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1
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Khan A, Khan B, Hussain S, Wang Y, Mai W, Hou Y. Permethrin exposure impacts zebrafish lipid metabolism via the KRAS-PPAR-GLUT signaling pathway, which is mediated by oxidative stress. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2024; 273:107021. [PMID: 38996480 DOI: 10.1016/j.aquatox.2024.107021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 07/01/2024] [Accepted: 07/06/2024] [Indexed: 07/14/2024]
Abstract
Permethrin (Per) is a widely used and frequently detected pyrethroid pesticide in agricultural products and the environment. It may pose potential toxicity to non-target organisms. Per has been reported to affect lipid homeostasis, although the mechanism is undefined. This study aims to explore the characteristic transcriptomic profiles and clarify the underlying signaling pathways of Per-induced lipid metabolism disorder in zebrafish liver. The results showed that environmental exposure to Per caused changes in the liver index, histopathology, and oxidative stress in zebrafish. Moreover, transcriptome results showed that Per heavily altered the pathways involved in metabolism, the immune system, and the endocrine system. We conducted a more in-depth analysis of the genes associated with lipid metabolism. Our findings revealed that exposure to Per led to a disruption in lipid metabolism by activating the KRAS-PPAR-GLUT signaling pathways through oxidative stress. The disruption of lipid homeostasis caused by exposure to Per may also contribute to obesity, hepatitis, and other diseases. The results may provide new insights for the risk of Permethrin to aquatic organisms and new horizons for the pathogenesis of hepatotoxicity.
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Affiliation(s)
- Afrasyab Khan
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China 212013
| | - Bibimaryam Khan
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China 212013
| | - Shakeel Hussain
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China 212013
| | - Yuhan Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China 212013
| | - Weijun Mai
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China 212013.
| | - Yongzhong Hou
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, China 212013.
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2
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Yu J, Hu G, Guo X, Cao H, Zhang C. Quercetin Alleviates Inflammation and Energy Deficiency Induced by Lipopolysaccharide in Chicken Embryos. Animals (Basel) 2023; 13:2051. [PMID: 37443849 DOI: 10.3390/ani13132051] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 07/15/2023] Open
Abstract
Energy deficiency causes multiple organ dysfunctions after LPS induction. Quercetin is a phenolic compound found in herbal medicines. However, the effects of quercetin in alleviating LPS-induced energy deficiency remain unclear. In the present study, an in vivo LPS-induced inflammation model was established in chicken embryos. Specific pathogen-free chicken embryos (n = 120) were allocated to control, PBS with or without ethanol, quercetin (10, 20, or 40 nmol, respectively), and LPS (125 ng/egg) with or without quercetin groups. Fifteen day old embryonated eggs were injected with the abovementioned solutions via the allantoic cavity. On embryonic day 19, the tissues of the embryos were collected for histopathological examination using frozen oil red O staining, RNA extraction, real-time quantitative polymerase chain reaction, and immunohistochemical investigations. The glycogen and lipid contents in the liver increased after LPS stimulation as compared with the PBS group, whereas quercetin decreased the accumulation as compared with the LPS group. The mRNA expressions of AMPKα1 and AMPKα2 in the duodena, ceca, and livers were upregulated after LPS induction as compared with the PBS group, while quercetin could downregulate these expressions as compared with the LPS group. The immunopositivity of AMPKα2 in the villus, crypt, lamina propria, tunica muscularis, and myenteric plexus in the duodena and in the cytoplasms of hepatocytes significantly increased after LPS induction when compared with the PBS group (p < 0.01), whereas the immunopositivity to AMPKα2 in the quercetin treatment group significantly decreased when compared with the LPS group (p < 0.01 or p < 0.05). The LPS-induced high expressions of transcription factor PPARα and glucose transporter (SGLT1) were blocked by quercetin in the duodena, ceca, and livers. Quercetin treatment improved the LPS-induced decrease in APOA4 in the duodena, ceca, and livers. The mRNA expression of PEPT1 in the duodena and ceca increased after LPS challenge, whereas quercetin could downregulate PEPT1 gene expression. These data demonstrate that quercetin improved the energy deficiency induced by LPS in chicken embryos. The LPS-induced inflammation model was established to avoid the effect of LPS exposure from the environment and intestinal flora. The results form the basis the administration of quercetin pretreatment (in ovo infection) to improve the energy state of chicken embryos and improve the inflammation response.
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Affiliation(s)
- Jinhai Yu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xiaoquan Guo
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
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3
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Qiao X, Kang L, Shi C, Ye A, Wu D, Huang Y, Deng M, Wang J, Zhao Y, Chen C. Exploring the precision redox map during fasting-refeeding and satiation in C. elegans. STRESS BIOLOGY 2023; 3:17. [PMID: 37676352 PMCID: PMC10442001 DOI: 10.1007/s44154-023-00096-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/22/2023] [Indexed: 09/08/2023]
Abstract
Fasting is a popular dietary strategy because it grants numerous advantages, and redox regulation is one mechanism involved. However, the precise redox changes with respect to the redox species, organelles and tissues remain unclear, which hinders the understanding of the metabolic mechanism, and exploring the precision redox map under various dietary statuses is of great significance. Twelve redox-sensitive C. elegans strains stably expressing genetically encoded redox fluorescent probes (Hyperion sensing H2O2 and Grx1-roGFP2 sensing GSH/GSSG) in three organelles (cytoplasm, mitochondria and endoplasmic reticulum (ER)) were constructed in two tissues (body wall muscle and neurons) and were confirmed to respond to redox challenge. The H2O2 and GSSG/GSH redox changes in two tissues and three organelles were obtained by confocal microscopy during fasting, refeeding, and satiation. We found that under fasting condition, H2O2 decreased in most compartments, except for an increase in mitochondria, while GSSG/GSH increased in the cytoplasm of body muscle and the ER of neurons. After refeeding, the redox changes in H2O2 and GSSG/GSH caused by fasting were reversed in most organelles of the body wall muscle and neurons. In the satiated state, H2O2 increased markedly in the cytoplasm, mitochondria and ER of muscle and the ER of neurons, while GSSG/GSH exhibited no change in most organelles of the two tissues except for an increase in the ER of muscle. Our study systematically and precisely presents the redox characteristics under different dietary states in living animals and provides a basis for further investigating the redox mechanism in metabolism and optimizing dietary guidance.
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Affiliation(s)
- Xinhua Qiao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lu Kang
- School of Basic Medical Sciences of Southwest Medical University, Luzhou, 646000, China
| | - Chang Shi
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Aojun Ye
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dongli Wu
- School of Basic Medical Sciences of Southwest Medical University, Luzhou, 646000, China
| | - Yuyunfei Huang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Minghao Deng
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jiarui Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuzheng Zhao
- School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
| | - Chang Chen
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- School of Basic Medical Sciences of Southwest Medical University, Luzhou, 646000, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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4
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Sant’ Ana CT, Agrizzi Verediano T, Grancieri M, Toledo RCL, Tako E, Costa NMB, Martino HSD, de Barros FAR. Macauba ( Acrocomia aculeata) Pulp Oil Prevents Adipogenesis, Inflammation and Oxidative Stress in Mice Fed a High-Fat Diet. Nutrients 2023; 15:nu15051252. [PMID: 36904250 PMCID: PMC10005707 DOI: 10.3390/nu15051252] [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: 02/03/2023] [Revised: 02/23/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Macauba is a palm tree native to Brazil, which fruits are rich in oil. Macauba pulp oil has high contents of oleic acid, carotenoids, and tocopherol, but its effect on health is unknown. We hypothesized that macauba pulp oil would prevent adipogenesis and inflammation in mice. Thus, the purpose of this study was to evaluate the effects of macauba pulp oil on the metabolic changes in C57Bl/6 mice fed a high-fat diet. Three experimental groups were used (n = 10): control diet (CD), high-fat diet (HFD), and high-fat diet with macauba pulp oil (HFM). The HFM reduced malondialdehyde and increased SOD activity and antioxidant capacity (TAC), showing high positive correlations between total tocopherol, oleic acid, and carotenoid intakes and SOD activity (r = 0.9642, r = 0.8770, and r = 0.8585, respectively). The animals fed the HFM had lower levels of PPAR-γ and NF-κB, which were negatively correlated with oleic acid intake (r = -0.7809 and r = -0.7831, respectively). Moreover, the consumption of macauba pulp oil reduced inflammatory infiltrate, adipocyte number and length, (mRNA) TNF-α, and (mRNA) SREBP-1c in the adipose tissue, and it increased (mRNA) Adiponectin. Therefore, macauba pulp oil prevents oxidative stress, inflammation, and adipogenesis and increases antioxidant capacity; these results highlight its potential against metabolic changes induced by an HFD.
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Affiliation(s)
- Cíntia Tomaz Sant’ Ana
- Department of Food Technology, Federal University of Viçosa, Viçosa 36570-900, MG, Brazil
| | | | - Mariana Grancieri
- Department of Nutrition and Health, Federal University of Viçosa, Viçosa 36570-900, MG, Brazil
| | | | - Elad Tako
- Department of Food Science, Cornell University, Stocking Hall, Ithaca, NY 14850, USA
- Correspondence:
| | - Neuza Maria Brunoro Costa
- Department of Pharmacy and Nutrition, Federal University of Espírito Santo, Alegre 29500-000, ES, Brazil
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Cho W, Park SY, Oh H, Abd El-Aty AM, Hacimüftüoğlu A, Kim DS, Jung TW, Jeong JH. Humulus japonicus Extract Ameliorates Hepatic Steatosis Through the PPAR α-Mediated Suppression of Alcohol-Induced Oxidative Stress. J Med Food 2023; 26:193-200. [PMID: 36827085 DOI: 10.1089/jmf.2022.k.0093] [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] [Indexed: 02/25/2023] Open
Abstract
Humulus japonicus has been used to treat obesity, hypertension, and nonalcoholic fatty liver and to alleviate inflammation and oxidative stress. In the present study, we aimed to investigate the effects of H. japonicus ethanol extracts (HE) and luteolin 7-O-β-d-glucoside (LU), which is identified as a major active component of H. japonicus, on ethanol-induced oxidative stress and lipid accumulation in primary hepatocytes. Mouse primary hepatocytes were treated with HE and stimulated with ethanol. The MTT test was used to determine cell viability. By using Western blotting, the effects of HE on the expression of different proteins were investigated. Experimental mice were given a 5% alcohol liquid Lieber-DeCarli diet to induce alcoholic fatty liver. We found that both HE and LU individually attenuated ethanol-induced lipid accumulation, lipogenic protein expression, and cellular oxidative stress in hepatocytes. Treatment with HE or LU increased PPARα and SOD1 expression and catalase activity in a dose-dependent manner. Small interfering RNA of PPARα reduced the effects of HE on oxidative stress, lipid metabolism, and levels of antioxidants. We also observed that orally administered HE treatment alleviated hepatic steatosis in a diet containing ethanol-fed mice. This study suggests HE as a functional food that can improve hepatic steatosis, thereby preventing hepatic injury caused by alcohol consumption.
