1
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Tan J, Chiamkunakorn C, Boonchuay K, Shi Y, Braeckman BP, Suthammarak W. Metformin modulates the unfolded protein responses, altering lifespan and health-promoting effects in UPR-activated worms. PLoS One 2025; 20:e0326100. [PMID: 40522955 PMCID: PMC12169583 DOI: 10.1371/journal.pone.0326100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 05/25/2025] [Indexed: 06/19/2025] Open
Abstract
Metformin has been demonstrated to extend lifespan in various model organisms, and its molecular effects are observed in the cytoplasm and multiple organelles, including mitochondria. However, its association with the unfolded protein response (UPR) and its impact on stress resistance and locomotion remain uncertain. In this study, metformin was found to exert differential influences on both UPRmt and UPRer. The correlation between metformin's lifespan-mediating effect and its interaction with UPRs was also inconsistent. We identified a metformin-mediated lifespan extension in wild-type C. elegans and in UPRmt-activated tomm-22 and cco-1 RNAi worms. Metformin suppressed the UPRmt without compromising the lifespan extension observed in tomm-22 worms. Conversely, metformin did not affect the UPRmt but extended the lifespan of long-lived cco-1 RNAi worms. Furthermore, we investigated the effects of metformin on UPRer-activated nematodes. We observed that metformin exhibited a slight increase in the UPRer in mdt-15 RNAi worms and failed to induce lifespan extension. Surprisingly, metformin appeared to mediate lifespan extension in tmem-131 RNAi worms while suppressing the UPRer. Notably, the correlation between thermotolerance, oxidative stress resistance, and the lifespan effects of metformin in UPR-activated worms was inconsistent. Activation of UPRs, but not metformin treatment, enhanced the locomotor phenotype of these worms.
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Affiliation(s)
- Jerald Tan
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chutipong Chiamkunakorn
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kanpapat Boonchuay
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Yiying Shi
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Wichit Suthammarak
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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2
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Coughlin TM, Makarewich CA. Emerging roles for microproteins as critical regulators of endoplasmic reticulum function and cellular homeostasis. Semin Cell Dev Biol 2025; 170:103608. [PMID: 40245464 PMCID: PMC12065929 DOI: 10.1016/j.semcdb.2025.103608] [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: 11/19/2024] [Revised: 02/20/2025] [Accepted: 04/04/2025] [Indexed: 04/19/2025]
Abstract
The endoplasmic reticulum (ER) is a multifunctional organelle essential for key cellular processes including protein synthesis, calcium homeostasis, and the cellular stress response. It is composed of distinct domains, such as the rough and smooth ER, as well as membrane regions that facilitate direct communication with other organelles, enabling its diverse functions. While many well-characterized ER proteins contribute to these processes, recent studies have revealed a previously underappreciated class of small proteins that play critical regulatory roles. Microproteins, typically under 100 amino acids in length, were historically overlooked due to size-based biases in genome annotation and often misannotated as noncoding RNAs. Advances in ribosome profiling, mass spectrometry, and computational approaches have now enabled the discovery of numerous previously unrecognized microproteins, significantly expanding our understanding of the proteome. While some ER-associated microproteins, such as phospholamban and sarcolipin, were identified decades ago, newly discovered microproteins share similar fundamental characteristics, underscoring the need to refine our understanding of the coding potential of the genome. Molecular studies have demonstrated that ER microproteins play essential roles in calcium regulation, ER stress response, organelle communication, and protein translocation. Moreover, growing evidence suggests that ER microproteins contribute to cellular homeostasis and are implicated in disease processes, including cardiovascular disease and cancer. This review examines the shared and unique functions of ER microproteins, their implications for health and disease, and their potential as therapeutic targets for conditions associated with ER dysfunction.
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Affiliation(s)
- Taylor M Coughlin
- The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Pathobiology and Molecular Medicine Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Catherine A Makarewich
- The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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3
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Madarász K, Mótyán JA, Chang Chien YC, Bedekovics J, Csoma SL, Méhes G, Mokánszki A. BCOR-rearranged sarcomas: In silico insights into altered domains and BCOR interactions. Comput Biol Med 2025; 191:110144. [PMID: 40228447 DOI: 10.1016/j.compbiomed.2025.110144] [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: 10/07/2024] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 04/16/2025]
Abstract
BCOR (BCL-6 corepressor) rearranged small round cell sarcoma (BRS) represents an uncommon soft tissue malignancy, frequently characterized by the BCOR::CCNB3 fusion. Other noteworthy fusions include BCOR::MAML3, BCOR::CLGN, BCOR::MAML1, ZC3H7B::BCOR, KMT2D::BCOR, CIITA::BCOR, RTL9::BCOR, and AHR::BCOR. The BCOR gene plays a pivotal role in the Polycomb Repressive Complex 1 (PRC1), essential for histone modification and gene silencing. It interfaces with the Polycomb group RING finger homolog (PCGF1). This study employed comprehensive in silico methodologies to investigate the structural and functional effects of BCOR fusion events in BRS. The analysis revealed significant alterations in the domain architecture of BCOR, which resulted in the loss of BCL6-regulated transcriptional repression. Furthermore, IUPred3 prediction indicated a significant increase in disorder in the C-terminal regions of the BCOR in the fusion proteins. A detailed analysis of the physicochemical properties by ProtParam revealed a decrease in isoelectric point, stability, and hydrophobicity. The analysis of protein structures predicted by AlphaFold3 using the PRODIGY algorithm revealed statistically significant deviations in binding affinities for BCOR-PCGF1 dimers and a non-canonical PRC1 variant tetramer compared to the wild-type BCOR. The findings provide a comprehensive summary and elucidation of the fusion proteome associated with BRS, suggesting a substantial impact on the stability and functionality of the fusion proteins, thereby contributing to the oncogenic mechanisms underlying BRS. In this study, we provide the first compilation and comparative analysis of the known BCOR fusions of BRS and introduce a new in silico approach to enhance a better understanding of the molecular basis of BRS.
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Affiliation(s)
- Kristóf Madarász
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - János András Mótyán
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Yi-Che Chang Chien
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Judit Bedekovics
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Szilvia Lilla Csoma
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Gábor Méhes
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Attila Mokánszki
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
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4
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Guo YJ, Zhu MY, Wang ZY, Chen HY, Qing YJ, Wang HZ, Xu JY, Hui H, Li H. Therapeutic Effect of V8 Affecting Mitophagy and Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Mediated by ROS and CHOP Signaling. FASEB J 2025; 39:e70622. [PMID: 40347076 DOI: 10.1096/fj.202500599r] [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: 02/27/2025] [Revised: 04/15/2025] [Accepted: 04/29/2025] [Indexed: 05/12/2025]
Abstract
Acute myeloid leukemia (AML) is characterized by the malignant proliferation of abnormally or poorly differentiated myeloid cells in the hematopoietic system. However, there is a lack of effective drugs for treating non-M3 AML. V8, a newly synthesized derivative of the natural flavonoid wogonin, which is a potential anticancer drug, has demonstrated significant antitumor activity both in vitro and in vivo. Here, we investigated the effects of V8 on AML cell lines and primary AML cells as well as its underlying mechanisms. Our results showed that V8 exerted significant concentration-dependent growth inhibition and apoptosis induction in AML cells, accompanied by characteristic pathological features including lysosomal functions suppression, mitochondrial dysfunction, and endoplasmic reticulum stress (ERS) activation. Mechanistic investigations revealed that V8 induced mitochondrial membrane potential collapse through elevation of intracellular reactive oxygen species (ROS) levels, while concurrently blocking mitophagy via lysosomal functional inhibition. Furthermore, V8 selectively activated the PERK/p-eIF2α/ATF4 and IRE1α/XBP1 signaling axes of ERS, ultimately triggering CHOP-mediated apoptosis through the ERS-specific pathway. In vivo studies confirmed that V8 treatment significantly prolonged survival duration in NOD/SCID mice bearing primary AML xenografts and suppressed tumor progression in BALB/c nude mice with U937 cell xenografts, with antitumor efficacy closely associated with CHOP-dependent ERS pathway modulation. These findings not only elucidate the multi-targeted mechanism of V8 against AML through coordinated regulation of the ROS-mitochondria-lysosome-ERS signaling network, but also provide critical theoretical foundations for developing natural product-based therapeutics for AML. The multi-pathway synergistic characteristics exhibited by V8 underscore its considerable potential as a clinically translatable candidate drug.
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Affiliation(s)
- Yong-Jian Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Meng-Yuan Zhu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Zhan-Yu Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Hong-Yu Chen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Ying-Jie Qing
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Hong-Zheng Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jing-Yan Xu
- Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Hui Hui
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Hui Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
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5
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Zhou H, Zhang J, Wang R, Huang J, Xin C, Song Z. The unfolded protein response is a potential therapeutic target in pathogenic fungi. FEBS J 2025. [PMID: 40227882 DOI: 10.1111/febs.70100] [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: 11/03/2024] [Revised: 01/15/2025] [Accepted: 04/04/2025] [Indexed: 04/16/2025]
Abstract
Pathogenic fungal infections cause significant morbidity and mortality, particularly in immunocompromised patients. The frequent emergence of multidrug-resistant strains challenges existing antifungal therapies, driving the need to investigate novel antifungal agents that target new molecular moieties. Pathogenic fungi are subjected to various environmental stressors, including pH, temperature, and pharmacological agents, both in natural habitats and the host body. These stressors elevate the risk of misfolded or unfolded protein production within the endoplasmic reticulum (ER) which, if not promptly mitigated, can lead to the accumulation of these proteins in the ER lumen. This accumulation triggers an ER stress response, potentially jeopardizing fungal survival. The unfolded protein response (UPR) is a critical cellular defense mechanism activated by ER stress to restore the homeostasis of protein folding. In recent years, the regulatory role of the UPR in pathogenic fungi has garnered significant attention, particularly for its involvement in fungal adaptation, regulation of virulence, and drug resistance. In this review, we comparatively analyze the UPRs of fungi and mammals and examine the potential utility of the UPR as a molecular antifungal target in pathogenic fungi. By clarifying the specificity and regulatory functions of the UPR in pathogenic fungi, we highlight new avenues for identifying potential therapeutic targets for antifungal treatments.
