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Bernal S, Prieto I, Kavanagh M, Del Real IH, La Manna S, Lázaro I, Quiceno H, López-Sanz L, Picatoste B, Valdecantos MP, Mas-Fontao S, Sala-Vila A, Valverde ÁM, Marasco D, Egido J, Gómez-Guerrero C. Development of SOCS1 mimetics as novel approach to harmonize inflammation, oxidative stress, and fibrogenesis in metabolic dysfunction-associated steatotic liver disease. Redox Biol 2025; 84:103670. [PMID: 40373621 DOI: 10.1016/j.redox.2025.103670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 04/28/2025] [Accepted: 05/10/2025] [Indexed: 05/17/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, encompassing a spectrum from simple steatosis to steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. As part of metabolic syndrome, MASLD/MASH is characterized by inflammation, oxidative stress, and fibrosis, highlighting the need for targeted therapies. The dysregulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and its negative regulators the suppressors of cytokine signaling (SOCS), plays a critical role in liver function and contributes to MASLD progression. AIM Based on a SOCS1 functional domain, we developed mimetic peptides (linear and cyclic) targeting JAK activity and assessed their hepatoprotective potential in experimental MASLD/MASH. RESULTS In dietary mouse models of MASLD/MASH, the administration of peptides ameliorated liver damage at both early and advanced stages, as evidenced by significant decreases in serum transaminases and hepatic content of lipids, inflammatory cells, and collagen. Treatment attenuated hepatic STAT1/3 activation and downregulated genes involved in inflammation, fibrosis, and lipid metabolism. Livers from treated mice exhibited lower levels of oxidative damage markers, reduced expression of NADPH oxidase 1 (NOX1), and upregulation of the antioxidant genes catalase and superoxide dismutase. In vitro, the peptides were safe for hepatocytes at different doses and effectively counteracted palmitate-induced cytotoxicity, superoxide anion production, and cytokine and NOX1 expression, while increasing anti-inflammatory and antioxidant genes. CONCLUSIONS SOCS1 mimetic peptides exhibit hepatoprotective effects in experimental MASLD/MASH by modulating lipotoxicity, inflammation, redox balance and fibrogenesis. This proof-of-concept supports their potential as candidates for preclinical MASLD therapy development.
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Affiliation(s)
- Susana Bernal
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain
| | - Ignacio Prieto
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain
| | - María Kavanagh
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain
| | - Isabel Herrero Del Real
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain
| | - Sara La Manna
- Department of Pharmacy, University of Naples Federico II, Naples, 80131, Italy
| | - Iolanda Lázaro
- Hospital del Mar Medical Research Institute, Barcelona, 08003, Spain; Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBEROBN), Madrid, 28029, Spain
| | - Hernán Quiceno
- Department of Pathology, IIS-Fundación Jiménez Díaz, Madrid, 28040, Spain
| | - Laura López-Sanz
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain
| | - Belén Picatoste
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Hepatic and Vascular Diseases Lab. Biochemistry and Molecular Biology Department. School of Pharmacy, Complutense University of Madrid, Madrid, 28040, Spain
| | - M Pilar Valdecantos
- Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain; Institute for Biomedical Research Sols-Morreale (IIBM), Spanish National Research Council- Autonomous University of Madrid (CSIC-UAM), Madrid, 28029, Spain
| | - Sebastián Mas-Fontao
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain
| | - Aleix Sala-Vila
- Hospital del Mar Medical Research Institute, Barcelona, 08003, Spain; Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBEROBN), Madrid, 28029, Spain
| | - Ángela M Valverde
- Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain; Institute for Biomedical Research Sols-Morreale (IIBM), Spanish National Research Council- Autonomous University of Madrid (CSIC-UAM), Madrid, 28029, Spain
| | - Daniela Marasco
- Department of Pharmacy, University of Naples Federico II, Naples, 80131, Italy
| | - Jesús Egido
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain
| | - Carmen Gómez-Guerrero
- Renal, Vascular and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid (IIS-FJD/UAM), Madrid, 28040, Spain; Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, 28029, Spain.
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Minjares M, Thepsuwan P, Zhang K, Wang JM. Unfolded protein responses: Dynamic machinery in wound healing. Pharmacol Ther 2025; 267:108798. [PMID: 39826569 PMCID: PMC11881203 DOI: 10.1016/j.pharmthera.2025.108798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 12/11/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
Skin wound healing is a dynamic process consisting of multiple cellular and molecular events that must be tightly coordinated to repair the injured tissue efficiently. The healing pace is decided by the type of injuries, the depth and size of the wounds, and whether wound infections occur. However, aging, comorbidities, genetic factors, hormones, and nutrition also impact healing outcomes. During wound healing, cells undergo robust processes of synthesizing new proteins and degrading multifunctional proteins. This imposes an increasing burden on the endoplasmic reticulum (ER), causing ER stress. Unfolded protein response (UPR) represents a collection of highly conserved stress signaling pathways originated from the ER to maintain protein homeostasis and modulate cell physiology. UPR is known to be beneficial for tissue healing. However, when excessive ER stress exceeds ER's folding potential, UPR pathways trigger cell apoptosis, interrupting tissue regeneration. Understanding how UPR pathways modulate the skin's response to injuries is critical for new interventions toward the control of acute and chronic wounds. Herein, in this review, we focus on the participation of the canonical and noncanonical UPR pathways during different stages of wound healing, summarize the available evidence demonstrating UPR's unique position in balancing homeostasis and pathophysiology of healing tissues, and highlight the understudied areas where therapeutic opportunities may arise.
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Affiliation(s)
- Morgan Minjares
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, USA
| | | | - Kezhong Zhang
- Centers for Molecular Medicine and Genetics, Wayne State University, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, USA.
| | - Jie-Mei Wang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, USA; Centers for Molecular Medicine and Genetics, Wayne State University, USA; Karmanos Cancer Institute, Detroit, MI, USA.
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3
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Yuan X, Sun W, Xu Y, Xiang M, Gao Y, Feng W, Xiao H, Zhang L, Tang Q, Lu J, Zhang Y. Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention. Sci Rep 2025; 15:3686. [PMID: 39881157 PMCID: PMC11779893 DOI: 10.1038/s41598-025-87190-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 01/16/2025] [Indexed: 01/31/2025] Open
Abstract
A high-calorie diet and lack of exercise are the most important risk factors contributing to metabolic dysfunction-associated steatotic liver disease (MASLD) initiation and progression. The precise molecular mechanisms of mitochondrial function alteration during MASLD development remain to be fully elucidated. In this study, a total of 60 male C57BL/6J mice were maintained on a normal or amylin liver NASH (AMLN) diet for 6 or 10 weeks. Some of the mice were then subjected to voluntary wheel running, while the other mice were fed a normal or AMLN diet until 14 and 18 weeks. The results showed that hepatic lipid deposition and the PERK-eIF2α-ATF4 pathway were significantly increased with prolonged duration of AMLN diet. However, expression of mitochondrial unfolded protein response (UPRmt) genes and mitokine FGF21 secretion were significantly enhanced in the 14-week AMLN diet mice, but were markedly reduced with the excessive lipid deposition induced by longer AMLN diet. Additionally, the exercise intervention acts as a regulator to optimize UPRmt signal transduction and to enhance mitochondrial homeostasis by improving mitochondrial function, reversing the UPRmt activation pattern, and increasing FGF21 secretion, which plays a pivotal role in delaying the occurrence and development of MASLD.
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Affiliation(s)
- Xinmeng Yuan
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Wen Sun
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Ye Xu
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Mengqi Xiang
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Yaran Gao
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Wanyu Feng
- Jiangsu Collaborative Innovation Center for Sport and Health Project, Nanjing, China
| | - Hongjian Xiao
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Liumei Zhang
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
| | - Qiang Tang
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
- Sport Science Research Institute, Nanjing Sport Institute, Nanjing, China
| | - Jiao Lu
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China
- Sport Science Research Institute, Nanjing Sport Institute, Nanjing, China
| | - Yuan Zhang
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China.
- Jiangsu Collaborative Innovation Center for Sport and Health Project, Nanjing, China.
- Sport Science Research Institute, Nanjing Sport Institute, Nanjing, China.
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4
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Ma C, Liu Y, Fu Z. Implications of endoplasmic reticulum stress and autophagy in aging and cardiovascular diseases. Front Pharmacol 2024; 15:1413853. [PMID: 39119608 PMCID: PMC11306071 DOI: 10.3389/fphar.2024.1413853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/24/2024] [Indexed: 08/10/2024] Open
Abstract
The average lifespan of humans has been increasing, resulting in a rapidly rising percentage of older individuals and high morbidity of aging-associated diseases, especially cardiovascular diseases (CVDs). Diverse intracellular and extracellular factors that interrupt homeostatic functions in the endoplasmic reticulum (ER) induce ER stress. Cells employ a dynamic signaling pathway of unfolded protein response (UPR) to buffer ER stress. Recent studies have demonstrated that ER stress triggers various cellular processes associated with aging and many aging-associated diseases, including CVDs. Autophagy is a conserved process involving lysosomal degradation and recycling of cytoplasmic components, proteins, organelles, and pathogens that invade the cytoplasm. Autophagy is vital for combating the adverse influence of aging on the heart. The present report summarizes recent studies on the mechanism of ER stress and autophagy and their overlap in aging and on CVD pathogenesis in the context of aging. It also discusses possible therapeutic interventions targeting ER stress and autophagy that might delay aging and prevent or treat CVDs.
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Affiliation(s)
- Chenguang Ma
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yang Liu
- 32295 Troops of P.L.A, Liaoyang, China
| | - Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
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Suhail H, Peng H, Matrougui K, Rhaleb NE. Ac-SDKP attenuates ER stress-stimulated collagen production in cardiac fibroblasts by inhibiting CHOP-mediated NF-κB expression. Front Pharmacol 2024; 15:1352222. [PMID: 38495093 PMCID: PMC10940518 DOI: 10.3389/fphar.2024.1352222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Inflammation and cardiac fibrosis are prevalent pathophysiologic conditions associated with hypertension, cardiac remodeling, and heart failure. Endoplasmic reticulum (ER) stress triggers the cells to activate unfolded protein responses (UPRs) and upregulate the ER stress chaperon, enzymes, and downstream transcription factors to restore normal ER function. The mechanisms that link ER stress-induced UPRs upregulation and NF-κB activation that results in cardiac inflammation and collagen production remain elusive. N-Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a natural tetrapeptide that negatively regulates inflammation and fibrosis, has been reported. Whether it can inhibit ER stress-induced collagen production in cardiac fibroblasts remains unclear. Thus, we hypothesized that Ac-SDKP attenuates ER stress-stimulated collagen production in cardiac fibroblasts by inhibiting CHOP-mediated NF-κB expression. We aimed to study whether Ac-SDKP inhibits tunicamycin (TM)-induced ER stress signaling, NF-κB signaling, the release of inflammatory cytokine interleukin-6, and collagen production in human cardiac fibroblasts (HCFs). HCFs were pre-treated with Ac-SDKP (10 nM) and then stimulated with TM (0.25 μg/mL). We found that Ac-SDKP inhibits TM-induced collagen production by attenuating ER stress-induced UPRs upregulation and CHOP/NF-κB transcriptional signaling pathways. CHOP deletion by specific shRNA maintains the inhibitory effect of Ac-SDKP on NF-κB and type-1 collagen (Col-1) expression at both protein and mRNA levels. Attenuating ER stress-induced UPR sensor signaling by Ac-SDKP seems a promising therapeutic strategy to combat detrimental cardiac inflammation and fibrosis.
