion and the dense, bluish-stained fibrous tissue by Masson's trichrome. Elevated gene expressions of CD34 and FGF23 after TAA hepatotoxicity were diminished by the antifibrotic effect of Hesp. Also, immunohistochemical expression showed reduction of TGF-β and α-SMA in hepatocytes in the dual therapy group. Hesp possesses a potent antioxidant, and antifibrotic activities against TAA induced hepatic fibrosis by modulating TGF-β/α-SMA pathways.
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Affiliation(s)
- Aya Megahed
- Clinical Pathology Department, Veterinary Medicine Faculty, University of Mansoura, Mansoura, Egypt
| | - Hossam Gadalla
- Clinical Pathology Department, Veterinary Medicine Faculty, University of Mansoura, Mansoura, Egypt
| | - Waheed A Filimban
- Pathology Department, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Talat A Albukhari
- Department of Hematology and Immunology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Hatem Sembawa
- Department of Surgery, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Rehab M Bagadood
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ghadir Sindi
- Clinical Laboratory Sciences Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Kingdom of Saudi Arabia
| | - Fatma M Abdelhamid
- Clinical Pathology Department, Veterinary Medicine Faculty, University of Mansoura, Mansoura, Egypt
| | - Mohamed E El-Boshy
- Clinical Pathology Department, Veterinary Medicine Faculty, University of Mansoura, Mansoura, Egypt
| | - Engy F Risha
- Clinical Pathology Department, Veterinary Medicine Faculty, University of Mansoura, Mansoura, Egypt
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Zhang Y, Wang L, Shao J, Liu Y, Lu Y, Yang J, Xu S, Zhang J, Li M, Liu X, Zheng M. Nano-calcipotriol as a potent anti-hepatic fibrosis agent. MedComm (Beijing) 2023; 4:e354. [PMID: 37638336 PMCID: PMC10458662 DOI: 10.1002/mco2.354] [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: 01/06/2023] [Revised: 07/30/2023] [Accepted: 08/04/2023] [Indexed: 08/29/2023] Open
Abstract
Calcipotriol (CAL) has been widely studied as a fibrosis inhibitor and used to treat plaque psoriasis via transdermal administration. The clinical application of CAL to treat liver fibrosis is bottlenecked by its unsatisfactory pharmacokinetics, biodistribution, and side effects, such as hypercalcemia in patients. The exploration of CAL as a safe and effective antifibrotic agent remains a major challenge. Therefore, we rationally designed and synthesized a self-assembled drug nanoparticle encapsulating CAL in its internal hydrophobic core for systematic injection (termed NPs/CAL) and further investigated the beneficial effect of the nanomaterial on liver fibrosis. C57BL/6 mice were used as the animal model, and human hepatic stellate cell line LX-2 was used as the cellular model of hepatic fibrogenesis. Immunofluorescence staining, flow cytometry, western blotting, immunohistochemical staining, and in vitro imaging were used for evaluating the efficacy of NPs/CAL treatment. We found NPs/CAL can be quickly internalized in vitro, thus potently deactivating LX-2 cells. In addition, NPs/CAL improved blood circulation and the accumulation of CAL in liver tissue. Importantly, NPs/CAL strongly contributed to the remission of liver fibrosis without inducing hypercalcemia. Overall, our work identifies a promising paradigm for the development of nanomaterial-based agents for liver fibrosis therapy.
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Affiliation(s)
- Yina Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Liying Wang
- Department of Pharmacology and Department of Gastroenterology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Department of General SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for BionanoengineeringCollege of Chemical and Biological EngineeringZhejiang UniversityHangzhouChina
| | - Jiajia Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Yining Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Jing Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Siduo Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Jingkang Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Minwei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
| | - Xiangrui Liu
- Department of Pharmacology and Department of Gastroenterology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for BionanoengineeringCollege of Chemical and Biological EngineeringZhejiang UniversityHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina
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Koç Yıldırım S, Najafova T, Ersoy Evans S, Lay İ, Karaduman A. Serum vitamin D levels and vitamin D receptor gene ApaI and TaqI polymorphisms in patients with morphea: a case-control study. Arch Dermatol Res 2023; 315:2119-2127. [PMID: 36964246 DOI: 10.1007/s00403-023-02612-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 02/11/2023] [Accepted: 03/14/2023] [Indexed: 03/26/2023]
Abstract
A uncommon inflammatory condition called morphea causes fibrosis in the skin and subcutaneous tissue. The key stages in the pathophysiology are vascular damage, immunological response, and fibrosis. Numerous research have examined the relationships between the immune system, fibrosis, and vitamin D, but the exact pathogenetic pathways of morphea remain poorly understood. The purpose of this study was to investigate serum 25(OH)D levels and the ApaI (rs7975232) and TaqI (rs731236) polymorphisms of the vitamin D receptor (VDR) in morphea patients. There were 48 age- and sex-matched controls and 41 morphea patients total. VDR polymorphisms were found using PCR tests and gel electrophoresis, and serum 25(OH)D levels were determined using liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). The patient group consisted of 37 females (90.2%) and 4 males (9.8%). The patients' mean age was 38.68 ± 17.54 years. In terms of VDR ApaI and TaqI polymorphisms, there was no discernible difference between the patient and control groups. TaqI polymorphism heterozygosity was discovered in all patients with progressive disease, and this finding was statistically significant (p = 0.012). Patients' mean serum 25(OH)D levels were 16.98 ± 11.55 ng/mL, while those in the control group were 18.02 ± 14.30 ng/mL. VDR polymorphisms, vitamin D levels, disease subtype, age of onset, and responsiveness to treatment did not significantly correlate. In our research, we discovered that TaqI polymorphism may be related to the severity of the disease and that the polymorphisms of the VDR ApaI and TaqI were not associated with morphea susceptibility.
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Affiliation(s)
- Sema Koç Yıldırım
- Department of Dermatology and Venereology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
- Department of Dermatology and Venereology, Uşak University Faculty of Medicine, Uşak, Turkey.
| | - Tahmina Najafova
- Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Sibel Ersoy Evans
- Department of Dermatology and Venereology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - İncilay Lay
- Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Ayşen Karaduman
- Department of Dermatology and Venereology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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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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Elsisi AE, Elmarhoumy EH, Osman EY. Protective effect of cilostazol and verapamil against thioacetamide-induced hepatotoxicity in rats may involve Nrf2/GSK-3β/NF-κB signaling pathway. Toxicol Res (Camb) 2022; 11:718-729. [PMID: 36337252 PMCID: PMC9618097 DOI: 10.1093/toxres/tfac045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 06/15/2022] [Accepted: 06/27/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Verapamil (VER) and cilostazol (Cilo) are mostly used as cardiovascular drugs; they have beneficial effects on different organs toxicities. AIM we investigated whether the Nuclear factor erythroid 2-related factor 2 (Nrf2), Glycogen synthase kinase-3β (GSK-3β), and Nuclear factor-kappa B (NF-κB) pathway involved in the protective role of these drugs against Thioacetamide (TAA) induced hepatotoxicity. METHOD male rats were randomized divided into five groups, each group (n = 10): control, TAA, VER+TAA, Cilo+TAA, and VER+Cilo+TAA groups. Hepatotoxicity induced in rats by TAA injection once on the 7th day of the experiment. RESULTS TAA-induced hepatotoxicity indicated by a significant elevated in serum markers (Alanine aminotransferases (ALT), Aspartate aminotransferases (AST), and bilirubin), oxidative stress markers (Malondialdehyde (MDA), and Nitric oxide (NO)), and protein levels markers (NF-κB, and S100 calcium-binding protein A4 (S100A4)). Also, TAA decreased Nrf2, and increased GSK-3β genes expression. Histopathological alterations in the liver also appeared as a response to TAA injection. On the other hand VER and/or Cilo significantly prevented TAA-induced hepatotoxicity in rats through significantly decreased in ALT, AST, bilirubin, MDA, NO, NF-κB, and S100A4 protein levels. Also, they increased Nrf2 and decreased GSK-3β genes expression which caused improvement in the histopathological changes of the liver. CONCLUSION the addition of verapamil to cilostazol potentiated the hepatoprotective activity, and inhibited the progression of hepatotoxicity caused by TAA through the Nrf2/GSK-3β/NF-κBpathway and their activity on oxidative stress, inflammation, and NF-κB protein expression.
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Affiliation(s)
- Alaa E Elsisi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Esraa H Elmarhoumy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Enass Y Osman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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Riemekasten G, Distler JH. A broad look into the future of systemic sclerosis. Ther Adv Musculoskelet Dis 2022; 14:1759720X221109404. [PMID: 35966183 PMCID: PMC9373175 DOI: 10.1177/1759720x221109404] [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: 11/25/2021] [Accepted: 06/07/2022] [Indexed: 11/28/2022] Open
Abstract
Systemic sclerosis (SSc) is a systemic autoimmune disease with the key features of inflammation, vasculopathy and fibrosis. This article focussed on emerging fields based on the authors' current work and expertise. The authors provide a hierarchical structure into the studies of the pathogenesis of SSc starting with the contribution of environmental factors. Regulatory autoantibodies (abs) are discussed, which are parts of the human physiology and are specifically dysregulated in SSc. Abs against the angiotensin II receptor subtype 1 (AT1R) and the endothelin receptor type A (ETAR) are discussed in more detail. Extracellular vesicles are another novel player to possess disease processes. Fibroblasts are a key effector cell in SSc. Therefore, the current review will provide an overview about their plasticity in the phenotype and function. Promising nuclear receptors as key regulators of transcriptional programmes will be introduced as well as epigenetic modifications, which are pivotal to maintain the profibrotic fibroblast phenotype independent of external stimuli. Fibroblasts from SSc patients exhibit a specific signalling and reactivate developmental pathways and stem cell maintenance such as by employing hedgehog and WNT, which promote fibroblast-to-myofibroblast transition and extracellular matrix generation. Pharmacological interventions, although for other indications, are already in clinical use to address pathologic signalling.
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Affiliation(s)
- Gabriela Riemekasten
- Clinic for Rheumatology and Clinical
Immunology, University Clinic Schleswig-Holstein and University
of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Jörg H.W. Distler
- Department of Internal Medicine 3,
Universitätsklinikum Erlangen, Friedrich-Alexander-University
(FAU) Erlangen-Nürnberg, Erlangen, Germany
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9
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Effects of Hypocalcemic Vitamin D Analogs in the Expression of DNA Damage Induced in Minilungs from hESCs: Implications for Lung Fibrosis. Int J Mol Sci 2022; 23:ijms23094921. [PMID: 35563311 PMCID: PMC9104735 DOI: 10.3390/ijms23094921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 12/03/2022] Open
Abstract
In our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D3, the biologically active form of vitamin D, in the context of bleomycin-induced lung fibrosis. Contrary to the expected, vitamin D supplementation increased the DNA damage expression and cellular senescence in alveolar epithelial type II cells and aggravated the overall lung pathology induced in mice by bleomycin. These effects were probably due to an alteration in the cellular DNA double-strand breaks’ repair capability. In the present work, we have evaluated the effects of two hypocalcemic vitamin D analogs (calcipotriol and paricalcitol) in the expression of DNA damage in the context of minilungs derived from human embryonic stem cells and in the cell line A549.
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Abstract
Introduction: Hepatic stellate cells (HSCs) are essential for physiological homeostasis of the liver extracellular matrix (ECM). Excessive transdifferentiation of HSC from a quiescent to an activated phenotype contributes to disrupt this balance and can lead to liver fibrosis. Accumulating evidence has suggested that nuclear receptors (NRs) are involved in the regulation of HSC activation, proliferation, and function. Therefore, these NRs may be therapeutic targets to balance ECM homeostasis and inhibit HSC activation in liver fibrosis.Areas covered: In this review, the authors summarized the recent progress in the understanding of the regulatory role of NRs in HSCs and their potential as drug targets in liver fibrosis.Expert opinion: NRs are still potential therapy targets for inhibiting HSCs activation and liver fibrosis. However, the development of NRs agonists or antagonists to inhibit HSCs requires fully consideration of systemic effects.
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Affiliation(s)
- Shiyun Pu
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Hongjing Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Yan Liu
- Department of Interventional Therapy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Jiao Liu
- Department of Interventional Therapy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
- Department of Hepatobiliary Surgery, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Yuanxin Guo
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
| | - Houfeng Zhou
- Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu University of TCM, Chengdu, China
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11
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Elshal M, Abu-Elsaad N, El-Karef A, Ibrahim T. Etanercept attenuates immune-mediated hepatitis induced by concanavalin A via differential regulation of the key effector cytokines of CD4+ T cells. Life Sci 2021; 277:119618. [PMID: 34004252 DOI: 10.1016/j.lfs.2021.119618] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/29/2021] [Accepted: 05/08/2021] [Indexed: 12/19/2022]
Abstract
AIMS The current study aims to investigate the role of the key effector cytokines produced by CD4+T cells in the pathogenesis of Con A-induced liver injury in mice and testing whether etanercept can be repurposed to differentially regulate these cytokines. MAIN METHODS Four groups of mice were used: group I: control group, group II: mice received 15 mg/kg Con A i.v, group III: mice received 15 mg/kg etanercept i.p, group IV: mice received both Con A and etanercept as described. Hepatic injury and necroinflammation were assessed. Infiltration of CD4+ T cells and neutrophils were evaluated. Hepatic levels of TNF-α, IL-4, IL-10, and MDA were assigned and expression of NF-κB as well. KEY FINDINGS A significant decrease in ALT, AST, and LDH levels occurred when etanercept was injected before Con A. Hepatic necrosis and infiltration of CD4+ T cells and neutrophils were reduced by etanercept. Levels of TNF-α, IL-4, and MDA were significantly decreased in group IV compared to group II while that of IL-10 was increased. Also, number of NF-κB positive cells was significantly low in group IV. SIGNIFICANCE The study elucidates an interplay between the two effector cytokines of CD4+ T cells, TNF-α and IL-4, and their key role in Con A-induced liver injury. Additionally, our results showed that etanercept could be repurposed to differentially regulate effector cytokines produced by CD4+ T cells. Not only TNF-α, but also IL-4 signaling pathways, through which it exerts immunomodulatory, anti-inflammatory, and anti-oxidant effects leading to attenuation of Con A-induced liver injury.
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Affiliation(s)
- Mahmoud Elshal
- Pharmacology and Toxicology Dep., Faculty of Pharmacy, Mansoura University, Egypt.
| | - Nashwa Abu-Elsaad
- Pharmacology and Toxicology Dep., Faculty of Pharmacy, Mansoura University, Egypt
| | - Amr El-Karef
- Pathology Dep., Faculty of Medicine, Mansoura University, Egypt
| | - Tarek Ibrahim
- Pharmacology and Toxicology Dep., Faculty of Pharmacy, Mansoura University, Egypt
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Jia R, Yang F, Yan P, Ma L, Yang L, Li L. Paricalcitol inhibits oxidative stress-induced cell senescence of the bile duct epithelium dependent on modulating Sirt1 pathway in cholestatic mice. Free Radic Biol Med 2021; 169:158-168. [PMID: 33872698 DOI: 10.1016/j.freeradbiomed.2021.04.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 03/30/2021] [Accepted: 04/13/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Clinical studies indicate that vitamin D receptor (VDR) expression is reduced in primary biliary cirrhosis patient livers. However, the mechanism by which activated VDR effect cholestatic liver injury remains unclear. METHODS Mice were injected intraperitoneally with the VDR agonist paricalcitol or a vehicle 3 days prior to bile duct ligation (BDL) and for 5 or 28 days after surgery. The analyses of liver morphology and necrotic areas were based on H&E staining. Serum biochemical indicators of liver damage were analyzed by commercial kits. The mechanisms of paricalcitol on cholestatic liver injury were determined by Western blot analysis. RESULTS Paricalcitol ameliorated the BDL-induced liver damage in mice. Paricalcitol increased the proliferation of BECs to promote the repair of the bile duct. Paricalcitol also reduced the BDL-induced oxidative stress level in the mice. Mechanistic analysis revealed that paricalcitol decreased the number of SA-β-gal-positive cells and downregulated the expression of p53, p21 and p16 proteins which was associated with reducing oxidative stress. Additionally, paricalcitol exerted the inhibitory effect of cell senescence was through reducing DNA damage and promoting DNA repair. Interesting, we found that paricalcitol prevented the downregulation of oxidative stress-induced Sirt1 expression in the BDL mice and t-BHP-induced BECs models. Moreover, paricalcitol suppressed cell senescence through a Sirt1-dependent pathway. These results were confirmed by antioxidant ALCAR and the Sirt1 inhibitor EX-527. CONCLUSION Paricalcitol alleviated cholestatic liver injury through promoting the repair of damaged bile ducts and reducing oxidative stress-induced cell senescence of the bile duct via modulating Sirt1 pathway.
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Affiliation(s)
- Rongjun Jia
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China; Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China.
| | - Fan Yang
- Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China.
| | - Pengfei Yan
- Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China.
| | - Liman Ma
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China.
| | - Longfei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, PR China.
| | - Lihua Li
- Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China.
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Gonzalez-Sanchez E, El Mourabit H, Jager M, Clavel M, Moog S, Vaquero J, Ledent T, Cadoret A, Gautheron J, Fouassier L, Wendum D, Chignard N, Housset C. Cholangiopathy aggravation is caused by VDR ablation and alleviated by VDR-independent vitamin D signaling in ABCB4 knockout mice. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166067. [PMID: 33418034 DOI: 10.1016/j.bbadis.2020.166067] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/19/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Cholangiopathies are chronic liver diseases in which damaged cholangiocytes trigger a proinflammatory and profibrotic reaction. The nuclear vitamin D receptor (VDR) is highly expressed in cholangiocytes and exerts immune-regulatory functions in these cells. In the present study, we examined the protective function of VDR and other vitamin D signaling pathways in chronic cholangiopathy and cholangiocytes. METHODS Vdr was invalidated in Abcb4 knockout mice, a widely used animal model of chronic cholangiopathy. The impact of vitamin D signaling on cholangiopathy features was examined in vivo and in cholangiocytes (primary and cell lines). RESULTS Cholangiopathy features (i.e, cholestasis, ductular reaction and fibrosis) were aggravated in Vdr;Abcb4 double knockout mice compared to the Abcb4 simple knockout, and associated with an overexpression of proinflammatory factors. The proinflammatory phenotype of cholangiocytes was also exacerbated following VDR silencing in vitro. The expression of proinflammatory factors and the severity of cholangiopathy were reduced in the double knockout mice treated with the vitamin D analog calcipotriol or with vitamin D. In vitro, the inflammatory response to TNFα was significantly reduced by calcipotriol in biliary cells silenced for VDR, and this effect was abolished by co-silencing the plasma membrane receptor of vitamin D, protein disulfide-isomerase A3 (PDIA3). CONCLUSIONS Our results demonstrate an anti-inflammatory role of VDR signaling in cholangiocytes and cholangiopathy. They also provide evidence for PDIA3-mediated anti-inflammatory effects of vitamin D and vitamin D analog in these settings.
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Affiliation(s)
- Ester Gonzalez-Sanchez
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Inovarion, Paris, France; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
| | - Haquima El Mourabit
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Marion Jager
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Marie Clavel
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Inovarion, Paris, France
| | - Sophie Moog
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Inovarion, Paris, France.
| | - Javier Vaquero
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; LPP (Laboratoire de Physique des Plasmas, UMR 7648), Sorbonne Université, Centre National de la Recherche Scientifique (CNRS), Ecole Polytechnique, 75005 Paris, France.
| | - Tatiana Ledent
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Axelle Cadoret
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Jérémie Gautheron
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
| | - Dominique Wendum
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP) Sorbonne Université, Hôpital St Antoine, Paris, France.
| | | | - Chantal Housset
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France; AP-HP, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR, MIVB-H), Department of Hepatology, Saint-Antoine Hospital, Paris, France.
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Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18:151-166. [PMID: 33128017 DOI: 10.1038/s41575-020-00372-7] [Citation(s) in RCA: 983] [Impact Index Per Article: 245.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2020] [Indexed: 01/18/2023]
Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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Sriphoosanaphan S, Thanapirom K, Kerr SJ, Suksawatamnuay S, Thaimai P, Sittisomwong S, Sonsiri K, Srisoonthorn N, Teeratorn N, Tanpowpong N, Chaopathomkul B, Treeprasertsuk S, Poovorawan Y, Komolmit P. Effect of vitamin D supplementation in patients with chronic hepatitis C after direct-acting antiviral treatment: a randomized, double-blind, placebo-controlled trial. PeerJ 2021; 9:e10709. [PMID: 33614272 PMCID: PMC7879942 DOI: 10.7717/peerj.10709] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/15/2020] [Indexed: 12/16/2022] Open
Abstract
Background Replacement of vitamin D (VD) among patients with chronic hepatitis C (CHC) before viral eradication has demonstrated a protective effect on serum markers associated with hepatic fibrogenesis. We therefore hypothesized that VD may facilitate further fibrosis amelioration following curative treatment with direct-acting antivirals (DAA). Methods This study was a randomized, double-blind, placebo-controlled trial conducted between February 2018 and August 2018. Patients with CHC and VD deficiency were randomized in a 1:1 ratio to either receive ergicalciferol or placebo over 6 weeks. Biochemical analysis indicators, including 25-hydroxyvitamin D (25(OH)D), fibrogenic markers [(transforming growth factor beta 1 (TGF-β1) and tissue inhibitors of matrix metalloproteinases 1 (TIMP-1)], and fibrolytic markers [matrix metalloproteinase 9 (MMP-9) and amino terminal type III procollagen peptide (P3NP)], were assessed at baseline and at 6 weeks. Serum 25(OH)D was analyzed by a chemiluminescence immunoassay. Serum hepatic fibrogenesis markers were measured using a quantitative sandwich enzyme-linked immunosorbent assay. Results Seventy-five patients with CHC and VD deficiency were randomly assigned to VD (n = 37) and placebo (n = 38) groups. At the end of the study, the mean serum 25(OH)D level had risen to a normal level in the VD group, but was still deficient in the placebo group (41.8 ± 9.1 vs. 18.1 ± 4.6 ng/mL, p < 0.001). Upon restoration of the VD level, there were no significant mean differences in the change from baseline for TGF-β1 (-0.6 ng/mL (95% confidence interval (95% CI) [-2.8-1.7]), p = 0.63), TIMP-1 (-5.5 ng/mL (95% CI [-26.4 -15.3]), p = 0.60), MMP-9 (122.9 ng/mL (95% CI [-69.0 -314.8]), p = 0.21), and P3NP (-0.1 ng/mL (95% CI [-2.4 -2.2]), p = 0.92) between the VD and placebo groups. Conclusion Short-term VD supplementation after DAA treatment in patients with CHC does not improve serum fibrogenesis markers and may not expedite the residual liver fibrosis healing process. Future studies are warranted to evaluate the long-term effect of VD supplementation on hepatic fibrosis regression.
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Affiliation(s)
- Supachaya Sriphoosanaphan
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Center of Excellence in Liver Diseases, Thai Red Cross, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kessarin Thanapirom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Center of Excellence in Liver Diseases, Thai Red Cross, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Liver Fibrosis and Cirrhosis Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Stephen J Kerr
- Biostatistics Excellence Center, Department of Research Affairs, Chulalongkorn University, Bangkok, Thailand
| | - Sirinporn Suksawatamnuay
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Center of Excellence in Liver Diseases, Thai Red Cross, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Liver Fibrosis and Cirrhosis Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Panarat Thaimai
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sukanya Sittisomwong
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kanokwan Sonsiri
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nunthiya Srisoonthorn
- Center of Excellence in Liver Diseases, Thai Red Cross, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Nicha Teeratorn
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaporn Tanpowpong
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Bundit Chaopathomkul
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Piyawat Komolmit
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Center of Excellence in Liver Diseases, Thai Red Cross, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Liver Fibrosis and Cirrhosis Research Unit, Chulalongkorn University, Bangkok, Thailand
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Lu W, Li X, Liu N, Zhang Y, Li Y, Pan Y, Yang J, Liu Z, Kong J. Vitamin D alleviates liver fibrosis by inhibiting histidine-rich calcium binding protein (HRC). Chem Biol Interact 2020; 334:109355. [PMID: 33309619 DOI: 10.1016/j.cbi.2020.109355] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver fibrosis may progress toward cirrhosis and cancer without effective therapy. Here, we investigated the underlying mechanism of Vitamin D as a therapeutic approach. METHODS Carbon tetrachloride (CCL4)-induced mice model and transforming growth factor-β1 (TGF-β1) induced human hepatic stellate cell line LX-2 were used in vivo and in vitro. The fibrotic profiles, degree of liver injury and HRC expression were assessed by histology, Western blot, immunohistochemistry and Real-Time PCR. The proliferation of cells transfected with HRC +/+ and HRC-/- plasmids was detected by MTS and cell cycle methods. RESULTS Vitamin D significantly suppressed the expression of HRC in liver fibrosis model both in vivo and in vitro (P < 0.01). The cell with overexpression of HRC significantly increased TGF-β1/Smad3 expressions and the percentage of the S peak in cell cycle (P < 0.05). However, Vitamin D can significantly reverse the levels of TGF-β1, Smad3 and p-smad3 caused by HRC in vitro. Furthermore, the overexpression of HRC in cell lines can attenuate the function of Vitamin D, suggesting that VD played a role by regulating HRC. Mechanically, HRC as the target of VDR is detected by CHIP method. CONCLUSIONS Vitamin D can delay hepatic fibrosis by reducing activation of hepatic stellate cells and TGF-β/Smad signaling through negative regulation of HRC. The findings revealed the important regulatory effect of Vitamin D in hepatic stellate cells and provided new insights into the therapeutic function of Vitamin D on liver fibrosis.
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Affiliation(s)
- Wanyi Lu
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Xiaofeng Li
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Ning Liu
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Yalin Zhang
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Ye Li
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Yiming Pan
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Jingxin Yang
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Zuwang Liu
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China
| | - Juan Kong
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, 110000, Liaoning, PR China.
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Wu P, Zhang R, Luo M, Zhang T, Pan L, Xu S, Pan L, Ren F, Ji C, Hu R, Noureddin M, Pandol SJ, Han YP. Liver Injury Impaired 25-Hydroxylation of Vitamin D Suppresses Intestinal Paneth Cell defensins, leading to Gut Dysbiosis and Liver Fibrogenesis. Am J Physiol Gastrointest Liver Physiol 2020; 319:G685-G695. [PMID: 33084400 PMCID: PMC7792671 DOI: 10.1152/ajpgi.00021.2020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 08/26/2020] [Accepted: 09/30/2020] [Indexed: 01/31/2023]
Abstract
Vitamin D deficiency is co-prevalent with various liver diseases including cirrhosis, while the underlying mechanism remains elusive. Vitamin D receptor (VDR) is abundantly expressed in the distal region of small intestine, where the Paneth cells are enriched, suggesting that vitamin D signaling may modulates the intestinal Paneth cells and their production of defensins to restrain microbiome growth in the small intestine. In this study we found that in carbon tetrachloride-induced liver injury, hepatic 25-hydroxylation of vitamin D was impaired, leading to down regulated expression of Paneth cell fensins in the small intestine, gut dysbiosis, and endotoxinemia. While intraperitoneal injection of endotoxin (lipopolysaccharides) alone did not elicit liver fibrosis, it exacerbated the carbon tetrachloride initiated liver fibrogenesis. Oral gavage of synthetic Paneth cell alpha-defensin 5 (DEFA5) restored the homeostasis of gut microbiota, reduced endotoxemia, relieved liver inflammation, and ameliorated liver fibrosis. Likewise, Cholestyramine, cationic resin that can sequestrate endotoxin in the intestine, attenuated the liver fibrosis as well. Fecal transplant of the microbes derived from the DEFA5-treated donors improved liver fibrosis in the recipient mice. The intestinal Vdrconditional knockout mice exhibited reduction of Paneth cell defensins and lysozyme production, and worsened liver injury and fibrogenesis. Thus, liver injury impairs synthesis of 25(OH)VD3, which consequently impedes the Paneth cells functions in the small intestine, leading to gut dysbiosis for liver fibrogenesis.
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Affiliation(s)
- Pengfei Wu
- College of Life Sciences, Sichuan University, China
| | - Ruofei Zhang
- College of Life Sciences, Sichuan University, China
| | - Mei Luo
- Medicine, Public Health and Clinical Center of Chengdu, China
| | - Tianci Zhang
- College of Life Sciences, Sichuan University, China
| | - Lisha Pan
- College of Life Sciences, Sichuan University, China
| | - Siya Xu
- College of Life Sciences, Sichuan University, China
| | - Liwei Pan
- The College of Life Sciences, Sichuan University, China
| | | | - Cheng Ji
- Medicine, Keck School of Medicine USC, United States
| | - Richard Hu
- Medicine, David Geffen School of Medicine, United States
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Sari E, Oztay F, Tasci AE. Vitamin D modulates E-cadherin turnover by regulating TGF-β and Wnt signalings during EMT-mediated myofibroblast differentiation in A459 cells. J Steroid Biochem Mol Biol 2020; 202:105723. [PMID: 32603782 DOI: 10.1016/j.jsbmb.2020.105723] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/07/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022]
Abstract
Vitamin D (VitD) has an anti-fibrotic effect on fibrotic lungs. It reduces epithelial-mesenchymal transition (EMT) on tumors. We aimed to investigate target proteins of VitD for the regression of EMT-mediated myofibroblast differentiation. A group of A549 cells were treated with 5 % cigarette smoke extract (CSE) and 5 %CSE + TGF-β (5 ng/ml) to induce EMT. The others were treated with 50 nM VitD 30 min before %5CSE and TGF-β treatments. All cells were collected at 24, 48 and 72 h following 5 %CSE and TGF-β administrations. The expression of p120ctn and NEDD9 proteins acted on E-cadherin turnover in addition to activations of TGF-β and Wnt pathways were examined in these cells and fibrotic human lungs. CSE and TGF-β induced EMT by reducing E-cadherin, p-VDR, SMAD7 and DKK1, increasing α-SMA, p120ctn, Kaiso, NEDD9 and stimulating TGF-β and Wnt/β-catenin signalings in A549 cells. VitD administration reversed these alterations and regressed EMT. Co-immunoprecipitation analysis revealed p-VDR interaction with β-catenin and Kaiso in fibrotic and non-fibrotic human lungs. VitD pre-treatments reduced TGF-β and Wnt/β-catenin signalings by increasing p-VDR, protected from E-cadherin degradation and led to the regression of EMT in A549 cells treated with CSE and TGF-β. Finally, VitD supplementation combined with anti-fibrotic therapeutics can be suggested for treatment of pulmonary fibrosis, which may be developed by smoking, in cases of VitD deficiency.
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Affiliation(s)
- Ezgi Sari
- Istanbul University, Faculty of Science, Department of Biology, 34134, Vezneciler, Istanbul, Turkey.
| | - Fusun Oztay
- Istanbul University, Faculty of Science, Department of Biology, 34134, Vezneciler, Istanbul, Turkey.
| | - Ahmet Erdal Tasci
- Lung Transplantation Center, Department of Thoracic Surgery, Kartal Kosuyolu High Speciality Educational and Research Hospital, Kartal, Istanbul, Turkey.
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Wang X, Wang G, Qu J, Yuan Z, Pan R, Li K. Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis. Front Pharmacol 2020; 11:200. [PMID: 32296329 PMCID: PMC7136474 DOI: 10.3389/fphar.2020.00200] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 02/14/2020] [Indexed: 12/13/2022] Open
Abstract
Cholestasis is common in multiple clinical circumstances. The NOD-like receptor protein 3 (NLRP3) inflammasome pathway has been demonstrated to play an important role in liver injury and fibrosis induced by cholestasis. We previously proved that MCC950, a selective NLRP3 inhibitor, alleviates liver fibrosis and injury in experimental liver cholestasis induced by bile-duct ligation (BDL) in mice. Herein, we investigate the role of calcipotriol, a potent vitamin D receptor agonist, in experimental liver cholestasis, test its therapeutic efficacy, and explore its potential protective mechanism. C57BL/6 mice were made to undergo BDL or fed the 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to establish two classic cholestatic models. Calcipotriol was administered intraperitoneally to these mice daily. Serum makers of liver damage and integrity, liver histological changes, levels of liver pro-fibrotic markers, bile acid synthetases and transporters were measured in vivo. The underlying mechanism by which calcipotriol alleviates cholestatic liver injury and fibrosis was further investigated. The results of the current study demonstrated that calcipotriol supplement significantly alleviate cholestatic liver injury and fibrosis. Moreover, calcipotriol supplement markedly inhibited NLRP3 inflammasome pathway activation to alleviate liver injury and fibrosis in vivo and inhibit hepatic stellate cell (HSC) activation in vitro. In addition, VDR agonist calcipotriol exert inhibitory effect on NLRP3 inflammasome activation through activating yes-associated protein 1 (YAP1). In conclusion, our findings proved that calcipotriol suppressed the NLRP3 signal by activating YAP1 to alleviate liver injury and retard fibrogenesis in cholestasis.
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Affiliation(s)
- Xiaopeng Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Guiyang Wang
- The First Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Second Military Medical University, Shanghai, China
| | - Junwen Qu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiqing Yuan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ruogu Pan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kewei Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Distler JHW, Györfi AH, Ramanujam M, Whitfield ML, Königshoff M, Lafyatis R. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol 2019; 15:705-730. [PMID: 31712723 DOI: 10.1038/s41584-019-0322-7] [Citation(s) in RCA: 373] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2019] [Indexed: 02/07/2023]
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Cimini FA, Barchetta I, Carotti S, Morini S, Cavallo MG. Overview of studies of the vitamin D/vitamin D receptor system in the development of non-alcoholic fatty liver disease. World J Gastrointest Pathophysiol 2019; 10:11-16. [PMID: 31559105 PMCID: PMC6751507 DOI: 10.4291/wjgp.v10.i2.11] [Citation(s) in RCA: 10] [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: 05/17/2019] [Revised: 08/09/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. NAFLD is known to be associated with obesity, type 2 diabetes, metabolic syndrome and increased cardiovascular events: for these reasons, it is becoming a global public health problem and represents an important challenge in terms of prevention and treatment. The mechanisms behind the pathogenesis of NAFLD are multiple and have not yet been completely unraveled; consequently, at moment there are not effective treatments. In the past few years a large body of evidence has been assembled that attributes an important role in hepatic aberrant fat accumulation, inflammation and fibrosis, to the vitamin D/vitamin D receptor (VD/VDR) axis, showing a strong association between hypovitaminosis D and the diagnosis of NAFLD. However, the data currently available, including clinical trials with VD supplementation, still provides a contrasting picture. The purpose of this editorial is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to VD/VDR. Based on recent data from literature, we focused in particular on the hypothesis that VDR itself, independently from its traditional ligand VD, may have a crucial function in promoting hepatic fat accumulation. This might also offer new possibilities for future innovative therapeutic approaches in the management of NAFLD.
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Affiliation(s)
- Flavia Agata Cimini
- Department of Experimental Medicine, Sapienza University of Rome, Rome I-00161, Italy
| | - Ilaria Barchetta
- Department of Experimental Medicine, Sapienza University of Rome, Rome I-00161, Italy
| | - Simone Carotti
- Department of Medicine and Surgery, Laboratory of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico of Rome, Rome I-00128, Italy
| | - Sergio Morini
- Department of Medicine and Surgery, Laboratory of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico of Rome, Rome I-00128, Italy
| | - Maria Gisella Cavallo
- Department of Experimental Medicine, Sapienza University of Rome, Rome I-00161, Italy
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22
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Maia-Ceciliano TC, Dutra RR, Aguila MB, Mandarim-De-Lacerda CA. The deficiency and the supplementation of vitamin D and liver: Lessons of chronic fructose-rich diet in mice. J Steroid Biochem Mol Biol 2019; 192:105399. [PMID: 31175967 DOI: 10.1016/j.jsbmb.2019.105399] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/25/2019] [Accepted: 06/05/2019] [Indexed: 01/01/2023]
Abstract
The fructose added to soft drinks and processed food, as well as frequent detection of vitamin D deficiency in the body, are two insults increasingly considered to cause lesions in target organs. We studied the liver after a chronic high-fructose diet deficient and supplemented with vitamin D. Sixty C57BL/6 mature male mice were allocated into six groups (n = 10) for ten weeks: control (C), control deficient in vitamin D (CDD), control supplemented with vitamin D (CDS), fructose (F), fructose deficient in vitamin D (FDD), and fructose supplemented with vitamin D (FDS). The gene expressions of vitamin D receptor and CYP27B1 and 25 hydroxyvitamin D plasma level ensured that the diets caused vitamin D deficiency or supplementation. Body mass did not change, but blood pressure (BP) increased in CDD, F, and FDD, whereas BP was controlled in FDS. Insulinemia, insulin tolerance and resistance were seen in both vitamin D deficiency and fructose groups but improved with vitamin D supplementation. The steatosis and fibrosis were observed in the CDD, F and FDD groups. Also, F and FDD showed activation of stellate cells (HSC). Lipogenesis and inflammation gene expressions were enhanced in the CDD, F and FDD groups, but diminished with vitamin D supplementation. In conclusion, we demonstrated the adverse effects of vitamin D deficiency on metabolism, liver steatosis and, combined with fructose intake, liver interstitial fibrosis with hepatic stellate cell activation, and alteration of the lipogenesis, beta-oxidation, and liver inflammation. All these data improved when vitamin D was supplemented in the animals.
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Affiliation(s)
- Thais C Maia-Ceciliano
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Rafaela R Dutra
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Marcia B Aguila
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Carlos A Mandarim-De-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
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23
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Huovinen J, Haj Hussain M, Niemelä M, Laaksonen S, Voipio HM, Jyrkäs J, Mannila J, Lassila T, Tolonen A, Turunen S, Bergmann U, Lehenkari P, Huhtakangas JA. Pharmacokinetics of intra-articular vitamin D analogue calcipotriol in sheep and metabolism in human synovial and mesenchymal stromal cells. J Steroid Biochem Mol Biol 2019; 188:172-184. [PMID: 30562554 DOI: 10.1016/j.jsbmb.2018.12.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 12/07/2018] [Accepted: 12/12/2018] [Indexed: 11/15/2022]
Abstract
Calcipotriol (MC903) is a side chain analogue of the biologically active 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Due to its anti-inflammatory and anti-proliferative effects on stromal cells, calcipotriol is a promising candidate for the local treatment of arthritis. In this preliminary work, we studied the pharmacokinetics and safety of calcipotriol after an IV (0.1 mg/kg given to one sheep) and intra-articular dose (0.054 mg/kg, 0.216 mg/kg and 0.560 mg/kg given to three sheep). The terminal half-life of calcipotriol was approximately 1 h after an IV dose. After intra-articular dosing, the systemic absorption was between 1 and 13% during the observed 24 h. Hypercalcemia or other clinical adverse effects did not occur in any animal during the study, and no macroscopic or microscopic alterations were seen in the synovium of the calcipotriol-injected knees compared to the vehicle knees. The in vitro metabolism of calcipotriol was analyzed with LC-MS from human synovial and mesenchymal stromal cell cultures. Both cell types were able to metabolize calcipotriol with MC1080 and MC1046 as the main metabolites. CYP24A1 transcripts were strongly induced by a 48-hour calcipotriol exposure in mesenchymal stromal cells, but not consistently in synovial stromal cells, as determined by RT-qPCR. Calcipotriol proved to be safe after a single intra-articular dose with applied concentrations, and it is metabolized by the cells of the joint. Slow dissolution of calcipotriol crystals in the joint can extend the pharmaceutical impact on the synovium, cartilage and subcortical bone.
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Affiliation(s)
- Jere Huovinen
- Cancer Research and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014, University of Oulu, Oulu, Finland.
| | - Maija Haj Hussain
- Cancer Research and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014, University of Oulu, Oulu, Finland
| | - Markus Niemelä
- Cancer Research and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014, University of Oulu, Oulu, Finland
| | - Sakari Laaksonen
- Department of Experimental Surgery, Laboratory Animal Centre, Oulu University Hospital and University of Oulu, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland
| | - Hanna-Marja Voipio
- Department of Experimental Surgery, Laboratory Animal Centre, Oulu University Hospital and University of Oulu, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland
| | | | | | | | | | - Sanna Turunen
- Cancer Research and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014, University of Oulu, Oulu, Finland
| | - Ulrich Bergmann
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 8000, FI-90014, Oulu, Finland
| | - Petri Lehenkari
- Cancer Research and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014, University of Oulu, Oulu, Finland; Division of Operative Care, Oulu University Hospital and University of Oulu, P.O. Box 10, 90029 OYS, Oulu, Finland
| | - Johanna A Huhtakangas
- Cancer Research and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 8000, FI-90014, University of Oulu, Oulu, Finland; Rheumatology Unit, Department of Medicine, Oulu University Hospital and University of Oulu, MRC, Oulu, P.O. Box 10, 90029 OYS, Finland
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24
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Abu-Elsaad N, El-Karef A. Protection against nonalcoholic steatohepatitis through targeting IL-18 and IL-1alpha by luteolin. Pharmacol Rep 2019; 71:688-694. [PMID: 31207429 DOI: 10.1016/j.pharep.2019.03.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 02/02/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The management of nonalcoholic steatohepatitis (NASH) is still a crosstalk so the current study was designed to evaluate the effect of different luteolin doses on an experimental model of NASH and to elucidate novel anti-inflammatory pathways underlying its effect. METHODS Adult male Wistar rats (200-220 g; n = 60) were used. Rats were fed a high carbohydrate/high fat diet (˜ 30% carbohydrate and 42% fat) daily for 12 weeks to induce NASH. Luteolin (10, 25, 50 or 100 mg/kg/day) was administered as a suspension (10% w/v in 0.9% NaCl) using an oral gavage. Histopathological changes (necrosis, inflammation and steatosis) were evaluated. Biomarkers for liver function, lipid peroxidation, extracellular matrix deposition and anti-oxidant activity were measured. Levels of IFN-γ, TNF-α and IL-1α and IL-18 were measured. RESULTS Obtained results showed ability of luteolin to reduce activity of ALT and AST and to decrease levels of bilirubin, hyaluronic acid and malondialdehyde significantly (p < 0.05). Also, luteolin showed an anti-oxidant activity as indicated by the significant (p < 0.05) increase in reduced glutathione. Finally, a significant (p < 0.05) decrease in IFN-γ, TNF-α, IL-1α and IL-18 levels was observed most notably in groups that received high doses of luteolin (50 and 100 mg/kg). CONCLUSIONS Luteolin can protect against non-alcoholic steatohepatitis through targeting the pro-inflammatory IL-1 and Il-18 pathways in addition to an antioxidant effect.
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Affiliation(s)
- Nashwa Abu-Elsaad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura, Egypt.
| | - Amr El-Karef
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
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25
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Hafez HM, Ibrahim MA, Zedan MZ, Hassan M, Hassanein H. Nephroprotective effect of cilostazol and verapamil against thioacetamide-induced toxicity in rats may involve Nrf2/HO-1/NQO-1 signaling pathway. Toxicol Mech Methods 2018; 29:146-152. [DOI: 10.1080/15376516.2018.1528648] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Heba M. Hafez
- Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Mohamed A. Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Mervat Z. Zedan
- Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Marwa Hassan
- Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Hanaa Hassanein
- Department of Histology, Faculty of Medicine, Minia University, Minia, Egypt
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26
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R Ebrahim A, El-Mesery M, El-Karef A, Eissa LA. Vitamin D potentiates anti-tumor activity of 5-fluorouracil via modulating caspase-3 and TGF-β1 expression in hepatocellular carcinoma-induced in rats. Can J Physiol Pharmacol 2018; 96:1218-1225. [PMID: 30205014 DOI: 10.1139/cjpp-2018-0445] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We investigated the role of vitamin D (Vit D) alone and in combination with 5-fluorouracil (5-FU) in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) in rats. Fifty male Sprague-Dawley rats were randomized into a control group and 4 groups that received TAA (200 mg/kg, i.p.) twice per week for 16 weeks. These 4 groups were further divided as follows: HCC group; 5-FU group (75 mg/kg, i.p., once weekly for 3 weeks starting from the 12th week); Vit D group (200 IU/kg daily by oral tube for 16 weeks); and 5-FU + Vit D group (received the previously mentioned dosage regimens of 5-FU and Vit D). HCC was detected by histopathological changes in liver sections and the elevation of serum α-fetoprotein (AFP). Treatment with 5-FU + Vit D significantly decreased gene expression of nuclear factor erythroid 2-related factor 2 (NrF2) and transforming growth factor β1 (TGF-β1) at both the gene and protein level and serum AFP concentrations in comparison with their corresponding monotherapy. Moreover, 5-FU + Vit D treatment enhanced apoptosis by increasing caspase-3 gene and protein expression. Conclusively, Vit D enhances antitumor activity of 5-FU in an HCC-induced model and improves liver function of treated animals. Combination therapy in a TAA-induced HCC rat model was more effective than 5-FU or Vit D through the modulation of TGF-β1, caspase-3, and NrF2 expressions.
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Affiliation(s)
- Amal R Ebrahim
- a Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Mohamed El-Mesery
- a Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Amro El-Karef
- b Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Laila A Eissa
- a Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
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27
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Györfi AH, Matei AE, Distler JH. Targeting TGF-β signaling for the treatment of fibrosis. Matrix Biol 2018; 68-69:8-27. [DOI: 10.1016/j.matbio.2017.12.016] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 12/18/2017] [Indexed: 01/02/2023]
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28
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Keane JT, Elangovan H, Stokes RA, Gunton JE. Vitamin D and the Liver-Correlation or Cause? Nutrients 2018; 10:nu10040496. [PMID: 29659559 PMCID: PMC5946281 DOI: 10.3390/nu10040496] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 04/09/2018] [Accepted: 04/11/2018] [Indexed: 02/06/2023] Open
Abstract
Vitamin D is becoming increasingly accepted as an important physiological regulator outside of its classical role in skeletal homeostasis. A growing body of evidence connects vitamin D with hepatic disease. This review summarises the role of vitamin D in liver homeostasis and disease and discusses the therapeutic potential of vitamin D-based treatments to protect against hepatic disease progression and to improve response to treatment. While pre-clinical experimental data is promising, clinical trials around liver diseases have mostly been under-powered, and further studies will be required to clarify whether vitamin D or vitamin D analogues have beneficial effects on liver disease.
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Affiliation(s)
- Jeremy T Keane
- Centre for Diabetes, Obesity & Endocrinology, The Westmead Institute for Medical Research (WIMR), Westmead, Sydney, NSW 2145, Australia.
| | - Harendran Elangovan
- The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Darlinghurst, Sydney, NSW 2010, Australia.
| | - Rebecca A Stokes
- Centre for Diabetes, Obesity & Endocrinology, The Westmead Institute for Medical Research (WIMR), Westmead, Sydney, NSW 2145, Australia.
- The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Darlinghurst, Sydney, NSW 2010, Australia.
| | - Jenny E Gunton
- Centre for Diabetes, Obesity & Endocrinology, The Westmead Institute for Medical Research (WIMR), Westmead, Sydney, NSW 2145, Australia.
- The Garvan Institute of Medical Research, The University of New South Wales (UNSW), Darlinghurst, Sydney, NSW 2010, Australia.
- Faculty of Medicine and Health, The University of Sydney, Westmead Hospital, Westmead, Sydney, NSW 2145, Australia.
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29
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Komolmit P, Kimtrakool S, Suksawatamnuay S, Thanapirom K, Chattrasophon K, Thaimai P, Chirathaworn C, Poovorawan Y. Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: A randomized, double-blind, placebo-controlled study. Sci Rep 2017; 7:8905. [PMID: 28827788 PMCID: PMC5566364 DOI: 10.1038/s41598-017-09512-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 07/26/2017] [Indexed: 12/14/2022] Open
Abstract
Hepatic fibrosis is the net accumulation of matrix tissue components which controlled by pro-fibrolytic enzymes, matrix metalloproteinases (MMPs), and pro-fibrotic cytokine, TGF-β1, and enzymes, tissue inhibitors of MMPs (TIMPs). Vitamin D (VD) supplementation has been shown to reverse these processes in vitro and in vivo. This study sought to determine the effect of VD supplementation on serum fibrotic markers in chronic hepatitis C (CHC) patients. Fifty-four CHC patients with VD deficiency were randomized into two groups, a VD group (n = 29) and a placebo group (n = 29). The serum levels of 25-hydroxy VD, TGF-β1, TIMP-1, MMP2 and MMP9 were measured at baseline and at the end of the 6-week study period. Upon correction of VD levels, TGF-β1 and TIMP-1 levels were decreased, and the MMP2 and MMP9 levels were significantly increased in the VD group. A comparison of the mean changes (delta) in the markers between groups showed that TGF-β1 and TIMP-1 levels were significantly decreased and the MMP2 and MMP9 were significantly higher in the VD group than in the placebo group. By using CHC patients as a model, this study provides additional evidence that VD plays an important role in the reversal of hepatic fibrogenesis.
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Affiliation(s)
- Piyawat Komolmit
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. .,Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
| | - Sayamon Kimtrakool
- Gastroenterology Unit, Department of Medicine, Lerdsin Hospital, Bangkok, Thailand
| | - Sirinporn Suksawatamnuay
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Kessarin Thanapirom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Center of Excellence in Liver Diseases: King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Kanita Chattrasophon
- Gastroenterology Unit, Department of Medicine, Taksin Hospital, Bangkok, Thailand
| | - Panarat Thaimai
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Chintana Chirathaworn
- Division of Immunology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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30
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Kabel AM, Abd Elmaaboud MA, Atef A, Baali MH. RETRACTED: Ameliorative potential of linagliptin and/or calcipotriol on bleomycin-induced lung fibrosis: In vivo and in vitro study. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2017; 50:216-226. [PMID: 28192751 DOI: 10.1016/j.etap.2017.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 02/02/2017] [Accepted: 02/03/2017] [Indexed: 06/06/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted due to the authors’ plagiarism of text and images from the work of Eman Said Abd-Elkhalek, Hatem Abdel-Rahman Salem, Ghada Mohamed SuddeK, Marwa Ahmed Zaghloul and Ramy Ahmed Abdel-Salam, Faculties of Pharmacy and Medicine, Mansoura University, Mansoura, Egypt.
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Affiliation(s)
- Ahmed M Kabel
- Pharmacology Department, Faculty of Medicine, Tanta University, Tanta, Egypt; Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia.
| | | | - Aliaa Atef
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohammed H Baali
- Senior Medical Student, Faculty of Medicine, Taif University, Taif, Saudi Arabia
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