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Affiliation(s)
- Hao Zhou
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Jinping Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Public Center of Experimental Technology, Southwest Medical University, Luzhou, China
| | - Rong Wang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Ju Huang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Caiyan Xin
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Zhangyong Song
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
- Public Center of Experimental Technology, Southwest Medical University, Luzhou, China
- Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou, China
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6
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Mellor P, Kendall S, Hammond SA, Plett R, Kyrylenko L, Saxena A, Anderson DH. Expression of CREB3L1 blocks key cancer pathways and suppresses metastasis of lung squamous cell carcinoma cells. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167845. [PMID: 40228676 DOI: 10.1016/j.bbadis.2025.167845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/20/2025] [Accepted: 04/08/2025] [Indexed: 04/16/2025]
Abstract
Lung cancer is the leading cause of death due to cancer, with higher mortality rates than cancers of the colon, breast and prostate combined. About one quarter of lung cancers are lung squamous cell carcinomas (LUSC), with a five-year survival rate of only 16 %. We discovered that the majority of LUSCs have reduced expression of a key transcription factor CREB3L1 (cAMP responsive element binding protein 3 like 1), known to function as a metastasis suppressor in breast, bladder and ovarian cancers. In this report, we set out to determine if CREB3L1 functions as a metastasis suppressor in LUSCs. A differential gene expression analysis showed that ectopic expression of CREB3L1 in NCI-H2170 and NCI-1703 cells caused significant reductions in many signaling pathway genes involved in promoting cell viability, survival, migration and angiogenesis. Expression of CREB3L1 was able to reduce cell migration and anchorage-independent growth in soft agar in NCI-H2170, NCI-H1703 and NCI-H226 LUSC cells. Expression of CREB3L1 had less impact on the growth of primary xenograft tumors for NCI-H2170 and NCI-H1703 cells, the latter of which formed atypical masses filled with blood. In contrast, xenografts of NCI-H226 expressing CREB3L1 showed significant reductions in primary tumor growth. Finally, in a mouse metastasis assay, expression of CREB3L1 in NCI-H2170 cells significantly reduced the formation of liver metastases and in NCI-H226 cells, lung metastases, as compared to their respective CREB3L1-deficient parental LUSC cells. Taken together, these results strongly support a role for CREB3L1 as a metastasis suppressor in lung squamous cell carcinoma cells.
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Affiliation(s)
- Paul Mellor
- Cancer Research Group, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Stephanie Kendall
- Cancer Research Group, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - S Austin Hammond
- Cancer Research Group, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Riley Plett
- Cancer Research Group, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Liliia Kyrylenko
- Cancer Research Group, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Anurag Saxena
- Department of Pathology and Lab Medicine, Royal University Hospital, 2841 - 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada
| | - Deborah H Anderson
- Cancer Research Group, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada; Department of Oncology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada; Discovery and Translational Research, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada.
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7
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Lamm V, Huang K, Deng R, Cao S, Wang M, Soleymanjahi S, Promlek T, Rodgers R, Davis D, Nix D, Escudero GO, Xie Y, Chen CH, Gremida A, Rood RP, Liu TC, Baldridge MT, Deepak P, Davidson NO, Kaufman RJ, Ciorba MA. Tauroursodeoxycholic Acid (TUDCA) Reduces ER Stress and Lessens Disease Activity in Ulcerative Colitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.02.25322684. [PMID: 40236400 PMCID: PMC11998832 DOI: 10.1101/2025.04.02.25322684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Background and Aims In inflammatory bowel disease, protein misfolding in the endoplasmic reticulum (ER) potentiates epithelial barrier dysfunction and impairs mucosal healing. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, acts as a chemical chaperone to reduce protein aggregation and colitis severity in preclinical models. We conducted an open label trial evaluating oral TUDCA as therapy in patients with active ulcerative colitis (UC). Methods Patients with moderate-to-severely active UC (Mayo score ≥6, endoscopic subscore ≥1) received oral TUDCA at 1.75 or 2 g/day for 6 weeks. Exclusion criteria included known hepatic disorders or change in UC therapy within 60 days. Clinical disease activity questionnaires, endoscopy with biopsy, blood, and stool were collected at enrollment and after 6 weeks. The primary outcome measure was change in ER stress markers while safety, tolerability and change in UC disease activity were secondary outcomes. Results Thirteen participants completed the study with eleven evaluable for clinical response. TUDCA was well-tolerated with transient dyspepsia being the most common side effect. Mucosal biopsies revealed significant reductions in ER stress and inflammation as well as an increase in markers of epithelial restitution. Clinical, endoscopic, and histologic disease activity were significantly improved at week 6 (mean total Mayo Score: 9 to 4.5, p<0.001). Conclusions Six weeks of oral TUDCA treatment was well-tolerated in patients with active ulcerative colitis and promoted mucosal healing, lessened ER stress, and reduced clinical disease activity. A randomized controlled trial of adjunctive TUDCA therapy in patients with UC is warranted. Trial registration ClinicalTrials.gov (NCT04114292).
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Affiliation(s)
- Vladimir Lamm
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Katherine Huang
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Ruishu Deng
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Siyan Cao
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Miao Wang
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Saeed Soleymanjahi
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Thanyarat Promlek
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Rachel Rodgers
- Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Deanna Davis
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Darren Nix
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Guadalupe Oliva Escudero
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Yan Xie
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Chien-Huan Chen
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Anas Gremida
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Richard P Rood
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Megan T Baldridge
- Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Parakkal Deepak
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Nicholas O Davidson
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Randal J Kaufman
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Matthew A Ciorba
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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8
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Mandl Š, Di Geronimo B, Alonso‐Gil S, Grininger C, George G, Ferstl U, Herzog SA, Žagrović B, Nusshold C, Pavkov‐Keller T, Sánchez‐Murcia PA. A new view of missense mutations in α-mannosidosis using molecular dynamics conformational ensembles. Protein Sci 2025; 34:e70080. [PMID: 40126164 PMCID: PMC11931667 DOI: 10.1002/pro.70080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 02/06/2025] [Accepted: 02/11/2025] [Indexed: 03/25/2025]
Abstract
The mutation of remote positions on enzyme scaffolds and how these residue changes can affect enzyme catalysis is still far from being fully understood. One paradigmatic example is the group of lysosomal storage disorders, where the enzyme activity of a lysosomal enzyme is abolished or severely reduced. In this work, we analyze molecular dynamics simulation conformational ensembles to unveil the molecular features controlling the deleterious effects of the 43 reported missense mutations in the human lysosomal α-mannosidase. Using residue descriptors for protein dynamics, their coupling with the active site, and their impact on protein stability, we have assigned the contribution of each of the missense mutations into protein stability, protein dynamics, and their connectivity with the active site. We demonstrate here that the use of conformational ensembles is a powerful approach not only to better understand missense mutations at the molecular level but also to revisit the missense mutations reported in lysosomal storage disorders in order to aid the treatment of these diseases.
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Affiliation(s)
- Špela Mandl
- Laboratory of Computer‐Aided Molecular Design, Division of Medicinal Chemistry, Otto‐Loewi Research CenterMedical University of GrazGrazAustria
| | - Bruno Di Geronimo
- Laboratory of Computer‐Aided Molecular Design, Division of Medicinal Chemistry, Otto‐Loewi Research CenterMedical University of GrazGrazAustria
- Present address:
School of Chemistry and BiochemistryGeorgia Institute of TechnologyAtlantaGeorgiaUSA
| | - Santiago Alonso‐Gil
- Max Perutz LabsVienna Biocenter Campus (VBC)ViennaAustria
- Department of Structural and Computational BiologyVienna BioCenter University of Vienna Campus‐Vienna‐Biocenter 5ViennaAustria
| | | | - Gibu George
- Institut de Química Computacional i Catàlisi and Departament de QuímicaUniversitat de GironaGironaCataloniaSpain
| | - Ulrika Ferstl
- Laboratory of Computer‐Aided Molecular Design, Division of Medicinal Chemistry, Otto‐Loewi Research CenterMedical University of GrazGrazAustria
| | - Sereina Annik Herzog
- Institute for Medical Informatics, Statistics and DocumentationMedical University of GrazGrazAustria
| | - Bojan Žagrović
- Max Perutz LabsVienna Biocenter Campus (VBC)ViennaAustria
- Department of Structural and Computational BiologyVienna BioCenter University of Vienna Campus‐Vienna‐Biocenter 5ViennaAustria
| | - Christoph Nusshold
- Laboratory of Computer‐Aided Molecular Design, Division of Medicinal Chemistry, Otto‐Loewi Research CenterMedical University of GrazGrazAustria
| | - Tea Pavkov‐Keller
- Institute of Molecular Biosciences, NAWI GrazUniversity of GrazGrazAustria
- Field of Excellence BioHealthUniversity of GrazGrazAustria
- BioTechMed‐GrazGrazAustria
| | - Pedro A. Sánchez‐Murcia
- Laboratory of Computer‐Aided Molecular Design, Division of Medicinal Chemistry, Otto‐Loewi Research CenterMedical University of GrazGrazAustria
- BioTechMed‐GrazGrazAustria
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9
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Almendra-Pegueros R, Rodriguez C, Camacho M, Sánchez-Infantes D, Luis Sánchez-Quesada J, Cáncer S, Pérez-Marlasca E, Medina-Gómez G, Martinez-González J, García-Redondo AB, Galán M. Identification of endoplasmic reticulum stress-associated lncRNAs influencing inflammation and VSMC function in abdominal aortic aneurysm. Clin Sci (Lond) 2025; 139:CS20242476. [PMID: 40072504 DOI: 10.1042/cs20242476] [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: 10/07/2024] [Revised: 02/13/2025] [Accepted: 03/12/2025] [Indexed: 03/14/2025]
Abstract
Endoplasmic reticulum (ER) stress plays a critical role in the abdominal aortic aneurysm (AAA), a life-threatening disease characterized by inflammation, destructive remodeling, and vascular smooth muscle cells (VSMCs) dysfunction. The current therapy relies on surgical repair, but no effective pharmacological strategies are available to limit aneurysm progression. Long non-coding RNAs (lncRNAs) are essential factors in health and disease; however, their specific contribution to AAA development and its relationship with ER stress remain unexplored. Here, we have performed a whole-genome transcriptomic analysis characterizing the expression profile of lncRNAs in AAA. RNA sequencing was carried out in abdominal aorta from patients with AAA and healthy donors. We identified 6576 differentially expressed (DE)-mRNAs and 1283 DE-lncRNAs. Interestingly, bioinformatic analysis revealed a set of 368 DE-lncRNAs related to ER stress. The differential expression of the most induced lncRNAs (IL-21-AS1, ITPKB-IT, PCED1B-AS1, TCL-6, LINC00494, LINC00582, LINC00626, LINC00861, and LINC00892) was validated in a large cohort of patients with AAA. The ability of these selected lncRNAs to discriminate patients with AAA from healthy subjects was established by receiveroperating characteristic curves and logistic regression analysis. In human aortic VSMC and Jurkat T-cells, tunicamycin-induced ER stress triggered the expression of IL21-AS1, LINC00626, LINC00494, LINC00892, PCED1B-AS1, ITPKB-IT, and TCL-6, while tauroursodeoxycholic acid counteracted these effects. Finally, an integrated analysis of mRNA-lncRNA co-expression revealed the correlation between the selected lncRNAs and the DE-mRNAs involved in immune response and muscle contraction. Therefore, these DE-lncRNAs potentially implicated in the ER stress response, a pathological process in AAA, could be considered as potential therapeutic target to handle AAA.