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Affiliation(s)
- Hamid Suhail
- Department of Internal Medicine, Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI, United States
| | - Hongmei Peng
- Department of Internal Medicine, Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI, United States
| | - Khalid Matrougui
- Department of Physiology Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Nour-Eddine Rhaleb
- Department of Internal Medicine, Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI, United States
- Department of Physiology, Wayne State University, Detroit, MI, United States
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6
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Yang AY, Kim K, Kwon HH, Leem J, Song JE. 6-Shogaol Ameliorates Liver Inflammation and Fibrosis in Mice on a Methionine- and Choline-Deficient Diet by Inhibiting Oxidative Stress, Cell Death, and Endoplasmic Reticulum Stress. Molecules 2024; 29:419. [PMID: 38257332 PMCID: PMC10818499 DOI: 10.3390/molecules29020419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/02/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is becoming an increasingly serious global health threat, distinguished by hepatic lipid accumulation, inflammation, and fibrosis. There is a lack of approved pharmaceutical interventions for this disease, highlighting the urgent need for effective treatment. This study explores the hepatoprotective potential of 6-shogaol, a natural compound derived from ginger, in a methionine- and choline-deficient (MCD) dietary mouse model of NASH. Male C57BL/6J mice were subjected to the MCD diet for 4 weeks to induce NASH, with concurrent intraperitoneal administration of 6-shogaol (20 mg/kg) three times a week. While 6-shogaol did not impact body weight, liver weight, or hepatic lipid accumulation, it effectively mitigated liver injury, inflammation, and fibrosis in MCD diet-fed mice. Mechanistically, 6-shogaol inhibited lipid and DNA oxidation, restored hepatic glutathione levels, and regulated the expression of pro-oxidant and antioxidant enzymes. Furthermore, 6-shogaol inhibited apoptosis and necroptosis, as indicated by a decrease in TUNEL-stained cells and downregulation of apoptosis- and necroptosis-associated proteins. Additionally, 6-shogaol alleviated endoplasmic reticulum (ER) stress, as demonstrated by decreased expression of molecules associated with unfolded protein response pathways. These findings underscore the potential of 6-shogaol as a therapeutic intervention for NASH by targeting pathways related to oxidative stress, cell death, and ER stress.
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Affiliation(s)
- Ah Young Yang
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (K.K.)
| | - Kiryeong Kim
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (K.K.)
| | - Hyun Hee Kwon
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea; (A.Y.Y.); (K.K.)
| | - Jeong Eun Song
- Department of Internal Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea;
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Ishiyama S, Kimura M, Nakagawa T, Kishigami S, Mochizuki K. Induction of the Lipid Droplet Formation Genes in Steatohepatitis Mice by Embryo/Postnatal Nutrient Environment Is Associated with Histone Acetylation around the Genes. J Nutr Sci Vitaminol (Tokyo) 2024; 70:318-327. [PMID: 39218693 DOI: 10.3177/jnsv.70.318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Recently, we have demonstrated that mice, cultured embryos in α-minimum essential medium (αMEM) and subsequent fed a high-fat, high-sugar diet, developed steatohepatitis. In this study, we investigated using these samples whether the expression of lipid droplet formation genes in the liver is higher in MEM mice, whether these expressions are regulated by histone acetylation, writers/readers of histone acetylation, and the transcriptional factors of endoplasmic reticulum stress. Mice were produced by two-cell embryos in αMEM or standard potassium simplex-optimized medium (control) in vitro for 48 h, and implanted into an oviduct for spontaneous delivery. MEM and control-mice were fed a high-fat, high-sugar diet for 18 wk, and then liver samples were collected and analyzed by histology, qRT-PCR, and chromatin immunoprecipitation assay. Gene expression of Cidea, Cidec, and Plin4 were higher in MEM mice and histone H3K9 acetylation, BRD4, and CBP were higher in MEM mice than in control mice around those genes. However, the binding of endoplasmic reticulum stress-related transcription factors (ATF4, CHOP and C/EBPα) around those genes in the liver, was not clearly differed between MEM mice and control mice. The increased expression of Cidea, Cidec and Plin4 in the liver, accompanied by the development of steatohepatitis in mice induced is positively associated with increased histone H3K9 acetylation and CBP and BRD4 binding around these genes.
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Affiliation(s)
- Shiori Ishiyama
- Faculty of Life and Environmental Sciences, University of Yamanashi
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
| | - Mayu Kimura
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
| | | | - Satoshi Kishigami
- Faculty of Life and Environmental Sciences, University of Yamanashi
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
- Advanced Biotechnology Center, University of Yamanashi
- Center for Advanced Assisted Reproductive Technologies, University of Yamanashi
| | - Kazuki Mochizuki
- Faculty of Life and Environmental Sciences, University of Yamanashi
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi
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Prajapat SK, Mishra L, Khera S, Owusu SD, Ahuja K, Sharma P, Choudhary E, Chhabra S, Kumar N, Singh R, Kaushal PS, Mahajan D, Banerjee A, Motiani RK, Vrati S, Kalia M. Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy. EMBO Mol Med 2024; 16:185-217. [PMID: 38177535 PMCID: PMC10897192 DOI: 10.1038/s44321-023-00014-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/24/2023] [Accepted: 11/24/2023] [Indexed: 01/06/2024] Open
Abstract
Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.
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Affiliation(s)
- Surendra K Prajapat
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Laxmi Mishra
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Sakshi Khera
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Shadrack D Owusu
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
- Institut de Biologie Moléculaire et Cellulaire (IBMC), Université de Strasbourg, 67000, Strasbourg, France
| | - Kriti Ahuja
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Puja Sharma
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Eira Choudhary
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Simran Chhabra
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Niraj Kumar
- Structural Biology & Translation Regulation Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Rajan Singh
- Advanced Technology Platform Centre, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
- Department of Life Sciences, Shiv Nadar University, Greater Noida, 201314, India
| | - Prem S Kaushal
- Structural Biology & Translation Regulation Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Dinesh Mahajan
- Chemistry and Pharmacology Lab, Centre for Drug Design and Discovery, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Arup Banerjee
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Rajender K Motiani
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Sudhanshu Vrati
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Manjula Kalia
- Virology Research Group, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India.
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9
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Liu K, Zhao C, Adajar RC, DeZwaan-McCabe D, Rutkowski DT. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress. EMBO Rep 2024; 25:228-253. [PMID: 38177915 PMCID: PMC10897205 DOI: 10.1038/s44319-023-00026-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 01/06/2024] Open
Abstract
Cellular stresses elicit signaling cascades that are capable of either mitigating the inciting dysfunction or initiating cell death. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. However, it is not clear whether CHOP also has a beneficial role during adaptation. Here, we combine a new, versatile, genetically modified Chop allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we find that CHOP promotes death in some cells, but proliferation-and hence recovery-in others. Strikingly, this function of CHOP confers to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggest that CHOP maximizes UPR activation, which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. Taken together, these findings suggest that CHOP's function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates-adaptation or death-during stresses of physiological intensity.
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Affiliation(s)
- Kaihua Liu
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Chaoxian Zhao
- Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Reed C Adajar
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Diane DeZwaan-McCabe
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - D Thomas Rutkowski
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
- Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
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Na M, Yang X, Deng Y, Yin Z, Li M. Endoplasmic reticulum stress in the pathogenesis of alcoholic liver disease. PeerJ 2023; 11:e16398. [PMID: 38025713 PMCID: PMC10655704 DOI: 10.7717/peerj.16398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/12/2023] [Indexed: 12/01/2023] Open
Abstract
The endoplasmic reticulum (ER) plays a pivotal role in protein synthesis, folding, and modification. Under stress conditions such as oxidative stress and inflammation, the ER can become overwhelmed, leading to an accumulation of misfolded proteins and ensuing ER stress. This triggers the unfolded protein response (UPR) designed to restore ER homeostasis. Alcoholic liver disease (ALD), a spectrum disorder resulting from chronic alcohol consumption, encompasses conditions from fatty liver and alcoholic hepatitis to cirrhosis. Metabolites of alcohol can incite oxidative stress and inflammation in hepatic cells, instigating ER stress. Prolonged alcohol exposure further disrupts protein homeostasis, exacerbating ER stress which can lead to irreversible hepatocellular damage and ALD progression. Elucidating the contribution of ER stress to ALD pathogenesis may pave the way for innovative therapeutic interventions. This review delves into ER stress, its basic signaling pathways, and its role in the alcoholic liver injury.
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Affiliation(s)
- Man Na
- Department of Pharmacy, The 926th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Kaiyuan, Yunan, China
| | - Xingbiao Yang
- Department of Pharmacy, The 926th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Kaiyuan, Yunan, China
| | - Yongkun Deng
- Department of Pharmacy, The 926th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Kaiyuan, Yunan, China
| | - Zhaoheng Yin
- Department of Pharmacy, The 926th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Kaiyuan, Yunan, China
| | - Mingwei Li
- Department of Pharmacy, The 926th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Kaiyuan, Yunan, China
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Chen C, Bao Y, Xing L, Jiang C, Guo Y, Tong S, Zhang J, Chen L, Mao Y. Exosomes Derived from M2 Microglial Cells Modulated by 1070-nm Light Improve Cognition in an Alzheimer's Disease Mouse Model. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2304025. [PMID: 37702115 PMCID: PMC10646245 DOI: 10.1002/advs.202304025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/01/2023] [Indexed: 09/14/2023]
Abstract
Near-infrared photobiomodulation has been identified as a potential strategy for Alzheimer's disease (AD). However, the mechanisms underlying this therapeutic effect remain poorly characterize. Herein, it is illustrate that 1070-nm light induces the morphological alteration of microglia from an M1 to M2 phenotype that secretes exosomes, which alleviates the β-amyloid burden to improve cognitive function by ameliorating neuroinflammation and promoting neuronal dendritic spine plasticity. The results show that 4 J cm-2 1070-nm light at a 10-Hz frequency prompts microglia with an M1 inflammatory type to switch to an M2 anti-inflammatory type. This induces secretion of M2 microglial-derived exosomes containing miR-7670-3p, which targets activating transcription factor 6 (ATF6) during endoplasmic reticulum (ER) stress. Moreover, it is found that miR-7670-3p reduces ATF6 expression to further ameliorate ER stress, thus attenuating the inflammatory response and protecting dendritic spine integrity of neurons in the cortex and hippocampus of 5xFAD mice, ultimately leading to improvements in cognitive function. This study highlights the critical role of exosomes derive from 1070-nm light-modulated microglia in treating AD mice, which may provide a theoretical basis for the treatment of AD with the use of near-infrared photobiomodulation.
