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Barik A, Bhoga D, Dhingra T, Karmarkar G, Ghosh B, Malik N, Parmar K, Datta A, Borah A, Bhattacharya P. Clemastine Reduces post-stroke Neurodegeneration by Alleviating Endoplasmic Reticulum stress-mediated Demyelination and Cognitive Impairment Through PERK/ATF4/CHOP Signaling Pathway. Neurochem Res 2025; 50:151. [PMID: 40274676 DOI: 10.1007/s11064-025-04403-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/02/2025] [Accepted: 04/15/2025] [Indexed: 04/26/2025]
Abstract
The progressive brain damage following ischemic stroke is primarily due to oxidative stress and activation of inflammatory pathways. Post-stroke neurodegeneration can lead to the loss of neurons and glial cells, including oligodendrocytes, contributing to demyelination. Following ischemic stroke, reperfusion results in increased intracellular calcium, generation of free radicals, and inflammation culminating in accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen augmenting the ER stress. ER stress has been shown to aggravate post-stroke neurodegeneration by triggering neuronal apoptosis and also contributing towards demyelination of neurons. To address the limitations of current stroke therapies, repurposing of drugs as future adjunctive therapy may be promising. Clemastine, an antihistaminic drug, improves post stroke outcome as evident in the present study. Male Sprague Dawley (SD) rats were treated with clemastine following ischemic stroke. Harvested brain tissues were subjected to different biochemical assays, molecular assays, and histopathological analysis. Clemastine was able to reduce infarct size, alleviate oxidative stress, improve neuronal count, and functional outcomes. Clemastine downregulated genes and proteins responsible for ER stress, apoptosis and demyelination as shown by the western blot and qPCR results. Our study suggests that clemastine may alleviate endoplasmic reticulum stress-mediated demyelination by modulating PERK/ATF4/CHOP axis, and may be used as one of the adjunctive therapies for stroke in future.
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Affiliation(s)
- Anirban Barik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Dipakkumar Bhoga
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Tannu Dhingra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Gautam Karmarkar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Bijoyani Ghosh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Nikita Malik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Krupanshu Parmar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, 788011, Assam, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Gandhinagar-382355, Ahmedabad, Gujarat, India.
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He P, Chang H, Qiu Y, Wang Z. Mitochondria associated membranes in dilated cardiomyopathy: connecting pathogenesis and cellular dysfunction. Front Cardiovasc Med 2025; 12:1571998. [PMID: 40166597 PMCID: PMC11955654 DOI: 10.3389/fcvm.2025.1571998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/27/2025] [Indexed: 04/02/2025] Open
Abstract
Dilated cardiomyopathy (DCM) is a leading cause of heart failure, yet therapeutic options remain limited. While traditional research has focused on mechanisms such as energy deficits and calcium dysregulation, increasing evidence suggests that mitochondria-associated membranes (MAMs) could provide new insights into understanding and treating DCM. In this narrative review, we summarize the key role of MAMs, crucial endoplasmic reticulum (ER)-mitochondria interfaces, in regulating cellular processes such as calcium homeostasis, lipid metabolism, and mitochondrial dynamics. Disruption of MAMs function may initiate pathological cascades, including ER stress, inflammation, and cell death. These disruptions in MAM function lead to further destabilization of cellular homeostasis. Identifying MAMs as key modulators of cardiac health may provide novel insights for early diagnosis and targeted therapies in DCM.
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Affiliation(s)
- Pingge He
- Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Hongbo Chang
- Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Yueqing Qiu
- Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Zhentao Wang
- Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, China
- Department of Cardiovascular Medicine, Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
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3
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Yakut S, Gelen V, Kara H, Özkanlar S, Yeşildağ A. Silver Nanoparticles Loaded With Oleuropein Alleviates LPS-Induced Acute Lung Injury by Modulating the TLR4/P2X7 Receptor-Mediated Inflammation and Apoptosis in Rats. ENVIRONMENTAL TOXICOLOGY 2024; 39:4960-4973. [PMID: 38980228 DOI: 10.1002/tox.24369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/30/2024] [Accepted: 05/23/2024] [Indexed: 07/10/2024]
Abstract
Toll-like receptor 4 (TLR-4) ligands were initially shown to be the source of lipopolysaccharide (LPS), a gram-negative bacterium's cell wall immunostimulatory component. Oxidative stress, apoptosis, and inflammation are all potential effects of LPS treatment on the lungs. By triggering oxidative stress and inflammation, these negative effects could be avoided. Robust flavonoid oleuropein (OLE) exhibits anti-inflammatory, antiproliferative, and antioxidative properties. A nanodelivery system could improve its low bioavailability, making it more effective and useful in treating chronic human ailments. This study evaluates the effects of AgNP-loaded OLE on LPS-induced lung injury in rats in terms of TLR4/P2X7 receptor-mediated inflammation and apoptosis. Forty-eight male albino rats were randomly divided into eight groups. Drugs were administered to the groups in the doses specified as follows: Control, LPS (8 mg/kg ip), OLE (50 mg/kg) AgNPs (100 mg/kg), OLE + AgNPs (50 mg/kg), LPS + OLE (oleuropein 50 mg/kg ig + LPS 8 mg/kg ip), LPS + AgNPs (AgNPs 100 mg/kg ig + LPS 8 mg/kg ip), and LPS + OLE + AgNPs (OLE + AgNPs 50 mg/kg + LPS 8 mg/kg ip). After the applications, the rats were decapitated under appropriate conditions, and lung tissues were obtained. Oxidative stress (SOD, MDA, and GSH), and inflammation (IL-6, IL-1β, TNF-α, Nrf2, P2X7R, AKT, and TLR4) parameters were evaluated in the obtained lung tissues. Additionally, histopathology studies were performed on lung tissue samples. The data obtained were evaluated by comparison between groups. Both OLE and OLE + AgNPs showed potential in reducing oxidative stress, inflammation, and apoptosis (p < 0.05). These findings were supported by histopathological analysis, which revealed that tissue damage was reduced in OLE and OLE + AgNPs-treated groups. According to the results, LPS-induced lung injury can be reduced by using nanotechnology and producing OLE + AgNP.
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Affiliation(s)
- Seda Yakut
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
| | - Volkan Gelen
- Department of Physiology, Faculty of Veterinary Medicine, Kafkas University, Kars, Turkey
| | - Hülya Kara
- Department of Anatomy, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Seçkin Özkanlar
- Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Ali Yeşildağ
- Department of Bioengineering, Faculty of Engineering and Architecture, Kafkas University, Kars, Turkey
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Xie Y, Tang Y, Yang J, Atta M, Wang N, Qin H. Sesamol Alleviated Lipotoxicity-Induced Dysfunction in MIN6 Cells via Facilitating Cellular Senescence Caused by Endoplasmic Reticulum Stress. J Biochem Mol Toxicol 2024; 38:e70038. [PMID: 39470143 DOI: 10.1002/jbt.70038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/21/2024] [Accepted: 10/18/2024] [Indexed: 10/30/2024]
Abstract
Obesity is found to be a significant risk factor for type 2 diabetes mellitus (T2DM), attributed to lipotoxicity-induced β-cell dysfunction. However, the specific mechanism involved in the process remains incompletely unclarified. The current study demonstrated lipotoxicity resulted in the activation of ER stress, which increased the protein level of TXNIP, thereby inducing senescence-assiciated dysfunction in MIN6 cells under high fat environment. And we also found sesamol, a natural functional component extracted from sesame, was able to alleviate senescence-associated β-cell dysfunction induced by lipotoxicity by inhibiting ER stress and TXNIP. Our findings provided novel insights into senescence-related T2DM and propose innovative therapeutic approaches for utilizing sesamol in the treatment of T2DM in the obese elderly population.
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Affiliation(s)
- Yan Xie
- Department of Nutrition and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha, China
| | - Yongyan Tang
- Department of Nutrition and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jinxin Yang
- Department of Nutrition and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha, China
| | - Mahnoor Atta
- Department of Nutrition and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha, China
| | - Nan Wang
- Department of Obstetrics, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Hong Qin
- Department of Nutrition and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha, China
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González Ibáñez F, VanderZwaag J, Deslauriers J, Tremblay MÈ. Ultrastructural features of psychological stress resilience in the brain: a microglial perspective. Open Biol 2024; 14:240079. [PMID: 39561812 PMCID: PMC11576122 DOI: 10.1098/rsob.240079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/25/2024] [Accepted: 10/15/2024] [Indexed: 11/21/2024] Open
Abstract
Psychological stress is the major risk factor for major depressive disorder. Sustained stress causes changes in behaviour, brain connectivity and in its cells and organelles. Resilience to stress is understood as the ability to recover from stress in a positive way or the resistance to the negative effects of psychological stress. Microglia, the resident immune cells of the brain, are known players of stress susceptibility, but less is known about their role in stress resilience and the cellular changes involved. Ultrastructural analysis has been a useful tool in the study of microglia and their function across contexts of health and disease. Despite increased access to electron microscopy, the interpretation of electron micrographs remains much less accessible. In this review, we will first present microglia and the concepts of psychological stress susceptibility and resilience. Afterwards, we will describe ultrastructural analysis, notably of microglia, as a readout to study the mechanisms underlying psychological stress resilience. Lastly, we will cover nutritional ketosis as a therapeutic intervention that was shown to be effective in promoting psychological stress resilience as well as modifying microglial function and ultrastructure.
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Affiliation(s)
- Fernando González Ibáñez
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec, Québec, Canada
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Jared VanderZwaag
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
- Neuroscience Graduate Program, University of Victoria, Victoria, British Columbia, Canada
| | | | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
- Department of Molecular Medicine, Université Laval, Québec, Québec, Canada
- Neurology and Neurosurgery Department, McGill University, Montréal, Québec, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Advanced Materials and Related Technology, University of Victoria, Victoria, British Columbia, Canada
- Institute on Aging and Lifelong Health, University of Victoria, Victoria, British Columbia, Canada
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6
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Wu TJ, Teng M, Jing X, Pritchard KA, Day BW, Naylor S, Teng RJ. Endoplasmic Reticulum Stress in Bronchopulmonary Dysplasia: Contributor or Consequence? Cells 2024; 13:1774. [PMID: 39513884 PMCID: PMC11544778 DOI: 10.3390/cells13211774] [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: 09/27/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Oxidative stress (OS) and inflammation are the major contributors to BPD. Despite aggressive treatments, BPD prevalence remains unchanged, which underscores the urgent need to explore more potential therapies. The endoplasmic reticulum (ER) plays crucial roles in surfactant and protein synthesis, assisting mitochondrial function, and maintaining metabolic homeostasis. Under OS, disturbed metabolism and protein folding transform the ER structure to refold proteins and help degrade non-essential proteins to resume cell homeostasis. When OS becomes excessive, the endogenous chaperone will leave the three ER stress sensors to allow subsequent changes, including cell death and senescence, impairing the growth potential of organs. The contributing role of ER stress in BPD is confirmed by reproducing the BPD phenotype in rat pups by ER stress inducers. Although chemical chaperones attenuate BPD, ER stress is still associated with cellular senescence. N-acetyl-lysyltyrosylcysteine amide (KYC) is a myeloperoxidase inhibitor that attenuates ER stress and senescence as a systems pharmacology agent. In this review, we describe the role of ER stress in BPD and discuss the therapeutic potentials of chemical chaperones and KYC, highlighting their promising role in future therapeutic interventions.
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Affiliation(s)
- Tzong-Jin Wu
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (M.T.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Michelle Teng
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (M.T.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Xigang Jing
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (M.T.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Kirkwood A. Pritchard
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
- Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
- ReNeuroGen LLC, 2160 San Fernando Dr., Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
| | - Billy W. Day
- ReNeuroGen LLC, 2160 San Fernando Dr., Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
| | - Stephen Naylor
- ReNeuroGen LLC, 2160 San Fernando Dr., Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
| | - Ru-Jeng Teng
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (T.-J.W.); (M.T.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
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Liu N, Xu Y, Sun L, Li M, Huang J, Hao B. The signal peptide of BmNPV GP64 activates the ERAD pathway to regulate heterogeneous secretory protein expression. Microb Cell Fact 2024; 23:284. [PMID: 39420373 PMCID: PMC11487928 DOI: 10.1186/s12934-024-02534-7] [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: 11/15/2023] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
As a powerful eukaryotic expression vector, the baculovirus expression vector system (BEVS) is widely applied to the production of heterogeneous proteins for research and pharmaceutical purposes, while optimization of BEVS remains a work in progress for membrane or secreted protein expression. In this study, the impact of the signal peptide (SP) derived from Bombyx mori nucleopolyhedrovirus (BmNPV) GP64 protein on protein expression, secretion, and the endoplasmic reticulum-associated degradation (ERAD) pathway were investigated in BmN cells and BEVS. Transient expression studies in BmN cells revealed that SP alters the localization and expression levels of recombinant proteins, reducing intracellular accumulation while enhancing secretion efficiency. Quantitative analysis demonstrated that SP-mediated secretion was markedly higher compared to controls, albeit with lower total expression levels. Further exploration into SP-mediated ERAD pathway activation showed increased expression of BiP and other ERAD-associated genes (PDI, UFD1, S1P, and ASK1), correlating with higher SP-driven protein expression levels. RNA interference (RNAi) experiments elucidated that knockdown of ERAD-associated genes enhances both the secretion efficiency of SP-guided proteins and the infectivity of BmNPV. Particularly, interference with BiP demonstrated the most pronounced effect on protein secretion enhancement. Viral infection experiments further supported these findings, showing upregulated ERAD-associated genes during BmNPV infection, indicating their role in viral protein processing and infectivity. In conclusion, this study elucidates the complex interplay between SP-mediated protein secretion, ERAD pathway activation, and viral infectivity in BmNPV-infected cells. These insights suggest strategies for optimizing recombinant protein production and viral protein processing in baculovirus expression systems, with potential implications for biotechnological and biomedical applications. Further research could refine our understanding and manipulation of protein secretion pathways in insect cell-based expression systems.