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MESH Headings
- Humans
- Endoplasmic Reticulum Stress/genetics
- Endoplasmic Reticulum Stress/drug effects
- Aortic Aneurysm, Abdominal/genetics
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/pathology
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Male
- Myocytes, Smooth Muscle/metabolism
- Aged
- Inflammation/genetics
- Inflammation/metabolism
- Female
- Middle Aged
- Gene Expression Profiling
- Aorta, Abdominal/metabolism
- Aorta, Abdominal/pathology
- Transcriptome
- Case-Control Studies
- Gene Expression Regulation
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Affiliation(s)
| | - Cristina Rodriguez
- Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Mercedes Camacho
- Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - David Sánchez-Infantes
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - J Luis Sánchez-Quesada
- Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Susana Cáncer
- Unidad de Angiología y Cirugía Vascular, Hospital Universitario Fundación de Alcorcón, Alcorcón, Madrid, Spain
| | - Elvira Pérez-Marlasca
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - Gema Medina-Gómez
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - José Martinez-González
- Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Barcelona, Spain
| | - Ana B García-Redondo
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - María Galán
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
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10
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Zakaria N, Menze ET, Elsherbiny DA, Tadros MG, George MY. Lycopene mitigates paclitaxel-induced cognitive impairment in mice; Insights into Nrf2/HO-1, NF-κB/NLRP3, and GRP-78/ATF-6 axes. Prog Neuropsychopharmacol Biol Psychiatry 2025; 137:111262. [PMID: 39848561 DOI: 10.1016/j.pnpbp.2025.111262] [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: 08/10/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 01/25/2025]
Abstract
Chemotherapy-induced cognitive impairment, referred to as "chemobrain", is widely acknowledged as a significant adverse effect of cancer therapy. Paclitaxel, a chemotherapeutic drug, has been reported to cause cognitive impairment clinically and in animal models. However, the precise mechanisms are not fully understood. The current study explored the potential neuroprotective effect of lycopene in paclitaxel-induced cognitive impairment in mice and its potential underlying mechanisms. Mice were randomly allocated into six groups: control, paclitaxel-treated (10 mg/kg), lycopene-treated (5, 10, and 20 mg/kg) + paclitaxel, and lycopene alone-treated (20 mg/kg) groups. The effect of lycopene treatment on behavioral function and histological examination was assessed. Lycopene (20 mg/kg) was selected for additional investigation into the underlying mechanisms. Lycopene treatment counteracted paclitaxel-induced oxidative stress by reducing lipid peroxidation and enhancing catalase levels. Additionally, lycopene-treated mice demonstrated a significant elevation in nuclear factor erythroid 2-related factor 2 with no significant effect on hemeoxygenase-1. Moreover, paclitaxel administration elevated endoplasmic reticulum stress markers; glucose-regulated protein78, activating Transcription Factor 6, C/EBP homologous protein, and apoptosis marker annexin V which were significantly reduced by lycopene treatment. Furthermore, lycopene mitigated paclitaxel-induced neuroinflammation through the reduction of the levels of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome axis markers; nuclear factor-κB, NLRP3, caspase-1, interleukin-1β, and interleukin-18. Our study findings may provide new evidence that lycopene mitigates paclitaxel-induced cognitive impairment in mice by reversing oxidative stress, endoplasmic reticulum stress, and inflammatory mechanisms.
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Affiliation(s)
- Nora Zakaria
- Armed Forces Medical Complex- Kobry El-Qobba, Ministry of Defense, Kobry El-Qobba, Cairo 11766, Egypt
| | - Esther T Menze
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Doaa A Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Mariane G Tadros
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Mina Y George
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
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11
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Peng C, Wang J, Wang S, Zhao Y, Wang H, Wang Y, Ma Y, Yang J. Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution. Cancer Med 2025; 14:e70684. [PMID: 40035165 PMCID: PMC11877002 DOI: 10.1002/cam4.70684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/23/2024] [Accepted: 01/29/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND The endoplasmic reticulum (ER) serves as a crucial hub for protein synthesis and processing, playing an essential role in maintaining protein homeostasis. Perturbations, such as hypoxia, oxidative stress, inadequate amino acid supply, Ca2+ imbalance, and acidosis, can disrupt cellular equilibrium and result in the accumulation of misfolded/unfolded proteins within the ER lumen. This triggers ER stress. In response to this stress, an unfolded protein response (UPR) is activated as a mechanism to cope with the stress and restore internal balance. The UPR is regulated by three sensors located in the ER: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). However, the UPR can promote tumor growth in vivo by affecting tumor angiogenesis, cell migration, cell metabolism, and treatment resistance, and has a huge impact on the tumor microenvironment. MATERIALS AND METHODS We conducted a literature review of scientific papers on the topic of ER stress in the tumor microenvironment. RESULTS AND DISCUSSION This review focuses on the inducing factors of ER stress, the mechanism of the UPR signaling pathway induced by ER stress, and the effect of ER stress on the tumor microenvironment and immune-infiltrating cells. Tumors can regulate their evolution by affecting themselves and the tumor microenvironment through endoplasmic reticulum stress. This study reveals the important role of endoplasmic reticulum stress in the occurrence and development of tumors, and provides new ideas and potential therapeutic targets for the precision treatment of tumors. Future studies can further explore the molecular mechanism of ER stress regulating tumor microenvironment and explore its application potential in clinical diagnosis and treatment.
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Affiliation(s)
- Chaosheng Peng
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
| | - Juan Wang
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
| | - Shu Wang
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
| | - Yan Zhao
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
| | - Haoyuan Wang
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
| | - Yuhao Wang
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
| | - Yuxuan Ma
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
| | - Jianjun Yang
- Department of Digestive SurgeryXijing Hospital of Digestive Diseases, Fourth Military Medical UniversityXi'anChina
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12
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Hopkins T, Ragsdale C, Seo J. Elevated ambient temperature reduces fat storage through the FoxO-mediated insulin signaling pathway. PLoS One 2025; 20:e0317971. [PMID: 40009607 PMCID: PMC11864546 DOI: 10.1371/journal.pone.0317971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 01/07/2025] [Indexed: 02/28/2025] Open
Abstract
Temperature profoundly impacts all living organisms, influencing development, growth, longevity, and metabolism. Specifically, when adult flies are exposed to high temperatures, there is a notable reduction in their body fat content. We investigate the roles of the insulin signaling pathway in temperature-mediated fat storage. This pathway is not only highly conserved from insects to mammals but also crucial in regulating lipid metabolism, cell proliferation, and tissue growth. The Forkhead box O (FoxO) protein functions as a key downstream signaling molecule in this pathway, mediating the inhibitory effects of insulin signaling. At elevated temperatures, direct targets of FoxO, such as insulin receptor (InR), Thor (Drosophila eukaryotic initiation factor 4E binding protein), and FoxO itself, are significantly upregulated, which indicates an inhibition of insulin signaling. Interestingly, this inhibition seems to occur independently of Drosophila insulin-like peptide (Ilp) stimuli, as not all Ilp transcripts were reduced at elevated temperatures. Furthermore, when S2R + Drosophila cells are incubated at high temperatures, there is a marked decrease in Akt phosphorylation, directly supporting the notion that elevated temperatures can inhibit insulin signaling in a cell-autonomous manner, independent of Ilp levels. Subsequent experiments demonstrated that either constitutively active InR or knockdown of FoxO prevents the reduction of body fat at high temperatures. Together, these findings highlight the critical role of the insulin signaling-FoxO branch in regulating lipid homeostasis under heat stress conditions.
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Affiliation(s)
- Tucker Hopkins
- Department of Biology, College of Arts and Sciences, Rogers State University, Claremore, Oklahoma, United States of America
| | - Cole Ragsdale
- Department of Biology, College of Arts and Sciences, Rogers State University, Claremore, Oklahoma, United States of America
| | - Jin Seo
- Department of Biology, College of Arts and Sciences, Rogers State University, Claremore, Oklahoma, United States of America
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13
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Uchinoumi H, Nakamura Y, Suetomi T, Nawata T, Fujinaka M, Kobayashi S, Yamamoto T, Yano M, Sano M. Structural instability of ryanodine receptor 2 causes endoplasmic reticulum (ER) dysfunction as well as sarcoplasmic reticulum (SR) dysfunction. J Cardiol 2025:S0914-5087(25)00038-3. [PMID: 39929264 DOI: 10.1016/j.jjcc.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 02/24/2025]
Abstract
The type 2 ryanodine receptor (RyR2) is a giant Ca2+ (Ca)-releasing channel on the sarcoplasmic reticulum (SR) membrane, with subunits composed of 5000 amino acids constituting a homotetrameric channel. The N-terminal (1-220) and central (2300-2500) domain interactions (inter-subunit zipping interfaces) within RyR2 are located in close proximity to each other between different neighboring subunits and play an important "cornerstone" role in maintaining the tetrameric structure of RyR2. External stress such as oxidative stress causes Ca leak by destabilizing RyR2 (instability of the tetrameric structure) due to domain unzipping between N-terminal (1-220) and central (2300-2500) domains, followed by dissociation of calmodulin (CaM: binds to the RyR2 and stabilize RyR2) from RyR2. Ca leak from SR causes arrhythmias and myocardial dysfunction. RyR2 is also present in the endoplasmic reticulum (ER), thus it is not surprising that undesired Ca release from RyR2 on the ER is closely associated with various diseases involving ER dysfunction such as neurodegenerative diseases, diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, and autoimmune diseases. Pharmacological or genetic (point mutations within RyR2 that increase CaM-RyR2 affinity: knock-in RyR2-V3599K) RyR2 structural stabilization has shown potential therapeutic effects not only for SR failure-related diseases (malignant hyperthermia, arrhythmia, and heart failure) but also for ER failure-related disease. RyR2-stabilizers may function as a panacea for aging-related diseases.
