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1
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Hao B, Liu Y, Wang B, Wu H, Chen Y, Zhang L. Hepatitis B surface antigen: carcinogenesis mechanisms and clinical implications in hepatocellular carcinoma. Exp Hematol Oncol 2025; 14:44. [PMID: 40141002 PMCID: PMC11938626 DOI: 10.1186/s40164-025-00642-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.
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Affiliation(s)
- Bingyan Hao
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bohan Wang
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Haofeng Wu
- Hepatic Surgery Center, Institute of Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan Chen
- Department of Paediatrics, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Lei Zhang
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Tongji Hospital, Tongji Medical College, Shanxi Medical University, Huazhong University of Science and Technology, Taiyuan, 030032, China.
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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2
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Moshood AY, Abdulraheem MI, Li L, Zhang Y, Raghavan V, Hu J. Deciphering nutrient stress in plants: integrative insight from metabolomics and proteomics. Funct Integr Genomics 2025; 25:38. [PMID: 39955391 DOI: 10.1007/s10142-025-01551-y] [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: 12/24/2024] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
To comprehend the responses and resilience of plants under unfavorable environmental conditions, it is crucial to study the metabolomics and proteomic insights into nutrient stress. Nutrient stress substantially challenges agriculture, impacting plant growth, development, and productivity due to a lack or imbalance of essential nutrients, which can happen due to poor soil quality, limited nutrient availability, or unfavorable climatic conditions. Although there has been significant progress in the study of plant nutrient stress using metabolomics and proteomics, several challenges and research gaps still need to be addressed, such as the standardized experimental protocols, data integration strategies, and bioinformatic tools are necessary for comparative analysis and interpretation of omics data. Hence, this review explores the theoretical frameworks of metabolomics and proteomics as powerful tools to decode plant responses to nutrient stress, addressing critical knowledge gaps in the field. This review highlights the advantages of integrative analyses, combining metabolomics, proteomics, and transcriptomics, to uncover the molecular networks governing nutrient stress resilience. Key findings underscore the potential of these techniques to enhance breeding strategies and genetic engineering efforts aimed at developing nutrient-efficient crops. Through metabolomics and proteomic analyses, novel molecular components and regulatory networks have been revealed as responsive to nutrient stress, and this breakthrough has the potential to bolster plant resilience and optimize nutrient utilization. Understanding the synergistic roles of metabolites and proteins in nutrient stress resilience has profound implications for crop improvement and agricultural sustainability. Future research should focus on refining integrative methodologies and exploring their applications across diverse plant species and environmental conditions, paving the way for innovative solutions to nutrient stress challenges.
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Affiliation(s)
- Abiodun Yusuff Moshood
- Department of Electrical Engineering, Henan Agricultural University, Zhengzhou, 450002, China
- Henan International Joint Laboratory of Laser Technology in Agriculture Science, Zhengzhou, 450002, China
| | - Mukhtar Iderawumi Abdulraheem
- Department of Electrical Engineering, Henan Agricultural University, Zhengzhou, 450002, China.
- Henan International Joint Laboratory of Laser Technology in Agriculture Science, Zhengzhou, 450002, China.
- Department of Agricultural Science, Oyo State College of Education, Lanlate, 202001, Nigeria.
| | - Linze Li
- Department of Electrical Engineering, Henan Agricultural University, Zhengzhou, 450002, China
- Henan International Joint Laboratory of Laser Technology in Agriculture Science, Zhengzhou, 450002, China
| | - Yanyan Zhang
- Department of Electrical Engineering, Henan Agricultural University, Zhengzhou, 450002, China
| | - Vijaya Raghavan
- Department of Bioresource Engineering, Faculty of Agriculture and Environmental Studies, McGill University, Sainte- Anne-de-Bellevue, QC, H9X 3V9, Canada
| | - Jiandong Hu
- Henan International Joint Laboratory of Laser Technology in Agriculture Science, Zhengzhou, 450002, China.
- Department of Agricultural Science, Oyo State College of Education, Lanlate, 202001, Nigeria.
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3
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Balestrero F, Gioiello L, Goutsiou G, Sangaletti S, Di Martino RMC, Condorelli F, Grolla AA, Pirali T. Versatile One-Pot Synthesis of Hydrophobic Tags by Multicomponent Reactions. ACS OMEGA 2025; 10:4745-4753. [PMID: 39959082 PMCID: PMC11822694 DOI: 10.1021/acsomega.4c09726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 02/18/2025]
Abstract
Among the various strategies being developed in the field of protein degraders, HyTags remain relatively underexplored, despite their advantages over PROTACs. Their synthesis typically involves multistep procedures, including the use of coupling reagents and protection/deprotection steps. To develop a more sustainable and streamlined approach, we designed a versatile multicomponent platform that generates HyTags with diverse linkers and hydrophobic moieties in high yields. Using (+)-JQ1 as the POI ligand, we synthesized a series of BRD4-targeting HyTags and discovered that compound 23 induces degradation of BRD4 via the autophagy-lysosome pathway through ER stress. This finding further supports the valuable application of this synthetic methodology in the search for effective degraders.
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Affiliation(s)
- Federica
Carolina Balestrero
- Department
of Pharmaceutical Sciences, Università
degli Studi del Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy
| | - Laura Gioiello
- Department
of Pharmaceutical Sciences, Università
degli Studi del Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy
- Molecular
Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan 20133, Italy
| | - Georgia Goutsiou
- Department
of Pharmaceutical Sciences, Università
degli Studi del Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy
| | - Sabina Sangaletti
- Molecular
Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan 20133, Italy
| | - Rita Maria Concetta Di Martino
- Department
of Pharmaceutical Sciences, Università
degli Studi del Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy
| | - Fabrizio Condorelli
- Department
of Pharmaceutical Sciences, Università
degli Studi del Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy
| | - Ambra A. Grolla
- Department
of Pharmaceutical Sciences, Università
degli Studi del Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy
| | - Tracey Pirali
- Department
of Pharmaceutical Sciences, Università
degli Studi del Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy
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4
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Darmadi D, Saleh RO, Oghenemaro EF, Shakir MN, Hjazi A, Hassan ZF, Zwamel AH, Matlyuba S, Deorari M, Oudah SK. Role of SEL1L in the progression of solid tumors, with a special focus on its recent therapeutic potential. Cell Biol Int 2025; 49:16-32. [PMID: 39364680 DOI: 10.1002/cbin.12242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/24/2024] [Accepted: 09/02/2024] [Indexed: 10/05/2024]
Abstract
Since suppressor/enhancer of Lin-12-like (SEL1L) was cloned in 1997, various pieces of evidence from lower species suggest it plays a significant role in protein degradation via the ubiquitin-proteasome system. The relevance of SEL1L in many aspects of malignant transformation and tumorigenic events has been the subject of research, which has shown compelling in vitro and in vivo findings relating its altered expression to changes in tumor aggressiveness. The Endoplasmic Reticulum (ER) in tumor cells is crucial for preserving cellular proteostasis by inducing the unfolded protein response (UPR), a stress response. A crucial component of the UPR is ER-associated degradation (ERAD), which guards against ER stress-induced apoptosis and the removal of unfolded or misfolded proteins by the ubiquitin-proteasome system. As a protein stabilizer of HMG-CoA reductase degradation protein 1 (HRD1), one of the main components of ERAD, SEL1L plays an important role in ER homeostasis. Notably, the expression levels of these two proteins fluctuate independently in various cancer types, yet changes in their expression affect the levels of other associated proteins during cancer pathogenesis. Recent studies have also outlined the function of SEL1L in cancer medication resistance. This review explores the value of targeting SEL1L as a novel treatment approach for cancer, focusing on the molecular processes of SEL1L and its involvement in cancer etiology.
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Affiliation(s)
- Darmadi Darmadi
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Enwa Felix Oghenemaro
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Delta State University, Abraka, Nigeria
| | - Maha Noori Shakir
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Ahmed Hussein Zwamel
- Medical laboratory technique college, the Islamic University, Najaf, Iraq
- Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
| | - Sanoeva Matlyuba
- Department of Neurology, Vice rektor of Bukhara State Medical Institute, Bukhara, Uzbekistan
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Shamam Kareem Oudah
- College of Pharmacy/National University of Science and Technology, Dhi Qar, Iraq
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McFarland KS, Hegadorn K, Betenbaugh MJ, Handlogten MW. Elevated endoplasmic reticulum pH is associated with high growth and bisAb aggregation in CHO cells. Biotechnol Bioeng 2025; 122:137-148. [PMID: 39435744 DOI: 10.1002/bit.28866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 10/03/2024] [Accepted: 10/07/2024] [Indexed: 10/23/2024]
Abstract
Chinese hamster ovary (CHO) bioprocesses, the dominant platform for therapeutic protein production, are increasingly used to produce complex multispecific proteins. Product quantity and quality are affected by intracellular conditions, but these are challenging to measure and often overlooked during process optimization studies. pH is known to impact quality attributes like protein aggregation across upstream and downstream processes, yet the effects of intracellular pH on cell culture performance are largely unknown. Recently, advances in protein biosensors have enabled investigations of intracellular environments with high spatiotemporal resolution. In this study, we integrated a fluorescent pH-sensitive biosensor into a bispecifc (bisAb)-producing cell line to investigate changes in endoplasmic reticulum pH (pHER). We then investigated how changes in lactate metabolism impacted pHER, cellular redox, and product quality in fed-batch and perfusion bioreactors. Our data show pHER rapidly increased during exponential growth to a maximum of pH 7.7, followed by a sharp drop in the stationary phase in all perfusion and fed-batch conditions. pHER decline in the stationary phase was driven by an apparent loss of cellular pH regulation that occurred despite differences in redox profiles. Finally, we found protein aggregate levels correlated most closely with pHER which provides new insights into product aggregate formation in CHO processes. An improved understanding of the intracellular changes impacting bioprocesses can ultimately help guide media optimizations, improve bioprocess control strategies, or provide new targets for cell engineering.
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Affiliation(s)
- Kevin S McFarland
- Cell Culture and Fermentation Sciences, BioPharmaceuticals Development R&D, AstraZeneca, Gaithersburg, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, USA
| | - Kaitlin Hegadorn
- Cell Culture and Fermentation Sciences, BioPharmaceuticals Development R&D, AstraZeneca, Gaithersburg, USA
| | - Michael J Betenbaugh
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, USA
| | - Michael W Handlogten
- Cell Culture and Fermentation Sciences, BioPharmaceuticals Development R&D, AstraZeneca, Gaithersburg, USA
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Ekaratcharoenchai N, Nualsanit T, Krajarng A. Detoxification of paraoxon-ethyl by Lysiphyllum strychnifolium extracts in undifferentiated human neuroblastoma SH-SY5Y cells. PHARMACEUTICAL BIOLOGY 2024; 62:882-891. [PMID: 39587439 PMCID: PMC11600548 DOI: 10.1080/13880209.2024.2430262] [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: 06/11/2024] [Revised: 10/01/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024]
Abstract
CONTEXT Lysiphyllum strychnifolium (Craib) A. Schmitz. (Fabaceae) is a Thai traditional medicine used to remove food and alcohol toxins from the body. OBJECTIVE This study investigates the molecular mechanism of L. strychnifolium extracts against paraoxon-ethyl-induced apoptosis in SH-SY5Y cells. MATERIALS AND METHODS The ethanol and water extracts of leaves and stems of L. strychnifolium were prepared at various concentrations (0-100 μg/mL) and co-treated to the cells with 0.375 mM paraoxon-ethyl for 24 and 48 h. Cell viability was performed using the PrestoBlue assay. ROS and caspase activity were detected using 2',7'-dichlorodihydrofluorecein diacetate and caspase-Glo® 3/7, 8, and 9 assay kits. Apoptotic and ER stress-related gene expression were determined by real-time PCR, and nuclear and mitochondrial morphology were observed using Hoechst 33342 and MitoTracker® Deep Red FM staining. RESULTS The most effective concentrations of each extract against paraoxon-ethyl-induced cell death were 25 μg/mL of leaf ethanol, 12.5 μg/mL of stem ethanol, 100 μg/mL of leaf water, and 25 μg/mL of stem water extracts. The leaf ethanol extract was the most effective at detoxifying, while stem extracts were highly toxic in high doses. The detoxifying L. strychnifolium extracts against paraoxon-ethyl-induced oxidative stress decreased p53, BiP/GRP78, and CHOP gene expression and minimized caspase 9 and caspase 3, protecting cells from apoptosis. The extracts could also restore mitochondrial membrane potential and reduce the swollen globule mitochondrial shape. DISCUSSION AND CONCLUSION These findings could potentially protect neuron cells from neurodegenerative issues due to oxidative damage, apoptosis, and other potential consequences.
