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Kim H, Jeon HJ, Jeong JW, Lee K, Gwon H, Lee D, Kim JY, Shim JJ, Lee JH. Lactobacillus helveticus HY7804 Modulates the Gut-Liver Axis to Improve Metabolic Dysfunction-Associated Steatotic Liver Disease in a Mouse Model. Int J Mol Sci 2025; 26:3557. [PMID: 40332012 PMCID: PMC12027198 DOI: 10.3390/ijms26083557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/03/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common type of liver disease worldwide. In a previous study, we confirmed that Lactobacillus helveticus HY7804 (HY7804) improves MASLD by suppressing the expression of mRNAs encoding genes related to hepatic lipogenesis, inflammation, and fibrosis in model mice. Here, we evaluated the ability of HY7804 to restore intestinal barrier function and modulate the gut microbiota, as well as improve MASLD symptoms. Mice fed an MASLD-inducing diet for 7 weeks received HY7804 (109 CFU/kg/day), the Type strain, or positive control (Pioglitazone) during the same period. HY7804 alleviated physiological (p < 0.001) and blood biochemical indicators and reduced MASLD activity scores (p < 0.05) on histological analysis. In addition, HY7804 increased the expression of genes related to fatty acid oxidation (p < 0.001); decreased the expression of apoptosis-related genes (p < 0.001); rescued the expression of tight junction (TJ)-related genes (p < 0.05); and suppressed the expression of pro-inflammatory cytokines and TLR4/MyD88/NF-κB signaling (p < 0.01) in the intestine. Finally, HY7804 modulated the composition of the gut microbiota in MASLD-induced mice. HY7804 increased the abundance of MASLD-suppressive Bacteroidaceae and Bacteroides, which positively correlated with the expression of TJ- and fatty acid oxidation-related genes. By contrast, HY7804 decreased the abundance of bacteria related to the progression of MASLD, including Cloastridaceae, Clostridium, Streptococcaceae, Lactococcus, and Lachnospiraceae, which correlated with intestinal immune responses and MASLD symptoms. In conclusion, L. helveticus HY7804 may be suitable as a functional supplement that alleviates MASLD symptoms and improves intestinal health.
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Affiliation(s)
| | | | | | | | | | | | - Joo-Yun Kim
- R&BD Center, hy Co., Ltd., 22, Giheungdanji-ro 24beon-gil, Giheung-gu, Yongin-si 17086, Republic of Korea; (H.K.); (H.-J.J.); (J.-W.J.); (K.L.); (H.G.); (D.L.); (J.-J.S.); (J.-H.L.)
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Xiong Q, Wang H, Feng J, Song L, Wu G, Xu Y. Lack of Nr2e1 expression in hepatocytes impaired cell survival and aggravated palmitate-induced oxidative stress. Adv Med Sci 2024; 69:320-330. [PMID: 38901547 DOI: 10.1016/j.advms.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/11/2024] [Accepted: 06/14/2024] [Indexed: 06/22/2024]
Abstract
PURPOSE Nuclear receptor subfamily 2 group E member 1 (Nr2e1) has been regarded as an essential regulator in neural stem cells. However, its function is still not clear in hepatocytes. This study aimed to clarify the effects of Nr2e1-deficiency in hepatocytes in lipotoxic conditions. MATERIALS/METHODS Nr2e1-knockdown AML12 cells were generated by lentiviral vector transfection. The influences of Nr2e1-deficiency on hepatocyte survival were determined by cell cycle progression and cell apoptosis rate using flow cytometry. Real-time quantitative PCR and Western blot were used to examine the genes and protein expression related to apoptosis, lipid metabolism, and oxidative stress. Meanwhile, RNA sequencing was adopted in liver samples from Nr2e1-knockout (Nr2e1-KO) mice. RESULTS Nr2e1 expression was observed with a significant decrease in AML12 cells after palmitic acid-stimulation. Knockdown of Nr2e1 in AML12 cells resulted in increased sensitivity to lipotoxicity, evidenced by a partial G0/G1 cell-cycle arrest and higher rates of cell apoptosis. Moreover, Nr2e1-knockdown AML12 cells presented increased gene expressions relative to lipid synthesis but decreased levels of β-oxidation related genes. Lack of Nr2e1 augmented palmitate-induced oxidative stress in hepatocytes. In vivo, differential genes in Nr2e1-KO mice liver were enriched in pathways associated with liver regeneration and cell proliferation. CONCLUSIONS This study indicated that hepatocytes lacking Nr2e1 were more susceptible to lipotoxic-mediated damage. Nr2e1 may serve as a potential target for the development of novel therapies for lipotoxicity-induced liver injury.
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Affiliation(s)
- Qing Xiong
- Department of Endocrinology, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan, China; Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Huawei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jieyuan Feng
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Linyang Song
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Guijun Wu
- Clinical Teaching and Research Sections, School of Nursing, Dalian University, Dalian, Liaoning, China; Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
| | - Yancheng Xu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
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Yahya MA, Alshammari GM, Osman MA, Al-Harbi LN, Yagoub AEA, AlSedairy SA. Liquorice root extract and isoliquiritigenin attenuate high-fat diet-induced hepatic steatosis and damage in rats by regulating AMPK. Arch Physiol Biochem 2024; 130:385-400. [PMID: 36121371 DOI: 10.1080/13813455.2022.2102654] [Citation(s) in RCA: 5] [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: 02/21/2022] [Revised: 07/05/2022] [Accepted: 07/08/2022] [Indexed: 11/11/2022]
Abstract
Objective: This study compared the ability of Liquorice roots aqueous extract (LRE) and its ingredient, isoliquiritigenin (ISL), in alleviating high-fat diet (HFD)-induced hepatic steatosis and examined if this effect involves activation of AMPK.Materials and methods: Control or HFD-fed rats were treated with the vehicle, LRE (200 mg/kg), or ISL (30 mg/kg) for 8 weeks orally.Results: ISL and LRE reduced HFD-induced hyperglycaemia, improved liver structure, lowered serum and hepatic lipids, and attenuated hepatic oxidative stress and inflammation. In the control and HFD-fed rats, ISL and LRE significantly stimulated the muscular and hepatic mRNA and protein levels of AMPK, improved oral glucose tolerance, reduced hepatic mRNA levels of SREBP1/2, and upregulated hepatic levels of PPARα and Bcl2. These effects were comparable for ISL and LRE and were prevented by co-administration of compound C, an AMPK inhibitor.Discussion and conclusion: ISL and LRE provide an effective theory to alleviate hepatic steatosis through activating AMPK.
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Affiliation(s)
- Mohammed Abdo Yahya
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Ghedeir M Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Magdi A Osman
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Laila Naif Al-Harbi
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Abu ElGasim A Yagoub
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Sahar Abdulaziz AlSedairy
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia
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Ni K, Meng L. Mechanism of PANoptosis in metabolic dysfunction-associated steatotic liver disease. Clin Res Hepatol Gastroenterol 2024; 48:102381. [PMID: 38821484 DOI: 10.1016/j.clinre.2024.102381] [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: 04/26/2024] [Revised: 05/16/2024] [Accepted: 05/23/2024] [Indexed: 06/02/2024]
Abstract
In recent years, the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been steadily rising, emerging as a major chronic liver disease of global concern. The course of MASLD is varied, spanning from MASLD to metabolic dysfunction associated steatohepatitis (MASH). MASH is an important contributor to cirrhosis, which may subsequently lead to hepatocellular carcinoma. It has been found that PANoptosis, an emerging inflammatory programmed cell death (PCD), is involved in the pathogenesis of MASLD and facilitates the development of NASH, eventually resulting in inflammatory fibrosis and hepatocyte death. This paper reviews the latest research progress on PANoptosis and MASLD to understand the mechanism of MASLD and provide new directions for future treatment and drug development.
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Affiliation(s)
- Keying Ni
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medical), Key Laboratory of Digestive Pathophysiology of Zhejiang Province, Hangzhou, China
| | - Lina Meng
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medical), Key Laboratory of Digestive Pathophysiology of Zhejiang Province, Hangzhou, China.