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Affiliation(s)
- Hitoshi Uchinoumi
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
| | - Yoshihide Nakamura
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Takeshi Suetomi
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Takashi Nawata
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Masafumi Fujinaka
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Shigeki Kobayashi
- Department of Therapeutic Science for Heart Failure in the Elderly, Yamaguchi University School of Medicine, Yamaguchi, Japan
| | - Takeshi Yamamoto
- Department of Laboratory Medicine, Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Masafumi Yano
- Department of Therapeutic Science for Heart Failure in the Elderly, Yamaguchi University School of Medicine, Yamaguchi, Japan
| | - Motoaki Sano
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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14
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Yang Y, Li W, Zhao Y, Sun M, Xing F, Yang J, Zhou Y. GRP78 in Glioma Progression and Therapy: Implications for Targeted Approaches. Biomedicines 2025; 13:382. [PMID: 40002794 PMCID: PMC11852679 DOI: 10.3390/biomedicines13020382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/24/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Glioma is the most common primary malignant brain tumor, accounting for the majority of brain cancer-related deaths. Considering the limited efficacy of conventional therapies, novel molecular targeted therapies have been developed to improve outcomes and minimize toxicity. Glucose-regulated protein 78 (GRP78), a molecular chaperone primarily localized in the endoplasmic reticulum (ER), has received increasing attention for its role in glioma progression and resistance to conventional therapies. Overexpressed in gliomas, GRP78 supports tumor growth, survival, and therapeutic resistance by maintaining cellular homeostasis and regulating multiple signaling pathways. Its aberrant expression correlates with higher tumor grades and poorer patient prognosis. Beyond its intracellular functions, GRP78's presence on the cell surface and its role in the tumor microenvironment underscore its potential as a therapeutic target. Recent studies have explored innovative strategies to target GRP78, including small molecule inhibitors, monoclonal antibodies, and chimeric antigen receptor (CAR) T cell therapy, showing significant potential in glioma treatment. This review explores the biological characteristics of GRP78, its role in glioma pathophysiology, and the potential of GRP78-targeted therapy as a novel strategy to overcome treatment resistance and improve clinical outcomes. GRP78-targeted therapy, either alone or in combination with conventional treatments, could be a novel and attractive strategy for future glioma treatment.
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Affiliation(s)
- Yue Yang
- Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
| | - Wen Li
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
| | - Yu Zhao
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
| | - Minxuan Sun
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
| | - Feifei Xing
- Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
| | - Jiao Yang
- Suzhou Research Center of Medical School, Institute of Clinical Medicine Research, Suzhou Hospital, The Affiliated Hospital of Medical School, Nanjing University, Lijiang Road No. 1, Suzhou 215153, China
- Jiangsu Province Engineering Research Center of Molecular Target Therapy and Companion Diagnostics in Oncology, Suzhou Vocational Health College, Suzhou 215009, China
| | - Yuanshuai Zhou
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
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15
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Kabir S, Hossain MAA, Jahan I, Ahmed B, Malik A, Goni MA, Hoque MA, Anis-Ul-Haque KM. Exploration of the micellization behavior of sodium dodecyl sulfate in aqueous solution of gastric enzyme pepsin: Assessment of the consequences of sodium electrolytes and temperature. Int J Biol Macromol 2025; 291:138990. [PMID: 39716714 DOI: 10.1016/j.ijbiomac.2024.138990] [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: 10/26/2024] [Revised: 12/03/2024] [Accepted: 12/17/2024] [Indexed: 12/25/2024]
Abstract
This study explores the interactions between pepsin and sodium dodecyl sulfate (SDS) using conductometric analysis and molecular docking to deepen our understanding of the role of pepsin. Conductometric studies were conducted to examine the micellization behavior of SDS with pepsin in aqueous solutions of various sodium electrolytes (NaBr, Na₂SO₄, Na₃PO₄, and CH₃COONa) at temperatures ranging from 300.55 K to 320.55 K in 5 K increments. The critical micelle concentration (CMC) of the SDS-pepsin system was influenced by pepsin concentration, electrolyte type, and temperature. Pepsin was found to inhibit SDS micellization, increasing the CMC, while electrolytes promoted micellization, decreasing the CMC. Thermodynamic parameters-Gibbs free energy (∆Gm0), enthalpy (∆Hm0), and entropy (∆Sm0)-were analyzed to identify the driving forces behind micellization. The negative ∆Gm0 indicated spontaneous aggregation, with ∆Hm0 and ∆Sm0 suggesting hydrophobic and electrostatic interactions. Molecular docking further confirmed these interactions, revealing binding between the hydrophobic tail of SDS and nonpolar binding pocket of pepsin at the interdomain cleft. These findings provide insights into surfactant-enzyme interactions, with potential applications in biochemistry, pharmacology, and food science.
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Affiliation(s)
- Shahanaz Kabir
- Department of Chemistry, Jashore University of Science and Technology, Jashore 7408, Bangladesh
| | - Md Al Amin Hossain
- Department of Chemistry, Jashore University of Science and Technology, Jashore 7408, Bangladesh
| | - Israt Jahan
- Department of Chemistry, Jashore University of Science and Technology, Jashore 7408, Bangladesh.
| | - Bulbul Ahmed
- Department of Chemistry, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh
| | - Ajamaluddin Malik
- Department of Biochemistry, Collage of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
| | - Md Abdul Goni
- Department of Biological and Physical Sciences, South Carolina State University, Orangeburg, SC 29117, USA
| | - Md Anamul Hoque
- Department of Chemistry, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh
| | - K M Anis-Ul-Haque
- Department of Chemistry, Jashore University of Science and Technology, Jashore 7408, Bangladesh.
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16
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Yang Z, Song J, Guo J, Li J, Gao F, Zheng W, Jin Z, Li J. Effects of PGE1 on the ERS pathway in neonatal rats with hyperoxic lung injury. Pediatr Res 2025; 97:835-842. [PMID: 39014239 DOI: 10.1038/s41390-024-03381-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/27/2024] [Accepted: 06/21/2024] [Indexed: 07/18/2024]
Abstract
BACKGROUND With the increase in the number of low birth weight infants, oxygen therapy is more widely used. However, chronic high-concentration oxygen environments lead to hyperoxic lung injury in children, which in turn leads to bronchopulmonary dysplasia (BPD). PGE1 is widely used in the clinic for its ability to inhibit inflammation and improve circulation. Therefore, we further investigated whether PGE-1 has a therapeutic effect on hyperoxic lung injury. METHODS Hyperoxic lung injury model was adopted for investigating the interventional effects and underlying mechanisms of intraperitoneal injection of prostaglandin E1 (PGE-1) on hyperoxic lung injury in newborn rats via relevant experimental techniques, such as Diff-Quick staining, lung wet dry specific gravity measurements, HE staining, TUNEL staining, ELISA, and the Western blot method. RESULTS Inflammatory and apoptotic cells in the PGE1-treated group were significantly lower than those in the hyperoxic lung injury group (p < 0.05); and the contents of IL-1β, IL-6 and TNF-α in the treated group were significantly lower than those in the model group (p < 0.05). Caspase-3, CHOP, GRP78 and Bcl-2/Bax protein expression in the treatment group was significantly lower than that in the model group (p < 0.05). CONCLUSION PGE-1 has a therapeutic effect on hyperoxic lung injury in neonatal rats. IMPACT PGE1 treatment reduces levels of inflammatory cells and pro-inflammatory cytokines and decreases apoptosis. PGE1 has a therapeutic effect on BPD through the endoplasmic reticulum stress pathway. This study offers the possibility of PGE1 for the treatment of BPD.
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Affiliation(s)
- Zhenlin Yang
- Department of Pediatrics, Yanbian University Hospital, Yanji, 133000, China
| | - Jianing Song
- Liaocheng City Hospital of Traditional Chinese, Liaocheng, 252000, China
| | - Jingjing Guo
- Department of Pediatrics, Yanbian University Hospital, Yanji, 133000, China
| | - Jiarui Li
- Department of Pediatrics, Yanbian University Hospital, Yanji, 133000, China
| | - Fan Gao
- Department of Pediatrics, Yanbian University Hospital, Yanji, 133000, China
| | - Weiwei Zheng
- Department of Pediatrics, Yanbian University Hospital, Yanji, 133000, China
| | - Zhengyong Jin
- Department of Pediatrics, Yanbian University Hospital, Yanji, 133000, China
| | - Jinzi Li
- Department of Pediatrics, Yanbian University Hospital, Yanji, 133000, China.
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17
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Wang F, Xu Y, Wang Y, Liu Q, Li Y, Zhang W, Nong H, Zhang J, Zhao H, Yang H, Guo L, Li J, Li H, Yang Q. FAM134B-mediated endoplasmic reticulum autophagy protects against cisplatin-induced spiral ganglion neuron damage. Front Pharmacol 2025; 15:1462421. [PMID: 39949397 PMCID: PMC11821923 DOI: 10.3389/fphar.2024.1462421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/31/2024] [Indexed: 02/16/2025] Open
Abstract
Introduction Cochlear spiral ganglion neurons (SGNs) could be damaged by ototoxic drug, cisplatin (Cis), during which process autophagy was involved. FAM134B, the first detected endoplasmic reticulum autophagy (ER-phagy) receptor, plays an important part in the dynamic remodelling of the ER, the mutation of which affects sensory and autonomic neurons. However whether FAM134B-mediated ER-phagy involved in Cis-induced SGN damage or not was unknown. The present study was designed to determine whether FAM134B is expressed in SGNs of C57BL/6 mice and, if so, to explore the potential function of FAM134B in Cis-induced SGN damage in vitro. Methods Middle turns of neonatal murine cochleae were cultured and treated with 30 μM Cis in vitro. The distribution of FAM134B, morphological changes of SGNs, and the colocalization of ER segments with lysosomes were measured by immunofluorescence (IF). Apoptosis was measured by TUNEL staining. The expression of FAM134B, proteins associated with ER stress, autophagy and apoptosis was measured by western blot. The reactive oxygen specie (ROS) levels were evaluated by MitoSOX Red and 2',7'-Dchlorodihydrofluorescein diacetate (DCFH-DA) probe. Anc80-Fam134b shRNA was used to knockdown the expression of FAM134B in SGNs. Results We first found the expression of FAM134B in the cytoplasm of SGNs, especially in the fourth postnatal day mice. Results showed decreases in the number of SGNs and FAM134B expression, as well as increases of ROS level, ER stress, ER-phagy, and apoptosis after Cis stimulus. Inhibiting autophagy increased the expression of FAM134B, and aggravated Cis-induced SGN damage, while the opposite changes were observed when autophagy was activated. Additionally, co-treatment with the N-Acetyl-L-Cysteine (NAC), ROS scavenger, alleviated Cis-induced ER stress, ER-phagy, and apoptosis. What's more, knockdown the expression of FAM134B in SGNs made SGNs more vulnerable to cisplatin-induced injury. Discussion The present study revealed the expression pattern of FAM134B in C57BL/6 murine SGNs for the first time. Moreover, our work further verified the protective function of FAM134B mediated by ER-phagy in Cis-induced SGN apoptosis, at least partially, correlated with the accumulation of ROS and induction of ER stress, though the detailed regulatory mechanism through which needs much more work to reveal.