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Affiliation(s)
| | - Thararat Nualsanit
- Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand
| | - Aungkana Krajarng
- Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand
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7
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Ketkar M, Desai S, Rana P, Thorat R, Epari S, Dutt A, Dutt S. Inhibition of PERK-mediated unfolded protein response acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma. Neuro Oncol 2024; 26:2027-2043. [PMID: 39021199 PMCID: PMC11534322 DOI: 10.1093/neuonc/noae134] [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: 02/13/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Glioblastoma due to recurrence is clinically challenging with 10-15 months overall survival. Previously we showed that therapy-induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate the TIS reversal mechanism for potential therapeutic intervention to prevent glioblastoma (GBM) recurrence. METHODS Residual senescent (RS) and end of residual senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenarios. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays, and IHCs were performed for the mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model. RESULTS Transcriptome analysis showed co-expression of endoplasmic reticulum (ER) stress-unfolded protein response (UPR) and senescence-associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, Reactive oxygen specis (ROS), DNA damage, and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1β, suppressed SASP, and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in ER, RS cells displayed stressed ER morphology, upregulated ER stress markers, and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21, and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival. CONCLUSION We demonstrate that PERK-mediated UPR regulates senescence reversal and its inhibition can be exploited as a potential seno-therapeutic option in glioblastoma.
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Affiliation(s)
- Madhura Ketkar
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India
- Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India
| | - Sanket Desai
- Integrated Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Navi Mumbai, 410210India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India
| | - Pranav Rana
- Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India
| | - Rahul Thorat
- Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai 410210, India
| | - Sridhar Epari
- Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India
| | - Amit Dutt
- Integrated Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Navi Mumbai, 410210India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India
- Integrated Cancer Genomics Laboratory, Department of Genetics, University of Delhi South Campus, Benito Juarez Marg, New Delhi 110021, India
| | - Shilpee Dutt
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India
- Shilpee Dutt Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, India
- Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India
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Yang K, Zhang P, Li J, Zhang G, Chang X. Potential of natural drug modulation of endoplasmic reticulum stress in the treatment of myocardial injury. J Pharm Anal 2024; 14:101034. [PMID: 39720623 PMCID: PMC11667710 DOI: 10.1016/j.jpha.2024.101034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 06/09/2024] [Accepted: 06/29/2024] [Indexed: 12/26/2024] Open
Abstract
Myocardial injury (MI) is a common occurrence in clinical practice caused by various factors such as ischemia, hypoxia, infection, metabolic abnormalities, and inflammation. Such damages are characterized by a reduction in myocardial function and cardiomyocyte death that can result in dangerous outcomes such as cardiac failure and arrhythmias. An endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) is triggered by several stressors, and its intricate signaling networks are instrumental in both cell survival and death. Cardiac damage frequently triggers ERS in response to different types of injuries and stress. High levels of ERS can exacerbate myocardial damage by inducing necrosis and apoptosis. To target ERS in MI prevention and treatment, current medical research is focused on identifying effective therapy approaches. Traditional Chinese medicine (TCM) is frequently used because of its vast range of applications and low risk of adverse effects. Various studies have demonstrated that active components of Chinese medicines, including polyphenols, saponins, and alkaloids, can reduce myocardial cell death, inflammation, and modify the ERS pathway, thus preventing and mitigating cardiac injury. Thus, this paper aims to provide a new direction and scientific basis for targeting ERS in MI prevention and treatment. We specifically summarize recent research progress on the regulation mechanism of ERS in MI by active ingredients of TCM.
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Affiliation(s)
- Kai Yang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Ping Zhang
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Jixin Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Genming Zhang
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Xing Chang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
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9
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Rakhe N, Bhatt LK. Valosin-containing protein: A potential therapeutic target for cardiovascular diseases. Ageing Res Rev 2024; 101:102511. [PMID: 39313037 DOI: 10.1016/j.arr.2024.102511] [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: 01/30/2024] [Revised: 09/10/2024] [Accepted: 09/17/2024] [Indexed: 09/25/2024]
Abstract
Valosin-containing protein (VCP), also known as p97, plays a crucial role in various cellular processes, including protein degradation, endoplasmic reticulum-associated degradation, and cell cycle regulation. While extensive research has been focused on VCP's involvement in protein homeostasis and its implications in neurodegenerative diseases, emerging evidence suggests a potential link between VCP and cardiovascular health. VCP is a key regulator of mitochondrial function, and its overexpression or mutations lead to pathogenic diseases and cellular stress responses. The present review explores VCP's roles in numerous cardiovascular disorders including myocardial ischemia/reperfusion injury, cardiac hypertrophy, and heart failure. The review dwells on the roles of VCP in modifying mitochondrial activity, promoting S-nitrosylation, regulating mTOR signalling and demonstrating cardioprotective effects. Further research into VCP might lead to novel interventions for cardiovascular disease, particularly those involving ischemia/reperfusion injury and hypertrophy.
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Affiliation(s)
- Nameerah Rakhe
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India.
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10
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Islam MN, Ebara F, Kawasaki K, Konno T, Tatemoto H, Yamanaka KI. Attenuation of endoplasmic reticulum stress improves invitro growth and subsequent maturation of bovine oocytes. Theriogenology 2024; 228:54-63. [PMID: 39096624 DOI: 10.1016/j.theriogenology.2024.07.027] [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: 05/06/2024] [Revised: 07/03/2024] [Accepted: 07/30/2024] [Indexed: 08/05/2024]
Abstract
Endoplasmic reticulum (ER) stress interferes with developmental processes in oocyte maturation and embryo development. Invitro growth (IVG) is associated with low developmental competence, and ER stress during IVG culture may play a role. Therefore, this study aimed to examine the effect of tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, on the IVG of bovine oocytes to understand the role of ER stress. Oocyte-granulosa cell complexes (OGCs) were collected from early antral follicles (1.5-1.8 mm) and allowed to grow in vitro for 5 days at 38.5 °C in a humidified atmosphere containing 5 % CO2. Basic growth culture medium was supplemented with TUDCA at various concentrations (0, 50, 100, 250, and 500 μM). After IVG, oocyte diameters were similar among groups, but the antrum formation rate tended to be higher in the TUDCA 100 μM group. The mRNA expression levels of ER stress-associated genes (PERK, ATF6, ATF4, CHOP, BAX, IRE1, and XBP1) in OGCs were downregulated in the TUDCA 100 μM group than those in the control group. Moreover, the TUDCA 100 μM group exhibited reduced ROS production with higher GSH levels and improved in vitro-grown oocyte maturation compared with those in the control group. In contrast, no difference in the developmental competence of embryos following invitro fertilization was observed between the control and TUDCA 100 μM groups. These results indicate that ER stress could impair IVG and subsequent maturation rate of bovine oocytes, and TUDCA could alleviate these detrimental effects. These outcomes might improve the quality of oocytes in IVG culture in assisted reproductive technology.
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Affiliation(s)
- Md Nuronnabi Islam
- Faculty of Agriculture, Saga University, Saga, Japan; The United Graduate School of Agricultural Science, Kagoshima University, Kagoshima, Japan; Department of Animal Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Fumio Ebara
- Faculty of Agriculture, Saga University, Saga, Japan; The United Graduate School of Agricultural Science, Kagoshima University, Kagoshima, Japan
| | - Kokoro Kawasaki
- Faculty of Agriculture, University of the Ryukyus, Okinawa, Japan
| | - Toshihiro Konno
- The United Graduate School of Agricultural Science, Kagoshima University, Kagoshima, Japan; Faculty of Agriculture, University of the Ryukyus, Okinawa, Japan
| | - Hideki Tatemoto
- The United Graduate School of Agricultural Science, Kagoshima University, Kagoshima, Japan; Faculty of Agriculture, University of the Ryukyus, Okinawa, Japan
| | - Ken-Ichi Yamanaka
- Faculty of Agriculture, Saga University, Saga, Japan; The United Graduate School of Agricultural Science, Kagoshima University, Kagoshima, Japan.
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11
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Tian M, Cao H, Gao H, Zhu L, Wu Y, Li G. Rotenone-induced cell apoptosis via endoplasmic reticulum stress and PERK-eIF2α-CHOP signalling pathways in TM3 cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 284:116972. [PMID: 39232300 DOI: 10.1016/j.ecoenv.2024.116972] [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: 06/11/2024] [Revised: 08/14/2024] [Accepted: 08/27/2024] [Indexed: 09/06/2024]
Abstract
Rotenone (ROT), a widely used natural pesticide, has an uncertain effect on reproductive toxicity. In this study, we used 20 mice distributed randomly into four groups, with each group receiving ROT doses of 0, 2, 4, and 8 mg/kg/day for 28 days. The results demonstrated that ROT induced significant testicular damage, including impaired spermatogenesis, inhibition of testosterone synthesis, and apoptosis of Leydig cells. Additionally, ROT disrupted the normal ultrastructure of the endoplasmic reticulum (ER) in testicular tissue, leading to ER stress in Leydig cells. To further explore whether ROT-induced apoptosis in Leydig cells is related to ER stress, the mouse Leydig cell line (TM3 cells) was treated with ROT at 0, 250, 500, and 1000 nM. ROT inhibited TM3 cell viability, induced cytotoxicity, and reduced testosterone content in the culture supernatants. Furthermore, ROT treatment triggered apoptosis in TM3 cells by activating ER stress and the PERK-eIF2α-CHOP signalling pathway. Pre-treatment of TM3 cells exposed to ROT with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated these effects, decreasing apoptosis and preserving testosterone levels. Further intervention with the PERK inhibitor GSK2606414 reduced ROT-induced apoptosis and testosterone reduction by inhibiting PERK activity. In summary, ROT-induced male reproductive toxicity is specifically driven by apoptosis, with the PERK-eIF2α-CHOP signalling pathway activated by ER stress playing a crucial role in the apoptosis of Leydig cells triggered by ROT.
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Affiliation(s)
- Mi Tian
- School of Public Health, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Hongting Cao
- School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Haoxuan Gao
- School of Public Health, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Lingqin Zhu
- School of Public Health, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Yang Wu
- Department of Ultrasound Medicine, Ningxia Women and Children's Hospital, Peking University First Hospital, Yinchuan, Ningxia 750004, China.
| | - Guanghua Li
- School of Public Health, Ningxia Medical University, Yinchuan, Ningxia 750004, China; School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
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12
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Saadi HF, Zamani M, Koohpeyma F, Raeisi A, Amirahmadi Z, Rezaei N, Joolidehpoor Z, Shams M, Dastghaib S. Therapeutic potential of aquatic Stevia extract in alleviating endoplasmic reticulum stress and liver damage in streptozotocin-induced diabetic rats. Mol Biol Rep 2024; 51:993. [PMID: 39292293 DOI: 10.1007/s11033-024-09907-6] [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: 06/06/2024] [Accepted: 09/03/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Misfolded proteins accumulate in the liver due to endoplasmic reticulum stress (ERS) caused by high blood glucose levels in diabetes. This triggers the unfolded protein response (UPR), which if persistently activated, results in cellular dysfunction. Chronic ER stress increases inflammation, insulin resistance, and apoptosis. There is growing interest in using native plants and traditional medicine for diabetes treatment. The stevia plant has recently gained attention for its potential therapeutic effects. This study investigates the protective effects of aquatic stevia extract on liver damage, ER stress, and the UPR pathway in streptozotocin (STZ)-induced diabetic rats. METHODS Rats were randomly divided into four groups: a control group that received 1 ml of water; a diabetic group induced by intraperitoneal injection of STZ (60 mg/kg); a diabetic group treated with metformin (500 mg/kg); and a diabetic group treated with aquatic extracts of stevia (400 mg/kg). After 28 days, various parameters were assessed, including inflammatory markers, oxidative stress indices, antioxidant levels, gene expression, stereology, and liver tissue pathology. RESULT Compared to the diabetic control group, treatment with stevia significantly decreased serum glucose, liver enzymes, inflammatory markers, and oxidative stress while increasing body weight and antioxidant levels. Additionally, stevia extract manipulated UPR gene expression and reduced apoptosis pathway activation. Histological examination revealed improved liver tissue morphology in stevia-treated diabetic rats. CONCLUSION These findings suggest that aquatic stevia extract mitigates ER stress in diabetic rats by modulating the IRE-1 arm of the UPR and apoptosis pathways, highlighting its potential therapeutic benefits for diabetes-related liver complications.