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Affiliation(s)
- Chengwei Chen
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghai200040China
- National Center for Neurological DisordersShanghai200040China
- Shanghai Key Laboratory of Brain Function Restoration and Neural RegenerationShanghai200040China
- Neurosurgical Institute of Fudan UniversityShanghai200040China
- Shanghai Clinical Medical Center of NeurosurgeryShanghai200040China
| | - Yuting Bao
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghai200040China
- National Center for Neurological DisordersShanghai200040China
- Shanghai Key Laboratory of Brain Function Restoration and Neural RegenerationShanghai200040China
- Neurosurgical Institute of Fudan UniversityShanghai200040China
- Shanghai Clinical Medical Center of NeurosurgeryShanghai200040China
| | - Lu Xing
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghai200040China
- National Center for Neurological DisordersShanghai200040China
- Shanghai Key Laboratory of Brain Function Restoration and Neural RegenerationShanghai200040China
- Neurosurgical Institute of Fudan UniversityShanghai200040China
- Shanghai Clinical Medical Center of NeurosurgeryShanghai200040China
| | - Chengyong Jiang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain ScienceFudan UniversityShanghai200032China
| | - Yu Guo
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghai200040China
- National Center for Neurological DisordersShanghai200040China
- Shanghai Key Laboratory of Brain Function Restoration and Neural RegenerationShanghai200040China
- Neurosurgical Institute of Fudan UniversityShanghai200040China
- Shanghai Clinical Medical Center of NeurosurgeryShanghai200040China
| | - Shuangmei Tong
- Department of Pharmacy, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghai200040China
| | - Jiayi Zhang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institutes of Brain ScienceFudan UniversityShanghai200032China
| | - Liang Chen
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghai200040China
- National Center for Neurological DisordersShanghai200040China
- Shanghai Key Laboratory of Brain Function Restoration and Neural RegenerationShanghai200040China
- Neurosurgical Institute of Fudan UniversityShanghai200040China
- Shanghai Clinical Medical Center of NeurosurgeryShanghai200040China
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghai200040China
- National Center for Neurological DisordersShanghai200040China
- Shanghai Key Laboratory of Brain Function Restoration and Neural RegenerationShanghai200040China
- Neurosurgical Institute of Fudan UniversityShanghai200040China
- Shanghai Clinical Medical Center of NeurosurgeryShanghai200040China
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Abdelrahman BA, El-Khatib AS, Attia YM. Insights into the role of vitamin D in targeting the culprits of non-alcoholic fatty liver disease. Life Sci 2023; 332:122124. [PMID: 37742738 DOI: 10.1016/j.lfs.2023.122124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
Vitamin D (VD) is a secosteroid hormone that is renowned for its crucial role in phospho-calcium homeostasis upon binding to the nuclear vitamin D receptor (VDR). Over and above, the pleiotropic immunomodulatory, anti-inflammatory, and metabolic roles VD plays in different disease settings started to surface in the past few decades. On the other hand, a growing body of evidence suggests a correlation between non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) with vitamin D deficiency (VDD) owing to the former's ingrained link with obesity and metabolic syndrome. Accordingly, a better understanding of the contribution of disrupted VDR signalling to NAFLD incidence and progression would provide further insights into its diagnosis, treatment modalities, and prognosis. This is especially significant as, hitherto, no drug for NAFLD has been approved. This review, therefore, sought to set forth the likely contribution of VDR signalling in NAFLD and how it might influence its multiple drivers.
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Affiliation(s)
- Basma A Abdelrahman
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Aiman S El-Khatib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Yasmeen M Attia
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
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Liu K, Zhao C, Adajar RC, DeZwaan-McCabe D, Rutkowski DT. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.19.533325. [PMID: 36993175 PMCID: PMC10055232 DOI: 10.1101/2023.03.19.533325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Cellular stresses elicit signaling cascades that are capable of either mitigating the inciting dysfunction or initiating cell death. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. However, it is not clear whether CHOP also has a beneficial role during adaptation. Here, we have combined a new, versatile, genetically modified Chop allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we found that CHOP promoted death in some cells, but proliferation-and hence recovery-in others. Strikingly, this function of CHOP conferred to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggested that CHOP maximizes UPR activation, which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. Taken together, these findings suggest that CHOP's function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates-adaptation or death-during stresses of physiological intensity.
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Affiliation(s)
- Kaihua Liu
- Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Chaoxian Zhao
- Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Reed C. Adajar
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Diane DeZwaan-McCabe
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - D. Thomas Rutkowski
- Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
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Supriyadi R, Yanto TA, Hariyanto TI, Suastika K. Utility of non-invasive liver fibrosis markers to predict the incidence of chronic kidney disease (CKD): A systematic review, meta-analysis, and meta-regression. Diabetes Metab Syndr 2023; 17:102814. [PMID: 37354810 DOI: 10.1016/j.dsx.2023.102814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/26/2023]
Abstract
BACKGROUND AND AIMS Chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) share common risk factors and pathogenesis mechanisms. However, the association between the degree of liver fibrosis and the incidence of CKD remains unclear. This study aims to examine the utility of non-invasive fibrosis markers to predict the occurrence of CKD. METHODS Cochrane Library, Scopus, and Medline were searched up to May 20th, 2023 using combined keywords. Literature that analyzes FIB-4, NFS, and APRI to predict CKD incidence was included in this review. We used random-effect models of odds ratio (OR) with 95% confidence intervals (CI) to express the outcomes in this review. RESULTS Twenty-one studies were included. Our meta-analysis showed that high FIB-4 was associated with a higher incidence of CKD (OR 2.51; 95%CI: 1.87-3.37, p < 0.00001, I2 = 96%). Further regression analysis revealed that this association was significantly influenced by hypertension (p = 0.0241), NAFLD (p = 0.0029), and body mass index (BMI) (p = 0.0025). Our meta-analysis also showed that high NFS (OR 2.49; 95%CI: 1.89-3.30, p < 0.00001, I2 = 96%) and high APRI (OR 1.40; 95%CI: 1.14-1.72, p = 0.001, I2 = 26%) were associated with a higher incidence of CKD. CONCLUSIONS This study suggests that these non-invasive liver fibrosis markers can be routinely measured both in NAFLD patients and the general population to enable better risk stratification and early detection of CKD.
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Affiliation(s)
- Rudi Supriyadi
- Division of Nephrology and Hypertension, Department of Internal Medicine, Padjadjaran University, Bandung, West Java, 45363, Indonesia
| | - Theo Audi Yanto
- Department of Internal Medicine, Faculty of Medicine, Pelita Harapan University, Karawaci, Tangerang, 15811, Indonesia
| | | | - Ketut Suastika
- Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Udayana University, Denpasar, Bali, 80232, Indonesia
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Shatta MA, El-Derany MO, Gibriel AA, El-Mesallamy HO. Rhamnetin ameliorates non-alcoholic steatosis and hepatocellular carcinoma in vitro. Mol Cell Biochem 2023; 478:1689-1704. [PMID: 36495373 PMCID: PMC10267014 DOI: 10.1007/s11010-022-04619-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022]
Abstract
Non-alcoholic fatty liver (NAFLD) is a widespread disease with various complications including Non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis and ultimately hepatocellular carcinoma (HCC). Up till now there is no FDA approved drug for treatment of NAFLD. Flavonoids such as Rhamnetin (Rhm) have been ascribed effective anti-inflammatory and anti-oxidative properties. Thus, Rhm as a potent flavonoid could target multiple pathological cascades causing NAFLD to prevent its progression into HCC. NAFLD is a multifactorial disease and its pathophysiology is complex and is currently challenged by the 'Multiple-hit hypothesis' that includes wider range of comorbidities rather than previously established theory of 'Two-hit hypothesis'. Herein, we aimed at establishing reliable in vitro NASH models using different mixtures of variable ratios and concentrations of oleic acid (OA) and palmitic acid (PA) combinations using HepG2 cell lines. Moreover, we compared those models in the context of oil red staining, triglyceride levels and their altered downstream molecular signatures for genes involved in de novo lipogenesis, inflammation, oxidative stress and apoptotic machineries as well. Lastly, the effect of Rhm on NASH and HCC models was deeply investigated. Over the 10 NASH models tested, PA 500 µM concentration was the best model to mimic the molecular events of steatosis induced NAFLD. Rhm successfully ameliorated the dysregulated molecular events caused by the PA-induced NASH. Additionally, Rhm regulated inflammatory and oxidative machinery in the HepG2 cancerous cell lines. In conclusion, PA 500 µM concentration is considered an effective in vitro model to mimic NASH. Rhm could be used as a promising therapeutic modality against both NASH and HCC pathogenesis.