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Affiliation(s)
- Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Seung Yeon Park
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea.,Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Korea
| | - Heeseung Oh
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.,Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkiye
| | - Ahmet Hacimüftüoğlu
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkiye.,Vaccine Development Application and Research Center, Ataturk University, Erzurum, Turkiye
| | - Dae-Sung Kim
- Hanpoong Pharm and Foods Co., Ltd., Wanju, Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Korea.,Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Korea
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6
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Rostami E, Maleki M, Koohestani R, Oghazi MR, Safavi EA, Hayati F. Effect of intermittent fasting on saving zone of stasis in burn wounds in rats. Burns 2022; 49:901-913. [PMID: 35787965 DOI: 10.1016/j.burns.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/30/2022] [Accepted: 06/15/2022] [Indexed: 11/02/2022]
Abstract
BACKGROUND Intermittent Fasting (IF) has proved to have various positive effects on life span, diseases, and healing of tissues in rodents. We evaluated the protective effect of fasting in maintaining the ischemic zones in burn wounds. METHODS In this study, 20 rats were divided into two groups where the IF rats were deprived of food for three months. Burn wounds were created by burn comb model on the back of all rats. On days 3 and 21 after injury, five rats in each group were euthanized whereby samples were collected for histopathological, immunohistochemical (Bcl2, P53 and VEGF), and biochemical (MDA, TAC, HP) evaluations. RESULTS Histopathological analysis revealed epithelial layer and zone of ischemia remained viable in the intermittent fasting group on day 3. On the 21st day, epithelialization, angiogenesis, inflammation, fibrocyte-fibroblast, and collagen density were different in the ischemic and necrotic zones between the control and intermittent fasting groups (p<0.05). We found no statistical differences in Bcl2, P53, VEGF, MDA, TAC, and HP on day 3 between the intermittent fasting and control groups. CONCLUSIONS Intermittent fasting before burn wounds reduces tissue damage caused by ischemia and enhanced the viability of cells in zone of stasis. It also accelerated wound healing by increasing epithelialization and collagen production in the skin and regulating inflammatory responses. This intervention appears to be related to better collagen arrangement and angiogenesis.
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7
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Xu S, Qiao X, Peng P, Zhu Z, Li Y, Yu M, Chen L, Cai Y, Xu J, Shi X, Proud CG, Xie J, Shen K. Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα. Front Pharmacol 2022; 13:847483. [PMID: 35370715 PMCID: PMC8965327 DOI: 10.3389/fphar.2022.847483] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/15/2022] [Indexed: 12/12/2022] Open
Abstract
Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to α-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80 mg/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875 g/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875 g/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH/GSSG ratio) and increased in the mRNA levels for Il6, Il1b and Tnfa associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPARα increased luciferase levels from a PPARα-driven reporter. PPARα agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPARα antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK/IL-6/NF-κB/STAT3 related to PPARα might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works via PPARα activation.
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Affiliation(s)
- Shihao Xu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xi Qiao
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Peike Peng
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ziyi Zhu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yaoting Li
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Fudan University, Shanghai, China
| | - Mengyuan Yu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Long Chen
- Experimental Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yin Cai
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Jin Xu
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinwei Shi
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Christopher G Proud
- Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.,Molecular and Biomedical Sciences, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Jianling Xie
- Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.,Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA, Australia
| | - Kaikai Shen
- School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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8
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Koga T, Peters JM. Targeting Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) for the Treatment or Prevention of Alcoholic Liver Disease. Biol Pharm Bull 2021; 44:1598-1606. [PMID: 34719638 DOI: 10.1248/bpb.b21-00486] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Excessive, chronic alcohol consumption can lead to alcoholic liver disease. The etiology of alcoholic liver disease is multifactorial and is influenced by alterations in gene expression and changes in fatty acid metabolism, oxidative stress, and insulin resistance. These events can lead to steatosis, fibrosis, and eventually to cirrhosis and liver cancer. Many of these functions are regulated by peroxisome proliferator-activated receptors (PPARs). Thus, it is not surprising that PPARs can modulate the mechanisms that cause alcoholic liver disease. While the roles of PPARα and PPARγ are clearer, the role of PPARβ/δ in alcoholic liver disease requires further clarification. This review summarizes the current understanding based on recent studies that indicate that PPARβ/δ can likely be targeted for the treatment and/or the prevention of alcoholic liver disease.
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Affiliation(s)
- Takayuki Koga
- Laboratory of Hygienic Chemistry, Department of Health Science and Hygiene, Daiichi University of Pharmacy
| | - Jeffrey M Peters
- Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University
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9
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Bárcena B, Salamanca A, Pintado C, Mazuecos L, Villar M, Moltó E, Bonzón-Kulichenko E, Vázquez J, Andrés A, Gallardo N. Aging Induces Hepatic Oxidative Stress and Nuclear Proteomic Remodeling in Liver from Wistar Rats. Antioxidants (Basel) 2021; 10:antiox10101535. [PMID: 34679670 PMCID: PMC8533122 DOI: 10.3390/antiox10101535] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022] Open
Abstract
Aging is a continuous, universal, and irreversible process that determines progressive loss of adaptability. The liver is a critical organ that supports digestion, metabolism, immunity, detoxification, vitamin storage, and hormone signaling. Nevertheless, the relationship between aging and the development of liver diseases remains elusive. In fact, although prolonged fasting in adult rodents and humans delays the onset of the disease and increases longevity, whether prolonged fasting could exert adverse effects in old organisms remains incompletely understood. In this work, we aimed to characterize the oxidative stress and nuclear proteome in the liver of 3-month- and 24-month-old male Wistar rats upon 36 h of fasting and its adaptation in response to 30 min of refeeding. To this end, we analyzed the hepatic lipid peroxidation levels (TBARS) and the expression levels of genes associated with fat metabolism and oxidative stress during aging. In addition, to gain a better insight into the molecular and cellular processes that characterize the liver of old rats, the hepatic nuclear proteome was also evaluated by isobaric tag quantitation (iTRAQ) mass spectrometry-based proteomics. In old rats, aging combined with prolonged fasting had great impact on lipid peroxidation in the liver that was associated with a marked downregulation of antioxidant genes (Sod2, Fmo3, and Cyp2C11) compared to young rats. Besides, our proteomic study revealed that RNA splicing is the hepatic nuclear biological process markedly affected by aging and this modification persists upon refeeding. Our results suggest that aged-induced changes in the nuclear proteome could affect processes associated with the adaptative response to refeeding after prolonged fasting, such as those involved in the defense against oxidative stress.
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Affiliation(s)
- Brenda Bárcena
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Aurora Salamanca
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Cristina Pintado
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Environmental Sciences and Biochemistry, University of Castilla-La Mancha, Avda. Carlos III s/n, 45071 Toledo, Spain; (C.P.); (E.M.)
| | - Lorena Mazuecos
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Margarita Villar
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
- SaBio, Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ronda de Toledo s/n, 13005 Ciudad Real, Spain
- Correspondence: (M.V.); (N.G.)
| | - Eduardo Moltó
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Environmental Sciences and Biochemistry, University of Castilla-La Mancha, Avda. Carlos III s/n, 45071 Toledo, Spain; (C.P.); (E.M.)
| | - Elena Bonzón-Kulichenko
- Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III and CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.B.-K.); (J.V.)
| | - Jesús Vázquez
- Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III and CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; (E.B.-K.); (J.V.)
| | - Antonio Andrés
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
| | - Nilda Gallardo
- Biochemistry Section, Regional Center for Biomedical Research (CRIB), Faculty of Sciences and Chemical Technologies, University of Castilla-La Mancha, Avda. Camilo Jose Cela 10, 13071 Ciudad Real, Spain; (B.B.); (A.S.); (L.M.); (A.A.)
- Correspondence: (M.V.); (N.G.)
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10
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Rungratanawanich W, Qu Y, Wang X, Essa MM, Song BJ. Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury. Exp Mol Med 2021; 53:168-188. [PMID: 33568752 PMCID: PMC8080618 DOI: 10.1038/s12276-021-00561-7] [Citation(s) in RCA: 196] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 01/30/2023] Open
Abstract
Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer. Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE-alcohol-adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.
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Affiliation(s)
- Wiramon Rungratanawanich
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
| | - Ying Qu
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
| | - Xin Wang
- Neuroapoptosis Drug Discovery Laboratory, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA 02115 USA
| | - Musthafa Mohamed Essa
- grid.412846.d0000 0001 0726 9430Department of Food Science and Nutrition, Aging and Dementia Research Group, College of Agricultural and Marine Sciences, Sultan Qaboos University, Al-Khoud, Muscat, Oman ,grid.412846.d0000 0001 0726 9430Aging and Dementia Research Group, Sultan Qaboos University, Muscat, Oman
| | - Byoung-Joon Song
- grid.420085.b0000 0004 0481 4802Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892 USA
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11
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Rajavel A, Schmitt AO, Gültas M. Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle. Int J Mol Sci 2021; 22:ijms22020562. [PMID: 33429951 PMCID: PMC7827104 DOI: 10.3390/ijms22020562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/31/2020] [Accepted: 01/05/2021] [Indexed: 12/15/2022] Open
Abstract
African Animal Trypanosomiasis (AAT) is transmitted by the tsetse fly which carries pathogenic trypanosomes in its saliva, thus causing debilitating infection to livestock health. As the disease advances, a multistage progression process is observed based on the progressive clinical signs displayed in the host’s body. Investigation of genes expressed with regular monotonic patterns (known as Monotonically Expressed Genes (MEGs)) and of their master regulators can provide important clue for the understanding of the molecular mechanisms underlying the AAT disease. For this purpose, we analysed MEGs for three tissues (liver, spleen and lymph node) of two cattle breeds, namely trypanosusceptible Boran and trypanotolerant N’Dama. Our analysis revealed cattle breed-specific master regulators which are highly related to distinguish the genetic programs in both cattle breeds. Especially the master regulators MYC and DBP found in this study, seem to influence the immune responses strongly, thereby susceptibility and trypanotolerance of Boran and N’Dama respectively. Furthermore, our pathway analysis also bolsters the crucial roles of these master regulators. Taken together, our findings provide novel insights into breed-specific master regulators which orchestrate the regulatory cascades influencing the level of trypanotolerance in cattle breeds and thus could be promising drug targets for future therapeutic interventions.
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Affiliation(s)
- Abirami Rajavel
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (A.R.); (A.O.S.)
| | - Armin Otto Schmitt
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (A.R.); (A.O.S.)
- Center for Integrated Breeding Research (CiBreed), Albrecht-Thaer-Weg 3, Georg-August University, 37075 Göttingen, Germany
| | - Mehmet Gültas
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (A.R.); (A.O.S.)
- Center for Integrated Breeding Research (CiBreed), Albrecht-Thaer-Weg 3, Georg-August University, 37075 Göttingen, Germany
- Correspondence:
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12
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Increased risk of acute liver failure by pain killer drugs in NAFLD: Focus on nuclear receptors and their coactivators. Dig Liver Dis 2021; 53:26-34. [PMID: 32546444 DOI: 10.1016/j.dld.2020.05.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/05/2020] [Accepted: 05/18/2020] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global condition characterized by an accumulation of lipids in the hepatocytes. NAFLD ranges from simple steatosis, a reversible and relatively benign condition, to fibrosis with non-alcoholic steatohepatitis (NASH), potentially leading to cirrhosis and hepatocarcinoma. NAFLD can increase the susceptibility to severe liver injury with eventual acute liver failure induced by specific hepatotoxic drugs, including acetaminophen (APAP), which is commonly used as analgesic and antipyretic. Although several animal models have been used to clarify the predisposing role of hepatic steatosis to APAP intoxication, the exact mechanism is still not clear. Here, we shed a light into the association between NAFLD and APAP toxicity by examining the peculiar role of nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and coactivator peroxisome proliferator-activated receptor gamma coactivator 1-β (PGC-1β) in driving fatty acid metabolism, inflammation and mitochondria redox balance. The knowledge of the mechanism that exposes patients with NAFLD to higher risk of acute liver failure by pain killer drug is the first step to eventually claim for a reduction of the maximal diurnal dose of APAP for subjects with liver steatosis.
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13
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Wang W, Fang Q, Zhang Z, Wang D, Wu L, Wang Y. PPARα Ameliorates Doxorubicin-Induced Cardiotoxicity by Reducing Mitochondria-Dependent Apoptosis via Regulating MEOX1. Front Pharmacol 2020; 11:528267. [PMID: 33132907 PMCID: PMC7578427 DOI: 10.3389/fphar.2020.528267] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 09/16/2020] [Indexed: 11/28/2022] Open
Abstract
Doxorubicin (DOX), a chemotherapeutic drug widely used in the clinical setting, is known to cause serious cardiotoxicity and greatly reduces the survival rate as well as quality of life of patients receiving chemotherapy. Peroxisome proliferation activated receptor α (PPARα) is a type of ligand activated receptor of the nuclear hormone receptor family that regulates multiple gene expression. Several studies have shown that PPARα has anti-apoptotic and cardio-protective effects. However, its role in DOX-induced cardiotoxicity is rarely reported. In this study, we observed decreased expression of PPARα in the heart of tumor-bearing mice already treated with DOX; however, no such phenomenon was observed in tumor tissues. Next, we observed that the PPARα agonist, fenofibrate (FENO), had no effect on tumor progression; however, it enhanced cardiac function in tumor-bearing mice treated with DOX. Subsequently, recombinant adeno-associated virus serotype 9 (rAAV9) was used to manipulate the expression of PPARα in the heart of DOX-induced mice. Our results showed that PPARα gene delivery reduced cardiac dysfunction and mitochondria-dependent apoptosis in DOX-induced mice. Furthermore, we found that PPARα directly regulated the expression of mesenchyme homeobox 1 (MEOX1). Most importantly, the cardioprotective effects of PPARα could be neutralized by knocking down MEOX1. In summary, PPARα plays a vital role in DOX-induced cardiotoxicity and is a promising treatment target.
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Affiliation(s)
- Wei Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Fang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihao Zhang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Daowen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Lujin Wu
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China
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14
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Ikeda S, Sugihara T, Hoshino Y, Matsuki Y, Nagahara T, Okano JI, Kitao S, Fujioka Y, Yamamoto K, Isomoto H. Pemafibrate Dramatically Ameliorated the Values of Liver Function Tests and Fibrosis Marker in Patients with Non-Alcoholic Fatty Liver Disease. Yonago Acta Med 2020; 63:188-197. [PMID: 32884438 DOI: 10.33160/yam.2020.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/30/2020] [Indexed: 12/14/2022]
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease related to metabolic syndrome, which can progress to liver cirrhosis. Standard medication has not been established. Pemafibrate is a selective peroxisome proliferator-activated receptor (PPAR) α modulator. We retrospectively evaluated the efficacy of pemafibrate in patients with NAFLD. Methods We retrospectively enrolled 17 patients (ten men, seven women; median age, 63 years; range, 27-81 years). They were all proven to have fatty liver through imaging and had little or no history of drinking (ethanol consumption of < 20 g/day for women and < 30 g/day for men). They were administered pemafibrate from October 2018 to June 2020. Results After administration, serum triglyceride (TG) tended to be decreased (300.5 ± 22.5 to 239.5 ± 34.3 mg/dL, P = 0.06). Serum high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels did not change. ALT was significantly decreased (-47.4%) for six months (57.5 ± 8.8 to 30.3 ± 5.8 U/L, P < 0.01). The values of serum GGT significantly decreased (-48.7%) for sixth months (63.9 ± 10.3 to 32.8 ± 6.6 U/L, P < 0.01). Aspartate aminotransferase (AST) to platelet ratio (APRI), a fibrosis marker, also was significantly decreased in the sixth month (0.7 ± 0.1 to 0.4 ± 0.1, P < 0.05). Body mass index (BMI) and hemoglobin A1c (HbA1c) showed no significant change. Conclusion Pemafibrate dramatically ameliorated the values of liver function tests and APRI in patients with NAFLD.
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Affiliation(s)
- Suguru Ikeda
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Takaaki Sugihara
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Yoshiki Hoshino
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Yukako Matsuki
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Takakazu Nagahara
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Jun-Ichi Okano
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
| | - Sonoko Kitao
- Division of Medicine and Clinical Science, Department of Cardiovascular Medicine and Endocrinology and Metabolism, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Youhei Fujioka
- Division of Medicine and Clinical Science, Department of Cardiovascular Medicine and Endocrinology and Metabolism, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Kazuhiro Yamamoto
- Division of Medicine and Clinical Science, Department of Cardiovascular Medicine and Endocrinology and Metabolism, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and
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15
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Roles of peroxisome proliferator-activated receptor α in the pathogenesis of ethanol-induced liver disease. Chem Biol Interact 2020; 327:109176. [PMID: 32534989 DOI: 10.1016/j.cbi.2020.109176] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/02/2020] [Accepted: 06/09/2020] [Indexed: 12/18/2022]
Abstract
Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.
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16
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Association of EPAS1 and PPARA Gene Polymorphisms with High-Altitude Headache in Chinese Han Population. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1593068. [PMID: 32185192 PMCID: PMC7060407 DOI: 10.1155/2020/1593068] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/09/2019] [Accepted: 12/14/2019] [Indexed: 11/17/2022]
Abstract
Background High-altitude headache (HAH) is the most common complication after high-altitude exposure. Hypoxia-inducible factor- (HIF-) related genes have been confirmed to contribute to high-altitude acclimatization. We aim to investigate a possible association between HIF-related genes and HAH in the Chinese Han population. Methods In total, 580 healthy Chinese Han volunteers were recruited in Chengdu (500 m) and carried to Lhasa (3700 m) by plane in 2 hours. HAH scores and basic physiological parameters were collected within 18-24 hours after the arrival. Thirty-five single nucleotide polymorphisms (SNPs) in HIF-related genes were genotyped, and linkage disequilibrium (LD) was evaluated by Haploview software. The functions of SNPs/haplotypes for HAH were developed by using logistic regression analysis. Results In comparison with wild types, the rs4953354 "G" allele (P=0.013), rs6756667 "A" allele (P=0.013), rs6756667 "A" allele (EPAS1, and rs6520015 "C" allele in PPARA (P=0.013), rs6756667 "A" allele (PPARA (P=0.013), rs6756667 "A" allele (EPAS1, and rs6520015 "C" allele in PPARA (P=0.013), rs6756667 "A" allele (. Conclusions EPAS1 and PPARA polymorphisms were associated with HAH in the Chinese Han population. Our findings pointed out potentially predictive gene markers, provided new insights into understanding pathogenesis, and may further provide prophylaxis and treatment strategies for HAH.EPAS1, and rs6520015 "C" allele in PPARA (.
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17
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Yin F, Gupta R, Vergnes L, Driscoll WS, Ricks J, Ramanathan G, Stewart JA, Shih DM, Faull KF, Beaven SW, Lusis AJ, Reue K, Rosenfeld ME, Araujo JA. Diesel Exhaust Induces Mitochondrial Dysfunction, Hyperlipidemia, and Liver Steatosis. Arterioscler Thromb Vasc Biol 2019; 39:1776-1786. [PMID: 31340670 PMCID: PMC6703953 DOI: 10.1161/atvbaha.119.312736] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 06/17/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Air pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and β-oxidation. CONCLUSIONS DE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.
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Affiliation(s)
- Fen Yin
- Division of Cardiology, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, CHS 43-264, Los Angeles, CA
| | - Rajat Gupta
- Division of Cardiology, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, CHS 43-264, Los Angeles, CA
| | - Laurent Vergnes
- Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, 659 Charles E. Young Drive South, Los Angeles, CA
| | | | - Jerry Ricks
- Department of Pathology, University of Washington, Seattle, WA
| | - Gajalakshmi Ramanathan
- Division of Cardiology, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, CHS 43-264, Los Angeles, CA
| | - James A. Stewart
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA
| | - Diana M. Shih
- Division of Cardiology, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, CHS 43-264, Los Angeles, CA
| | - Kym F. Faull
- Pasarow Mass Spectrometry Laboratory, Semel Institute for Neuroscience and Human Behavior and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California Los Angeles, 760 Westwood Boulevard, Los Angeles, CA
| | - Simon W. Beaven
- Division of Gastroenterology, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, CHS 44-144, Los Angeles, CA
| | - Aldons J. Lusis
- Division of Cardiology, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, CHS 43-264, Los Angeles, CA
- Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, 659 Charles E. Young Drive South, Los Angeles, CA
| | - Karen Reue
- Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, 659 Charles E. Young Drive South, Los Angeles, CA
| | - Michael E. Rosenfeld
- Department of Pathology, University of Washington, Seattle, WA
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA
| | - Jesus A. Araujo
- Division of Cardiology, David Geffen School of Medicine at University of California Los Angeles, 10833 Le Conte Avenue, CHS 43-264, Los Angeles, CA
- Department of Environmental Health Sciences, Fielding School of Public Health, University of California Los Angeles, 10833 Le Conte Avenue, CHS 43-264, Los Angeles, CA
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Li T, Qi M, Gatesoupe FJ, Tian D, Jin W, Li J, Lin Q, Wu S, Li H. Adaptation to Fasting in Crucian Carp (Carassius auratus): Gut Microbiota and Its Correlative Relationship with Immune Function. MICROBIAL ECOLOGY 2019; 78:6-19. [PMID: 30343437 DOI: 10.1007/s00248-018-1275-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/09/2018] [Indexed: 06/08/2023]
Abstract
Fasting influences the overall physiology of fish, and the knowledge how the gut microbiota, growth performances, and immune function in response to intermittent and long-term fasting is still insufficient. Here, we characterized the effects of fasting on the host-gut microbiota in crucian carp, which would enhance our insight into physiological adaptation to fasting. To achieve this, we investigated the gut microbial communities of crucian carp with different fasting stress, and corresponding immune and growth parameters. The gut microbial communities were structured into four clusters according to different fasting stress, namely one control group (feed regularly), two intermittent fasting groups (fasting period and re-feeding period, respectively), and one long-term fasting group. Intermittent fasting significantly improved the activity of superoxide dismutase (SOD) and lysozyme (LZM) (ANOVA, p < 0.05) and significantly increased alpha diversity and ecosystem stability of gut microbiota (ANOVA, p < 0.05). Gut length (GL) and condition factor (CF) showed no significant difference between the control group (CG) and intermittent fasting group under re-feeding period (RIF) (ANOVA, p = 0.11), but relative gut length (RGL) in group RIF was higher than that in the CG (ANOVA, p = 0.00). The bacterial genera Bacteroides, Akkermansia, and Erysipelotrichaceae were enriched in fishes under intermittent fasting. Two Bacteroides OTUs (OTU50 and OTU1292) correlated positively with immune (SOD, complement, and LZM) and growth (GL and RGL) parameters. These results highlight the possible interplay between growth performances, immune function, and gut microbiota in response to fasting.
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Affiliation(s)
- Tongtong Li
- Department of Applied Biology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Mengting Qi
- Department of Applied Biology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | | | - Dongcan Tian
- Department of Applied Biology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Weihua Jin
- Department of Applied Biology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Jun Li
- Department of Applied Biology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China
| | - Qiang Lin
- Key Laboratory of Environmental and Applied Microbiology, CAS; Environmental Microbiology Key Laboratory of Sichuan Province, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
| | - Shijin Wu
- Department of Applied Biology, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
| | - Huan Li
- Institute of Occupational Health and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, 730000, China.
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Qi L, Zhou Y, Li W, Zheng M, Zhong R, Jin X, Lin Y. Effect of Moringa oleifera stem extract on hydrogen peroxide-induced opacity of cultured mouse lens. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:144. [PMID: 31226981 PMCID: PMC6588927 DOI: 10.1186/s12906-019-2555-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 06/10/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Moringa oleifera, also known as horseradish tree or drumstick tree, has strong antioxidant properties. In the present study, we investigated the potential effect of Moringa oleifera stem extract (MOSE) on cataract formation induced by oxidative stress in cultured mouse lenses. METHODS Mouse lenses cultured in vitro were pretreated with MOSE (0.5 and 1 mg/mL) for 24 h. Then, 1 mM hydrogen peroxide was added, and mouse lenses were cultured for a further 24 h. The medium was then changed to normal culture medium. After 48 h, lens opacification, reactive oxygen species (ROS) generation, reduced glutathione (GSH) content, and activities of superoxide dismutase (SOD) and catalase (CAT) were measured in lens tissues. In addition, the protein expression of peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor with potential benefits to improve vision-threatening eye diseases, was assayed. RESULTS MOSE (1 mg/mL) alleviated lens opacification, reduced ROS generation, increased GSH content, and elevated SOD and CAT activities in cultured lenses. Moreover, MOSE upregulated the expressions of SOD, CAT, and PPARα. CONCLUSIONS This study showed that MOSE alleviates oxidative stress-induced cataract formation, and the mechanism of the effect is mainly related to its improvement of the endogenous antioxidant system in the lens.
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Affiliation(s)
- Lei Qi
- Department of Ophthalmology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361005 People’s Republic of China
| | - Yu Zhou
- Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Weijie Li
- Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Mali Zheng
- Department of Ophthalmology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361005 People’s Republic of China
| | - Ruisheng Zhong
- Department of Ophthalmology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361005 People’s Republic of China
| | - Xin Jin
- Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102 People’s Republic of China
| | - Yuan Lin
- Department of Ophthalmology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, 361005 People’s Republic of China
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Sonnay S, Chakrabarti A, Thevenet J, Wiederkehr A, Christinat N, Masoodi M. Differential Metabolism of Medium-Chain Fatty Acids in Differentiated Human-Induced Pluripotent Stem Cell-Derived Astrocytes. Front Physiol 2019; 10:657. [PMID: 31214043 PMCID: PMC6558201 DOI: 10.3389/fphys.2019.00657] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/09/2019] [Indexed: 12/23/2022] Open
Abstract
Medium-chain triglyceride (MCT) ketogenic diets increase ketone bodies, which are believed to act as alternative energy substrates in the injured brain. Octanoic (C8:0) and decanoic (C10:0) acids, which produce ketone bodies through β-oxidation, are used as part of MCT ketogenic diets. Although the ketogenic role of MCT is well-established, it remains unclear how the network metabolism underlying β-oxidation of these medium-chain fatty acids (MCFA) differ. We aim to elucidate basal β-oxidation of these commonly used MCFA at the cellular level. Human-induced pluripotent stem cell-derived (iPSC) astrocytes were incubated with [U-13C]-C8:0 or [U-13C]-C10:0, and the fractional enrichments (FE) of the derivatives were used for metabolic flux analysis. Data indicate higher extracellular concentrations and faster secretion rates of β-hydroxybutyrate (βHB) and acetoacetate (AcAc) with C8:0 than C10:0, and an important contribution from unlabeled substrates. Flux analysis indicates opposite direction of metabolic flux between the MCFA intermediates C6:0 and C8:0, with an important contribution of unlabeled sources to the elongation in the C10:0 condition, suggesting different β-oxidation pathways. Finally, larger intracellular glutathione concentrations and secretions of 3-OH-C10:0 and C6:0 were measured in C10:0-treated astrocytes. These findings reveal MCFA-specific ketogenic properties. Our results provide insights into designing different MCT-based ketogenic diets to target specific health benefits.
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Affiliation(s)
- Sarah Sonnay
- Lipid Metabolism, Nestlé Institute of Health Sciences, Lausanne, Switzerland
| | - Anirikh Chakrabarti
- Lipid Metabolism, Nestlé Institute of Health Sciences, Lausanne, Switzerland
| | - Jonathan Thevenet
- Mitochondrial Function, Nestlé Institute of Health Sciences, Lausanne, Switzerland
| | - Andreas Wiederkehr
- Mitochondrial Function, Nestlé Institute of Health Sciences, Lausanne, Switzerland
| | - Nicolas Christinat
- Lipid Metabolism, Nestlé Institute of Health Sciences, Lausanne, Switzerland
| | - Mojgan Masoodi
- Lipid Metabolism, Nestlé Institute of Health Sciences, Lausanne, Switzerland.,Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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21
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de Lima SLS, Gomes MJC, da Silva BP, Alves NEG, Toledo RCL, Theodoro JMV, Moreira MEDC, Bento JAC, Bassinello PZ, da Matta SLP, De Mejía EG, Martino HSD. Whole flour and protein hydrolysate from common beans reduce the inflammation in BALB/c mice fed with high fat high cholesterol diet. Food Res Int 2019; 122:330-339. [PMID: 31229086 DOI: 10.1016/j.foodres.2019.04.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/04/2019] [Accepted: 04/06/2019] [Indexed: 01/07/2023]
Abstract
Common bean (Phaseolus vulgaris L.) is a source of bioactive peptides, but little is known about its effects on hypercholesterolemia, oxidative stress, and the inflammatory process. Therefore, the aim of this study was to evaluate the effect of whole flour and bean protein hydrolysate of common bean variety Carioca on inflammation and oxidative stress in BALB/c mice. Four experimental groups were included in the study: standard diet (SD), high fat high cholesterol diet (HFC), high fat high cholesterol diet and whole bean flour (HFC-F); and high fat high cholesterol diet and bean protein hydrolysate (HFC-PH). Animals fed with bean protein hydrolysate showed lower weight gain and food intake. Animals fed with whole bean flour showed lower alanine aminotransferase and low-density lipoprotein cholesterol levels than animals fed with bean protein hydrolysate. SOD mRNA was lower in HFC, HFC-F and HFC-PH groups whereas SOD concentration was higher in HFC-F and HFC-PH groups. HSP72 mRNA expression was lower in the HFC-F group in relation to HFC-PH. IL-10 and PPARα mRNA expression was lower in HFC-F and HFC-PH groups in comparison with SD. The whole bean flour and bean protein hydrolysate reduced inflammation and the risk factors for cardiovascular diseases in BALB/c mice.
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Affiliation(s)
| | | | - Bárbara Pereira da Silva
- Department of Nutrition and Health, Federal University of Viçosa, Viçosa, Minas Gerais 36570000, Brazil
| | | | - Renata Celi Lopes Toledo
- Department of Nutrition and Health, Federal University of Viçosa, Viçosa, Minas Gerais 36570000, Brazil
| | | | | | | | - Priscila Zaczuk Bassinello
- Embrapa Rice and Bean, Rodovia GO-462, Km 12. Zona Rural, Santo Antônio de Goiás, Goiás 75375000, Brazil
| | | | - Elvira Gonzalez De Mejía
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign. 228 ERML, MC-051, 1201 West Gregory Drive, Urbana, IL 61801, USA
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22
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Brocker CN, Patel DP, Velenosi TJ, Kim D, Yan T, Yue J, Li G, Krausz KW, Gonzalez FJ. Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice. J Lipid Res 2018; 59:2140-2152. [PMID: 30158201 DOI: 10.1194/jlr.m088419] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/22/2018] [Indexed: 02/06/2023] Open
Abstract
PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT (Ppara +/+), total body Ppara-null (Ppara -/-), and hepatocyte-specific Ppara-null (Ppara ΔHep) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in Ppara ΔHep versus Ppara -/- mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in Ppara ΔHep mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in Ppara -/- mice. In Ppara ΔHep mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.
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Affiliation(s)
- Chad N Brocker
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Daxesh P Patel
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Thomas J Velenosi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Donghwan Kim
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Tingting Yan
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Jiang Yue
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Guolin Li
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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23
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Effect of caloric restriction and subsequent re-alimentation on oxidative stress in the liver of Hu sheep ram lambs. Anim Feed Sci Technol 2018. [DOI: 10.1016/j.anifeedsci.2018.01.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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24
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Henderson LE, Abdelmegeed MA, Yoo SH, Rhee SG, Zhu X, Smith MA, Nguyen RQ, Perry G, Song BJ. Enhanced Phosphorylation of Bax and Its Translocation into Mitochondria in the Brains of Individuals Affiliated with Alzheimer's Disease. Open Neurol J 2017; 11:48-58. [PMID: 29290835 PMCID: PMC5738752 DOI: 10.2174/1874205x01711010048] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 09/05/2017] [Accepted: 10/10/2017] [Indexed: 12/22/2022] Open
Abstract
Background: Despite increased neuronal death, senile plaques, and neurofibrillary tangles observed in patients suffering from Alzheimer’s disease (AD), the detailed mechanism of cell death in AD is still poorly understood. Method: We hypothesized that p38 kinase activates and then phosphorylates Bax, leading to its translocation to mitochondria in AD brains compared to controls. The aim of this study was to investigate the role of p38 kinase in phosphorylation and sub-cellular localization of pro-apoptotic Bax in the frontal cortex of the brains from AD and control subjects. Increased oxidative stress in AD individuals compared to control was evaluated by measuring the levels of carbonylated proteins and oxidized peroxiredoxin, an antioxidant enzyme. The relative amounts of p38 kinase and phospho-Bax in mitochondria in AD brains and controls were determined by immunoblot analysis using the respective antibody against each protein following immunoprecipitation. Results: Our results showed that the levels of oxidized peroxiredoxin-SO3 and carbonylated proteins are significantly elevated in AD brains compared to controls, demonstrating the increased oxidative stress. Conclusion: The amount of phospho-p38 kinase is increased in AD brains and the activated p38 kinase appears to phosphorylate Thr residue(s) of Bax, which leads to its mitochondrial translocation, contributing to apoptosis and ultimately, neurodegeneration.
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Affiliation(s)
- L E Henderson
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9410, USA
| | - M A Abdelmegeed
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9410, USA
| | - S H Yoo
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9410, USA
| | - S G Rhee
- Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
| | - X Zhu
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - M A Smith
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - R Q Nguyen
- Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA
| | - G Perry
- Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA
| | - B J Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9410, USA
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25
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Franklin MP, Sathyanarayan A, Mashek DG. Acyl-CoA Thioesterase 1 (ACOT1) Regulates PPARα to Couple Fatty Acid Flux With Oxidative Capacity During Fasting. Diabetes 2017; 66:2112-2123. [PMID: 28607105 PMCID: PMC5521868 DOI: 10.2337/db16-1519] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 05/17/2017] [Indexed: 12/18/2022]
Abstract
Hepatic acyl-CoA thioesterase 1 (ACOT1) catalyzes the conversion of acyl-CoAs to fatty acids (FAs) and CoA. We sought to determine the role of ACOT1 in hepatic lipid metabolism in C57Bl/6J male mice 1 week after adenovirus-mediated Acot1 knockdown. Acot1 knockdown reduced liver triglyceride (TG) as a result of enhanced TG hydrolysis and subsequent FA oxidation. In vitro experiments demonstrated that Acot1 knockdown led to greater TG turnover and FA oxidation, suggesting that ACOT1 is important for controlling the rate of FA oxidation. Despite increased FA oxidation, Acot1 knockdown reduced the expression of peroxisome proliferator-activated receptor α (PPARα) target genes, whereas overexpression increased PPARα reporter activity, suggesting ACOT1 regulates PPARα by producing FA ligands. Moreover, ACOT1 exhibited partial nuclear localization during fasting and cAMP/cAMP-dependent protein kinase signaling, suggesting local regulation of PPARα. As a consequence of increased FA oxidation and reduced PPARα activity, Acot1 knockdown enhanced hepatic oxidative stress and inflammation. The effects of Acot1 knockdown on PPARα activity, oxidative stress, and inflammation were rescued by supplementation with Wy-14643, a synthetic PPARα ligand. We demonstrate through these results that ACOT1 regulates fasting hepatic FA metabolism by balancing oxidative flux and capacity.
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Affiliation(s)
- Mallory P Franklin
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | | | - Douglas G Mashek
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN
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26
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Cipak Gasparovic A, Zarkovic N, Zarkovic K, Semen K, Kaminskyy D, Yelisyeyeva O, Bottari SP. Biomarkers of oxidative and nitro-oxidative stress: conventional and novel approaches. Br J Pharmacol 2017; 174:1771-1783. [PMID: 27864827 PMCID: PMC5446576 DOI: 10.1111/bph.13673] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 10/04/2016] [Accepted: 10/11/2016] [Indexed: 12/14/2022] Open
Abstract
The concept of oxidative stress (OS) that connects altered redox biology with various diseases was introduced 30 years ago and has generated intensive research over the past two decades. Whereas it is now commonly accepted that macromolecule oxidation in response to ROS is associated with a variety of pathologies, the emergence of NO as a key regulator of redox signalling has led to the discovery of the pathophysiological significance of reactive nitrogen species (RNS). RNS can elicit various modifications of macromolecules and lead to nitrative or nitro-OS. In order to investigate oxidative and nitro-OS in human and in live animal models, circulating biomarker assays have been developed. This article provides an overview of key biomarkers used to assess lipid peroxidation and NO/NO2 signalling, thereby stressing the necessity to analyse several OS biomarkers in relation to the overall (aerobic) metabolism and health condition of patients. In addition, the potential interest of heart rate variability as the non-invasive integrative biomarker of OS is discussed. LINKED ARTICLES This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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Affiliation(s)
| | | | - Kamelija Zarkovic
- Division of Pathology, Clinical Hospital Centre, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Khrystyna Semen
- Department of Propedeutics of Internal Medicine #2, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Danylo Kaminskyy
- Department of Pharmaceutical, Organic, and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Olha Yelisyeyeva
- Department of Histology, Cytology and Embryology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Serge P Bottari
- Institute for Advanced Biosciences, INSERM U1029, CNRS UMR 5309, Grenoble-Alps University Medical School, Grenoble, France
- Radioanalysis Laboratory, CHU Grenoble-Alpes, Grenoble, France
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27
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Choi Y, Abdelmegeed MA, Song BJ. Diet high in fructose promotes liver steatosis and hepatocyte apoptosis in C57BL/6J female mice: Role of disturbed lipid homeostasis and increased oxidative stress. Food Chem Toxicol 2017; 103:111-121. [PMID: 28257781 DOI: 10.1016/j.fct.2017.02.039] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/17/2017] [Accepted: 02/28/2017] [Indexed: 02/06/2023]
Abstract
The effects of high (H)-fructose (FR) diet (D) (HFRD) on hepatic lipid homeostasis, oxidative stress, inflammation and hepatocyte apoptosis were investigated in 6-week old female C57BL/6J mice fed a regular chow (ContD) or HFRD (35% fructose-derived calories) for 3 weeks. HFRD-fed mice exhibited increased levels of hepatic steatosis with a significant elevation of serum levels of triglyceride, cholesterol and TNFα compared to ContD-fed mice (P<0.05). HFRD-fed mice exhibited ∼2.7- fold higher levels FAS along with significantly decreased protein levels of adiponection-R2 (∼30%), P-AMPK (∼60%), P-ACC (∼70%) and RXR-α (∼55%), suggesting decreased hepatic fat oxidation compared to controls. Interestingly, hepatic fatty acid uptake into hepatocytes and lipolysis were significantly increased in HFRD-fed mice, as shown by decreased CD36 and fatty acid transporter protein-2, and increased adipose triglyceride lipase, respectively (P<0.05). Increased hepatic levels of iNOS and GSSG/GSH suggest elevated oxidative stress with a higher number of macrophages in the adipose tissue in HFRD-fed mice (P<0.05). Significantly elevated rates of hepatocyte apoptosis (∼2.4-fold), as determined by TUNEL analysis with increased Bax/Bcl2 ratio and PARP-1 levels (∼2- and 1.5-fold, respectively), were observed in HFRD-fed mice. Thus, HFRD exposure increased hepatic steatosis accompanied by oxidative stress and inflammation, leading to hepatocyte apoptosis.
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Affiliation(s)
- Youngshim Choi
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Mohamed A Abdelmegeed
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
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28
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Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment. Antimicrob Agents Chemother 2016; 60:5285-93. [PMID: 27324775 DOI: 10.1128/aac.00854-16] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 06/11/2016] [Indexed: 12/22/2022] Open
Abstract
Isoniazid (INH) remains the core drug in tuberculosis management, but serious hepatotoxicity and potentially fatal liver injury continue to accompany INH consumption. Among numerous theories that have been established to explain INH-induced liver injury, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. Inflammatory stress usually sensitizes tissues to a drug's toxic consequences. Therefore, the present study was conducted to verify whether bacterial lipopolysaccharide (LPS)-induced inflammation may have a role in enhancing INH hepatotoxicity. While single INH or LPS administration showed no major toxicity signs, INH-LPS cotreatment intensified liver toxicity. Both blood biomarkers and histological evaluations clearly showed positive signs of severe liver damage accompanied by massive necrosis, inflammatory infiltration, and hepatic steatosis. Furthermore, elevated serum levels of bile acid associated with the repression of bile acid synthesis and transport regulatory parameters were observed. Moreover, the principal impact of cytochrome P450 2E1 (CYP2E1) on INH toxicity could be anticipated, as its protein expression showed enormous increases in INH-LPS-cotreated animals. Furthermore, the crucial role of CYP2E1 in the production of reactive oxygen species (ROS) was clearly obvious in the repression of hepatic antioxidant parameters. In summary, these results confirmed that this LPS-induced inflammation model might prove valuable in revealing the hepatotoxic mechanisms of INH and the crucial role played by CYP2E1 in the initiation and propagation of INH-induced liver damage, information which could be very useful to clinicians in understanding the pathogenesis of drug-induced liver injury.
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Kuwata K, Inoue K, Ichimura R, Takahashi M, Kodama Y, Shibutani M, Yoshida M. Involvement of Mouse Constitutive Androstane Receptor in Acifluorfen-Induced Liver Injury and Subsequent Tumor Development. Toxicol Sci 2016; 151:271-85. [DOI: 10.1093/toxsci/kfw040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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Abdelmegeed MA, Choi Y, Ha SK, Song BJ. Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress. Free Radic Biol Med 2016; 91:188-202. [PMID: 26703967 PMCID: PMC4761508 DOI: 10.1016/j.freeradbiomed.2015.12.016] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 12/10/2015] [Accepted: 12/14/2015] [Indexed: 12/19/2022]
Abstract
The role of ethanol-inducible cytochrome P450-2E1 (CYP2E1) in promoting aging-dependent hepatic disease is unknown and thus was investigated in this study. Young (7 weeks) and aged female (16 months old) wild-type (WT) and Cyp2e1-null mice were used in this study to evaluate age-dependent changes in liver histology, steatosis, apoptosis, fibrosis and many nitroxidative stress parameters. Liver histology showed that aged WT mice exhibited markedly elevated hepatocyte vacuolation, ballooning degeneration, and inflammatory cell infiltration compared to all other groups. These changes were accompanied with significantly higher hepatic triglyceride and serum cholesterol in aged WT mice although serum ALT and insulin resistance were not significantly altered. Aged WT mice showed the highest rates of hepatocyte apoptosis and hepatic fibrosis. Further, the highest levels of hepatic hydrogen peroxide, lipid peroxidation, protein carbonylation, nitration, and oxidative DNA damage were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of mitochondrial nitroxidative stress and alteration of mitochondrial complex III and IV proteins in aged WT mice, although hepatic ATP levels seems to be unchanged. In contrast, the aging-related nitroxidative changes were very low in aged Cyp2e1-null mice. These results suggest that CYP2E1 is important in causing aging-dependent hepatic steatosis, apoptosis and fibrosis possibly through increasing nitroxidative stress and that CYP2E1 could be a potential target for translational research in preventing aging-related liver disease.
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Affiliation(s)
- Mohamed A Abdelmegeed
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Youngshim Choi
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Seung-Kwon Ha
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
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31
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Naquet P, Giessner C, Galland F. Metabolic adaptation of tissues to stress releases metabolites influencing innate immunity. Curr Opin Immunol 2015; 38:30-8. [PMID: 26605965 DOI: 10.1016/j.coi.2015.10.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 10/03/2015] [Accepted: 10/21/2015] [Indexed: 12/11/2022]
Abstract
Recent developments have demonstrated that metabolic rewiring imposed by adaptation of tissues to stress leads to the release of various metabolites which directly or indirectly impact innate immune responses and inflammation. Some metabolites can behave as second messengers and leave local cues in tissues. Immune cells which infiltrate stressed tissues reorient their metabolism to cope with these microenvironmental cues while preserving their effector functions in tissues.
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Affiliation(s)
- Philippe Naquet
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France.
| | - Caroline Giessner
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France
| | - Franck Galland
- Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France
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Pantazi E, Folch-Puy E, Bejaoui M, Panisello A, Varela AT, Rolo AP, Palmeira CM, Roselló-Catafau J. PPARα Agonist WY-14643 Induces SIRT1 Activity in Rat Fatty Liver Ischemia-Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2015; 2015:894679. [PMID: 26539534 PMCID: PMC4619850 DOI: 10.1155/2015/894679] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 08/11/2015] [Indexed: 01/16/2023]
Abstract
Ischemia-reperfusion injury (IRI) remains a frequent complication in surgery, especially in case of steatotic livers that present decreased tolerance towards IRI. Apart from its major role in metabolism, activation of peroxisome proliferator-activated receptor α (PPARα) has been related with positive effects on IRI. In addition, the deacetylase enzyme sirtuin 1 (SIRT1) has recently emerged as a promising target for preventing IRI, through its interaction with stress-related mechanisms, such as endoplasmic reticulum stress (ERS). Taking this into account, this study aims to explore whether PPARα agonist WY-14643 could protect steatotic livers against IRI through sirtuins and ERS signaling pathway. Obese Zucker rats were pretreated or not pretreated with WY-14643 (10 mg/kg intravenously) and then submitted to partial (70%) hepatic ischemia (1 hour) followed by 24 hours of reperfusion. Liver injury (ALT levels), lipid peroxidation (MDA), SIRT1 activity, and the protein expression of SIRT1 and SIRT3 and ERS parameters (IRE1α, peIF2, caspase 12, and CHOP) were evaluated. Treatment with WY-14643 reduced liver injury in fatty livers, enhanced SIRT1 activity, and prevented ERS. Together, our results indicated that PPARα agonist WY-14643 may exert its protective effect in fatty livers, at least in part, via SIRT1 induction and ERS prevention.
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Affiliation(s)
- Eirini Pantazi
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Emma Folch-Puy
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Mohamed Bejaoui
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Arnau Panisello
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
| | - Ana Teresa Varela
- Department of Life Sciences and Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
| | | | - Carlos Marques Palmeira
- Department of Life Sciences and Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
| | - Joan Roselló-Catafau
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB-CSIC), IDIBAPS, Barcelona, 08036 Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, 08036 Catalonia, Spain
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Choi BK, Kim TW, Lee DR, Jung WH, Lim JH, Jung JY, Yang SH, Suh JW. A polymethoxy flavonoids-rich Citrus aurantium
extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model. Phytother Res 2015; 29:1577-84. [DOI: 10.1002/ptr.5415] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 06/01/2015] [Accepted: 06/18/2015] [Indexed: 12/20/2022]
Affiliation(s)
- Bong-Keun Choi
- NutraPham Tech; Giheung-gu, Yongin Gyeonggi 446-916 Korea
| | - Tae-Won Kim
- College of Veterinary Medicine and Institute of Veterinary Science; Chungnam National University; Yusung-gu Daejeon 305-764 Republic of Korea
| | - Dong-Ryung Lee
- NutraPham Tech; Giheung-gu, Yongin Gyeonggi 446-916 Korea
| | - Woon-Ha Jung
- College of Veterinary Medicine and Institute of Veterinary Science; Chungnam National University; Yusung-gu Daejeon 305-764 Republic of Korea
| | - Jong-Hwan Lim
- Center for Nutraceutical and Pharmaceutical Materials; Myongji University; Yongin Gyeonggi 449-728 Republic of Korea
| | - Ju-Young Jung
- College of Veterinary Medicine and Institute of Veterinary Science; Chungnam National University; Yusung-gu Daejeon 305-764 Republic of Korea
| | - Seung Hwan Yang
- Center for Nutraceutical and Pharmaceutical Materials; Myongji University; Yongin Gyeonggi 449-728 Republic of Korea
| | - Joo-Won Suh
- Center for Nutraceutical and Pharmaceutical Materials; Myongji University; Yongin Gyeonggi 449-728 Republic of Korea
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Hrycay EG, Bandiera SM. Involvement of Cytochrome P450 in Reactive Oxygen Species Formation and Cancer. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2015; 74:35-84. [PMID: 26233903 DOI: 10.1016/bs.apha.2015.03.003] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This review examines the involvement of cytochrome P450 (CYP) enzymes in the formation of reactive oxygen species in biological systems and discusses the possible involvement of reactive oxygen species and CYP enzymes in cancer. Reactive oxygen species are formed in biological systems as byproducts of the reduction of molecular oxygen and include the superoxide radical anion (∙O2-), hydrogen peroxide (H2O2), hydroxyl radical (∙OH), hydroperoxyl radical (HOO∙), singlet oxygen ((1)O2), and peroxyl radical (ROO∙). Two endogenous sources of reactive oxygen species are the mammalian CYP-dependent microsomal electron transport system and the mitochondrial electron transport chain. CYP enzymes catalyze the oxygenation of an organic substrate and the simultaneous reduction of molecular oxygen. If the transfer of oxygen to a substrate is not tightly controlled, uncoupling occurs and leads to the formation of reactive oxygen species. Reactive oxygen species are capable of causing oxidative damage to cellular membranes and macromolecules that can lead to the development of human diseases such as cancer. In normal cells, intracellular levels of reactive oxygen species are maintained in balance with intracellular biochemical antioxidants to prevent cellular damage. Oxidative stress occurs when this critical balance is disrupted. Topics covered in this review include the role of reactive oxygen species in intracellular cell signaling and the relationship between CYP enzymes and cancer. Outlines of CYP expression in neoplastic tissues, CYP enzyme polymorphism and cancer risk, CYP enzymes in cancer therapy and the metabolic activation of chemical procarcinogens by CYP enzymes are also provided.
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Affiliation(s)
- Eugene G Hrycay
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
| | - Stelvio M Bandiera
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
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35
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Soliman MM, Attia HF, El-Ella GAA. Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil. Int J Immunopathol Pharmacol 2015; 28:508-20. [DOI: 10.1177/0394632015575950] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 12/02/2014] [Indexed: 01/12/2023] Open
Abstract
Pesticides are widespread synthesized substances used for public health protection and agricultural programs. However, they cause environmental pollution and health hazards. This study aimed to examine the protective effects of sesame oil (SO) on the genetic alterations induced by cypermethrin (CYP) in the liver and kidney of Wistar rats. Male rats were divided into four groups, each containing 10 rats: the control group received vehicle, SO group (5 mL/kg b.w), CYP group (12 mg/kg b.w), and protective group received SO (5 mL/kg b.w) plus CYP (12 mg/kg b.w). Biochemical analysis showed an increase in albumin, urea, creatinine, GPT, GOT, and lipid profiles in the CYP group. Co-administration of SO with CYP normalized such biochemical changes. CYP administration decreased both the activity and mRNA expression of the examined antioxidants. SO co-administration recovered CYP, downregulating the expression of glutathione-S-transferase (GST), catalase, and superoxide dismutase. Additionally, SO co-administration with CYP counteracted the CYP- altering the expression of renal interleukins (IL-1 and IL-6), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), anigotensinogen (AGT), AGT receptors (AT1), and genes of hepatic glucose and fatty acids metabolism. CYP induced degenerative changes in the kidney and liver histology which are ameliorated by SO. In conclusion, SO has a protective effect against alterations and pathological changes induced by CYP in the liver and kidney at genetic and histological levels.
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Affiliation(s)
- Mohamed Mohamed Soliman
- Medical Laboratory Department, Faculty of Applied Medical Sciences, Turabah, Taif University, Taif, Saudi Arabia
- Department of Biochemistry, Faculty of Veterinary Medicine, Benha University, Qalyubia, Egypt
| | - Hossam F Attia
- Medical Laboratory Department, Faculty of Applied Medical Sciences, Turabah, Taif University, Taif, Saudi Arabia
- Department of Histology, Faculty of Veterinary Medicine, Benha University, Qalyubia, Egypt
| | - Ghada A Abou El-Ella
- Clinical Laboratory Diagnosis, Department of Animal Medicine, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
- Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Mecca, Saudi Arabia
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36
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Kim JY, Lee DY, Lee YJ, Park KJ, Kim KH, Kim JW, Kim WH. Chronic alcohol consumption potentiates the development of diabetes through pancreatic β-cell dysfunction. World J Biol Chem 2015; 6:1-15. [PMID: 25717351 PMCID: PMC4317634 DOI: 10.4331/wjbc.v6.i1.1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 10/29/2014] [Accepted: 12/10/2014] [Indexed: 02/05/2023] Open
Abstract
Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic β-cell and the exact mechanisms associated with ethanol-mediated β-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic β-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic β-cell dysfunction and metabolic syndrome.
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Yun JW, Son MJ, Abdelmegeed MA, Banerjee A, Morgan TR, Yoo SH, Song BJ. Binge alcohol promotes hypoxic liver injury through a CYP2E1-HIF-1α-dependent apoptosis pathway in mice and humans. Free Radic Biol Med 2014; 77:183-94. [PMID: 25236742 PMCID: PMC4304203 DOI: 10.1016/j.freeradbiomed.2014.08.030] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 08/27/2014] [Accepted: 08/28/2014] [Indexed: 12/11/2022]
Abstract
Binge drinking, a common pattern of alcohol ingestion, is known to potentiate liver injury caused by chronic alcohol abuse. This study was aimed at investigating the effects of acute binge alcohol on hypoxia-inducible factor-1α (HIF-1α)-mediated liver injury and the roles of alcohol-metabolizing enzymes in alcohol-induced hypoxia and hepatotoxicity. Mice and human specimens assigned to binge or nonbinge groups were analyzed for blood alcohol concentration (BAC), alcohol-metabolizing enzymes, HIF-1α-related protein nitration, and apoptosis. Binge alcohol promoted acute liver injury in mice with elevated levels of ethanol-inducible cytochrome P450 2E1 (CYP2E1) and hypoxia, both of which were colocalized in the centrilobular areas. We observed positive correlations among elevated BAC, CYP2E1, and HIF-1α in mice and humans exposed to binge alcohol. The CYP2E1 protein levels (r = 0.629, p = 0.001) and activity (r = 0.641, p = 0.001) showed a significantly positive correlation with BAC in human livers. HIF-1α levels were also positively correlated with BAC (r = 0.745, p < 0.001) or CYP2E1 activity (r = 0.792, p < 0.001) in humans. Binge alcohol promoted protein nitration and apoptosis with significant correlations observed between inducible nitric oxide synthase and BAC, CYP2E1, or HIF-1α in human specimens. Binge-alcohol-induced HIF-1α activation and subsequent protein nitration or apoptosis seen in wild type were significantly alleviated in the corresponding Cyp2e1-null mice, whereas pretreatment with an HIF-1α inhibitor, PX-478, prevented HIF-1α elevation with a trend of decreased levels of 3-nitrotyrosine and apoptosis, supporting the roles of CYP2E1 and HIF-1α in binge-alcohol-mediated protein nitration and hepatotoxicity. Thus binge alcohol promotes acute liver injury in mice and humans at least partly through a CYP2E1-HIF-1α-dependent apoptosis pathway.
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Affiliation(s)
- Jun-Won Yun
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Min-Jeong Son
- Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Mohamed A Abdelmegeed
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Atrayee Banerjee
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Timothy R Morgan
- Gastroenterology Service, Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, USA; Division of Gastroenterology, University of California at Irvine, Irvine, CA 92697, USA
| | - Seong-Ho Yoo
- Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea.
| | - Byoung-Joon Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
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38
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Alleman RJ, Katunga LA, Nelson MAM, Brown DA, Anderson EJ. The "Goldilocks Zone" from a redox perspective-Adaptive vs. deleterious responses to oxidative stress in striated muscle. Front Physiol 2014; 5:358. [PMID: 25278906 PMCID: PMC4166897 DOI: 10.3389/fphys.2014.00358] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 09/02/2014] [Indexed: 01/17/2023] Open
Abstract
Consequences of oxidative stress may be beneficial or detrimental in physiological systems. An organ system's position on the “hormetic curve” is governed by the source and temporality of reactive oxygen species (ROS) production, proximity of ROS to moieties most susceptible to damage, and the capacity of the endogenous cellular ROS scavenging mechanisms. Most importantly, the resilience of the tissue (the capacity to recover from damage) is a decisive factor, and this is reflected in the disparate response to ROS in cardiac and skeletal muscle. In myocytes, a high oxidative capacity invariably results in a significant ROS burden which in homeostasis, is rapidly neutralized by the robust antioxidant network. The up-regulation of key pathways in the antioxidant network is a central component of the hormetic response to ROS. Despite such adaptations, persistent oxidative stress over an extended time-frame (e.g., months to years) inevitably leads to cumulative damages, maladaptation and ultimately the pathogenesis of chronic diseases. Indeed, persistent oxidative stress in heart and skeletal muscle has been repeatedly demonstrated to have causal roles in the etiology of heart disease and insulin resistance, respectively. Deciphering the mechanisms that underlie the divergence between adaptive and maladaptive responses to oxidative stress remains an active area of research for basic scientists and clinicians alike, as this would undoubtedly lead to novel therapeutic approaches. Here, we provide an overview of major types of ROS in striated muscle and the divergent adaptations that occur in response to them. Emphasis is placed on highlighting newly uncovered areas of research on this topic, with particular focus on the mitochondria, and the diverging roles that ROS play in muscle health (e.g., exercise or preconditioning) and disease (e.g., cardiomyopathy, ischemia, metabolic syndrome).
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Affiliation(s)
- Rick J Alleman
- Departments of Physiology, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA
| | - Lalage A Katunga
- East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA ; Pharmacology and Toxicology, Brody School of Medicine, East Carolina University Greenville, NC, USA
| | - Margaret A M Nelson
- East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA ; Pharmacology and Toxicology, Brody School of Medicine, East Carolina University Greenville, NC, USA
| | - David A Brown
- Departments of Physiology, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA
| | - Ethan J Anderson
- East Carolina Diabetes and Obesity Institute, East Carolina University Greenville, NC, USA ; Pharmacology and Toxicology, Brody School of Medicine, East Carolina University Greenville, NC, USA
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Wang W, Wang C, Ding XQ, Pan Y, Gu TT, Wang MX, Liu YL, Wang FM, Wang SJ, Kong LD. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol 2014; 169:1352-71. [PMID: 23647015 DOI: 10.1111/bph.12226] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2012] [Revised: 02/21/2013] [Accepted: 04/11/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND AND PURPOSE Thioredoxin-interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD-like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes-associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP. EXPERIMENTAL APPROACH Diabetes was induced in male Sprague-Dawley rats by a single i.p. injection of 55 mg · kg⁻¹ streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL-3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase-1 inhibitor, Ac-YVAD-CMK. KEY RESULTS Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down-regulation of PPARα and up-regulation of sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL-1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down-regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs. CONCLUSIONS AND IMPLICATIONS Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes-associated NAFLD.
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Affiliation(s)
- Wei Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
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Nan YM, Wang RQ, Fu N. Peroxisome proliferator-activated receptor α, a potential therapeutic target for alcoholic liver disease. World J Gastroenterol 2014; 20:8055-8060. [PMID: 25009377 PMCID: PMC4081676 DOI: 10.3748/wjg.v20.i25.8055] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/02/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease.
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41
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Kulkarni SR, Donepudi AC, Xu J, Wei W, Cheng QC, Driscoll MV, Johnson DA, Johnson JA, Li X, Slitt AL. Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human. Antioxid Redox Signal 2014; 20:15-30. [PMID: 23725046 PMCID: PMC3880903 DOI: 10.1089/ars.2012.5082] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIMS The purpose of this study was to determine whether 3'-5'-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) dependent mechanisms modulate ATP-binding Cassette (ABC) transport protein expression. ABC transport proteins (ABCC2-4) are essential for chemical elimination from hepatocytes and biliary excretion. Nuclear factor-E2 related-factor 2 (NRF2) is a transcription factor that mediates ABCC induction in response to chemical inducers and liver injury. However, a role for NRF2 in the regulation of transporter expression in nonchemical models of liver perturbation is largely undescribed. RESULTS Here we show that fasting increased NRF2 target gene expression through NRF2- and SIRT1-dependent mechanisms. In intact mouse liver, fasting induces NRF2 target gene expression by at least 1.5 to 5-fold. In mouse and human hepatocytes, treatment with 8-Bromoadenosine-cAMP, a cAMP analogue, increased NRF2 target gene expression and antioxidant response element activity, which was decreased by the PKA inhibitor, H-89. Moreover, fasting induced NRF2 target gene expression was decreased in liver and hepatocytes of SIRT1 liver-specific null mice and NRF2-null mice. Lastly, NRF2 and SIRT1 were recruited to MAREs and Antioxidant Response Elements (AREs) in the human ABCC2 promoter. INNOVATION Oxidative stress mediated NRF2 activation is well described, yet the influence of basic metabolic processes on NRF2 activation is just emerging. CONCLUSION The current data point toward a novel role of nutrient status in regulation of NRF2 activity and the antioxidant response, and indicates that cAMP/PKA and SIRT1 are upstream regulators for fasting-induced activation of the NRF2-ARE pathway.
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Affiliation(s)
- Supriya R Kulkarni
- 1 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island , Kingston, Rhode Island
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Abdelmegeed MA, Banerjee A, Jang S, Yoo SH, Yun JW, Gonzalez FJ, Keshavarzian A, Song BJ. CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. Free Radic Biol Med 2013; 65:1238-1245. [PMID: 24064383 PMCID: PMC3859835 DOI: 10.1016/j.freeradbiomed.2013.09.009] [Citation(s) in RCA: 163] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 09/12/2013] [Accepted: 09/17/2013] [Indexed: 02/07/2023]
Abstract
Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK, and peroxisome proliferator-activated receptor-α, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis.
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Affiliation(s)
- Mohamed A Abdelmegeed
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Atrayee Banerjee
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Sehwan Jang
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Seong-Ho Yoo
- Department of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Jun-Won Yun
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ali Keshavarzian
- Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Byoung-Joon Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
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Serviddio G, Bellanti F, Vendemiale G. Free radical biology for medicine: learning from nonalcoholic fatty liver disease. Free Radic Biol Med 2013; 65:952-968. [PMID: 23994574 DOI: 10.1016/j.freeradbiomed.2013.08.174] [Citation(s) in RCA: 204] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 08/20/2013] [Accepted: 08/20/2013] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species, when released under controlled conditions and limited amounts, contribute to cellular proliferation, senescence, and survival by acting as signaling intermediates. In past decades there has been an epidemic diffusion of nonalcoholic fatty liver disease (NAFLD) that represents the result of the impairment of lipid metabolism, redox imbalance, and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the processes leading toward the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) α/γ/δ, PPARγ coactivators 1α and 1β, sterol-regulatory element-binding proteins, AMP-activated protein kinase, liver-X-receptors, and farnesoid-X-receptor, play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate various metabolic pathways in response to specific molecules that act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to metabolism alterations in fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.
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Affiliation(s)
- Gaetano Serviddio
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy.
| | - Francesco Bellanti
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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Periasamy S, Chien SP, Chang PC, Hsu DZ, Liu MY. Sesame oil mitigates nutritional steatohepatitis via attenuation of oxidative stress and inflammation: a tale of two-hit hypothesis. J Nutr Biochem 2013; 25:232-40. [PMID: 24445049 DOI: 10.1016/j.jnutbio.2013.10.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 10/16/2013] [Accepted: 10/22/2013] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease, the most common chronic liver disorder worldwide, comprises conditions from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is associated with an increased risk of hepatocellular carcinoma. Sesame oil, a healthful food, increases resistance to oxidative stress, inflammation and protects against multiple organ injury in various animal models. We investigated the protective effect of sesame oil against nutritional steatohepatitis in mice. C57BL/6 J mice were fed with methionine-choline deficient (MCD) diet for 28 days to induce NASH. Sesame oil (1 and 2 ml/kg) was treated from 22nd to 28th day. Body weight, steatosis, triglycerides, aspartate transaminase, alanine transaminase, nitric oxide, malondialdehyde, tumor necrosis factor-α, interlukin-6, interleukin-1β, leptin, and transforming growth factor-β1 (TGF-β1) were assessed after 28 days. All tested parameters were higher in MCD-fed mice than in normal control mice. Mice fed with MCD diet for 4 weeks showed severe liver injury with steatosis, oxidative stress, and necrotic inflammation. In sesame-oil-treated mice, all tested parameters were significantly attenuated compared with MCD-alone mice. Sesame oil inhibited oxidative stress, inflammatory cytokines, leptin, and TGF-β1 in MCD-fed mice. In addition, histological analysis showed that sesame oil provided significant protection against fibrotic collagen. We conclude that sesame oil protects against steatohepatitic fibrosis by decreasing oxidative stress, inflammatory cytokines, leptin and TGF-β1.
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Affiliation(s)
- Srinivasan Periasamy
- Department of Environmental and Occupational Health, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan
| | - Se-Ping Chien
- Department of Living Science, Tainan University of Technology, Tainan 71002, Taiwan
| | - Po-Cheng Chang
- Department of Environmental and Occupational Health, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan
| | - Dur-Zong Hsu
- Department of Environmental and Occupational Health, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan.
| | - Ming-Yie Liu
- Department of Environmental and Occupational Health, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan.
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45
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Banerjee A, Abdelmegeed MA, Jang S, Song BJ. Zidovudine (AZT) and hepatic lipid accumulation: implication of inflammation, oxidative and endoplasmic reticulum stress mediators. PLoS One 2013; 8:e76850. [PMID: 24146933 PMCID: PMC3795627 DOI: 10.1371/journal.pone.0076850] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 09/05/2013] [Indexed: 12/20/2022] Open
Abstract
The clinical effectiveness of Zidovudine (AZT) is constrained due to its side-effects including hepatic steatosis and toxicity. However, the mechanism(s) of hepatic lipid accumulation in AZT-treated individuals is unknown. We hypothesized that AZT-mediated oxidative and endoplasmic reticulum (ER) stress may play a role in the AZT-induced hepatic lipid accumulation. AZT treatment of C57BL/6J female mice (400 mg/day/kg body weight, i.p.) for 10 consecutive days significantly increased hepatic triglyceride levels and inflammation. Markers of oxidative stress such as protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT-treated mice compared to vehicle controls. Further, the levels of ER stress marker proteins like GRP78, p-PERK, and p-eIF2α were significantly elevated in AZT-treated mice. The level of nuclear SREBP-1c, a transcription factor involved in fat synthesis, was increased while significantly decreased protein levels of phospho-acetyl-CoA carboxylase, phospho-AMP kinase and PPARα as well as inactivation of 3-keto-acyl-CoA thiolase in the mitochondrial fatty acid β-oxidation pathway were observed in AZT-exposed mice compared to those in control animals. Collectively, these data suggest that elevated oxidative and ER stress plays a key role, at least partially, in lipid accumulation, inflammation and hepatotoxicity in AZT-treated mice.
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Affiliation(s)
- Atrayee Banerjee
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, United States of America
| | - Mohamed A. Abdelmegeed
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, United States of America
| | - Sehwan Jang
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, United States of America
| | - Byoung-Joon Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, United States of America
- * E-mail:
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Mladenović D, Ninković M, Aleksić V, Šljivančanin T, Vučević D, Todorović V, Stanković M, Stanojlović O, Radosavljević T. The effect of calorie restriction on acute ethanol-induced oxidative and nitrosative liver injury in rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2013; 36:296-302. [PMID: 23686010 DOI: 10.1016/j.etap.2013.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Revised: 04/09/2013] [Accepted: 04/10/2013] [Indexed: 02/05/2023]
Abstract
The aim of our study was to examine the effect of calorie restriction (CR) on oxidative and nitrosative liver injury in rats, induced by acute ethanol intoxication. Male Wistar rats were divided into groups: (1) control; (2) calorie-restricted groups with intake of 60-70% (CR60-70) and 40-50% of daily energy needs (CR40-50); (3) ethanol-treated group (E); (4) calorie-restricted, ethanol-treated groups (E+CR60-70 and E+CR40-50). Ethanol was administered in 5 doses of 2g/kg every 12h, and duration of CR was 5 weeks before ethanol treatment. Malondialdehyde and nitrite and nitrate level were significantly lower in E+CR60-70 and higher in E+CR40-50 vs. E group. Liver reduced glutathione content and activity of both superoxide dismutase izoenzymes were significantly higher in E+CR60-70 and lower in E+CR40-50 vs. E group. Oxidative stress may be a potential mechanism of hormetic effects of CR on acute ethanol-induced liver injury.
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Affiliation(s)
- Dušan Mladenović
- Institute of Pathophysiology, "Ljubodrag Buba Mihailović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milica Ninković
- Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
| | - Vuk Aleksić
- Institute of Pathophysiology, "Ljubodrag Buba Mihailović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Tamara Šljivančanin
- Clinics of Gynecology and Obstetrics, "Narodni front", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Danijela Vučević
- Institute of Pathophysiology, "Ljubodrag Buba Mihailović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vera Todorović
- Faculty of Dentistry,Pančevo, University of Business Economy, Novi Sad, Serbia
| | - Milena Stanković
- Institute of Pathophysiology, "Ljubodrag Buba Mihailović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Olivera Stanojlović
- Institute of Medical Physiology, "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Tatjana Radosavljević
- Institute of Pathophysiology, "Ljubodrag Buba Mihailović", Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
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47
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Stahlschmidt ZR, Lourdais O, Lorioux S, Butler MW, Davis JR, Salin K, Voituron Y, DeNardo DF. Morphological and Physiological Changes during Reproduction and Their Relationships to Reproductive Performance in a Capital Breeder. Physiol Biochem Zool 2013; 86:398-409. [DOI: 10.1086/670918] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Abdelmegeed MA, Jang S, Banerjee A, Hardwick JP, Song BJ. Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury. Free Radic Biol Med 2013; 60:211-22. [PMID: 23454065 PMCID: PMC3680365 DOI: 10.1016/j.freeradbiomed.2013.02.018] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 02/12/2013] [Accepted: 02/15/2013] [Indexed: 12/31/2022]
Abstract
Acetaminophen (APAP), a widely used analgesic/antipyretic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an antioxidant, N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2h in mice exposed to a single APAP dose (350mg/kg ip), which caused severe liver necrosis at 24h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3-hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins, including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase, involved in antioxidant defense, energy supply, or fatty acid metabolism. Immunoprecipitation followed by immunoblot with anti-3-nitrotyrosine antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-cotreated mice. Consistently, NAC cotreatment significantly restored the suppressed activity of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activity promotes APAP-induced mitochondrial dysfunction and hepatotoxicity.
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Affiliation(s)
- Mohamed A. Abdelmegeed
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Sehwan Jang
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Atrayee Banerjee
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - James P. Hardwick
- Department of Integrative Medicine, Northeastern Ohio University College of Medicine, Rootstown, OH, USA
| | - Byoung-Joon Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
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49
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Wen B, Li D, Shan J, Liu S, Li W, Zhao Y, Lin P, Zheng J, Li D, Gong Y, Yan C. Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation. Mol Genet Metab 2013; 109:154-60. [PMID: 23628458 DOI: 10.1016/j.ymgme.2013.04.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 04/04/2013] [Indexed: 11/30/2022]
Abstract
Multiple acyl-coenzyme A dehydrogenation deficiency (MADD) has a wide range of phenotypic variation ranging from a neonatal lethal form to a mild late-onset form. Our previous data showed that in a group of Chinese patients, a mild type of MADD characterized by myopathy with clinically no other systemic involvement was caused by mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene, which encodes electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO). Coenzyme Q10 (CoQ10), a downstream electron receptor of ETF:QO was first reported deficient in muscle of MADD patients with ETFDH gene mutations. Nevertheless, this result was not confirmed in a recently published study. Therefore to elucidate muscle CoQ10 level in a large group of MADD patients may provide further insight into the pathomechanism and therapeutic strategies. In this study, we found that 34 riboflavin responsive patients with ETFDH gene mutations had an elevated CoQ10 pool in muscle by high performance liquid chromatography (HPLC). However, when CoQ10 levels were normalized to citrate synthase, a marker of mitochondrial mass, there was no significant difference between patients and normal controls. Meanwhile, the increased mitochondrial DNA copy number in muscle also supported that the elevated CoQ10 pool was mainly due to mitochondrial mass proliferation. The expression of CoQ10 biosynthesis genes showed no significant changes whereas genes involved in lipid metabolism, such as PPARα, were marked up regulated. Our results suggested that CoQ10 seems not to be a primary factor in riboflavin responsive MADD and the apparent increase in CoQ10 may be secondary to mitochondrial proliferation.
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Affiliation(s)
- Bing Wen
- Laboratory of Neuromuscular Disorders, Brain Science Research Institute and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China
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50
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Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:781050. [PMID: 23691267 PMCID: PMC3649774 DOI: 10.1155/2013/781050] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 02/27/2013] [Indexed: 12/15/2022]
Abstract
Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins. Persistent mitochondrial dysfunction sensitizes the target cells/organs to other pathological risk factors and thus ultimately contributes to the development of more severe disease states in alcoholic and nonalcoholic fatty liver disease. The incidences of nonalcoholic fatty liver disease continuously increase due to high prevalence of metabolic syndrome including hyperlipidemia, hypercholesterolemia, obesity, insulin resistance, and diabetes. Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (including S-nitrosylation/nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion. To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease. The aims of this paper are to briefly describe the mechanisms, functional consequences, and detection methods of mitochondrial dysfunction. We also describe advantages and limitations of the Cys-targeted redox proteomics method with alternative approaches. Finally, we discuss various applications of this method in studying oxidatively modified mitochondrial proteins in extrahepatic tissues or different subcellular organelles and translational research.
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