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Affiliation(s)
- Na Liu
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, PR China
| | - Ying Xu
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, PR China
| | - Luping Sun
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, PR China
| | - Mengmeng Li
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, PR China
| | - Jinshan Huang
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, PR China
- Key Laboratory of Genetic Improvement of Sericulture in the Ministry of Agriculture, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu, PR China
| | - Bifang Hao
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, PR China.
- Key Laboratory of Genetic Improvement of Sericulture in the Ministry of Agriculture, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu, PR China.
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8
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Nguyen TH, Ko HJ, Tsai PY, Cheng TS, Tran TH, Doan LH, Hsiao M, Chang PMH, Liu HS, Hong YR, Huang CYF. Dehydroepiandrosterone suppresses human colorectal cancer progression through ER stress-mediated autophagy and apoptosis in a p53-independent manner. Front Pharmacol 2024; 15:1464647. [PMID: 39431156 PMCID: PMC11487585 DOI: 10.3389/fphar.2024.1464647] [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: 07/14/2024] [Accepted: 09/16/2024] [Indexed: 10/22/2024] Open
Abstract
Colorectal cancer (CRC) is one of the primary contributors to cancer-related fatalities, with up to 80% of advanced CRC cases exhibiting mutations in the p53 gene. Unfortunately, the development of new compounds targeting mutant p53 is quite limited. The anticancer effects of Dehydroepiandrosterone (DHEA) on various cancers have been reported. However, the suppressive effect of DHEA on CRC cells harboring wild-type or mutant p53 gene remains controversial. This study emphasized revealing the suppressive mechanism and the effect of DHEA on CRC cell tumorigenesis in the presence of wild-type or mutant p53 gene. We demonstrate that DHEA causes CRC cell death and cell cycle arrest in a dose and time-dependent manner. Notably, DHEA exhibits similar inhibitory effects on CRC cells regardless of the p53 gene status. Further study reveals that DHEA induces endoplasmic reticulum (ER) stress and triggers PERK/eIF2/ATF4/CHOP UPR signaling pathway to activate autophagy followed by apoptosis, which was confirmed by suppression of 4-phenylbutyric acid (an ER stress inhibitor) or knockdown either ATF4 or CHOP. DHEA-induced apoptosis was attenuated by silencing ATG5 gene in either p53+/+ or p53-/- CRC cells, indicating autophagy regulation of apoptosis. Furthermore, DHEA treatment accompanied by bafilomycin A1 (a blocker of autophagosome degradation) leads to the accumulation of ATF4, CHOP, DR5, and p21 levels in CRC cells, implying that the degradative autophagy machinery regulates these four molecules. Consistently, DHEA demonstrates its inhibitory effect by suppressing CRC tumor formation in vivo. Altogether, we provide compelling evidence that DHEA is a potential therapeutic candidate for CRC patient treatment regardless of the p53 status through ER stress-PERK-autophagy-apoptosis axis.
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Affiliation(s)
- Thi-Huong Nguyen
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biotechnology and Food Technology, Thai Nguyen University of Agriculture and Forestry, Thai Nguyen, Vietnam
| | - Huey-Jiun Ko
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Yu Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tai-Shan Cheng
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Thu-Ha Tran
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ly Hien Doan
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biotechnology, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Michael Hsiao
- Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Peter Mu-Hsin Chang
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsiao-Sheng Liu
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Ren Hong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chi-Ying F. Huang
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Mishra T, Sengupta P, Basu S. Biomaterials for Targeting Endoplasmic Reticulum in Cancer. Chem Asian J 2024; 19:e202400250. [PMID: 38602248 DOI: 10.1002/asia.202400250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/12/2024]
Abstract
Endoplasmic reticulum (ER) is one of the most important sub-cellular organelles which controls myriads of biological functions including protein biosynthesis with proper functional folded form, protein misfolding, protein transport into Golgi body for secretion, Ca2+ homeostasis and so on. Subsequently, dysregulation in ER function leads to ER stress followed by disease pathology like cancer. Hence, targeting ER in the cancer cells emerged as one of the futuristic strategies for cancer treatment. However, the major challenge is to selectively and specifically target ER in the sub-cellular milieu in the cancer tissues, due to the lack of ER targeting chemical moieties to recognize the ER markers. To address this, in the last decade, numerous biomaterials were explored to selectively impair and image ER in cancer cells to induce ER stress. This review outlines those biomaterials which consists of carbon and silicon materials, lipid nanoparticles (liposomes and micelles), supramolecular self-assembled nanostructures, cell membrane-coated nanoparticles and metallic nanoparticles. Moreover, we also discuss the challenges and possible solutions of this promising field to usher the readers towards next-generation ER targeted cancer therapy.
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Affiliation(s)
- Tripti Mishra
- Department of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gujarat, 382355, India
| | - Poulomi Sengupta
- Department of Chemistry, Indrashil University, Rajpur, Kadi, Mehsana, Gujarat, 382740, India
| | - Sudipta Basu
- Department of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gujarat, 382355, India
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10
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Liu X, Hong E, Xie J, Li J, Ding B, Chen Y, Xia Z, Jiang W, Lv H, Yang B, Chen Y. Txnrd2 Attenuates Early Brain Injury by Inhibition of Oxidative Stress and Endoplasmic Reticulum Stress via Trx2/Prx3 Pathway after Intracerebral Hemorrhage in Rats. Neuroscience 2024; 545:158-170. [PMID: 38513765 DOI: 10.1016/j.neuroscience.2024.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 03/13/2024] [Accepted: 03/17/2024] [Indexed: 03/23/2024]
Abstract
Thioredoxin-reductase 2 (Txnrd2) belongs to the thioredoxin-reductase family of selenoproteins and is a key antioxidant enzyme in mammalian cells to regulate redox homeostasis. Here, we reported that Txnrd2 exerted a major influence in brain damage caused by Intracerebral hemorrhage (ICH) by suppressing endoplasmic reticulum (ER) stress oxidative stress and via Trx2/Prx3 pathway. Furthermore, we demonstrated that pharmacological selenium (Se) rescued the brain damage after ICH by enhancing Txnrd2 expression. Primarily, expression and localization of Txnrd2, Trx2 and Prx3 were determined in collagenase IV-induced ICH model. Txnrd2 was then knocked down using siRNA interference in rats which were found to develop more severe encephaledema and neurological deficits. Mechanistically, we observed that loss of Txnrd2 leads to increased lipid peroxidation levels and ER stress protein expression in neurons and astrocytes. Additionally, it was revealed that Se effectively restored the expression of Txnrd2 in brain and inhibited both the activity of ER stress protein activity and the generation of reactive oxygen species (ROS) by promoting Trx2/Prx3 kilter when administrating sodium selenite in lateral ventricle. This study shed light on the effect of Txnrd2 in regulating oxidative stress and ER stress via Trx2/Prx3 pathway upon ICH and its promising potential as an ICH therapeutic target.
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Affiliation(s)
- Xuanbei Liu
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, China
| | - Enhui Hong
- Department of Neurosurgery, Jiu Jiang No.1 People's Hospital, Jiu Jiang, China
| | - Jiayu Xie
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, China
| | - Jiangwei Li
- Department of Neurosurgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Boyun Ding
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, China
| | - Yongsheng Chen
- Department of Neurosurgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Zhennan Xia
- Department of Neurosurgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Weiping Jiang
- Department of Neurosurgery, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Hongzhu Lv
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, China
| | - Bo Yang
- Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, China
| | - Yizhao Chen
- Department of Neurosurgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, The National Key Clinical Specialty, The Neurosurgery Institute of Guangdong Province, The Engineering Technology Research Center of Education Ministry of China, Southern Medical University, Guangzhou, China.
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11
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Mubarak SJ, Gupta S, Vedagiri H. Scaffold Hopping and Screening for Potent Small Molecule Agonists for GRP94: Implications to Alleviate ER Stress-Associated Pathogenesis. Mol Biotechnol 2024; 66:737-755. [PMID: 36763304 DOI: 10.1007/s12033-023-00685-3] [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: 09/30/2022] [Accepted: 01/27/2023] [Indexed: 02/11/2023]
Abstract
Disparity in the activity of Endoplasmic reticulum (ER) leads to degenerative diseases, mainly associated with protein misfolding and aggregation leading to cellular dysfunction and damage, ultimately contributing to ER stress. ER stress activates the complex network of Unfolded Protein Response (UPR) signaling pathways mediated by transmembrane proteins IRE1, ATF6, and PERK. In addition to UPR, many ER chaperones have evolved to optimize the output of properly folded secretory and membrane proteins. Glucose-regulated protein 94 (GRP94), an ER chaperone of heat shock protein HSP90 family, directs protein folding through interaction with other components of the ER protein folding machinery and assists in ER-associated degradation (ERAD). Activation of GRP94 would increase the efficacy of protein folding machinery and regulate the UPR pathway toward homeostasis. The present study aims to screen for novel agonists for GRP94 based on Core hopping, pharmacophore hypothesis, 3D-QSAR, and virtual screening with small-molecule compound libraries in order to improve the efficiency of native protein folding by enhancing GRP94 chaperone activity, therefore to reduce protein misfolding and aggregation. In this study, we have employed the strategy of small molecule-dependent ER programming to enhance the chaperone activity of GRP94 through scaffold hopping-based screening approach to identify specific GRP94 agonists. New scaffolds generated by altering the cores of NECA, the known GRP94 agonist, were validated by employing pharmacophore hypothesis testing, 3D-QSAR modeling, and molecular dynamics simulations. This facilitated the identification of small molecules to improve the efficiency of native protein folding by enhancing GRP94 activity. High-throughput virtual screening of the selected pharmacophore hypothesis against Selleckchem and ZINC databases retrieved a total of 2,27,081 compounds. Further analysis on docking and ADMET properties revealed Epimedin A, Narcissoside, Eriocitrin 1,2,3,4,6-O-Pentagalloylglucose, Secoisolariciresinol diglucoside, ZINC92952357, ZINC67650204, and ZINC72457930 as potential lead molecules. The stability and interaction of these small molecules were far better than the known agonist, NECA indicating their efficacy in selectively alleviating ER stress-associated pathogenesis. These results substantiate the fact that small molecule-dependent ER reprogramming would activate the ER chaperones and therefore reduce the protein misfolding as well as aggregation associated with ER stress in order to restore cellular homeostasis.
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Affiliation(s)
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Hemamalini Vedagiri
- Department of Bioinformatics, Bharathiar University, Coimbatore, Tamil Nadu, India.