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Affiliation(s)
- Fan Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Yue Xu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Yajie Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qian Liu
- Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanan Li
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Weiwei Zhang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Huiming Nong
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junhong Zhang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hao Zhao
- Department of Otolaryngology, Head and Neck Surgery, People’s Hospital, Peking University, Beijing, China
| | - Huaqian Yang
- Cyrus Tang Medical Institute, Soochow University, Suzhou, China
| | - Lingchuan Guo
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianfeng Li
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Otology, Jinan, China
| | - Hong Li
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Qianqian Yang
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
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18
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Mohd Faizal NF, Shai S, Savaliya BP, Karen-Ng LP, Kumari R, Kumar R, Vincent-Chong VK. A Narrative Review of Prognostic Gene Signatures in Oral Squamous Cell Carcinoma Using LASSO Cox Regression. Biomedicines 2025; 13:134. [PMID: 39857718 PMCID: PMC11759772 DOI: 10.3390/biomedicines13010134] [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: 09/12/2024] [Revised: 12/28/2024] [Accepted: 01/01/2025] [Indexed: 01/27/2025] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignancies of the head and neck squamous cell carcinoma (HNSCC). HNSCC is recognized as the eighth most commonly occurring cancer globally in men. It is essential to distinguish between cancers arising in the head and neck regions due to significant differences in their etiologies, treatment approaches, and prognoses. As the Cancer Genome Atlas (TCGA) dataset is available in HNSCC, the survival analysis prognosis of OSCC patients based on the TCGA dataset for discovering gene expression-based prognostic biomarkers is limited. To address this paucity, we aimed to provide comprehensive evidence by recruiting studies that have reported new biomarkers/signatures to establish a prognostic model to predict the survival of OSCC patients. Using PubMed search, we have identified 34 studies that have been using the least absolute shrinkage and selection operator (LASSO)-based Cox regression analyses to establish signature prognosis that related to different pathways in OSCC from the past 4 years. Our review was focused on summarizing these signatures and implications for targeted therapy using FDA-approved drugs. Furthermore, we conducted an analysis of the LASSO Cox regression gene signatures. Our findings revealed 13 studies that correlated a greater number of regulatory T cells (Tregs) cells in protective gene signatures with increased recurrence-free and overall survival rates. Conversely, two studies displayed an opposing trend in cases of OSCC. We will also explore how the dysregulation of these signatures impacts immune status, promoting tumor immune evasion or, conversely, enhancing immune surveillance. Overall, this review will provide new insight for future anti-cancer therapies based on the potential gene that is associated with poor prognosis in OSCC.
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Affiliation(s)
- Nur Fatinazwa Mohd Faizal
- Oral Cancer Research & Coordinating Centre (OCRCC), Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (N.F.M.F.); (L.P.K.-N.)
| | - Saptarsi Shai
- Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 77030, USA;
| | - Bansi P. Savaliya
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA;
| | - Lee Peng Karen-Ng
- Oral Cancer Research & Coordinating Centre (OCRCC), Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (N.F.M.F.); (L.P.K.-N.)
| | - Rupa Kumari
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Rahul Kumar
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Vui King Vincent-Chong
- Center for Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
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19
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Noori H, Alazzeh ZJ, Rehman OU, Idrees M, Marsool MDM, Abdul Rehman K, Gohil KM, Ahmad SS, Subash T, Dixon K. Endoplasmic reticulum's role in multiple sclerosis, exploring potential biomarkers, and pioneering therapeutic strategies: a comprehensive review of literature. Neurol Sci 2025; 46:113-123. [PMID: 39269572 DOI: 10.1007/s10072-024-07766-4] [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: 06/12/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND Multiple Sclerosis (MS) is a complex and chronic autoimmune disease that affects the central nervous system. Inflammation and demyelination characterize it, which results in a range of neurological impairments. The increasing worldwide occurrence of MS, affecting an estimated 2.8 million individuals in 2020, highlights the urgent requirement for further research to tackle the significant impact it has on individuals and healthcare systems globally. OBJECTIVE In this study, we wanted to explore the complex function of the endoplasmic reticulum (ER) in the origin, development, and resolution of MS, emphasizing its importance in neuroinflammatory illnesses. The ER has become a central focus in comprehending the pathogenesis of MS. Upon reviewing the literature, we observed a lack of thorough analysis that explores the involvement of endoplasmic reticulum stress in multiple sclerosis. Thus, we aimed through this research to examine the correlations between ER stress and its influence on immunological dysregulation, demyelination, and neurodegeneration in MS. FINDINGS Based on the latest clinical trials, we suggested theories that explore possible biomarkers linked to ER stress and the unfolded protein response. Identifying molecules that are suggestive of early stages of illness and can serve as prognostic tools for improving our understanding of the heterogeneity of MS and offering novel approaches for managing the disease. Finally, through our comprehensive search, we wanted to offer a plan for future research, suggesting new and creative methods for managing MS and encouraging the creation of specific treatments that aim to reduce the impact of MS on individuals worldwide.
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Affiliation(s)
- Hamid Noori
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 6, West Wing, Oxford, OX3 9DU, UK
| | | | - Obaid Ur Rehman
- Department of Medicine, Services Institute of Medical Sciences, Lahore, Pakistan
| | | | | | - Khawaja Abdul Rehman
- Department of Medicine, CMH Lahore Medical College and Institute of Dentistry, Lahore, Pakistan.
| | - Krutika Mahendra Gohil
- Topiwala National Medical College & Bai Yamunabai Laxman Nair Charitable Hospital, Mumbai, India
| | | | | | - Kayla Dixon
- University of Birmingham Medical School, Birmingham, UK
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20
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Tak J, Kim YS, Kim SG. Roles of X-box binding protein 1 in liver pathogenesis. Clin Mol Hepatol 2025; 31:1-31. [PMID: 39355873 PMCID: PMC11791611 DOI: 10.3350/cmh.2024.0441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/06/2024] [Accepted: 09/27/2024] [Indexed: 10/03/2024] Open
Abstract
The prevalence of drug-induced liver injury (DILI) and viral liver infections presents significant challenges in modern healthcare and contributes to considerable morbidity and mortality worldwide. Concurrently, metabolic dysfunctionassociated steatotic liver disease (MASLD) has emerged as a major public health concern, reflecting the increasing rates of obesity and leading to more severe complications such as fibrosis and hepatocellular carcinoma. X-box binding protein 1 (XBP1) is a distinct transcription factor with a basic-region leucine zipper structure, whose activity is regulated by alternative splicing in response to disruptions in endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR) activation. XBP1 interacts with a key signaling component of the highly conserved UPR and is critical in determining cell fate when responding to ER stress in liver diseases. This review aims to elucidate the emerging roles and molecular mechanisms of XBP1 in liver pathogenesis, focusing on its involvement in DILI, viral liver infections, MASLD, fibrosis/cirrhosis, and liver cancer. Understanding the multifaceted functions of XBP1 in these liver diseases offers insights into potential therapeutic strategies to restore ER homeostasis and mitigate liver damage.
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Affiliation(s)
- Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Korea
| | - Yun Seok Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Korea
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21
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Fornara B, Igel A, Béringue V, Martin D, Sibille P, Pujo-Menjouet L, Rezaei H. The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics. iScience 2024; 27:111381. [PMID: 39717079 PMCID: PMC11664133 DOI: 10.1016/j.isci.2024.111381] [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: 05/13/2024] [Revised: 08/29/2024] [Accepted: 11/11/2024] [Indexed: 12/25/2024] Open
Abstract
Prion diseases, or transmissible spongiform encephalopathies (TSEs), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrPSc) of the cellular prion protein (PrPC). During the pathogenesis, the PrPSc seeds disseminate in the central nervous system and convert PrPC leading to the formation of insoluble assemblies. As for conventional infectious diseases, variations in the clinical manifestation define a specific prion strain which correspond to different PrPSc structures. In this work, we implemented the recent developments on PrPSc structural diversity and tissue response to prion replication into a stochastic reaction-diffusion model using an application of the Gillespie algorithm. We showed that this combination of non-linearities can lead prion propagation to behave as a complex system, providing an alternative to the current paradigm to explain strain-specific phenotypes, tissue tropisms, and strain co-propagation while also clarifying the role of the connectome in the neuro-invasion process.
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Affiliation(s)
- Basile Fornara
- Université Paris-Saclay, INRAe, UVSQ, VIM, 78350 Jouy-en-Josas, France
| | - Angélique Igel
- Université Paris-Saclay, INRAe, UVSQ, VIM, 78350 Jouy-en-Josas, France
| | - Vincent Béringue
- Université Paris-Saclay, INRAe, UVSQ, VIM, 78350 Jouy-en-Josas, France
| | - Davy Martin
- Université Paris-Saclay, INRAe, UVSQ, VIM, 78350 Jouy-en-Josas, France
| | - Pierre Sibille
- Université Paris-Saclay, INRAe, UVSQ, VIM, 78350 Jouy-en-Josas, France
| | - Laurent Pujo-Menjouet
- Université Claude Bernard Lyon 1, ICJ UMR5208, CNRS, Ecole Centrale de Lyon, INSA Lyon, Université Jean Monnet, Inria Dracula, 69622 Villeurbanne, France
| | - Human Rezaei
- Université Paris-Saclay, INRAe, UVSQ, VIM, 78350 Jouy-en-Josas, France
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22
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Fu Z, Wang W, Gao Y. Understanding the impact of ER stress on lung physiology. Front Cell Dev Biol 2024; 12:1466997. [PMID: 39744015 PMCID: PMC11688383 DOI: 10.3389/fcell.2024.1466997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/22/2024] [Indexed: 01/04/2025] Open
Abstract
Human lungs consist of a distinctive array of cell types, which are subjected to persistent challenges from chemical, mechanical, biological, immunological, and xenobiotic stress throughout life. The disruption of endoplasmic reticulum (ER) homeostatic function, triggered by various factors, can induce ER stress. To overcome the elevated ER stress, an adaptive mechanism known as the unfolded protein response (UPR) is activated in cells. However, persistent ER stress and maladaptive UPR can lead to defects in proteostasis at the cellular level and are typical features of the lung aging. The aging lung and associated lung diseases exhibit signs of ER stress-related disruption in cellular homeostasis. Dysfunction resulting from ER stress and maladaptive UPR can compromise various cellular and molecular processes associated with aging. Hence, comprehending the mechanisms of ER stress and UPR components implicated in aging and associated lung diseases could enable to develop appropriate therapeutic strategies for the vulnerable population.
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Affiliation(s)
- Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Wang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuan Gao
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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23
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Hong J, Liu W, Xiao X, Gajendran B, Ben-David Y. Targeting pivotal amino acids metabolism for treatment of leukemia. Heliyon 2024; 10:e40492. [PMID: 39654725 PMCID: PMC11626780 DOI: 10.1016/j.heliyon.2024.e40492] [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: 06/27/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 12/12/2024] Open
Abstract
Metabolic reprogramming is a crucial characteristic of cancer, allowing cancer cells to acquire metabolic properties that support their survival, immune evasion, and uncontrolled proliferation. Consequently, targeting cancer metabolism has become an essential therapeutic strategy. Abnormal amino acid metabolism is not only a key aspect of metabolic reprogramming but also plays a significant role in chemotherapy resistance and immune evasion, particularly in leukemia. Changes in amino acid metabolism in tumor cells are typically driven by a combination of signaling pathways and transcription factors. Current approaches to targeting amino acid metabolism in leukemia include inhibiting amino acid transporters, blocking amino acid biosynthesis, and depleting specific amino acids to induce apoptosis in leukemic cells. Different types of leukemic cells rely on the exogenous supply of specific amino acids, such as asparagine, glutamine, arginine, and tryptophan. Therefore, disrupting the supply of these amino acids may represent a vulnerability in leukemia. This review focuses on the pivotal role of amino acids in leukemia metabolism, their impact on leukemic stem cells, and their therapeutic potential.