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Affiliation(s)
- Mahmoud A Shatta
- Department of Biochemistry, Faculty of Pharmacy, The British University in Egypt, Cairo, 11837, Egypt
| | - Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
| | - Abdullah A Gibriel
- Department of Biochemistry, Faculty of Pharmacy, The British University in Egypt, Cairo, 11837, Egypt
| | - Hala O El-Mesallamy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
- Dean of Faculty of Pharmacy, Sinai University, North Sinai, 45518, Egypt
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16
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Jo SL, Yang H, Lee HW, Hong EJ. Curcumae radix Reduces Endoplasmic Reticulum Stress in Mice with Chronic Neuroinflammation. Biomedicines 2023; 11:2107. [PMID: 37626603 PMCID: PMC10452873 DOI: 10.3390/biomedicines11082107] [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: 05/22/2023] [Revised: 06/16/2023] [Accepted: 06/26/2023] [Indexed: 08/27/2023] Open
Abstract
Endoplasmic reticulum (ER) stress is a condition in which the ER protein-folding machinery is impaired, leading to the accumulation of improperly folded proteins and triggering an unfolded-protein response. Excessive ER stress causes cell death and contributes to the development of chronic diseases. Interestingly, there is a bidirectional relationship between ER stress and the nuclear factor-kappa B (NF-κB) pathway. Curcumin, a natural polyphenolic compound found in Curcumae radix, exerts its neuroprotective effects by regulating ER stress and inflammation. Therefore, investigating the potential protective and regulatory effects of curcumin on ER stress, inflammation, and neurodegeneration under chronic neuroinflammatory conditions is of great interest. Mice were pretreated with Curcumae radix extract (CRE) for 19 days and then treated with CRE plus lipopolysaccharide for 1 week. We monitored pro-inflammatory cytokine levels in the serum and ER stress-, inflammation-, and neurodegeneration-related markers in the mouse cerebrum and hippocampus using Western blotting and qRT-PCR. CRE reduced Interleukin-1 beta levels in the blood and brain of mice with lipopolysaccharide-induced chronic inflammation. CRE also suppressed the expression of markers related to the ER stress and NF-κB signaling pathways. The expression of neurodegeneration-related markers was reduced in the mouse cerebrum and hippocampus. CRE exerts neuroprotective effects under chronic inflammatory conditions via multifaceted anti-inflammatory and ER stress-pathway regulatory mechanisms.
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Affiliation(s)
- Seong-Lae Jo
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea;
| | - Hyun Yang
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea;
| | - Hye Won Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea;
| | - Eui-Ju Hong
- College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea;
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Hu Q, Chen Y, Bao T, Huang Y. Association of metabolic dysfunction-associated fatty liver disease with chronic kidney disease: a Chinese population-based study. Ren Fail 2022; 44:1996-2005. [DOI: 10.1080/0886022x.2022.2144373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Qian Hu
- Health Management Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yao Chen
- Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Bao
- Health Management Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yan Huang
- Health Management Center, West China Hospital of Sichuan University, Chengdu, China
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18
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Zheng W, Sun Q, Li L, Cheng Y, Chen Y, Lv M, Xiang X. Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease. Int Immunopharmacol 2022; 113:109458. [DOI: 10.1016/j.intimp.2022.109458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/22/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022]
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Luo Y, Jiao Q, Chen Y. Targeting endoplasmic reticulum stress-the responder to lipotoxicity and modulator of non-alcoholic fatty liver diseases. Expert Opin Ther Targets 2022; 26:1073-1085. [PMID: 36657744 DOI: 10.1080/14728222.2022.2170780] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Endoplasmic reticulum (ER) stress occurs with aberrant lipid accumulation and resultant adverse effects and widely exists in nonalcoholic fatty liver disease (NAFLD). It triggers the unfolded protein response (UPR) to restore ER homeostasis and actively participates in NAFLD pathological processes, including hepatic steatosis, inflammation, hepatocyte death, and fibrosis. Such acknowledges drive the discovery of novel NAFLD biomarker and therapeutic targets and the development of ER-stress targeted NAFLD drugs. AREAS COVERED This article discusses and updates the role of ER stress and UPR in NAFLD, the underlying action mechanism, and especially their full participation in NAFLD pathophysiology. It characterizes key molecular targets useful for the prevention and treatment of NAFLD and highlights the recent ER stress-targeted therapeutic strategies for NAFLD. EXPERT OPINION Targeting ER Stress is a valuable and promising strategy for NAFLD treatment, but its smooth translation into clinical application still requires better clarification of the different UPR patterns in diverse NAFLD physiological states. Further understanding of the distinct effects of these various patterns on NAFLD, the thresholds deciding their final impacts, and their actions via non-liver tissues and cells would be of great help to develop a precise and effective therapy for NAFLD. [Figure: see text].
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Affiliation(s)
- Yu Luo
- School of Pharmaceutical Science, University of South China, Hengyang, Hunan, China
| | - Qiangqiang Jiao
- School of Pharmaceutical Science, University of South China, Hengyang, Hunan, China
| | - Yuping Chen
- School of Pharmaceutical Science, University of South China, Hengyang, Hunan, China.,Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China
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Linagliptin and Vitamin D3 Synergistically Rescue Testicular Steroidogenesis and Spermatogenesis in Cisplatin-Exposed Rats: The Crosstalk of Endoplasmic Reticulum Stress with NF-κB/iNOS Activation. Molecules 2022; 27:molecules27217299. [DOI: 10.3390/molecules27217299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/16/2022] [Accepted: 10/24/2022] [Indexed: 11/17/2022] Open
Abstract
This study investigated the therapeutic effect of linagliptin and/or vitamin D3 on testicular steroidogenesis and spermatogenesis in cisplatin-exposed rats including their impact on endoplasmic reticulum (ER) stress and NF-κB/iNOS crosstalk. Cisplatin (7 mg/kg, IP) was injected into adult male albino rats which then were orally treated with drug vehicle, linagliptin (3 mg/kg/day), vitamin D3 (10 μg/kg/day) or both drugs for four weeks. Age-matched rats were used as the control group. Serum samples and testes were collected for further analyses. Cisplatin induced testicular weight loss, deteriorated testicular architecture, loss of germ cells and declined serum and intra-testicular testosterone levels, compared to the control group. There was down-regulation of steroidogenic markers including StAR, CYP11A1, HSD3b and HSD17b in cisplatin-exposed rats, compared with controls. Cisplatin-exposed rats showed up-regulation of ER stress markers in testicular tissue along with increased expression of NF-κB and iNOS in spermatogenic and Leydig cells. These perturbations were almost reversed by vitamin D3 or linagliptin. The combined therapy exerted a more remarkable effect on testicular dysfunction than either monotherapy. These findings suggest a novel therapeutic application for linagliptin combined with vitamin D3 to restore testicular architecture, aberrant steroidogenesis and spermatogenesis after cisplatin exposure. These effects may be attributed to suppression of ER stress and NF-kB/iNOS.
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Sharma N, Sircar A, Anders HJ, Gaikwad AB. Crosstalk between kidney and liver in non-alcoholic fatty liver disease: mechanisms and therapeutic approaches. Arch Physiol Biochem 2022; 128:1024-1038. [PMID: 32223569 DOI: 10.1080/13813455.2020.1745851] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver and kidney are vital organs that maintain homeostasis and injury to either of them triggers pathogenic pathways affecting the other. For example, non-alcoholic fatty liver disease (NAFLD) promotes the progression of chronic kidney disease (CKD), vice versa acute kidney injury (AKI) endorses the induction and progression of liver dysfunction. Progress in clinical and basic research suggest a role of excessive fructose intake, insulin resistance, inflammatory cytokines production, activation of the renin-angiotensin system, redox imbalance, and their impact on epigenetic regulation of gene expression in this context. Recent developments in experimental and clinical research have identified several biochemical and molecular pathways for AKI-liver interaction, including altered liver enzymes profile, metabolic acidosis, oxidative stress, activation of inflammatory and regulated cell death pathways. This review focuses on the current preclinical and clinical findings on kidney-liver crosstalk in NAFLD-CKD and AKI-liver dysfunction settings and highlights potential molecular mechanisms and therapeutic targets.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Anannya Sircar
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
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Liu Z, Li Y, Yu C. Identification of the Non-Alcoholic Fatty Liver Disease Molecular Subtypes Associated With Clinical and Immunological Features via Bioinformatics Methods. Front Immunol 2022; 13:857892. [PMID: 35958576 PMCID: PMC9358963 DOI: 10.3389/fimmu.2022.857892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 06/21/2022] [Indexed: 01/14/2023] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome in the liver with varying severity. Heterogeneity in terms of molecules and immune cell infiltration drives NAFLD from one stage to the next. However, a precise molecular classification of NAFLD is still lacking, and the effects of complex clinical phenotypes on the efficacy of drugs are usually ignored. Methods We introduced multiple omics data to differentiate NAFLD subtypes via consensus clustering, and a weighted gene co-expression network analysis was used to identify eight co-expression modules. Further, eigengenes of eight modules were analyzed with regard to Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, the infiltration rates of 22 immune cell types were calculated with CIBERSORT and the ESTIMATE algorithm. Results In total, 111 NAFLD patients from three independent GEO datasets were divided into four molecular subtypes, and the corresponding clinical features and immune cell infiltration traits were determined. Based on high gene expression correlations, four molecular subtypes were further divided into eight co-expression modules. We also demonstrated a significant correlation between gene modules and clinical phenotypes. Moreover, we integrated phenotypic, immunologic, and genetic data to assess the potential for progression of different molecular subtypes. Furthermore, the efficacy of drugs against various NAFLD molecular subtypes was discussed to aid in individualized therapy. Conclusion Overall, this study could provide new insights into the underlying pathogenesis of and drug targets for NAFLD.
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Affiliation(s)
| | - Yufei Li
- *Correspondence: Yufei Li, ; Caihong Yu,
| | - Caihong Yu
- *Correspondence: Yufei Li, ; Caihong Yu,
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23
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Flessa C, Kyrou I, Nasiri‐Ansari N, Kaltsas G, Kassi E, Randeva HS. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD). J Cell Biochem 2022; 123:1585-1606. [PMID: 35490371 DOI: 10.1002/jcb.30247] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/09/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023]
Affiliation(s)
- Christina‐Maria Flessa
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing Coventry University Coventry UK
- Aston Medical School, College of Health and Life Sciences Aston University Birmingham UK
- Department of Food Science & Human Nutrition Agricultural University of Athens Athens Greece
| | - Narjes Nasiri‐Ansari
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
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Tao Z, Li Y, Cheng B, Zhou T, Gao Y. Influence of Nonalcoholic Fatty Liver Disease on the Occurrence and Severity of Chronic Kidney Disease. J Clin Transl Hepatol 2022; 10:164-173. [PMID: 35233386 PMCID: PMC8845149 DOI: 10.14218/jcth.2021.00171] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/10/2021] [Accepted: 08/25/2021] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is reported to affect 20-30% of adults and is accompanied by various metabolic comorbidities, where the economic and clinical burden of NAFLD is attributed to the progression of liver disease as well as the presence of extrahepatic diseases. Chronic kidney disease (CKD), which has a high incidence rate, high morbidity and mortality rates, and high medical costs, has been linked to NAFLD. CKD is associated with some metabolism-related risk factors that overlap with metabolic comorbidities of NAFLD. Therefore, to investigate the potential factors that influence CKD occurrence, the association between NAFLD and CKD should be clarified. Some studies have confirmed that NAFLD influences the occurrence and severity of CKD, whereas some studies have indicated that there is no correlation. In this review, the results of a few studies have been discussed, the potential risk factors for CKD in NAFLD are explored, and the respective biological mechanisms are elaborated to help clinicians identify CKD in patients much earlier than it is diagnosed now and thus help in reducing the incidence of liver and kidney transplants.