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12
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Eltayeb A, Al-Sarraj F, Alharbi M, Albiheyri R, Mattar EH, Abu Zeid IM, Bouback TA, Bamagoos A, Uversky VN, Rubio-Casillas A, Redwan EM. Intrinsic factors behind long COVID: IV. Hypothetical roles of the SARS-CoV-2 nucleocapsid protein and its liquid-liquid phase separation. J Cell Biochem 2024; 125:e30530. [PMID: 38349116 DOI: 10.1002/jcb.30530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 01/10/2024] [Accepted: 01/24/2024] [Indexed: 03/12/2024]
Abstract
When the SARS-CoV-2 virus infects humans, it leads to a condition called COVID-19 that has a wide spectrum of clinical manifestations, from no symptoms to acute respiratory distress syndrome. The virus initiates damage by attaching to the ACE-2 protein on the surface of endothelial cells that line the blood vessels and using these cells as hosts for replication. Reactive oxygen species levels are increased during viral replication, which leads to oxidative stress. About three-fifths (~60%) of the people who get infected with the virus eradicate it from their body after 28 days and recover their normal activity. However, a large fraction (~40%) of the people who are infected with the virus suffer from various symptoms (anosmia and/or ageusia, fatigue, cough, myalgia, cognitive impairment, insomnia, dyspnea, and tachycardia) beyond 12 weeks and are diagnosed with a syndrome called long COVID. Long-term clinical studies in a group of people who contracted SARS-CoV-2 have been contrasted with a noninfected matched group of people. A subset of infected people can be distinguished by a set of cytokine markers to have persistent, low-grade inflammation and often self-report two or more bothersome symptoms. No medication can alleviate their symptoms efficiently. Coronavirus nucleocapsid proteins have been investigated extensively as potential drug targets due to their key roles in virus replication, among which is their ability to bind their respective genomic RNAs for incorporation into emerging virions. This review highlights basic studies of the nucleocapsid protein and its ability to undergo liquid-liquid phase separation. We hypothesize that this ability of the nucleocapsid protein for phase separation may contribute to long COVID. This hypothesis unlocks new investigation angles and could potentially open novel avenues for a better understanding of long COVID and treating this condition.
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Affiliation(s)
- Ahmed Eltayeb
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Faisal Al-Sarraj
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mona Alharbi
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Raed Albiheyri
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Immunology Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ehab H Mattar
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Isam M Abu Zeid
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Thamer A Bouback
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Atif Bamagoos
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Moscow Region, Russia
| | - Alberto Rubio-Casillas
- Autlan Regional Hospital, Health Secretariat, Autlan, Jalisco, Mexico
- Biology Laboratory, Autlan Regional Preparatory School, University of Guadalajara, Autlan, Jalisco, Mexico
| | - Elrashdy M Redwan
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah, Saudi Arabia
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13
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Lin Y, Chen H, Lee W, Ho W, Chang S, Chen Y, Yang T, Chen M. Effect of His Bundle Pacing on Abnormal Myocardial Fatty Acid and Glucose Metabolism Induced by Right Ventricular Pacing. J Am Heart Assoc 2024; 13:e032386. [PMID: 38348809 PMCID: PMC11010098 DOI: 10.1161/jaha.123.032386] [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: 10/18/2023] [Accepted: 01/11/2024] [Indexed: 02/21/2024]
Abstract
BACKGROUND Metabolic disorder is noted for pacing-induced cardiomyopathy. The benefits of His bundle pacing over right ventricular (RV) pacing in preventing pacing-induced cardiomyopathy from a metabolic perspective are yet to be fully understood. METHOD AND RESULTS Three pig groups were established for this study: sham control, RV pacing (RV pacing for 6 months), and His pacing (RV pacing for 6 months, followed by His bundle pacing for 3 months). Complete atrioventricular block was created in the last 2 groups. Left ventricular function and dyssynchrony were assessed via echocardiography, while proteins linked to metabolism, endoplasmic reticulum stress, and inflammation in left ventricular myocardium were examined. The RV pacing group had significantly more left ventricular mechanical dyssynchrony compared with the other groups. The RV pacing group exhibited triglyceride and diacylglycerol accumulation in cardiomyocytes and higher expression of binding immunoglobulin protein and tumor necrosis factor-α than the other groups. Additionally, the expression of CD36 was activated, while the expression of hormone-sensitive lipase was downregulated in the RV pacing group compared with the His pacing and sham control groups. Furthermore, the expressions of GLUT4 and pyruvate dehydrogenase were higher in the RV pacing group than the sham control and His pacing groups. Notably, the abnormal fatty acid and glucose metabolic pathways in the left ventricular myocardium during RV pacing could be corrected by His bundle pacing. CONCLUSIONS His bundle pacing can mitigate the abnormal metabolism disorders, endoplasmic reticulum stress, and inflammation induced during RV pacing and may contribute to the superiority of conduction system pacing over RV pacing in reducing heart failure hospitalization.
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Affiliation(s)
- Yu‐Sheng Lin
- Division of CardiologyChang Gung Memorial HospitalChiayiTaiwan
- College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Huang‐Chung Chen
- Division of Cardiology, Department of Internal MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
| | - Wei‐Chieh Lee
- Division of Cardiology, Department of Internal MedicineChi Mei Medical CenterTainanTaiwan
| | - Wan‐Chun Ho
- Division of CardiologyChang Gung Memorial HospitalChiayiTaiwan
| | - Shun‐Fu Chang
- Department of Medical Research and DevelopmentChiayi Chang Gung Memorial HospitalChiayiTaiwan
| | - Yung‐Lung Chen
- College of MedicineChang Gung UniversityTaoyuanTaiwan
- Division of Cardiology, Department of Internal MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
| | - Teng‐Yao Yang
- Division of CardiologyChang Gung Memorial HospitalChiayiTaiwan
| | - Mien‐Cheng Chen
- College of MedicineChang Gung UniversityTaoyuanTaiwan
- Division of Cardiology, Department of Internal MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
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14
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Binmahfouz LS, Hassanein EH, Bagher AM, Hareeri RH, Alamri ZZ, Algandaby MM, Abdel-Daim MM, Abdel-Naim AB. Berberine alleviates chlorpyrifos-induced nephrotoxicity in rats via modulation of Nrf2/HO-1 axis. Heliyon 2024; 10:e25233. [PMID: 38327393 PMCID: PMC10847644 DOI: 10.1016/j.heliyon.2024.e25233] [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: 07/10/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/09/2024] Open
Abstract
Chlorpyrifos (CPS), an organophosphorus insecticide, is widely used for agricultural and non-agricultural purposes with hazardous health effects. Berberine (BBR) is a traditional Chinese medicine and a phytochemical with anti-inflammatory and anti-oxidative properties. The present study evaluated the effects of BBR against kidney damage induced by CPS and the underlying mechanisms. An initial study indicated that BBR 50 mg/kg was optimal under our experimental conditions. Then, 24 rats (6/group) were randomized into: control, BBR (50 mg/kg/day), CPS (10 mg/kg/day), and CPS + BBR. BBR was administration 1 h prior to CPS. Each treatment was delivered daily for a period of 28 consecutive days using a gastric gavage tube. Compared to CPS-alone treated rats, BBR effectively improved renal function by preventing the rise in serum urea, creatinine, and uric levels. The reno-protective effects of BBR were confirmed through a histological examination of kidney tissues. BBR restored oxidant-antioxidant balance in renal tissues mediated by Keap1/Nrf2/HO-1 axis modulation. In addition, BBR decreased nitric oxide (NO) and myeloperoxidase (MPO) activity. This was paralleled with the potent down-regulation of NF-κB. Furthermore, BBR exhibited anti-apoptotic activities supported by the upregulation of Bcl-2 and down-regulation of Bax and caspase-3 expression. In conclusion, our data suggest that BBR attenuates CPS-induced nephrotoxicity in rats by restoring oxidant-antioxidant balance and inhibiting inflammatory response and apoptosis in renal tissue. This is mediated, at least partly, by modulation of the Nrf2/HO-1 axis.
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Affiliation(s)
- Lenah S. Binmahfouz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Emad H.M. Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Amina M. Bagher
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Rawan H. Hareeri
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Zaenah Z. Alamri
- Department of Biological Sciences, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Mardi M. Algandaby
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Medicinal Plants Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Mohamed M. Abdel-Daim
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, Jeddah, 21442, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Ashraf B. Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Medicinal Plants Research Group, Deanship of Scientific Research, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
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15
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Gómez-Sierra T, Ortega-Lozano AJ, Rojas-Morales P, Medina-Reyes EI, Barrera-Oviedo D, Pedraza-Chaverri J. Isoliquiritigenin pretreatment regulates ER stress and attenuates cisplatin-induced nephrotoxicity in male Wistar rats. J Biochem Mol Toxicol 2023; 37:e23492. [PMID: 37561086 DOI: 10.1002/jbt.23492] [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: 09/13/2022] [Revised: 07/06/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023]
Abstract
Cisplatin (CP) is a chemotherapeutic drug used to treat solid tumors. However, studies have revealed its nephrotoxic effect. Oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction are involved in CP-induced renal damage. Thus, preconditioning (hormetic effect) of ER stress is a strategy to prevent CP-induced renal damage. On the other hand, isoliquiritigenin (IsoLQ) is recognized as a flavonoid with antioxidant properties and an inducer of ER stress. Therefore, we evaluated the ER stress-inducing capacity of IsoLQ and its possible protective effect against CP-induced nephrotoxicity in adult male Wistar rats. The findings reflected that IsoLQ pretreatment might decrease renal damage by reducing plasma creatinine and blood urea nitrogen levels in animals with CP-induced nephrotoxicity. These may be associated with IsoLQ activating ER stress and unfolded protein response (UPR). We found increased messenger RNA levels of the ER stress marker glucose-related protein 78 kDa (GRP78). In addition, we also found that pretreatment with IsoLQ reduced the levels of CCAAT/enhancer-binding protein-homologous protein (CHOP) and X-box-binding protein 1 (XBP1) in the renal cortex, reflecting that IsoLQ can regulate the UPR and activation of the apoptotic pathway. Moreover, this preconditioning with IsoLQ of ER stress had oxidative stress-regulatory effects, as it restored the activity of glutathione peroxidase and glutathione reductase enzymes. Finally, IsoLQ modifies the protein expression of mitofusin 2 (Mfn-2) and voltage-dependent anion channel (VDAC). In conclusion, these data suggest that IsoLQ pretreatment has a nephroprotective effect; it could functionally regulate the ER and mitochondria and reduce CP-induced renal damage by attenuating hormesis-mediated ER stress.
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Affiliation(s)
- Tania Gómez-Sierra
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico, Mexico
| | - Ariadna J Ortega-Lozano
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico, Mexico
| | - Pedro Rojas-Morales
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico, Mexico
| | - Estefany I Medina-Reyes
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico, Mexico
| | - Diana Barrera-Oviedo
- Department of Pharmacology, National Autonomous University of Mexico (UNAM), Mexico, Mexico
| | - José Pedraza-Chaverri
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico, Mexico
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16
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Nagar P, Sharma P, Dhapola R, Kumari S, Medhi B, HariKrishnaReddy D. Endoplasmic reticulum stress in Alzheimer's disease: Molecular mechanisms and therapeutic prospects. Life Sci 2023; 330:121983. [PMID: 37524162 DOI: 10.1016/j.lfs.2023.121983] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 07/22/2023] [Accepted: 07/25/2023] [Indexed: 08/02/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative condition that leads to memory loss and cognitive impairment over time. It is characterized by protein misfolding as well as prolonged cellular stress, such as perturbing calcium homeostasis and redox management. Numerous investigations have proven that endoplasmic reticulum failure may exhibit exacerbation of AD pathogenesis in AD patients, in-vivo and in-vitro models. The endoplasmic reticulum (ER) participates in a variety of biological functions including folding of protein, quality control, cholesterol production, and maintenance of calcium balance. A diverse range of physiological, pathological and pharmacological substances can interfere with ER activity and thus lead to exaggeration of ER stress. The unfolded protein response (UPR), an intracellular signaling network is stimulated due to ER stress. Three stress sensors found in the endoplasmic reticulum, the PERK, ATF6, and IRE1 transducers detect protein misfolding in the ER and trigger UPR, a complex system to maintain homeostasis. ER stress is linked to many of the major pathological processes that are seen in AD, including presenilin1 and 2 (PS1 and PS2) gene mutation, tau phosphorylation and β-amyloid formation. The role of ER stress and UPR in the pathophysiology of AD implies that they can be employed as potent therapeutic target. This study shows the relationship between ER and AD and how the pathogenesis of AD is influenced by the impact of ER stress. An effective method for the prevention or treatment of AD may involve therapeutic strategies that modify ER stress pathways.
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Affiliation(s)
- Pushank Nagar
- Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda 151401, Punjab, India
| | - Prajjwal Sharma
- Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda 151401, Punjab, India
| | - Rishika Dhapola
- Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda 151401, Punjab, India
| | - Sneha Kumari
- Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda 151401, Punjab, India
| | - Bikash Medhi
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Dibbanti HariKrishnaReddy
- Department of Pharmacology, School of Health Sciences, Central University of Punjab, Ghudda, Bathinda 151401, Punjab, India.
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17
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Suárez-Carrillo A, Álvarez-Córdoba M, Romero-González A, Talaverón-Rey M, Povea-Cabello S, Cilleros-Holgado P, Piñero-Pérez R, Reche-López D, Gómez-Fernández D, Romero-Domínguez JM, Munuera-Cabeza M, Díaz A, González-Granero S, García-Verdugo JM, Sánchez-Alcázar JA. Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN. Int J Mol Sci 2023; 24:14576. [PMID: 37834028 PMCID: PMC11340724 DOI: 10.3390/ijms241914576] [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: 05/25/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 10/15/2023] Open
Abstract
Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.