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Affiliation(s)
- Jiankun Hong
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guian New Disctrict, 561113, Guizhou, PR China
- Natural Products Research Center of Guizhou. PR China
| | - Wuling Liu
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guian New Disctrict, 561113, Guizhou, PR China
- Natural Products Research Center of Guizhou. PR China
| | - Xiao Xiao
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guian New Disctrict, 561113, Guizhou, PR China
- Natural Products Research Center of Guizhou. PR China
| | - Babu Gajendran
- Institute of Pharmacology and Biological Activity, Natural Products Research Center of Guizhou Province, Guiyang, Guizhou, 550014, PR China
- School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, Guizhou Province, PR China
| | - Yaacov Ben-David
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guian New Disctrict, 561113, Guizhou, PR China
- Natural Products Research Center of Guizhou. PR China
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24
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Czechowicz P, Gebert M, Bartoszewska S, Kalinowski L, Collawn JF, Bartoszewski R. The Yin and Yang of hsa-miR-1244 expression levels during activation of the UPR control cell fate. Cell Commun Signal 2024; 22:577. [PMID: 39623432 PMCID: PMC11610070 DOI: 10.1186/s12964-024-01967-2] [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: 10/01/2024] [Accepted: 11/28/2024] [Indexed: 12/06/2024] Open
Abstract
Regulation of endoplasmic reticulum (ER) homeostasis plays a critical role in maintaining cell survival. When ER stress occurs, a network of three pathways called the unfolded protein response (UPR) is activated to reestablish homeostasis. While it is known that there is cross-talk between these pathways, how this complex network is regulated is not entirely clear. Using human cancer and non-cancer cell lines, two different genome-wide approaches, and two different ER stress models, we searched for miRNAs that were decreased during the UPR and surprisingly found only one, miR-1244, that was found under all these conditions. We also verified that ER-stress related downregulation of miR-1244 expression occurred with 5 different ER stressors and was confirmed in another human cell line (HeLa S3). These analyses demonstrated that the outcome of this reduction during ER stress supported both IRE1 signaling and elevated BIP expression. Further analysis using inhibitors specific for IRE1, ATF6, and PERK also revealed that this miRNA is impacted by all three pathways of the UPR. This is the first example of a complex mechanism by which this miRNA serves as a regulatory check point for all 3 pathways that is switched off during UPR activation. In summary, the results indicate that ER stress reduction of miR-1244 expression contributes to the pro-survival arm of UPR.
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Affiliation(s)
- Paulina Czechowicz
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a Street, Wroclaw, 50- 383, Poland
| | - Magdalena Gebert
- Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Gdansk, Poland
| | - Sylwia Bartoszewska
- Department of Inorganic Chemistry, Medical University of Gdansk, Gdansk, Poland
| | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, Gdansk, Poland
- BioTechMed Center, Department of Mechanics of Materials and Structures, Gdansk University of Technology, Gdansk, Poland
| | - James F Collawn
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA
| | - Rafal Bartoszewski
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a Street, Wroclaw, 50- 383, Poland.
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25
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Seetharaman ATM, Owens CE, Gangaraju R. Cysteinyl Leukotriene Receptor Antagonism by Montelukast to Treat Visual Deficits. J Ocul Pharmacol Ther 2024; 40:617-628. [PMID: 39358316 DOI: 10.1089/jop.2024.0111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024] Open
Abstract
Montelukast, a Food and Drug Administration-approved drug for asthma and allergic rhinitis modulates leukotriene (LT) receptors and serves as a critical anti-inflammatory agent. Recent research suggests that the LT signaling pathway targeted by montelukast has broader implications for diseases such as fibrosis, cardiovascular diseases, cancer, cerebrovascular disease, and immune defense. This expanded understanding highlights montelukast's potential for repurposing in conditions involving aberrant stress mechanisms, including ocular diseases marked by inflammation, oxidative stress, ER stress, and apoptosis, among several others. This review delves into montelukast's therapeutic mechanisms across various diseases, draws parallels to ocular conditions, and examines clinical trials and associated adverse effects to underscore the unmet need for cysteinyl LT receptor antagonism by montelukast as an effective therapy for visual deficits.
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Affiliation(s)
- Amritha T M Seetharaman
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Caroline E Owens
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, Anatomy & Neurobiology, Neuroscience Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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26
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Hu D, Yang Y, Fang L, Fan S, Lin L, Luo P, Xiong Y, Su Y. Isoliquiritigenin induced hepatotoxicity and endoplasmic reticulum stress in zebrafish embryos. Sci Rep 2024; 14:28256. [PMID: 39548255 PMCID: PMC11568227 DOI: 10.1038/s41598-024-79016-8] [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: 08/02/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024] Open
Abstract
Isoliquiritigenin (ISL), a naturally occurring flavonoid derived from licorice root, exhibits antioxidant, anticancer, anti-inflammatory, and anti-allergic properties, and is frequently detected in both environmental and human samples. Previous studies from our lab have demonstrated that ISL exposure can lead to developmental deformities and aberrant immune responses. However, the molecular mechanisms underlying ISL toxicity in zebrafish embryos remain incompletely elucidated. Therefore, this study aimed to elucidate the effects of ISL exposure on endoplasmic reticulum (ER) stress in zebrafish embryos by assessing the expression levels of ER stress markers HSPA5 and CHOP, along with associated apoptosis factors, under various ISL concentrations, with tunicamycin (TM) serving as a positive control. Furthermore, targeted analyses of ER stress-related pathways were conducted using RNA transcriptome sequencing, and the up-regulated gene was verified by western blot. The results revealed that ISL exposure significantly elevated the expression levels of HSPA5 and CHOP, concomitantly activating ER stress pathways, including pPERK-eIF2α-ATF4 and ATF6 pathways in zebrafish embryos. These findings suggest that the activation of endoplasmic reticulum stress signaling pathways may contribute to the developmental deformities observed in zebrafish embryos following ISL exposure, thereby highlighting the potential ecological risks associated with ISL usage.
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Affiliation(s)
- Deliang Hu
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China
- Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China
| | - Yuqing Yang
- Department of Pharmacy , Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, P. R. China
| | - Lei Fang
- Emergency department, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, Jiangxi, P.R. China
| | - Shijie Fan
- Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China
| | - Ling Lin
- Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P.R. China
| | - Puying Luo
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China
| | - Yuanhuan Xiong
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China.
| | - Yufang Su
- Department of Oncology, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, P.R. China.
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27
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Wu M, Yan J, Qin S, Fu L, Sun S, Li W, Lv J, Chen L. Connections Between Endoplasmic Reticulum Stress and Prognosis of Hepatocarcinoma. Bioengineering (Basel) 2024; 11:1136. [PMID: 39593796 PMCID: PMC11591847 DOI: 10.3390/bioengineering11111136] [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: 09/26/2024] [Revised: 11/04/2024] [Accepted: 11/09/2024] [Indexed: 11/28/2024] Open
Abstract
Endoplasmic reticulum (ER) stress is a state in which misfolded or unfolded proteins accumulate in the lumen of the ER as a result of some exogenous or endogenous factors. It plays a crucial role in the pathogenesis of malignancies, affecting cell survival, proliferation, and metastasis in cancer. ER stress genes could provide new ideas for potential therapeutic targets in cancer. In our study, we aimed to construct an ER stress-related genes (ERGs) model for hepatocellular carcinoma (HCC). ERGs with differential expression and significant survival were screened to construct a prognostic model. The effectiveness of the model was successfully validated by external datasets. High and low-risk groups were classified based on risk scores. Functional analysis showed risk groups involved in the unfolded protein response, DNA repair, and other differential pathways. When compared to patients with low risk, the prognosis for HCC patients in the high-risk group might be worsened by disruptions in these pathways. Importantly, we considered genomic druggability and predicted drugs. Sorafenib-induced autophagy in HCC cells through an ES stress mechanism. Sorafenib was more sensitive for high-risk patients. In brief, our model predicted the prognosis of HCC and provided novel treatment strategies for the study of other cancers.
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Affiliation(s)
| | | | | | | | | | | | - Junjie Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China; (M.W.); (J.Y.); (S.Q.); (L.F.); (S.S.); (W.L.)
| | - Lina Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China; (M.W.); (J.Y.); (S.Q.); (L.F.); (S.S.); (W.L.)
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28
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Senese R, Petito G, Silvestri E, Ventriglia M, Mosca N, Potenza N, Russo A, Falvo S, Manfrevola F, Cobellis G, Chioccarelli T, Porreca V, Mele VG, Chianese R, de Lange P, Ricci G, Cioffi F, Lanni A. The impact of cannabinoid receptor 1 absence on mouse liver mitochondria homeostasis: insight into mitochondrial unfolded protein response. Front Cell Dev Biol 2024; 12:1464773. [PMID: 39512900 PMCID: PMC11541708 DOI: 10.3389/fcell.2024.1464773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 10/09/2024] [Indexed: 11/15/2024] Open
Abstract
Introduction The contribution of Cannabinoid type 1 receptor (CB1) in mitochondrial energy transduction mechanisms and mitochondrial activities awaits deeper investigations. Our study aims to assess the impact of CB1 absence on the mitochondrial compartment in the liver, focusing on both functional aspects and remodeling processes. Methods We used CB1-/- and CB1+/+ male mice. Cytochrome C Oxidase activity was determined polarographically. The expression and the activities of separated mitochondrial complexes and supercomplexes were performed by using Blue-Native Page, Western blotting and histochemical staining for in-gel activity. Key players of Mitochondrial Quality Control processes were measured using RT-qPCR and Western blotting. Liver fine sub-cellular ultrastructural features were analyzed by TEM analysis. Results and discussion In the absence of CB1, several changes in the liver occur, including increased oxidative capacity, reduced complex I activity, enhanced complex IV activity, general upregulation of respiratory supercomplexes, as well as higher levels of oxidative stress. The mitochondria and cellular metabolism may be affected by these changes, increasing the risk of ROS-related damage. CB1-/- mice show upregulation of mitochondrial fusion, fission and biogenesis processes which suggests a dynamic response to the absence of CB1. Furthermore, oxidative stress disturbs mitochondrial proteostasis, initiating the mitochondrial unfolded protein response (UPRmt). We noted heightened levels of pivotal enzymes responsible for maintaining mitochondrial integrity, along with heightened expression of molecular chaperones and transcription factors associated with cellular stress reactions. Additionally, our discoveries demonstrate a synchronized reaction to cellular stress, involving both UPRmt and UPRER pathways.