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Affiliation(s)
| | | | | | | | - Yanjing Gao
- Correspondence to: Yanjing Gao, Department of Gastroenterology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, China. ORCID: https://orcid.org/0000-0001-8153-3754. Tel: +86-18560086087, E-mail:
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25
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Cargo proteins in extracellular vesicles: potential for novel therapeutics in non-alcoholic steatohepatitis. J Nanobiotechnology 2021; 19:372. [PMID: 34789265 PMCID: PMC8600817 DOI: 10.1186/s12951-021-01120-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Extracellular vesicles (EVs) are recognized as novel cell-free therapeutics. Non-alcoholic steatohepatitis (NASH) remains a critical health problem. Herein, we show that EVs from pan peroxisome proliferator-activated receptor agonist-primed induced mesenchymal stem cell (pan PPAR-iMSC-EVs) has unique cargo protein signatures, and demonstrate its therapeutic function in NASH. RESULTS A unique protein signatures were identified in pan PPAR-iMSC-EVs against those from non-stimulated iMSC-EVs. NASH mice receiving pan PPAR-iMSC-EVs showed reduced steatotic changes and ameliorated ER stress and mitochondiral oxidative stress induced by inflammation. Moreover, pan PPAR-iMSC-EVs promoted liver regeneration via inhibiting apoptosis and enhancing proliferation. CONCLUSIONS We conclude that our strategy for enriching unique cargo proteins in EVs may facilitate the development of novel therapeutic option for NASH.
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26
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SREBP1c silencing reduces endoplasmic reticulum stress and related apoptosis in oleic acid induced lipid accumulation. MARMARA MEDICAL JOURNAL 2021. [DOI: 10.5472/marumj.1009096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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27
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Yamazaki K, Kato T, Tsuboi Y, Miyauchi E, Suda W, Sato K, Nakajima M, Yokoji-Takeuchi M, Yamada-Hara M, Tsuzuno T, Matsugishi A, Takahashi N, Tabeta K, Miura N, Okuda S, Kikuchi J, Ohno H, Yamazaki K. Oral Pathobiont-Induced Changes in Gut Microbiota Aggravate the Pathology of Nonalcoholic Fatty Liver Disease in Mice. Front Immunol 2021; 12:766170. [PMID: 34707622 PMCID: PMC8543001 DOI: 10.3389/fimmu.2021.766170] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
Background & Aims Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology. Methods C57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction. Results CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different. Conclusions Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.
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Affiliation(s)
- Kyoko Yamazaki
- Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tamotsu Kato
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama, Japan
| | - Yuuri Tsuboi
- RIKEN Center for Sustainable Resource Science, Yokohama, Japan
| | - Eiji Miyauchi
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama, Japan
| | - Wataru Suda
- Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Keisuke Sato
- Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Mayuka Nakajima
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Mai Yokoji-Takeuchi
- Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Miki Yamada-Hara
- Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takahiro Tsuzuno
- Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Aoi Matsugishi
- Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Naoki Takahashi
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Koichi Tabeta
- Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Nobuaki Miura
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shujiro Okuda
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Medical AI Center, Niigata University School of Medicine, Niigata, Japan
| | - Jun Kikuchi
- RIKEN Center for Sustainable Resource Science, Yokohama, Japan
| | - Hiroshi Ohno
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama, Japan
- Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Japan
| | - Kazuhisa Yamazaki
- Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Laboratory for Intestinal Ecosystem, RIKEN Centre for Integrative Medical Sciences (IMS), Yokohama, Japan
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Takeichi Y, Miyazawa T, Sakamoto S, Hanada Y, Wang L, Gotoh K, Uchida K, Katsuhara S, Sakamoto R, Ishihara T, Masuda K, Ishihara N, Nomura M, Ogawa Y. Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor. Diabetologia 2021; 64:2092-2107. [PMID: 34052855 PMCID: PMC8382662 DOI: 10.1007/s00125-021-05488-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 03/22/2021] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. METHODS We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. RESULTS MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. CONCLUSIONS/INTERPRETATION We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH.
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Affiliation(s)
- Yukina Takeichi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Miyazawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Shohei Sakamoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Hanada
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Lixiang Wang
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuhito Gotoh
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiichiro Uchida
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shunsuke Katsuhara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryuichi Sakamoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takaya Ishihara
- Department of Protein Biochemistry, Institute of Life Science, Kurume University, Fukuoka, Japan
- Department of Biological Science, Graduate School of Science, Osaka University, Osaka, Japan
| | - Keiji Masuda
- Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Naotada Ishihara
- Department of Protein Biochemistry, Institute of Life Science, Kurume University, Fukuoka, Japan
- Department of Biological Science, Graduate School of Science, Osaka University, Osaka, Japan
| | - Masatoshi Nomura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
- Japan Agency for Medical Research and Development, CREST, Tokyo, Japan.
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29
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Bilbao-Malavé V, González-Zamora J, de la Puente M, Recalde S, Fernandez-Robredo P, Hernandez M, Layana AG, Saenz de Viteri M. Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age Related Macular Degeneration, Role in Pathophysiology, and Possible New Therapeutic Strategies. Antioxidants (Basel) 2021; 10:1170. [PMID: 34439418 PMCID: PMC8388889 DOI: 10.3390/antiox10081170] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/14/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023] Open
Abstract
Age related macular degeneration (AMD) is the main cause of legal blindness in developed countries. It is a multifactorial disease in which a combination of genetic and environmental factors contributes to increased risk of developing this vision-incapacitating condition. Oxidative stress plays a central role in the pathophysiology of AMD and recent publications have highlighted the importance of mitochondrial dysfunction and endoplasmic reticulum stress in this disease. Although treatment with vascular endothelium growth factor inhibitors have decreased the risk of blindness in patients with the exudative form of AMD, the search for new therapeutic options continues to prevent the loss of photoreceptors and retinal pigment epithelium cells, characteristic of late stage AMD. In this review, we explain how mitochondrial dysfunction and endoplasmic reticulum stress participate in AMD pathogenesis. We also discuss a role of several antioxidants (bile acids, resveratrol, melatonin, humanin, and coenzyme Q10) in amelioration of AMD pathology.
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Affiliation(s)
- Valentina Bilbao-Malavé
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
| | - Jorge González-Zamora
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
| | - Miriam de la Puente
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
| | - Sergio Recalde
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Patricia Fernandez-Robredo
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - María Hernandez
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alfredo Garcia Layana
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Manuel Saenz de Viteri
- Department of Opthalmology, Clínica Universidad de Navarra, 31008 Pamplona, Spain; (V.B.-M.); (J.G.-Z.); (M.d.l.P.); (A.G.L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Universidad de Navarra, 31008 Pamplona, Spain; (S.R.); (P.F.-R.); (M.H.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa en Salud: ‘Prevention, Early Detection, and Treatment of the Prevalent Degenerative and Chronic Ocular Pathology’ from (RD16/0008/0011), Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, 28029 Madrid, Spain
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30
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Misra J, Holmes MJ, T Mirek E, Langevin M, Kim HG, Carlson KR, Watford M, Dong XC, Anthony TG, Wek RC. Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress. Nucleic Acids Res 2021; 49:5726-5742. [PMID: 34023907 PMCID: PMC8191763 DOI: 10.1093/nar/gkab362] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 04/07/2021] [Accepted: 04/23/2021] [Indexed: 11/13/2022] Open
Abstract
Appropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation for amino acids. Halofuginone (HF) is a potent inhibitor of aminoacylation of tRNAPro with broad biomedical applications. Here, we show that in addition to translational control directed by activation of the ISR by general control nonderepressible 2 (GCN2), HF increased free amino acids and directed translation of genes involved in protein biogenesis via sustained mTORC1 signaling. Deletion of GCN2 reduced cell survival to HF whereas pharmacological inhibition of mTORC1 afforded protection. HF treatment of mice synchronously activated the GCN2-mediated ISR and mTORC1 in liver whereas Gcn2-null mice allowed greater mTORC1 activation to HF, resulting in liver steatosis and cell death. We conclude that HF causes an amino acid imbalance that uniquely activates both GCN2 and mTORC1. Loss of GCN2 during HF creates a disconnect between metabolic state and need, triggering proteostasis collapse.
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Affiliation(s)
- Jagannath Misra
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Michael J Holmes
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA.,Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Emily T Mirek
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901 USA
| | - Michael Langevin
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901 USA
| | - Hyeong-Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Kenneth R Carlson
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Malcolm Watford
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901 USA
| | - X Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA.,Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Tracy G Anthony
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ 08901 USA
| | - Ronald C Wek
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
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Flessa CM, Kyrou I, Nasiri-Ansari N, Kaltsas G, Papavassiliou AG, Kassi E, Randeva HS. Endoplasmic Reticulum Stress and Autophagy in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): Current Evidence and Perspectives. Curr Obes Rep 2021; 10:134-161. [PMID: 33751456 DOI: 10.1007/s13679-021-00431-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease with rising prevalence worldwide. Herein, we provide a comprehensive overview of the current knowledge supporting the role of ER stress and autophagy processes in NAFLD pathogenesis and progression. We also highlight the interrelation between these two pathways and the impact of ER stress and autophagy modulators on NAFLD treatment. RECENT FINDINGS The pathophysiological mechanisms involved in NAFLD progression are currently under investigation. The endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR) seem to contribute to its pathogenesis mainly due to high ER content in the liver which exerts significant metabolic functions and can be dysregulated. Furthermore, disruption of autophagy processes has also been identified in NAFLD. The crucial role of these two pathways in NAFLD is underlined by the fact that they have recently emerged as promising targets of therapeutic interventions. There is a greater need for finding the natural/chemical compounds and drugs which can modulate the ER stress pathway and autophagy for the treatment of NAFLD. Clarifying the inter-relation between these two pathways and their interaction with inflammatory and apoptotic mechanisms will allow the development of additional therapeutic options which can better target and reprogram the underlying pathophysiological pathways, aiming to attenuate NAFLD progression.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, B4 7ET, Birmingham, UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
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Heda R, Yazawa M, Shi M, Bhaskaran M, Aloor FZ, Thuluvath PJ, Satapathy SK. Non-alcoholic fatty liver and chronic kidney disease: Retrospect, introspect, and prospect. World J Gastroenterol 2021; 27:1864-1882. [PMID: 34007127 PMCID: PMC8108029 DOI: 10.3748/wjg.v27.i17.1864] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/07/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
With the growing prevalence of obesity and diabetes in the United States and across the world, a rise in the overall incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is expected. The risk factors for NAFLD are also associated with the development of chronic kidney disease (CKD). We review the epidemiology, risk factors, genetics, implications of gut dysbiosis, and specific pathogenic mechanisms linking NAFLD to CKD. Mechanisms such as ectopic lipid accumulation, cellular signaling abnormalities, and the interplay between fructose consumption and uric acid accumulation have led to the emergence of potential therapeutic implications for this patient population. Transplant evaluation in the setting of both NAFLD and CKD is also reviewed. Potential strategies for surveillance and management include the monitoring of comorbidities, the use of non-invasive fibrosis scoring systems, and the measurement of laboratory markers. Lastly, we discuss the management of patients with NAFLD and CKD, from preventative measures to experimental interventions.