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Affiliation(s)
- Hediye Fahandezh Saadi
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Biochemistry, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farhad Koohpeyma
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Raeisi
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran
| | - Zahra Amirahmadi
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran
| | - Narges Rezaei
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Joolidehpoor
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran
| | - Mesbah Shams
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Science, P.O. Box: 71345-1744, Shiraz, Iran.
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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13
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Roshdy M, Zaky DA, Abbas SS, Abdallah DM. Niacin, an innovative protein kinase-C-dependent endoplasmic reticulum stress reticence in murine Parkinson's disease. Life Sci 2024; 351:122865. [PMID: 38914304 DOI: 10.1016/j.lfs.2024.122865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/08/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
AIMS Niacin (NIA) supplementation showed effectiveness against Parkinson's disease (PD) in clinical trials. The depletion of NAD and endoplasmic reticulum stress response (ERSR) are implicated in the pathogenesis of PD, but the potential role for NAD precursors on ERSR is not yet established. This study was undertaken to decipher NIA molecular mechanisms against PD-accompanied ERSR, especially in relation to PKC. METHODS Alternate-day-low-dose-21 day-subcutaneous exposure to rotenone (ROT) in rats induced PD. Following the 5th ROT injection, rats received daily doses of either NIA alone or preceded by the PKC inhibitor tamoxifen (TAM). Extent of disease progression was assessed by behavioral, striatal biochemical and striatal/nigral histopathological/immunohistochemical analysis. KEY FINDINGS Via activating PKC/LKB1/AMPK stream, NIA post-treatment attenuated the ERSR reflected by the decline in ATF4, ATF6 and XBP1s to downregulate the apoptotic markers, CHOP/GADD153, p-JNK and active caspase-3. Such amendments congregated in motor activity/coordination improvements in open field and rotarod tasks, enhanced grid test latency and reduced overall PD scores, while boosting nigral/striatal tyrosine hydroxylase immunoreactivity and increasing intact neurons (Nissl stain) in both SNpc and striatum that showed less neurodegeneration (H&E stain). To different extents, TAM reverted all the NIA-related actions to prove PKC as a fulcrum in conveying the drug neurotherapeutic potential. SIGNIFICANCE PKC activation is a pioneer mechanism in the drug ERSR inhibitory anti-apoptotic modality to clarify NIA promising clinical and potent preclinical anti-PD efficacy. This kinase can be tagged as a druggable target for future add-on treatments that can assist dopaminergic neuronal aptitude against this devastating neurodegenerative disease.
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Affiliation(s)
- Merna Roshdy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr International University, Ahmed Orabi District, Cairo 44971, Egypt
| | - Doaa A Zaky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
| | - Samah S Abbas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr International University, Ahmed Orabi District, Cairo 44971, Egypt
| | - Dalaal M Abdallah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
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14
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Zheng Y, Zha X, Zhang B, Elsabagh M, Wang H, Wang M, Zhang H. The interaction of ER stress and autophagy in trophoblasts: navigating pregnancy outcome†. Biol Reprod 2024; 111:292-311. [PMID: 38678504 DOI: 10.1093/biolre/ioae066] [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: 11/27/2023] [Revised: 04/12/2024] [Accepted: 04/22/2024] [Indexed: 05/01/2024] Open
Abstract
The endoplasmic reticulum is a complex and dynamic organelle that initiates unfolded protein response and endoplasmic reticulum stress in response to the accumulation of unfolded or misfolded proteins within its lumen. Autophagy is a paramount intracellular degradation system that facilitates the transportation of proteins, cytoplasmic components, and organelles to lysosomes for degradation and recycling. Preeclampsia and intrauterine growth retardation are two common complications of pregnancy associated with abnormal trophoblast differentiation and placental dysfunctions and have a major impact on fetal development and maternal health. The intricate interplay between endoplasmic reticulum stress, and autophagy and their impact on pregnancy outcomes, through mediating trophoblast differentiation and placental development, has been highlighted in various reports. Autophagy controls trophoblast regulation through a variety of gene expressions and signaling pathways while excessive endoplasmic reticulum stress triggers downstream apoptotic signaling, culminating in trophoblast apoptosis. This comprehensive review delves into the intricacies of placental development and explores the underlying mechanisms of preeclampsia and intrauterine growth retardation. In addition, this review will elucidate the molecular mechanisms of endoplasmic reticulum stress and autophagy, both individually and in their interplay, in mediating placental development and trophoblast differentiation, particularly highlighting their roles in preeclampsia and intrauterine growth retardation development. This research seeks to the interplay between endoplasmic reticulum stress and impaired autophagy in the placental trophoderm, offering novel insights into their contribution to pregnancy complications.
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Affiliation(s)
- Yi Zheng
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Xia Zha
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Bei Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Mabrouk Elsabagh
- Department of Animal Production and Technology, Faculty of Agricultural Sciences and Technologies, Niğde Ömer Halisdemir University, Nigde, Turkey
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh University, KafrelSheikh, Egypt
| | - Hongrong Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
| | - Mengzhi Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Science, Shihezi, P. R. China
| | - Hao Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, People's Repubic of China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, People's Republic of China
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15
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Mustakim KR, Eo MY, Seo MH, Yang HC, Kim MK, Myoung H, Kim SM. Ultrastructural and immunohistochemical evaluation of hyperplastic soft tissues surrounding dental implants in fibular jaws. Sci Rep 2024; 14:10717. [PMID: 38730018 PMCID: PMC11087521 DOI: 10.1038/s41598-024-60474-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/23/2024] [Indexed: 05/12/2024] Open
Abstract
In reconstructive surgery, complications post-fibula free flap (FFF) reconstruction, notably peri-implant hyperplasia, are significant yet understudied. This study analyzed peri-implant hyperplastic tissue surrounding FFF, alongside peri-implantitis and foreign body granulation (FBG) tissues from patients treated at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Using light microscopy, pseudoepitheliomatous hyperplasia, anucleate and pyknotic prickle cells, and excessive collagen deposition were observed in FFF hyperplastic tissue. Ultrastructural analyses revealed abnormal structures, including hemidesmosome dilation, bacterial invasion, and endoplasmic reticulum (ER) swelling. In immunohistochemical analysis, unfolded protein-response markers ATF6, PERK, XBP1, inflammatory marker NFκB, necroptosis marker MLKL, apoptosis marker GADD153, autophagy marker LC3, epithelial-mesenchymal transition, and angiogenesis markers were expressed variably in hyperplastic tissue surrounding FFF implants, peri-implantitis, and FBG tissues. NFκB expression was higher in peri-implantitis and FBG tissues compared to hyperplastic tissue surrounding FFF implants. PERK expression exceeded XBP1 significantly in FFF hyperplastic tissue, while expression levels of PERK, XBP1, and ATF6 were not significantly different in peri-implantitis and FBG tissues. These findings provide valuable insights into the interconnected roles of ER stress, necroptosis, apoptosis, and angiogenesis in the pathogenesis of oral pathologies, offering a foundation for innovative strategies in dental implant rehabilitation management and prevention.
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Affiliation(s)
- Kezia Rachellea Mustakim
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Mi Young Eo
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Mi Hyun Seo
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Hyeong-Cheol Yang
- Department of Dental Biomaterials Science, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
| | - Min-Keun Kim
- Department of Oral and Maxillofacial Surgery, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea
| | - Hoon Myoung
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Soung Min Kim
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
- Oral and Maxillofacial Microvascular Reconstruction LAB, Brong Ahafo Regional Hospital, P.O.Box 27, Sunyani, Ghana.
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16
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Keramidas P, Pitou M, Papachristou E, Choli-Papadopoulou T. Insights into the Activation of Unfolded Protein Response Mechanism during Coronavirus Infection. Curr Issues Mol Biol 2024; 46:4286-4308. [PMID: 38785529 PMCID: PMC11120126 DOI: 10.3390/cimb46050261] [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: 03/28/2024] [Revised: 04/24/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Coronaviruses represent a significant class of viruses that affect both animals and humans. Their replication cycle is strongly associated with the endoplasmic reticulum (ER), which, upon virus invasion, triggers ER stress responses. The activation of the unfolded protein response (UPR) within infected cells is performed from three transmembrane receptors, IRE1, PERK, and ATF6, and results in a reduction in protein production, a boost in the ER's ability to fold proteins properly, and the initiation of ER-associated degradation (ERAD) to remove misfolded or unfolded proteins. However, in cases of prolonged and severe ER stress, the UPR can also instigate apoptotic cell death and inflammation. Herein, we discuss the ER-triggered host responses after coronavirus infection, as well as the pharmaceutical targeting of the UPR as a potential antiviral strategy.
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Affiliation(s)
| | | | | | - Theodora Choli-Papadopoulou
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (P.K.); (M.P.); (E.P.)
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17
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Al Otaibi A, Al Shaikh Mubarak S, Al Hejji F, Almasaud A, Al Jami H, Iqbal J, Al Qarni A, Harbi NKA, Bakillah A. Thapsigargin and Tunicamycin Block SARS-CoV-2 Entry into Host Cells via Differential Modulation of Unfolded Protein Response (UPR), AKT Signaling, and Apoptosis. Cells 2024; 13:769. [PMID: 38727305 PMCID: PMC11083125 DOI: 10.3390/cells13090769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/05/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in host cells, which may contribute to the pathogenesis of COVID-19. To understand the complex interplay between SARS-Co-V2 infection and UPR signaling, we examined the effects of acute pre-existing ER stress on SARS-Co-V2 infectivity. METHODS Huh-7 cells were treated with Tunicamycin (TUN) and Thapsigargin (THA) prior to SARS-CoV-2pp transduction (48 h p.i.) to induce ER stress. Pseudo-typed particles (SARS-CoV-2pp) entry into host cells was measured by Bright GloTM luciferase assay. Cell viability was assessed by cell titer Glo® luminescent assay. The mRNA and protein expression was evaluated by RT-qPCR and Western Blot. RESULTS TUN (5 µg/mL) and THA (1 µM) efficiently inhibited the entry of SARS-CoV-2pp into host cells without any cytotoxic effect. TUN and THA's attenuation of virus entry was associated with differential modulation of ACE2 expression. Both TUN and THA significantly reduced the expression of stress-inducible ER chaperone GRP78/BiP in transduced cells. In contrast, the IRE1-XBP1s and PERK-eIF2α-ATF4-CHOP signaling pathways were downregulated with THA treatment, but not TUN in transduced cells. Insulin-mediated glucose uptake and phosphorylation of Ser307 IRS-1 and downstream p-AKT were enhanced with THA in transduced cells. Furthermore, TUN and THA differentially affected lipid metabolism and apoptotic signaling pathways. CONCLUSIONS These findings suggest that short-term pre-existing ER stress prior to virus infection induces a specific UPR response in host cells capable of counteracting stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection.
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Affiliation(s)
- Abeer Al Otaibi
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia; (A.A.O.); (S.A.S.M.); (F.A.H.); (J.I.); (A.A.Q.)
- Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Sindiyan Al Shaikh Mubarak
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia; (A.A.O.); (S.A.S.M.); (F.A.H.); (J.I.); (A.A.Q.)
- Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Fatimah Al Hejji
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia; (A.A.O.); (S.A.S.M.); (F.A.H.); (J.I.); (A.A.Q.)
| | - Abdulrahman Almasaud
- Vaccine Development Unit, Department of Infectious Disease Research, King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia; (A.A.); (H.A.J.); (N.K.A.H.)
| | - Haya Al Jami
- Vaccine Development Unit, Department of Infectious Disease Research, King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia; (A.A.); (H.A.J.); (N.K.A.H.)
| | - Jahangir Iqbal
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia; (A.A.O.); (S.A.S.M.); (F.A.H.); (J.I.); (A.A.Q.)
- Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ali Al Qarni
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia; (A.A.O.); (S.A.S.M.); (F.A.H.); (J.I.); (A.A.Q.)
- Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Naif Khalaf Al Harbi
- Vaccine Development Unit, Department of Infectious Disease Research, King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia; (A.A.); (H.A.J.); (N.K.A.H.)
| | - Ahmed Bakillah
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia; (A.A.O.); (S.A.S.M.); (F.A.H.); (J.I.); (A.A.Q.)
- Biomedical Research Department, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
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18
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Pornsukjantra T, Saikachain N, Sutjarit N, Khongkrapan A, Tubsuwan A, Bhukhai K, Tim-Aroon T, Anurathapan U, Hongeng S, Asavapanumas N. An increase in ER stress and unfolded protein response in iPSCs-derived neuronal cells from neuronopathic Gaucher disease patients. Sci Rep 2024; 14:9177. [PMID: 38649404 PMCID: PMC11035702 DOI: 10.1038/s41598-024-59834-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024] Open
Abstract
Gaucher disease (GD) is a lysosomal storage disorder caused by a mutation in the GBA1 gene, responsible for encoding the enzyme Glucocerebrosidase (GCase). Although neuronal death and neuroinflammation have been observed in the brains of individuals with neuronopathic Gaucher disease (nGD), the exact mechanism underlying neurodegeneration in nGD remains unclear. In this study, we used two induced pluripotent stem cells (iPSCs)-derived neuronal cell lines acquired from two type-3 GD patients (GD3-1 and GD3-2) to investigate the mechanisms underlying nGD by biochemical analyses. These iPSCs-derived neuronal cells from GD3-1 and GD3-2 exhibit an impairment in endoplasmic reticulum (ER) calcium homeostasis and an increase in unfolded protein response markers (BiP and CHOP), indicating the presence of ER stress in nGD. A significant increase in the BAX/BCL-2 ratio and an increase in Annexin V-positive cells demonstrate a notable increase in apoptotic cell death in GD iPSCs-derived neurons, suggesting downstream signaling after an increase in the unfolded protein response. Our study involves the establishment of iPSCs-derived neuronal models for GD and proposes a possible mechanism underlying nGD. This mechanism involves the activation of ER stress and the unfolded protein response, ultimately leading to apoptotic cell death in neurons.
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Affiliation(s)
- Tanapat Pornsukjantra
- Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Nongluk Saikachain
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Pla, Bang Phli, Samut Prakan, 10540, Thailand
| | - Nareerat Sutjarit
- Graduate Program in Nutrition, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Arthaporn Khongkrapan
- Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Alisa Tubsuwan
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Kanit Bhukhai
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Thipwimol Tim-Aroon
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Usanarat Anurathapan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Suradej Hongeng
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Nithi Asavapanumas
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Pla, Bang Phli, Samut Prakan, 10540, Thailand.
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19
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Ma M, Jiang W, Zhou R. DAMPs and DAMP-sensing receptors in inflammation and diseases. Immunity 2024; 57:752-771. [PMID: 38599169 DOI: 10.1016/j.immuni.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/17/2024] [Accepted: 03/01/2024] [Indexed: 04/12/2024]
Abstract
Damage-associated molecular patterns (DAMPs) are endogenous danger molecules produced in cellular damage or stress, and they can activate the innate immune system. DAMPs contain multiple types of molecules, including nucleic acids, proteins, ions, glycans, and metabolites. Although these endogenous molecules do not trigger immune response under steady-state condition, they may undergo changes in distribution, physical or chemical property, or concentration upon cellular damage or stress, and then they become DAMPs that can be sensed by innate immune receptors to induce inflammatory response. Thus, DAMPs play an important role in inflammation and inflammatory diseases. In this review, we summarize the conversion of homeostatic molecules into DAMPs; the diverse nature and classification, cellular origin, and sensing of DAMPs; and their role in inflammation and related diseases. Furthermore, we discuss the clinical strategies to treat DAMP-associated diseases via targeting DAMP-sensing receptors.
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Affiliation(s)
- Ming Ma
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China
| | - Wei Jiang
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China
| | - Rongbin Zhou
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China; Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
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20
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AlBashtawi J, Al-Jaber H, Ahmed S, Al-Mansoori L. Impact of Obesity-Related Endoplasmic Reticulum Stress on Cancer and Associated Molecular Targets. Biomedicines 2024; 12:793. [PMID: 38672148 PMCID: PMC11047871 DOI: 10.3390/biomedicines12040793] [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: 12/10/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 04/28/2024] Open
Abstract
Obesity, characterized by excessive body fat, is closely linked to endoplasmic reticulum (ER) stress, leading to insulin resistance and type 2 diabetes. Inflammatory pathways like c-Jun N-terminal kinase (JNK) worsen insulin resistance, impacting insulin signaling. Moreover, ER stress plays a substantial role in cancer, influencing tumor cell survival and growth by releasing factors like vascular endothelial growth factor (VEGF). The unfolded protein response (UPR) is pivotal in this process, offering both pro-survival and apoptotic pathways. This review offers an extensive exploration of the sophisticated connection between ER stress provoked by obesity and its role in both the onset and advancement of cancer. It delves into the intricate interplay between oncogenic signaling and the pathways associated with ER stress in individuals who are obese. Furthermore, this review sheds light on potential therapeutic strategies aimed at managing ER stress induced by obesity, with a focus on addressing cancer initiation and progression. The potential to alleviate ER stress through therapeutic interventions, which may encompass the use of small molecules, FDA-approved medications, and gene therapy, holds great promise. A more in-depth examination of pathways such as UPR, ER-associated protein degradation (ERAD), autophagy, and epigenetic regulation has the potential to uncover innovative therapeutic approaches and the identification of predictive biomarkers.
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Affiliation(s)
- Joud AlBashtawi
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Hend Al-Jaber
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar; (H.A.-J.); (S.A.)
| | - Sara Ahmed
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar; (H.A.-J.); (S.A.)
| | - Layla Al-Mansoori
- Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar; (H.A.-J.); (S.A.)
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21
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Singh R, Kaur N, Choubey V, Dhingra N, Kaur T. Endoplasmic reticulum stress and its role in various neurodegenerative diseases. Brain Res 2024; 1826:148742. [PMID: 38159591 DOI: 10.1016/j.brainres.2023.148742] [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: 08/18/2023] [Revised: 12/07/2023] [Accepted: 12/24/2023] [Indexed: 01/03/2024]
Abstract
The Endoplasmic reticulum (ER), a critical cellular organelle, maintains cellular homeostasis by regulating calcium levels and orchestrating essential functions such as protein synthesis, folding, and lipid production. A pivotal aspect of ER function is its role in protein quality control. When misfolded proteins accumulate within the ER due to factors like protein folding chaperone dysfunction, toxicity, oxidative stress, or inflammation, it triggers the Unfolded protein response (UPR). The UPR involves the activation of chaperones like calnexin, calreticulin, glucose-regulating protein 78 (GRP78), and Glucose-regulating protein 94 (GRP94), along with oxidoreductases like protein disulphide isomerases (PDIs). Cells employ the Endoplasmic reticulum-associated degradation (ERAD) mechanism to counteract protein misfolding. ERAD disruption causes the detachment of GRP78 from transmembrane proteins, initiating a cascade involving Inositol-requiring kinase/endoribonuclease 1 (IRE1), Activating transcription factor 6 (ATF6), and Protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathways. The accumulation and deposition of misfolded proteins within the cell are hallmarks of numerous neurodegenerative diseases. These aberrant proteins disrupt normal neuronal signalling and contribute to impaired cellular homeostasis, including oxidative stress and compromised protein degradation pathways. In essence, ER stress is defined as the cellular response to the accumulation of misfolded proteins in the endoplasmic reticulum, encompassing a series of signalling pathways and molecular events that aim to restore cellular homeostasis. This comprehensive review explores ER stress and its profound implications for the pathogenesis and progression of neurodegenerative diseases.
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Affiliation(s)
- Rimaljot Singh
- Department of Biophysics, Panjab University Chandigarh, India
| | - Navpreet Kaur
- Department of Biophysics, Panjab University Chandigarh, India
| | - Vinay Choubey
- Department of Pharmacology, University of Tartu, Ravila 19, 51014 Tartu, Estonia
| | - Neelima Dhingra
- University Institute of Pharmaceutical Sciences, Panjab University Chandigarh, India
| | - Tanzeer Kaur
- Department of Biophysics, Panjab University Chandigarh, India.
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22
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Ma W, Ahmad SAI, Hashimoto M, Khalilnezhad A, Kataoka M, Arima Y, Tanaka Y, Yanagi S, Umemoto T, Suda T. MITOL deficiency triggers hematopoietic stem cell apoptosis via ER stress response. EMBO J 2024; 43:339-361. [PMID: 38238476 PMCID: PMC10897143 DOI: 10.1038/s44318-024-00029-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 02/02/2024] Open
Abstract
Hematopoietic stem cell (HSC) divisional fate and function are determined by cellular metabolism, yet the contribution of specific cellular organelles and metabolic pathways to blood maintenance and stress-induced responses in the bone marrow remains poorly understood. The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 (encoded by the Mitol gene) is known to regulate mitochondrial and endoplasmic reticulum (ER) interaction and to promote cell survival. Here, we investigated the functional involvement of MITOL in HSC maintenance by generating MX1-cre inducible Mitol knockout mice. MITOL deletion in the bone marrow resulted in HSC exhaustion and impairment of bone marrow reconstitution capability in vivo. Interestingly, MITOL loss did not induce major mitochondrial dysfunction in hematopoietic stem and progenitor cells. In contrast, MITOL deletion induced prolonged ER stress in HSCs, which triggered cellular apoptosis regulated by IRE1α. In line, dampening of ER stress signaling by IRE1α inihibitor KIRA6 partially rescued apoptosis of long-term-reconstituting HSC. In summary, our observations indicate that MITOL is a principal regulator of hematopoietic homeostasis and protects blood stem cells from cell death through its function in ER stress signaling.
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Affiliation(s)
- Wenjuan Ma
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan
| | - Shah Adil Ishtiyaq Ahmad
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh
| | - Michihiro Hashimoto
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan
| | - Ahad Khalilnezhad
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan
| | - Miho Kataoka
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan
| | - Yuichiro Arima
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan
| | - Yosuke Tanaka
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan
| | - Shigeru Yanagi
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Terumasa Umemoto
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan.
| | - Toshio Suda
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, 8620811, Japan.
- Cancer Science Institute of Singapore, National University of Singapore; Centre for Translation Medicine, Singapore, 117599, Singapore.