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Affiliation(s)
- Alejandra Suárez-Carrillo
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Mónica Álvarez-Córdoba
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Ana Romero-González
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Marta Talaverón-Rey
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Suleva Povea-Cabello
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Paula Cilleros-Holgado
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Rocío Piñero-Pérez
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Diana Reche-López
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - David Gómez-Fernández
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - José Manuel Romero-Domínguez
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Manuel Munuera-Cabeza
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
| | - Antonio Díaz
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY 10461, USA;
- Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Susana González-Granero
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46100 Valencia, Spain; (S.G.-G.); (J.M.G.-V.)
| | - José Manuel García-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46100 Valencia, Spain; (S.G.-G.); (J.M.G.-V.)
| | - José A. Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo, ABD-CSIC-Universidad Pablo de Olavide, 41013 Sevilla, Spain; (A.S.-C.); (M.Á.-C.); (A.R.-G.); (M.T.-R.); (S.P.-C.); (P.C.-H.); (R.P.-P.); (D.R.-L.); (D.G.-F.); (J.M.R.-D.); (M.M.-C.)
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18
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Beltran-Huarac J, Yamaleyeva DN, Dotti G, Hingtgen S, Sokolsky-Papkov M, Kabanov AV. Magnetic Control of Protein Expression via Magneto-mechanical Actuation of ND-PEGylated Iron Oxide Nanocubes for Cell Therapy. ACS APPLIED MATERIALS & INTERFACES 2023; 15:19877-19891. [PMID: 37040569 PMCID: PMC10143622 DOI: 10.1021/acsami.3c00179] [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: 01/05/2023] [Accepted: 04/05/2023] [Indexed: 05/03/2023]
Abstract
Engineered cells used as smart vehicles for delivery of secreted therapeutic proteins enable effective treatment of cancer and certain degenerative, autoimmune, and genetic disorders. However, current cell-based therapies use mostly invasive tools for tracking proteins and do not allow for controlled secretion of therapeutic proteins, which could result in unconstrained killing of surrounding healthy tissues or ineffective killing of host cancer cells. Regulating the expression of therapeutic proteins after success of therapy remains elusive. In this study, a noninvasive therapeutic approach mediated by magneto-mechanical actuation (MMA) was developed to remotely regulate the expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein, which is secreted by transduced cells. Stem cells, macrophages, and breast cancer cells were transduced with a lentiviral vector encoding the SGpL2TR protein. SGpL2TR comprises TRAIL and GpLuc domains optimized for cell-based applications. Our approach relies on the remote actuation of cubic-shape highly magnetic field responsive superparamagnetic iron oxide nanoparticles (SPIONs) coated with nitrodopamine PEG (ND-PEG), which are internalized within the cells. Cubic ND-PEG-SPIONs actuated by superlow frequency alternating current magnetic fields can translate magnetic forces into mechanical motion and in turn spur mechanosensitive cellular responses. Cubic ND-PEG-SPIONs were artificially designed to effectively operate at low magnetic field strengths (<100 mT) retaining approximately 60% of their saturation magnetization. Compared to other cells, stems cells were more sensitive to the interaction with actuated cubic ND-PEG-SPIONs, which clustered near the endoplasmic reticulum (ER). Luciferase, ELISA, and RT-qPCR analyses revealed a marked TRAIL downregulation (secretion levels were depleted down to 30%) when intracellular particles at 0.100 mg/mL Fe were actuated by magnetic fields (65 mT and 50 Hz for 30 min). Western blot studies indicated actuated, intracellular cubic ND-PEG-SPIONs can cause mild ER stress at short periods (up to 3 h) of postmagnetic field treatment thus leading to the unfolded protein response. We observed that the interaction of TRAIL polypeptides with ND-PEG can also contribute to this response. To prove the applicability of our approach, we used glioblastoma cells, which were exposed to TRAIL secreted from stem cells. We demonstrated that in the absence of MMA treatment, TRAIL essentially killed glioblastoma cells indiscriminately, but when treated with MMA, we were able to control the cell killing rate by adjusting the magnetic doses. This approach can expand the capabilities of stem cells to serve as smart vehicles for delivery of therapeutic proteins in a controlled manner without using interfering and expensive drugs, while retaining their potential to regenerate damaged tissue after treatment. This approach brings forth new alternatives to regulate protein expression noninvasively for cell therapy and other cancer therapies.
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Affiliation(s)
- Juan Beltran-Huarac
- Center
for Nanotechnology in Drug Delivery and Division of Pharmacoengineering
and Molecular Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Department
of Physics, Howell Science Complex, East
Carolina University, Greenville, North Carolina 27858, United States
| | - Dina N. Yamaleyeva
- Joint
UNC/NC State Department of Biomedical Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Gianpietro Dotti
- Lineberger
Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Shawn Hingtgen
- Division
of Pharmacoengineering and Molecular Therapeutics, Eshelman School
of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Marina Sokolsky-Papkov
- Center
for Nanotechnology in Drug Delivery and Division of Pharmacoengineering
and Molecular Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
| | - Alexander V. Kabanov
- Center
for Nanotechnology in Drug Delivery and Division of Pharmacoengineering
and Molecular Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
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19
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Bansal A, Kumar S, Rai N, Kumari S, Kumar V, Kumar A, Chandra NC. A Pilot Study on Blood Components in COVID-19 Affected Subjects: A Correlation to UPR Signalling and ER-Stress. Indian J Clin Biochem 2023; 38:374-384. [PMCID: PMC9997434 DOI: 10.1007/s12291-023-01121-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 02/20/2023] [Indexed: 03/12/2023]
Abstract
Abstract The endoplasmic reticulum (ER) is the site for protein synthesis, its folding and secretion. An intricate set of signalling pathways, called UPR pathways, have been evolved by ER in mammalian cells, to allow the cell to respond the presence of misfolded proteins within the ER. Breaching of these signalling systems by disease oriented accumulation of unfolded proteins may develop cellular stress. The aim of this study is to explore whether COVID-19 infection is responsible for developing this kind of endoplasmic reticulum related stress (ER-stress). ER-stress was evaluated by checking the expression of ER-stress markers e.g. PERK (adapting) and TRAF2 (alarming). ER-stress was correlated to several blood parameters viz. IgG, pro- and anti-inflammatory cytokines, leukocytes, lymphocytes, RBC, haemoglobin and PaO2/FiO2 ratio (ratio of arterial oxygen partial pressure to fractional inspired oxygen) in COVID-19 affected subjects. COVID-19 infection was found to be a state of protein homeostasis (proteostasis) collapse. Changes in IgG levels showed very poor immune response by the infected subjects. At the initial phase of the disease, pro-inflammatory cytokine levels were high and anti-inflammatory cytokines levels were low; though they were partly compromised at later phase of the disease. Total leukocyte concentration increased over the period of time; while percentage of lymphocytes were dropped. No significant changes were observed in cases of RBC counts and haemoglobin (Hb) levels. Both RBC and Hb were maintained at their normal range. In mildly stressed group, PaO2/FiO2 ratio (oxygenation status) was in the higher side of normal range; whereas in other two groups the ratio was in respiratory distress syndrome mode. Virus could induce mild to severe ER-stress, which could be the cause of cellular death and systemic dysfunction introducing fatal consequences. Graphical Abstract Schematic representation of SARS-CoV-2 infection and related consequences.![]()
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Affiliation(s)
- Akash Bansal
- Department of Biochemistry, All India Institute of Medical Sciences, Patna, 801507 India
| | - Sushil Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Patna, 801507 India
| | - Neha Rai
- Department of Biochemistry, All India Institute of Medical Sciences, Patna, 801507 India
| | - Shilpi Kumari
- Department of Biochemistry, School of Basic Applied Sciences, Galgotias University, Greater Noida, Gautam Budh Nagar, Uttar Pradesh 201301 India
| | - Visesh Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Patna, 801507 India
| | - Ajeet Kumar
- Department of Anesthesiology, All India Institute of Medical Sciences, Patna, 801507 India
| | - Nimai Chand Chandra
- Department of Biochemistry, All India Institute of Medical Sciences, Patna, 801507 India ,Present Address: Department of Biochemistry, SGT University, Budhera, Gurugram, Haryana 122505 India
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20
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Kwon J, Kim J, Kim KI. Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases. Anim Cells Syst (Seoul) 2023; 27:29-37. [PMID: 36860271 PMCID: PMC9970256 DOI: 10.1080/19768354.2023.2181217] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Cells activate protective mechanisms to overcome stressful conditions that threaten cellular homeostasis, including imbalances in calcium, redox, and nutrient levels. Endoplasmic reticulum (ER) stress activates an intracellular signaling pathway, known as the unfolded protein response (UPR), to mitigate such circumstances and protect cells. Although ER stress is sometimes a negative regulator of autophagy, UPR induced by ER stress typically activates autophagy, a self-degradative pathway that further supports its cytoprotective role. Sustained activation of ER stress and autophagy is known to trigger cell death and is considered a therapeutic target for certain diseases. However, ER stress-induced autophagy can also lead to treatment resistance in cancer and exacerbation of certain diseases. Since the ER stress response and autophagy affect each other, and the degree of their activation is closely related to various diseases, understanding their relationship is very important. In this review, we summarize the current understanding of two fundamental cellular stress responses, the ER stress response and autophagy, and their crosstalk under pathological conditions to help develop therapies for inflammatory diseases, neurodegenerative disorders, and cancer.
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Affiliation(s)
- Junhee Kwon
- Department of Biological Sciences, Sookmyung Women’s University, Seoul, Republic of Korea
| | - Jihyun Kim
- Department of Biological Sciences, Sookmyung Women’s University, Seoul, Republic of Korea
| | - Keun Il Kim
- Department of Biological Sciences, Sookmyung Women’s University, Seoul, Republic of Korea, Keun Il Kim Department of Biological Sciences, Sookmyung Women’s University, Seoul04310, Republic of Korea
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21
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Arab HH, Khames A, Alsufyani SE, El-Sheikh AAK, Gad AM. Targeting the Endoplasmic Reticulum Stress-Linked PERK/GRP78/CHOP Pathway with Magnesium Sulfate Attenuates Chronic-Restraint-Stress-Induced Depression-like Neuropathology in Rats. Pharmaceuticals (Basel) 2023; 16:300. [PMID: 37259443 PMCID: PMC9961498 DOI: 10.3390/ph16020300] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 09/29/2023] Open
Abstract
Magnesium sulfate has demonstrated marked neuroprotection in eclampsia, hypoxia, stroke, and post-traumatic brain injury rodent models. However, its potential impact against chronic-restraint-stress (CRS)-induced depression-like neuropathology and associated alterations in endoplasmic reticulum (ER) stress have not been adequately examined. The present study aimed to investigate the neuroprotective potential of magnesium sulfate in a rat model of CRS-triggered depression-like behavioral disturbance and the underlying molecular mechanisms. Herein, CRS was induced by placing rats into restraining tubes for 6 h/day for 21 days and the animals were intraperitoneally injected with magnesium sulfate (100 mg/kg/day) during the study period. After stress cessation, the depression-like behavior was examined by the open-field test, sucrose preference test, and forced swimming test. The present data demonstrated that CRS triggered typical depression-like behavioral changes which were confirmed by the Z-normalization scores. Mechanistically, serum circulating corticosterone levels spiked, and the hippocampi of CRS-exposed animals demonstrated a significant decline in serotonin, norepinephrine, and dopamine neurotransmitters. At the molecular level, the hippocampal pro-inflammatory TNF-alpha and IL-1β cytokines and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-HG) increased in stressed animals. In tandem, enhancement of hippocampal ER stress was evidenced by the activation of iNOS/PERK/GRP78/CHOP axis seen by increased protein expression of iNOS, PERK, GRP78, and CHOP signal proteins in the hippocampi of stressed rats. Interestingly, magnesium sulfate administration attenuated the depression-like behavioral outcomes and the histopathological changes in the brain hippocampi. These favorable actions were driven by magnesium sulfate's counteraction of corticosterone spike, and hippocampal neurotransmitter decline, alongside the attenuation of neuroinflammation, pro-oxidation, and ER stress. In conclusion, the current results suggest the promising neuroprotective/antidepressant actions of magnesium sulfate in CRS by dampening inflammation, ER stress, and the associated PERK/GRP78/CHOP pathway.
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Affiliation(s)
- Hany H. Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Ali Khames
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sohag University, Sohag 82511, Egypt
| | - Shuruq E. Alsufyani
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Azza A. K. El-Sheikh
- Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Amany M. Gad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Kantara Branch, Ismailia 41636, Egypt
- Department of Pharmacology, Egyptian Drug Authority (EDA)—Formerly NODCAR, Giza 12654, Egypt
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22
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Binayi F, Moslemi M, Khodagholi F, Hedayati M, Zardooz H. Long-term high-fat diet disrupts lipid metabolism and causes inflammation in adult male rats: possible intervention of endoplasmic reticulum stress. Arch Physiol Biochem 2023; 129:204-212. [PMID: 32907408 DOI: 10.1080/13813455.2020.1808997] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This study investigated the effect of long-term high-fat diet (HFD) on plasma lipid profile and probability of inflammation in adult rats. After weaning, male offspring were divided into six groups based on diet type and medication. After 20 weeks of dietary intake, 4-PBA (endoplasmic reticulum (ER) stress inhibitor) was injected for three days. Then, blood samples were taken to measure plasma concentrations of low-density lipoprotein (LDL), triglyceride (TG), high-density lipoprotein (HDL), cholesterol, leptin and interleukin 1-β (IL 1-β). The HFD increased body weight and food intake and intra-abdominal fat and thymus weights, which were associated with elevated plasma leptin level. Moreover, HFD increased plasma concentrations of TG, LDL, cholesterol and IL 1-β and decreased HDL level. Injection of 4-PBA reversed the plasma parameters changes caused by HFD. It seems that long-term HFD feeding through inducing the ER stress, disrupted the lipid metabolism and resulted in inflammation.
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Affiliation(s)
- Fateme Binayi
- Department of Physiology, School of Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Moslemi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Homeira Zardooz
- Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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23
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Deka D, D'Incà R, Sturniolo GC, Das A, Pathak S, Banerjee A. Role of ER Stress Mediated Unfolded Protein Responses and ER Stress Inhibitors in the Pathogenesis of Inflammatory Bowel Disease. Dig Dis Sci 2022; 67:5392-5406. [PMID: 35318552 DOI: 10.1007/s10620-022-07467-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 02/28/2022] [Indexed: 01/05/2023]
Abstract
Previous investigations have increased the knowledge about the pathological processes of inflammatory bowel diseases. Besides the complex organization of immune reactions, the mucosal epithelial lining has been recognized as a crucial regulator in the commencement and persistence of intestinal inflammation. As the intestinal epithelium is exposed to various environmental factors, the intestinal epithelial cells are confronted with diverse cellular stress conditions. In eukaryotic cells, an imbalance in the endoplasmic reticulum (ER) might cause aggregation of unfolded or misfolded proteins in the lumen of ER, a condition known as endoplasmic reticulum stress. This cellular mechanism stimulates the unfolded protein response (UPR), which elevates the potential of the endoplasmic reticulum protein folding, improves protein production and its maturation, and also stimulates ER-associated protein degradation. Current analyses reported that in the epithelium, the ER stress might cause the pathogenesis of inflammatory bowel disease that affects the synthesis of protein, inducing the apoptosis of the epithelial cell and stimulating the proinflammatory reactions in the gut. There have been significant efforts to develop small molecules or molecular chaperones that will be potent in ameliorating ER stress. The restoration of UPR balance in the endoplasmic reticulum via pharmacological intervention might be a novel therapeutic approach for the treatment of inflammatory bowel diseases (IBDs). This review provides novel insights into the role of chemical chaperone UPR modulators to modify ER stress levels. We further discuss the future directions/challenges in the development of therapeutic strategies for IBDs by targeting the ER stress. Figure depicting the role of endoplasmic reticulum stress-mediated inflammatory bowel disease and the therapeutic role of endoplasmic reticulum stress inhibitors in alleviating the diseased condition.
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Affiliation(s)
- Dikshita Deka
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Renata D'Incà
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy
| | - Giacomo Carlo Sturniolo
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy
| | - Alakesh Das
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India.
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24
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de la Calle CM, Shee K, Yang H, Lonergan PE, Nguyen HG. The endoplasmic reticulum stress response in prostate cancer. Nat Rev Urol 2022; 19:708-726. [PMID: 36168057 DOI: 10.1038/s41585-022-00649-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2022] [Indexed: 11/09/2022]
Abstract
In order to proliferate in unfavourable conditions, cancer cells can take advantage of the naturally occurring endoplasmic reticulum-associated unfolded protein response (UPR) via three highly conserved signalling arms: IRE1α, PERK and ATF6. All three arms of the UPR have key roles in every step of tumour progression: from cancer initiation to tumour growth, invasion, metastasis and resistance to therapy. At present, no cure for metastatic prostate cancer exists, as targeting the androgen receptor eventually results in treatment resistance. New research has uncovered an important role for the UPR in prostate cancer tumorigenesis and crosstalk between the UPR and androgen receptor signalling pathways. With an improved understanding of the mechanisms by which cancer cells exploit the endoplasmic reticulum stress response, targetable points of vulnerability can be uncovered.
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Affiliation(s)
- Claire M de la Calle
- Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Kevin Shee
- Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Heiko Yang
- Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Peter E Lonergan
- Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Department of Urology, St. James's Hospital, Dublin, Ireland
- Department of Surgery, Trinity College, Dublin, Ireland
| | - Hao G Nguyen
- Department of Urology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
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25
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Gómez-Sierra T, Jiménez-Uribe AP, Ortega-Lozano AJ, Ramírez-Magaña KJ, Pedraza-Chaverri J. Antioxidants affect endoplasmic reticulum stress-related diseases. VITAMINS AND HORMONES 2022; 121:169-196. [PMID: 36707134 DOI: 10.1016/bs.vh.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
The endoplasmic reticulum (ER) is a complex multifunctional organelle that maintains cell homeostasis. Intrinsic and extrinsic factors alter ER functions, including the rate of protein folding that triggers the accumulation of misfolded proteins and alters homeostasis, thus generating stress in the ER, which activates the unfolded protein response (UPR) pathway to promote cell survival and restore their homeostasis; however, if the damage is not corrected, it could also trigger cell death. In addition, ER stress and oxidative stress are closely related because excessive production of reactive oxygen species (ROS), a well-known inducer of ER stress, promotes the accumulation of misfolded proteins; at the same time, the ER stress enhances ROS production, generating a pathological cycle. Furthermore, it has been described that the dysregulation of the UPR contributes to the progression of various diseases, so the use of compounds capable of regulating ER stress, such as antioxidants, has been used in several experimental models of diseases to alleviate the damage induced by the maladaptive signaling of the UPR, the mechanism of action of antioxidants generally is dose-dependent, and it is specific in each tissue and pathology, could decrease or enhance specific proteins of the UPR to have beneficial or detrimental effects.
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Affiliation(s)
- Tania Gómez-Sierra
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Alexis Paulina Jiménez-Uribe
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Ariadna Jazmín Ortega-Lozano
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Karla Jaqueline Ramírez-Magaña
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - José Pedraza-Chaverri
- Antioxidant Biochemistry Laboratory, Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico.
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26
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Singla RK, Sharma P, Kumar D, Gautam RK, Goyal R, Tsagkaris C, Dubey AK, Bansal H, Sharma R, Shen B. The role of nanomaterials in enhancing natural product translational potential and modulating endoplasmic reticulum stress in the treatment of ovarian cancer. Front Pharmacol 2022; 13:987088. [PMID: 36386196 PMCID: PMC9643842 DOI: 10.3389/fphar.2022.987088] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/03/2022] [Indexed: 10/21/2023] Open
Abstract
Ovarian cancer, and particularly its most frequent type, epithelial ovarian carcinoma, constitutes one of the most dangerous malignant tumors among females. Substantial evidence has described the potential of phytochemicals against ovarian cancer. The effect of natural compounds on endoplasmic reticulum (ER) stress is of great relevance in this regard. In ovarian cancer, the accumulation of misfolded proteins in the ER lumen results in decompensated ER stress. This leads to deregulation in the physiological processes for the posttranslational modification of proteins, jeopardizes cellular homeostasis, and increases apoptotic signaling. Several metabolites and metabolite extracts of phytochemical origin have been studied in the context of ER stress in ovarian cancer. Resveratrol, quercetin, curcumin, fucosterol, cleistopholine, fucoidan, and epicatechin gallate, among others, have shown inhibitory potential against ER stress. The chemical structure of each compound plays an important role concerning its pharmacodynamics, pharmacokinetics, and overall effectiveness. Studying and cross-comparing the chemical features that render different phytochemicals effective in eliciting particular anti-ER stress actions can help improve drug design or develop multipotent combination regimens. Many studies have also investigated the properties of formulations such as nanoparticles, niosomes, liposomes, and intravenous hydrogel based on curcumin and quercetin along with some other phytomolecules in ovarian cancer. Overall, the potential of phytochemicals in targeting genetic mechanisms of ovarian cancer warrants further translational and clinical investigation.
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Affiliation(s)
- Rajeev K. Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Pooja Sharma
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India
- Khalsa College of Pharmacy, Amritsar, India
| | - Dinesh Kumar
- Chitkara University School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Rupesh K. Gautam
- Department of Pharmacology, Indore Institute of Pharmacy, IIST Campus, Opposite IIM Indore, Indore, India
| | - Rajat Goyal
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, India
| | | | | | - Himangini Bansal
- Delhi Institute of Pharmaceutical Sciences and Research, New Delhi, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, India
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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27
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Guo J, Nie J, Chen Z, Wang X, Hu H, Xu J, Lu J, Ma L, Ji H, Yuan J, Xu B. Cold exposure-induced endoplasmic reticulum stress regulates autophagy through the SIRT2/FoxO1 signaling pathway. J Cell Physiol 2022; 237:3960-3970. [PMID: 35938526 DOI: 10.1002/jcp.30856] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/21/2022] [Accepted: 07/27/2022] [Indexed: 01/14/2023]
Abstract
Cold is a factor affecting health in humans and animals. The liver, a major metabolic center, is highly susceptible to ambient air temperature. Recent studies have shown that endoplasmic reticulum (ER) stress is associated with the liver, and regulates the occurrence and development of liver injury and autophagy. However, the mechanism underlying the relationship between cold exposure and ER stress in the liver is not well understood. In this study, we investigated the effect of ER stress on liver autophagy and its mechanism under cold exposure. AML12 cells were treated with Tg to construct an ER stress model, and the level of autophagy increased. To further explore the mechanism through which ER stress regulates autophagy, we knocked down SIRT2 with shRNA in Tg-treated AML12 cells. Knockdown of SIRT2 significantly increased ER stress and autophagy, increased FoxO1 acetylation, and promoted its entry into the nucleus. To further verify the results of in vitro experiments, we exposed mice to 4°C for 3 h per day for 3 weeks to exacerbate the burden on the liver after cold exposure. Cold exposure damaged the structure and function of the liver and promoted the inflammatory response. It also activated ER stress and promoted autophagy. In addition, cold exposure inhibited the expression of SIRT2, promoted FoxO1 acetylation, and enhanced the interaction with autophagy. Our findings indicated that cold exposure induces liver damage, ER stress, and autophagy through the SIRT2/FoxO1 pathway. These findings suggest that SIRT2 may be a potential target for regulating health under cold exposure.
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Affiliation(s)
- Jingru Guo
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Junshu Nie
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Zhuo Chen
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Xian Wang
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Huijie Hu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jing Xu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jingjing Lu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Li Ma
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Hong Ji
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jianbin Yuan
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Bin Xu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
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28
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Zhou R, He M, Fan J, Li R, Zuo Y, Li B, Gao G, Sun T. The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review. Front Neurosci 2022; 16:947295. [PMID: 36188456 PMCID: PMC9523121 DOI: 10.3389/fnins.2022.947295] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022] Open
Abstract
Schizophrenia (SCZ) is a serious mental illness that affects 1% of people worldwide. SCZ is associated with a higher risk of developing metabolic disorders such as obesity. Antipsychotics are the main treatment for SCZ, but their side effects include significant weight gain/obesity. Despite extensive research, the underlying mechanisms by which SCZ and antipsychotic treatment induce weight gain/obesity remain unclear. Hypothalamic endoplasmic reticulum (ER) stress is one of the most important pathways that modulates inflammation, neuronal function, and energy balance. This review aimed to investigate the role of hypothalamic ER stress in SCZ and antipsychotic-induced weight gain/obesity. Preliminary evidence indicates that SCZ is associated with reduced dopamine D2 receptor (DRD2) signaling, which significantly regulates the ER stress pathway, suggesting the importance of ER stress in SCZ and its related metabolic disorders. Antipsychotics such as olanzapine activate ER stress in hypothalamic neurons. These effects may induce decreased proopiomelanocortin (POMC) processing, increased neuropeptide Y (NPY) and agouti-related protein (AgRP) expression, autophagy, and leptin and insulin resistance, resulting in hyperphagia, decreased energy expenditure, and central inflammation, thereby causing weight gain. By activating ER stress, antipsychotics such as olanzapine activate hypothalamic astrocytes and Toll-like receptor 4 signaling, thereby causing inflammation and weight gain/obesity. Moreover, evidence suggests that antipsychotic-induced ER stress may be related to their antagonistic effects on neurotransmitter receptors such as DRD2 and the histamine H1 receptor. Taken together, ER stress inhibitors could be a potential effective intervention against SCZ and antipsychotic-induced weight gain and inflammation.
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Affiliation(s)
- Ruqin Zhou
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Meng He
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
- *Correspondence: Meng He,
| | - Jun Fan
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Ruoxi Li
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufeng Zuo
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Benben Li
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Guanbin Gao
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, China
- Guanbin Gao,
| | - Taolei Sun
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
- Taolei Sun,
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29
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Lead Exposure Causes Spinal Curvature during Embryonic Development in Zebrafish. Int J Mol Sci 2022; 23:ijms23179571. [PMID: 36076969 PMCID: PMC9455242 DOI: 10.3390/ijms23179571] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/20/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
Lead (Pb) is an important raw material for modern industrial production, they enter the aquatic environment in several ways and cause serious harm to aquatic ecosystems. Lead ions (Pb2+) are highly toxic and can accumulate continuously in organisms. In addition to causing biological deaths, it can also cause neurological damage in vertebrates. Our experiment found that Pb2+ caused decreased survival, delayed hatching, decreased frequency of voluntary movements at 24 hpf, increased heart rate at 48 hpf and increased malformation rate in zebrafish embryos. Among them, the morphology of spinal malformations varied, with 0.4 mg/L Pb2+ causing a dorsal bending of the spine of 72 hpf zebrafish and a ventral bending in 120 hpf zebrafish. It was detected that spinal malformations were mainly caused by Pb2+-induced endoplasmic reticulum stress and apoptosis. The genetic changes in somatic segment development which disrupted developmental polarity as well as osteogenesis, resulting in uneven myotomal development. In contrast, calcium ions can rescue the series of responses induced by lead exposure and reduce the occurrence of spinal curvature. This article proposes new findings of lead pollution toxicity in zebrafish.
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30
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Li B, Zhang T, Tang M. Toxicity mechanism of nanomaterials: Focus on endoplasmic reticulum stress. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 834:155417. [PMID: 35472346 DOI: 10.1016/j.scitotenv.2022.155417] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/06/2022] [Accepted: 04/17/2022] [Indexed: 06/14/2023]
Abstract
Over the years, although the broad application of nanomaterials has not brought convenience to people's life, growing concern surrounds their safety. Recently, much emphasis has been placed on exploring the toxicity mechanism of nanoparticles. Currently established toxic mechanisms include oxidative stress, inflammatory response, autophagy, and DNA damage. In recent years, endoplasmic reticulum stress (ERS) has gained widespread attention as another toxic mechanism of nanomaterials. It is widely acknowledged that the endoplasmic reticulum (ER) is an important site for protein synthesis, and lipids and Ca+ storage, playing an esseential role in the normal operation of the body functions. When the body's internal environment is damaged, the structure and function of the endoplasmic reticulum are destroyed, leading to a series of biological reactions called endoplasmic reticulum stress (ERS.) This paper reviews the mechanism of ERS in nanomaterial-associated toxicity. The process of ERS and its related unfolded protein response were briefly introduced, summarizing the factors affecting the nanoparticle ability to induce ERS and expounding on the changes of ER morphology after exposure to nanoparticles. Finally, the specific role and molecular mechanism of ERS under the action of different nanoparticles were comprehensively analyzed, including the relationship between ERS and inflammation, oxidative stress, lipid metabolism and apoptosis. This review provides a foothold for future studies on the toxic mechanism of nanoparticles, and provides novel insights into the safe application of nanoparticles and the treatment of diseases.
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Affiliation(s)
- Binjing Li
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu 210009, China
| | - Ting Zhang
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu 210009, China.
| | - Meng Tang
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu 210009, China.
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31
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Caillet C, Stofberg ML, Muleya V, Shonhai A, Zininga T. Host cell stress response as a predictor of COVID-19 infectivity and disease progression. Front Mol Biosci 2022; 9:938099. [PMID: 36032680 PMCID: PMC9411049 DOI: 10.3389/fmolb.2022.938099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
The coronavirus disease (COVID-19) caused by a coronavirus identified in December 2019 has caused a global pandemic. COVID-19 was declared a pandemic in March 2020 and has led to more than 6.3 million deaths. The pandemic has disrupted world travel, economies, and lifestyles worldwide. Although vaccination has been an effective tool to reduce the severity and spread of the disease there is a need for more concerted approaches to fighting the disease. COVID-19 is characterised as a severe acute respiratory syndrome . The severity of the disease is associated with a battery of comorbidities such as cardiovascular diseases, cancer, chronic lung disease, and renal disease. These underlying diseases are associated with general cellular stress. Thus, COVID-19 exacerbates outcomes of the underlying conditions. Consequently, coronavirus infection and the various underlying conditions converge to present a combined strain on the cellular response. While the host response to the stress is primarily intended to be of benefit, the outcomes are occasionally unpredictable because the cellular stress response is a function of complex factors. This review discusses the role of the host stress response as a convergent point for COVID-19 and several non-communicable diseases. We further discuss the merits of targeting the host stress response to manage the clinical outcomes of COVID-19.
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Affiliation(s)
- Celine Caillet
- Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa
| | | | - Victor Muleya
- Department of Biochemistry, Midlands State University, Gweru, Zimbabwe
| | - Addmore Shonhai
- Department of Biochemistry and Microbiology, University of Venda, Thohoyandou, South Africa
| | - Tawanda Zininga
- Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa
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32
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Khan S. Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis. Mol Neurobiol 2022; 59:5630-5655. [PMID: 35739409 DOI: 10.1007/s12035-022-02916-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 06/05/2022] [Indexed: 11/29/2022]
Abstract
The ER (endoplasmic reticulum) is a Ca2+ reservoir and the unique protein-synthesizing machinery which is distributed throughout the neuron and composed of multiple different structural domains. One such domain is called EMC (endoplasmic reticulum membrane protein complex), pleiotropic nature in cellular functions. The ER/EMC position inside the neurons unmasks its contribution to synaptic plasticity via regulating various cellular processes from protein synthesis to Ca2+ signaling. Since presynaptic Ca2+ channels and postsynaptic ionotropic receptors are organized into the nanodomains, thus ER can be a crucial player in establishing TMNCs (transsynaptic molecular nanocolumns) to shape efficient neural communications. This review hypothesized that ER is not only involved in stress-mediated neurodegeneration but also axon regrowth, remyelination, neurotransmitter switching, information processing, and regulation of pre- and post-synaptic functions. Thus ER might not only be a protein-synthesizing and quality control machinery but also orchestrates plasticity of plasticity (metaplasticity) within the neuron to execute higher-order brain functions and neural repair.
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Affiliation(s)
- Shumsuzzaman Khan
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA.
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33
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Wang DK, Zheng HL, Zhou WS, Duan ZW, Jiang SD, Li B, Zheng XF, Jiang LS. Mitochondrial Dysfunction in Oxidative Stress-Mediated Intervertebral Disc Degeneration. Orthop Surg 2022; 14:1569-1582. [PMID: 35673928 PMCID: PMC9363752 DOI: 10.1111/os.13302] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 11/29/2022] Open
Abstract
Intervertebral disc degeneration (IVDD) is the most common contributor to low back pain (LBP). Recent studies have found that oxidative stress and reactive oxygen species (ROS) play an important role in IVDD. As a by‐product of aerobic respiration, ROS is mainly produced in the mitochondria by the electron transport chain and other mitochondrial located proteins. With the excessive accumulation of ROS, mitochondria are also the primary target of ROS attack in disc cells. A disrupted balance between intracellular ROS production and antioxidant capacity will lead to oxidative stress, which is the key contributor to cell apoptosis, cell senescence, excessive autophagy, and mitochondrial dysfunction. As the pivotal ingredient of oxidative stress, mitochondrial dysfunction manifests as imbalanced mitochondrial dynamics and dysregulated mitophagy. Mitochondria can alter their own dynamics through the process of fusion and fission, so that disabled mitochondria can be separated from the mitochondrial pool. Moreover, mitophagy participates by clearing these dysfunctional mitochondria. Abnormality in any of these processes either increases the production or decreases the clearance of ROS, leading to a vicious cycle that results in the death of intervertebral disc cells in large quantities, combined with degradation of the extracellular matrix and overproduction of matrix metalloproteinase. In this review, we explain the changes in mitochondrial morphology and function during oxidative stress‐mediated IVDD and highlight the important role of mitochondria in this process. Eventually, we summarize the IVDD therapeutic strategies targeting mitochondrial dysfunction based on current understanding of the role of oxidative stress in IVDD.
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Affiliation(s)
- Dian-Kai Wang
- Department of Spine Centre, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huo-Liang Zheng
- Department of Spine Centre, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen-Sheng Zhou
- Department of Spine Centre, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng-Wei Duan
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng-Dan Jiang
- Department of Spine Centre, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Li
- Department of Spine Centre, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin-Feng Zheng
- Department of Spine Centre, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei-Sheng Jiang
- Department of Spine Centre, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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34
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Wang L, Liu Y, Zhang X, Ye Y, Xiong X, Zhang S, Gu L, Jian Z, Wang H. Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cerebral Ischemia/Reperfusion Injury. Front Cell Neurosci 2022; 16:864426. [PMID: 35602556 PMCID: PMC9114642 DOI: 10.3389/fncel.2022.864426] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/07/2022] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke is an acute cerebrovascular disease characterized by sudden interruption of blood flow in a certain part of the brain, leading to serious disability and death. At present, treatment methods for ischemic stroke are limited to thrombolysis or thrombus removal, but the treatment window is very narrow. However, recovery of cerebral blood circulation further causes cerebral ischemia/reperfusion injury (CIRI). The endoplasmic reticulum (ER) plays an important role in protein secretion, membrane protein folding, transportation, and maintenance of intracellular calcium homeostasis. Endoplasmic reticulum stress (ERS) plays a crucial role in cerebral ischemia pathophysiology. Mild ERS helps improve cell tolerance and restore cell homeostasis; however, excessive or long-term ERS causes apoptotic pathway activation. Specifically, the protein kinase R-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways are significantly activated following initiation of the unfolded protein response (UPR). CIRI-induced apoptosis leads to nerve cell death, which ultimately aggravates neurological deficits in patients. Therefore, it is necessary and important to comprehensively explore the mechanism of ERS in CIRI to identify methods for preserving brain cells and neuronal function after ischemia.
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Affiliation(s)
- Lei Wang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan Liu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingze Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shudi Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
- Zhihong Jian,
| | - Hongfa Wang
- Rehabilitation Medicine Center, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
- *Correspondence: Hongfa Wang,
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35
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Szewczyk MM, Luciani GM, Vu V, Murison A, Dilworth D, Barghout SH, Lupien M, Arrowsmith CH, Minden MD, Barsyte-Lovejoy D. PRMT5 regulates ATF4 transcript splicing and oxidative stress response. Redox Biol 2022; 51:102282. [PMID: 35305370 PMCID: PMC8933703 DOI: 10.1016/j.redox.2022.102282] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/18/2022] [Accepted: 03/08/2022] [Indexed: 02/07/2023] Open
Abstract
Protein methyltransferase 5 (PRMT5) symmetrically dimethylates arginine residues leading to regulation of transcription and splicing programs. Although PRMT5 has emerged as an attractive oncology target, the molecular determinants of PRMT5 dependency in cancer remain incompletely understood. Our transcriptomic analysis identified PRMT5 regulation of the activating transcription factor 4 (ATF4) pathway in acute myelogenous leukemia (AML). PRMT5 inhibition resulted in the expression of unstable, intron-retaining ATF4 mRNA that is detained in the nucleus. Concurrently, the decrease in the spliced cytoplasmic transcript of ATF4 led to lower levels of ATF4 protein and downregulation of ATF4 target genes. Upon loss of functional PRMT5, cells with low ATF4 displayed increased oxidative stress, growth arrest, and cellular senescence. Interestingly, leukemia cells with EVI1 oncogene overexpression demonstrated dependence on PRMT5 function. EVI1 and ATF4 regulated gene signatures were inversely correlated. We show that EVI1-high AML cells have reduced ATF4 levels, elevated baseline reactive oxygen species and increased sensitivity to PRMT5 inhibition. Thus, EVI1-high cells demonstrate dependence on PRMT5 function and regulation of oxidative stress response. Overall, our findings identify the PRMT5-ATF4 axis to be safeguarding the cellular redox balance that is especially important in high oxidative stress states, such as those that occur with EVI1 overexpression.
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Affiliation(s)
| | - Genna M Luciani
- Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Victoria Vu
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Ontario, Canada
| | - Alex Murison
- Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - David Dilworth
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
| | - Samir H Barghout
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
| | - Mathieu Lupien
- Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Cheryl H Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Mark D Minden
- Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
| | - Dalia Barsyte-Lovejoy
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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36
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Shyam R, Ogando DG, Bonanno JA. Mitochondrial ROS in Slc4a11 KO Corneal Endothelial Cells Lead to ER Stress. Front Cell Dev Biol 2022; 10:878395. [PMID: 35557943 PMCID: PMC9086159 DOI: 10.3389/fcell.2022.878395] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/30/2022] [Indexed: 11/13/2022] Open
Abstract
Recent studies from Slc4a11 -/- mice have identified glutamine-induced mitochondrial dysfunction as a significant contributor toward oxidative stress, impaired lysosomal function, aberrant autophagy, and cell death in this Congenital Hereditary Endothelial Dystrophy (CHED) model. Because lysosomes are derived from endoplasmic reticulum (ER)-Golgi, we asked whether ER function is affected by mitochondrial ROS in Slc4a11 KO corneal endothelial cells. In mouse Slc4a11 -/- corneal endothelial tissue, we observed the presence of dilated ER and elevated expression of ER stress markers BIP and CHOP. Slc4a11 KO mouse corneal endothelial cells incubated with glutamine showed increased aggresome formation, BIP and GADD153, as well as reduced ER Ca2+ release as compared to WT. Induction of mitoROS by ETC inhibition also led to ER stress in WT cells. Treatment with the mitochondrial ROS quencher MitoQ, restored ER Ca2+ release and relieved ER stress markers in Slc4a11 KO cells in vitro. Systemic MitoQ also reduced BIP expression in Slc4a11 KO endothelium. We conclude that mitochondrial ROS can induce ER stress in corneal endothelial cells.
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Affiliation(s)
- Rajalekshmy Shyam
- Vision Science Program, School of Optometry, Indiana University, Bloomington, IN, United States
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37
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Zhang WH, Koyuncu S, Vilchez D. Insights Into the Links Between Proteostasis and Aging From C. elegans. FRONTIERS IN AGING 2022; 3:854157. [PMID: 35821832 PMCID: PMC9261386 DOI: 10.3389/fragi.2022.854157] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/22/2022] [Indexed: 04/20/2023]
Abstract
Protein homeostasis (proteostasis) is maintained by a tightly regulated and interconnected network of biological pathways, preventing the accumulation and aggregation of damaged or misfolded proteins. Thus, the proteostasis network is essential to ensure organism longevity and health, while proteostasis failure contributes to the development of aging and age-related diseases that involve protein aggregation. The model organism Caenorhabditis elegans has proved invaluable for the study of proteostasis in the context of aging, longevity and disease, with a number of pivotal discoveries attributable to the use of this organism. In this review, we discuss prominent findings from C. elegans across the many key aspects of the proteostasis network, within the context of aging and disease. These studies collectively highlight numerous promising therapeutic targets, which may 1 day facilitate the development of interventions to delay aging and prevent age-associated diseases.
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Affiliation(s)
- William Hongyu Zhang
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Seda Koyuncu
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Faculty of Medicine, University Hospital Cologne, Cologne, Germany
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38
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Lebeau PF, Platko K, Byun JH, Makda Y, Austin RC. The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases. Metabolites 2022; 12:metabo12030215. [PMID: 35323658 PMCID: PMC8954296 DOI: 10.3390/metabo12030215] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/20/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
The importance of the proprotein convertase subtilisin/kexin type-9 (PCSK9) gene was quickly recognized by the scientific community as the third locus for familial hypercholesterolemia. By promoting the degradation of the low-density lipoprotein receptor (LDLR), secreted PCSK9 protein plays a vital role in the regulation of circulating cholesterol levels and cardiovascular disease risk. For this reason, the majority of published works have focused on the secreted form of PCSK9 since its initial characterization in 2003. In recent years, however, PCSK9 has been shown to play roles in a variety of cellular pathways and disease contexts in LDLR-dependent and -independent manners. This article examines the current body of literature that uncovers the intracellular and LDLR-independent roles of PCSK9 and also explores the many downstream implications in metabolic diseases.
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39
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Cui Y, Zhou X, Chen L, Tang Z, Mo F, Li XC, Mao H, Wei X, Wang C, Wang H. Crosstalk between Endoplasmic Reticulum Stress and Oxidative Stress in Heat Exposure-Induced Apoptosis Is Dependent on the ATF4-CHOP-CHAC1 Signal Pathway in IPEC-J2 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:15495-15511. [PMID: 34919378 DOI: 10.1021/acs.jafc.1c03361] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The intestinal epithelium is susceptible to heat stress (HS), which leads to gut leakage and inflammation. However, the mechanisms underlying HS-induced intestine dysfunction have yet to be elucidated. We established an in vitro chronic heat exposure-induced intestinal injury of intestinal porcine epithelial cells (IPEC-J2) exposed to high temperatures (43 °C) for 12 h. The results revealed that HS increased reactive oxygen species (ROS) generation and decreased superoxide dismutase 2 (SOD2) expression, leading to oxidative stress. Western blotting analysis demonstrated that HS induced apoptosis as evidenced by increased cytochrome c (Cyt c) release in the cytoplasm and caspase 3 activation. Transcriptome sequencing analysis revealed that HS activated the endoplasmic reticulum stress (ERS) response/unfolded protein response (UPR) but inhibited glutathione metabolism. Specifically, HS triggered the pro-apoptotic activating transcription factor 4 (ATF4)/CEBP-homologous protein (CHOP) branch of the UPR. Interestingly, glutathione-specific gamma-glutamylcyclotransferase1 (CHAC1) involved in glutathione degradation was upregulated due to heat exposure and was proved to be downstream of the ATF4-CHOP signal pathway. Knockdown of CHAC1 attenuated the HS-induced decrease in glutathione level and cell apoptosis. These studies suggest that crosstalk between ERS and oxidative stress in HS-induced apoptosis might be dependent on the ATF4-CHOP-CHAC1 signal pathway in IPEC-J2 cells.
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Affiliation(s)
- Yanjun Cui
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Xu Zhou
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Leyi Chen
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Zhining Tang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Fan Mo
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Xiang Chen Li
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Huiling Mao
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Xiaoshi Wei
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Chong Wang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Lin'an 311300, P. R. China
| | - Haifeng Wang
- College of Animal Science, MOE Key Laboratory of Molecular Animal Nutrition, Zhejiang University, Hangzhou 310058, P. R. China
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Chen TC, da Fonseca CO, Levin D, Schönthal AH. The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers. Pharmaceutics 2021; 13:2167. [PMID: 34959448 PMCID: PMC8709132 DOI: 10.3390/pharmaceutics13122167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/02/2021] [Accepted: 12/11/2021] [Indexed: 12/20/2022] Open
Abstract
Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood-brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH's value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.
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Affiliation(s)
- Thomas C. Chen
- Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Clovis O. da Fonseca
- Department of Neurological Surgery, Federal Hospital of Ipanema, Rio de Janeiro 22411-020, Brazil;
| | | | - Axel H. Schönthal
- Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
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Chipurupalli S, Samavedam U, Robinson N. Crosstalk Between ER Stress, Autophagy and Inflammation. Front Med (Lausanne) 2021; 8:758311. [PMID: 34805224 PMCID: PMC8602556 DOI: 10.3389/fmed.2021.758311] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/14/2021] [Indexed: 12/23/2022] Open
Abstract
The endoplasmic reticulum (ER) is not only responsible for protein synthesis and folding but also plays a critical role in sensing cellular stress and maintaining cellular homeostasis. Upon sensing the accumulation of unfolded proteins due to perturbation in protein synthesis or folding, specific intracellular signaling pathways are activated, which are collectively termed as unfolded protein response (UPR). UPR expands the capacity of the protein folding machinery, decreases protein synthesis and enhances ER-associated protein degradation (ERAD) which degrades misfolded proteins through the proteasomes. More recent evidences suggest that UPR also amplifies cytokines-mediated inflammatory responses leading to pathogenesis of inflammatory diseases. UPR signaling also activates autophagy; a lysosome-dependent degradative pathwaythat has an extended capacity to degrade misfolded proteins and damaged ER. Thus, activation of autophagy limits inflammatory response and provides cyto-protection by attenuating ER-stress. Here we review the mechanisms that couple UPR, autophagy and cytokine-induced inflammation that can facilitate the development of novel therapeutic strategies to mitigate cellular stress and inflammation associated with various pathologies.
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Affiliation(s)
- Sandhya Chipurupalli
- Cellular-Stress and Immune Response Laboratory, Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
| | - Unni Samavedam
- College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Nirmal Robinson
- Cellular-Stress and Immune Response Laboratory, Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
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Jiang Y, Tao Z, Chen H, Xia S. Endoplasmic Reticulum Quality Control in Immune Cells. Front Cell Dev Biol 2021; 9:740653. [PMID: 34660599 PMCID: PMC8511527 DOI: 10.3389/fcell.2021.740653] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/07/2021] [Indexed: 12/18/2022] Open
Abstract
The endoplasmic reticulum quality control (ERQC) system, including endoplasmic reticulum-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy, presides over cellular protein secretion and maintains proteostasis in mammalian cells. As part of the immune system, a variety of proteins are synthesized and assembled correctly for the development, activation, and differentiation of immune cells, such as dendritic cells (DCs), macrophages, myeloid-derived-suppressor cells (MDSCs), B lymphocytes, T lymphocytes, and natural killer (NK) cells. In this review, we emphasize the role of the ERQC in these immune cells, and also discuss how the imbalance of ER homeostasis affects the immune response, thereby suggesting new therapeutic targets for immunotherapy.
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Affiliation(s)
- Yalan Jiang
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zehua Tao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hua Chen
- Department of Colorectal Surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Sheng Xia
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
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Cui YJ, Chen LY, Zhou X, Tang ZN, Wang C, Wang HF. Heat stress induced IPEC-J2 cells barrier dysfunction through endoplasmic reticulum stress mediated apoptosis by p-eif2α/CHOP pathway. J Cell Physiol 2021; 237:1389-1405. [PMID: 34661912 DOI: 10.1002/jcp.30603] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 02/06/2023]
Abstract
Heat stress (HS) induced by high ambient temperatures compromises intestinal epithelial cell. However, the underlying mechanisms by which HS causes intestinal barrier dysfunction remain unclear. In this study, we established an in vitro acute-HS-induced intestinal damage using porcine small intestinal epithelial cell (IPEC-J2) that exposed to the high temperatures (43°C) for 2 h. The cell proliferation, apoptosis, tight junction (TJ) barrier integrity and transcriptomic profiles were measured. The results showed that HS decreased cell viability while increased proapoptotic signaling evidenced by Bax/bcl2 ratio, cytochrome C release to cytosol and active-caspase 3 increases (p < 0.01). HS led to decreased transepithelial electrical resistance, increased cell permeability, and downregulated TJ proteins including ZO1, occludin, and claudin 3 (p < 0.05). Transcriptome sequencing and KEGG pathway analysis revealed HS-induced cell cycle arrest and activation of endoplasmic reticulum stress (ERS) response mediated by a critical transcript eif2α and proapoptotic molecule DDIT3 (known as CHOP). Furthermore, inhibition of ERS by 4-phenylbutyrate (4-PBA) administration and knockdown of eif2α and CHOP significantly attenuated IPEC-J2 cells apoptosis (p < 0.05). Transmission electron microscopy analysis suggested that 4-PBA inhibited HS-induced increase in ER lumen diameter, indicating ultrastructural sign of ERS. In addition, HS-induced impairment of TJs was significantly attenuated by 4-PBA (p < 0.05). Collectively, HS induces ERS and activates the p-eif2α/CHOP signaling pathway to impair epithelial barrier integrity through triggering the intestinal epithelial cell apoptosis.
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Affiliation(s)
- Yan-Jun Cui
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Le-Yi Chen
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Xu Zhou
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Zhi-Ning Tang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Chong Wang
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, China-Australian Joint Laboratory for Animal Health Big Data Analytics, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Zhejiang A&F University, Lin'an, China
| | - Hai-Feng Wang
- College of Animal Science, MOE Key Laboratory of Molecular Animal Nutrition, Zhejiang University, Hangzhou, China
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Biochemical and histological alterations induced by nickel oxide nanoparticles in the ground beetle Blaps polychresta (Forskl, 1775) (Coleoptera: Tenebrionidae). PLoS One 2021; 16:e0255623. [PMID: 34559804 PMCID: PMC8462711 DOI: 10.1371/journal.pone.0255623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 06/30/2021] [Indexed: 12/03/2022] Open
Abstract
The present study evaluates the effect of nickel oxide nanoparticles on some biochemical parameters and midgut tissues in the ground beetle Blaps polychresta as an indicator organism for nanotoxicity. Serial doses of the NiO-NPs colloid (0.01, 0.02, 0.03, 0.04, 0.05, and 0.06 mg/g) were prepared for injecting into the adult beetles. Insect survival was reported daily for 30 days, and the sublethal dose of 0.02 mg/g NiO-NPs was selected for the tested parameters. After the treatment, nickel was detected in the midgut tissues by X-ray microanalysis. The treated group demonstrated a significant increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities when compared to the untreated group. However, the treated group demonstrated a significant decrease in ascorbate peroxidase (APOX) activity when compared to the untreated group. Histological and ultrastructural changes in the midgut tissues of treated and untreated beetles were also observed. The current findings provide a precedent for describing the physiological and histological changes caused by NiO-NPs in the ground beetle B. polychresta.
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Pandey S, Sharma VK, Biswas A, Lahiri M, Basu S. Small molecule-mediated induction of endoplasmic reticulum stress in cancer cells. RSC Med Chem 2021; 12:1604-1611. [PMID: 34671742 PMCID: PMC8459384 DOI: 10.1039/d1md00095k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 07/15/2021] [Indexed: 11/21/2022] Open
Abstract
The endoplasmic reticulum (ER) is one of the crucial sub-cellular organelles controlling myriads of functions including protein biosynthesis, folding, misfolding and unfolding. As a result, dysregulation of these pathways in the ER is implicated in cancer development and progression. Subsequently, targeting the ER in cancer cells emerged as an interesting unorthodox strategy in next-generation anticancer therapy. However, development of small molecules to selectively target the ER for cancer therapy remained elusive and unexplored. To address this, herein, we have developed a novel small molecule library of sulfonylhydrazide-hydrazones through a short and concise chemical synthetic strategy. We identified a fluorescent small molecule that localized into the endoplasmic reticulum (ER) of HeLa cells, induced ER stress followed by triggering autophagy which was subsequently inhibited by chloroquine (autophagy inhibitor) to initiate apoptosis. This small molecule showed remarkable cancer cell killing efficacy in different cancer cells as mono and combination therapy with chloroquine, thus opening a new direction to illuminate ER-biology towards the development of novel anticancer therapeutics.
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Affiliation(s)
- Shalini Pandey
- Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune Homi Bhabha Road, Pashan Pune 411008 India
- Discipline of Chemistry, Indian Institute of Technology (IIT) Gandhinagar Palaj Gandhinagar Gujarat 382355 India
| | - Virender Kumar Sharma
- Department of Biology, Indian Institute of Science Education and Research (IISER)-Pune Homi Bhabha Road, Pashan Pune 411008 India
| | - Ankur Biswas
- Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune Homi Bhabha Road, Pashan Pune 411008 India
| | - Mayurika Lahiri
- Department of Biology, Indian Institute of Science Education and Research (IISER)-Pune Homi Bhabha Road, Pashan Pune 411008 India
| | - Sudipta Basu
- Discipline of Chemistry, Indian Institute of Technology (IIT) Gandhinagar Palaj Gandhinagar Gujarat 382355 India
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Chaudhary P, Sharma S, Singh R, Arya R. Elucidation of ER stress and UPR pathway in sialic acid-deficient cells: Pathological relevance to GNEM. J Cell Biochem 2021; 122:1886-1902. [PMID: 34555215 DOI: 10.1002/jcb.30148] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 12/31/2022]
Abstract
Accumulation of misfolded proteins in endoplasmic reticulum (ER) generates a stress condition in the cell. The cell combats ER stress by activating unfolded protein response (UPR) and ERAD (ER stress-associated degradation) pathway. Failure to restore favorable folding environment results in cell dysfunction and apoptosis. Various neurodegenerative disorders are characterized by the accumulation of misfolded protein, protein aggregates, and ER stress. GNE myopathy (GNEM) is a neuromuscular disorder pathologically characterized by rimmed vacuole formation due to the accumulation of protein aggregates. More than 200 mutations in key sialic acid biosynthetic enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) have been identified worldwide in the muscle biopsies of GNE myopathy patients. However, the cellular and molecular pathomechanism leading to the disease ar poorly understood. In the present study, the phenomenon of ER stress has been elucidated in GNE mutant cells overexpressing GNE mutations of Indian origin. The effect of GNE mutations on activation of UPR signaling via inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE-1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6) were deciphered to understand the effect of GNE mutations on these proteins. GRP78 was upregulated with increased X-box-binding protein-1 (XBP-1) splicing and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) upregulation leading to increased apoptosis of GNE mutant cells. Insulin-like growth factor 1 (IGF-1) ligand rescued the cells from apoptotic phenotype by supporting cell survival mechanism. Our study indicates a balance of cell death and survival that decides cell fate and offers potential therapeutic targets to combat ER stress in diseases associated with dysfunctional UPR pathway.
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Affiliation(s)
| | - Shweta Sharma
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Reema Singh
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Ranjana Arya
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.,Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
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Chien CY, Chen YC, Hsu CC, Chou YT, Shiah SG, Liu SY, Hsieh ACT, Yen CY, Lee CH, Shieh YS. YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy. Cells 2021; 10:2080. [PMID: 34440849 PMCID: PMC8392082 DOI: 10.3390/cells10082080] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 01/18/2023] Open
Abstract
Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral cancer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent manners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-mediated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial-mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear translocation and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observations suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.
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Affiliation(s)
- Chu-Yen Chien
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan; (C.-Y.C.); (C.-C.H.)
| | - Ying-Chen Chen
- Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei 114, Taiwan;
| | - Chia-Chen Hsu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan; (C.-Y.C.); (C.-C.H.)
| | - Yu-Ting Chou
- Institute of Biotechnology, National Tsing Hua University, Hsinchu 300, Taiwan;
| | - Shine-Gwo Shiah
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 350, Taiwan;
| | - Shyun-Yeu Liu
- Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan 710, Taiwan;
| | | | - Ching-Yu Yen
- Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan 710, Taiwan;
- School of Dentistry, Taipei Medical University, Taipei 110, Taiwan
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan
| | - Yi-Shing Shieh
- Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan
- Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
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Coker-Gurkan A, Can E, Sahin S, Obakan-Yerlikaya P, Arisan ED. Atiprimod triggered apoptotic cell death via acting on PERK/eIF2α/ATF4/CHOP and STAT3/NF-ΚB axis in MDA-MB-231 and MDA-MB-468 breast cancer cells. Mol Biol Rep 2021; 48:5233-5247. [PMID: 34244887 DOI: 10.1007/s11033-021-06528-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/27/2021] [Indexed: 12/23/2022]
Abstract
PURPOSE The constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth and invasion-metastasis. Atiprimod impacts anti-proliferative, anti-carcinogenic effects in hepatocellular carcinoma, lymphoma, multiple myeloma via hindering the biological activity of STAT3. Dose-dependent atiprimod evokes first autophagy as a survival mechanism and then apoptosis due to prolonged ER stress in pituitary adenoma cells. The therapeutic efficiency and mechanistic action of atiprimod in breast cancer cells have not been investigated yet. Thus, we aimed to modulate the pivotal role of ER stress in atiprimod-triggered apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells. RESULTS Dose- and time-dependent atiprimod treatment inhibits cell viability and colony formation in MDA-MB-468 and MDA-MB-231 breast cancer cells. A moderate dose of atiprimod (2 μM) inhibited STAT3 phosphorylation at Tyr705 residue and also suppressed the total expression level of p65. In addition, nuclear localization of STAT1, 3, and NF-κB was prevented by atiprimod exposure in MDA-MB-231 and MDA-MB-468 cells. Atiprimod evokes PERK, BiP, ATF-4, CHOP upregulation, and PERK (Thr980), eIF2α (Ser51) phosphorylation's. However, atiprimod suppressed IRE1α-mediated Atg-3, 5, 7, 12 protein expressions and no alteration was observed on Beclin-1, p62 expression levels. PERK/eIF2α/ATF4/CHOP axis pivotal role in atiprimod-mediated G1/S arrest and apoptosis via Bak, Bax, Bim, and PUMA upregulation in MDA-MB-468 cells. Moreover, atiprimod renders MDA-MB-231 more vulnerable to type I programmed cell death by plasmid-mediated increased STAT3 expression. CONCLUSION Atiprimod induced prolonged ER stress-mediated apoptosis via both activating PERK/eIF2α/ATF4/CHOP axis and suppressing STAT3/NF-κB transcription factors nuclear migration in TBNC cells.
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Affiliation(s)
- Ajda Coker-Gurkan
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Biruni University, Topkapı Campus, 34010, Istanbul, Turkey.
| | - Esin Can
- Department of Molecular Biology and Genetics, Science and Letters Faculty, Istanbul Kultur University, Atakoy Campus, 34156, Istanbul, Turkey
| | - Semanur Sahin
- Department of Molecular Biology and Genetics, Science and Letters Faculty, Istanbul Kultur University, Atakoy Campus, 34156, Istanbul, Turkey
| | - Pınar Obakan-Yerlikaya
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Biruni University, Topkapı Campus, 34010, Istanbul, Turkey
| | - Elif-Damla Arisan
- Institute of Biotechnology, Gebze Technical University, Gebze, Turkey
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Head and Neck Cancer Cell Death due to Mitochondrial Damage Induced by Reactive Oxygen Species from Nonthermal Plasma-Activated Media: Based on Transcriptomic Analysis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9951712. [PMID: 34306318 PMCID: PMC8281449 DOI: 10.1155/2021/9951712] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/20/2021] [Accepted: 06/15/2021] [Indexed: 12/21/2022]
Abstract
Mitochondrial targeted therapy is a next-generation therapeutic approach for cancer that is refractory to conventional treatments. Mitochondrial damage caused by the excessive accumulation of reactive oxygen species (ROS) is a principle of mitochondrial targeted therapy. ROS in nonthermal plasma-activated media (NTPAM) are known to mediate anticancer effects in various cancers including head and neck cancer (HNC). However, the signaling mechanism of HNC cell death via NTPAM-induced ROS has not been fully elucidated. This study evaluated the anticancer effects of NTPAM in HNC and investigated the mechanism using transcriptomic analysis. The viability of HNC cells decreased after NTPAM treatment due to enhanced apoptosis. A human fibroblast cell line and three HNC cell lines were profiled by RNA sequencing. In total, 1 610 differentially expressed genes were identified. Pathway analysis showed that activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) were upstream regulators. Mitochondrial damage was induced by NTPAM, which was associated with enhancements of mitochondrial ROS (mtROS) and ATF4/CHOP regulation. These results suggest that NTPAM induces HNC cell death through the upregulation of ATF4/CHOP activity by damaging mitochondria via excessive mtROS accumulation, similar to mitochondrial targeted therapy.
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Borrello MT, Santofimia-Castaño P, Bocchio M, Listi A, Fraunhoffer N, Soubeyran P, Chevet E, Pin C, Iovanna J. NUPR1 interacts with eIF2α and is required for resolution of the ER stress response in pancreatic tissue. FEBS J 2021; 288:4081-4097. [PMID: 33403797 DOI: 10.1111/febs.15700] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 11/20/2020] [Accepted: 01/04/2021] [Indexed: 12/22/2022]
Abstract
Nuclear protein 1 (NUPR1) is a stress response protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1's well-established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely debated. In this study, we uncover a new role for NUPR1, participating in the unfolded protein response (UPR) and the integrated stress response. Biochemical results and ultrastructural morphological observations revealed alterations in the UPR of acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein synthesis after stress induction. Bioinformatic analysis of NUPR1-interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2α. Co-immunoprecipitation and proximity ligation assays confirmed the interaction between NUPR1 and eIF2α and its phosphorylated form (p-eIF2α). Furthermore, our data suggest loss of NUPR1 in cells results in maintained eIF2α phosphorylation and evaluation of nascent proteins by click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower poststress protein synthesis recovery when compared to wild-type. Combined, these data propose a novel role for NUPR1 in the integrated stress response pathway, at least partially through promoting efficient PERK branch activity and resolution through a unique interaction with eIF2α.
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Affiliation(s)
- Maria Teresa Borrello
- Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Patricia Santofimia-Castaño
- Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Marco Bocchio
- INMED (INSERM U1249), Turing Center for Living Systems, Aix-Marseille University, Marseille, France
| | - Angela Listi
- Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Nicolas Fraunhoffer
- Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Philippe Soubeyran
- Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Eric Chevet
- INSERM U1242, Proteostasis and Cancer Team, Chemistry Oncogenesis Stress Signaling, Université de Rennes 1, Rennes, France
| | - Christopher Pin
- Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
- Departments of Pediatrics, Oncology, and Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, Children's Health Research Institute, London, ON, Canada
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
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