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Affiliation(s)
- Rajiv Heda
- Department of Internal Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Masahiko Yazawa
- Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Michelle Shi
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
| | - Madhu Bhaskaran
- Department of Nephrology, Northwell Health/Zucker School of Medicine at Hosftra, Manhasset, NY 11030, United States
| | - Fuad Zain Aloor
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Paul J Thuluvath
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD 21202, United States
| | - Sanjaya K Satapathy
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
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Wu Y, Xiao H, Pi J, Zhang H, Pan A, Pu Y, Liang Z, Shen J, Du J, Huang T. LncRNA lnc_13814 promotes the cells apoptosis in granulosa cells of duck by acting as apla-miR-145-4 sponge. Cell Cycle 2021; 20:927-942. [PMID: 33843432 DOI: 10.1080/15384101.2021.1911102] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Follicle development is a vital factor which determines the reproductive performance of poultry. Long noncoding RNAs (lncRNAs) have been reported to maintain animal reproductive function and play key roles in ovarian development and hormone secretion. But the regulatory mechanism of lncRNAs in duck follicle development has seldom been reported. In this study, to better explore the molecular mechanism of follicle development in ducks, the follicular lncRNA was sequenced and analyzed. A total of 9,551 lncRNAs were predicted in the duck follicles. Four hundred and forty-five lncRNAs were differentially expressed between the white follicles and yellow follicles. The results of our studies showed that lnc_13814 promoted cell apoptosis in duck GCs. Furthermore, the bioinformatics analysis results demonstrated that lnc_13814 was involved in a lncRNA-miRNA-mRNA coexpression network and it was observed to sponge two follicle-related miRNAs by a luciferase activity assay. Moreover, we found that overexpression of lnc_13814 significantly increased DNA damage inducible transcript 3 (DDIT3) expression and downregulated GCs apoptosis. Finally, we found that lnc_13814 directly binds to and inhibits apla-mir-145-4; then, lnc_13814 increases the expression of DDIT3 and up-regulates GCs apoptosis. Taken together, our findings demonstrate that lncRNAs have potential effects on duck ovarian follicles and lncRNAs may represent a new approach to understand follicular development.
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Affiliation(s)
- Yan Wu
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China.,Hubei Key Laboratory of Animal Embryo and Molecular Breeding, Hubei Academy of Agricultural Science, Wuhan, China
| | - Hongwei Xiao
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Jinsong Pi
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Hao Zhang
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Ailuan Pan
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Yuejin Pu
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Zhenhua Liang
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Jie Shen
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Jinping Du
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
| | - Tao Huang
- Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Science, Wuhan, China
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Fernandes-da-Silva A, Miranda CS, Santana-Oliveira DA, Oliveira-Cordeiro B, Rangel-Azevedo C, Silva-Veiga FM, Martins FF, Souza-Mello V. Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas. Eur J Nutr 2021; 60:2949-2960. [PMID: 33742254 DOI: 10.1007/s00394-021-02542-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 03/11/2021] [Indexed: 12/11/2022]
Abstract
Obesity challenges lipid and carbohydrate metabolism. The resulting glucolipotoxicity causes endoplasmic reticulum (ER) dysfunction, provoking the accumulation of immature proteins, which triggers the unfolded protein reaction (UPR) as an attempt to reestablish ER homeostasis. When the three branches of UPR fail to correct the unfolded/misfolded proteins, ER stress happens. Excessive dietary saturated fatty acids or fructose exhibit the same impact on the ER stress, induced by excessive ectopic fat accumulation or rising blood glucose levels, and meta-inflammation. These metabolic abnormalities can alleviate through dietary interventions. Many pathways are disrupted in adipose tissue, liver, and pancreas during ER stress, compromising browning and thermogenesis, favoring hepatic lipogenesis, and impairing glucose-stimulated insulin secretion within pancreatic beta cells. As a result, ER stress takes part in obesity, hepatic steatosis, and diabetes pathogenesis, arising as a potential target to treat or even prevent metabolic diseases. The scientific community seeks strategies to alleviate ER stress by avoiding inflammation, apoptosis, lipogenesis suppression, and insulin sensitivity augmentation through pharmacological and non-pharmacological interventions. This comprehensive review aimed to describe the contribution of excessive dietary fat or sugar to ER stress and the impact of this adverse cellular environment on adipose tissue, liver, and pancreas function.
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Affiliation(s)
- Aline Fernandes-da-Silva
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Carolline Santos Miranda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Daiana Araujo Santana-Oliveira
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Brenda Oliveira-Cordeiro
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Camilla Rangel-Azevedo
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Flávia Maria Silva-Veiga
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Fabiane Ferreira Martins
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil.
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Gindin Y, Chung C, Jiang Z, Zhou JZ, Xu J, Billin AN, Myers RP, Goodman Z, Landi A, Houghton M, Green RM, Levy C, Kowdley KV, Bowlus CL, Muir AJ, Trauner M. A Fibrosis-Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis. Hepatology 2021; 73:1105-1116. [PMID: 32745270 PMCID: PMC8048608 DOI: 10.1002/hep.31488] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/23/2020] [Accepted: 07/07/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (n = 74) enrolled in a 96-week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events. APPROACH AND RESULTS The effect of fibrosis was subtracted from gene expression using a computational approach. The fibrosis-adjusted gene expression patterns were associated with time to first PSC-related clinical event (e.g., cholangitis, hepatic decompensation), and differential expression based on risk groups and Ingenuity Pathway Analysis were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA-sequencing data accounted for 18% of variance and correlated with fibrosis stage (ρ = -0.80; P < 0.001). After removing the effect of fibrosis-related genes, the first principle component was not associated with fibrosis (ρ = -0.19; P = 0.11), and a semisupervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC-related event (P < 0.0001). The two groups had similar fibrosis stage, hepatic collagen content, and α-smooth muscle actin expression by morphometry, Enhanced Liver Fibrosis score, and serum liver biochemistry, bile acids, and IL-8 (all P > 0.05). The top pathways identified by Ingenuity Pathway Analysis were eukaryotic translation inhibition factor 2 (eIF2) signaling and regulation of eIF4/p70S6K signaling. Genes involved in the unfolded protein response, activating transcription factor 6 (ATF6) and eIF2, were differentially expressed between the PSC clusters (down-regulated in the high-risk group by log-fold changes of -0.18 [P = 0.02] and -0.16 [P = 0.02], respectively). Clinical events were enriched in the high-risk versus low-risk group (38% [12/32] vs. 2.4% [1/42], P < 0.0001). CONCLUSIONS Removing the contribution of fibrosis-related pathways uncovered alterations in the unfolded protein response, which were associated with liver-related complications in PSC.
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Affiliation(s)
| | | | | | | | - Jun Xu
- Gilead Sciences, Inc.Foster CityCA
| | | | | | | | - Abdolamir Landi
- Department of Medical Microbiology and ImmunologyLi Ka Shing Institute of VirologyUniversity of AlbertaEdmontonABCanada
| | - Michael Houghton
- Department of Medical Microbiology and ImmunologyLi Ka Shing Institute of VirologyUniversity of AlbertaEdmontonABCanada
| | - Richard M Green
- Division of Gastroenterology and HepatologyDepartment of MedicineFeinberg School of Medicine atNorthwestern UniversityChicagoIL
| | | | | | - Christopher L Bowlus
- Division of Gastroenterology and HepatologyUniversity of California at DavisSacramentoCA
| | | | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
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Amanatidou AI, Dedoussis GV. Construction and analysis of protein-protein interaction network of non-alcoholic fatty liver disease. Comput Biol Med 2021; 131:104243. [PMID: 33550014 DOI: 10.1016/j.compbiomed.2021.104243] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/15/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease with multidimensional complexities. Many attempts have been made over the years to treat this disease but its incidence is rising. For this reason, the need to identify and study new candidate proteins that may be associated with NAFLD is of utmost importance. Systems-based approaches such as the analysis of protein-protein interaction (PPI) network could lead to the discovery of new proteins associated with a disease that can then be translated into clinical practice. The aim of this study is to analyze the interaction network of human proteins associated with NAFLD as well as their experimentally verified interactors and to identify novel associations with other human proteins that may be involved in this disease. Computational analysis made it feasible to detect 77 candidate proteins associated with NAFLD, having high network scores. Furthermore, clustering analysis was performed to identify densely connected regions with biological significance in this network. Additionally, gene expression analysis was conducted to validate part of the findings of this research work. We believe that our research will be helpful in extending experimental efforts to address the pathogenesis and progression of NAFLD.
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Affiliation(s)
- Athina I Amanatidou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, El. Venizelou 70, 17671, Athens, Greece.
| | - George V Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, El. Venizelou 70, 17671, Athens, Greece.
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37
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Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence. Cells 2020; 9:cells9112458. [PMID: 33187255 PMCID: PMC7698018 DOI: 10.3390/cells9112458] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/28/2020] [Accepted: 11/07/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)—the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.