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Guo R, Huang K, Yu K, Li J, Huang J, Wang D, Li Y. Effects of Fat and Carnitine on the Expression of Carnitine Acetyltransferase and Enoyl-CoA Hydratase Short-Chain 1 in the Liver of Juvenile GIFT ( Oreochromis niloticus). Genes (Basel) 2024; 15:480. [PMID: 38674414 PMCID: PMC11050330 DOI: 10.3390/genes15040480] [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: 03/10/2024] [Revised: 04/06/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Carnitine acetyltransferase (CAT) and Enoyl-CoA hydratase short-chain 1 (ECHS1) are considered key enzymes that regulate the β-oxidation of fatty acids. However, very few studies have investigated their full length and expression in genetically improved farmed tilapia (GIFT, Oreochromis niloticus), an important aquaculture species in China. Here, we cloned CAT and ECHS1 full-length cDNA via the rapid amplification of cDNA ends, and the expressions of CAT and ECHS1 in the liver of juvenile GIFT were detected in different fat and carnitine diets, as were the changes in the lipometabolic enzymes and serum biochemical indexes of juvenile GIFT in diets with different fat and carnitine levels. CAT cDNA possesses an open reading frame (ORF) of 2167 bp and encodes 461 amino acids, and the ECHS1 cDNA sequence is 1354 bp in full length, the ORF of which encodes a peptide of 391 amino acids. We found that juvenile GIFT had higher lipometabolic enzyme activity and lower blood CHOL, TG, HDL-C, and LDL-C contents when the dietary fat level was 2% or 6% and when the carnitine level was 500 mg/kg. We also found that the expression of ECHS1 and CAT genes in the liver of juvenile GIFT can be promoted by a 500 mg/kg carnitine level and 6% fat level feeding. These results suggested that CAT and ECHS1 may participate in regulating lipid metabolism, and when 2% or 6% fat and 500 mg/kg carnitine are added to the feed, it is the most beneficial to the liver and lipid metabolism of juvenile GIFT. Our results may provide a theoretical basis for GIFT feeding and treating fatty liver disease.
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Affiliation(s)
- Ruijie Guo
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; (R.G.); (K.Y.); (J.H.); (D.W.); (Y.L.)
| | - Kai Huang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; (R.G.); (K.Y.); (J.H.); (D.W.); (Y.L.)
| | - Kai Yu
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; (R.G.); (K.Y.); (J.H.); (D.W.); (Y.L.)
| | - Jinghua Li
- Fisheries Research and Technology Extension Center of Shaanxi, Xi’an 710086, China;
| | - Jiao Huang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; (R.G.); (K.Y.); (J.H.); (D.W.); (Y.L.)
| | - Dandan Wang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; (R.G.); (K.Y.); (J.H.); (D.W.); (Y.L.)
| | - Yuda Li
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; (R.G.); (K.Y.); (J.H.); (D.W.); (Y.L.)
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Salem GA, Mohamed AAR, Khater SI, Noreldin AE, Alosaimi M, Alansari WS, Shamlan G, Eskandrani AA, Awad MM, El-Shaer RAA, Nassan MA, Mostafa M, Khamis T. Enhancement of biochemical and genomic pathways through lycopene-loaded nano-liposomes: Alleviating insulin resistance, hepatic steatosis, and autophagy in obese rats with non-alcoholic fatty liver disease: Involvement of SMO, GLI-1, and PTCH-1 genes. Gene 2023; 883:147670. [PMID: 37516284 DOI: 10.1016/j.gene.2023.147670] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/11/2023] [Accepted: 07/25/2023] [Indexed: 07/31/2023]
Abstract
Non-alcoholic fatty liver (NAFL) is a prevalent hepatic disorder of global significance that can give rise to severe complications. This research endeavor delves into the potential of nano-liposomal formulated Lycopene (Lip-Lyco) in averting the development of obesity and insulin resistance, both of which are major underlying factors contributing to NAFL. The investigation further scrutinizes the impact of Lip-Lyco on intricate cellular pathways within the liver tissue of rats induced with NAFL, specifically focusing on the progression of steatosis and fibrosis. To establish an obesity-NAFL model, twenty rats were subjected to a high-fat diet (HFD) for a duration of twelve weeks, after which they received an oral treatment of Lip-Lyco (10mg/kg) for an additional eight weeks. Another group of sixteen non-obese rats were subjected to treatment with or without Lip-Lyco, serving as a control for comparison. Results: The rats on a hypercaloric diet had high body mass index (BMI) and insulin resistance, reflected in disturbed serum adipokines and lipid profiles. Oxidative stress, inflammation, and apoptosis were evident in hepatic tissue, and the autophagic process in hepatocytes was inhibited. Additionally, the hedgehog pathway was activated in the liver tissue of NAFL group. Lip-Lyco was found to counteract all these aspects of NAFL pathogenesis. Lip-Lyco exhibited antioxidant, anti-inflammatory, hypoglycemic, antiapoptotic, autophagy-inducing, and Hedgehog signaling inhibitory effects. This study concludes that Lip-Lyco, a natural compound, has promising therapeutic potential in combating NAFLdisease. However, more experimental and clinical studies are required to confirm the effectiveness of lycopene in treating NAFLdisease.
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Affiliation(s)
- Gamal A Salem
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44511 Zagazig, Egypt
| | - Amany Abdel-Rahman Mohamed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.
| | - Safaa I Khater
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Ahmed E Noreldin
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt
| | - Manal Alosaimi
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Wafa S Alansari
- Biochemistry Department, Faculty of Science, University of Jeddah, Jeddah 21577, Saudi Arabia
| | - Ghalia Shamlan
- Department of Food Science and Nutrition, College of Food and Agriculture Sciences, King Saud University, Riyadh 11362, Saudi Arabia
| | - Areej A Eskandrani
- Chemistry Department, College of Science, Taibah University, Medina 30002, Saudi Arabia
| | - Marwa Mahmoud Awad
- Physiology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
| | | | - Mohamed A Nassan
- Department of Clinical Laboratory Sciences, Turabah University College, Taif University, PO Box 11099, Taif 21944, Saudi Arabia
| | - Mahmoud Mostafa
- Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Tarek Khamis
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44511 Zagazig, Egypt; Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, 44519 Zagazig, Egypt
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Ren L, Liu X, Huang X, Zhang H, Fei W, Yu X, Hu Z, Zhen Y, Chen S. Oxymatrine relieves high-fructose/fat-induced obesity via reprogramming the activity of lipid metabolism-related enhancer. Front Endocrinol (Lausanne) 2023; 14:1145575. [PMID: 37600712 PMCID: PMC10437059 DOI: 10.3389/fendo.2023.1145575] [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: 01/16/2023] [Accepted: 04/11/2023] [Indexed: 08/22/2023] Open
Abstract
Introduction Emerging evidence demonstrates that the high-fructose and high-fat diet (HFHF) induced obesity and fatty liver disease has become one of the most common metabolic disorders worldwide. Therefore, innovative investigations on compounds targeting obesity and fatty liver diseases are urgently needed. Methods The high-throughput natural compounds screen was performed to screen the important compounds. A rat HFHF model was constructed, the regulatory function of Oxymatrine in HFHF-induced obesity was further explored. Results We identified Oxymatrine, a natural compound extracted from Sophora flavescens, showed a potential compacity in high-fat diet-induced fatty liver disease. We found that oxymatrine significantly inhibited HFHF-induced obesity using a rat HFHF model. Additionally, we found that oxymatrine altered the enhancer landscape of subcutaneous adipose tissues by ChIP-seq analysis using antibodies against the H3K27ac histone modification. Motif enrichment analysis showed the Smad motif was significantly enriched in enhancers altered post-oxymatrine treatment. Further chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) analysis and luciferase reporter assays showed oxymatrine alters the binding of Smad3 on the enhancer regions of B-cell lymphoma 2 (Bcl2) and the enhancer activity of Bcl2. Discussion Together, our study highlighted oxymatrine could suppress high-fructose and high-fat diet-induced obesity by inhibiting the suppressor of mothers against decapentaplegic 3 (Smad3) binding on obesity-related enhancers.
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Affiliation(s)
- Luping Ren
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xuehua Liu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
- Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Xitong Huang
- Department of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - He Zhang
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Wenjie Fei
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xian Yu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Zhijuan Hu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yunfeng Zhen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Shuchun Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
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Xue L, Liu K, Yan C, Dun J, Xu Y, Wu L, Yang H, Liu H, Xie L, Wang G, Liang Y. Schisandra lignans ameliorate nonalcoholic steatohepatitis by regulating aberrant metabolism of phosphatidylethanolamines. Acta Pharm Sin B 2023; 13:3545-3560. [PMID: 37655337 PMCID: PMC10465965 DOI: 10.1016/j.apsb.2023.04.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/16/2023] [Accepted: 04/19/2023] [Indexed: 09/02/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a spectrum of chronic liver disease characterized by hepatic lipid metabolism disorder. Recent reports emphasized the contribution of triglyceride and diglyceride accumulation to NASH, while the other lipids associated with the NASH pathogenesis remained unexplored. The specific purpose of our study was to explore a novel pathogenesis and treatment strategy of NASH via profiling the metabolic characteristics of lipids. Herein, multi-omics techniques based on LC-Q-TOF/MS, LC-MS/MS and MS imaging were developed and used to screen the action targets related to NASH progress and treatment. A methionine and choline deficient (MCD) diet-induced mouse model of NASH was then constructed, and Schisandra lignans extract (SLE) was applied to alleviate hepatic damage by regulating the lipid metabolism-related enzymes CES2A and CYP4A14. Hepatic lipidomics indicated that MCD-diet led to aberrant accumulation of phosphatidylethanolamines (PEs), and SLE could significantly reduce the accumulation of intrahepatic PEs. Notably, exogenous PE (18:0/18:1) was proved to significantly aggravate the mitochondrial damage and hepatocyte apoptosis. Supplementing PE (18:0/18:1) also deteriorated the NASH progress by up regulating intrahepatic proinflammatory and fibrotic factors, while PE synthase inhibitor exerted a prominent hepatoprotective role. The current work provides new insights into the relationship between PE metabolism and the pathogenesis of NASH.