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23
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Mekala N, Trivedi J, Bhoj P, Togre N, Rom S, Sriram U, Persidsky Y. Alcohol and e-cigarette damage alveolar-epithelial barrier by activation of P2X7r and provoke brain endothelial injury via extracellular vesicles. Cell Commun Signal 2024; 22:39. [PMID: 38225580 PMCID: PMC10789007 DOI: 10.1186/s12964-023-01461-1] [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: 11/03/2023] [Accepted: 12/26/2023] [Indexed: 01/17/2024] Open
Abstract
BACKGROUND Use of nicotine containing products like electronic cigarettes (e-Cig) and alcohol are associated with mitochondrial membrane depolarization, resulting in the extracellular release of ATP, and mitochondrial DNA (mtDNA), mediating inflammatory responses. While nicotine effects on lungs is well-known, chronic alcohol (ETH) exposure also weakens lung immune responses and cause inflammation. Extracellular ATP (eATP) released by inflammatory/stressed cells stimulate purinergic P2X7 receptors (P2X7r) activation in adjacent cells. We hypothesized that injury caused by alcohol and e-Cig to pulmonary alveolar epithelial cells (hPAEpiC) promote the release of eATP, mtDNA and P2X7r in circulation. This induces a paracrine signaling communication either directly or via EVs to affect brain cells (human brain endothelial cells - hBMVEC). METHODS We used a model of primary human pulmonary alveolar epithelial cells (hPAEpiC) and exposed the cells to 100 mM ethanol (ETH), 100 µM acetaldehyde (ALD), or e-Cig (1.75 µg/mL of 1.8% or 0% nicotine) conditioned media, and measured the mitochondrial efficiency using Agilent Seahorse machine. Gene expression was measured by Taqman RT-qPCR and digital PCR. hPAEpiC-EVs were extracted from culture supernatant and characterized by flow cytometric analysis. Calcium (Ca2+) and eATP levels were quantified using commercial kits. To study intercellular communication via paracrine signaling or by EVs, we stimulated hBMVECs with hPAEpiC cell culture medium conditioned with ETH, ALD or e-cig or hPAEpiC-EVs and measured Ca2+ levels. RESULTS ETH, ALD, or e-Cig (1.8% nicotine) stimulation depleted the mitochondrial spare respiration capacity in hPAEpiC. We observed increased expression of P2X7r and TRPV1 genes (3-6-fold) and increased intracellular Ca2+ accumulation (20-30-fold increase) in hPAEpiC, resulting in greater expression of endoplasmic reticulum (ER) stress markers. hPAEpiC stimulated by ETH, ALD, and e-Cig conditioned media shed more EVs with larger particle sizes, carrying higher amounts of eATP and mtDNA. ETH, ALD and e-Cig (1.8% nicotine) exposure also increased the P2X7r shedding in media and via EVs. hPAEpiC-EVs carrying P2X7r and eATP cargo triggered paracrine signaling in human brain microvascular endothelial cells (BMVECs) and increased Ca2+ levels. P2X7r inhibition by A804598 compound normalized mitochondrial spare respiration, reduced ER stress and diminished EV release, thus protecting the BBB function. CONCLUSION Abusive drugs like ETH and e-Cig promote mitochondrial and endoplasmic reticulum stress in hPAEpiC and disrupts the cell functions via P2X7 receptor signaling. EVs released by lung epithelial cells against ETH/e-cig insults, carry a cargo of secondary messengers that stimulate brain cells via paracrine signals.
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Affiliation(s)
- Naveen Mekala
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Jayshil Trivedi
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Priyanka Bhoj
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Namdev Togre
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Slava Rom
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Uma Sriram
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Yuri Persidsky
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
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24
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Toosinia S, Davoodian N, Arabi M, Kadivar A. Ameliorating Effect of Sodium Selenite on Developmental and Molecular Response of Bovine Cumulus-Oocyte Complexes Matured in Vitro Under Heat Stress Condition. Biol Trace Elem Res 2024; 202:161-174. [PMID: 37127784 DOI: 10.1007/s12011-023-03678-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 04/18/2023] [Indexed: 05/03/2023]
Abstract
Selenium (Se), an essential trace element, plays an important role in the antioxidative defense mechanism, and it has been proven to improve fertility and reproductive efficiency in dairy cattle. The present study evaluated the potential protective action of Se supplement of in vitro maturation (IVM) media on the maturation and subsequent development of bovine cumulus-oocyte complexes (COCs) exposed to heat stress (HS). The treatment with Se improved the viability of cumulus cells (CCs) and oocytes (P < 0.05). The proportion of oocytes reached metaphase II (MII) and those arrested at metaphase I (MI) was greater and lower in treatment than control respectively (P < 0.05). Supplementation with Se increased the percentage of cleaved embryos, total blastocysts, and blastocyst/cleavage ratio (P < 0.05). Moreover, the upregulation of CCND1, SEPP1, GPX-4, SOD, CAT, and downregulation of GRP78, CHOP, and BAX in both Se-treated CCs and oocytes were recorded. The upregulation of NRF2 was detected in Se-treated CCs other than in oocytes, which showed upregulation of IGF2R and SOX-2 as the markers of quality as well. Se supplement in IVM media improved the viability, maturation, and the level of transcripts related to antioxidant defense and quality of heat-treated oocytes, which coincided with greater subsequent development outcomes. Se ameliorated the viability of CCs along with upregulation of antioxidative candidate gene expression and downregulation of apoptosis-related ones to support their protective role on restoring the quality of oocytes against compromising effects of HS.
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Affiliation(s)
- Shervin Toosinia
- Department of Animal Sciences, Faculty of Basic Science, Shahrekord University, Shahrekord, Iran
| | - Najmeh Davoodian
- Research Institute of Animal Embryo Technology, Shahrekord University, Shahrekord, Iran.
| | - Mehran Arabi
- Department of Animal Sciences, Faculty of Basic Science, Shahrekord University, Shahrekord, Iran
| | - Ali Kadivar
- Research Institute of Animal Embryo Technology, Shahrekord University, Shahrekord, Iran
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran
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25
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Thomas P, Gallagher MT, Da Silva Xavier G. Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding. Front Endocrinol (Lausanne) 2023; 14:1275835. [PMID: 38144558 PMCID: PMC10739424 DOI: 10.3389/fendo.2023.1275835] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 11/13/2023] [Indexed: 12/26/2023] Open
Abstract
The propensity to develop type 2 diabetes (T2D) is known to have both environmental and hereditary components. In those with a genetic predisposition to T2D, it is widely believed that elevated concentrations of circulatory long-chain fatty acids (LC-FFA) significantly contribute towards the demise of insulin-producing pancreatic β-cells - the fundamental feature of the development of T2D. Over 25 years of research support that LC-FFA are deleterious to β-cells, through a process termed lipotoxicity. However, the work underpinning the theory of β-cell lipotoxicity is mostly based on rodent studies. Doubts have been raised as to whether lipotoxicity also occurs in humans. In this review, we examine the evidence, both in vivo and in vitro, for the pathogenic effects of LC-FFA on β-cell viability and function in humans, highlighting key species differences. In this way, we aim to uncover the role of lipotoxicity in the human pathogenesis of T2D and motivate the need for species-specific understanding.
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Affiliation(s)
- Patricia Thomas
- Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Birmingham, United Kingdom
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Meurig T. Gallagher
- Centre for Systems Modelling and Quantitative Biomedicine, University of Birmingham, Birmingham, United Kingdom
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Gabriela Da Silva Xavier
- Institute for Metabolism and Systems Research, Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom
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26
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Mekala N, Trivedi J, Bhoj P, Togre N, Rom S, Sriram U, Persidsky Y. Alcohol and e-cigarette damage alveolar-epithelial barrier by activation of P2X7r and provoke brain endothelial injury via extracellular vesicles. RESEARCH SQUARE 2023:rs.3.rs-3552555. [PMID: 38014253 PMCID: PMC10680944 DOI: 10.21203/rs.3.rs-3552555/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Background Use of nicotine containing products like electronic cigarettes (e-Cig) and alcohol are associated with mitochondrial membrane depolarization, resulting in the extracellular release of ATP, and mitochondrial DNA (mtDNA), mediating inflammatory responses. While nicotine effects on lungs is well-known, chronic alcohol (ETH) exposure also weakens lung immune responses and cause inflammation. Extracellular ATP (eATP) released by inflammatory/stressed cells stimulate purinergic P2X7 receptors (P2X7r) activation in adjacent cells. We hypothesized that injury caused by alcohol and e-Cig to pulmonary alveolar epithelial cells (hPAEpiC) promote the release of eATP, mtDNA and P2X7r in circulation. This induces a paracrine signaling communication either directly or via EVs to affect brain cells (human brain endothelial cells - hBMVEC). Methods We used a model of primary human pulmonary alveolar epithelial cells (hPAEpiC) and exposed the cells to 100 mM ethanol (ETH), 100 μM acetaldehyde (ALD), or e-Cig (1.75μg/mL of 1.8% or 0% nicotine) conditioned media, and measured the mitochondrial efficiency using Agilent Seahorse machine. Gene expression was measured by Taqman RT-qPCR and digital PCR. hPAEpiC-EVs were extracted from culture supernatant and characterized by flow cytometric analysis. Calcium (Ca2+) and eATP levels were quantified using commercial kits. To study intercellular communication via paracrine signaling or by EVs, we stimulated hBMVECs with hPAEpiC cell culture medium conditioned with ETH, ALD or e-cig or hPAEpiC-EVs and measured Ca2+ levels. Results ETH, ALD, or e-Cig (1.8% nicotine) stimulation depleted the mitochondrial spare respiration capacity in hPAEpiC. We observed increased expression of P2X7r and TRPV1 genes (3-6-fold) and increased intracellular Ca2+ accumulation (20-30-fold increase) in hPAEpiC, resulting in greater expression of endoplasmic reticulum (ER) stress markers. hPAEpiC stimulated by ETH, ALD, and e-Cig conditioned media shed more EVs with larger particle sizes, carrying higher amounts of eATP and mtDNA. ETH, ALD and e-Cig (1.8% nicotine) exposure also increased the P2X7r shedding in media and via EVs. hPAEpiC-EVs carrying P2X7r and eATP cargo triggered paracrine signaling in human brain microvascular endothelial cells (BMVECs) and increased Ca2+ levels. P2X7r inhibition by A804598 compound normalized mitochondrial spare respiration, reduced ER stress and diminished EV release, thus protecting the BBB function. Conclusion Abusive drugs like ETH and e-Cig promote mitochondrial and endoplasmic reticulum stress in hPAEpiC and disrupts the cell functions via P2X7 receptor signaling. EVs released by lung epithelial cells against ETH/e-cig insults, carry a cargo of secondary messengers that stimulate brain cells via paracrine signals.
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27
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Patel S, Pangarkar A, Mahajan S, Majumdar A. Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy. Metab Brain Dis 2023; 38:1841-1856. [PMID: 37289403 DOI: 10.1007/s11011-023-01239-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 05/19/2023] [Indexed: 06/09/2023]
Abstract
Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain. Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE).
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Affiliation(s)
- Shivangi Patel
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India
| | - Arnika Pangarkar
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India
| | - Sakshi Mahajan
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India
| | - Anuradha Majumdar
- Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India.
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28
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Pathak U, Pal RB, Malik N. The Viral Knock: Ameliorating Cancer Treatment with Oncolytic Newcastle Disease Virus. Life (Basel) 2023; 13:1626. [PMID: 37629483 PMCID: PMC10455894 DOI: 10.3390/life13081626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/16/2023] [Accepted: 07/19/2023] [Indexed: 08/27/2023] Open
Abstract
The prospect of cancer treatment has drastically transformed over the last four decades. The side effects caused by the traditional methods of cancer treatment like surgery, chemotherapy, and radiotherapy through the years highlight the prospect for a novel, complementary, and alternative cancer therapy. Oncolytic virotherapy is an evolving treatment modality that utilizes oncolytic viruses (OVs) to selectively attack cancer cells by direct lysis and can also elicit a strong anti-cancer immune response. Newcastle disease virus (NDV) provides a very high safety profile compared to other oncolytic viruses. Extensive research worldwide concentrates on experimenting with and better understanding the underlying mechanisms by which oncolytic NDV can be effectively applied to intercept cancer. This review encapsulates the potential of NDV to be explored as an oncolytic agent and discusses current preclinical and clinical research scenarios involving various NDV strains.