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38
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Sun DQ, Ye FZ, Kani HT, Yang JR, Zheng KI, Zhang HY, Targher G, Byrne CD, Chen YP, Yuan WJ, Yilmaz Y, Zheng MH. Higher liver stiffness scores are associated with early kidney dysfunction in patients with histologically proven non-cirrhotic NAFLD. DIABETES & METABOLISM 2020; 46:288-295. [PMID: 31786360 DOI: 10.1016/j.diabet.2019.11.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/03/2019] [Accepted: 11/09/2019] [Indexed: 12/18/2022]
Abstract
AIM The association between Liver fibrosis (LF), as assessed by either histology or Liver stiffness measurement (LSM), and the presence of Early kidney dysfunction (EKD) was investigated in this study, as was also the diagnostic performance of LSM for identifying the presence of EKD in patients with Non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS A total of 214 adults with non-cirrhotic biopsy-proven NAFLD were recruited from two independent medical centres. Their histological stage of LF was quantified using Brunt's criteria. Vibration-controlled Transient elastography (TE), using M-probe (FibroScan®) ultrasound, was performed in 154 patients and defined as significant when LSM was≥8.0kPa. EKD was defined as the presence of microalbuminuria with an estimated glomerular filtration rate≥60mL/min/1.73 m2. Logistic regression modelling was used to estimate the likelihood of having EKD with NAFLD (LSM-EKD model). RESULTS The prevalence of EKD was higher in patients with vs without LF on histology (22.14% vs 4.82%, respectively; P<0.001) and, similarly, EKD prevalence was higher in patients with LSM≥8.0kPa vs LSM<8.0kPa (23.81% vs 6.59%, respectively; P<0.05). The area under the ROC curve of the LSM-EKD model for identifying EKD was 0.80 (95% CI: 0.72-0.89). LF detected by either method was associated with EKD independently of established renal risk factors and potential confounders. CONCLUSION LF was independently associated with EKD in patients with biopsy-proven NAFLD. Thus, TE-measured LSM, a widely used technique for quantifying LF, can accurately identify those patients with NAFLD who are at risk of having EKD.
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Affiliation(s)
- D-Q Sun
- Department of Nephrology, Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China; Department of Nephrology, Shanghai General Hospital of Nanjing Medical University, Shanghai, China
| | - F-Z Ye
- NAFLD Research Centre, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - H T Kani
- Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey
| | - J-R Yang
- Department of Clinical Laboratory, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - K I Zheng
- NAFLD Research Centre, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - H-Y Zhang
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, China
| | - G Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - C D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Y-P Chen
- NAFLD Research Centre, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - W-J Yuan
- Department of Nephrology, Shanghai General Hospital of Nanjing Medical University, Shanghai, China
| | - Y Yilmaz
- Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey; Institute of Gastroenterology, Marmara University, Istanbul, Turkey.
| | - M-H Zheng
- NAFLD Research Centre, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.
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39
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Chen Y, Tian Z. Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis. Front Immunol 2020; 11:1500. [PMID: 32765518 PMCID: PMC7378363 DOI: 10.3389/fimmu.2020.01500] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), is accompanied by steatosis, hepatocyte injury and liver inflammation, which has been a health problem in the world as one of the major high risk factors of cirrhosis and hepatocellular carcinoma (HCC). Complex immune responses involving T cells, B cells, Kupffer cells, monocytes, neutrophils, DCs and other innate lymphocytes account for the pathogenesis of NASH; however, the underlying mechanisms have not been clearly elucidated in detail. In the liver, innate and innate-like lymphocytes account for more than two-thirds of total lymphocytes and play an important role in maintaining the immune homeostasis. Therefore, their roles in the progression of NASH deserves investigation. In this review, we summarized murine NASH models for immunological studies, including the diet-induced NASH, chemical-induced NASH and genetic-induced NASH. The role of innate and innate-like lymphocytes including NK cells, ILCs, NKT, γδT and MAIT cells in the progression of NASH were elucidated. Further, the metabolic regulation of the innate immune response was addressed in consideration to explain the molecular mechanisms. Based on the findings of the reviewed studies, strategies of immune intervention are proposed to control the progression of NASH.
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Affiliation(s)
- Yongyan Chen
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Zhigang Tian
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
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40
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Gansemer ER, McCommis KS, Martino M, King-McAlpin AQ, Potthoff MJ, Finck BN, Taylor EB, Rutkowski DT. NADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis. iScience 2020; 23:101116. [PMID: 32417402 PMCID: PMC7254477 DOI: 10.1016/j.isci.2020.101116] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 03/25/2020] [Accepted: 04/27/2020] [Indexed: 02/08/2023] Open
Abstract
Many metabolic diseases disrupt endoplasmic reticulum (ER) homeostasis, but little is known about how metabolic activity is communicated to the ER. Here, we show in hepatocytes and other metabolically active cells that decreasing the availability of substrate for the tricarboxylic acid (TCA) cycle diminished NADPH production, elevated glutathione oxidation, led to altered oxidative maturation of ER client proteins, and attenuated ER stress. This attenuation was prevented when glutathione oxidation was disfavored. ER stress was also alleviated by inhibiting either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity increased NADPH production, glutathione reduction, and ER stress. Validating these findings, deletion of the Mitochondrial Pyruvate Carrier-which is known to decrease TCA cycle activity and protect the liver from steatohepatitis-also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. Together, our results demonstrate a novel pathway by which mitochondrial metabolic activity is communicated to the ER through the relay of redox metabolites.
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Affiliation(s)
- Erica R Gansemer
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Kyle S McCommis
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USA
| | - Michael Martino
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USA
| | - Abdul Qaadir King-McAlpin
- Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Matthew J Potthoff
- Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Obesity Research Initiative, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Brian N Finck
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USA
| | - Eric B Taylor
- Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Obesity Research Initiative, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - D Thomas Rutkowski
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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Chen Z, Tian R, She Z, Cai J, Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med 2020; 152:116-141. [PMID: 32156524 DOI: 10.1016/j.freeradbiomed.2020.02.025] [Citation(s) in RCA: 777] [Impact Index Per Article: 155.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 02/20/2020] [Accepted: 02/26/2020] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide and is strongly associated with the presence of oxidative stress. Disturbances in lipid metabolism lead to hepatic lipid accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. Mitochondrial function adapts to NAFLD mainly through the downregulation of the electron transport chain (ETC) and the preserved or enhanced capacity of mitochondrial fatty acid oxidation, which stimulates ROS overproduction within different ETC components upstream of cytochrome c oxidase. However, non-ETC sources of ROS, in particular, fatty acid β-oxidation, appear to produce more ROS in hepatic metabolic diseases. Endoplasmic reticulum stress and NADPH oxidase alterations are also associated with NAFLD, but the degree of their contribution to oxidative stress in NAFLD remains unclear. Increased ROS generation induces changes in insulin sensitivity and in the expression and activity of key enzymes involved in lipid metabolism. Moreover, the interaction between redox signaling and innate immune signaling forms a complex network that regulates inflammatory responses. Based on the mechanistic view described above, this review summarizes the mechanisms that may account for the excessive production of ROS, the potential mechanistic roles of ROS that drive NAFLD progression, and therapeutic interventions that are related to oxidative stress.
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Affiliation(s)
- Ze Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Institute of Model Animals of Wuhan University, Wuhan, 430072, PR China
| | - Ruifeng Tian
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Institute of Model Animals of Wuhan University, Wuhan, 430072, PR China
| | - Zhigang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Institute of Model Animals of Wuhan University, Wuhan, 430072, PR China; Basic Medical School, Wuhan University, Wuhan, 430071, PR China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, PR China
| | - Jingjing Cai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, 410013, PR China; Institute of Model Animals of Wuhan University, Wuhan, 430072, PR China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Institute of Model Animals of Wuhan University, Wuhan, 430072, PR China; Basic Medical School, Wuhan University, Wuhan, 430071, PR China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, PR China.
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Salminen A, Kaarniranta K, Kauppinen A. ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease. J Mol Med (Berl) 2020; 98:633-650. [PMID: 32279085 PMCID: PMC7220864 DOI: 10.1007/s00109-020-01904-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/24/2020] [Accepted: 03/26/2020] [Indexed: 12/14/2022]
Abstract
The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer’s disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer’s disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer’s disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.,Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029, Kuopio, Finland
| | - Anu Kauppinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
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Maiwall R, Gupta M. Peri-transplant renal dysfunction in patients with non-alcoholic steatohepatitis undergoing liver transplantation. Transl Gastroenterol Hepatol 2020; 5:18. [PMID: 32258522 DOI: 10.21037/tgh.2019.10.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/15/2019] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most common etiology of chronic liver disease (CLD) caused by an accumulation of fat in the liver and globally is the leading indication of liver transplantation. Emerging data has recognized an increased association of NAFLD with risk of other metabolic liver diseases like type 2 diabetes mellitus, chronic kidney disease (CKD) and cardiovascular diseases. Pathophysiologically, NAFLD patients have a state of low-grade systemic inflammation, insulin resistance and atherogenic dyslipidemia which causes renal dysfunction. Patients with NAFLD cirrhosis awaiting liver transplant (LT) face unique challenges and have a significantly higher requirement of simultaneous-liver-kidney transplant as compared to other etiologies. Further, NAFLD not only recurs but also occurs as a de novo manifestation post-LT. There is also a significantly higher risk of waiting list stagnation and dropouts due to burdensome cardiometabolic disorders in NAFLD patients. The current review aims to understand the prevalence and pathogenetic basis of renal dysfunction in NAFLD. Additionally, the review describes the choice of immunosuppression protocols and use of intraoperative renal replacement therapy in context of intra and post-operative renal dysfunction in NAFLD patients. Prospective controlled trials focusing on NAFLD and development of CKD are needed to assess the existence of a causal and/or a bidirectional relationship between NAFLD and CKD.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manasvi Gupta
- Department of Internal Medicine, University of Connecticut School of Medicine, Hartford, CT, USA
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Vallée D, Blanc M, Lebeaupin C, Bailly-Maitre B. [Endoplasmic reticulum stress response and pathogenesis of non-alcoholic steatohepatitis]. Med Sci (Paris) 2020; 36:119-129. [PMID: 32129747 DOI: 10.1051/medsci/2020008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. Non-alcoholic fatty liver disease (NAFLD) is currently affecting 20-30% of the general population and 75-100% of obese individuals. NAFLD ranges from simple steatosis to damaging non-alcoholic steatohepatitis (NASH), potentially developing into hepatocellular carcinoma. No efficient pharmacological treatment is yet available. During obesity, the hepatic ER stress response can arise from extracellular stress (lipids, glucose, cytokines) and from intracellular stress including lipid buildup in the hepatocyte (steatosis), a hallmark of NAFLD. The chronic activation of the hepatic ER stress response may be a crucial event in the steatosis-NASH transition, triggering cell death, inflammation and accelerating metabolic disorders. We discuss these aspects and we propose that targeting the ER stress response could be effective in treating NAFLD.
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Affiliation(s)
- Déborah Vallée
- Centre méditerranéen de médecine moléculaire (C3M), Inserm U1065, 151, Route de St Antoine de Ginestière, 06204 Nice, France
| | - Marina Blanc
- Centre méditerranéen de médecine moléculaire (C3M), Inserm U1065, 151, Route de St Antoine de Ginestière, 06204 Nice, France
| | - Cynthia Lebeaupin
- Centre méditerranéen de médecine moléculaire (C3M), Inserm U1065, 151, Route de St Antoine de Ginestière, 06204 Nice, France
| | - Béatrice Bailly-Maitre
- Centre méditerranéen de médecine moléculaire (C3M), Inserm U1065, 151, Route de St Antoine de Ginestière, 06204 Nice, France
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Yang W, Liu R, Xia C, Chen Y, Dong Z, Huang B, Li R, Li M, Xu C. Effects of different fatty acids on BRL3A rat liver cell damage. J Cell Physiol 2020; 235:6246-6256. [PMID: 32012270 DOI: 10.1002/jcp.29553] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 01/10/2020] [Indexed: 12/15/2022]
Abstract
To evaluate the effects of fatty acids on endoplasmic reticulum (ER) stress, oxidative stress, and lipid damage. We treated BRL3A rat liver cells with, linoleic (LA), linolenic, oleic (OA), palmitic (PA), palmitoleic (POA), or stearic (SA) acid for 12 hr. The characteristics of cell lipid deposition, oxidative stress indexes, ER stress markers, nuclear factor κB p65 (NF-κB p65), lipid synthesis and transport regulators, and cholesterol metabolism regulators were analyzed. Endoplasmic chaperones like glucose-regulated protein 78, CCAAT-enhancer-binding protein, NF-κB p65, hydrogen peroxide, and malonaldehyde in PA- and SA-treated cells were significantly higher than in other treated cells. Deposition of fatty acids especially LA and POA were significantly increased than in other treated cells. De novo lipogenesis regulators sterol regulatory element-binding protein 1c, fatty acid synthase, and acetyl-coenzyme A carboxylase 1 (ACC1) expression were significantly increased in all fatty acid stimulation groups, and PA- and SA-treated cells showed lower p-ACC1 expression and higher scd1 expression than other fatty acid groups. Very low-density lipoprotein synthesis and apolipoprotein B100 expression in free fatty acids treated cells were significantly lower than control. PA, SA, OA, and POA had shown significantly increased cholesterol synthesis than other treated cells. PA and SA showed the lower synthesis of cytochrome P7A1 and total bile acids than other fatty acids treated cells. Excess of saturated fatty acids led to severe ER and oxidative stress. Excess unsaturated fatty acids led to increased lipid deposition in cultured hepatocytes. A balanced fatty acid intake is needed to maintain lipid homeostasis.
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Affiliation(s)
- Wei Yang
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Runqi Liu
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Cheng Xia
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yuanyuan Chen
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Zhihao Dong
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Baoyin Huang
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Ruirui Li
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Ming Li
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Chuang Xu
- Clinical Veterinary Medicine, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
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Palmitic acid damages gut epithelium integrity and initiates inflammatory cytokine production. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158530. [DOI: 10.1016/j.bbalip.2019.158530] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 07/16/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023]
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Ramalingam L, Sopontammarak B, Menikdiwela KR, Moustaid-Moussa N. Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells. Diabetes Metab Syndr Obes 2020; 13:2843-2853. [PMID: 32884312 PMCID: PMC7443445 DOI: 10.2147/dmso.s257797] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/24/2020] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION The renin angiotensin aldosterone system (RAAS) is a hormone system known for its role in regulating blood pressure and fluid balance. Numerous RAAS inhibitors routinely prescribed for hypertension have also beneficial effects in type 2 diabetes (T2D) prevention. RAAS components are expressed locally in many tissues, including adipose tissue and pancreas, where they exert metabolic effects through RAAS bioactive hormone angiotensin II (Ang II). Pancreatic beta cells are specialized insulin-producing cells; they have also developed endoplasmic reticulum (ER), which contributes to beta cell dysfunction, when proteins are misfolded in disease states such as T2D. However, no studies have investigated the relationship between RAAS and ER stress in beta cells as a mechanism linking pancreatic RAAS to T2D. Hence, we hypothesized that Ang II treatment of beta cells increases ER stress and inflammation leading to reduced insulin secretion. METHODS To test this hypothesis, we treated clonal INS-1E beta cells and human islets with Ang II and assessed changes in ER stress markers. INS-1E beta cells were also used for measuring insulin secretion and for assessing the effects of various RAAS and ER stress inhibitors. RESULTS We demonstrated that Ang II significantly increased the expression of ER stress genes such as Chop and Atf4 and reduced insulin secretion. Furthermore, inhibition of Ang II production with an angiotensin converting enzyme inhibitor (ACEi, captopril) significantly reduced ER stress. Moreover, the Ang II receptor blockade reduced ER stress significantly and rescued insulin secretion. DISCUSSION This research provides new mechanistic insight into the role of RAAS activation via ER stress on beta cell dysfunction and provides additional evidence for protective effects of RAAS inhibition in T2D.
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Affiliation(s)
- Latha Ramalingam
- Department of Nutritional Sciences, And Obesity Research Institute, Texas Tech University, Lubbock, TX79424, USA
| | - Boontharick Sopontammarak
- Department of Nutritional Sciences, And Obesity Research Institute, Texas Tech University, Lubbock, TX79424, USA
| | - Kalhara R Menikdiwela
- Department of Nutritional Sciences, And Obesity Research Institute, Texas Tech University, Lubbock, TX79424, USA
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, And Obesity Research Institute, Texas Tech University, Lubbock, TX79424, USA
- Correspondence: Naima Moustaid-Moussa Texas Tech University, Department of Nutritional Sciences & Obesity Research Institute, 1301 Akron Street, Lubbock, TX79409-1270, USATel + 806-834-7946 Email
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Duvigneau JC, Luís A, Gorman AM, Samali A, Kaltenecker D, Moriggl R, Kozlov AV. Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases. Cytokine 2019; 124:154577. [DOI: 10.1016/j.cyto.2018.10.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/18/2018] [Indexed: 12/11/2022]
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Dai P, Shen D, Shen J, Tang Q, Xi M, Li Y, Li C. The roles of Nrf2 and autophagy in modulating inflammation mediated by TLR4 - NFκB in A549 cell exposed to layer house particulate matter 2.5 (PM 2.5). CHEMOSPHERE 2019; 235:1134-1145. [PMID: 31561304 DOI: 10.1016/j.chemosphere.2019.07.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/23/2019] [Accepted: 07/01/2019] [Indexed: 06/10/2023]
Abstract
Particulate matter (PM) from layer house has adverse effect on people and chicken respiratory health, which can further influence animal performance and reduce production efficiency. However, little study focus on the respiratory inflammation induced by PM2.5 from layer house and the underlying mechanism also unclear. In this study, human adenocarcinoma alveolar basal epithelial cells (A549 cell) was subjected to the PM2.5 from layer house to evaluate the inflammation reaction caused by PM2.5 and explore the role of Nrf2 and autophagy in regulating the inflammation. Results showed that the viability of A549 cell decreased in a time - and concentration - dependent manner after PM2.5 treatment. TNFα, IL6, and IL8 increased significantly treated with PM2.5 at 12 h. RNA sequencing indicated differentially expressed genes were enriched in immune system process, oxidative stress (OS), endoplasmic reticulum stress (ERS), and autophagy. Further studies showed TLR4 - NFκB p65 signal pathway involved in the inflammation reaction caused by PM2.5. The overexpression of Nrf2 decreased the level of TNFα, IL6, IL8 markedly as well as the level of NFκB p65 and NFκB pp65. OS and ERS were also limited under overactivation of Nrf2 in PM2.5 treated cells. Autophagy induced by PM2.5 promoted the inflammation through increasing the level of NFκB p65 and NFκB pp65. Autophagy deficient strengthened the expression of Nrf2. Collectively, our study revealed Nrf2 prevents inflammation caused by layer house PM2.5 stimulation, however, autophagy exerts a promotive role in TLR4 - NFκB p65 mediating inflammation in A549 cell.
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Affiliation(s)
- Pengyuan Dai
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, PR China
| | - Dan Shen
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, PR China
| | - Jiakun Shen
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, PR China
| | - Qian Tang
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, PR China
| | - Mengxue Xi
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, PR China
| | - Yansen Li
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, PR China
| | - Chunmei Li
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, PR China.
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Zai JA, Khan MR, Mughal ZUN, Batool R, Naz I, Maryam S, Zahra Z. Methanol extract of Iphiona aucheri ameliorates CCl 4 induced hepatic injuries by regulation of genes in rats. Toxicol Res (Camb) 2019; 8:815-832. [PMID: 34055308 PMCID: PMC8142630 DOI: 10.1039/c9tx00157c] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/18/2019] [Indexed: 12/13/2022] Open
Abstract
We have investigated the protective potential of methanol extract of Iphiona aucheri (IAM) on the expression of endoplasmic reticulum (ER) stress associated genes and inflammatory genes on carbon tetrachloride (CCl4) induced hepatic toxicity in rats. Hepatic damage markers: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin were elevated while the content of antioxidants: catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and reduced glutathione (GSH) were decreased significantly (p < 0.05) in CCl4 treated rats as compared to the control group. The CCl4 intoxication induced a higher expression of glucose-regulated protein 78 kDa (GRP78), X-box-binding protein 1 total (XBP1t), spliced X-box-binding protein 1 (XBP1s), unspliced X-box-binding protein 1 (XBP1u), C/EBP homologous protein (CHOP) and genes involved in inflammation and fibrosis: tumor necrosis factor alpha (TNF-α), transforming growth factor-beta (TGF-β), mothers against DPP homolog 3 (SMAD3), alpha skeletal muscle actin (αSMA) and collagen type I alpha 1 chain (COL1A1). The intoxicated rats showed a low expression of the glutamate-cysteine ligase catalytic subunit (GCLC), protein disulfide isomerase (PDI) and nuclear factor (erythroid-derived 2) like-2 (Nrf2). The administration of IAM to intoxicated rats restored the expression of ER stress, inflammatory, fibrosis and antioxidant genes in a dose dependent manner. Our results indicated that IAM can impede the ER stress and inflammatory genes and it could be a complementary and alternative therapeutic agent for oxidative stress associated disorders.
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Affiliation(s)
- Jawaid Ahmed Zai
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Muhammad Rashid Khan
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Zaib Un Nisa Mughal
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Riffat Batool
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Irum Naz
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Sonia Maryam
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
| | - Zartash Zahra
- Department of Biochemistry , Faculty of Biological Sciences , Quaid-i-azam University Islamabad , Islamabad , Pakistan . ; ; ; ; ; ;
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