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Affiliation(s)
- Rosalba Senese
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Giuseppe Petito
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Elena Silvestri
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Maria Ventriglia
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Nicola Mosca
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Aniello Russo
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Sara Falvo
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Francesco Manfrevola
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Gilda Cobellis
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Teresa Chioccarelli
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Veronica Porreca
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Vincenza Grazia Mele
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Rosanna Chianese
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Pieter de Lange
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
| | - Giulia Ricci
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Federica Cioffi
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Antonia Lanni
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy
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Wang X, Di W, Wang Z, Qi P, Liu Z, Zhao H, Ding W, Di S. Cadmium stress alleviates lipid accumulation caused by chiral penthiopyrad through regulating endoplasmic reticulum stress and mitochondrial dysfunction in zebrafish liver. JOURNAL OF HAZARDOUS MATERIALS 2024; 478:135560. [PMID: 39173367 DOI: 10.1016/j.jhazmat.2024.135560] [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: 06/27/2024] [Revised: 08/15/2024] [Accepted: 08/15/2024] [Indexed: 08/24/2024]
Abstract
The coexistence of cadmium (Cd) can potentiate (synergism) or reduce (antagonism) the pesticide effects on organisms, which may change with chiral pesticide enantiomers. Previous studies have reported the toxic effects of chiral penthiopyrad on lipid metabolism in zebrafish (Danio rerio) liver. The Cd effects and toxic mechanism on lipid accumulation were investigated from the perspective of endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The coexistence of Cd increased the concentrations of penthiopyrad and its metabolites in zebrafish. Penthiopyrad exposure exhibited significant effects on lipid metabolism and mitochondrial function-related indicators, which were verified by lipid droplets and mitochondrial damage in subcellular structures. Moreover, penthiopyrad activated the genes of ER unfolded protein reaction (UPR) and Ca2+ permeable channels, and S-penthiopyrad exhibited more serious effects on ER stress with ER hyperplasia than R-penthiopyrad. As a mitochondrial uncoupler, the coexistence of Cd could decrease lipid accumulation by alleviating ER stress and mitochondrial dysfunction, and these effects were the most significant for R-penthiopyrad. There were antagonistic effects between Cd and penthiopyrad, which could reduce the damage caused by penthiopyrad in zebrafish, thus increasing the bioaccumulation of penthiopyrad in zebrafish. These findings highlighted the importance and necessity of evaluating the ecological risks of metal-chiral pesticide mixtures.
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Affiliation(s)
- Xinquan Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/ Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, PR China; Agricultural Ministry Key Laboratory for Pesticide Residue Detection, Hangzhou 310021, PR China
| | - Weixuan Di
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/ Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, PR China; Agricultural Ministry Key Laboratory for Pesticide Residue Detection, Hangzhou 310021, PR China; College of Plant Protection, Northeast agricultural university, Harbin 150030, PR China
| | - Zhiwei Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/ Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, PR China; Agricultural Ministry Key Laboratory for Pesticide Residue Detection, Hangzhou 310021, PR China
| | - Peipei Qi
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/ Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, PR China; Agricultural Ministry Key Laboratory for Pesticide Residue Detection, Hangzhou 310021, PR China
| | - Zhenzhen Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/ Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, PR China; Agricultural Ministry Key Laboratory for Pesticide Residue Detection, Hangzhou 310021, PR China
| | - Huiyu Zhao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/ Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, PR China; Agricultural Ministry Key Laboratory for Pesticide Residue Detection, Hangzhou 310021, PR China
| | - Wei Ding
- College of Plant Protection, Northeast agricultural university, Harbin 150030, PR China
| | - Shanshan Di
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/ Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, PR China; Agricultural Ministry Key Laboratory for Pesticide Residue Detection, Hangzhou 310021, PR China.
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Brito ML, Coutinho-Wolino KS, Almeida PP, Trigueira PDC, Alves APDP, Magliano DC, Stockler-Pinto MB. Unstressing the Reticulum: Nutritional Strategies for Modulating Endoplasmic Reticulum Stress in Obesity. Mol Nutr Food Res 2024; 68:e2400361. [PMID: 39363792 DOI: 10.1002/mnfr.202400361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 09/03/2024] [Indexed: 10/05/2024]
Abstract
The progression of obesity involves several molecular mechanisms that are closely associated with the pathophysiological response of the disease. Endoplasmic reticulum (ER) stress is one such factor. Lipotoxicity disrupts endoplasmic reticulum homeostasis in the context of obesity. Furthermore, it induces ER stress by activating several signaling pathways via inflammatory responses and oxidative stress. ER performs crucial functions in protein synthesis and lipid metabolism; thus, triggers such as lipotoxicity can promote the accumulation of misfolded proteins in the organelle. The accumulation of these proteins can lead to metabolic disorders and chronic inflammation, resulting in cell death. Thus, alternatives, such as flavonoids, amino acids, and polyphenols that are associated with antioxidant and anti-inflammatory responses have been proposed to attenuate this response by modulating ER stress via the administration of nutrients and bioactive compounds. Decreasing inflammation and oxidative stress can reduce the expression of several ER stress markers and improve clinical outcomes through the management of obesity, including the control of body weight, visceral fat, and lipid accumulation. This review explores the metabolic changes resulting from ER stress and discusses the role of nutritional interventions in modulating the ER stress pathway in obesity.
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Affiliation(s)
- Michele Lima Brito
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24070-090, Brazil
| | - Karen Salve Coutinho-Wolino
- Cardiovascular Sciences Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24070-090, Brazil
| | - Patricia Pereira Almeida
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24070-090, Brazil
| | | | - Ana Paula de Paula Alves
- Endocrinology Post Graduate Program, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 24210-201, Brazil
| | - D'Angelo Carlo Magliano
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24070-090, Brazil
- Cardiovascular Sciences Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24070-090, Brazil
- Endocrinology Post Graduate Program, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 24210-201, Brazil
- Morphology Department, Biomedical Institute, Fluminense Federal University (UFF), Niterói, RJ, 24020-150, Brazil
| | - Milena Barcza Stockler-Pinto
- Pathology Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24070-090, Brazil
- Cardiovascular Sciences Post Graduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24070-090, Brazil
- Nutrition Sciences Postgraduate Program, Fluminense Federal University (UFF), Niterói, RJ, 24020-140, Brazil
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Lee CK, Wang FT, Huang CH, Chan WH. Dose-dependent effects of silver nanoparticles on cell death modes in mouse blastocysts induced via endoplasmic reticulum stress and mitochondrial apoptosis. Toxicol Res (Camb) 2024; 13:tfae158. [PMID: 39371680 PMCID: PMC11447381 DOI: 10.1093/toxres/tfae158] [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: 03/03/2024] [Revised: 08/19/2024] [Accepted: 09/27/2024] [Indexed: 10/08/2024] Open
Abstract
In view of the rapidly expanding medical and commercial applications of silver nanoparticles (AgNPs), their potential health risks and environmental effects are a significant growing concern. Earlier research by our group uncovered the embryotoxic potential of AgNPs, showing detrimental impacts of these nanoparticles on both pre- and post-implantation embryonic development. In the current study, we showed that low (50-100 μM) and high (200-400 μM) dose ranges of AgNPs trigger distinct cell death programs affecting mouse embryo development and further explored the underlying mechanisms. Treatment with low concentrations of AgNPs (50-100 μM) triggered ROS generation, in turn, inducing mitochondria-dependent apoptosis, and ultimately, harmful effects on embryo implantation, post-implantation development, and fetal development. Notably, high concentrations of AgNPs (200-400 μM) evoked more high-level ROS generation and endoplasmic reticulum (ER) stress-mediated necrosis. Interestingly, pre-incubation with Trolox, a strong antioxidant, reduced ROS generation in the group treated with 200-400 μM AgNPs to the level induced by 50-100 μM AgNPs, resulting in switching of the cell death mode from necrosis to apoptosis and a significant improvement in the impairment of embryonic development. Our findings additionally indicate that activation of PAK2 is a crucial step in AgNP-triggered apoptosis and sequent detrimental effects on embryonic development. Based on the collective results, we propose that the levels of ROS generated by AgNP treatment of embryos serve as a critical regulator of cell death type, leading to differential degrees of damage to embryo implantation, post-implantation development and fetal development through triggering apoptosis, necrosis or other cell death signaling cascades.
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Affiliation(s)
- Cheng-Kai Lee
- Department of Obstetrics and Gynecology, Taoyuan General Hospital, Ministry of Health & Welfare, Zhongshan Road, Taoyuan District, Taoyuan City 33004, Taiwan
| | - Fu-Ting Wang
- Rehabilitation and Technical Aid Center, Taipei Veterans General Hospital, Section 2, Shipai Road, Beitou District, Taipei City 11217, Taiwan
| | - Chien-Hsun Huang
- Hungchi Gene IVF Center, Taoyuan District, Daxing West Road, Taoyuan District, Taoyuan City 330012, Taiwan
| | - Wen-Hsiung Chan
- Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Zhongbei Road, Zhongli District, Taoyuan City 32023, Taiwan
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Cifric S, Turi M, Folino P, Clericuzio C, Barello F, Maciel T, Anderson KC, Gulla A. DAMPening Tumor Immune Escape: The Role of Endoplasmic Reticulum Chaperones in Immunogenic Chemotherapy. Antioxid Redox Signal 2024; 41:661-674. [PMID: 38366728 DOI: 10.1089/ars.2024.0558] [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] [Indexed: 02/18/2024]
Abstract
Significance: Preclinical and clinical research in the past two decades has redefined the mechanism of action of some chemotherapeutics that are able to activate the immune system against cancer when cell death is perceived by the immune cells. This immunogenic cell death (ICD) activates antigen-presenting cells (APCs) and T cells to induce immune-mediated tumor clearance. One of the key requirements to achieve this effect is the externalization of the damage-associated molecular patterns (DAMPs), molecules released or exposed by cancer cells during ICD that increase the visibility of the cancer cells by the immune system. Recent Advances: In this review, we focus on the role of calreticulin (CRT) and other endoplasmic reticulum (ER) chaperones, such as the heat-shock proteins (HSPs) and the protein disulfide isomerases (PDIs), as surface-exposed DAMPs. Once exposed on the cell membrane, these proteins shift their role from that of ER chaperone and regulator of Ca2+ and protein homeostasis to act as an immunogenic signal for APCs, driving dendritic cell (DC)-mediated phagocytosis and T-mediated antitumor response. Critical Issues: However, cancer cells exploit several mechanisms of resistance to immune attack, including subverting the exposure of ER chaperones on their surface to avoid immune recognition. Future Directions: Overcoming these mechanisms of resistance represents a potential therapeutic opportunity to improve cancer treatment effectiveness and patient outcomes.