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Affiliation(s)
- Upasana Pathak
- Sir H.N. Medical Research Society, Sir H.N. Reliance Foundation Hospital and Research Centre, Mumbai 400004, Maharashtra, India
- Vivekanand Education Society’s College of Arts, Science and Commerce, Chembur, Mumbai 400071, Maharashtra, India
| | - Ramprasad B. Pal
- Sir H.N. Medical Research Society, Sir H.N. Reliance Foundation Hospital and Research Centre, Mumbai 400004, Maharashtra, India
| | - Nagesh Malik
- Vivekanand Education Society’s College of Arts, Science and Commerce, Chembur, Mumbai 400071, Maharashtra, India
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29
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Guo H, Zhang S, Zhang B, Shang Y, Liu X, Wang M, Wang H, Fan Y, Tan K. Immunogenic landscape and risk score prediction based on unfolded protein response (UPR)-related molecular subtypes in hepatocellular carcinoma. Front Immunol 2023; 14:1202324. [PMID: 37457742 PMCID: PMC10348016 DOI: 10.3389/fimmu.2023.1202324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 06/14/2023] [Indexed: 07/18/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common type of cancer and causes a significant number of cancer-related deaths worldwide. The molecular mechanisms underlying the development of HCC are complex, and the heterogeneity of HCC has led to a lack of effective prognostic indicators and drug targets for clinical treatment of HCC. Previous studies have indicated that the unfolded protein response (UPR), a fundamental pathway for maintaining endoplasmic reticulum homeostasis, is involved in the formation of malignant characteristics such as tumor cell invasiveness and treatment resistance. The aims of our study are to identify new prognostic indicators and provide drug treatment targets for HCC in clinical treatment based on UPR-related genes (URGs). Methods Gene expression profiles and clinical information were downloaded from the TCGA, ICGC and GEO databases. Consensus cluster analysis was performed to classify the molecular subtypes of URGs in HCC patients. Univariate Cox regression and machine learning LASSO algorithm were used to establish a risk prognosis model. Kaplan-Meier and ROC analyses were used to evaluate the clinical prognosis of URGs. TIMER and XCell algorithms were applied to analyze the relationships between URGs and immune cell infiltration. Real time-PCR was performed to analyze the effect of sorafenib on the expression levels of four URGs. Results Most URGs were upregulated in HCC samples. According to the expression pattern of URGs, HCC patients were divided into two independent clusters. Cluster 1 had a higher expression level, worse prognosis, and higher expression of immunosuppressive factors than cluster 2. Patients in cluster 1 were more prone to immune escape during immunotherapy, and were more sensitive to chemotherapeutic drugs. Four key UPR genes (ATF4, GOSR2, PDIA6 and SRPRB) were established in the prognostic model and HCC patients with high risk score had a worse clinical prognosis. Additionally, patients with high expression of four URGs are more sensitive to sorafenib. Moreover, ATF4 was upregulated, while GOSR2, PDIA6 and SRPRB were downregulated in sorafenib-treated HCC cells. Conclusion The UPR-related prognostic signature containing four URGs exhibits high potential application value and performs well in the evaluation of effects of chemotherapy/immunotherapy and clinical prognosis.
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Affiliation(s)
| | | | | | | | | | | | | | - Yumei Fan
- *Correspondence: Yumei Fan, ; Ke Tan,
| | - Ke Tan
- *Correspondence: Yumei Fan, ; Ke Tan,
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30
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Yadav N, Thelma BK. Deletion induced splicing in RIC3 drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes. Glia 2023; 71:1217-1232. [PMID: 36602087 DOI: 10.1002/glia.24333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/25/2022] [Accepted: 12/22/2022] [Indexed: 01/06/2023]
Abstract
Nicotinic acetylcholine receptor (nAChR) dysregulation in astrocytes is reported in neurodegenerative disorders. Modulation of nAChRs through agonists confers protection to astrocytes from stress but regulation of chaperones involved in proteostasis with pathological implications is unclear. Resistance to inhibitors of cholinesterase 3 (RIC3), a potential chaperone of nAChRs is poorly studied in humans. We characterized RIC3 in astrocytes derived from an isogenic wild-type and Cas9 edited "del" human iPSC line harboring a 25 bp homozygous deletion in exon2. Altered RIC3 transcript ratio due to deletion induced splicing and an unexpected gain of α7nAChR expression were observed in "del" astrocytes. Transcriptome analysis showed higher expression of neurotransmitter/G-protein coupled receptors mediated by cAMP and calcium/calmodulin-dependent kinase signaling with increased cytokines/glutamate secretion. Functional implications examined using tunicamycin induced ER stress in wild-type astrocyte stress model showed cell cycle arrest, RIC3 upregulation, reduction in α7nAChR membrane levels but increased α4nAChR membrane expression. Conversely, tunicamycin-treated "del" astrocytes showed a comparatively higher α4nAChR membrane expression and upsurged cAMP signaling. Furthermore, reduced expression of stress markers CHOP, phospho-PERK and lowered XBP1 splicing in western blot and qPCR, validated by proteome-based pathway analysis indicated lowered disease severity. Findings indicate (i) a complex RNA regulatory mechanism via exonic deletion induced splicing; (ii) RIC-3 as a disordered protein having contrasting effects on co-expressed nAChR subtypes under basal/stress conditions; and (iii) RIC3 as a potential drug target against ER stress in astrocytes for neurodegenerative/nicotine-related brain disorders. Cellular rescue mechanism through deletion induced exon skipping may encourage ASO-based therapies for tauopathies.
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Affiliation(s)
- Navneesh Yadav
- Department of Genetics, University of Delhi South Campus, New Delhi, India
| | - B K Thelma
- Department of Genetics, University of Delhi South Campus, New Delhi, India
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Petrosyan E, Fares J, Fernandez LG, Yeeravalli R, Dmello C, Duffy JT, Zhang P, Lee-Chang C, Miska J, Ahmed AU, Sonabend AM, Balyasnikova IV, Heimberger AB, Lesniak MS. Endoplasmic Reticulum Stress in the Brain Tumor Immune Microenvironment. Mol Cancer Res 2023; 21:389-396. [PMID: 36652630 PMCID: PMC10159901 DOI: 10.1158/1541-7786.mcr-22-0920] [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: 11/16/2022] [Revised: 01/05/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023]
Abstract
Immunotherapy has emerged as a powerful strategy for halting cancer progression. However, primary malignancies affecting the brain have been exempt to this success. Indeed, brain tumors continue to portend severe morbidity and remain a globally lethal disease. Extensive efforts have been directed at understanding how tumor cells survive and propagate within the unique microenvironment of the central nervous system (CNS). Cancer genetic aberrations and metabolic abnormalities provoke a state of persistent endoplasmic reticulum (ER) stress that in turn promotes tumor growth, invasion, therapeutic resistance, and the dynamic reprogramming of the infiltrating immune cells. Consequently, targeting ER stress is a potential therapeutic approach. In this work, we provide an overview of how ER stress response is advantageous to brain tumor development, discuss the significance of ER stress in governing antitumor immunity, and put forth therapeutic strategies of regulating ER stress to augment the effect of immunotherapy for primary CNS tumors.
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Affiliation(s)
- Edgar Petrosyan
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Jawad Fares
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Luis G. Fernandez
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Ragini Yeeravalli
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Crismita Dmello
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Joseph T. Duffy
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Peng Zhang
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Catalina Lee-Chang
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Jason Miska
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Atique U. Ahmed
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Adam M. Sonabend
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Irina V. Balyasnikova
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Amy B. Heimberger
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Maciej S. Lesniak
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
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Jeong S, Shin EC, Lee JH, Ha JH. Particulate Matter Elevates Ocular Inflammation and Endoplasmic Reticulum Stress in Human Retinal Pigmented Epithelium Cells. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:4766. [PMID: 36981676 PMCID: PMC10049273 DOI: 10.3390/ijerph20064766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 06/18/2023]
Abstract
Because of their exposure to air, eyes can come into contact with air pollutants such as particulate matter (PM), which may cause severe ocular pathologies. Prolonged ocular PM exposure may increase inflammation and endoplasmic reticulum stress in the retina. Herein, we investigated whether PM exposure induces ocular inflammation and endoplasmic reticulum (ER) stress-related cellular responses in human retinal epithelium-19 (ARPE-19) cells. To understand how PM promotes ocular inflammation, we monitored the activation of the mitogen-activated protein kinase (MAPK)/nuclear factor kappa beta (NFκB) axis and the expression of key inflammatory mRNAs. We also measured the upregulation of signature components for the ER-related unfolded protein response (UPR) pathways, as well as intracellular calcium ([Ca2+]i) levels, as readouts for ER stress induction following PM exposure. Ocular PM exposure significantly elevated the expression of multiple cytokine mRNAs and increased phosphorylation levels of NFκB-MAPK axis in a PM dose-dependent manner. Moreover, incubation with PM significantly increased [Ca2+]i levels and the expression of UPR-related proteins, which indicated ER stress resulting from cell hypoxia, and upregulation of hypoxic adaptation mechanisms such as the ER-associated UPR pathways. Our study demonstrated that ocular PM exposure increased inflammation in ARPE-19 cells, by activating the MAPK/NFκB axis and cytokine mRNA expression, while also inducing ER stress and stress adaptation responses. These findings may provide helpful insight into clinical and non-clinical research examining the role of PM exposure in ocular pathophysiology and delineating its underlying molecular mechanisms.
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Affiliation(s)
- Sunyoung Jeong
- Bioanalytical and Pharmacokinetic Research Group, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea
- Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Eui-Cheol Shin
- Department of GreenBio Science/Food Science and Technology, Gyeongsang National University, Jinju 52725, Republic of Korea
| | - Jong-Hwa Lee
- Bioanalytical and Pharmacokinetic Research Group, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea
- Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Jung-Heun Ha
- Department of Food Science and Nutrition, Dankook University, Cheonan 31116, Republic of Korea
- Research Center for Industrialization of Natural Neutralization, Dankook University, Yongin 16890, Republic of Korea
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Vestuto V, Di Sarno V, Musella S, Di Dona G, Moltedo O, Gomez-Monterrey IM, Bertamino A, Ostacolo C, Campiglia P, Ciaglia T. New Frontiers on ER Stress Modulation: Are TRP Channels the Leading Actors? Int J Mol Sci 2022; 24:185. [PMID: 36613628 PMCID: PMC9820239 DOI: 10.3390/ijms24010185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
The endoplasmic reticulum (ER) is a dynamic structure, playing multiple roles including calcium storage, protein synthesis and lipid metabolism. During cellular stress, variations in ER homeostasis and its functioning occur. This condition is referred as ER stress and generates a cascade of signaling events termed unfolded protein response (UPR), activated as adaptative response to mitigate the ER stress condition. In this regard, calcium levels play a pivotal role in ER homeostasis and therefore in cell fate regulation since calcium signaling is implicated in a plethora of physiological processes, but also in disease conditions such as neurodegeneration, cancer and metabolic disorders. A large body of emerging evidence highlighted the functional role of TRP channels and their ability to promote cell survival or death depending on endoplasmic reticulum stress resolution, making them an attractive target. Thus, in this review we focused on the TRP channels' correlation to UPR-mediated ER stress in disease pathogenesis, providing an overview of their implication in the activation of this cellular response.
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Affiliation(s)
- Vincenzo Vestuto
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Veronica Di Sarno
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Simona Musella
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Giorgio Di Dona
- Pineta Grande Hospital, Via Domiziana, km 30/00, 81030 Castel Volturno, CE, Italy
| | - Ornella Moltedo
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | | | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
| | - Carmine Ostacolo
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
- Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, NA, Italy
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
- European Biomedical Research Institute of Salerno, Via S. De Renzi 50, 84125 Salerno, SA, Italy
| | - Tania Ciaglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy
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Chemical chaperones ameliorate neurodegenerative disorders in Derlin-1-deficient mice via improvement of cholesterol biosynthesis. Sci Rep 2022; 12:21840. [PMID: 36528738 PMCID: PMC9759528 DOI: 10.1038/s41598-022-26370-0] [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: 09/02/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
There are no available therapies targeting the underlying molecular mechanisms of neurodegenerative diseases. Although chaperone therapies that alleviate endoplasmic reticulum (ER) stress recently showed promise in the treatment of neurodegenerative diseases, the detailed mechanisms remain unclear. We previously reported that mice with central nervous system-specific deletion of Derlin-1, which encodes an essential component for ER quality control, are useful as models of neurodegenerative diseases such as spinocerebellar degeneration. Cholesterol biosynthesis is essential for brain development, and its disruption inhibits neurite outgrowth, causing brain atrophy. In this study, we report a novel mechanism by which chemical chaperones ameliorate brain atrophy and motor dysfunction. ER stress was induced in the cerebella of Derlin-1 deficiency mice, whereas the administration of a chemical chaperone did not alleviate ER stress. However, chemical chaperone treatment ameliorated cholesterol biosynthesis impairment through SREBP-2 activation and simultaneously relieved brain atrophy and motor dysfunction. Altogether, these findings demonstrate that ER stress may not be the target of action of chaperone therapies and that chemical chaperone-mediated improvement of brain cholesterol biosynthesis is a promising novel therapeutic strategy for neurodegenerative diseases.
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Sex-Dependent Responses to Maternal Exposure to PM2.5 in the Offspring. Antioxidants (Basel) 2022; 11:antiox11112255. [PMID: 36421441 PMCID: PMC9686974 DOI: 10.3390/antiox11112255] [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: 10/12/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/17/2022] Open
Abstract
Objective: Particulate matter (PM) with a diameter of 2.5 μm or less (PM2.5) can cross the blood-placental barrier causing adverse foetal outcomes. However, the impact of maternal exposure to low-levels of PM2.5 on liver health and the metabolic profile is unclear. This study aimed to investigate hepatic responses to long-term gestational low-dose PM2.5 exposure, and whether the removal of PM after conception can prevent such effects. Method: Female Balb/c mice (8 weeks) were exposed to PM2.5 (5 μg/day) for 6 weeks prior to mating, during gestation and lactation to model living in a polluted environment (PM group). In a sub-group, PM2.5 exposure was stopped post-conception to model mothers moving to areas with clean air (pre-gestation, Pre) group. Livers were studied in 13-week old offspring. Results: Female offspring in both PM and Pre groups had increased liver triglyceride and glycogen levels, glucose intolerance, but reduced serum insulin and insulin resistance. Male offspring from only the Pre group had increased liver and serum triglycerides, increased liver glycogen, glucose intolerance and higher fasting glucose level. Markers of oxidative stress and inflammation were increased in females from PM and Pre groups. There was also a significant sex difference in the hepatic response to PM2.5 with differential changes in several metabolic markers identified by proteomic analysis. Conclusions: Maternal PM exposure exerted sex-dependent effects on liver health with more severe impacts on females. The removal of PM2.5 during gestation provided limited protection in the offspring’s metabolism regardless of sex.
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Márton M, Bánhegyi G, Gyöngyösi N, Kálmán EÉ, Pettkó‐Szandtner A, Káldi K, Kapuy O. A systems biological analysis of the ATF4-GADD34-CHOP regulatory triangle upon endoplasmic reticulum stress. FEBS Open Bio 2022; 12:2065-2082. [PMID: 36097827 PMCID: PMC9623533 DOI: 10.1002/2211-5463.13484] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 08/24/2022] [Accepted: 09/10/2022] [Indexed: 01/25/2023] Open
Abstract
Endoplasmic reticulum (ER) stress-dependent accumulation of incorrectly folded proteins leads to activation of the unfolded protein response. The role of the unfolded protein response (UPR) is to avoid cell damage and restore the homeostatic state by autophagy; however, excessive ER stress results in apoptosis. Here we investigated the ER stress-dependent feedback loops inside one of the UPR branches by focusing on PERK-induced ATF4 and its two targets, called CHOP and GADD34. Our goal was to qualitatively describe the dynamic behavior of the system by exploring the key regulatory motifs using both molecular and theoretical biological techniques. Using the HEK293T cell line as a model system, we confirmed that the life-or-death decision is strictly regulated. We investigated the dynamic characteristics of the crucial elements of the PERK pathway at both the RNA and protein level upon tolerable and excessive levels of ER stress. Of particular note, inhibition of GADD34 or CHOP resulted in various phenotypes upon high levels of ER stress. Our computer simulations suggest the existence of two new feedback loops inside the UPR. First, GADD34 seems to have a positive effect on ATF4 activity, while CHOP inhibits it. We claim that these newly described feedback loops ensure the fine-tuning of the ATF4-dependent stress response mechanism of the cell.
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Affiliation(s)
- Margita Márton
- Department of Molecular Biology at the Institute of Biochemistry and Molecular BiologySemmelweis UniversityBudapestHungary
| | - Gábor Bánhegyi
- Department of Molecular Biology at the Institute of Biochemistry and Molecular BiologySemmelweis UniversityBudapestHungary
| | - Norbert Gyöngyösi
- Department of Molecular Biology at the Institute of Biochemistry and Molecular BiologySemmelweis UniversityBudapestHungary
| | - Eszter Éva Kálmán
- Department of Molecular Biology at the Institute of Biochemistry and Molecular BiologySemmelweis UniversityBudapestHungary
| | | | - Krisztina Káldi
- Department of PhysiologySemmelweis UniversityBudapestHungary
| | - Orsolya Kapuy
- Department of Molecular Biology at the Institute of Biochemistry and Molecular BiologySemmelweis UniversityBudapestHungary
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Qin W, Zhang T, Ge M, Zhou H, Xu Y, Mu R, Huang C, Liu D, Huang B, Wang Q, Kong Q, Kong Q, Li F, Xiong W. Hepatic RACK1 deletion disturbs lipid and glucose homeostasis independently of insulin resistance. J Endocrinol 2022; 254:137-151. [PMID: 35608066 DOI: 10.1530/joe-22-0076] [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: 05/12/2022] [Accepted: 05/23/2022] [Indexed: 11/08/2022]
Abstract
Receptor for activated C kinase 1 (RACK1) is a versatile protein involved in multiple biological processes. In a previous study by Zhao et al., hepatic RACK1 deletion in mice led to an inhibition of autophagy, blocked autophagy-dependent lipolysis, and caused steatosis. Using the same mouse model (RACK1hep-/-), we revealed new roles of RACK1 in maintaining bile acid homeostasis and hepatic glucose uptake, which further affected circulatory lipid and glucose levels. To be specific, even under hepatic steatosis, the plasma lipids were generally reduced in RACK1hep-/- mouse, which was due to the suppression of intestinal lipid absorption. Accordingly, a decrease in total bile acid level was found in RACK1hep-/- livers, gallbladders, and small intestine tissues, and specific decrease of 12-hydroxylated bile acids was detected by liquid chromatography-mass spectrometry. Consistently, reduced expression of CYP8B1 was found. A decrease in hepatic glycogen storage was also observed, which might be due to the inhibited glucose uptake by GLUT2 insufficiency. Interestingly, RACK1-KO-inducing hepatic steatosis did not raise insulin resistance (IR) nor IR-inducing factors like endoplasmic reticulum stress and inflammation. In summary, this study uncovers that hepatic RACK1 might be required in maintaining bile acid homeostasis and glucose uptake in hepatocytes. This study also provides an additional case of hepatic steatosis disassociation with insulin resistance.
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Affiliation(s)
- Wanying Qin
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
- University of the Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Ting Zhang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
- University of the Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Mingxia Ge
- University of the Chinese Academy of Sciences, Beijing, People's Republic of China
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Huimin Zhou
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
| | - Yuhui Xu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
| | - Rongfang Mu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
| | - Chaoguang Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, People's Republic of China
| | - Daowei Liu
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, People's Republic of China
| | - Bangrui Huang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
- University of the Chinese Academy of Sciences, Beijing, People's Republic of China
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, People's Republic of China
| | - Qian Wang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, People's Republic of China
| | - Qinghua Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
| | - Qingpeng Kong
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Fei Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
- Laboratory of Metabolomics and Drug-induced Liver Injury, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Wenyong Xiong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, People's Republic of China
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Budi YP, Li YH, Huang C, Wang ME, Lin YC, Jong DS, Chiu CH, Jiang YF. The role of autophagy in high-fat diet-induced insulin resistance of adipose tissues in mice. PeerJ 2022; 10:e13867. [PMID: 35990905 PMCID: PMC9387522 DOI: 10.7717/peerj.13867] [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: 04/28/2022] [Accepted: 07/19/2022] [Indexed: 01/18/2023] Open
Abstract
Aims Studies have observed changes in autophagic flux in the adipose tissue of type 2 diabetes patients with obesity. However, the role of autophagy in obesity-induced insulin resistance is unclear. We propose to confirm the effect of a high-fat diet (HFD) on autophagy and insulin signaling transduction from adipose tissue to clarify whether altered autophagy-mediated HFD induces insulin resistance, and to elucidate the possible mechanisms in autophagy-regulated adipose insulin sensitivity. Methods Eight-week-old male C57BL/6 mice were fed with HFD to confirm the effect of HFD on autophagy and insulin signaling transduction from adipose tissue. Differentiated 3T3-L1 adipocytes were treated with 1.2 mM fatty acids (FAs) and 50 nM Bafilomycin A1 to determine the autophagic flux. 2.5 mg/kg body weight dose of Chloroquine (CQ) in PBS was locally injected into mouse epididymal adipose (10 and 24 h) and 40 µM of CQ to 3T3-L1 adipocytes for 24 h to evaluate the role of autophagy in insulin signaling transduction. Results The HFD treatment resulted in a significant increase in SQSTM1/p62, Rubicon expression, and C/EBP homologous protein (CHOP) expression, yet the insulin capability to induce Akt (Ser473) and GSK3β (Ser9) phosphorylation were reduced. PHLPP1 and PTEN remain unchanged after CQ injection. In differentiated 3T3-L1 adipocytes treated with CQ, although the amount of phospho-Akt stimulated by insulin in the CQ-treated group was significantly lower, CHOP expressions and cleaved caspase-3 were increased and bafilomycin A1 induced less accumulation of LC3-II protein. Conclusion Long-term high-fat diet promotes insulin resistance, late-stage autophagy inhibition, ER stress, and apoptosis in adipose tissue. Autophagy suppression may not affect insulin signaling transduction via phosphatase expression but indirectly causes insulin resistance through ER stress or apoptosis.
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Affiliation(s)
- Yovita Permata Budi
- Graduate Institute of Molecular and Comparative Pathobiology, National Taiwan University, Taipei, Taiwan,School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Hsuan Li
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Chien Huang
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Mu-En Wang
- Department of Pathology, Duke University, North Carolina, Durham, United States of America
| | - Yi-Chun Lin
- Department of Animal Science, National Chung Hsing University, Taichung, Taichung, Taiwan
| | - De-Shien Jong
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Chih-Hsien Chiu
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Yi-Fan Jiang
- Graduate Institute of Molecular and Comparative Pathobiology, National Taiwan University, Taipei, Taiwan,School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
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Jangra A, Verma M, Kumar D, Chandrika C, Rachamalla M, Dey A, Dua K, Jha SK, Ojha S, Alexiou A, Kumar D, Jha NK. Targeting Endoplasmic Reticulum Stress using Natural Products in Neurological Disorders. Neurosci Biobehav Rev 2022; 141:104818. [DOI: 10.1016/j.neubiorev.2022.104818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/23/2022] [Accepted: 08/03/2022] [Indexed: 10/16/2022]
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40
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Suksri K, Semprasert N, Limjindaporn T, Yenchitsomanus PT, Kooptiwoot S, Kooptiwut S. Cytoprotective effect of genistein against dexamethasone-induced pancreatic β-cell apoptosis. Sci Rep 2022; 12:12950. [PMID: 35902739 PMCID: PMC9334585 DOI: 10.1038/s41598-022-17372-z] [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: 12/17/2021] [Accepted: 07/25/2022] [Indexed: 11/10/2022] Open
Abstract
Steroid-induced diabetes is a well-known metabolic side effect of long-term use of glucocorticoid (GC). Our group recently demonstrated dexamethasone-induced pancreatic β-cell apoptosis via upregulation of TRAIL and TRAIL death receptor (DR5). Genistein protects against pancreatic β-cell apoptosis induced by toxic agents. This study aimed to investigate the cytoprotective effect of genistein against dexamethasone-induced pancreatic β-cell apoptosis in cultured rat insulinoma (INS-1) cell line and in isolated mouse islets. In the absence of genistein, dexamethasone-induced pancreatic β-cell apoptosis was associated with upregulation of TRAIL, DR5, and superoxide production, but downregulation of TRAIL decoy receptor (DcR1). Dexamethasone also activated the expression of extrinsic and intrinsic apoptotic proteins, including Bax, NF-κB, caspase-8, and caspase-3, but suppressed the expression of the anti-apoptotic Bcl-2 protein. Combination treatment with dexamethasone and genistein protected against pancreatic β-cell apoptosis, and reduced the effects of dexamethasone on the expressions of TRAIL, DR5, DcR1, superoxide production, Bax, Bcl-2, NF-κB, caspase-8, and caspase-3. Moreover, combination treatment with dexamethasone and genistein reduced the expressions of TRAIL and DR5 in isolated mouse islets. The results of this study demonstrate the cytoprotective effect of genistein against dexamethasone-induced pancreatic β-cell apoptosis in both cell line and islets via reduced TRAIL and DR5 protein expression.
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Affiliation(s)
- Kanchana Suksri
- Division of Endocrinology, Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
| | - Namoiy Semprasert
- Division of Endocrinology, Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand
| | - Thawornchai Limjindaporn
- Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pa-Thai Yenchitsomanus
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sirirat Kooptiwoot
- Department of Psychiatry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Suwattanee Kooptiwut
- Division of Endocrinology, Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand.
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The Achilles' heel of cancer: targeting tumors via lysosome-induced immunogenic cell death. Cell Death Dis 2022; 13:509. [PMID: 35637197 PMCID: PMC9151667 DOI: 10.1038/s41419-022-04912-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 03/10/2022] [Accepted: 05/04/2022] [Indexed: 12/14/2022]
Abstract
Interest in the lysosome's potential role in anticancer therapies has recently been appreciated in the field of immuno-oncology. Targeting lysosomes triggers apoptotic pathways, inhibits cytoprotective autophagy, and activates a unique form of apoptosis known as immunogenic cell death (ICD). This mechanism stimulates a local and systemic immune response against dead-cell antigens. Stressors that can lead to ICD include an abundance of ROS which induce lysosome membrane permeability (LMP). Dying cells express markers that activate immune cells. Dendritic cells engulf the dying cell and then present the cell's neoantigens to T cells. The discovery of ICD-inducing agents is important due to their potential to trigger autoimmunity. In this review, we discuss the various mechanisms of activating lysosome-induced cell death in cancer cells specifically and the strategies that current laboratories are using to selectively promote LMP in tumors.
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Endoplasmic reticulum stress promotes blood-testis barrier impairment in mice with busulfan-induced oligospermia through PERK-eIF2α signaling pathway. Toxicology 2022; 473:153193. [DOI: 10.1016/j.tox.2022.153193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 11/19/2022]
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White A, Parekh RU, Theobald D, Pakala P, Myers AL, Van Dross R, Sriramula S. Kinin B1R Activation Induces Endoplasmic Reticulum Stress in Primary Hypothalamic Neurons. Front Pharmacol 2022; 13:841068. [PMID: 35350763 PMCID: PMC8957924 DOI: 10.3389/fphar.2022.841068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/07/2022] [Indexed: 11/30/2022] Open
Abstract
The endoplasmic reticulum (ER) is a key organelle involved in homeostatic functions including protein synthesis and transport, and the storage of free calcium. ER stress potentiates neuroinflammation and neurodegeneration and is a key contributor to the pathogenesis of neurogenic hypertension. Recently, we showed that kinin B1 receptor (B1R) activation plays a vital role in modulating neuroinflammation and hypertension. However, whether B1R activation results in the progression and enhancement of ER stress has not yet been studied. In this brief research report, we tested the hypothesis that B1R activation in neurons contributes to unfolded protein response (UPR) and the development of ER stress. To test this hypothesis, we treated primary hypothalamic neuronal cultures with B1R specific agonist Lys-Des-Arg9-Bradykinin (LDABK) and measured the components of UPR and ER stress. Our data show that B1R stimulation via LDABK, induced the upregulation of GRP78, a molecular chaperone of ER stress. B1R stimulation was associated with an increased expression and activation of transmembrane ER stress sensors, ATF6, IRE1α, and PERK, the critical components of UPR. In the presence of overwhelming ER stress, activated ER stress sensors can lead to oxidative stress, autophagy, or apoptosis. To determine whether B1R activation induces apoptosis we measured intracellular Ca2+ and extracellular ATP levels, caspases 3/7 activity, and cell viability. Our data show that LDABK treatment does increase Ca2+ and ATP levels but does not alter caspase activity or cell viability. These findings suggest that B1R activation initiates the UPR and is a key factor in the ER stress pathway.
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Affiliation(s)
- Acacia White
- Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Rohan Umesh Parekh
- Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Drew Theobald
- Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Pranaya Pakala
- Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Ariel Lynn Myers
- Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Rukiyah Van Dross
- Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Srinivas Sriramula
- Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
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Prasad M K, Mohandas S, Ramkumar KM. Role of ER stress inhibitors in the management of diabetes. Eur J Pharmacol 2022; 922:174893. [DOI: 10.1016/j.ejphar.2022.174893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 12/14/2022]
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Gariballa N, Kizhakkedath P, Akawi N, John A, Ali BR. Endoglin Wild Type and Variants Associated With Hereditary Hemorrhagic Telangiectasia Type 1 Undergo Distinct Cellular Degradation Pathways. Front Mol Biosci 2022; 9:828199. [PMID: 35281255 PMCID: PMC8916587 DOI: 10.3389/fmolb.2022.828199] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/27/2022] [Indexed: 02/05/2023] Open
Abstract
Endoglin, also known as cluster of differentiation 105 (CD105), is an auxiliary receptor in the TGFβ signaling pathway. It is predominantly expressed in endothelial cells as a component of the heterotetrameric receptor dimers comprising type I, type II receptors and the binding ligands. Mutations in the gene encoding Endoglin (ENG) have been associated with hereditary hemorrhagic telangiectasia type 1 (HHT1), an autosomal dominant inherited disease that is generally characterized by vascular malformation. Secretory and many endomembrane proteins synthesized in the Endoplasmic reticulum (ER) are subjected to stringent quality control mechanisms to ensure that only properly folded and assembled proteins are trafficked forward through the secretory pathway to their sites of action. We have previously demonstrated that some Endoglin variants causing HHT1 are trapped in the ER and fail to traffic to their normal localization in plasma membrane, which suggested the possible involvement of ER associated protein degradation (ERAD) in their molecular pathology. In this study, we have investigated, for the first time, the degradation routes of Endoglin wild type and two mutant variants, P165L and V105D, and previously shown to be retained in the ER. Stably transfected HEK293 cells were treated with proteasomal and lysosomal inhibitors in order to elucidate the exact molecular mechanisms underlying the loss of function phenotype associated with these variants. Our results have shown that wild type Endoglin has a relatively short half-life of less than 2 hours and degrades through both the lysosomal and proteasomal pathways, whereas the two mutant disease-causing variants show high stability and predominantly degrades through the proteasomal pathway. Furthermore, we have demonstrated that Endoglin variants P165L and V105D are significantly accumulated in HEK293 cells deficient in HRD1 E3 ubiquitin ligase; a major ERAD component. These results implicate the ERAD mechanism in the pathology of HHT1 caused by the two variants. It is expected that these results will pave the way for more in-depth research studies that could provide new windows for future therapeutic interventions.
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Affiliation(s)
- Nesrin Gariballa
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Praseetha Kizhakkedath
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Nadia Akawi
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Anne John
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Bassam R Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.,Zayed Center for Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
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46
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Redding A, Aplin AE, Grabocka E. RAS-mediated tumor stress adaptation and the targeting opportunities it presents. Dis Model Mech 2022; 15:dmm049280. [PMID: 35147163 PMCID: PMC8844456 DOI: 10.1242/dmm.049280] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cellular stress is known to function in synergistic cooperation with oncogenic mutations during tumorigenesis to drive cancer progression. Oncogenic RAS is a strong inducer of a variety of pro-tumorigenic cellular stresses, and also enhances the ability of cells to tolerate these stresses through multiple mechanisms. Many of these oncogenic, RAS-driven, stress-adaptive mechanisms have also been implicated in tolerance and resistance to chemotherapy and to therapies that target the RAS pathway. Understanding how oncogenic RAS shapes cellular stress adaptation and how this functions in drug resistance is of vital importance for identifying new therapeutic targets and therapeutic combinations to treat RAS-driven cancers.
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Affiliation(s)
| | | | - Elda Grabocka
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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47
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Ganesan SM, Dabdoub SM, Nagaraja HN, Mariotti AJ, Ludden CW, Kumar PS. Biome‐microbiome interactions in peri‐implantitis: a pilot investigation. J Periodontol 2022; 93:814-823. [DOI: 10.1002/jper.21-0423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/31/2021] [Accepted: 11/07/2021] [Indexed: 11/12/2022]
Affiliation(s)
- Sukirth M Ganesan
- Division of Periodontology College of Dentistry The Ohio State University Columbus Ohio USA
| | - Shareef M Dabdoub
- Division of Periodontology College of Dentistry The Ohio State University Columbus Ohio USA
| | - Haikady N Nagaraja
- Division of Biostatistics College of Public Health The Ohio State University Columbus Ohio USA
| | - Angelo J. Mariotti
- Division of Periodontology College of Dentistry The Ohio State University Columbus Ohio USA
| | - Christopher W. Ludden
- Division of Periodontology College of Dentistry The Ohio State University Columbus Ohio USA
| | - Purnima S Kumar
- Division of Periodontology College of Dentistry The Ohio State University Columbus Ohio USA
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48
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Membrane polarization in non-neuronal cells as a potential mechanism of metabolic disruption by depolarizing insecticides. Food Chem Toxicol 2022; 160:112804. [PMID: 34990786 DOI: 10.1016/j.fct.2021.112804] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/22/2021] [Accepted: 12/31/2021] [Indexed: 01/01/2023]
Abstract
A significant rise in the incidence of obesity and type 2 diabetes has occurred worldwide in the last two decades. Concurrently, a growing body of evidence suggests a connection between exposure to environmental pollutants, particularly insecticides, and the development of obesity and type 2 diabetes. This review summarizes key evidence of (1) the presence of different types of neuronal receptors - target sites for neurotoxic insecticides - in non-neuronal cells, (2) the activation of these receptors in non-neuronal cells by membrane-depolarizing insecticides, and (3) changes in metabolic functions, including lipid and glucose accumulation, associated with changes in membrane potential. Based on these findings, we propose that changes in membrane potential (Vmem) by certain insecticides serve as a novel regulator of lipid and glucose metabolism in non-excitable cells associated with obesity and type 2 diabetes.
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49
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Zhao F, Zhou R, Wang JL, Liu H, Jing ZC. 18β-glycyrrhetinic acid ameliorates endoplasmic reticulum stress-induced inflammation in pulmonary arterial hypertension through PERK/eIF2α/NF-κB signaling. CHINESE J PHYSIOL 2022; 65:187-198. [DOI: 10.4103/0304-4920.354801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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50
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Rehni AK, Cho S, Dave KR. Ischemic brain injury in diabetes and endoplasmic reticulum stress. Neurochem Int 2022; 152:105219. [PMID: 34736936 PMCID: PMC8918032 DOI: 10.1016/j.neuint.2021.105219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 10/07/2021] [Accepted: 10/29/2021] [Indexed: 01/03/2023]
Abstract
Diabetes is a widespread disease characterized by high blood glucose levels due to abnormal insulin activity, production, or both. Chronic diabetes causes many secondary complications including cardiovascular disease: a life-threatening complication. Cerebral ischemia-related mortality, morbidity, and the extent of brain injury are high in diabetes. However, the mechanism of increase in ischemic brain injury during diabetes is not well understood. Multiple mechanisms mediate diabetic hyperglycemia and hypoglycemia-induced increase in ischemic brain injury. Endoplasmic reticulum (ER) stress mediates both brain injury as well as brain protection after ischemia-reperfusion injury. The pathways of ER stress are modulated during diabetes. Free radical generation and mitochondrial dysfunction, two of the prominent mechanisms that mediate diabetic increase in ischemic brain injury, are known to stimulate the pathways of ER stress. Increased ischemic brain injury in diabetes is accompanied by a further increase in the activation of ER stress. As there are many metabolic changes associated with diabetes, differential activation of the pathways of ER stress may mediate pronounced ischemic brain injury in subjects suffering from diabetes. We presently discuss the literature on the significance of ER stress in mediating increased ischemia-reperfusion injury in diabetes.
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Affiliation(s)
- Ashish K Rehni
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Sunjoo Cho
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Kunjan R Dave
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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