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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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Galal SA, El-Barbary RA, Madkour DKAEW. Efficacy of intralesional pentoxifylline versus intralesional steroid versus intralesional vitamin D in treatment of keloid. Arch Dermatol Res 2025; 317:307. [PMID: 39853434 DOI: 10.1007/s00403-025-03799-7] [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: 12/06/2024] [Revised: 12/07/2024] [Accepted: 01/03/2025] [Indexed: 01/26/2025]
Abstract
Several treatment modalities have been used for the treatment of keloid scarring but the optimal treatment has not yet been identified. Corticosteroids reduce excessive scarring by reducing collagen synthesis. Vitamin D can curb inflammation by inhibiting the activation and migration of leukocytes. Pentoxifylline is a methyl xanthine derivative initially developed for its vasodilatory properties. Evaluation and comparison between three modalities of treatment for keloid; intralesional vitamin D, pentoxifylline, and steroid. Forty-five patients with keloid lesions were divided into 3 groups; The first group: 15 patients were treated with intralesional triamcinolone acetonide. The second group: 15 patients treated with intralesional pentoxifylline. The third group: 15 patients treated with intralesional vitamin D. The response was evaluated clinically, Vancouver scar scale and patient satisfaction scale. At the end of the study, all groups showed highly statistically significant improvement compared to the baseline. The first group which was treated with triamcinolone acetonide showed excellent and good improvement 53% and 47% respectively. The second group which was treated with pentoxifylline showed excellent and good improvement 6.7% and 73.3% respectively. The third group which was treated with vitamin D showed excellent and good 6.7% and 86.7% respectively. Intralesional vitamin D and pentoxifylline are safe and effective therapeutic options for keloid lesions.
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Affiliation(s)
- Sara Ahmed Galal
- Dermatology and Venereology Department, Faculty of Medicine (Girls), Al-Azhar University, 53, New Cairo, 3rd Zone Fifth, Settlement, Cairo, Egypt.
| | - Rasha Aly El-Barbary
- Dermatology and Venereology Department, Faculty of Medicine (Girls), Al-Azhar University, 53, New Cairo, 3rd Zone Fifth, Settlement, Cairo, Egypt
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Vrzalova A, Vrzal R. Orchestra of ligand-activated transcription factors in the molecular symphony of SERPINE 1 / PAI-1 gene regulation. Biochimie 2025; 228:138-157. [PMID: 39321911 DOI: 10.1016/j.biochi.2024.09.010] [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: 06/12/2024] [Revised: 09/04/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024]
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a crucial serine protease inhibitor that prevents plasminogen activation by inhibiting tissue- and urokinase-type plasminogen activators (tPA, uPA). PAI-1 is well-known for its role in modulating hemocoagulation or extracellular matrix formation by inhibiting plasmin or matrix metalloproteinases, respectively. PAI-1 is induced by pro-inflammatory cytokines across various tissues, yet its regulation by ligand-activated transcription factors is partly disregarded. Therefore, we have attempted to summarize the current knowledge on the transcriptional regulation of PAI-1 expression by the most relevant xenobiotic and endocrine receptors implicated in modulating PAI-1 levels. This review aims to contribute to the understanding of the specific, often tissue-dependent regulation of PAI-1 and provide insights into the modulation of PAI-1 levels beyond its direct inhibition.
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Affiliation(s)
- Aneta Vrzalova
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic
| | - Radim Vrzal
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic.
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Pang J, Yang C, Liu J, Wang Z, Tao X, Cao Z. Correlation between vitamin D metabolic pathway-related gene polymorphisms and cardiovascular disease. Food Funct 2024; 15:11342-11364. [PMID: 39494806 DOI: 10.1039/d4fo03234a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Abstract
Vitamin D plays important roles in various physiological processes such as cardiovascular health, calcium balance regulation, bone health, immune system support, neurological function regulation, muscle function maintenance, and anti-inflammatory effects. Therefore, maintaining its adequate levels is essential for overall health. Genetic polymorphisms in vitamin D metabolic pathways have become a key factor affecting the susceptibility and progression of cardiovascular disease (CVD). This article reviews the relationship between gene polymorphisms in vitamin D metabolic pathways and vitamin D levels or CVD. It is emphasized that the polymorphisms of key genes such as GC, VDR, CYP2R1, CYP24A1 and CYP27B1 are related to the pathogenesis of CVD. These polymorphisms can regulate serum levels of vitamin D, thereby affecting the susceptibility, comorbidities and clinical manifestations of CVD. Despite the progress made, there are still inconsistencies and gaps in the literature. Thus, it is necessary to conduct large-scale, multicenter studies to verify these findings and deepen our understanding of the intricate interactions between gene polymorphisms in vitamin D metabolic pathways and CVD.
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Affiliation(s)
- Jiao Pang
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China.
- College of Life Science, Northwest University, Xi'an City, 710069, China
| | - Chunshuo Yang
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China.
- Department of Pain Medicine, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Jiaqi Liu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211103, China
| | - Zhilin Wang
- Department of Pain Medicine, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Xueshu Tao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China.
- Department of Pain Medicine, The First Hospital of China Medical University, Shenyang, 110001, China.
| | - Zhipeng Cao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China.
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Rastegar-Moghaddam SH, Akbarian M, Rajabian A, Alipour F, Hojjati Shargh A, Masoomi R, Ebrahimzadeh Bideskan A, Hosseini M. Potential therapeutic impacts of vitamin D on hypothyroid-induced heart and kidney fibrosis and oxidative status in male rat. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024:10.1007/s00210-024-03593-8. [PMID: 39535596 DOI: 10.1007/s00210-024-03593-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
There are several interactions between thyroid hormones (THs) and kidney and heart function. Consequently, THs deficit results in profound changes in renal and cardiac function regulation. Interestingly, emerging evidence suggests that vitamin D (Vit D) may benefit to fibrotic lesions in various tissues. Herein, this study was designed to investigate the potential impact of Vit D on renal and cardiac fibrosis in hypothyroid rats. Forty male Wistar rats were divided into four groups as follow: control, hypothyroid (0.05% PTU in drinking water), and hypothyroid + Vit D (PTU and doses of 100 or 500 IU/kg/day, by gavage) groups. After 6 weeks, biochemical parameters such as creatinine and urea in serum samples, and oxidative stress markers including malondialdehyde (MDA), total thiol groups, and superoxide dismutase (SOD) in renal and cardiac tissues homogenate were measured. Also, renal and cardiac fibrosis was evaluated histologically using Masson's trichrome staining. Hypothyroidism significantly increased creatinine and urea. Also, in hypothyroid group renal and cardiac fibrosis as well as MDA were increased, while anti-oxidative markers including total thiol group and SOD were decreased. Administration of Vit D significantly improved these alterations in oxidative stress markers and fibrosis in renal and cardiac tissues. In conclusion, this study highlighted that Vit D supplementation reduced renal and cardiac fibrosis and improved oxidative stress. These results support the emerging experimental findings linking Vit D being introduced as a potential therapeutic agent.
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Affiliation(s)
| | - Mahsan Akbarian
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arezoo Rajabian
- Department of Neuroscience, Faculty of Medicine, 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
| | | | - Reza Masoomi
- Applied Biomedical Research Center, 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
- 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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Elangovan H, Stokes RA, Keane J, Chahal S, Samer C, Agoncillo M, Yu J, Chen J, Downes M, Evans RM, Liddle C, Gunton JE. Vitamin D Receptor Regulates Liver Regeneration After Partial Hepatectomy in Male Mice. Endocrinology 2024; 165:bqae077. [PMID: 38963813 PMCID: PMC11250209 DOI: 10.1210/endocr/bqae077] [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: 02/14/2024] [Revised: 06/12/2024] [Accepted: 06/25/2024] [Indexed: 07/06/2024]
Abstract
Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. hVDR mice have impaired liver regeneration and impaired hepatocyte proliferation associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. Real-time PCR of hVDR and control livers showed significant changes in expression of cell-cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death. Together, these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, the studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.
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Affiliation(s)
- Harendran Elangovan
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Rebecca A Stokes
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Jeremy Keane
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Sarinder Chahal
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Caroline Samer
- Pharmacogenomics and Personalized Therapy Unit, Geneva University Hospitals, Geneva 1205, Switzerland
| | - Miguel Agoncillo
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Josephine Yu
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Jennifer Chen
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037-1002, USA
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037-1002, USA
| | - Christopher Liddle
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia
| | - Jenny E Gunton
- The Centre for Diabetes, Obesity and Endocrinology Research (CDOER), The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2145, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW 2145, Australia
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Nardin M, Verdoia M, Nardin S, Cao D, Chiarito M, Kedhi E, Galasso G, Condorelli G, De Luca G. Vitamin D and Cardiovascular Diseases: From Physiology to Pathophysiology and Outcomes. Biomedicines 2024; 12:768. [PMID: 38672124 PMCID: PMC11048686 DOI: 10.3390/biomedicines12040768] [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: 02/20/2024] [Revised: 03/18/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Vitamin D is rightly recognized as an essential key factor in the regulation of calcium and phosphate homeostasis, affecting primary adequate bone mineralization. In the last decades, a more complex and wider role of vitamin D has been postulated and demonstrated. Cardiovascular diseases have been found to be strongly related to vitamin D levels, especially to its deficiency. Pre-clinical studies have suggested a direct role of vitamin D in the regulation of several pathophysiological pathways, such as endothelial dysfunction and platelet aggregation; moreover, observational data have confirmed the relationship with different conditions, including coronary artery disease, heart failure, and hypertension. Despite the significant evidence available so far, most clinical trials have failed to prove any positive impact of vitamin D supplements on cardiovascular outcomes. This discrepancy indicates the need for further information and knowledge about vitamin D metabolism and its effect on the cardiovascular system, in order to identify those patients who would benefit from vitamin D supplementation.
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Affiliation(s)
- Matteo Nardin
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
- Internal Medicine, Department of Medicine, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Monica Verdoia
- Division of Cardiology, Ospedale degli Infermi, ASL Biella, 13875 Biella, Italy
- Department of Translational Medicine, Eastern Piedmont University, 28100 Novara, Italy
| | - Simone Nardin
- U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
- Department of Internal Medicine and Medical Sciences, School of Medicine, University of Genova, 16126 Genova, Italy
| | - Davide Cao
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
- Department of Cardiology, Humanitas Gavazzeni Hospital, 24125 Bergamo, Italy
| | - Mauro Chiarito
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
- Department of Cardiovascular Medicine, IRCCS-Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Elvin Kedhi
- McGill University Health Center, Montreal, QC H3G 1A4, Canada
- Department of Cardiology and Structural Heart Disease, University of Silesia, 40-032 Katowice, Poland
| | - Gennaro Galasso
- Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy
| | - Gianluigi Condorelli
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
- Department of Cardiovascular Medicine, IRCCS-Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Giuseppe De Luca
- Division of Cardiology, AOU “Policlinico G. Martino”, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
- Division of Cardiology, IRCCS Hospital Galeazzi-Sant’Ambrogio, 20157 Milan, Italy
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Gallo P, Flagiello V, Falcomatà A, Di Pasquale G, D’Avanzo G, Terracciani F, Picardi A, Vespasiani-Gentilucci U. Approaching the Sarcopenic Patient with Nonalcoholic Steatohepatitis-related Cirrhosis. J Clin Transl Hepatol 2024; 12:278-286. [PMID: 38426198 PMCID: PMC10899871 DOI: 10.14218/jcth.2023.00207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 10/31/2023] [Accepted: 11/09/2023] [Indexed: 03/02/2024] Open
Abstract
Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.
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Affiliation(s)
- Paolo Gallo
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
| | - Valentina Flagiello
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
| | - Andrea Falcomatà
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
| | - Giulia Di Pasquale
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
| | - Giorgio D’Avanzo
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
| | - Francesca Terracciani
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
| | - Antonio Picardi
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
- Research Unit of Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
| | - Umberto Vespasiani-Gentilucci
- Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, Roma, Italy
- Research Unit of Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, Roma, Italy
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Ebrahimpour-Koujan S, Sohrabpour AA, Giovannucci E, Vatannejad A, Esmaillzadeh A. Effects of vitamin D supplementation on liver fibrogenic factors, vitamin D receptor and liver fibrogenic microRNAs in metabolic dysfunction-associated steatotic liver disease (MASLD) patients: an exploratory randomized clinical trial. Nutr J 2024; 23:24. [PMID: 38413933 PMCID: PMC10898146 DOI: 10.1186/s12937-024-00911-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 01/03/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global metabolic problem which can lead to irreversible liver fibrosis. It has been shown that vitamin D and its receptors contribute to fibrogenic pathways in the liver. However, the effect of vitamin D supplementation on liver fibrosis related factors have not been examined. This double blinded placebo controlled clinical trial was designed to investigate the effects on vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients. METHODS Forty six MASLD patients after block matching for sex and BMI were randomly assigned to receive 4000 IU/d vitamin D or placebo for 12 weeks. Weight, height and waist circumference were measured. Serum fibrogenic microRNAs, laminin, collagen type IV, hyaluronic acid, vitamin D, VDR, PTH, blood fasting glucose, serum fasting insulin, lipid profile, ALT and AST were determined at the baseline and at the end of the trial. Insulin resistance and insulin sensitivity were calculated using the HOMA-IR and QUICKI equation. RESULTS Supplementation with vitamin D for 12 weeks led to the significant increases in serum 25(OH) vitamin D, VDR and HDL-C compared to placebo (P < 0.001, P = 0.008 and P < 0.001). There were significant decreases in ALT, AST, FBS and LDL-C levels in the vitamin D group as compared to the placebo (P < 0.05). Laminin and hyaluronic acid concentrations were significantly decreased in the vitamin D group as compared to the placebo group, by -10.6 and - 28.7 ng/mL, respectively. Supplementation with vitamin D for 12 weeks resulted in a significant lower MiR-21 and MiR-122 gene expressions compared to the placebo group (P = 0.01 and P < 0.001, respectively). DISCUSSION As the first randomized controlled trial on the effect of vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients, we found a significant reduction in some liver fibrogenic factors, in liver transaminases and corresponding changes in some fibrosis-related MiRs and some metabolic factors. Further clinical trials with larger sample sizes and direct measures of liver fibrosis are needed to confirm these findings. TRIAL REGISTRATION NUMBER (available at: http://www.irct.ir , identifier: IRCT201405251485N13), Registration date: 14-03-2017.
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Affiliation(s)
- Soraiya Ebrahimpour-Koujan
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, PO Box 14155-6117, Tehran, Iran
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Sohrabpour
- The Liver, Pancreatic, and Biliary Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Edward Giovannucci
- Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Akram Vatannejad
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Ahmad Esmaillzadeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, PO Box 14155-6117, Tehran, Iran.
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
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Kaneva AM, Bojko ER. Fatty liver index (FLI): more than a marker of hepatic steatosis. J Physiol Biochem 2024; 80:11-26. [PMID: 37875710 DOI: 10.1007/s13105-023-00991-z] [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: 07/21/2023] [Accepted: 10/12/2023] [Indexed: 10/26/2023]
Abstract
Fatty liver index (FLI) was developed as a simple and accurate marker of hepatic steatosis. FLI is derived from an algorithm based on body mass index, waist circumference, and levels of triglycerides and gamma-glutamyltransferase, and it is widely used in clinical and epidemiological studies as a screening tool for discriminating between healthy and nonalcoholic fatty liver disease (NAFLD) subjects. However, a systematic review of the literature regarding FLI revealed that this index has more extensive relationships with biochemical and physiological parameters. FLI is associated with key parameters of lipid, protein and carbohydrate metabolism, hormones, vitamins and markers of inflammation, or oxidative stress. FLI can be a predictor or risk factor for a number of metabolic and nonmetabolic diseases and mortality. FLI is also used as an indicator for determining the effects of health-related prevention interventions, medications, and toxic substances on humans. Although in most cases, the exact mechanisms underlying these associations have not been fully elucidated, they are most often assumed to be mediated by insulin resistance, inflammation, and oxidative stress. Thus, FLI may be a promising marker of metabolic health due to its multiple associations with parameters of physiological and pathological processes. In this context, the present review summarizes the data from currently available literature on the associations between FLI and biochemical variables and physiological functions. We believe that this review will be of interest to researchers working in this area and can provide new perspectives and directions for future studies on FLI.
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Affiliation(s)
- Anastasiya M Kaneva
- Institute of Physiology of Кomi Science Centre of the Ural Branch of the Russian Academy of Sciences, FRC Komi SC UB RAS, 50 Pervomayskaya str., 167982, Syktyvkar, Russia.
| | - Evgeny R Bojko
- Institute of Physiology of Кomi Science Centre of the Ural Branch of the Russian Academy of Sciences, FRC Komi SC UB RAS, 50 Pervomayskaya str., 167982, Syktyvkar, Russia
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11
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Janubová M, Žitňanová I. The effects of vitamin D on different types of cells. Steroids 2024; 202:109350. [PMID: 38096964 DOI: 10.1016/j.steroids.2023.109350] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 11/24/2023] [Accepted: 12/07/2023] [Indexed: 12/25/2023]
Abstract
Vitamin D is neccessary for regulation of calcium and phosphorus metabolism in bones, affects imunity, the cardiovascular system, muscles, skin, epithelium, extracellular matrix, the central nervous system, and plays arole in prevention of aging-associated diseases. Vitamin D receptor is expressed in almost all types of cells and its activation leads to modulation of different signaling pathways. In this review, we have analysed the current knowledge of 1,25-dihydroxyvitamin D3 or 25-hydroxyvitamin D3 effects on metabolism of cells important for the function of the cardiovascular system (endothelial cells, vascular smooth muscle cells, cardiac cells and pericytes), tissue healing (fibroblasts), epithelium (various types of epithelial cells) and the central nervous system (neurons, astrocytes and microglia). The goal of this review was to compare the effects of vitamin D on the above mentioned cells in in vitro conditions and to summarize what is known in this field of research.
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Affiliation(s)
- Mária Janubová
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Comenius University, 813 72 Bratislava, Slovakia.
| | - Ingrid Žitňanová
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Comenius University, 813 72 Bratislava, Slovakia
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12
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Janjetovic Z, Qayyum S, Reddy SB, Podgorska E, Scott SG, Szpotan J, Mobley AA, Li W, Boda VK, Ravichandran S, Tuckey RC, Jetten AM, Slominski AT. Novel Vitamin D3 Hydroxymetabolites Require Involvement of the Vitamin D Receptor or Retinoic Acid-Related Orphan Receptors for Their Antifibrogenic Activities in Human Fibroblasts. Cells 2024; 13:239. [PMID: 38334631 PMCID: PMC10854953 DOI: 10.3390/cells13030239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/18/2024] [Accepted: 01/23/2024] [Indexed: 02/10/2024] Open
Abstract
We investigated multiple signaling pathways activated by CYP11A1-derived vitamin D3 hydroxymetabolites in human skin fibroblasts by assessing the actions of these molecules on their cognate receptors and by investigating the role of CYP27B1 in their biological activities. The actions of 20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3 and 1,20,23(OH)3D3 were compared to those of classical 1,25(OH)2D3. This was undertaken using wild type (WT) fibroblasts, as well as cells with VDR, RORs, or CYP27B1 genes knocked down with siRNA. Vitamin D3 hydroxymetabolites had an inhibitory effect on the proliferation of WT cells, but this effect was abrogated in cells with silenced VDR or RORs. The collagen expression by WT cells was reduced upon secosteroid treatment. This effect was reversed in cells where VDR or RORs were knocked down where the inhibition of collagen production and the expression of anti-fibrotic genes in response to the hydroxymetabolites was abrogated, along with ablation of their anti-inflammatory action. The knockdown of CYP27B1 did not change the effect of either 20(OH)D3 or 20,23(OH)2D3, indicating that their actions are independent of 1α-hydroxylation. In conclusion, the expression of the VDR and/or RORα/γ receptors in fibroblasts is necessary for the inhibition of both the proliferation and fibrogenic activity of hydroxymetabolites of vitamin D3, while CYP27B1 is not required.
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Affiliation(s)
- Zorica Janjetovic
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
| | - Shariq Qayyum
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
- Brigham’s Women’s Hospital, Harvard University, Boston, MA 02115, USA
| | - Sivani B. Reddy
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
| | - Ewa Podgorska
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
| | - S. Gates Scott
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
| | - Justyna Szpotan
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
| | - Alisa A. Mobley
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
| | - Wei Li
- College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; (W.L.); (V.K.B.)
| | - Vijay K. Boda
- College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; (W.L.); (V.K.B.)
| | - Senthilkumar Ravichandran
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
| | - Robert C. Tuckey
- School of Molecular Science, The University of Western Australia, Perth 6009, Australia;
| | - Anton M. Jetten
- Cell Biology Section, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA;
| | - Andrzej T. Slominski
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (Z.J.); (S.Q.); (S.B.R.); (E.P.); (S.G.S.); (J.S.); (A.A.M.); (S.R.)
- Cancer Chemoprevention Program, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- VA Medical Center, Birmingham, AL 35294, USA
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13
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Trifan DF, Tirla AG, Moldovan AF, Moș C, Bodog F, Maghiar TT, Manole F, Ghitea TC. Can Vitamin D Levels Alter the Effectiveness of Short-Term Facelift Interventions? Healthcare (Basel) 2023; 11:healthcare11101490. [PMID: 37239776 DOI: 10.3390/healthcare11101490] [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: 02/12/2023] [Revised: 04/26/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Facelifting is increasingly popular among the population. It exceeded the limits of post-traumatic facia-reconstruction. Both the demand and the methods available are getting increasingly diverse. The minimally invasive technique revolutionized the facelift, although it took some time to completely comprehend the mechanics. The roles of vitamin D in numerous physiological processes in which it is involved have mostly been elucidated in the last decade. Our hypothesis is based on one of these roles, that is, vitamin D intervenes in changing the type of collagen by changing its location; therefore, collagen will have a supporting role for the subcutaneous tissue. A group of 156 patients with different facelifting methods was followed: 93 minimally invasive (NC), 49 classical surgery (C) and 14 with the combined technique (NC + C). The change in the subcutaneous tissue was monitored by an elastograph. The level of vitamin D was monitored in order to assess the immediate and long-term effects of vitamin D on the progression of subcutaneous fibrosis. It was proven that an optimal level of vitamin D has a beneficial effect in maintaining the volume of subcutaneous tissue in patients from the NC and NC + C groups, the best results being in the NC + C group. An increase in the subcutaneous volume was recorded, which leads to a decrease in elasticity (statistical significance p < 0.05) and the lowering of the subcutaneous tissue, and an increased amount of lowering corresponds to a lowering of vitamin D levels.
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Affiliation(s)
- Daniela Florina Trifan
- Faculty of Medicine and Pharmacy, Doctoral School, University of Oradea, 410068 Oradea, Romania
| | - Adrian Gheorghe Tirla
- Faculty of Medicine and Pharmacy, Medicine Department, University of Oradea, 410068 Oradea, Romania
| | - Andrada Florina Moldovan
- Faculty of Medicine and Pharmacy, Medicine Department, University of Oradea, 410068 Oradea, Romania
| | - Calin Moș
- Faculty of Medicine and Pharmacy, Medicine Department, University of Oradea, 410068 Oradea, Romania
| | - Florian Bodog
- Faculty of Medicine and Pharmacy, Medicine Department, University of Oradea, 410068 Oradea, Romania
| | - Teodor Traian Maghiar
- Faculty of Medicine and Pharmacy, Medicine Department, University of Oradea, 410068 Oradea, Romania
| | - Felicia Manole
- Faculty of Medicine and Pharmacy, Medicine Department, University of Oradea, 410068 Oradea, Romania
| | - Timea Claudia Ghitea
- Faculty of Medicine and Pharmacy, Department of Pharmacy, University of Oradea, 10, 410068 Oradea, Romania
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14
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Dal-Bekar NE, İşlekel GH, Köken-Avşar A, Yarkan-Tuğsal H, Tuna G, Zengin B, Birlik AM. Vitamin D attenuates elevated oxidative DNA damage in scleroderma patients with organ involvement: A prospective study. J Steroid Biochem Mol Biol 2023; 229:106273. [PMID: 36813139 DOI: 10.1016/j.jsbmb.2023.106273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/17/2023] [Accepted: 02/19/2023] [Indexed: 02/23/2023]
Abstract
Scleroderma is a rare autoimmune disease characterized by progressive fibrosis of the skin and internal organs. Oxidative damage to macromolecules has been reported to occur in scleroderma. Among the macromolecular damages, oxidative DNA damage is a sensitive and cumulative marker of oxidative stress and is of particular interest because of its cytotoxic and mutagenic effects. Vitamin D supplementation is an important part of treatment, as vitamin D deficiency is a common problem in scleroderma. Furthermore, the antioxidant role of vitamin D has been demonstrated in recent studies. In light of this information, the present study aimed to comprehensively investigate oxidative DNA damage in scleroderma at baseline and to evaluate the contribution of vitamin D supplementation to the attenuation of DNA damage in a prospectively designed study. In accordance with these objectives, oxidative DNA damage in scleroderma was evaluated by measurement of stable damage products (8-oxo-dG, S-cdA, and R-cdA) in urine by liquid chromatography-tandem mass spectrometry (LC-MS/MS); serum vitamin D levels were determined by high-resolution mass spectrometry (HR-MS); VDR gene expression and four polymorphisms in the VDR gene (rs2228570, rs1544410, rs7975232, and rs731236) were analyzed by RT-PCR and compared with healthy subjects. In the prospective part, the DNA damage and the VDR expression of the patients who received vitamin D were re-evaluated after the replacement. As a result of this study, we demonstrated that all DNA damage products were increased in scleroderma patients compared to healthy controls, whereas vitamin D levels and VDR expression were significantly lower (p < 0.05). After supplementation, statistical significance (p < 0.05) was reached for the decrease in 8-oxo-dG and the increase in VDR expression. Attenuated 8-oxo-dG after replacement in patients with lung, joint, and gastrointestinal system involvement demonstrated the efficacy of vitamin D in scleroderma patients with organ involvement. To the best of our knowledge, this is the first study to examine oxidative DNA damage in scleroderma comprehensively and to evaluate the effects of vitamin D on DNA damage using a prospective design.
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Affiliation(s)
- Nazlı Ecem Dal-Bekar
- Dokuz Eylül University, Institute of Health Sciences, Department of Molecular Medicine, Izmir, Turkey; Izmir University of Economics, Faculty of Medicine, Department of Medical Biochemistry, Izmir, Turkey.
| | - Gül Hüray İşlekel
- Dokuz Eylül University, Institute of Health Sciences, Department of Molecular Medicine, Izmir, Turkey; Dokuz Eylül University, Faculty of Medicine, Department of Medical Biochemistry, Izmir, Turkey
| | - Aydan Köken-Avşar
- Dokuz Eylül University, Faculty of Medicine, Department of Immunology and Rheumatology, Izmir, Turkey; Kocaeli State Hospital, Department of Rheumatology, Izmit, Turkey
| | - Handan Yarkan-Tuğsal
- Ankara Training and Research Hospital, Department of Rheumatology, Ankara, Turkey
| | - Gamze Tuna
- Dokuz Eylül University, Institute of Health Sciences, Department of Molecular Medicine, Izmir, Turkey
| | - Berrin Zengin
- Dokuz Eylül University, Faculty of Medicine, Department of Immunology and Rheumatology, Izmir, Turkey; Izmir Bozyaka Training and Research Hospital, Department of Rheumatology, Izmir, Turkey
| | - Ahmet Merih Birlik
- Dokuz Eylül University, Institute of Health Sciences, Department of Molecular Medicine, Izmir, Turkey; Dokuz Eylül University, Faculty of Medicine, Department of Immunology and Rheumatology, Izmir, Turkey
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15
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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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16
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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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18
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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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19
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Wang D, Li Y, Ge H, Ghadban T, Reeh M, Güngör C. The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers (Basel) 2022; 14:cancers14163998. [PMID: 36010993 PMCID: PMC9406497 DOI: 10.3390/cancers14163998] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.
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20
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Nguyen MT, Huynh NNY, Nguyen DD, Ta NH, Van Nguyen T, Dang HT, Le NT. Vitamin D intake and gastric cancer in Viet Nam: a case-control study. BMC Cancer 2022; 22:838. [PMID: 35915393 PMCID: PMC9341043 DOI: 10.1186/s12885-022-09933-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/20/2022] [Indexed: 12/24/2022] Open
Abstract
Background Most recent laboratory studies have suggested a promising role of vitamin D and its analogs as novel chemotherapeutic agents for cancer treatment. However, epidemiological evidence, especially regarding the effects of vitamin D on gastric cancer is still inconsistent. Objectives Our research aimed to evaluate the associations between vitamin D intake and the risk of developing gastric cancer through a case-control study in North Vietnam. Methods We accessed databases of the previous completed case-control studies to derive 1182 incident gastric cancer cases and 2995 hospital controls selected from hospitals in Hanoi from 2003 to 2019. Vitamin D intake was computed by multiplying the food frequency intake with nutrient content based on the Viet Nam Food Composition Tables. Data were collected through face-to-face interviews by trained interviewers using the validated semi-quantitative food frequency and demographic lifestyle questionnaires. The odds ratio and 95% confidence interval (OR and 95%CI) were estimated using unconditional logistic regression analysis. Results We observed a continual decline in gastric cancer risk according to the level-up of vitamin D intake in both genders, men, and women [Fifth vs. bottom quintile, OR, 95%CI: 0.68 (0.53, 0.86), OR, 95%CI: 0.72 (0.53, 0.97), OR, 95%CI: 0.58 (0.38, 0.89), respectively. Per increment quintile, the statistically significant decreased risk was seen by 7% in men and 13% in women. The significant inverse association between vitamin D intake remained in the subgroups of ever and never tobacco smoking; negative and positive H. pylori infection. Conclusion The findings suggested that sufficient vitamin D intake was associated with a lower risk of Gastric Cancer in the Vietnamese population.
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Affiliation(s)
- Minh Thien Nguyen
- School of Medicine, International University of Health and Welfare, Narita City, Japan
| | - Nhi Ngoc Yen Huynh
- School of Medicine, International University of Health and Welfare, Narita City, Japan
| | - Dai Duc Nguyen
- School of Medicine, International University of Health and Welfare, Narita City, Japan
| | - Nguyen Ha Ta
- School of Medicine, International University of Health and Welfare, Narita City, Japan
| | - Tai Van Nguyen
- School of Medicine, International University of Health and Welfare, Narita City, Japan
| | - Huy Thanh Dang
- School of Medicine, International University of Health and Welfare, Narita City, Japan
| | - Ngoan Tran Le
- Institute of Research and Development, Duy Tan University, Da Nang City, Viet Nam. .,Department of Public Health, School of Medicine, International University of Health and Welfare, Narita City, Japan.
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21
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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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22
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Bae JH, Choe HJ, Holick MF, Lim S. Association of vitamin D status with COVID-19 and its severity : Vitamin D and COVID-19: a narrative review. Rev Endocr Metab Disord 2022; 23:579-599. [PMID: 34982377 PMCID: PMC8724612 DOI: 10.1007/s11154-021-09705-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2021] [Indexed: 01/08/2023]
Abstract
Vitamin D is associated with biological activities of the innate and adaptive immune systems, as well as inflammation. In observational studies, an inverse relationship has been found between serum 25-hydroxyvitamin D (25(OH)D) concentrations and the risk or severity of coronavirus disease 2019 (COVID-19). Several mechanisms have been proposed for the role of vitamin D in COVID-19, including modulation of immune and inflammatory responses, regulation of the renin-angiotensin-aldosterone system, and involvement in glucose metabolism and cardiovascular system. Low 25(OH)D concentrations might predispose patients with COVID-19 to severe outcomes not only via the associated hyperinflammatory syndrome but also by worsening preexisting impaired glucose metabolism and cardiovascular diseases. Some randomized controlled trials have shown that vitamin D supplementation is beneficial for reducing severe acute respiratory syndrome coronavirus 2 RNA positivity but not for reducing intensive care unit admission or all-cause mortality in patients with moderate-to-severe COVID-19. Current evidence suggests that taking a vitamin D supplement to maintain a serum concentration of 25(OH)D of at least 30 ng/mL (preferred range 40-60 ng/mL), can help reduce the risk of COVID-19 and its severe outcomes, including mortality. Although further well designed studies are warranted, it is prudent to recommend vitamin D supplements to people with vitamin D deficiency/insufficiency during the COVID-19 pandemic according to international guidelines.
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Affiliation(s)
- Jae Hyun Bae
- grid.411134.20000 0004 0474 0479Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Hun Jee Choe
- grid.412484.f0000 0001 0302 820XDepartment of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Michael F. Holick
- grid.189504.10000 0004 1936 7558Section of Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University Medical Campus, 715 Albany St #437, Boston, MA 02118 USA
| | - Soo Lim
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam, 13620 South Korea
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23
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Cespiati A, Meroni M, Lombardi R, Oberti G, Dongiovanni P, Fracanzani AL. Impact of Sarcopenia and Myosteatosis in Non-Cirrhotic Stages of Liver Diseases: Similarities and Differences across Aetiologies and Possible Therapeutic Strategies. Biomedicines 2022; 10:biomedicines10010182. [PMID: 35052859 PMCID: PMC8773740 DOI: 10.3390/biomedicines10010182] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/15/2022] Open
Abstract
Sarcopenia is defined as a loss of muscle strength, mass and function and it is a predictor of mortality. Sarcopenia is not only a geriatric disease, but it is related to several chronic conditions, including liver diseases in both its early and advanced stages. Despite the increasing number of studies exploring the role of sarcopenia in the early stages of chronic liver disease (CLD), its prevalence and the relationship between these two clinical entities are still controversial. Myosteatosis is characterized by fat accumulation in the muscles and it is related to advanced liver disease, although its role in the early stages is still under researched. Therefore, in this narrative review, we firstly aimed to evaluate the prevalence and the pathogenetic mechanisms underlying sarcopenia and myosteatosis in the early stage of CLD across different aetiologies (mainly non-alcoholic fatty liver disease, alcohol-related liver disease and viral hepatitis). Secondly, due to the increasing prevalence of sarcopenia worldwide, we aimed to revise the current and the future therapeutic approaches for the management of sarcopenia in CLD.
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Affiliation(s)
- Annalisa Cespiati
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
| | - Rosa Lombardi
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
- Correspondence: ; Tel.: +39-02-5503-4192; Fax: +39-02-5503-3509
| | - Giovanna Oberti
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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24
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Corrado A, Rotondo C, Sanpaolo ER, Altomare A, Maruotti N, Cici D, Cantatore FP. 1,25OH-Vitamin D3 and IL-17 Inhibition Modulate Pro-Fibrotic Cytokines Production in Peripheral Blood Mononuclear Cells of Patients with Systemic Sclerosis. Int J Med Sci 2022; 19:867-877. [PMID: 35693738 PMCID: PMC9149638 DOI: 10.7150/ijms.70984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/21/2022] [Indexed: 11/25/2022] Open
Abstract
Objectives: IL-17 modulates the synthesis of several molecules involved in the pathogenesis of Systemic Sclerosis (SSc). Vitamin D (1,25(OH)2D3) shows anti-fibrotic properties and it is able to affect the IL-17 production in several experimental conditions. The aim of this study is to assess the production of IL-17A and pro-fibrotic cytokines in peripheral blood mononuclear cells (PBMCs) from subjects with SSc in basal conditions and after treatment with 1,25(OH)2D3 and IL-17A neutralizing antibodies. Methods: The production of IL-17A and pro-fibrotic cytokines (TGFβ, CTGF and FGF2) in PBMCs obtained from 51 SSc patients and 31 healthy subjects was assessed both in basal conditions and in presence of anti-IL17A antibodies and several concentrations of 1,25(OH)2D3. The association of cytokines production with clinical disease characteristics and the in vitro effect of 1,25(OH)2D3 and IL-17A inhibition were assessed. Results: PBMCs from SSc subjects produced higher amount IL-17A, TGFβ, CTGF and FGF2 compared to healthy controls. IL17, TGFβ, CTGF and FGF2 levels were higher in SSc patients with interstitial lung disease and digital ulcers, whereas IL-17A production was lower in patients with PAH. IL- 17A inhibition reduced the production of FGF2, whereas enhanced the synthesis of TGFβ and CTGF. 1,25(OH)2D3 decreased the production of IL17A and pro-fibrotic cytokines in a dose- dependent manner. Conclusions: IL-17A is involved in the regulation of fibrogenesis in SSc, and could represent an intriguing potential therapeutic target, even if its role remains controversial. 1,25(OH)2D3 inhibits both IL-17A and pro-fibrotic cytokines, confirming its potential anti-fibrotic effect.
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Affiliation(s)
- Addolorata Corrado
- Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
| | - Cinzia Rotondo
- Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
| | - Eliana Rita Sanpaolo
- Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
| | - Alberto Altomare
- Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
| | - Nicola Maruotti
- Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
| | - Daniela Cici
- Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
| | - Francesco Paolo Cantatore
- Rheumatology Clinic - Department of Medical and Surgical Sciences, University of Foggia, Foggia- Italy
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25
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Modulation by 17,20S(OH) 2pD of Fibrosis-Related Mediators in Dermal Fibroblast Lines from Healthy Donors and from Patients with Systemic Sclerosis. Int J Mol Sci 2021; 23:ijms23010367. [PMID: 35008794 PMCID: PMC8745512 DOI: 10.3390/ijms23010367] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/16/2021] [Accepted: 12/27/2021] [Indexed: 12/15/2022] Open
Abstract
We previously demonstrated that the non-calcemic pregnacalciferol (pD) analog 17,20S (OH)2pD suppressed TGF-β1-induced type I collagen production in cultured normal human dermal fibroblasts. In the present studies, we examined fibroblasts cultured from the lesional skin of patients with systemic sclerosis (scleroderma (SSc)) and assessed the effects of 17,20S(OH)2pD on fibrosis-related mediators. Dermal fibroblast lines were established from skin biopsies from patients with SSc and healthy controls. Fibroblasts were cultured with either 17,20S(OH)2pD or 1,25(OH)2D3 (positive control) with/without TGF-β1 stimulation and extracted for protein and/or mRNA for collagen synthesis and mediators of fibrosis (MMP-1, TIMP-1, PAI-1, BMP-7, PGES, GLI1, and GLI2). 1 7,20S(OH)2pD (similar to 1,25(OH)2D3) significantly suppressed net total collagen production in TGF-β1-stimulated normal donor fibroblast cultures and in cultures of SSc dermal fibroblasts. 17,20S(OH)2pD (similar to 1,25(OH)2D3) also increased MMP-1, BMP-7, and PGES and decreased TIMP-1 and PAI1 expression in SSc fibroblasts. Although 17,20S(OH)2pD had no effect on Gli1 or Gli2 in SSc fibroblasts, it increased Gli2 expression when cultured with TGF-β1 in normal fibroblasts. These studies demonstrated that 17,20S(OH)2pD modulates mediators of fibrosis to favor the reduction of fibrosis and may offer new noncalcemic secosteroidal therapeutic approaches for treating SSc and fibrosis.
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26
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Girgis CM, Brennan-Speranza TC. Vitamin D and Skeletal Muscle: Current Concepts From Preclinical Studies. JBMR Plus 2021; 5:e10575. [PMID: 34950830 PMCID: PMC8674777 DOI: 10.1002/jbm4.10575] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/07/2021] [Accepted: 10/24/2021] [Indexed: 12/12/2022] Open
Abstract
Muscle weakness has been recognized as a hallmark feature of vitamin D deficiency for many years. Until recently, the direct biomolecular effects of vitamin D on skeletal muscle have been unclear. Although in the past, some reservations have been raised regarding the expression of the vitamin D receptor in muscle tissue, this special issue review article outlines the clear evidence from preclinical studies for not only the expression of the receptor in muscle but also the roles of vitamin D activity in muscle development, mass, and strength. Additionally, muscle may also serve as a dynamic storage site for vitamin D, and play a central role in the maintenance of circulating 25-hydroxy vitamin D levels during periods of low sun exposure. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Christian M Girgis
- Faculty of Medicine and Health University of Sydney Sydney NSW Australia.,Department of Diabetes and Endocrinology Westmead Hospital Sydney NSW Australia.,Department of Endocrinology Royal North Shore Hospital Sydney NSW Australia
| | - Tara C Brennan-Speranza
- Faculty of Medicine and Health University of Sydney Sydney NSW Australia.,School of Medical Sciences University of Sydney Sydney NSW Australia.,School of Public Health University of Sydney Sydney NSW Australia
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27
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Crescioli C. The Role of Estrogens and Vitamin D in Cardiomyocyte Protection: A Female Perspective. Biomolecules 2021; 11:1815. [PMID: 34944459 PMCID: PMC8699224 DOI: 10.3390/biom11121815] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/23/2021] [Accepted: 11/30/2021] [Indexed: 12/20/2022] Open
Abstract
Women experience a dramatical raise in cardiovascular events after menopause. The decline in estrogens is pointed to as the major responsible trigger for the increased risk of cardiovascular disease (CVD). Indeed, the menopausal transition associates with heart macro-remodeling, which results from a fine-tuned cell micro-remodeling. The remodeling of cardiomyocytes is a biomolecular response to several physiologic and pathologic stimuli, allowing healthy adaptation in normal conditions or maladaptation in an unfavorable environment, ending in organ architecture disarray. Estrogens largely impinge on cardiomyocyte remodeling, but they cannot fully explain the sex-dimorphism of CVD risk. Albeit cell remodeling and adaptation are under multifactorial regulation, vitamin D emerges to exert significant protective effects, controlling some intracellular paths, often shared with estrogen signaling. In post-menopause, the unfavorable association of hypoestrogenism-D hypovitaminosis may converge towards maladaptive remodeling and contribute to increased CVD risk. The aim of this review is to overview the role of estrogens and vitamin D in female cardiac health, speculating on their potential synergistic effect in cardiomyocyte remodeling, an issue that is not yet fully explored. Further learning the crosstalk between these two steroids in the biomolecular orchestration of cardiac cell fate during adaptation may help the translational approach to future cardioprotective strategies for women health.
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Affiliation(s)
- Clara Crescioli
- Department of Movement, Human and Health Sciences, Section of Health Sciences, University of Rome "Foro Italico", 00135 Rome, Italy
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28
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Elkafas H, Badary O, Elmorsy E, Kamel R, Yang Q, Al-Hendy A. Endocrine-Disrupting Chemicals and Vitamin D Deficiency in the Pathogenesis of Uterine Fibroids. JOURNAL OF ADVANCED PHARMACY RESEARCH 2021; 5:260-275. [PMID: 34746367 DOI: 10.21608/aprh.2021.66748.1124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Uterine fibroids (UFs) are the most prevalent gynecologic neoplasm, affecting 70-80% of women over their lifespan. Although UFs are benign they can become life-threatening and require invasive surgeries such as myomectomy and hysterectomy. Notwithstanding the significant negative influence UFs have on female reproductive health, very little is known about early events that initiate tumor development. Several risk factors for UFs have been identified including vitamin D deficiency, inflammation, DNA repair deficiency, and environmental exposures to endocrine-disrupting chemicals (EDCs). EDCs have come under scrutiny recently due to their role in UF development. Epidemiologic studies have found an association between increased risk for early UF diagnosis and in utero EDC exposure. Environmental exposure to EDCs during uterine development increases UF incidence in a UF animal model. Notably, several studies demonstrated that abnormal myometrial stem cells (MMSCs) are the cell origin for UFs development. Our recent studies demonstrated that early-life EDC exposure reprogrammed the MMSCs toward a pro-fibroid landscape and altered the DNA repair and inflammation pathways. Notably, Vitamin D3 (VITD3) as a natural compound shrank the UF growth concomitantly with the reversion of several abnormal biological pathways and ameliorated the developmental exposure-induced DNA damage and pro-inflammation pathway in primed MMSCs. This review highlights and emphasizes the importance of multiple pathway interactions in the context of hypovitaminosis D at the MMSCs level and provides proof-of-concept information that can help develop a safe, long-term, durable, and non-surgical therapeutic option for UFs.
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Affiliation(s)
- Hoda Elkafas
- Department of Pharmacology and Toxicology, Egyptian Drug Authority (EDA) formally, (NODCAR), Cairo 35521, Egypt.,Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Osama Badary
- Department of Clinical Pharmacy, Faculty of Pharmacy, British University in Egypt, Cairo 11837, Egypt
| | - Engy Elmorsy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
| | - Rehab Kamel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt
| | - Qiwei Yang
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, 60637, USA
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29
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Perez VM, Kearney JF, Yeh JJ. The PDAC Extracellular Matrix: A Review of the ECM Protein Composition, Tumor Cell Interaction, and Therapeutic Strategies. Front Oncol 2021; 11:751311. [PMID: 34692532 PMCID: PMC8526858 DOI: 10.3389/fonc.2021.751311] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for a dense fibrotic stroma that is interlaced with a collagen-based extracellular matrix (ECM) that plays an important role in tumor biology. Traditionally thought to only provide a physical barrier from host responses and systemic chemotherapy, new studies have demonstrated that the ECM maintains biomechanical and biochemical properties of the tumor microenvironment (TME) and restrains tumor growth. Recent studies have shown that the ECM augments tumor stiffness, interstitial fluid pressure, cell-to-cell junctions, and microvascularity using a mix of biomechanical and biochemical signals to influence tumor fate for better or worse. In addition, PDAC tumors have been shown to use ECM-derived peptide fragments as a nutrient source in nutrient-poor conditions. While collagens are the most abundant proteins found in the ECM, several studies have identified growth factors, integrins, glycoproteins, and proteoglycans in the ECM. This review focuses on the dichotomous nature of the PDAC ECM, the types of collagens and other proteins found in the ECM, and therapeutic strategies targeting the PDAC ECM.
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Affiliation(s)
- Vincent M Perez
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Joseph F Kearney
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jen Jen Yeh
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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30
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Sun S, Xu M, Zhuang P, Chen G, Dong K, Dong R, Zheng S. Effect and mechanism of vitamin D activation disorder on liver fibrosis in biliary atresia. Sci Rep 2021; 11:19883. [PMID: 34615940 PMCID: PMC8494743 DOI: 10.1038/s41598-021-99158-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
To investigate the mechanism of 25 hydroxyvitamin D (25(OH)D) deficiency in children with biliary atresia (BA) and its effect on liver fibrosis. The serum vitamin D and 25(OH)D, and expression of 25 hydroxylase (CYP2R1 and CYP27A1) in the liver of BA patients were detected and compared with those in the control group. We investigated the effect of differential expression of CYP2R1 in hepatocytes on the expression of genes related to liver fibrosis in primary hepatic stellate cells (HSCs) of BA and animal models of cholestasis. The ratio of 25(OH)D/vitamin D in the BA group was significantly lower than that in the control group. The mRNA and protein expression of CYP2R1 and CYP27A1 in liver tissue of the BA group was significantly lower than that in the control group. Exogenous active vitamin D (calcitriol) inhibited the proliferation and migration of primary HSCs isolated from BA patients, and reduced the expression of fibrosis-related genes in vitro. Downregulation of expression of CYP2R1 in hepatocytes increased expression of transforming growth factor (TGF)-β1, collagen (Col)-1α1 and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased the expression of matrix metalloproteinase (MMP)-2 in cocultured primary HSCs of BA. Upregulation of expression of CYP2R1 in mice with bile duct ligation significantly increased the level of 25(OH)D, decreased the expression of TGF-β1, Col-1α1 and TIMP-1, and increased the expression of MMP-2. Children with BA have impaired vitamin D activation due to CYP2R1 deficiency. The dysactivation of vitamin D can promote the proliferation and activation of HSCs and participate in the development of hepatic fibrosis in BA.
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Affiliation(s)
- Song Sun
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Menghua Xu
- The Center of Laboratory Medicine, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Peijun Zhuang
- Anesthesiology Department, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Gong Chen
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Kuiran Dong
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Rui Dong
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
| | - Shan Zheng
- Surgical Department, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
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31
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17,20S(OH) 2pD Can Prevent the Development of Skin Fibrosis in the Bleomycin-Induced Scleroderma Mouse Model. Int J Mol Sci 2021; 22:ijms22168926. [PMID: 34445632 PMCID: PMC8396226 DOI: 10.3390/ijms22168926] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/11/2021] [Accepted: 08/15/2021] [Indexed: 12/15/2022] Open
Abstract
Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-β1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-β1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses fibrosis and mediators of the TGF-β1 pathway in the bleomycin (BLM) model of fibrosis. Fibrosis was induced into the skin of female C57BL/6 mice by repeated injections of BLM (50 μg/100 μL) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)2pD using 5, 15, or 30 μg/kg for 21 days. The injected skin was biopsied; analyzed histologically; examined for total collagen by Sircol; and examined for mRNA expression of MMP-13, BMP-7, MCP-1, Gli1, and Gli2 by TR-PCR. Spleen was analyzed for lymphocytes using flow cytometry. Serum was analyzed for cytokines using a multiplexed ELISA. Results showed that all three doses of 17,20S(OH)2pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)2pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-α, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)2pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)2pD offers new therapeutic approaches for fibrotic disorders.
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32
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Sprague SM, Martin KJ, Coyne DW. Phosphate Balance and CKD-Mineral Bone Disease. Kidney Int Rep 2021; 6:2049-2058. [PMID: 34386654 PMCID: PMC8343779 DOI: 10.1016/j.ekir.2021.05.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 05/10/2021] [Indexed: 12/29/2022] Open
Abstract
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a common comorbidity in patients with CKD. Characterized by laboratory abnormalities, bone abnormality, and vascular calcification, CKD-MBD encompasses a group of mineral and hormone disturbances that are strongly associated with increased cardiovascular (CV) morbidity and mortality. Abnormal serum phosphate concentrations are an independent risk factor for CV morbidity and mortality, and overall mortality. Phosphate retention plays a central role in initiating and driving many other disturbances in CKD-MBD (e.g., increased parathyroid hormone and fibroblast growth factor 23 concentrations, hypocalcemia, low vitamin D) that are also linked to increased CV risk. Thus, effective phosphate control is a logical therapeutic target for CKD-MBD treatment. Current phosphate management strategies (dietary restrictions, dialysis, phosphate binders) are insufficient to consistently achieve and maintain target phosphate concentrations in patients on dialysis. Phosphate binders reduce available phosphate for intestinal absorption but do not impair the dominant phosphate absorption pathway. Novel therapies that consider new mechanistic understandings of intestinal phosphate absorption are needed. One such therapy is tenapanor, a targeted sodium-hydrogen exchanger isoform 3 inhibitor that has been shown to reduce serum phosphate concentrations in multiple clinical trials. Tenapanor has a novel mechanism of action that reduces intestinal phosphate absorption in the primary paracellular phosphate absorption pathway.
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Affiliation(s)
- Stuart M. Sprague
- Division of Nephrology and Hypertension, NorthShore University Health System, Evanston, IL, USA
| | | | - Daniel W. Coyne
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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McCullough PA. Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality. Cardiorenal Med 2021; 11:123-132. [PMID: 34120113 DOI: 10.1159/000516286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/24/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. SUMMARY Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to <5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels <5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. Key Messages: Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.
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Affiliation(s)
- Peter A McCullough
- Baylor University Medical Center, Dallas, Texas, USA.,Department of Internal Medicine, Texas A & M College of Medicine, Baylor Heart and Vascular Institute, Dallas, Texas, USA.,Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Texas, USA
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Bianchi F, Sommariva M, Le Noci V, Camelliti S, Gagliano N, Giussani M, Balsari A, Tagliabue E, Sfondrini L. Aerosol 1,25-dihydroxyvitamin D3 supplementation: A strategy to boost anti-tumor innate immune activity. PLoS One 2021; 16:e0248789. [PMID: 33780475 PMCID: PMC8007042 DOI: 10.1371/journal.pone.0248789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/05/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] plays a role in calcium homeostasis but can also exert immunomodulatory effects. In lungs, characterized by a particular immunosuppressive environment primarily due to the presence of alveolar macrophages (AM), 1,25(OH)2D3 has been shown to favor the immune response against pathogens. Here, we explored the ability of aerosolized 1,25(OH)2D3 to locally promote an anti-tumor phenotype in alveolar macrophages (AM) in the treatment of lung metastases. METHODS Cytotoxicity assay has been used to assess the capability of AM, in vitro treated of not with 1,25(OH)2D3, to stimulate NK cells. Sulforhodamine B (SRB) assay has been used to assess the effect of 1,25(OH)2D3 on MC-38 and B16 tumor cells in vitro growth. 1,25(OH)2D3 was aerosolized in immunocompetent mouse models to evaluate the effect of local administration of 1,25(OH)2D3 on in vivo growth of MC-38 and B16 tumor cells within lungs and on infiltrating immune cells. RESULTS In vitro incubation of naïve AM with 1,25(OH)2D3 improved their ability to stimulate NK cell cytotoxicity. In vivo aerosolized 1,25(OH)2D3 significantly reduced the metastatic growth of MC-38 colon carcinoma, a tumor histotype that frequently metastasizes to lung in human. Immune infiltrate obtained from digested lungs of 1,25(OH)2D3-treated mice bearing MC-38 metastases revealed an increased expression of MHCII and CD80 on AM and an up-modulation of CD69 expression on effector cells that paralleled a strong increased ability of these cells to kill MC-38 tumor in vitro. CONCLUSIONS Together, these data show that aerosol delivery can represent a feasible and novel approach to supplement 1,25(OH)2D3 directly to the lungs promoting the activation of local immunity against cancer.
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Affiliation(s)
- Francesca Bianchi
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Sommariva
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
| | - Valentino Le Noci
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
| | - Simone Camelliti
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
| | - Nicoletta Gagliano
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
| | - Marta Giussani
- Laboratory Medicine Unit, Department of Diagnostic Pathology and Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Andrea Balsari
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elda Tagliabue
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Lucia Sfondrini
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
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Huang CZ, Zhang J, Zhang L, Yu CH, Mo Y, Mo LY. Serum vitamin D and vitamin-D-binding protein levels in children with chronic hepatitis B. World J Gastroenterol 2021; 27:255-266. [PMID: 33519140 PMCID: PMC7814368 DOI: 10.3748/wjg.v27.i3.255] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/29/2020] [Accepted: 01/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Vitamin D is an essential fat-soluble secosteroid hydroxylated by the liver to form the intermediate metabolite calcidiol {25-hydroxy vitamin D [25(OH)D]}, which is a reliable indicator to investigate individual vitamin D status. Vitamin-D-binding protein (VDBP) is a multifunctional glycoprotein mainly synthesized in the liver and the major transport protein for vitamin D and its metabolites. Serum vitamin D and VDBP are both associated with hepatitis B. However, few studies have reported the relationship and clinical significance of vitamin D and VDBP with hepatitis B virus (HBV) replication and hepatic fibrosis in children with chronic hepatitis B (CHB).
AIM To explore vitamin D and VDBP serum levels in children with CHB and the association of vitamin D and VDBP with HBV replication and hepatic fibrosis.
METHODS We enrolled 204 children with CHB admitted to Hunan Children’ Hospital in summer and autumn between 2018 and 2019 and 170 healthy controls. CHB patients included: 164 hepatitis B e antigen (HBeAg) positive and 40 HBeAg negative; 193 hepatitis B surface antigen (HBsAg) positive and 11 HBsAg negative; 164 with detectable HBV deoxyribonucleic acid (DNA) and 40 with undetectable HBV DNA; 131 with HBV genotype B and 23 with HBV genotype C; and 27 without hepatic fibrosis and 97 with hepatic fibrosis. Serum levels of 25(OH)D, VDBP, liver function markers, and other clinical parameters were collected to analyze their association with vitamin D and VDBP. Mann-Whitney U test, Kruskal-Wallis H test, or t test was used to analyze serum 25(OH)D and VDBP levels in different groups. Spearman rank correlation test was utilized to analyze the correlation of 25(OH)D and VDBP with other markers. Statistically significant factors determined by univariate analysis were further analyzed by binary multivariate logistic regression analysis. P < 0.05 was considered statistically significant.
RESULTS Children with CHB had lower serum 25(OH)D (56.64 ± 17.89 nmoL/L) and VDBP [122.40 (70.74-262.84 μg/L)] levels than healthy controls had (P < 0.001). Serum 25(OH)D and VDBP levels were significantly different among the different grades of hepatic fibrosis (P < 0.05). VDBP levels in children with HBV genotype C, HBsAg, HBeAg, and detectable HBV DNA were significantly lower than those in children with HBV genotype B, no HBsAg, no HBeAg, and undetectable HBV DNA (P < 0.05). Serum 25(OH)D level was negatively correlated with age and serum total bilirubin level (r = -0.396 and -0.280, respectively, P < 0.001). Serum VDBP level was negatively correlated with HBV DNA (log10 IU/mL) (r = -0.272, P < 0.001). Serum 25(OH)D level was not correlated with VDBP level (P > 0.05). Univariate (P < 0.05) and multivariate logistic regression analysis showed that low level of 25(OH)D (odds ratio = 0.951, 95% confidence interval: 0.918-0.985) and high level of HBV DNA (odds ratio = 1.445, 95% confidence interval: 1.163-1.794) were independently correlated with hepatic fibrosis (P < 0.01).
CONCLUSION Serum levels of 25(OH)D and VDBP are decreased in children with CHB. Serum VDBP level is negatively correlated with HBV replication. Low level of 25(OH)D is independently associated with hepatic fibrosis in children with CHB. There is no significant association between serum levels of 25(OH)D and VDBP.
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Affiliation(s)
- Cai-Zhi Huang
- Department of Laboratory Medicine, Hunan Children’s Hospital, Changsha 410007, Hunan Province, China
| | - Jie Zhang
- Department of Laboratory Medicine, Hunan Children’s Hospital, Changsha 410007, Hunan Province, China
| | - Lin Zhang
- Department of Laboratory Medicine, Hunan Children’s Hospital, Changsha 410007, Hunan Province, China
| | - Cui-Hua Yu
- Department of GCP Certified Sites, The Third Hospital of Changsha City, Changsha 410005, Hunan Province, China
| | - Yi Mo
- Department of Laboratory Medicine, Hunan Children’s Hospital, Changsha 410007, Hunan Province, China
| | - Li-Ya Mo
- Department of Laboratory Medicine, Hunan Children’s Hospital, Changsha 410007, Hunan Province, China
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Vitamin D and Cardiovascular Disease, with Emphasis on Hypertension, Atherosclerosis, and Heart Failure. Int J Mol Sci 2020; 21:ijms21186483. [PMID: 32899880 PMCID: PMC7555466 DOI: 10.3390/ijms21186483] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/24/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022] Open
Abstract
Vitamin D deficiency is the most common nutritional deficiency, affecting almost one billion people worldwide. Vitamin D is mostly known for its role in intestinal calcium absorption and bone mineralization. However, the observation of seasonal changes in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in cardiomyocytes, as well as endothelial and vascular smooth muscle cells, implicated a role of vitamin D in the cardiovascular system. Animal studies provided compelling evidence that vitamin D signaling is essential for cardiovascular integrity, especially for the regulation of vascular tone and as an antifibrotic and antihypertrophic signaling pathway in the heart. In addition, observational studies reported an association between vitamin D deficiency and risk of hypertension, atherosclerosis, and heart failure. However, recent clinical intervention studies failed to prove the causal relationship between vitamin D supplementation and beneficial effects on cardiovascular health. In this review, we aim to highlight our current understanding of the role of vitamin D in the cardiovascular system and to find potential explanations for the large discrepancies between the outcome of experimental studies and clinical intervention trials.
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Plesa M, Gaudet M, Mogas A, Olivenstein R, Al Heialy S, Hamid Q. Action of 1,25(OH) 2D 3 on Human Asthmatic Bronchial Fibroblasts: Implications for Airway Remodeling in Asthma. J Asthma Allergy 2020; 13:249-264. [PMID: 32982316 PMCID: PMC7492716 DOI: 10.2147/jaa.s261271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/11/2020] [Indexed: 11/23/2022] Open
Abstract
Background Airway fibroblasts are major contributors to the histopathological feature of airway remodeling in asthma by their implication in the cell invasiveness and profibrogenic secretory phenotype observed in subepithelial fibrosis. 1,25 Dihydroxy vitamin D3 (1,25(OH)2D3) is an important therapeutic agent that blocks many features of airway remodeling induced by profibrogenic mediators, such as transforming growth factor beta 1 (TGF-β1) or T helper type 1 inflammatory cytokines. Objective We hypothesized that 1,25(OH)2D3 opposes the TGF-β1 or tumor necrosis factor alpha (TNF-α)-Interleukin 1 beta (IL-1β) stimulation on airway fibroblast profibrogenic secretory phenotype observed in severe asthmatic patients. Our aim was to investigate the anti-fibrogenic effect of 1,25(OH)2D3 in TGF-β1 or TNF-α-IL-1β-stimulated human bronchial fibroblast cells (HBFCs) from severe asthmatic compared with non-asthmatic subjects. Patients and Methods All experiments were performed on primary HBFCs from asthmatic (DHBFCs, n=4) and non-asthmatic subjects (NHBFCs, n=4). mRNA expression and protein quantification of key fibrogenic markers were analyzed by RT-qPCR and ELISA, comparing HBFCs from asthmatic and non-asthmatic subjects. Vitamin D receptor (VDR) mRNA expression and its functionality in HBFCs were assessed by RT-qPCR. HBFCs proliferation was assessed by flow cytometry using BrdU-FITC/7AAD bivariate staining, while HBFCs apoptosis by Annexin V-FITC/7AAD. Results VDR is constitutively expressed in HBFCs and the addition of 1,25(OH)2D3 significantly increased mRNA expression of CYP24A1 (a direct VDRs’ target gene) in both HBFCs groups. DHBFCs cultured in the presence of TGF-β1 or TNF-α-IL-1β showed increased mRNA expression and protein secretion of fibrogenic markers when compared to NHBFCs. Additionally, we observed decreased mRNA expression of FN 1, LUM, BGN, MMP2, COL5A1, TIMP1 and CC-chemokines (CCL2, CCL5, CCL11) in response to 1,25(OH)2D3 addition to the TGF-β1 or TNF-α-IL-1β-stimulated HBFCs. Cell culture media obtained from TGF-β1 or TNF-α-IL-1β-stimulated DHBFCs showed decreased protein secretion (fibronectin 1, lumican, MCP1, RANTES and eotaxin-1) in response to 1,25(OH)2D3 when compared to NHBFCs. 1,25(OH)2D3 inhibited proliferation in TGF-β1-stimulated HBFCs through G0/G1 cell cycle arrest and these effects were not correlated with the induction of apoptosis. Conclusion DHBFCs under TGF-β1 or TNF-α-IL-1β stimulation showed higher fibrogenic capacity when compared to NHBFCs. 1,25(OH)2D3 significantly blocked these effects and highlight 1,25(OH)2D3 as a possible therapeutic target for severe asthma.
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Affiliation(s)
- Maria Plesa
- Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada
| | - Mellissa Gaudet
- Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada
| | - Andrea Mogas
- Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada
| | - Ronald Olivenstein
- Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada.,Faculty of Medicine, McGill University, Montréal, QC, Canada
| | - Saba Al Heialy
- Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada.,Mohammed Bin Rashid University of Medicine and Health Sciences, College of Medicine, Dubai, United Arab Emirates
| | - Qutayba Hamid
- Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada.,Faculty of Medicine, McGill University, Montréal, QC, Canada.,College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
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Bellan M, Andreoli L, Mele C, Sainaghi PP, Rigamonti C, Piantoni S, De Benedittis C, Aimaretti G, Pirisi M, Marzullo P. Pathophysiological Role and Therapeutic Implications of Vitamin D in Autoimmunity: Focus on Chronic Autoimmune Diseases. Nutrients 2020; 12:E789. [PMID: 32192175 PMCID: PMC7146294 DOI: 10.3390/nu12030789] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023] Open
Abstract
Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology. Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies. Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date. Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases. The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications. In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.
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Affiliation(s)
- Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Laura Andreoli
- Rheumatology and Clinical Immunology Unit and Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, 25128 Brescia, Italy; (L.A.); (S.P.)
| | - Chiara Mele
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Cristina Rigamonti
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Silvia Piantoni
- Rheumatology and Clinical Immunology Unit and Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, 25128 Brescia, Italy; (L.A.); (S.P.)
| | - Carla De Benedittis
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Gianluca Aimaretti
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of Internal Medicine, “AOU Maggiore della Carità”, 28100 Novara, Italy
- CAAD, Centre for Autoimmune and Allergic Diseases, 28100 Novara, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (M.B.); (C.M.); (P.P.S.); (C.R.); (C.D.B.); (G.A.); (M.P.)
- Division of General Medicine, Ospedale S. Giuseppe, I.R.C.C.S. Istituto Auxologico Italiano, 28921 Verbania, Italy
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Nejm MB, Guimarães-Marques MJ, Oliveira LF, Damasceno L, Andersen ML, Tufik S, Fonseca F, Olszewer E, Leça R, de Almeida ACG, Scorza FA, Scorza CA. Assessment of vitamin D and inflammatory markers profile in cardiac tissue on Parkinson disease animal model. Pharmacol Rep 2020; 72:296-304. [PMID: 32124387 DOI: 10.1007/s43440-020-00074-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 11/13/2019] [Accepted: 12/30/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cardiovascular dysfunctions are common non-motor symptoms in patients with Parkinson's disease (PD) that can result in reduced quality of life and even death. Research in animal models designed to characterize the pathological association between PD and cardiovascular abnormalities is still in its infancy. This study assessed the early impact of the nigrostriatal dopaminergic damage on cardiological features in the unilateral 6-OHDA rat model of PD. METHODS Male Wistar rats received unilateral intrastriatal injections of 6-OHDA and sham rats were injected with saline. Animals were studied 15 days later. Immunohistochemistry was used for visualization of tyrosine hydroxylase (TH)-positive neurons in the nigrostriatal system. Electrocardiogram recordings of heart rate were performed in conscious rats. Heart levels of vitamin D, inflammatory cytokines and C-reactive protein were assessed through electrochemiluminescence immunoassay, quantitative reverse transcription PCR and turbidimetric method, respectively. RESULTS We found a post-injury reduction of TH-immunoreactivity of approximately 45% in the substantia nigra pars compacta and 20% in the striatum. Heart rate reduction was found in 6-OHDA-lesioned rats as compared with sham counterparts. Reduced levels of vitamin D and increased levels of inflammatory factors (C-reactive protein, IL-6, TNF-α and TGF-β) were detected in the heart tissue of PD rats in comparison with sham. CONCLUSION Our findings suggest a link between cardiac tissue changes and cardiac functional changes early after the central dopaminergic damage induced by 6-OHDA. Knowledge of the cardiac abnormalities in the 6-OHDA model is critical in identifying future therapeutic targets and disease-modifying approaches for PD non-motor features.
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Affiliation(s)
- Mariana Bocca Nejm
- Departamento de Neurologia/Neurociência, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), Av. Pedro de Toledo, 699, 1º andar, São Paulo, SP, Brazil
| | - Marcia Jonathas Guimarães-Marques
- Departamento de Neurologia/Neurociência, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), Av. Pedro de Toledo, 699, 1º andar, São Paulo, SP, Brazil
| | - Leandro Freitas Oliveira
- Departamento de Neurologia/Neurociência, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), Av. Pedro de Toledo, 699, 1º andar, São Paulo, SP, Brazil
| | - Laís Damasceno
- Departamento de Neurologia/Neurociência, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), Av. Pedro de Toledo, 699, 1º andar, São Paulo, SP, Brazil
| | - Monica L Andersen
- Departamento de Psicobiologia, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, SP, Brazil
| | - Sergio Tufik
- Departamento de Psicobiologia, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, SP, Brazil
| | - Fernando Fonseca
- Laboratório de Análises Clínicas da Faculdade de Medicina do ABC, Santo André, SP, Brazil
- Departamento de Ciências Farmacêuticas da, Universidade Federal de São Paulo (UNIFESP), Diadema, SP, Brazil
| | - Efrain Olszewer
- Fundação de Apoio à Pesquisa e Estudo na Área de Saúde (FAPES), São Paulo, SP, Brazil
| | - Renato Leça
- Departamento de Cirurgia II, Faculdade de Medicina do ABC, Santo André, SP, Brazil
| | - Antonio Carlo G de Almeida
- Departamento de Engenharia de Biossistemas, Universidade Federal de São João Del Rei (UFSJ), São João Del Rei, MG, Brazil
| | - Fulvio Alexandre Scorza
- Departamento de Neurologia/Neurociência, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), Av. Pedro de Toledo, 699, 1º andar, São Paulo, SP, Brazil
| | - Carla Alessandra Scorza
- Departamento de Neurologia/Neurociência, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), Av. Pedro de Toledo, 699, 1º andar, São Paulo, SP, Brazil.
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Cheung WW, Hao S, Wang Z, Ding W, Zheng R, Gonzalez A, Zhan J, Zhou P, Li S, Esparza MC, Hoffman HM, Lieber RL, Mak RH. Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis-associated cachexia. J Cachexia Sarcopenia Muscle 2020; 11:120-134. [PMID: 31721480 PMCID: PMC7015252 DOI: 10.1002/jcsm.12497] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 07/30/2019] [Accepted: 08/25/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Ctns-/- mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns-/- mice are 25(OH)D3 and 1,25(OH)2 D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns-/- mice. METHODS Twelve-month-old Ctns-/- mice and wild-type controls were treated with 25(OH)D3 and 1,25(OH)2 D3 (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns-/- mice using RNAseq. RESULTS Supplementation of 25(OH)D3 and 1,25(OH)2 D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2 D3 in Ctns-/- mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns-/- mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF-κB pathway) in inguinal white adipose tissue in Ctns-/- mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns-/- mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL-1β, IL-6, and TNF-α as well as an increased gene expression of Murf-2, atrogin-1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns-/- mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns-/- mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2 D3 normalized the top 20 differentially expressed genes in Ctns-/- mice. CONCLUSIONS We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2 D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns-/- mice via multiple cellular and molecular mechanisms.
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Affiliation(s)
- Wai W. Cheung
- Pediatric NephrologyRady Children's Hospital—San Diego, University of California, San DiegoSan DiegoCAUSA
| | - Sheng Hao
- Department of Nephrology and RheumatologyShanghai Children's Hospital, Shanghai Jiao Tong UniversityShanghaiChina
| | - Zhen Wang
- Department of PediatricsShanghai General Hospital, Shanghai Jiao Tong UniversityShanghaiChina
| | - Wei Ding
- Division of NephrologyShanghai 9th People's Hospital, Shanghai Jiao Tong UniversityShanghaiChina
| | - Ronghao Zheng
- Department of Pediatric Nephrology, Rheumatology, and ImmunologyMaternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Alex Gonzalez
- Pediatric NephrologyRady Children's Hospital—San Diego, University of California, San DiegoSan DiegoCAUSA
| | | | - Ping Zhou
- Department of PediatricsThe 2 Hospital of Harbin Medical UniversityHarbinChina
| | - Shiping Li
- College of Bioscience and BiotechnologyYangzhou UniversityYangzhouChina
| | - Mary C. Esparza
- Department of Orthopedic SurgeryUniversity of California, San DiegoSan DiegoCAUSA
| | - Hal M. Hoffman
- Department of PediatricsUniversity of California, San DiegoSan DiegoCAUSA
| | - Richard L. Lieber
- Department of Orthopedic SurgeryUniversity of California, San DiegoSan DiegoCAUSA
- Rehabilitation Institute of ChicagoChicagoILUSA
| | - Robert H. Mak
- Pediatric NephrologyRady Children's Hospital—San Diego, University of California, San DiegoSan DiegoCAUSA
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Abstract
Sarcopenia, the age-dependent decline of muscle mass and performance, is a common condition among elderly population and is related to numerous adverse health outcomes. Due to the effect of sarcopenia on quality of life, disability, and mortality, a greater awareness is important in order to correctly recognize the condition both in community and geriatric settings. Research on sarcopenia prevention and treatment is growing quickly, but many questions are still unanswered. The core of the sarcopenia state includes quantitative and qualitative declines of skeletal muscle. These two aspects should therefore be considered when designing and examining preventive and therapeutic interventions. The role of vitamin D in skeletal muscle metabolism has been highlighted in recent years. The interest arises from the important findings of studies indicating multiple impacts of vitamin D on this tissue, which can be divided into genomic (direct impacts) and non-genomic impacts (indirect impacts). Another important dimension to be considered in the study of vitamin D and muscle fiber metabolism is associated with different expressions of the vitamin D receptor, which differs in muscle tissue, depending on age, gender, and pathology. Vitamin D inadequacy or deficiency is related to muscle fiber atrophy, elevated risk of chronic musculoskeletal pain, sarcopenia, and falls. This review describes the effect of vitamin D in skeletal muscle tissue function and metabolism and includes discussion of possible mechanisms in skeletal muscle.
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Girgis CM. Vitamin D and Skeletal Muscle: Emerging Roles in Development, Anabolism and Repair. Calcif Tissue Int 2020; 106:47-57. [PMID: 31312865 DOI: 10.1007/s00223-019-00583-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 04/29/2019] [Indexed: 12/17/2022]
Abstract
This special issue article will focus on morphologic and functional roles of vitamin D in muscle, from strength to contraction to development and ageing and will characterise the controversy of VDR's expression in skeletal muscle, central to our understanding of vitamin D's effects on this tissue.
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Affiliation(s)
- Christian M Girgis
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia.
- Department of Diabetes and Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia.
- University of Sydney, Sydney, NSW, Australia.
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Associations between Vitamin D and Liver Function and Liver Fibrosis in Patients with Biliary Atresia. Gastroenterol Res Pract 2019; 2019:4621372. [PMID: 31781188 PMCID: PMC6875370 DOI: 10.1155/2019/4621372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 08/19/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Objectives To detail the effects of vitamin D (VD) deficiency and assess the relationships between VD deficiency and liver function and liver fibrosis in patients with biliary atresia (BA). Methods In this study, BA patients confirmed by intraoperative cholangiography were enrolled between January 2017 and February 2019. Preoperative serum 25-(OH)D level, liver function, serum biomarker levels of liver fibrosis, and histopathologic features were recorded. Deficiency, insufficiency, and sufficiency of VD were defined as serum 25-(OH)D concentrations of <10, 10-20, and >20 ng/ml, respectively. Associations between serum 25-(OH)D level and liver function and liver fibrosis were analyzed. Results A total of 161 BA infants were included. The median (interquartile range (IQR)) serum 25-(OH)D level in all patients was 7.56 (IQR: 4.48–11.40) ng/ml. The rates of 25-(OH)D deficiency, insufficiency, and sufficiency were 67.1% (108/161), 29.2% (47/161), and 3.7% (6/161), respectively. Serum 25-(OH)D level was negatively correlated with alkaline phosphatase (r = ‐0.232, P = 0.003). After adjusting for age, a decrease in serum 25-(OH)D level was correlated with the increase of the Batts-Ludwig stage score (odds ratio (OR): 0.94, 95% confidence interval (CI): 0.88–0.99; P = 0.028). Serum 25-(OH)D level was also correlated with the N-terminal propeptide of type III procollagen (PIIINP) (r = ‐0.246, P = 0.002). Additionally, PIIINP (P = 0.038) and ALP (P = 0.031) were independently associated with serum 25-(OH)D level. Conclusions VD deficiency was common and inversely correlated with liver fibrosis in BA patients. Furthermore, VD was not correlated with liver function except alkaline phosphatase.
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Ma D, Peng L. Vitamin D and pulmonary fibrosis: a review of molecular mechanisms. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:3171-3178. [PMID: 31934161 PMCID: PMC6949840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 02/18/2019] [Indexed: 06/10/2023]
Abstract
Pulmonary fibrosis is a serious interstitial disease characterized by initial diffuse alveolar inflammation, fibroblast proliferation, ECM accumulation, and the destruction of normal pulmonary tissues, whose etiology remains unknown and therapeutic options remain limited. The prevalence of Vitamin D deficiency is increasing and has been linked to pulmonary fibrosis. In recent years, many studies focused on the mechanistic pathway of Vitamin D in the prevention of fibrosis. This review highlights the current evidence on the molecular mechanisms of Vitamin D in pulmonary fibrosis. We want to provide new clues to the clinical management of pulmonary fibrosis.
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Affiliation(s)
- Dandan Ma
- Department of Critical-Care Medicine, Affiliated Jining First People’s HospitalShandong, China
| | - Lipan Peng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan 250000, Shandong, China
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Abstract
Vitamin D receptor expression and associated function have been reported in various muscle models, including C2C12, L6 cell lines and primary human skeletal muscle cells. It is believed that 1,25-hydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has a direct regulatory role in skeletal muscle function, where it participates in myogenesis, cell proliferation, differentiation, regulation of protein synthesis and mitochondrial metabolism through activation of various cellular signalling cascades, including the mitogen-activated protein kinase pathway(s). It has also been suggested that 1,25(OH)2D3 and its associated receptor have genomic targets, resulting in regulation of gene expression, as well as non-genomic functions that can alter cellular behaviour through binding and modification of targets not directly associated with transcriptional regulation. The molecular mechanisms of vitamin D signalling, however, have not been fully clarified. Vitamin D inadequacy or deficiency is associated with muscle fibre atrophy, increased risk of chronic musculoskeletal pain, sarcopenia and associated falls, and may also decrease RMR. The main purpose of the present review is to describe the molecular role of vitamin D in skeletal muscle tissue function and metabolism, specifically in relation to proliferation, differentiation and protein synthesis processes. In addition, the present review also includes discussion of possible genomic and non-genomic pathways of vitamin D action.
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Crosstalk among adipose tissue, vitamin D level, and biomechanical properties of hypertrophic burn scars. Burns 2019; 45:1430-1437. [PMID: 31076207 DOI: 10.1016/j.burns.2019.04.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/05/2019] [Accepted: 04/16/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE This cross-sectional study aimed to investigate whether adipose tissue loss and reduced vitamin D levels following severe burn injury are associated with pathologic scar formation and biomechanical scar properties. METHODS A total of 492 male subjects with hypertrophic burn scars were enrolled from January 2014 to July 2018 and analyzed. Body fat content was measured using dual-energy X-ray absorptiometry. Values of melanin, erythema, and trans-epidermal water loss (TEWL) and the distensibility and elasticity of hypertrophic scars were examined using pigment- and TEWL-measuring devices and a suction skin elasticity meter. RESULTS Burn patients with higher fat percentage tended to have higher 25(OH) vitamin D levels (P < 0.001). As body fat percentage increased, hypertrophic scars showed higher mean value of Uf (distensibility, P < 0.001) and lower mean value of Uv/Ue (viscoelasticity or interstitial fluid shifting, P < 0.001). Burn patients with higher 25(OH) vitamin D levels tended to have higher mean values of Uf (P < 0.001) and Ua/Uf (gross elasticity, P = 0.013) and lower mean value of Uv/Ue (P = 0.008). CONCLUSION Adipose tissue loss and decreased 25(OH) vitamin D levels following burn injury were related to scar rigidity and slow interstitial fluid shifting in hypertrophic scars.
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Tavakoli H, Rostami H, Avan A, Bagherniya M, Ferns GA, Khayyatzadeh SS, Ghayour-Mobarhan M. High dose vitamin D supplementation is associated with an improvement in serum markers of liver function. Biofactors 2019; 45:335-342. [PMID: 30761636 DOI: 10.1002/biof.1496] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 01/31/2019] [Indexed: 12/29/2022]
Abstract
Limited studies have examined the effects of vitamin D on liver enzymes in patients with liver disease but none has explored its effects in the healthy subjects. The aim of present study was to evaluate the effects of a high dose vitamin D supplementation on measures of liver function. A total of 988 adolescent girls were recruited; all were assessed for liver function tests (LFTs) including alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (ϒGT), alkaline phosphatase (ALP), total bilirubin, direct bilirubin, albumin, and total protein before and after supplementation with 50,000 IU cholecalciferol perls. Significant reductions were observed for AST, ALT, direct bilirubin, total bilirubin, LDH, and ϒGT at the end of supplementation, only in the group with abnormal reference value. Serum levels of total protein and albumin were higher at the end of follow up in the group with abnormal value. No significant change was obtained for LFTs in the group with normal value. Our findings suggest that vitamin D supplementation may improve markers of liver function in adolescents with abnormal LFTs. More randomized controlled trial with longer follow-up time will be required. © 2019 BioFactors, 45(3):335-342, 2019.
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Affiliation(s)
- Hamidreza Tavakoli
- Health research center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Hossein Rostami
- Health research center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Avan
- Metabolic syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Bagherniya
- Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, UK
| | - Sayyed Saeid Khayyatzadeh
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Cho YS, Seo CH, Joo SY, Song J, Cha E, Ohn SH. The Association Between Postburn Vitamin D Deficiency and the Biomechanical Properties of Hypertrophic Scars. J Burn Care Res 2019; 40:274-280. [PMID: 30806461 DOI: 10.1093/jbcr/irz028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Fibroblasts, keratinocytes, mast cells, and other cells participate in hypertrophic scar formation and express the vitamin D receptor. We investigated the association between vitamin D deficiency and the biomechanical properties of hypertrophic burn scars. This cross-sectional study analyzed 486 participants enrolled from May 1, 2013 to April 30, 2017. When complete wound healing was agreed with by the two opinions, blood sampling and scar evaluation were performed. The values of melanin and erythema, trans-epidermal water loss (TEWL), and scar distensibility and elasticity were measured using pigment- and TEWL-measuring devices and a suction skin elasticity meter. 25(OH) vitamin D deficiency was defined as plasma level of <20 ng/ml. The vitamin D-deficient patients had significantly higher mean values of scar melanin and TEWL (P = .032, P = .007), whereas scar erythema level was similar. They also showed significantly lower values of Uf (final distensibility; P < .001), Ua/Uf (gross elasticity; P < .001) and Ur/Uf (biological elasticity; P = .014), and higher value of Uv/Ue (viscoelasticity or potency against interstitial fluid shift; P = .016). In multiple linear regression analysis, Uf, Ua/Uf, Uv/Ue, and Ur/Uf were significantly affected by 25(OH)-vitamin D level in deficient patients (Uf, P = .017; Ua/Uf, P = .045; Uv/Ue, P = .024; Ur/Uf, P = .021). Our results demonstrated that vitamin D deficiency was significantly related to increased pigmentation, decreased skin barrier function, low scar distensibility and elasticity, and slow interstitial fluid movement in burn patients.
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Affiliation(s)
- Yoon Soo Cho
- Department of Rehabilitation Medicine, Hangang Sacred Heart Hospital, Seoul
| | - Cheong Hoon Seo
- Department of Rehabilitation Medicine, Hangang Sacred Heart Hospital, Seoul
| | - So Young Joo
- Department of Rehabilitation Medicine, Hangang Sacred Heart Hospital, Seoul
| | - Jimin Song
- Department of Physical Medicine and Rehabilitation, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Eunsil Cha
- Department of Physical Medicine and Rehabilitation, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Suk Hoon Ohn
- Department of Physical Medicine and Rehabilitation, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
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Caimmi C, Bertoldo E, Pozza A, Caramaschi P, Orsolini G, Gatti D, Rossini M, Viapiana O. Vitamin D serum levels and the risk of digital ulcers in systemic sclerosis: A longitudinal study. Int J Rheum Dis 2019; 22:1041-1045. [PMID: 30938067 DOI: 10.1111/1756-185x.13554] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 02/19/2019] [Accepted: 02/28/2019] [Indexed: 12/25/2022]
Abstract
AIM Low levels of vitamin D (25OHD) have been found to associated with digital ulcers (DUs) in systemic sclerosis (SSc), although only cross-sectional studies have been performed. We aimed to investigate if variations in vitamin D serum levels over time affect DU in SSc. METHODS This is a retrospective study on 65 patients. 25OHD was measured in 2011 and 2016 and its variations correlated with DU. RESULTS The mean age of our cohort was 58 (SD 12) years with a mean disease duration of 9.5 (5.3) years. Most of our patients had a limited SSc (69.2%). At baseline 50.8% and 41.5% after 5 years had 25OHD <30 ng/mL. Patients receiving supplementation (8750 IU/wk) at baseline numbered 39 (60.0%) and 45 (69.2%) at the end of follow up. Nevertheless, 31 (47.7%) had a decrease of 25OHD in 5 years. In univariate analysis, patients with incident DU had a decrease in 25OHD as compared to patients with no incident DU (-17.4 [37.0] vs 13.0 [89.5], P = 0.018). No differences in 25OHD variations were found for other disease characteristics. In multivariate analysis correcting for previous DU and modified Rodnan Skin Score at baseline, patients with a decrease in 25OHD had an increased risk of developing DU (odds ratio 16.6; 95% CI 1.7-164.5, P = 0.017). CONCLUSIONS A decrease in 25OHD is associated with the risk of developing DUs. In addition, vitamin D supplementation with the doses currently recommended may be insufficient in SSc. Further studies in wider cohorts are needed to confirm these results.
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Affiliation(s)
| | | | - Alice Pozza
- Rheumatology Unit, University of Verona, Verona, Italy
| | | | | | - Davide Gatti
- Rheumatology Unit, University of Verona, Verona, Italy
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Schwarz N, Nicholls SJ, Psaltis PJ. Vitamin D and Cardiovascular Disease. Heart Lung Circ 2019; 27:903-906. [PMID: 30047471 DOI: 10.1016/j.hlc.2018.05.098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 05/02/2018] [Indexed: 10/28/2022]
Affiliation(s)
- Nisha Schwarz
- Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Stephen J Nicholls
- Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Peter J Psaltis
- Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
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