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Affiliation(s)
- Lijuan Xue
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Keanqi Liu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Caixia Yan
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Junling Dun
- Analytical Applications Center, Shimadzu (China) Co., Ltd., Shanghai 200233, China
| | - Yexin Xu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Linlin Wu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Huizhu Yang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Huafang Liu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Lin Xie
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Guangji Wang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Yan Liang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
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Abdelrahman SA, Raafat N, Abdelaal GMM, Aal SMA. Electric field-directed migration of mesenchymal stem cells enhances their therapeutic potential on cisplatin-induced acute nephrotoxicity in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1077-1093. [PMID: 36640200 PMCID: PMC10185611 DOI: 10.1007/s00210-022-02380-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 12/29/2022] [Indexed: 01/15/2023]
Abstract
Cisplatin is widely used as an anti-neoplastic agent but is limited by its nephrotoxicity. The use of mesenchymal stem cells (MSCs) for the management of acute kidney injury (AKI) represents a new era in treatment but effective homing of administered cells is needed. This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) on cisplatin-induced AKI in rats after directed migration by electric field (EF). Forty-eight adult male albino rats were equally classified into four groups: control, cisplatin-treated, cisplatin plus BM-MSCs, and cisplatin plus BM-MSCs exposed to EF. Serum levels of IL-10 and TNF-α were measured by ELISA. Quantitative real-time PCR analysis for gene expression of Bcl2, Bax, caspase-3, and caspase-8 was measured. Hematoxylin and eosin (H&E) staining, periodic acid Schiff staining, and immunohistochemical analysis were also done. MSC-treated groups showed improvement of kidney function; increased serum levels of IL-10 and decreased levels of TNF-α; and increased mRNA expression of Bcl2 and decreased expression of Bax, caspase-3, and caspase-8 proteins comparable to the cisplatin-injured group. EF application increased MSCs homing with significant decrease in serum urea level and caspase-3 gene expression together with significant increase in Bcl2 expression than occurred in the MSCs group. Restoration of normal kidney histomorphology with significant decrease in immunohistochemical expression of caspase-3 protein was observed in the BM-MSCs plus EF group compared to the BM-MSCs group. EF stimulation enhanced the MSCs homing and improved their therapeutic potential on acute cisplatin nephrotoxicity.
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Affiliation(s)
- Shaimaa A. Abdelrahman
- Medical Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nermin Raafat
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ghadeer M. M. Abdelaal
- Forensic Medicine & Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sara M. Abdel Aal
- Medical Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Ayyadurai VAS, Deonikar P, Fields C. Mechanistic Understanding of D-Glucaric Acid to Support Liver Detoxification Essential to Muscle Health Using a Computational Systems Biology Approach. Nutrients 2023; 15:733. [PMID: 36771439 PMCID: PMC9921405 DOI: 10.3390/nu15030733] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/10/2023] [Accepted: 01/24/2023] [Indexed: 02/04/2023] Open
Abstract
Liver and muscle health are intimately connected. Nutritional strategies that support liver detoxification are beneficial to muscle recovery. Computational-in silico-molecular systems' biology analysis of supplementation of calcium and potassium glucarate salts and their metabolite D-glucaric acid (GA) reveals their positive effect on mitigation of liver detoxification via four specific molecular pathways: (1) ROS production, (2) deconjugation, (3) apoptosis of hepatocytes, and (4) β-glucuronidase synthesis. GA improves liver detoxification by downregulating hepatocyte apoptosis, reducing glucuronide deconjugates levels, reducing ROS production, and inhibiting β-Glucuronidase enzyme that reduces re-absorption of toxins in hepatocytes. Results from this in silico study provide an integrative molecular mechanistic systems explanation for the mitigation of liver toxicity by GA.
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Affiliation(s)
- V. A. Shiva Ayyadurai
- Systems Biology Group, CytoSolve Research Division, CytoSolve, Inc., Cambridge, MA 02138, USA
| | - Prabhakar Deonikar
- Systems Biology Group, CytoSolve Research Division, CytoSolve, Inc., Cambridge, MA 02138, USA
| | - Christine Fields
- Applied Food Sciences Inc., 8708 South Congress Suite 290, Austin, TX 78745, USA
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Chakraborty S, Dissanayake M, Godwin J, Wang X, Bhandari RK. Ancestral BPA exposure caused defects in the liver of medaka for four generations. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 856:159067. [PMID: 36174697 PMCID: PMC10593180 DOI: 10.1016/j.scitotenv.2022.159067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 07/01/2022] [Accepted: 09/23/2022] [Indexed: 06/16/2023]
Abstract
Environmental chemicals can induce liver defects in experimental animals due to their direct and acute exposure. It is not clear whether environmental chemical exposures result in the transgenerational passage of liver defects in subsequent generations living in an uncontaminated environment. Bisphenol A (BPA), a plasticizer chemical, has been ubiquitous in the environment in the recent decade. Every organism is exposed to this chemical at some point during its lifetime. Literature suggests that direct BPA exposure can result in several metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Despite the phasing out of BPA from several consumer goods, it is unclear whether ancestral BPA exposure causes liver health problems in the unexposed future generations. Here, we demonstrate an advanced stage of NAFLD in the grandchildren (F2 generation) of medaka fish (Oryzias latipes) due to embryonic BPA exposure in the grandparental generation (F0), which persists for five generations (F4) even in the absence of BPA. The severity of transgenerational NAFLD phenotype included steatosis together with perisinusoidal fibrosis and apoptosis of hepatocytes. Adult females developed more severe histopathological conditions in the liver than males. Genes encoding enzymes involved in lipolytic pathways were significantly decreased. The present results suggest that ancestral BPA exposure can result in transgenerational metabolic diseases that can persist for five generations and that the NAFLD trait is sexually dimorphic. Given that ancestral BPA exposure can lead to altered metabolic health outcomes in the subsequent unexposed generations, the development of the methods and strategies to mitigate the transgenerational onset of metabolic diseases seem imperative to protect future generations.
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Affiliation(s)
- Sourav Chakraborty
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA
| | - Manthi Dissanayake
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA
| | - Julia Godwin
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA
| | - Xuegeng Wang
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA; Institute of Modern Aquaculture Science and Engineering, College of Life Sciences, South China Normal University, Guangzhou 510631, PR China
| | - Ramji Kumar Bhandari
- Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA.
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Lu Z, Sun GF, Pan XA, Qu XH, Yang P, Chen ZP, Han XJ, Wang T. BCATc inhibitor 2 ameliorated mitochondrial dysfunction and apoptosis in oleic acid-induced non-alcoholic fatty liver disease model. Front Pharmacol 2022; 13:1025551. [PMID: 36386234 PMCID: PMC9650408 DOI: 10.3389/fphar.2022.1025551] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/18/2022] [Indexed: 09/14/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent hepatic disease in the world. Disorders of branched chain amino acid (BCAA) metabolism is involved in various diseases. In this study, we aim to explore the role of BCAA metabolism in the development of NAFLD and the protective effect of BCATc Inhibitor 2, an inhibitor of cytosolic branched chain amino acid transaminase, against NAFLD as well as its underlying mechanism. It was found that oleic acid induced lipid accumulation and apoptosis in HepG2 and LO2 cells. Supplementation of BCAAs further aggravated oleic acid-induced lipid accumulation and apoptosis. In contrast, treatment of BCATc Inhibitor 2 ameliorated oleic acid-induced lipid accumulation and apoptosis. Molecularly, supplementation of BCAAs or treatment of BCATc Inhibitor 2 up-regulated or down-regulated the expression of SREBP1 and lipogenesis-related genes without affecting lipolysis-related genes. BCATc Inhibitor 2 maintained mitochondrial function by ameliorating oleic acid-induced mitochondrial ROS generation and mitochondrial membrane potential disruption. In addition, BCATc Inhibitor 2 treatment alleviated oleic acid-induced activation of JNK and AKT signaling pathway and Bcl2/Bax/Caspase axis. In conclusion, our results indicate BCAA metabolism is involved in NAFLD and BCATc Inhibitor 2 protects against oleic acid-induced lipid accumulation and apoptosis. These findings suggest that BCATc Inhibitor 2 is a promising candidate drug for the treatment of NAFLD.
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Affiliation(s)
- Zhuo Lu
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Gui-Feng Sun
- Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China
| | - Xiao-An Pan
- Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China
| | - Xin-Hui Qu
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- Department of Neurology, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Ping Yang
- Department of Neurology, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Zhi-Ping Chen
- Department of Critical Care Medicine, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Xiao-Jian Han
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China
- Department of Neurology, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Tao Wang
- Institute of Geriatrics, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Zhang YY, Li SQ, Song Y, Wang P, Song XG, Zhu WF, Wang DM. Silencing the ADAM9 Gene through CRISPR/Cas9 Protects Mice from Alcohol-Induced Acute Liver Injury. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5110161. [PMID: 35707386 PMCID: PMC9192226 DOI: 10.1155/2022/5110161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 04/30/2022] [Accepted: 05/11/2022] [Indexed: 11/17/2022]
Abstract
Alcoholic liver injury is a major global public health concern at present. The ADAM9 gene plays a crucial role in the occurrence and development of various liver diseases, but its role in acute alcoholic liver injury remains ambiguous. In this study, a chimeric single-guide RNA targeting the genomic regions of mouse ADAM9 was designed using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology. Next, the role of ADAM9 in acute alcoholic liver injury in vitro in cultured mouse cells and in vivo in a hydrodynamic injection-based alcoholic liver injury mouse model was documented. The findings of this study suggest that ADAM9 induces by regulating cell proliferation, apoptosis, and stress metabolism in mice. Thus, inhibiting the expression of ADAM9 gene using CRISPR/Cas9 can attenuate alcohol-induced acute liver injury in mice.
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Affiliation(s)
- Yong-Yong Zhang
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471003, China
- Orthopedic Institute of Henan Province, Luoyang, 471003 Henan, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang 471003, China
| | - San-Qiang Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471003, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang 471003, China
| | - Ying Song
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471003, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang 471003, China
| | - Ping Wang
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471003, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang 471003, China
| | - Xiao-Gai Song
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471003, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang 471003, China
| | - Wen-Feng Zhu
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471003, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang 471003, China
| | - Dong-Mei Wang
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang 471003, China
- Henan Center for Engineering and Technology Research on Prevention and Treatment of Liver Diseases, Luoyang 471003, China
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Huang J, Li M, Zhoua WJ, Yao ZM, Ji G, Zhang L, Zhu MZ. Integrated miRNA and mRNA Analysis Identified Potential Mechanisms and Targets of Qianggan Extracts in Preventing Nonalcoholic Steatohepatitis. WORLD JOURNAL OF TRADITIONAL CHINESE MEDICINE 2022; 8:77-86. [DOI: 10.4103/wjtcm.wjtcm_48_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Objective:
Qianggan (QG) extract is a patented traditional Chinese medicine that has been widely used for the clinical treatment of nonalcoholic steatohepatitis (NASH). However, its mechanism remains unclear.
Methods:
The efficacy of QG was evaluated in mice with methionine-and-choline-deficient diet-induced NASH by measuring serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels and by H and E staining of liver sections. Microarray and bioinformatics analyses were performed to obtain hepatic microRNA (miRNA) and mRNA expression profiles and to mine potential mechanisms and therapeutic targets. Furthermore, representative miRNA and mRNA expression levels were validated by quantitative real-time polymerase chain reaction (qRT-PCR).
Results:
QG extract significantly improved NASH. Twelve differentially expressed miRNAs and 1124 differentially changed mRNAs were identified as potential targets of QG extract. Integrated analysis detected 976 miRNA–mRNA regulatory pairs, and networks including 11 miRNAs and 427 mRNAs were constructed by Cytoscape. Hub nodes including miR-7050-5p, miR-212-3p, Bcl2l11, and Kras were filtered out. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that 427 mRNAs were enriched in pathways including apoptotic process, immune response, FoxO signaling pathway, and natural killer cell-mediated cytotoxicity. We also constructed a protein–protein interaction network with 254 nodes, and identified hub genes including Kras, Fasl, and Ncam1. Finally, the results of qRT-PCR were in good accordance with microarray data.
Conclusion:
This study identified important hub miRNAs and mRNAs involved in the mechanism of QG extract and which might provide potential therapeutic targets for patients with NASH.
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Zhu MZ, Huanga J, Lia M, Zhou WJ, Yao ZM, Ji G, Zhang L. Integrated miRNA and mRNA analysis identified potential mechanisms and targets of qianggan extracts in preventing nonalcoholic steatohepatitis. WORLD JOURNAL OF TRADITIONAL CHINESE MEDICINE 2022. [DOI: 10.4103/2311-8571.335135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Beta vulgaris L. (Beetroot) Methanolic Extract Prevents Hepatic Steatosis and Liver Damage in T2DM Rats by Hypoglycemic, Insulin-Sensitizing, Antioxidant Effects, and Upregulation of PPARα. BIOLOGY 2021; 10:biology10121306. [PMID: 34943221 PMCID: PMC8698622 DOI: 10.3390/biology10121306] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/04/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
Simple Summary Beetroot is one of the most consumable plants across the world. Previous studies have shown many health benefits of beetroot, with evidence of having potent hypoglycemic, antioxidant, and anti-inflammatory effects. The data obtained from this study further confirmed this effect in streptozotocin-diabetic animals. They showed the ability of methanolic beetroot extract to prevent the associated hepatic oxidative stress, inflammation, steatosis, and dyslipidaemia. However, the protection mechanisms involve, at least, upregulation of endogenous antioxidants, anti-apoptotic Bcl2, and PPARα. Abstract The present study examined if methanolic beetroot extract (BE) could prevent dyslipidemia and hepatic steatosis and damage in a type-2 diabetes mellitus (T2DM) rat model and studied some mechanisms of action. T2DM was induced in adult male Wistar rats by a low single dose of streptozotocin (STZ) (35 mg/kg, i.p) and a high-fat diet (HFD) feeding for 5 weeks. Control or T2DM rats then continued on standard or HFDs for another 12 weeks and were treated with the vehicle or BE (250 or 500 mg/kg). BE, at both doses, significantly improved liver structure and reduced hepatic lipid accumulation in the livers of T2DM rats. They also reduced body weight gain, serum glucose, insulin levels, serum and hepatic levels of cholesterol, triglycerides, free fatty acids, and serum levels of low-density lipoproteins in T2DM rats. In concomitant, they significantly reduced serum levels of aspartate and alanine aminotransferases, hepatic levels of malondialdehyde, tumor-necrosis factor-α, interleukin-6, and mRNA of Bax, cleaved caspase-3, and SREBP1/2. However, both doses of BE significantly increased hepatic levels of total glutathione, superoxide dismutase, and mRNA levels of Bcl2 and PPARα in the livers of both the control and T2DM rats. All of these effects were dose-dependent and more profound with doses of 500 mg/kg. In conclusion, chronic feeding of BE to STZ/HFD-induced T2DM in rats prevents hepatic steatosis and liver damage by its hypoglycemic and insulin-sensitizing effects and its ability to upregulate antioxidants and PPARα.
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Ruan L, Li F, Li S, Zhang M, Wang F, Lv X, Liu Q. Effect of Different Exercise Intensities on Hepatocyte Apoptosis in HFD-Induced NAFLD in Rats: The Possible Role of Endoplasmic Reticulum Stress through the Regulation of the IRE1/JNK and eIF2 α/CHOP Signal Pathways. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6378568. [PMID: 33815655 PMCID: PMC7987464 DOI: 10.1155/2021/6378568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 01/19/2021] [Accepted: 03/02/2021] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To investigate the impact of different-intensity exercise on lipid metabolism, oxidative stress, hepatocyte injury, and apoptosis and the related protein expression of endoplasmic reticulum stress on nonalcoholic fatty liver disease rats. METHOD 50 male Sprague-Dawley rats, 2 months old, were randomly divided into the normal control (CON) group, high-fat diet (HFD) group, low-intensity exercise (LIE) group, moderate-intensity exercise (MIE) group, and incremental-intensity exercise (IIE) group. Blood lipids were tested by the automatic biochemical analyzer. The changes in liver tissues were observed by hematoxylin-eosin staining (HE). The protein expression of Bax and Bcl-2 was detected by the immunohistochemical method. The apoptosis of hepatocytes was detected by the TUNEL method. The protein expression of GRP78, Caspase-3, IRE1, p-IRE1, JNK1, CHOP, PERK, eIF2α, and ATF4 was detected by Western blotting. RESULTS Our study showed that compared with the HFD group, TG, TC, FFA, and LDL-c were reduced in all exercise groups. The different exercise intensities could reduce the protein expression of ATF4, Bax, and hepatocyte apoptosis. Meanwhile, the antioxidant function and Bcl-2 were increased. However, the moderate-intensity exercise demonstrated more effect on improving the antioxidant capacity and inhibiting hepatocyte apoptosis. Compared with the HFD group, Caspase-3 and JNK were significantly decreased in all exercise groups (P < 0.01) and CHOP was decreased in the LIE and MIE groups (P < 0.05). IRE1, eIF2α, the ratio of p-IRE1/IRE1 (P < 0.01), and ATF4 were decreased (P < 0.05) in the MIE group. Compared with the IIE group, p-IRE1 was decreased (P < 0.05) in the MIE group. GRP78 had no significant difference among the exercise groups. CONCLUSION Exercise at different intensities improved blood lipid and hepatic injury in NAFLD rats. However, the body weight of the rats in each exercise group was not significantly different. Moderate-intensity exercise demonstrated more effect on improving the antioxidant ability and inhibiting hepatocyte apoptosis. The possible mechanism depends on the regulation of endoplasmic reticulum stress signaling pathways IRE1/JNK and eIF2α/CHOP.
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Affiliation(s)
- Ling Ruan
- Department of Physical Education, Xi'an Shiyou University, Xi'an, Shaanxi, China
| | - Fanghui Li
- School of Sports Sciences, Nanjing Normal University, Nanjing, Jiangsu, China
| | - Shoubang Li
- Department of Physical Education, Xi'an Shiyou University, Xi'an, Shaanxi, China
| | - Mingjun Zhang
- School of Sports and Health Sciences, Xi'an Physical Education University, Xi'an, Shaanxi, China
| | - Feng Wang
- Ankang Traditional Chinese Medicine, Ankang, Shaanxi, China
| | - Xianli Lv
- School of Physical Education, Ankang University, Ankang, Shaanxi, China
| | - Qin Liu
- School of Physical Education, Ankang University, Ankang, Shaanxi, China
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Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci 2021; 22:ijms22042163. [PMID: 33671547 PMCID: PMC7926723 DOI: 10.3390/ijms22042163] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.
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Affiliation(s)
- Yetirajam Rajesh
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Massey Cancer Center, Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence: ; Tel.: +1-804-827-2339
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Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE (-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int J Mol Sci 2021; 22:818. [PMID: 33467546 PMCID: PMC7829901 DOI: 10.3390/ijms22020818 ] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
AIMS/HYPOTHESIS SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. METHODS Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. RESULTS Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. CONCLUSION These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
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Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, Chatzigeorgiou A, Kalotychou V, Randeva MS, Chatha K, Kontzoglou K, Kaltsas G, Papavassiliou AG, Randeva HS, Kassi E. Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE (-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int J Mol Sci 2021; 22:818. [PMID: 33467546 PMCID: PMC7829901 DOI: 10.3390/ijms22020818] [Citation(s) in RCA: 188] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 12/11/2022] Open
Abstract
AIMS/HYPOTHESIS SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. METHODS Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. RESULTS Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. CONCLUSION These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Chrysa Nikolopoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Katerina Papoutsi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
- Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, UK
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Christos S. Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
- Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02215, USA
| | - Georgios Kyriakopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
- Department of Pathology, Evangelismos Hospital, 10676 Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vassiliki Kalotychou
- 1st Department of Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Manpal S. Randeva
- Human Metabolism Research Unit, WISDEM Centre, NHS Trust, Coventry CV2 2DX, UK;
| | - Kamaljit Chatha
- Department of Biochemistry & Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
| | - Konstantinos Kontzoglou
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens University Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Gregory Kaltsas
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK;
- Human Metabolism Research Unit, WISDEM Centre, NHS Trust, Coventry CV2 2DX, UK;
- Division of Translational and Experimental Medicine-Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.N.-A.); (C.N.); (K.P.); (G.K.); (A.G.P.)
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Joaquim M, Escobar-Henriques M. Role of Mitofusins and Mitophagy in Life or Death Decisions. Front Cell Dev Biol 2020; 8:572182. [PMID: 33072754 PMCID: PMC7539839 DOI: 10.3389/fcell.2020.572182] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Mitochondria entail an incredible dynamism in their morphology, impacting death signaling and selective elimination of the damaged organelles. In turn, by recycling the superfluous or malfunctioning mitochondria, mostly prevalent during aging, mitophagy contributes to maintain a healthy mitochondrial network. Mitofusins locate at the outer mitochondrial membrane and control the plastic behavior of mitochondria, by mediating fusion events. Besides deciding on mitochondrial interconnectivity, mitofusin 2 regulates physical contacts between mitochondria and the endoplasmic reticulum, but also serves as a decisive docking platform for mitophagy and apoptosis effectors. Thus, mitofusins integrate multiple bidirectional inputs from and into mitochondria and ensure proper energetic and metabolic cellular performance. Here, we review the role of mitofusins and mitophagy at the cross-road between life and apoptotic death decisions. Furthermore, we highlight the impact of this interplay on disease, focusing on how mitofusin 2 and mitophagy affect non-alcoholic fatty liver disease.
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Affiliation(s)
- Mariana Joaquim
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Mafalda Escobar-Henriques
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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Rajcic D, Brandt A, Jin CJ, Sánchez V, Engstler AJ, Jung F, Nier A, Baumann A, Bergheim I. Exchanging dietary fat source with extra virgin olive oil does not prevent progression of diet-induced non-alcoholic fatty liver disease and insulin resistance. PLoS One 2020; 15:e0237946. [PMID: 32881925 PMCID: PMC7470337 DOI: 10.1371/journal.pone.0237946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/05/2020] [Indexed: 12/19/2022] Open
Abstract
Dietary fat is discussed to be critical in the development of non-alcoholic fatty liver disease. Here, we assess the effect of exchanging dietary fat source from butterfat to extra virgin olive oil on the progression of an already existing diet-induced non-alcoholic fatty liver disease in mice. Female C57BL/6J mice were fed a liquid butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% from butterfat) or control diet (C, 12%E from soybean oil) for 13 weeks. In week 9, fat sources of some BFC- and C-fed mice were switched either to 25E% or 12E% olive oil (OFC and CO). Glucose and insulin tolerance tests were performed, and markers of liver damage and glucose metabolism were assessed. After 6 weeks of feeding, BFC-fed mice had developed marked signs of insulin resistance, which progressed to week 12 being not affected by the exchange of fat sources. Liver damage was similar between BFC- and OFC-fed mice. Markers of lipid metabolism and lipid peroxidation in liver and of insulin signaling in liver and muscle were also similarly altered in BFC- and OFC-fed mice. Taken together, our data suggest that exchanging butterfat with extra virgin olive oil has no effect on the progression of non-alcoholic fatty liver disease and glucose tolerance in mice.
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Affiliation(s)
- Dragana Rajcic
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Cheng Jun Jin
- Institute of Nutrition, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University of Jena, Jena, Germany
| | - Victor Sánchez
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Anna Janina Engstler
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Anika Nier
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
- * E-mail:
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Ibrahim AAS, Morsy MM, Abouhashem SE, Aly O, Sabbah NA, Raafat N. Role of mesenchymal stem cells and their culture medium in alleviating kidney injury in rats diabetic nephropathy. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020. [DOI: 10.1186/s43042-020-00064-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Background
Diabetic nephropathy (DN) is considered as one of the most serious complications resulting from diabetes mellitus and end-stage of renal failure globally. Up to 40% of diabetic patients will develop DN. The involvement of mesenchymal stem cells (MSCs) in diabetic renal lesions management has been established in many animal models of DN. The aim is to evaluate the capability of MSCs and their culture medium (CM) to alleviate DN in streptozotocin (STZ)-induced diabetic rat model. Female albino rats were made diabetic and were further categorized into 4 subgroups of 15 each: DN group, DN group received fibroblasts, MSCs group received one dose of 1 × 106 cells of MSCs, and CM group received one dose of 500 μl of CM. In all groups, the treatment was delivered by intravenous injection (IV) into the tail vein.
Results
MSCs insinuated themselves into the injured kidney as detected by CD44 expression. Biochemical and histological results showed that MSCs and/or CM effectively attenuated DN manifestations in rat model through their possible anti-inflammatory (tumor necrosis factor-α and transforming growth factor-β1 were decreased), anti-apoptotic (Bcl2 was increased while Bax and caspases were decreased), and anti-oxidant role (malondialdehyde was decreased while glutathione and catalase were increased).
Conclusion
These results provide a potential therapeutic tool for DN management through the administration of the CM from MSCs that ameliorates the effects of diabetes. It is also possible to treat DN using CM alone thus avoiding cell transplantation.
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25
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Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis. Cells 2020; 9:cells9030590. [PMID: 32131439 PMCID: PMC7140508 DOI: 10.3390/cells9030590] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/21/2020] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. The global prevalence of NAFLD is constantly increasing. NAFLD is a disease spectrum comprising distinct stages with different prognoses. Non-alcoholic steatohepatitis (NASH) is a progressive condition, characterized by liver inflammation and hepatocyte ballooning, with or without fibrosis. The natural history of NAFLD is negatively influenced by NASH onset and by the progression towards advanced fibrosis. Pathogenetic mechanisms and cellular interactions leading to NASH and fibrosis involve hepatocytes, liver macrophages, myofibroblast cell subpopulations, and the resident progenitor cell niche. These cells are implied in the regenerative trajectories following liver injury, and impairment or perturbation of these mechanisms could lead to NASH and fibrosis. Recent evidence underlines the contribution of extra-hepatic organs/tissues (e.g., gut, adipose tissue) in influencing NASH development by interacting with hepatic cells through various molecular pathways. The present review aims to summarize the role of hepatic parenchymal and non-parenchymal cells, their mutual influence, and the possible interactions with extra-hepatic tissues and organs in the pathogenesis of NAFLD.
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26
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Protective effects of Kangxian ruangan capsule against nonalcoholic fatty liver disease fibrosis in rats induced by MCD diet. Biomed Pharmacother 2018; 108:424-434. [PMID: 30236852 DOI: 10.1016/j.biopha.2018.06.134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/25/2018] [Accepted: 06/25/2018] [Indexed: 12/19/2022] Open
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Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, Kaneko T, Fujisawa M, Higuchi T, Nakamura H, Matsumoto N, Yamagami H, Ogawa M, Imazu H, Kuroda K, Moriyama M. Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 2018; 24:2661-2672. [PMID: 29991872 PMCID: PMC6034146 DOI: 10.3748/wjg.v24.i25.2661] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/04/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023] Open
Abstract
The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Motomi Yamazaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Toshikatsu Shibata
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroshi Takahashi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tomohiro Kaneko
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mariko Fujisawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Teruhisa Higuchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroo Imazu
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazumichi Kuroda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
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Huang L, Cheng Y, Huang K, Zhou Y, Ma Y, Zhang M. Ameliorative effect of Sedum sarmentosum Bunge extract on Tilapia fatty liver via the PPAR and P53 signaling pathway. Sci Rep 2018; 8:8456. [PMID: 29855491 PMCID: PMC5981579 DOI: 10.1038/s41598-018-26084-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 05/02/2018] [Indexed: 02/07/2023] Open
Abstract
Fatty liver disease is a growing problem in fish aquaculture and there is an urgent need to identify causes and possible remedies. In the present study, the effects of treating fatty liver disease in the Nile tilapia (Oreochromis niloticus Linnaeus, 1758) with an extract derived from a herb, Sedum sarmentosum Bunge (SSB), was investigated. We found that the SSB extract could restore the changes to feed coefficient, immune capacity, and pathological index caused by fatty liver disease, and also prevent apoptosis in hepatocytes. An RNA-seq analysis showed that treatment with SSB extract altered expression of genes in the lipid metabolic process, metabolic process, and oxidation-reduction process. Our results suggest that disorders of the PPAR and p53 signaling pathways may be involved in steatohepatitis development and in the therapeutic mechanism of the SSB extract treatment; these observations shed new light on possible treatment of steatohepatitis.
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Affiliation(s)
- Lida Huang
- College of Animal Science and Technology of Guangxi University, Nanning, China.,Zhanjiang Haiyuan Biological Technology Co. Ltd, Zhanjiang, China
| | - Yuan Cheng
- College of Animal Science and Technology of Guangxi University, Nanning, China.,Guangxi Academy of Fishery Sciences, Nanning, China
| | - Kai Huang
- College of Animal Science and Technology of Guangxi University, Nanning, China.
| | - Yu Zhou
- Guangxi Academy of Fishery Sciences, Nanning, China.
| | - Yanqun Ma
- College of Animal Science and Technology of Guangxi University, Nanning, China
| | - Mengci Zhang
- College of Animal Science and Technology of Guangxi University, Nanning, China
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29
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Kumar P, Singh AK, Raj V, Rai A, Keshari AK, Kumar D, Maity B, Prakash A, Maiti S, Saha S. Poly(lactic- co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations. Int J Nanomedicine 2018; 13:975-990. [PMID: 29497292 PMCID: PMC5818879 DOI: 10.2147/ijn.s157391] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic-co-glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare its anti-hepatocellular carcinoma (HCC) activity with parent B. METHODS BNP were synthesized and characterized using different methods such as scanning electron microscopy (SEM), fourier-transform infrared (FTIR) spectrometry and particle size analyses. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol (PVA). The anti-HCC response was evaluated through in vitro cell line study using Hep-G2 cells, confocal microscopy, in vivo oral pharmacokinetics and animal studies. Further, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was conducted to observe the changes in the expression of specific genes. RESULTS Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol. Physicochemical characterization exhibited particle size of 257.1 nm with zeta potential -0.170 mV (optimized batch B, BNP). SEM and FTIR analyses of BNP showed that cylindrical particles of B converted to spherical particles in BNP and there were no interaction between B and used polymers. The release study of optimized BNP was highest (≥80%) than any other formulation. Later, in vitro cell culture analysis using Hep-G2 cells and confocal microscopy studies revealed that BNP had the highest inhibition and penetration properties than parent B. Oral pharmacokinetics studies using albino Wistar rats at single 100 mg dose again exhibited BNP had the higher 50% of plasma concentration (t1/2), a higher maximum plasma concentration (Cmax) and took longer to reach the maximum plasma concentration (Tmax) than parent B. Next, our in vivo study using nitrosodiethyl amine (NDEA)-induced HCC model documented BNP decreased in number of nodules, restored body weight, oxidative stress parameters, liver marker enzymes and histological architecture than parent B. Lastly, qRT-PCR studies further demonstrated that anti-HCC properties of BNP may be due to over expression of antiapoptotic caspases i.e., caspase 3 and 8. CONCLUSION The prepared BNP showed a better therapeutic response against HCC and could be attributed as future candidate molecule for HCC treatment.
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Affiliation(s)
- Pranesh Kumar
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India
| | - Ashok K Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India
| | - Vinit Raj
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India
| | - Amit Rai
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India
| | - Amit K Keshari
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India
| | - Dinesh Kumar
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
| | - Biswanath Maity
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
| | - Anand Prakash
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India
| | - Sabyasachi Maiti
- Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Anuppur, Madhya Pradesh, India
| | - Sudipta Saha
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India
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30
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Shaqura M, Mohamed DM, Aboryag NB, Bedewi L, Dehe L, Treskatsch S, Shakibaei M, Schäfer M, Mousa SA. Pathological alterations in liver injury following congestive heart failure induced by volume overload in rats. PLoS One 2017; 12:e0184161. [PMID: 28934226 PMCID: PMC5608213 DOI: 10.1371/journal.pone.0184161] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/19/2017] [Indexed: 12/31/2022] Open
Abstract
Heart failure has emerged as a disease with significant public health implications. Following progression of heart failure, heart and liver dysfunction are frequently combined in hospitalized patients leading to increased morbidity and mortality. Here, we investigated the underlying pathological alterations in liver injury following heart failure. Heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. Sham operated and ACF rats were compared for their morphometric and hemodynamic data, for histopathological and ultrastructural changes in the liver as well as differences in the expression of apoptotic factors. ACF-induced heart failure is associated with light microscopic signs of apparent congestion of blood vessels, increased apoptosis and breakdown of hepatocytes and inflammatory cell inifltration were observed. The glycogen content depletion associated with the increased hepatic fibrosis, lipid globule formation was observed in ACF rats. Moreover, cytoplasmic organelles are no longer distinguishable in many ACF hepatocytes with degenerated fragmented rough endoplasmic reticulum, shrunken mitochondria and heavy cytoplasm vacuolization. ACF is associated with the upregulation of the hepatic TUNEL-positive cells and proapoptotic factor Bax protein concomitant with the mitochondrial leakage of cytochrome C into the cell cytoplasm and the transfer of activated caspase 3 from the cytoplasm into the nucleus indicating intrinsic apoptotic events. Taken together, the results demonstrate that ACF-induced congestive heart failure causes liver injury which results in hepatocellular apoptotic cell death mediated by the intrinsic pathway of mitochondrial cytochrome C leakage and subsequent transfer of activated caspase 3 into to the nucleus to initiate overt DNA fragmentation and cell death.
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Affiliation(s)
- Mohammed Shaqura
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Doaa M. Mohamed
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Noureddin B. Aboryag
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Lama Bedewi
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Lukas Dehe
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Sascha Treskatsch
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Mehdi Shakibaei
- Department of Anatomy, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Michael Schäfer
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Shaaban A. Mousa
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
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Wu LH, Zhang Q, Zhang S, Meng LY, Wang YC, Sheng CJ. Effects of gene knockdown of CNP on ventricular remodeling after myocardial ischemia-reperfusion injury through NPRB/Cgmp signaling pathway in rats. J Cell Biochem 2017; 119:1804-1818. [PMID: 28796407 DOI: 10.1002/jcb.26341] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 08/08/2017] [Indexed: 01/27/2023]
Abstract
This study aimed to explore effects of CNP on ventricular remodeling following myocardial ischemia-reperfusion (I/R) injury through the NPRB/cGMP signaling pathway. Rat cardiomyocytes were assigned into: control, I/R, I/R + CNP, and I/R + 8-Br-cGMP groups. ELISA, qRT-PCR, and Western blotting were used to detect cGMP content and expression, respectively. After model establishment of I/R rats, normal control, CNP-/- control, I/R, and CNP-/- groups were set. Indexes of heart were detected using echocardiography and hemodynamics. ELISA was used to measure serum CNP, cGMP, LDH, cTn I, CK-MB, TNF-α, and IL-6 levels. Myocardial infarct was identified by TTC staining, and apoptosis conditions by TUNEL staining. QRT-PCR and Western blotting were adopted to detect expressions of CNP, NPRB, cGMP, and apoptosis-related genes. Compared with control group, cGMP contents and expression in the I/R, I/R + CNP and I/R + 8-Br-cGMP groups were decreased. Levels of LVEDV, LVESV, LVDS, LVDD, IVSD, LVM, LVEDP, and LVSP were higher in the I/R, CNP-/- control, and CNP-/- groups than normal control group while LVEF, SV, CO, and ±dp/dtmax were lower. Compared with the normal control group, LDH, cTn I, CK-MB, TNF-α, and IL-6 were higher in the I/R, CNP-/- control and CNP-/- groups; pathological changes and myocardial infarction were observed in the I/R, CNP-/- control, and CNP-/- groups; expressions of apoptosis-related genes in those groups were higher; while CNP, NPRB, cGMP, and Bcl-2 expressions were decreased. We came to the conclusion that gene knockdown of CNP blocks the NPRB/cGMP signaling pathway, thereby aggravating myocardial I/R injury and causing ventricular remodeling in rats.
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Affiliation(s)
- Lian-He Wu
- Department of Cardiac Surgery, Jining No.1 People's Hospital, Jining, China
| | - Qi Zhang
- Department of Cardiology, Dongying City People's Hospital, Dongying, China
| | - Shen Zhang
- Department of Cardiac Surgery, Jining No.1 People's Hospital, Jining, China
| | - Lu-Yu Meng
- Department of Cardiac Surgery, Jining No.1 People's Hospital, Jining, China
| | - Yan-Chi Wang
- Department of Cardiac Surgery, Jining No.1 People's Hospital, Jining, China
| | - Cun-Jian Sheng
- Department of Cardiac Surgery, Jining No.1 People's Hospital, Jining, China
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Aboryag NB, Mohamed DM, Dehe L, Shaqura M, Treskatsch S, Shakibaei M, Schäfer M, Mousa SA. Histopathological Changes in the Kidney following Congestive Heart Failure by Volume Overload in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:6894040. [PMID: 28831296 PMCID: PMC5555028 DOI: 10.1155/2017/6894040] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 04/07/2017] [Accepted: 05/02/2017] [Indexed: 01/18/2023]
Abstract
BACKGROUND This study investigated histopathological changes and apoptotic factors that may be involved in the renal damage caused by congestive heart failure in a rat model of infrarenal aortocaval fistula (ACF). METHODS Heart failure was induced using a modified approach of ACF in male Wistar rats. Sham-operated controls and ACF rats were characterized by their morphometric and hemodynamic parameters and investigated for their histopathological, ultrastructural, and apoptotic factor changes in the kidney. RESULTS ACF-induced heart failure is associated with histopathological signs of congestion and glomerular and tubular atrophy, as well as nuclear and cellular degeneration in the kidney. In parallel, overexpression of proapoptotic Bax protein, release of cytochrome C from the outer mitochondrial membrane into cell cytoplasm, and nuclear transfer of activated caspase 3 indicate apoptotic events. This was confirmed by electron microscopic findings of apoptotic signs in the kidney such as swollen mitochondria and degenerated nuclei in renal tubular cells. CONCLUSIONS This study provides morphological evidence of renal injury during heart failure which may be due to caspase-mediated apoptosis via overexpression of proapoptotic Bax protein, subsequent mitochondrial cytochrome C release, and final nuclear transfer of activated caspase 3, supporting the notion of a cardiorenal syndrome.
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Affiliation(s)
- Noureddin B. Aboryag
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Doaa M. Mohamed
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Lukas Dehe
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Mohammed Shaqura
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Sacha Treskatsch
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Mehdi Shakibaei
- Department of Anatomy, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Michael Schäfer
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Shaaban A. Mousa
- Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany
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Glesse N, Vianna P, Paim LMG, Matte MCC, Aguiar AKK, Palhano PL, Monticielo OA, Brenol CV, Xavier RM, Chies JAB. Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus. Lupus 2016; 26:746-755. [PMID: 27909160 DOI: 10.1177/0961203316678671] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the disruption of the immune homeostasis. Patients exhibit a wide range of clinical manifestations, and environmental and genetic factors are involved in SLE pathogenesis. Evidence suggests that abnormalities in the cellular and molecular events that coordinate apoptosis may favour the generation of autoantigens involved in autoimmunity. In this way, the apoptotic deregulation may be affected by polymorphic variants in apoptotic-related genes. Methods We analyzed FAS, FASL, BCL-2 and BAX polymorphisms in order to correlate to SLE susceptibility and clinical features. A total of 427 SLE patients from the Hospital de Clínicas de Porto Alegre and 543 controls from southern Brazil were evaluated. Results We observed higher frequencies of the FASL -844CC genotype and -844C allele, as well as of the FASL-844C/IVS2nt-124A haplotype in African-derived SLE patients when compared to controls ( P < 0.001). FASL -844C, which is related to high FasL expression, could contribute to increased apoptosis and to the breakdown of immunological tolerance, favouring autoantibody production and inflammation. On the other hand, the BAX -248GA genotype and the -248A allele , related to low protein expression, were observed as a protective factor against SLE in this same population. The rate of apoptosis and cell death was evaluated in peripheral lymphocytes, and SLE patients presented a higher percentage of dead lymphocytes (CD3+Annexin V+ 7-AAD+) compared to the control group. Conclusion Our data support a role for apoptosis in SLE susceptibility.
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Affiliation(s)
- N Glesse
- 1 Laboratory of Immunogenetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - P Vianna
- 1 Laboratory of Immunogenetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - L M G Paim
- 1 Laboratory of Immunogenetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - M C C Matte
- 1 Laboratory of Immunogenetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - A K K Aguiar
- 1 Laboratory of Immunogenetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - P L Palhano
- 1 Laboratory of Immunogenetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - O A Monticielo
- 2 Division of Rheumatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - C V Brenol
- 2 Division of Rheumatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - R M Xavier
- 2 Division of Rheumatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - J A B Chies
- 1 Laboratory of Immunogenetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Ozkececi ZT, Gonul Y, Karavelioglu A, Bozkurt MF, Kacar E, Bal A, Ozsoy M, Turamanlar O, Celep B. The effect of enoxaparin on seroma and mesh-tissue adhesion in a hernia model. Clin Exp Pharmacol Physiol 2016; 43:690-7. [DOI: 10.1111/1440-1681.12582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 04/07/2016] [Accepted: 04/21/2016] [Indexed: 11/29/2022]
Affiliation(s)
- Ziya T Ozkececi
- Department of General Surgery; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Yucel Gonul
- Department of Anatomy; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Afra Karavelioglu
- Department of Pediatric Surgery; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Mehmet F Bozkurt
- Department of Pathology; Faculty of Veterinary Medicine; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Emre Kacar
- Department of Radiology; Faculty of Medicine; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Ahmet Bal
- Department of General Surgery; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Mustafa Ozsoy
- Department of General Surgery; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Ozan Turamanlar
- Department of Anatomy; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Bahadir Celep
- Department of General Surgery; Afyon Kocatepe University; Afyonkarahisar Turkey
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Yang B, Yang Q, Yang X, Yan HB, Lu QP. Hyperoside protects human primary melanocytes against H2O2-induced oxidative damage. Mol Med Rep 2016; 13:4613-9. [PMID: 27082158 PMCID: PMC4878558 DOI: 10.3892/mmr.2016.5107] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 01/26/2016] [Indexed: 11/12/2022] Open
Abstract
Cuscutae semen has been shown to have beneficial effects in the treatment of vitiligo, recorded in the Chinese Pharmacopoeia, whereas the effects of its constituent compounds remains to be elucidated. Using a tetrazolium bromide assay, the present study found that hyperoside (0.5–200 µg/ml) significantly increased the viability of human melanocytes in a time- and dose-dependent manner. The present study used a cell model of hydrogen peroxide (H2O2)-induced oxidative damage to examine the effect of hyperoside on human primary melanocytes. The results demonstrated that hyperoside pretreatment for 2 h decreased cell apoptosis from 54.03±9.11 to 17.46±3.10% in the H2O2-injured melanocytes. The levels of oxidative stress in the mitochondrial membrane potential of the melanocytes increased following hyperoside pretreatment. The mRNA and protein levels of B-cell lymphoma-2/Bcl-2-associated X protein and caspase 3 were regulated by hyperoside, and phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase signaling were also mediated by hyperoside. In conclusion, the results of the present study demonstrated that hyperoside protected the human primary melanocytes against oxidative damage.
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Affiliation(s)
- Bin Yang
- Department of Dermatology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei 430070, P.R. China
| | - Qin Yang
- Department of Laboratory Medicine, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei 430070, P.R. China
| | - Xin Yang
- Department of Dermatology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei 430070, P.R. China
| | - Hong-Bo Yan
- Department of Dermatology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei 430070, P.R. China
| | - Qi-Ping Lu
- Department of General Surgery, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei 430070, P.R. China
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Effects of 4-nonylphenol on oxidant/antioxidant balance system inducing hepatic steatosis in male rat. Toxicol Rep 2015; 2:1423-1433. [PMID: 28962484 PMCID: PMC5598540 DOI: 10.1016/j.toxrep.2015.10.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 10/04/2015] [Accepted: 10/12/2015] [Indexed: 12/30/2022] Open
Abstract
Intraperitoneal administration of 4-NP induces hepatic steatosis in male Sprague-Dawley rats. Hepatocytes apoptosis is highly implicated in the occurrence and development of NAFLD. Hepatic mitochondrial disturbance promotes deleterious consequences, such as OS and accumulation of triglycerides (steatosis). An emerging literature suggests that early life exposure to 4-nonylphenol (4-NP), a widespread endocrine disrupting chemical, may increase the risk of metabolic syndrome. In this study, we investigated the hypothesis that intraperitoneal administration of 4-NP induces hepatic steatosis in rat. 24 male Sprague-Dawley rats were administered with 4-NP (0, 2, 10 and 50 mg/kg b.wt) in corn oil for 30 days. Liver histology, biochemical analysis and gene expression profiling were examined. After treatment, abnormal liver morphology and function were observed in the 4-NP-treated rat, and significant changes in gene expression an indicator of hepatic steatosis and apoptosis were observed compared with controls. Up-regulated genes involved in apoptosis, hepatotoxity and oxidative stress, increased ROS and decrease of antioxidant enzyme were observed in the 4-NP exposed rat. Extensive fatty accumulation in liver section and elevated serum GOT, GPT, LDH and γ-GT were also observed. Incidence and severity of liver steatosis was scored and taken into consideration (steatosis, ballooning and lobular inflammation). Hepatocytes apoptosis could promote NAFLD progression; Fas/FasL, TNF-α and Caspase-9 mRNA activation were important contributing factors to hepatic steatosis. These findings provide the first evidence that 4-NP affects the gene expression related to liver hepatotoxicity, which is correlated with hepatic steatosis.
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Key Words
- 4-NP, 4-nonylphenol
- 4-Nonylphenol
- 4-Nonylphenol (PubChem CID: 1752)
- APNEIs, alkylphenol polyethoxylates
- AhR, aril hydrocarbon receptor
- Apoptosis
- Aprotinin (PubChem CID: 22833874)
- Bouin's fluid (PubChem CID: 124013)
- Collagenase (PubChem CID: 5046512)
- Cyt c, cytochrome c
- Diamninobenzidine Tetrahydrochloride (PubChem CID: 23892)
- FAO, fatty acid oxidation
- FFA, free fatty acid
- GOT, glutamic-oxalacetic transaminase
- GPT, glutamate pyruvate transaminase
- Genes
- HSC, hepatic stellate cell
- Hematoxylin Eosin (PubChem CID: 86598188)
- Hepatic steatosis
- Hydrogen peroxide (PubChem CID: 784)
- IR, insulin resistance
- LDH, lactate dehydrogenase
- Liver
- Malondialdehyde (PubChem CID: 10964)
- NAFLD, nonalcoholic fatty liver disease
- NASH, non-alcoholic hepatic steatosis
- Nitrotetrazolium Blue chloride (PubChem CID: 9281)
- OS, oxidative stress
- Oxidative stress
- PPAR, peroxisome proliferation-activated receptor
- Phenylmethylsulfonyl fluoride (PubChem CID: 4784)
- ROS, reactive oxygen species
- Sodium chloride (PubChem CID: 5234)
- Superoxide (PubChem CID: 5359597)
- TAG, triacylglycerol
- Thiobarbituric Acid (PubChem CID: 2723628)
- Trizol (PubChem CID: 378478)
- Tromethamine (Tris) (PubChem CID: 6503)
- Xylene (PubChem CID: 6850715)
- γ-GT, gamma glutamyltransferase
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Wang G, Jiang L, Song J, Zhou SF, Zhang H, Wang K, Xiao X. Mipu1 protects H9c2 myogenic cells from hydrogen peroxide-induced apoptosis through inhibition of the expression of the death receptor Fas. Int J Mol Sci 2014; 15:18206-20. [PMID: 25310648 PMCID: PMC4227212 DOI: 10.3390/ijms151018206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 09/04/2014] [Accepted: 09/11/2014] [Indexed: 11/16/2022] Open
Abstract
Mipu1 (myocardial ischemic preconditioning upregulated protein 1), a novel rat gene recently identified in our lab, was expressed abundantly and predominantly in the brain and heart and upregulated in myocardium during myocardial ischemia/reperfusion in rats. In our previous study we found that Mipu1 was an evolutionarily conserved zinc finger-containing transcription factor. However, whether Mipu1 confers myocardial protection remains unknown. In this study, H9c2 myogenic cells were treated with hydrogen peroxide (H2O2) to simulate oxidative stress during myocardial ischemia-reperfusion injury. The expression of Mipu1 at mRNA and protein levels was detected by RT-PCR and Western blotting analysis. To study the effect of Mipu1 on apoptosis and expression of Fas induced by H2O2, full-length Mipu1 cDNA and Mipu1-RNAi plasmids were transiently transfected into H9c2 myogenic cells, and flow cytometry was used to quantitate the percentage of apoptotic cells. The expression of Fas was analyzed by Western blotting assay. The DNA binding and transcription activities of Mipu1 to the Fas promoter were detected by chromatin immunoprecipitation and luciferase reporter assays. The results showed that exposure of H9c2 myogenic cells to H2O2 resulted in a dose- and time-dependent increase in Mipu1 mRNA and protein levels; Mipu1 over-expression inhibited H2O2-induced apoptosis and upregulation of Fas induced by H2O2 in H9c2 myogenic cells; and knockdown of Mipu1 by RNAi promoted apoptosis and upregulation of Fas induced by H2O2. The chromatin immunoprecipition and reporter assays showed the DNA binding and transcription suppressor activities of Mipu1 to Fas promoter region. These results indicate that Mipu1 protected H9c2 myogenic cells from H2O2-induced apoptosis through inhibiting the expression of Fas.
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Affiliation(s)
- Guiliang Wang
- Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China.
| | - Lei Jiang
- Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China.
| | - Juan Song
- Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China.
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
| | - Huali Zhang
- Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China.
| | - Kangkai Wang
- Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China.
| | - Xianzhong Xiao
- Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan, China.
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