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Affiliation(s)
- Selma Cifric
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Marcello Turi
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Pietro Folino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Cole Clericuzio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Tallya Maciel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Kenneth C Anderson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
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Ying Y, Zhang J, Ren D, Zhao P, Zhang W, Lu X. ERP29 regulates the proliferation of endometrial carcinoma via M6A modification. Life Sci 2024; 354:122976. [PMID: 39142507 DOI: 10.1016/j.lfs.2024.122976] [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: 04/10/2024] [Revised: 07/10/2024] [Accepted: 08/10/2024] [Indexed: 08/16/2024]
Abstract
AIMS Endoplasmic reticulum protein 29 (ERP29) is crucial for endoplasmic reticulum stress (ERS). M6A plays an important role in the progression of endometrial cancer (EC). The study investigated the role of ERS-related gene (ERP29) and m6A in EC. MATERIALS AND METHODS We screened ERS-related genes based on the GEO dataset, GSEA dataset and TCGA-UCEC database using WGCNA and two machine learning algorithms. The m6A-related GEO dataset was employed to identify the ERS-related hub genes with m6A. Expression of hub genes in different cell types were visualize through scRNA-seq data analyzing. Using qPCR, Western blot, and Immunohistochemical assays to detect the expression of ERP29, the effect of ERP29 on cancer cell proliferation was investigated through CCK8, EdU and clone formation experiments. M6A modifications were studied using m6A Dot blot and MeRIP-qPCR. Finally, we conducted rescue experiments. KEY FINDINGS Ten ERS-related hub genes with m6A were identified. ERP29 is highly expressed in EC. ERP29 knockdown inhibits EC cell proliferation. METTL3 overexpression increases the ERP29 mRNA m6A and decreases the expression of ERP29. Cycloleucine (Cyc), a nucleic acid methylation inhibitor, treatment reduces ERP29 mRNA m6A and increases the expression of ERP29. Cyc rescue the low expression of ERP29 caused by overexpression of METTL3 through m6A. ERP29 knockdown rescued the increased proliferation of EC cells caused by low m6A. SIGNIFICANCE ERP29 is highly expressed in EC. m6A regulates ERP29 expression and affects the proliferation of endometrial cancer cells. This represents the premise for applying ERP29 and m6A modifications in diagnosing and treating EC.
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Affiliation(s)
- Yanqi Ying
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, 2nd, Jingba Road, Zhengzhou 450053, Henan Province, China
| | - Jingyan Zhang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, 2nd, Jingba Road, Zhengzhou 450053, Henan Province, China
| | - Dan Ren
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, 2nd, Jingba Road, Zhengzhou 450053, Henan Province, China
| | - Panpan Zhao
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, 2nd, Jingba Road, Zhengzhou 450053, Henan Province, China
| | - Wenyi Zhang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, 2nd, Jingba Road, Zhengzhou 450053, Henan Province, China
| | - Xiaoqin Lu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, 2nd, Jingba Road, Zhengzhou 450053, Henan Province, China.
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Eze FN. Transthyretin Amyloidosis: Role of oxidative stress and the beneficial implications of antioxidants and nutraceutical supplementation. Neurochem Int 2024; 179:105837. [PMID: 39154837 DOI: 10.1016/j.neuint.2024.105837] [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: 03/16/2024] [Revised: 06/28/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
Transthyretin (ATTR) amyloidosis constitutes a spectrum of debilitating neurodegenerative diseases instigated by systemic extracellular deposition of partially unfolded/aggregated aberrant transthyretin. The homotetrameric protein, TTR, is abundant in the plasma, and to a lesser extent the cerebrospinal fluid. Rate-limiting tetramer dissociation of the native protein is regarded as the critical step in the formation of morphologically heterogenous toxic aggregates and the onset of clinical manifestations such as polyneuropathy, cardiomyopathy, disturbances in motor and autonomic functions. Over the past few decades there has been increasing evidence suggesting that in addition to destabilization in TTR tetramer structure, oxidative stress may also play an important role in the pathogenesis of ATTR amyloidosis. In this review, an update on the impact of oxidative stress in TTR amyloidogenesis as well as TTR aggregate-mediated pathologies is discussed. The counteracting effects of antioxidants and nutraceutical agents explored in the treatment of ATTR amyloidosis based on recent evidence is also critically examined. The insights unveiled could further strengthen current understanding of the mechanisms underlying ATTR amyloidosis as well as extend the range of strategies for effective management of ATTR amyloidoses.
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Affiliation(s)
- Fredrick Nwude Eze
- Office of Research Administration, Chiang Mai University, Chiang Mai, 50200, Thailand; Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand.
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Kim DH. Endoplasmic reticulum stress induces hepatic steatosis through interaction between PPARα and FoxO6 in vivo and in vitro. J Mol Med (Berl) 2024; 102:1267-1284. [PMID: 39198274 PMCID: PMC11416408 DOI: 10.1007/s00109-024-02480-2] [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: 03/06/2024] [Revised: 08/12/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024]
Abstract
Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress-induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress-induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study-lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. KEY MESSAGES: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice.
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Affiliation(s)
- Dae Hyun Kim
- Department of Food Science & Technology, College of Natural Resources and Life Science, Pusan National University, Miryang-Si, Gyeongsangnam-Do, 50463, Republic of Korea.
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Scordino M, Stepanova P, Srinivasan V, Pham DD, Eriksson O, Lalowski M, Mudò G, Di Liberto V, Korhonen L, Voutilainen MH, Lindholm D. CNPY2 protects against ER stress and is expressed by corticostriatal neurons together with CTIP2 in a mouse model of Huntington's disease. Front Mol Neurosci 2024; 17:1473058. [PMID: 39359687 PMCID: PMC11446244 DOI: 10.3389/fnmol.2024.1473058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/29/2024] [Indexed: 10/04/2024] Open
Abstract
Canopy Homolog 2 (CNPY2) is an endoplasmic reticulum (ER) localized protein belonging to the CNPY gene family. We show here that CNPY2 is protective against ER stress induced by tunicamycin in neuronal cells. Overexpression of CNPY2 enhanced, while downregulation of CNPY2 using shRNA expression, reduced the viability of neuroblastoma cells after tunicamycin. Likewise, recombinant CNPY2 increased survival of cortical neurons in culture after ER stress. CNPY2 reduced the activating transcription factor 6 (ATF6) branch of ER stress and decreased the expression of CCAT/Enhancer-Binding Protein Homologous Protein (CHOP) involved in cell death. Immunostaining using mouse brain sections revealed that CNPY2 is expressed by cortical and striatal neurons and is co-expressed with the transcription factor, COUPTF-interacting protein 2 (CTIP2). In transgenic N171-82Q mice, as a model for Huntington's disease (HD), the number of CNPY2-immunopositive neurons was increased in the cortex together with CTIP2. In the striatum, however, the number of CNPY2 decreased at 19 weeks of age, representing a late-stage of pathology. Striatal cells in culture were shown to be more susceptible to ER stress after downregulation of CNPY2. These results demonstrate that CNPY2 is expressed by corticostriatal neurons involved in the regulation of movement. CNPY2 enhances neuronal survival by reducing ER stress and is a promising factor to consider in HD and possibly in other brain diseases.
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Affiliation(s)
- Miriana Scordino
- Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, Helsinki, Finland
- Biomedicum-2, Minerva Foundation Institute for Medical Research, Helsinki, Finland
- Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BiND), University of Palermo, Palermo, Italy
| | | | - Vignesh Srinivasan
- Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, Helsinki, Finland
- Biomedicum-2, Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Dan Duc Pham
- Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, Helsinki, Finland
- Biomedicum-2, Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Ove Eriksson
- Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, Helsinki, Finland
- Biomedicum-2, Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Maciej Lalowski
- Meilahti Clinical Proteomics Core Facility, HiLIFE, University of Helsinki, Helsinki, Finland
- Department of Gene Expression, Institute of Molecular Biology and Biochemistry, Adam Mickiewicz University, Poznań, Poland
| | - Giuseppa Mudò
- Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BiND), University of Palermo, Palermo, Italy
| | - Valentina Di Liberto
- Department of Biomedicine, Neuroscience, and Advanced Diagnostic (BiND), University of Palermo, Palermo, Italy
| | - Laura Korhonen
- Department of Child and Adolescent Psychiatry, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | | | - Dan Lindholm
- Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, Helsinki, Finland
- Biomedicum-2, Minerva Foundation Institute for Medical Research, Helsinki, Finland
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Wang J, Wang XY, Yuan ZY, Wang XH, Guan YY, Zhu JX, Huang WF, Liu Q, Xu GH, Yi LT. Blueberry extract attenuates DSS-induced inflammatory bowel disease in mice through inhibiting ER stress-mediated colonic apoptosis in mice. Food Funct 2024; 15:9541-9551. [PMID: 39225067 DOI: 10.1039/d4fo00194j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic, debilitating condition with limited therapeutic options. Dietary components like blueberries have emerged as potential modulators of inflammation and tissue repair in gastrointestinal diseases. This study investigated endoplasmic reticulum (ER) stress-mediated apoptosis mediated protective effects of blueberries in ameliorating dextran sulfate sodium (DSS)-induced IBD. Firstly, a total of 86 anthocyanin compounds were identified in blueberry extract by LC-MS spectroscopy, including 35 cyanidin, 9 delphinidin, 14 malvidin, 10 peonidin, and 9 petunidin. Then, the animal study showed that blueberry supplementation notably ameliorated DSS-induced IBD symptoms, as evidenced by improved histopathological scores and a reduced disease activity index (DAI) score. Additionally, blueberries attenuated ER stress by inhibiting the colonic PERK/eIF2α/ATF4/CHOP signaling pathway. Furthermore, blueberries inhibited the expression of the pro-apoptotic protein, caspase-3, and decreased colonic apoptosis, as evidenced by TUNEL assay results. However, it did not affect the expression of anti-apoptotic proteins, bcl-2 and bcl-xl. Finally, blueberries enhanced the intestinal barrier by upregulating ZO-1, claudin-1, occludin, and E-cadherin. In conclusion, blueberries demonstrate therapeutic potential against DSS-induced IBD-like symptoms in mice, possibly by regulating ER stress-mediated apoptosis pathways. These findings suggest that blueberries might be an effective dietary intervention for IBD management.
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Affiliation(s)
- Jun Wang
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
| | - Xin-Yu Wang
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
| | - Zhong-Yu Yuan
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
| | - Xiao-Han Wang
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
| | - Yu-Ying Guan
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
| | - Ji-Xiao Zhu
- Research Center of Traditional Chinese Medicine Resources and Ethnic Medicine, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330004, PR China
| | - Wei-Feng Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen 361003, Fujian Province, PR China
| | - Qing Liu
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
| | - Guang-Hui Xu
- Xiamen Medicine Research Institute, Xiamen 361008, Fujian Province, PR China
| | - Li-Tao Yi
- Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China.
- Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, Fujian Province, PR China
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen, 361021, Fujian Province, PR China
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Koszła O, Sołek P. Misfolding and aggregation in neurodegenerative diseases: protein quality control machinery as potential therapeutic clearance pathways. Cell Commun Signal 2024; 22:421. [PMID: 39215343 PMCID: PMC11365204 DOI: 10.1186/s12964-024-01791-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024] