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Balta C, Herman H, Ciceu A, Lepre CC, Mladin B, Rosu M, Oatis D, Russo M, Peteu VE, Gherghiceanu M, Fenyvesi F, Cotoraci C, Trotta MC, D'Amico M, Hermenean A. Chrysin-loaded calixarene-cyclodextrin ternary drug delivery system inhibits TGF-β and galectin-1 mediated pathways in diabetic liver fibrosis. Biochem Pharmacol 2024; 229:116474. [PMID: 39122218 DOI: 10.1016/j.bcp.2024.116474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/12/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
This study investigated the efficacy of a new chrysin-loaded calixarene-cyclodextrin ternary drug delivery system (DDS) in reversing liver fibrosis in a mouse model of chronic diabetes. The system was designed to enhance the solubility and bioavailability of chrysin (CHR) and calixarene 0118 (OTX008). Adult male CD1 mice received streptozotocin (STZ) injections to induce diabetes. After 20 weeks, they underwent intraperitoneal treatments twice weekly for a two-week period. Histological analyses revealed that long-term hyperglycaemia increased liver fibrosis and altered hepatic ultrastructure, characterized by lipid accumulation, hepatic stellate cell activation, and collagen deposition. The treatment with the chrysin-loaded DDS restored liver structure closely to normal levels, as opposed to the minimal impact observed with sulfobutylated β-cyclodextrin (SBECD) alone. The treatment significantly decreased serum activities of alanine /aspartate transaminases and reduced the gene expression of collagen type I (Col-I). It also modulated the transforming growth factor beta 1 (TGF-β1)/Smad signalling pathway, inhibiting the activation and proliferation of hepatic stellate cells. The treatment led to a downregulation of the TGF-β1 gene and its receptors TGFβR1 and TGFβR2, together with a decrease in Smad 2 and 3 mRNA levels. Conversely, Smad 7 mRNA expression was increased by the DDS. Furthermore, it downregulated galectin-1 (Gal-1) gene and protein levels, which correlated with fibrotic markers. In conclusion, the chrysin-loaded calixarene-cyclodextrin ternary DDS presents a promising therapeutic approach for diabetic liver fibrosis, effectively targeting fibrotic pathways and restoring hepatic function and structure.
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Affiliation(s)
- Cornel Balta
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania
| | - Hildegard Herman
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania
| | - Alina Ciceu
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania
| | - Caterina Claudia Lepre
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy; PhD Course in Translational Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Bianca Mladin
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania
| | - Marcel Rosu
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania
| | - Daniela Oatis
- Doctoral School of Biology, Faculty of Medicine, Vasile Goldis Western University of Arad, Arad, Romania
| | - Marina Russo
- PhD Course in National Interest in Public Administration and Innovation for Disability and Social Inclusion, Department of Mental, Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy; School of Pharmacology and Clinical Toxicology, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | | | - Mihaela Gherghiceanu
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; Department of Cell Biology, Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Ferenc Fenyvesi
- Department of Molecular Pharmaceutics and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, H-4032 Debrecen, Hungary
| | - Coralia Cotoraci
- Department of Haematology, Faculty of Medicine, Vasile Goldis Western University of Arad, 310025 Arad, Romania
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
| | - Michele D'Amico
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Anca Hermenean
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, 310025 Arad, Romania; Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, 310025 Arad, Romania.
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Biondi G, Marrano N, Borrelli A, Rella M, D’Oria R, Genchi VA, Caccioppoli C, Cignarelli A, Perrini S, Laviola L, Giorgino F, Natalicchio A. The p66 Shc Redox Protein and the Emerging Complications of Diabetes. Int J Mol Sci 2023; 25:108. [PMID: 38203279 PMCID: PMC10778847 DOI: 10.3390/ijms25010108] [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: 10/31/2023] [Revised: 12/11/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Diabetes mellitus is a chronic metabolic disease, the prevalence of which is constantly increasing worldwide. It is often burdened by disabling comorbidities that reduce the quality and expectancy of life of the affected individuals. The traditional complications of diabetes are generally described as macrovascular complications (e.g., coronary heart disease, peripheral arterial disease, and stroke), and microvascular complications (e.g., diabetic kidney disease, retinopathy, and neuropathy). Recently, due to advances in diabetes management and the increased life expectancy of diabetic patients, a strong correlation between diabetes and other pathological conditions (such as liver diseases, cancer, neurodegenerative diseases, cognitive impairments, and sleep disorders) has emerged. Therefore, these comorbidities have been proposed as emerging complications of diabetes. P66Shc is a redox protein that plays a role in oxidative stress, apoptosis, glucose metabolism, and cellular aging. It can be regulated by various stressful stimuli typical of the diabetic milieu and is involved in various types of organ and tissue damage under diabetic conditions. Although its role in the pathogenesis of diabetes remains controversial, there is strong evidence regarding the involvement of p66Shc in the traditional complications of diabetes. In this review, we will summarize the evidence supporting the role of p66Shc in the pathogenesis of diabetes and its complications, focusing for the first time on the emerging complications of diabetes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, 70124 Bari, Italy (M.R.); (R.D.); (V.A.G.)
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Alqahtani QH, Alshehri S, Alhusaini AM, Sarawi WS, Alqarni SS, Mohamed R, Kumar MN, Al-Saab J, Hasan IH. Protective Effects of Sitagliptin on Streptozotocin-Induced Hepatic Injury in Diabetic Rats: A Possible Mechanisms. Diseases 2023; 11:184. [PMID: 38131990 PMCID: PMC10743245 DOI: 10.3390/diseases11040184] [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: 10/28/2023] [Revised: 12/09/2023] [Accepted: 12/11/2023] [Indexed: 12/23/2023] Open
Abstract
Diabetes is a ubiquitous disease that causes several complications. It is associated with insulin resistance, which affects the metabolism of proteins, carbohydrates, and fats and triggers liver diseases such as fatty liver disease, steatohepatitis, fibrosis, and cirrhosis. Despite the effectiveness of Sitagliptin (ST) as an antidiabetic drug, its role in diabetes-induced liver injury is yet to be fully investigated. Therefore, this study aims to investigate the effect of ST on hepatic oxidative injury, inflammation, apoptosis, and the mTOR/NF-κB/NLRP3 signaling pathway in streptozotocin (STZ)-induced liver injury. Rats were allocated into four groups: two nondiabetic groups, control rats and ST rats (100 mg/kg), and two diabetic groups induced by STZ, and they received either normal saline or ST for 90 days. Diabetic rats showed significant hyperglycemia, hyperlipidemia, and elevation in liver enzymes. After STZ induction, the results revealed remarkable increases in hepatic oxidative stress, inflammation, and hepatocyte degeneration. In addition, STZ upregulated the immunoreactivity of NF-κB/p65, NLRP3, and mTOR but downregulated IKB-α in liver tissue. The use of ST mitigated metabolic and hepatic changes induced by STZ; it also reduced oxidative stress, inflammation, and hepatocyte degeneration. The normal expression of NF-κB/p65, NLRP3, mTOR, and IKB-α were restored with ST treatment. Based on that, our study revealed for the first time the hepatoprotective effect of ST that is mediated by controlling inflammation, oxidative stress, and mTOR/NF-κB/NLRP3 signaling.
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Affiliation(s)
- Qamraa H. Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia; (Q.H.A.); (S.A.); (A.M.A.); (W.S.S.); (J.A.-S.)
| | - Samiyah Alshehri
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia; (Q.H.A.); (S.A.); (A.M.A.); (W.S.S.); (J.A.-S.)
| | - Ahlam M. Alhusaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia; (Q.H.A.); (S.A.); (A.M.A.); (W.S.S.); (J.A.-S.)
| | - Wedad S. Sarawi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia; (Q.H.A.); (S.A.); (A.M.A.); (W.S.S.); (J.A.-S.)
| | - Sana S. Alqarni
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia;
| | - Raessa Mohamed
- Department of Histology, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia;
| | - Meha N. Kumar
- Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai 200233, China;
| | - Juman Al-Saab
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia; (Q.H.A.); (S.A.); (A.M.A.); (W.S.S.); (J.A.-S.)
| | - Iman H. Hasan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia; (Q.H.A.); (S.A.); (A.M.A.); (W.S.S.); (J.A.-S.)
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Abounouh K, Tanouti IA, Ouladlahsen A, Tahiri M, Badre W, Dehbi H, Sarih M, Benjelloun S, Pineau P, Ezzikouri S. The peroxisome proliferator-activated receptor γ coactivator-1 alpha rs8192678 (Gly482Ser) variant and hepatitis B virus clearance. Infect Dis (Lond) 2023; 55:614-624. [PMID: 37376899 DOI: 10.1080/23744235.2023.2228403] [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: 01/09/2023] [Revised: 06/06/2023] [Accepted: 06/18/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (CHB) infection is still incurable a major public health problem. It is yet unclear how host genetic factors influence the development of HBV infection. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) has been shown to regulate hepatitis B virus (HBV). Several reports found that PPARGC1A variants are involved in a number of distinct liver diseases. Here we investigate whether the PPARGC1A rs8192678 (Gly482Ser) variant is involved in the spontaneous clearance of acute HBV infection and if it participates in chronic disease progression in Moroccan patients. METHODS Our study included 292 chronic hepatitis B (CHB) patients and 181 individuals who spontaneously cleared-HBV infection. We genotyped the rs8192678 SNP using a TaqMan allelic discrimination assay and then explored its association with spontaneous HBV clearance and CHB progression. RESULTS Our data showed that individuals carrying CT and TT genotypes were more likely to achieve spontaneous clearance (OR = 0.48, 95% CI (0.32-0.73), p = 0.00047; OR = 0.28, 95% CI (0.15-0.53), p = 0.00005, respectively). Subjects carrying the mutant allele T were more likely to achieve spontaneous clearance (OR = 0.51, 95% CI (0.38-0.67), P = 2.68E-06). However, when we investigated the impact of rs8192678 on the progression of liver diseases, we neither observe any influence (p > 0.05) nor found any significant association between ALT, AST, HBV viral loads, and the PPARGC1A rs8192678 genotypes in patients with CHB (p > 0.05). CONCLUSION Our result suggests that PPARGC1A rs8192678 may modulate acute HBV infection, and could therefore represent a potential predictive marker in the Moroccan population.
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Affiliation(s)
- Karima Abounouh
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
- Laboratory of Cellular and Molecular Pathology, Medical School, University Hassan II
| | - Ikram-Allah Tanouti
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Ahd Ouladlahsen
- Faculté de médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Mohamed Tahiri
- Faculté de médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Wafaa Badre
- Faculté de médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Hind Dehbi
- Laboratory of Cellular and Molecular Pathology, Medical School, University Hassan II
| | - M'hammed Sarih
- Service de Parasitologie et des Maladies Vectorielles, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
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Malekpour K, Hazrati A, Soudi S, Roshangar L, Pourfathollah AA, Ahmadi M. Combinational administration of mesenchymal stem cell-derived exosomes and metformin reduces inflammatory responses in an in vitro model of insulin resistance in HepG2 cells. Heliyon 2023; 9:e15489. [PMID: 37153436 PMCID: PMC10160701 DOI: 10.1016/j.heliyon.2023.e15489] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/30/2023] [Accepted: 04/11/2023] [Indexed: 05/09/2023] Open
Abstract
Diabetes is a highly common metabolic disorder in advanced societies. One of the causes of diabetes is insulin resistance, which is associated with a loss of sensitivity to insulin-sensitive cells. Insulin resistance develops in the body of a person prone to diabetes many years before diabetes development. Insulin resistance is associated with complications such as hyperglycemia, hyperlipidemia, and compensatory hyperinsulinemia and causes liver inflammation, which, if left untreated, can lead to cirrhosis, fibrosis, and even liver cancer. Metformin is the first line of treatment for patients with diabetes, which lowers blood sugar and increases insulin sensitivity by inhibiting gluconeogenesis in liver cells. The use of metformin has side effects, including a metallic taste in the mouth, vomiting, nausea, diarrhea, and upset stomach. For this reason, other treatments, along with metformin, are being developed. Considering the anti-inflammatory role of mesenchymal stem cells (MSCs) derived exosomes, their use seems to help improve liver tissue function and prevent damage caused by inflammation. This study investigated the anti-inflammatory effect of Wharton's jelly MSCs derived exosomes in combination with metformin in the HepG2 cells insulin resistance model induced by high glucose. This study showed that MSCs derived exosomes as an anti-inflammatory agent in combination with metformin could increase the therapeutic efficacy of metformin without needing to change metformin doses by decreasing inflammatory cytokines production, including IL-1, IL-6, and TNF-α and apoptosis in HepG2 cells.
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Affiliation(s)
- Kosar Malekpour
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Pourfathollah
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Corresponding author.
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Corresponding author.
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Ebrahimi M, Seyedi SA, Nabipoorashrafi SA, Rabizadeh S, Sarzaeim M, Yadegar A, Mohammadi F, Bahri RA, Pakravan P, Shafiekhani P, Nakhjavani M, Esteghamati A. Lipid accumulation product (LAP) index for the diagnosis of nonalcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis. Lipids Health Dis 2023; 22:41. [PMID: 36922815 PMCID: PMC10015691 DOI: 10.1186/s12944-023-01802-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/03/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND Lipid accumulation product (LAP) is an index calculated by waist circumference (WC) and triglyceride (TG), which reflects lipid toxicity. This study aims to investigate the association between the LAP index and nonalcoholic fatty liver disease (NAFLD) in a systematic review and meta-analysis. METHODS AND RESULTS PubMed, Scopus, and Web of Science online databases were searched for eligible studies that investigated the association of the LAP index and NAFLD. Sixteen observational studies with 96,101 participants, including four cohort studies, one case‒control study and 11 cross-sectional studies with baseline data, were entered into this analysis. Fourteen studies reported a significant association between the LAP index and NAFLD, and two reported that this relation was not significant; two different meta-analyses (1- mean difference (MD) and 2- bivariate diagnostic test accuracy [DTA]) were conducted using Stata version 14. The LAP index was compared in subjects with and without NAFLD, and the difference was significant with 34.90 units (CI 95: 30.59-39.31, P < 0.001) of the LAP index. The DTA meta-analysis was conducted and showed that the LAP index pooled sensitivity and specificity for screening of NAFLD were 94% (CI95: 72%-99%, I2 = 99%, P < 0.001) and 85% (CI95: 62%-96%, I2 = 99%, P < 0.001), respectively. CONCLUSION The LAP Index is an inexpensive, sensitive, and specific method to evaluate NAFLD and may be valuable for NAFLD screening.
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Affiliation(s)
- Menooa Ebrahimi
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Seyed Arsalan Seyedi
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Seyed Ali Nabipoorashrafi
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Mojdeh Sarzaeim
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Yadegar
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Fatemeh Mohammadi
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Razman Arabzadeh Bahri
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Peyman Pakravan
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Paria Shafiekhani
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Vali-Asr Hospital, Tehran, P.O. Box 13145784 Iran
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Mohamed AA, Halim AA, Mohamed S, Mahmoud SM, Bahgat Eldemiry EM, Mohamed RS, Shaheen MM, Naguib GG, Muharram NM, Khalil MG, Saed S, Ibrahim R, Salah Seif A, Kamal N, Nasraldin K, Abdelrahman AE, El Borolossy R. The effect of high oral loading dose of cholecalciferol in non-alcoholic fatty liver disease patients. A randomized placebo controlled trial. Front Pharmacol 2023; 14:1149967. [PMID: 36998617 PMCID: PMC10043211 DOI: 10.3389/fphar.2023.1149967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 03/02/2023] [Indexed: 03/15/2023] Open
Abstract
Background and Aim: Non-alcoholic fatty liver (NAFLD) is one of the most common progressive metabolic disorders worldwide. There are increasing scientific interests nowadays for the association between vitamin D status and Non-alcoholic fatty liver. Earlier studies have revealed that vitamin D deficiency is highly prevalent in Non-alcoholic fatty liver patients that contributes to poor outcomes. Hence, the present study aimed to assess the efficacy and safety of oral cholecalciferol on Non-alcoholic fatty liver patients.Subjects and Methods: This study was conducted on 140 patients that were randomized either to group 1 that received the standard conventional therapy in addition to placebo or group 2 that received the standard conventional therapy in addition to cholecalciferol during the 4 months study period.Results: At the end of the study group 2 revealed significant decrease (p < 0.05) in the mean serum level of TG, LDL-C, TC, hsCRP as compared to their baseline results and group 1 results. Additionally, a significant improvement in the serum levels of ALT (p = 0.001) was seen in group 2 at the end of the study when compared to group 1. Whereas group 1 did not show any change in these parameters when compared to group 2 and their baseline results.Conclusion: Cholecalciferol was shown to have beneficial effects on serum ALT levels, hsCRP levels and lipid profile of NAFLD patients.Clinical Trial Registration:https://prsinfo.clinicaltrials.gov/prs-users-guide.html, identifier NCT05613192
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Affiliation(s)
- Amal Ahmed Mohamed
- Department of Biochemistry and Molecular Biology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Ahmed Abdel Halim
- Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Sahar Mohamed
- Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | | | | | - Rasha Sobh Mohamed
- Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Gina G. Naguib
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nashwa M. Muharram
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Mona G. Khalil
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Salma Saed
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Randa Ibrahim
- Clinical and Chemical Pathology Department, Nutrition Institute, Cairo, Egypt
| | - Ahmed Salah Seif
- Tropical Medicine Hepatology and Gastroenterology Department, Shebeen El-Kom Teaching Hospital, Menoufia, Egypt
| | - Noha Kamal
- Clinical Pathology Department, Theodor Bilharz Research Institute (TBRI), Ministry of Scientific Research and Higher Education, Gulf Medical University (GMU), Cairo, Egypt
| | - Karima Nasraldin
- Faculty of Biotechnology, Modern Science and Arts University, Cairo, Egypt
| | - Ali Elsaid Abdelrahman
- Diagnostic and Intervention Radiology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Radwa El Borolossy
- Department of Clinical Pharmacy, Faculty of Pharmacy Ain Shams University, Cairo, Egypt
- *Correspondence: Radwa El Borolossy,
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Yang Y, Yu J, Huo J, Yan Y. Sesamin Attenuates Obesity-Associated Nonalcoholic Steatohepatitis in High-Fat and High-Fructose Diet-Fed Mice. J Med Food 2023; 26:176-184. [PMID: 36637806 DOI: 10.1089/jmf.2022.k.0091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
This study explored the effects of sesamin on nonalcoholic steatohepatitis (NASH). High-fat and high-fructose diet-fed mice supplemented with or without sesamin. The results suggested that sesamin-treated mice lost body weight and fat tissue weight, had lower levels of serum metabolic parameters, and insulin resistance was mitigated. Histological examinations showed that sesamin treatment mitigated the progression of hepatic steatosis, and inflammation. In addition, sesamin enhanced hepatic antioxidant capacity, and decreased the activations of hepatic c-jun N-terminal kinase, inhibitor of kappa B kinase α, and insulin receptor substrate 1 as well as hepatic interleukin-6 and tumor necrosis factor-alpha levels. Further experiments indicated that sesamin treatment downregulated GRP78 and phospho-inositol-requiring enzyme 1 (IRE1) expression, and upregulated x-box binding protein 1 (XBP1) expression in hepatic tissue. The aforementioned results suggest that sesamin alleviates obesity-associated NASH, which might be linked to the effect of sesamin on the regulation of the hepatic endoplasmic reticulum stress-IRE1/XBP1 pathway. Thus, sesamin may be a good food functional ingredient in the treatment of obesity-associated NASH.
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Affiliation(s)
- Yang Yang
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Jing Yu
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Jiayao Huo
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Yaping Yan
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China
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Pathophysiology of obesity and its associated diseases. Acta Pharm Sin B 2023. [DOI: 10.1016/j.apsb.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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10
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Tourkochristou E, Assimakopoulos SF, Thomopoulos K, Marangos M, Triantos C. NAFLD and HBV interplay - related mechanisms underlying liver disease progression. Front Immunol 2022; 13:965548. [PMID: 36544761 PMCID: PMC9760931 DOI: 10.3389/fimmu.2022.965548] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/15/2022] [Indexed: 12/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Stelios F. Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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11
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Abstract
The traditional complications of diabetes mellitus are well known and continue to pose a considerable burden on millions of people living with diabetes mellitus. However, advances in the management of diabetes mellitus and, consequently, longer life expectancies, have resulted in the emergence of evidence of the existence of a different set of lesser-acknowledged diabetes mellitus complications. With declining mortality from vascular disease, which once accounted for more than 50% of deaths amongst people with diabetes mellitus, cancer and dementia now comprise the leading causes of death in people with diabetes mellitus in some countries or regions. Additionally, studies have demonstrated notable links between diabetes mellitus and a broad range of comorbidities, including cognitive decline, functional disability, affective disorders, obstructive sleep apnoea and liver disease, and have refined our understanding of the association between diabetes mellitus and infection. However, no published review currently synthesizes this evidence to provide an in-depth discussion of the burden and risks of these emerging complications. This Review summarizes information from systematic reviews and major cohort studies regarding emerging complications of type 1 and type 2 diabetes mellitus to identify and quantify associations, highlight gaps and discrepancies in the evidence, and consider implications for the future management of diabetes mellitus.
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Affiliation(s)
- Dunya Tomic
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Jonathan E Shaw
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Dianna J Magliano
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
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12
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The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical Implications. J Clin Med 2022; 11:jcm11133649. [PMID: 35806934 PMCID: PMC9267803 DOI: 10.3390/jcm11133649] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/09/2022] [Accepted: 06/21/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a predominant hepatopathy that is rapidly becoming the most common cause of hepatocellular carcinoma worldwide. The close association with metabolic syndrome’s extrahepatic components has suggested the nature of the systemic metabolic-related disorder based on the interplay between genetic, nutritional, and environmental factors, creating a complex network of yet-unclarified pathogenetic mechanisms in which the role of insulin resistance (IR) could be crucial. This review detailed the clinical and pathogenetic evidence involved in the NAFLD–IR relationship, presenting both the classic and more innovative models. In particular, we focused on the reciprocal effects of IR, oxidative stress, and systemic inflammation on insulin-sensitivity disruption in critical regions such as the hepatic and the adipose tissue, while considering the impact of genetics/epigenetics on the regulation of IR mechanisms as well as nutrients on specific insulin-related gene expression (nutrigenetics and nutrigenomics). In addition, we discussed the emerging capability of the gut microbiota to interfere with physiological signaling of the hormonal pathways responsible for maintaining metabolic homeostasis and by inducing an abnormal activation of the immune system. The translation of these novel findings into clinical practice could promote the expansion of accurate diagnostic/prognostic stratification tools and tailored pharmacological approaches.
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13
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Cadamuro M, Lasagni A, Sarcognato S, Guido M, Fabris R, Strazzabosco M, Strain AJ, Simioni P, Villa E, Fabris L. The Neglected Role of Bile Duct Epithelial Cells in NASH. Semin Liver Dis 2022; 42:34-47. [PMID: 34794182 DOI: 10.1055/s-0041-1739455] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and affects 25% of the population in Western countries. NAFLD is the hepatic manifestation of the metabolic syndrome, linked to insulin resistance, which is the common pathogenetic mechanism. In approximately 40% of NAFLD patients, steatosis is associated with necro-inflammation and fibrosis, resulting in nonalcoholic steatohepatitis (NASH), a severe condition that may progress to cirrhosis and liver cancer. Although the hepatocyte represents the main target of the disease, involvement of the bile ducts occurs in a subset of patients with NASH, and is characterized by ductular reaction and activation of the progenitor cell compartment, which incites portal fibrosis and disease progression. We aim to dissect the multiple biological effects that adipokines and metabolic alterations exert on cholangiocytes to derive novel information on the mechanisms driven by insulin resistance, which promote fibro-inflammation and carcinogenesis in NASH.
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Affiliation(s)
| | - Alberto Lasagni
- Division of General Medicine, Padua University-Hospital, Padua, Italy
| | | | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Roberto Fabris
- Division of Clinica Medica 3, Center for the Study and the Integrated Management of Obesity, Padua University-Hospital, Padua, Italy
| | - Mario Strazzabosco
- Department of Internal Medicine, Digestive Disease Section, Liver Center, Yale University, New Haven, Connecticut
| | - Alastair J Strain
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Paolo Simioni
- Division of General Medicine, Padua University-Hospital, Padua, Italy.,Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Erica Villa
- Gastroenterology Unit, Department of Medical Specialties, University of Modena & Reggio Emilia and Modena University-Hospital, Modena, Italy
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua, Italy.,Division of General Medicine, Padua University-Hospital, Padua, Italy.,Department of Internal Medicine, Digestive Disease Section, Liver Center, Yale University, New Haven, Connecticut
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14
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Abstract
ANGPTL8 is an important cytokine, which is significantly increased in type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome. Many studies have shown that ANGPTL8 can be used as a bio-marker of these metabolic disorders related diseases, and the baseline ANGPTL8 level has also been found to be positively correlated with retinopathy and all-cause mortality in patients with T2DM. This may be related to the inhibition of lipoprotein lipase activity and the reduction of circulating triglyceride (TG) clearance by ANGPTL8. Consistently, inhibition of ANGPTL8 seems to prevent or improve atherosclerosis. However, it is puzzling that ANGPTL8 seems to have a directing function for TG uptake in peripheral tissues; that is, ANGPTL8 specifically enhances the reserve and buffering function of white adipose tissue, which may alleviate the ectopic lipid accumulation to a certain extent. Furthermore, ANGPTL8 can improve insulin sensitivity and inhibit hepatic glucose production. These contradictory results lead to different opinions on the role of ANGPTL8 in metabolic disorders. In this paper, the correlation between ANGPTL8 and metabolic diseases, the regulation of ANGPTL8 and the physiological role of ANGPTL8 in the process of glucose and lipid metabolism were summarized, and the physiological/pathological significance of ANGPTL8 in the process of metabolic disorder was discussed.
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Affiliation(s)
- Chang Guo
- Department of Nephrology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Chenxi Wang
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Xia Deng
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Jianqiang He
- Department of Nephrology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Ling Yang
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
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15
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Rojas Ortiz V, Nieves J, Fernandez EC. Clinical Management of Nonalcoholic Steatohepatitis (NASH) With the Use of Thiazolidinediones and the Additive Effect of Thiazolidinediones and a GLP-1 Agonist: Case Series. Cureus 2021; 13:e14082. [PMID: 33903842 PMCID: PMC8063915 DOI: 10.7759/cureus.14082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
We present five cases where patients were diagnosed with nonalcoholic steatohepatitis (NASH) and were treated pharmacologically. This is a common disease that is gaining clinical importance due to the long-term sequelae it may bring to a patient, such as cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Diagnosis and treatment are crucial to make a difference in these patients. Diagnosis is mainly through obtaining alanine transaminase (ALT) and aspartate aminotransferase (AST) levels and excluding excessive alcohol use and other identified liver diseases. Diet and lifestyle are the first options in the treatment of NASH, but some pharmacotherapy has been tested for the cure of NASH. Insulin-sensitizing medications, such as Pioglitazone, have shown beneficial effects but with limited success and increase weight as a side effect. The GLP-1 receptor agonist, which are used in diabetes mellitus type two, has shown significant results in patients with NASH such as decreasing ALT levels, body weight, and hepatic fat.
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16
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Mohamed AAR, Khater SI, Hamed Arisha A, Metwally MM, Mostafa-Hedeab G, El-Shetry ES. Chitosan-stabilized selenium nanoparticles alleviate cardio-hepatic damage in type 2 diabetes mellitus model via regulation of caspase, Bax/Bcl-2, and Fas/FasL-pathway. Gene 2021; 768:145288. [PMID: 33181259 DOI: 10.1016/j.gene.2020.145288] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/26/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023]
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17
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Mabuza LP, Gamede MW, Maikoo S, Booysen IN, Nguban PS, Khathi A. Hepatoprotective Effects of a Ruthenium(II) Schiff Base Complex in Rats with Diet-Induced Prediabetes. Curr Ther Res Clin Exp 2019; 91:66-72. [PMID: 31871510 PMCID: PMC6911857 DOI: 10.1016/j.curtheres.2019.100570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 10/13/2019] [Indexed: 12/18/2022] Open
Abstract
Ruthenium(II) Schiff-base complex normalizes liver damage biomarker enzymes. Ruthenium(II) Schiff-base complex reduced hepatic lipid accumulation and restored liver and body weight. Ruthenium(II) Schiff-base complex decreased plasma SREBP-1c levels. Ruthenium(II) Schiff-base complex prevented hepatomegaly and prediabetes-related NAFLD progression. Background Progressive insulin resistance in a prediabetic state has been reported to be the predominant causative factor for the development of nonalcoholic fatty liver disease. The combination of dietary modification and pharmacotherapy has been recommended to manage diabetic liver complications. However, poor patient compliance and toxicity of current drug therapy on liver function still results; thus, newer alternative drugs are required. Objective This study sought to investigate the hepatoprotective effects of the ruthenium(II) Schiff base complex in the presence and absence of dietary intervention in a diet-induced pre-diabetic rat model. Methods Prediabetic rats were randomly allocated to respective treatment groups. The ruthenium-based compound (15 mg/kg) was administered to the prediabetic rats in both the presence and absence of dietary intervention once a day every third day for 12 weeks. Results The administration of the ruthenium compound in both the presence and absence of dietary intervention resulted in the restoration of liver and body weights. This treatment also reduced liver damage enzyme biomarkers, bilirubin, and sterol regulatory element binding protein 1c concentrations in the plasma. Conclusions The ruthenium(II) complex showed beneficial effects as it ameliorated and prevented the progression of diabetes-related liver derangements while eliminating the hepatotoxicity associated with the use of metal compounds. However, further studies are still required to further determine the physiological mechanisms behind this effect.
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Affiliation(s)
- Lindokuhle Patience Mabuza
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
- Address correspondence to: L.P. Mabuza, Lindokuhle Patience Mabuza, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, South Africa.
| | - Mlindeli Wilkinson Gamede
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Sanam Maikoo
- School of Chemistry and Physics, College of Engineering and Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa
| | - Irvin Noel Booysen
- School of Chemistry and Physics, College of Engineering and Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa
| | - Phikelelani Siphosethu Nguban
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Andile Khathi
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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18
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Cheraghpour M, Imani H, Ommi S, Alavian SM, Karimi-Shahrbabak E, Hedayati M, Yari Z, Hekmatdoost A. Hesperidin improves hepatic steatosis, hepatic enzymes, and metabolic and inflammatory parameters in patients with nonalcoholic fatty liver disease: A randomized, placebo-controlled, double-blind clinical trial. Phytother Res 2019; 33:2118-2125. [PMID: 31264313 DOI: 10.1002/ptr.6406] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/05/2019] [Accepted: 05/19/2019] [Indexed: 01/09/2023]
Abstract
This study aimed to evaluate the effects of hesperidin on nonalcoholic fatty liver disease (NAFLD) characteristics. In this randomized, double-blind, controlled clinical trial, 50 NAFLD patients were supplemented with either 1-g hesperidin capsule or identical placebo capsule for 12 weeks. During the intervention, both groups were advised to follow healthy lifestyle habits including dietary and physical activity recommendations. At the end of the study, hesperidin supplementation, compared with placebo, was associated with a significant reduction in alanine aminotransferase (p = .005), γ-glutamyltransferase (p = .004), total cholesterol (p = .016), triglyceride (p = .049), hepatic steatosis (p = .041), high-sensitivity C-reactive protein (p = .029), tumor necrosis factor-α, and nuclear factor-κB (NF-κB). In conclusion, our results indicate that hesperidin supplementation accompanied with lifestyle modification is superior to lifestyle modification alone in management of NAFLD at least partially through inhibiting NF-κB activation and improving lipid profile. Further studies with higher dose of hesperidin are required to find the optimal dose.
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Affiliation(s)
- Makan Cheraghpour
- Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Imani
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Shahrzad Ommi
- Department of Dietetics and Nutrition, Florida International University, Miami, Florida
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Yari
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Division of Gastroenterology, BC Children's Hospital, Vancouver, British Columbia, Canada
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19
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Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76:99-128. [PMID: 30343320 PMCID: PMC11105781 DOI: 10.1007/s00018-018-2947-0] [Citation(s) in RCA: 400] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the "first hit" for NAFLD development. NAFLD progression seems to involve the occurrence of "parallel, multiple-hit" injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina.
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20
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Abstract
BACKGROUND/OBJECTIVES The relationship between nonalcoholic fatty liver disease (NAFLD) and albuminuria has been shown in many epidemiologic studies, although the results were inconsistent. This meta-analysis was conducted to summarize all available data and to estimate the risk of albuminuria among patients with NAFLD. METHODS Comprehensive literature review was conducted utilizing Medline and Embase database through January 2018 to identify studies that compared the risk of albuminuria among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS Nineteen studies (17 cross-sectional studies and two cohort studies) with 24 804 participants fulfilled the eligibility criteria and were included in this meta-analysis. The risk of albuminuria among patients with NAFLD was significantly higher than those without NAFLD with the pooled odds ratio (OR) of 1.67 [95% confidence interval (CI): 1.32-2.11]. Subgroup analysis demonstrated the significantly increased risk of albuminuria among patients with NAFLD without diabetes with pooled OR of 2.25 (95% CI: 1.65-3.06). However, we found no significant association between albuminuria and NAFLD among diabetic patients [pooled OR 1.28 (95% CI: 0.94-1.75)]. CONCLUSION A significantly increased risk of albuminuria among patients with NAFLD was observed in this meta-analysis. Physicians should pay more attention to the early detection and subsequent treatment of individuals with microalbuminuria especially in patients with NAFLD.
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Feizollahzadeh S, Ghiasvand R, Rezaei A, Khanahmad H, Sadeghi A, Hariri M. Effect of Probiotic Soy Milk on Serum Levels of Adiponectin, Inflammatory Mediators, Lipid Profile, and Fasting Blood Glucose Among Patients with Type II Diabetes Mellitus. Probiotics Antimicrob Proteins 2018; 9:41-47. [PMID: 27757829 DOI: 10.1007/s12602-016-9233-y] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Probiotic therapies are going to be an effective alternative therapeutic strategy in the treatment and management of diabetes. The mechanism behind the essential effects of probiotic therapies in diabetic patients was not fully understood. The objective of this study was to evaluate the effects of probiotic soy milk containing Lactobacillus planetarum A7 on inflammation, lipid profile, fasting blood glucose, and serum adiponectin among patients with type 2 diabetes mellitus. Forty patients with type 2 diabetes, at the age of 35-68 years old, were assigned to two groups in this randomized, double-blind, controlled clinical trial. The patients in the intervention group consumed 200 ml/day of probiotic soy milk containing L. planetarum A7 and those in control group consumed 200 ml/day of pure soy milk for 8 weeks. Serum TNF-α, C reactive protein, adiponectin, lipid profile, and fasting blood glucose were determined before and after intervention. In intervention group, serum adiponectin in pre- and post-treatment did not show any significant changes (2.52 ± 0.74 vs 2.84 ± 0.61, P = 0.658), as well as changes in serum TNF-α and C reactive protein (172.44 ± 5.7 vs 172.83 ± 7.6, P = 0.278, 4.2 ± 1.4 vs 4.5 ± 1.9, P = 0.765, respectively). Low-density cholesterol and high-density cholesterol changed significantly (P = 0.023, P = 0.017, respectively), but fasting blood glucose did not show any significant changes. The results of this study showed that consumption of probiotic soy milk and soy milk has no effect on serum adiponectin and inflammation, but it can change lipid profile among type 2 diabetic patients.
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Affiliation(s)
- Sadegh Feizollahzadeh
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Ghiasvand
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abbas Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Khanahmad
- Department of Molecular Biology and Genetics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Akram Sadeghi
- Department of Anatomical Sciences and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mitra Hariri
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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22
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Li CC, Liu C, Fu M, Hu KQ, Aizawa K, Takahashi S, Hiroyuki S, Cheng J, von Lintig J, Wang XD. Tomato Powder Inhibits Hepatic Steatosis and Inflammation Potentially Through Restoring SIRT1 Activity and Adiponectin Function Independent of Carotenoid Cleavage Enzymes in Mice. Mol Nutr Food Res 2018; 62:e1700738. [PMID: 29266812 DOI: 10.1002/mnfr.201700738] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 12/04/2017] [Indexed: 12/16/2022]
Abstract
SCOPE Beta-carotene-15,15'-oxygenase (BCO1) and beta-carotene-9',10'-oxygenase (BCO2) metabolize lycopene to biologically active metabolites, which can ameliorate nonalcoholic fatty liver disease (NAFLD). We investigate the effects of tomato powder (TP containing substantial lycopene (2.3 mg/g)) on NAFLD development and gut microbiome in the absence of both BCO1 and BCO2 in mice. METHOD AND RESULTS BCO1-/- /BCO2-/- double knockout mice were fed a high fat diet (HFD) alone (n = 9) or with TP feeding (n = 9) for 24 weeks. TP feeding significantly reduced pathological severity of steatosis and hepatic triglyceride levels in BCO1-/- /BCO2-/- mice (p < 0.04 vs HFD alone). This was associated with increased SIRT1 activity, nicotinamide phosphoribosyltransferase expression and AMP-activated protein kinase phosphorylation, and subsequently decreased lipogenesis, hepatic fatty acid uptake, and increasing fatty acid β-oxidation (p < 0.05). TP feeding significantly decreased mRNA expression of proinflammatory genes (tnf-α, il-1β, and il-6) in both liver and mesenteric adipose tissue, which were associated with increased plasma adiponectin and hepatic adiponectin receptor-2. Multiplexed 16S rRNA gene sequencing was performed using DNA extracted from cecum fecal samples. TP feeding increased microbial richness and decreased relative abundance of the genus Clostridium. CONCLUSION Dietary TP can inhibit NAFLD independent of carotenoid cleavage enzymes, potentially through increasing SIRT1 activity and adiponectin production and decreasing Clostridium abundance.
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Affiliation(s)
- Cheng-Chung Li
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Chun Liu
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Maobin Fu
- Nature and Wellness Research Department, Research and Development Division, Kagome Co., Ltd., Tochigi, Japan
| | - Kang-Quan Hu
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Koichi Aizawa
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.,Nature and Wellness Research Department, Research and Development Division, Kagome Co., Ltd., Tochigi, Japan
| | - Shingo Takahashi
- Nature and Wellness Research Department, Research and Development Division, Kagome Co., Ltd., Tochigi, Japan
| | - Suganuma Hiroyuki
- Nature and Wellness Research Department, Research and Development Division, Kagome Co., Ltd., Tochigi, Japan
| | - Junrui Cheng
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Johannes von Lintig
- Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Xiang-Dong Wang
- Nutrition and Cancer Biology Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
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Dai H, Wang W, Chen R, Chen Z, Lu Y, Yuan H. Lipid accumulation product is a powerful tool to predict non-alcoholic fatty liver disease in Chinese adults. Nutr Metab (Lond) 2017; 14:49. [PMID: 28775758 PMCID: PMC5539973 DOI: 10.1186/s12986-017-0206-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 07/27/2017] [Indexed: 02/07/2023] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD), recognized as the liver manifestation of metabolic syndrome, is highly prevalent in the general population. Recent studies suggest that lipid accumulation product is significantly associated with metabolic abnormalities. The aim of this study was to assess the accuracy of lipid accumulation product (LAP) as an effective screening tool for diagnosing NAFLD in the general population. Methods A total of 40,459 subjects aged ≥18 years were enrolled in this cross-sectional study. LAP was calculated as [waist circumference (cm) – 65] × triglyceride concentration (mmol//L) in men and [waist circumference (cm) – 58] × triglyceride concentration (mmol/L) in women. Multiple logistic regression and receiver operating characteristic (ROC) analyses were performed. Results According to multiple logistic regression analyses, LAP was significantly associated with a higher prevalence and severity of NAFLD in both men and women. When assessed using ROC curve analyses, LAP exhibited high diagnostic accuracy for identifying NAFLD, and the areas under the curves (AUC) in men and women were 0.843 (95% CI 0.837, 0.849) and 0.887 (95% CI 0.882, 0.892), respectively. After further analyzed in different age groups, the diagnostic accuracy of LAP was found to be significantly better in younger age groups (aged 18-34 for men; aged 18-34 and 35-44 years for women) for both sexes. Conclusions LAP is significantly associated with the presence and severity of NAFLD, and has a high diagnostic accuracy for identifying NAFLD in the general population. The diagnostic accuracy of LAP was especially high among younger age groups. Electronic supplementary material The online version of this article (doi:10.1186/s12986-017-0206-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Haijiang Dai
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, 138 Tong-Zi-Po Road, Changsha, Hunan 410013 People's Republic of China.,Center of Health Management, the Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013 People's Republic of China
| | - Weijun Wang
- Division of Gastroenterology, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022 People's Republic of China
| | - Ruifang Chen
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, 138 Tong-Zi-Po Road, Changsha, Hunan 410013 People's Republic of China
| | - Zhiheng Chen
- Center of Health Management, the Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013 People's Republic of China
| | - Yao Lu
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, 138 Tong-Zi-Po Road, Changsha, Hunan 410013 People's Republic of China
| | - Hong Yuan
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, 138 Tong-Zi-Po Road, Changsha, Hunan 410013 People's Republic of China
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Shin JH, Jung JH. Non-alcoholic fatty liver disease and flavonoids: Current perspectives. Clin Res Hepatol Gastroenterol 2017; 41:17-24. [PMID: 27545758 DOI: 10.1016/j.clinre.2016.07.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 06/21/2016] [Accepted: 07/07/2016] [Indexed: 02/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an accumulation of fat in the liver despite a low level of alcohol intake, with signs of hepatomegaly. Although in the past, NAFLD was predominantly viewed as an aspect of metabolic syndrome, it is now considered that it should be classified as an independent condition similar to obesity, diabetes, and hypertension. Therefore, new treatment strategies, not based on correcting insulin resistance, are needed for NAFLD. This work analyzes methods of prevention, therapeutic approaches, and mechanisms involved in NAFLD, focusing on the use of flavonoids (epigallocatechin-3-gallate, resveratrol, anthocyanins, and isoflavones) with high antioxidant capacity. In addition, the mechanisms of cholesterol accumulation in the liver are identified as potential avenues for entirely new approaches to NAFLD treatment, contrasting the well-known relation between neutral fat and NAFLD.
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Affiliation(s)
- Jung Hee Shin
- Department of Food & Nutrition, Joongbu University, 201 Daehak-ro, Chubu-myeon, Geumsan-gun, Chungcheongnam-Do, Republic of Korea.
| | - Ji Hye Jung
- Institute for Clinical Nutrition, Inje University, Mareunnae-ro 9, Jung-gu, Seoul, Republic of Korea.
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Yamamoto R, Iida A, Tanikawa K, Shiratsuchi H, Tokuda M, Matsui T, Nakamura T. Dietary D-Allose Ameliorates Hepatic Inflammation in Mice with Non-alcoholic Steatohepatitis. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2017. [DOI: 10.3136/fstr.23.319] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Ryoko Yamamoto
- Department of Food and Health Sciences, Faculty of Environmental and Symbiotic Sciences, Prefectural University of Kumamoto
- Division of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University
| | - Ayaka Iida
- School of Nutrition and Dietetics, Kanagawa University of Human Services
| | | | - Hideki Shiratsuchi
- Department of Food and Health Sciences, Faculty of Environmental and Symbiotic Sciences, Prefectural University of Kumamoto
| | - Masaaki Tokuda
- Department of Cell Physiology, Faculty of Medicine, Kagawa University
| | - Toshiro Matsui
- Division of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University
| | - Tsuyoshi Nakamura
- International College of Arts and Sciences, Fukuoka Women's University
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Shao J, Zeng S, Zhou B, Xu H, Bian Y, Xu Y. Angiogenic factor with G patch and FHA domains 1 (Aggf1) promotes hepatic steatosis in mice. Biochem Biophys Res Commun 2016; 482:134-140. [PMID: 27865839 DOI: 10.1016/j.bbrc.2016.10.071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 10/19/2016] [Indexed: 11/18/2022]
Abstract
Increased uptake of nutrients coupled with reduced activity leads to the development of a host of metabolic disorders in humans. In the present study we examined the role of angiogenic factor with G patch and FHA domains 1 (Aggf1) in the pathogenesis of steatosis, characterized by accumulation of lipids in the liver and consequently hepatic insulin resistance. We report here that Aggf1 expression was up-regulated in the liver in both genetically predisposed and diet-induced mouse model of steatosis. Aggf1 expression was also stimulated by free fatty acids in primary hepatocytes. Over-expression of Aggf1 in mice promoted steatosis. On the contrary, Aggf1 depletion ameliorated steatosis in mice. Mechanistically, Aggf1 activated the expression of gluconeogenesis gene and skewed the insulin signaling pathway to induce insulin resistance. Taken together, our data suggest that Aggf1 plays a role in steatosis in vivo and as such may be a new target in the development of therapeutics solutions against steatosis.
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Affiliation(s)
- Jing Shao
- College of Basic Medical Sciences, Nanjing University of Chinese Medicine, Nanjing, China
| | - Sheng Zeng
- Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China
| | - Bisheng Zhou
- Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
| | - Huihui Xu
- Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China
| | - Yaoyao Bian
- School of Nursing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yong Xu
- Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
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Lin L, Lu J, Huang X, Ding L, Huang Y, Wang P, Peng K, Zhang D, Xu Y, Xu M, Chen Y, Bi Y, Wang W, Xu Y. Nonalcoholic fatty liver disease is associated with low-grade albuminuria in Chinese adults (change not displayed). QJM 2016; 109:737-743. [PMID: 27317608 DOI: 10.1093/qjmed/hcw070] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 03/24/2016] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) was associated with higher risk of cardiovascular disease (CVD). Low-grade albuminuria was recognized as an early indicator of CVD. Epidemiological studies investigating the association between NAFLD and low-grade albuminuria were limited. AIM To determine whether NAFLD is independently associated with the presence of low-grade albuminuria in Chinese adults. DESIGN A cross-sectional community-based population study was performed in 8270 Chinese adults aged 40 years or older. METHODS A first-voided early morning spot urine sample was obtained for urinary albumin and creatinine measurements. The highest quartile of urinary albumin-to-creatinine ratio was defined as low-grade albuminuria, after excluding the participants with micro- or macroalbuminuria. NAFLD was diagnosed by using ultrasonography findings after the exclusion of alcohol abuse and other liver diseases. RESULTS The prevalence of low-grade albuminuria was significantly higher in participants with NAFLD than in those without NAFLD (33.6% vs. 21.3% in men and 30.4% vs. 22.8% in women, respectively). Multivariate-adjusted logistic regression analysis revealed that NAFLD was significantly associated with increased odds ratio of low-grade albuminuria in men (odds ratio, 1.47; 95% CI, 1.16-1.87) after adjusting for multiple confounders. The significant association was not detected in women. CONCLUSIONS NAFLD was significantly associated with an increased risk of present low-grade albuminuria in middle-aged and elderly Chinese men.
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Affiliation(s)
- L Lin
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - J Lu
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - X Huang
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - L Ding
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - Y Huang
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - P Wang
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - K Peng
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - D Zhang
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - Y Xu
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - M Xu
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - Y Chen
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - Y Bi
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - W Wang
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - Y Xu
- From the State Key Laboratory of Medical Genomics, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
- Department of Research and Development, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
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He L, Liu X, Wang L, Yang Z. Thiazolidinediones for nonalcoholic steatohepatitis: A meta-analysis of randomized clinical trials. Medicine (Baltimore) 2016; 95:e4947. [PMID: 27759627 PMCID: PMC5079311 DOI: 10.1097/md.0000000000004947] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta-analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity. We searched the literature using the following MeSH terms: "nonalcoholic steatohepatitis," "non-alcoholic steatohepatitis," "thiazolidinedione," "pioglitazone," "rosiglitazone," "randomized," and "clinical trial." Five eligible RCTs were selected, in which patients were treated with either pioglitazone or rosiglitazone, with or without lifestyle changes. We compared the effects of TZD treatment on hepatic fibrosis, lobular inflammation, IR improvement, fasting serum insulin, adiposity, and dyslipidemia between the various studies using fixed and random effects models, and heterogeneity in clinical outcomes was assessed. Significant improvement in hepatic fibrosis did not occur among the patients treated with TZDs alone or in those who underwent both lifestyle changes and TZD therapy. Lobular inflammation decreased in NASH patients who received TZD treatment and in those who underwent both TZD therapy and lifestyle changes. Although TZD treatment resulted in no significant improvement in IR, NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in their fasting insulin level than that observed in the control patients, whereas patients treated with TZDs alone did not. Although TZD-treated patients experienced significantly greater weight gain than the control patients, TZD treatment had no significant impact on body-mass index, percentage of body fat, or serum levels of cholesterol and triglyceride. Our findings indicate that additional variables should be assessed to obtain a more comprehensive evaluation of the effects of TZD treatment on IR and comorbidity risk factors in NASH patients, and suggest that including lifestyle changes and additional insulin-sensitizing agents in TZD regimens might improve the benefits of TZD therapy for NASH.
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Affiliation(s)
- Lingling He
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
| | - Xiaoli Liu
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
| | - Lijia Wang
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
| | - Zhiyun Yang
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
- Collabrorative Innovation Center of Infectious Diseases (ZY), Capital Medical University, Chaoyang, Beijing, China
- Correspondence: Zhiyun Yang, Department of Traditional Chinese Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun Dong Road, Chaoyang, Beijing 100015, P.R. China (e-mail: )
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Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J 2016; 16:e132-41. [PMID: 27226903 PMCID: PMC4868511 DOI: 10.18295/squmj.2016.16.02.002] [Citation(s) in RCA: 280] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 12/18/2015] [Accepted: 02/25/2016] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus is a non-communicable disease that occurs in both developed and developing countries. This metabolic disease affects all systems in the body, including the liver. Hyperglycaemia, mainly caused by insulin resistance, affects the metabolism of lipids, carbohydrates and proteins and can lead to non-alcoholic fatty liver disease, which can further progress to non-alcoholic steatohepatitis, cirrhosis and, finally, hepatocellular carcinomas. The underlying mechanism of diabetes that contributes to liver damage is the combination of increased oxidative stress and an aberrant inflammatory response; this activates the transcription of pro-apoptotic genes and damages hepatocytes. Significant involvement of pro-inflammatory cytokines-including interleukin (IL)-1β, IL-6 and tumour necrosis factor-α-exacerbates the accumulation of oxidative damage products in the liver, such as malondialdehyde, fluorescent pigments and conjugated dienes. This review summarises the biochemical, histological and macromolecular changes that contribute to oxidative liver damage among diabetic individuals.
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Affiliation(s)
- Jamaludin Mohamed
- Department of Biomedical Sciences, Faculty of Health Sciences, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - A. H. Nazratun Nafizah
- Department of Biomedical Sciences, Faculty of Health Sciences, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - A. H. Zariyantey
- Department of Biomedical Sciences, Faculty of Health Sciences, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - S. B. Budin
- Department of Biomedical Sciences, Faculty of Health Sciences, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Yari Z, Rahimlou M, Eslamparast T, Ebrahimi-Daryani N, Poustchi H, Hekmatdoost A. Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized, open labeled, controlled study. Int J Food Sci Nutr 2016; 67:461-9. [PMID: 26983396 DOI: 10.3109/09637486.2016.1161011] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A two-arm randomized open labeled controlled clinical trial was conducted on 50 patients with non-alcoholic fatty liver disease (NAFLD). Participants were assigned to take either a lifestyle modification (LM), or LM +30 g/day brown milled flaxseed for 12 weeks. At the end of the study, body weight, liver enzymes, insulin resistance and hepatic fibrosis and steatosis decreased significantly in both groups (p< 0.05); however, this reduction was significantly greater in those who took flaxseed supplementation (p < 0.05). The significant mean differences were reached in hepatic markers between flaxseed and control group, respectively: ALT [-11.12 compared with -3.7 U/L; P< 0.001], AST [-8.29 compared with -4 U/L; p < 0.001], GGT [-15.7 compared with -2.62 U/L; p < 0.001], fibrosis score [-1.26 compared with -0.77 kPa; p = 0.013] and steatosis score [-47 compared with -15.45 dB/m; p = 0.022]. In conclusion, flaxseed supplementation plus lifestyle modification is more effective than lifestyle modification alone for NAFLD management.
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Affiliation(s)
- Zahra Yari
- a Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology , National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science , Tehran , Iran
| | - Mehran Rahimlou
- b Department of Nutrition, Faculty of Nutrition and Dietetics , Tehran University of Medical Sciences , Tehran , Iran
| | - Tannaz Eslamparast
- a Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology , National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science , Tehran , Iran
| | - Naser Ebrahimi-Daryani
- c Digestive Disease Research Institute, ImamKhomeini Hospital , Tehran University of Medical Sciences , Tehran , Iran
| | - Hossein Poustchi
- d Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute , Tehran University of Medical Sciences , Tehran , Iran
| | - Azita Hekmatdoost
- a Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology , National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Science , Tehran , Iran
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Rahimlou M, Yari Z, Hekmatdoost A, Alavian SM, Keshavarz SA. Ginger Supplementation in Nonalcoholic Fatty Liver Disease: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. HEPATITIS MONTHLY 2016; 16:e34897. [PMID: 27110262 PMCID: PMC4834197 DOI: 10.5812/hepatmon.34897] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 12/06/2015] [Accepted: 12/07/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. The pathogenesis of this disease is closely associated with obesity and insulin resistance. Ginger can have hypolipidemic and antioxidant effects, and act as an insulinsensitizer. OBJECTIVES The aim of this study was to evaluate the effects of ginger supplementation in NAFLD management. PATIENTS AND METHODS In a randomized, double-blind, placebo-controlled clinical trial, 44 patients with NAFLD were assigned to take either two grams per day of a ginger supplement or the identical placebo, for 12 weeks. In both groups, patients were advised to follow a modified diet and physical activity program. The metabolic parameters and indicators of liver damage were measured at study baseline and after the 12 week intervention. RESULTS Ginger supplementation resulted in a significant reduction in alanine aminotransferase, γ-glutamyl transferase, inflammatory cytokines, as well as the insulin resistance index and hepatic steatosis grade in comparison to the placebo. We did not find any significant effect of taking ginger supplements on hepatic fibrosis and aspartate aminotransferase. CONCLUSIONS Twelve weeks of two grams of ginger supplementation showed beneficial effects on some NAFLD characteristics. Further studies are recommended to assess the long-term supplementation effects.
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Affiliation(s)
- Mehran Rahimlou
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallh University of Medical Sciences, Tehran, IR Iran
| | - Zahra Yari
- Department of Nutrition, Faculty of Nutrition and Dietetics, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallh University of Medical Sciences, Tehran, IR Iran
| | - Seyed Ali Keshavarz
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, IR Iran
- Corresponding Author: Seyed Ali Keshavarz, Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, IR Iran. Tel: +98-88973901; +98-88973905, E-mail:
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Wu R, Nakatsu G, Zhang X, Yu J. Pathophysiological mechanisms and therapeutic potentials of macrophages in non-alcoholic steatohepatitis. Expert Opin Ther Targets 2016; 20:615-26. [PMID: 26609894 DOI: 10.1517/14728222.2016.1125883] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Non-alcoholic steatohepatitis (NASH), a hepatic manifestation of metabolic syndrome, is a major cause of morbidity and healthcare burden worldwide. While the molecular pathogenesis of NASH remains unclear and therapeutic options are limited, inflammation is recognized as an essential factor for NASH development. Factors that link NASH to inflammation are macrophages and their secreted cytokines. AREAS COVERED This review summarizes the current knowledge of macrophage-mediated molecular pathways in NASH to shed insights on potential pharmacotherapeutic applications. EXPERT OPINION Macrophages are not only known for their role of phagocytosis in innate immunity, but also for both extrinsic and intrinsic regulation of inflammatory functions of many cytokines. Recent advances have revealed the effects of macrophage recruitment and polarization on the development of NASH. We and others have shown that the proliferation of hepatic macrophages and the subsequent production of pro-inflammatory cytokines initiates inflammatory cascades, orchestrates activities of transcription factors involved in lipid metabolism/translocation, and modulates programmed cell death. Together, these findings support the pathophysiological role of macrophages in the pathogenesis of NASH. Thus, evaluating potential therapeutic targets against the infiltration and/or polarization of specific macrophage subtypes is of clinical interest for alleviation of early-stage NASH, with the goal of halting disease progression.
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Affiliation(s)
- Ruonan Wu
- a Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences , CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong , Shatin , Hong Kong
| | - Geicho Nakatsu
- a Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences , CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong , Shatin , Hong Kong
| | - Xiang Zhang
- a Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences , CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong , Shatin , Hong Kong
| | - Jun Yu
- a Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences , CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong , Shatin , Hong Kong
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Gorgani-Firuzjaee S, Meshkani R. SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells. Free Radic Biol Med 2015; 89:679-89. [PMID: 26456051 DOI: 10.1016/j.freeradbiomed.2015.10.036] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 09/28/2015] [Accepted: 10/06/2015] [Indexed: 12/25/2022]
Abstract
Hepatic de-novo lipogenesis and production of triglyceride rich very low density lipoprotein (VLDL) is increased in the state of insulin resistance, however, the role of a negative regulator of the insulin signaling pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to high glucose (33 mM). The results showed that high glucose induced SHIP2 mRNA and protein levels in HepG2 cells. Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) ameliorated high glucose-induced de-novo lipogenesis and secretion of apoB containing lipoprotein in HepG2 cells, as demonstrated by a reduction in both secreted apoB and MTP expression, and decreased triglyceride levels and the expression of lipogenic genes such as SREBP1c, FAS and ACC. Overexpression of the SHIP2-DN decreased high glucose-induced apoB containing lipoproteins secretion via reduction in ROS generation, JNK phosphorylation and Akt activation. Furthermore, using the specific inhibitor and activator, it was found that the AMPK/mTOR/SREBP1 is the signaling pathway that mediates the effects of SHIP2 modulation on hepatic de-novo lipogenesis. Taken together, these findings suggest that SHIP2 is an important regulator of hepatic lipogenesis and lipoprotein secretion in insulin resistance state.
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Affiliation(s)
- Sattar Gorgani-Firuzjaee
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R Iran
| | - Reza Meshkani
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R Iran.
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Lee J, Hong SW, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY. AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol 2015; 414:148-55. [PMID: 26254015 DOI: 10.1016/j.mce.2015.07.031] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 07/14/2015] [Accepted: 07/31/2015] [Indexed: 02/08/2023]
Abstract
ANGPTL8 is a liver-derived secretory protein that leads to elevated serum triglyceride and the level of circulating ANGPTL8 is strongly associated with obesity and diabetes. Here we investigated the mechanisms of activation and inhibition of ANGPTL8 expression in hepatocytes. The expression of ANGPTL8 was significantly increased in HepG2 cells exposed to palmitic acid, tunicamycin, or T0901317, and was reversed in cells treated with AICAR. Palmitic acid, tunicamycin, and T0901317 increased LXRα and SREBP-1c mRNA expression. The inhibitory effect of AICAR on the expression of T0901317-induced ANGPTL8 was most strongly evident in cells that were transfected with SREBP-1 siRNA. AICAR increased phosphorylation of PPARα and the effect of AICAR was not observed in cells treated with PPARα inhibitor. Metformin had a similar effect on ANGPTL8 expression to that of AICAR. These data suggest that AMPK can suppress the expression of LXR/SREBP-1 signal-induced ANGPTL8 in HepG2 cells.
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Affiliation(s)
- Jinmi Lee
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Seok-Woo Hong
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Se Eun Park
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Eun-Jung Rhee
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Cheol-Young Park
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Ki-Won Oh
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Sung-Woo Park
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Won-Young Lee
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea.
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Kim YM, Kim IH, Choi JW, Lee MK, Nam TJ. The anti-obesity effects of a tuna peptide on 3T3-L1 adipocytes are mediated by the inhibition of the expression of lipogenic and adipogenic genes and by the activation of the Wnt/β-catenin signaling pathway. Int J Mol Med 2015; 36:327-34. [PMID: 26046125 PMCID: PMC4501660 DOI: 10.3892/ijmm.2015.2231] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 05/28/2015] [Indexed: 01/25/2023] Open
Abstract
The differentiation of 3T3-L1 cells into adipocytes involves the activation of an organized system of obesity-related genes, of which those encoding CCAAT/enhancer-binding proteins (C/EBPs) and the Wnt-10b protein may play integral roles. In a previous study of ours, we found that a specific peptide found in tuna (sequence D-I-V-D-K-I-E-I; termed TP-D) inhibited 3T3-L1 cell differentiation. In the present study, we observed that the expression of expression of C/EBPs and Wnt-10b was associated with obesity. The initial step of 3T3-L1 cell differentiation involved the upregulation of C/EBP-α expression, which in turn activated various subfactors. An upstream effector of glycogen synthase kinase-3β (GSK-3β) inhibited Wnt-10b expression in 3T3-L1 adipocytes. In a previous study of ours, we sequenced the tuna peptide via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and quadrupole time-of-flight mass spectrometry (Q-TOF MS/MS) and confirmed the anti-obesity effects thereof in 3T3-L1 adipocytes. In the present study, we demonstrate that TP-D inhibits C/EBP and promotes Wnt-10b mRNA expression, thus activating the Wnt pathway. The inhibition of lipid accumulation was measured using a glucose and triglyceride (TG) assay. Our results confirmed that TP-D altered the expression levels of C/EBP-related genes in a dose-dependent manner and activated the Wnt signaling pathway. In addition, we confirmed that total adiponectin and high-molecular weight (HMW) adiponectin levels were reduced by treatment with TP-D. These data indicate that TP-D inhibits adipocyte differentiation through the inhibition of C/EBP genes and the subsequent activation of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Young-Min Kim
- Department of Food Science and Nutrition, Pukyong National University, Busan 608‑737, Republic of Korea
| | - In-Hye Kim
- Department of Food Science and Nutrition, Pukyong National University, Busan 608‑737, Republic of Korea
| | - Jeong-Wook Choi
- Department of Food Science and Nutrition, Pukyong National University, Busan 608‑737, Republic of Korea
| | - Min-Kyeong Lee
- Department of Food Science and Nutrition, Pukyong National University, Busan 608‑737, Republic of Korea
| | - Taek-Jeong Nam
- Department of Food Science and Nutrition, Pukyong National University, Busan 608‑737, Republic of Korea
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Abstract
Nonalcoholic fatty liver disease is a common cause of chronic liver disease and has been an increasingly studied topic of research as the obesity epidemic has been growing. There is a significant morbidity and mortality with uncontrolled steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. The prevalence of this disease has been estimated to be roughly one-third of the western population, thought to be largely due to diet and sedentary lifestyle. Several treatments have been studied including vitamin E, insulin-sensitizing agents and ursodeoxycholic acid; however, the only treatment shown to improve the histologic changes of nonalcoholic fatty liver disease is weight loss. Given the proven benefit of weight loss, there may be reason to screen at-risk populations; however, limited availability of other disease-modifying treatments may limit the cost-benefit ratios. A better understanding of the diagnosis and management of this condition is required to alter the course of this modifiable disease.
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Affiliation(s)
- Amanda Tamar Schneier
- Department of Liver Diseases, Icahn School of Medicine at Mount Sinai,1 Gustave Levy Place, New York, NY 10029, USA
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Qiu LX, Chen T. Novel insights into the mechanisms whereby isoflavones protect against fatty liver disease. World J Gastroenterol 2015; 21:1099-1107. [PMID: 25632182 PMCID: PMC4306153 DOI: 10.3748/wjg.v21.i4.1099] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/11/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Fatty liver disease (FLD) is a growing public health problem worldwide. There is an urgent requirement for alternative and natural medicine to treat this disease. As phytochemicals, isoflavones have attracted considerable attention for the prevention of FLD. Numerous studies have revealed that isoflavones protect against FLD through various pathways which modulate fatty acid β-oxidation, lipid synthesis, and oxidative stress. Recently, the aldose reductase (AR)/polyol pathway has been reported to be involved in the development of FLD by modulating hepatic fructose production, peroxisome proliferator-activated receptor (PPAR)α activity, cytochrome P450 (CYP)2E1 expression, and gut bacterial endotoxin-induced cytokine release. It has been reported that some isoflavones are potent AR inhibitors. Here, we review the anti-FLD actions of isoflavones and the proposed mechanism whereby isoflavones protect against FLD, with regard to the AR/polyol pathway. We propose that isoflavones block the AR/polyol pathway and in turn reduce fructose production and subsequent fat accumulation in the liver in diabetic or high-glucose-diet mice. In addition, in rodents with alcoholic liver disease or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, inhibition of AR by isoflavones may improve PPARα-mediated fatty acid oxidation, reduce hepatic steatosis, and attenuate CYP2E1-mediated oxidative stress or AR/gut bacterial endotoxin-mediated cytokine overproduction, to alleviate progression of FLD.
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Hígado graso no alcohólico. Documento de posicionamiento de la Societat Catalana de Digestologia. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:372-83. [DOI: 10.1016/j.gastrohep.2014.03.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 03/03/2014] [Indexed: 12/13/2022]
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Vespasiani-Gentilucci U, Gallo P, Vincentis AD, Galati G, Picardi A. Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol 2014; 20:2825-2838. [PMID: 24659875 PMCID: PMC3961987 DOI: 10.3748/wjg.v20.i11.2825] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.
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Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A. Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr 2014; 99:535-42. [PMID: 24401715 DOI: 10.3945/ajcn.113.068890] [Citation(s) in RCA: 276] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Oral administration of synbiotic has been proposed as an effective treatment of NAFLD because of its modulating effect on the gut flora, which can influence the gut-liver axis. OBJECTIVE The objective was to evaluate the effects of supplementation with synbiotic on hepatic fibrosis, liver enzymes, and inflammatory markers in patients with NAFLD. DESIGN In a randomized, double-blind, placebo-controlled clinical trial conducted as a pilot study, 52 patients with NAFLD were supplemented twice daily for 28 wk with either a synbiotic or a placebo capsule. Both groups were advised to follow an energy-balanced diet and physical activity recommendations. RESULTS At the end of the study, the alanine aminotransferase (ALT) concentration decreased in both groups; this reduction was significantly greater in the synbiotic group. At the end of the study, the following significant differences [means (95% CIs)] were seen between the synbiotic and placebo groups, respectively: ALT [-25.1 (-26.2, -24) compared with -7.29 (-9.5, -5.1) IU/L; P < 0.001], aspartate aminotransferase [-31.33 (-32.1, -30.5) compared with -7.94 (-11.1, -4.8) IU/L; P < 0.001], γ-glutamyltransferase [-15.08 (-15.5, -14.7) compared with -5.21 (-6.6, -3.9) IU/L; P < 0.001], high-sensitivity C-reactive protein [-2.3 (-3, -1.5) compared with -1.04 (-1.5, -0.6) mmol/L; P < 0.05], tumor necrosis factor-α [-1.4 (-1.7, -1.1) compared with -0.59 (-0.8, -0.3) mmol/L; P < 0.001], total nuclear factor κ-B p65 [-0.016 (-0.022, -0.011) compared with 0.001 (-0.004, -0.007) mmol/L; P < 0.001], and fibrosis score as determined by transient elastography [- 2.98 (-3.6, -2.37) compared with -0.77 (-1.32, -0.22) kPa; P < 0.001]. CONCLUSIONS Synbiotic supplementation in addition to lifestyle modification is superior to lifestyle modification alone for the treatment of NAFLD, at least partially through attenuation of inflammatory markers in the body. Whether these effects will be sustained with longer treatment durations remains to be determined.
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Affiliation(s)
- Tannaz Eslamparast
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology, Research Institute Shahid Beheshti University of Medical Science, Tehran, Iran (TE and AH); the Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran (TE, HP, MS, and RM); and the Gastroenterology and Liver Disease Research Center, Firoozgar Hospital, Tehran University of Medical Sciences, Tehran, Iran (FZ)
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Qiu L, Lin J, Ying M, Chen W, Yang J, Deng T, Chen J, Shi D, Yang JY. Aldose reductase is involved in the development of murine diet-induced nonalcoholic steatohepatitis. PLoS One 2013; 8:e73591. [PMID: 24066058 PMCID: PMC3774689 DOI: 10.1371/journal.pone.0073591] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 07/30/2013] [Indexed: 12/21/2022] Open
Abstract
Hepatic aldose reductase (AR) expression is known to be induced in liver diseases, including hepatitis and hepatocellular carcinoma. However, the role of AR in the development of these diseases remains unclear. We performed this current study to determine whether and how AR might be involved in the development of diet-induced nonalcoholic steatohepatitis. Our results showed that the level of AR protein expression was significantly higher in db/db mice fed the methionine-choline-deficient (MCD) diet than in mice fed the control diet. In parallel with the elevation in AR, steatohepatitis was observed in MCD diet-fed mice, and this diet-induced steatohepatitis was significantly attenuated by lentiviral-mediated knock-down of the AR gene. This suppressive effect of AR knock-down was associated with repressed levels of serum alanine aminotransferase and hepatic lipoperoxides, reduced mRNA and protein expression of hepatic cytochrome P450 2E1 (CYP2E1), and decreased mRNA expression of pro-inflammatory tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Moreover, AR-induced elevations on the level of CYP2E1 expression, reactive oxygen species, mRNA expression of TNF-α and IL-6 were confirmed in AML12 hepatocytes. Further, lentiviral-mediated knock-down of AR ameliorated MCD diet-induced collagen deposition in the livers of db/db mice. With the improvement in liver fibrosis, the mRNA levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-2 (MMP-2), two genes involved in hepatic fibrogenesis, were found to be significantly suppressed, while TIMP-2 and MMP-13 were unaffected. Together these data indicate that inhibition of AR alleviates the MCD diet-induced liver inflammation and fibrosis in db/db mice, probably through dampening CYP2E1 mediated-oxidative stress and ameliorating the expression of pro-inflammatory cytokines.
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Affiliation(s)
- Longxin Qiu
- School of Life Sciences, Longyan University, Longyan, China
- Fujian Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Longyan, China
- * E-mail: (LQ); (JYY)
| | - Jianhui Lin
- School of Life Sciences, Longyan University, Longyan, China
| | - Miao Ying
- School of Life Sciences, Longyan University, Longyan, China
| | - Weiqiang Chen
- School of Life Sciences, Longyan University, Longyan, China
| | - Jinmei Yang
- School of Life Sciences, Longyan University, Longyan, China
| | - Tiantian Deng
- School of Life Sciences, Longyan University, Longyan, China
| | - Jinfeng Chen
- School of Life Sciences, Longyan University, Longyan, China
| | - Duanyu Shi
- School of Life Sciences, Longyan University, Longyan, China
| | - James Y. Yang
- State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiang’an, Xiamen, China
- * E-mail: (LQ); (JYY)
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Seth RK, Kumar A, Das S, Kadiiska MB, Michelotti G, Diehl AM, Chatterjee S. Environmental toxin-linked nonalcoholic steatohepatitis and hepatic metabolic reprogramming in obese mice. Toxicol Sci 2013; 134:291-303. [PMID: 23640861 PMCID: PMC3707434 DOI: 10.1093/toxsci/kft104] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 04/16/2013] [Indexed: 12/14/2022] Open
Abstract
Obesity is associated with strong risks of development of chronic inflammatory liver disease and metabolic syndrome following a second hit. This study tests the hypothesis that free radical metabolism of low chronic exposure to bromodichloromethane (BDCM), a disinfection byproduct of drinking water, causes nonalcoholic steatohepatitis (NASH), mediated by cytochrome P450 isoform CYP2E1 and adipokine leptin. Using diet-induced obese mice (DIO), mice deficient in CYP2E1, and mice with spontaneous knockout of the leptin gene, we show that BDCM caused increased lipid peroxidation and increased tyrosine nitration in DIO mice, events dependent on reductive metabolism by CYP2E1. DIO mice, exposed to BDCM, exhibited increased hepatic leptin levels and higher levels of proinflammatory gene expression and Kupffer cell activation. Obese mice exposed to BDCM also showed profound hepatic necrosis, Mallory body formation, collagen deposition, and higher alpha smooth muscle actin expression, events that are hallmarks of NASH. The absence of CYP2E1 gene in mice that were fed with a high-fat diet did not show NASH symptoms and were also protected from hepatic metabolic alterations in Glut-1, Glut-4, phosphofructokinase and phosphoenolpyruvate carboxykinase gene expressions (involved in carbohydrate metabolism), and UCP-1, PGC-1α, SREBP-1c, and PPAR-γ genes (involved in hepatic fat metabolism). Mice lacking the leptin gene were significantly protected from both NASH and metabolic alterations following BDCM exposure, suggesting that higher levels of leptin induction by BDCM in the liver contribute to the development of NASH and metabolic alterations in obesity. These results provide novel insights into BDCM-induced NASH and hepatic metabolic reprogramming and show the regulation of obesity-linked susceptibility to NASH by environmental factors, CYP2E1, and leptin.
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Affiliation(s)
- Ratanesh Kumar Seth
- *Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208
| | - Ashutosh Kumar
- †Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and
| | - Suvarthi Das
- *Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208
| | - Maria B. Kadiiska
- †Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and
| | - Gregory Michelotti
- ‡Division of Gastroenterology, Duke University, Durham, North Carolina 27707
| | - Anna Mae Diehl
- ‡Division of Gastroenterology, Duke University, Durham, North Carolina 27707
| | - Saurabh Chatterjee
- *Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208
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Macaluso FS, Maida M, Minissale MG, Li Vigni T, Attardo S, Orlando E, Petta S. Metabolic factors and chronic hepatitis C: a complex interplay. BIOMED RESEARCH INTERNATIONAL 2013; 2013:564645. [PMID: 23956991 PMCID: PMC3730187 DOI: 10.1155/2013/564645] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/29/2013] [Indexed: 12/15/2022]
Abstract
In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.
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Affiliation(s)
- Fabio Salvatore Macaluso
- Section of Gastroenterology, DiBiMIS, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.
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Kelishadi R, Farajian S, Mirlohi M. Probiotics as a novel treatment for non-alcoholic Fatty liver disease; a systematic review on the current evidences. HEPATITIS MONTHLY 2013; 13:e7233. [PMID: 23885277 PMCID: PMC3719124 DOI: 10.5812/hepatmon.7233] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 08/01/2012] [Accepted: 08/22/2012] [Indexed: 12/11/2022]
Abstract
CONTEXT Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with 5-10% of liver having extra fat. Increase in its prevalence in all age groups is linked with obesity and Type II diabetes. The treatment of NAFLD remains controversial. A growing body of evidence suggests a relation between overgrowth of gut microbiota with NAFLD and non-alcoholic steatohepatitis (NASH). The objective of this review is to provide an overview on experimental and clinical studies assessing all positive and negative effects of probiotics. EVIDENCE ACQUISITION We made a critical appraisal on various types of documents published from 1999 to March 2012 in journals, electronic books, seminars, and symposium contexts including Medline, PubMed, and Cochrane Central Register of Controlled Trials databases. We used the key words: "non-alcoholic fatty liver disease, probiotics, non-alcoholic steatohepatitis, liver disease, and fatty liver". RESULTS Probiotics, as biological factors, control the gut microbiota and result in its progression. It is in this sense that they are suggestive of a new and a natural way of promoting liver function. Correspondingly, limited evidence suggests that probiotics could be considered as a new way of treatment for NAFLD. CONCLUSIONS Various experimental studies and clinical trials revealed promising effects of probiotics in improving NAFLD; however given the limited experience in this field, generalization of probiotics as treatment of NAFLD needs substantiation through more trials with a larger sample sizes and with longer-term follow up.
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Affiliation(s)
- Roya Kelishadi
- Faculty of Medicine and Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran
| | - Sanam Farajian
- Faculty of Nutrition and Food Sciences, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran
- Corresponding author: Sanam Farajian, Faculty of Nutrition and Food Sciences, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran. Tel.: +98-3117923060, Fax: +98-31187898, E-mail:
| | - Maryam Mirlohi
- Faculty of Nutrition and Food Sciences, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran
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Pereira IVA, Souza de Oliveira CPM, Stefano JT, Halla NC, Alves JAF, Laurindo FRM, Carrilho FJ. Yo Jyo Hen Shi Ko (YHK) Modulates the Expression of Proteins Involved in de novo Lipogenesis and Lipid Exportation in Experimental Nonalcoholic Steatohepatitis (NASH). JOURNAL OF PHARMACY AND NUTRITION SCIENCES 2013; 3:48-58. [DOI: 10.6000/1927-5951.2013.03.01.6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
Previous study by our group showed the protective effect of Yo Jyo Hen Shi Ko (YHK) a natural compound in experimental nonalcoholic steatohepatitis (NASH). The aim of this study was to evaluate whether YHK modulates lipid metabolism.NASH was induced in male ob/ob mice by methionine/choline-deficient (MCD) diet for 4 weeks. YHK-treated animals (YHK) received YHK solution orally (20 mg/kg/day) by gavage while MCD (n=6) group received only vehicle. The control animals (CTRL; n=6) received standard diet. Liver fragments were collected for mRNA and protein isolation. The analysis of gene expression and protein was performed by RT-qPCR and western blot, respectively.A significant decrease in srebp1c mRNA and protein expression and fasn mRNA expression was observed in MCD+YHK group. A significant increase in MTP protein expression was observed in the MCD+YHK vs MCD group while a decreased expression was observed in the MCD vs CTRL group. The expression of the scd1 in the MCD group was diminished. The Perilipin protein expression was augmented in the MCD group in comparison with MCD+YHK and CTRL groups.YHK modulated genes involved in the synthesis and exportation of hepatic lipids, probably limiting hepatocyte lipid accumulation, reducing lipogenesis and upregulating lipid exportation suggesting that the YHK can be a promising drug for treat non-alcoholic fatty liver disease (NAFLD).
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Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide, encompasses a spectrum of abnormal liver histology ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Population studies show that NAFLD is strongly associated with insulin resistance, obesity, type 2 diabetes mellitus, and lipid abnormalities. In the context of hepatic steatosis, factors that promote cell injury, inflammation, and fibrosis include oxidative stress, early mitochondrial dysfunction, endoplasmic reticulum stress, iron accumulation, apoptosis, adipocytokines, and stellate cell activation. The exact NASH prevalence is unknown because of the absence of simple noninvasive diagnostic tests. Although liver biopsy is the "gold standard" for the diagnosis of NASH, other tests are needed to facilitate the diagnosis and greatly reduce the requirement for invasive liver biopsy. In addition, the development of new fibrosis markers in NASH is needed to facilitate the assessment of its progression and the effectiveness of new therapies. The aim of this chapter, which is overview of biomarkers in NASH, is to establish a systematic approach to laboratory findings of the disease.
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Effects of palmitic acid on TNF-α-induced cytotoxicity in SK-Hep-1 cells. Toxicol In Vitro 2012; 26:783-90. [DOI: 10.1016/j.tiv.2012.05.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 05/15/2012] [Accepted: 05/29/2012] [Indexed: 01/14/2023]
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Farrell GC, van Rooyen D, Gan L, Chitturi S. NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications. Gut Liver 2012; 6:149-71. [PMID: 22570745 PMCID: PMC3343154 DOI: 10.5009/gnl.2012.6.2.149] [Citation(s) in RCA: 283] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 01/18/2012] [Indexed: 12/12/2022] Open
Abstract
While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH.
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Affiliation(s)
- Geoffrey C. Farrell
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Australian National University Medical School, Garran, Australia
| | - Derrick van Rooyen
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Australian National University Medical School, Garran, Australia
| | - Lay Gan
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Australian National University Medical School, Garran, Australia
| | - Shivrakumar Chitturi
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Australian National University Medical School, Garran, Australia
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Hsu CS, Liu CH, Wang CC, Tseng TC, Liu CJ, Chen CL, Chen PJ, Chen DS, Kao JH. Impact of hepatitis B virus infection on metabolic profiles and modifying factors. J Viral Hepat 2012; 19:e48-e57. [PMID: 22239526 DOI: 10.1111/j.1365-2893.2011.01535.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The metabolic syndrome may cause disease progression in patients with chronic hepatitis B (CHB). However, the interactions between hepatitis B virus (HBV) infection and metabolic factors remain unknown. We investigated the association of HBV infection with metabolic profiles in HBV-infected and noninfected subjects. In addition, the impacts of serum HBV DNA level on metabolic profiles were studied. Initially, a case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 322 patients with chronic HBV infection, and the control group consisted of 870 matched subjects without HBV infection. Fasting blood glucose, lipid profiles and adiponectin levels were compared. The results were then confirmed in a second retrospective cohort study in 122 CHB patients with serum HBV DNA levels and HOMA-IR index values. In the case-control analysis, the HBV group had significantly higher serum adiponectin, but lower triglyceride (TG) and high-density lipoprotein cholesterol (HDL) levels than the control group. These relationships already existed in subjects younger than 45 years of age and were modified by serum alanine aminotransferase (ALT) levels. In the retrospective cohort, serum HBV DNA levels were negatively proportional to TG levels, but not to other metabolic parameters. Moreover, this relationship was significant only in subjects with higher ALT levels. Compared with healthy adults, patients with chronic HBV infection have significantly higher serum adiponectin, but lower TG and HDL levels. These relationships are modified by ALT levels and already exist in middle-age patients with chronic HBV infection, implying HBV may interact with host metabolism.
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Affiliation(s)
- C-S Hsu
- Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei, Taiwan
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Metabolic disorders and cardiovascular risk enhanced by nonalcoholic fatty liver disease in patients with metabolic syndrom. ROMANIAN JOURNAL OF DIABETES NUTRITION AND METABOLIC DISEASES 2012. [DOI: 10.2478/v10255-012-0019-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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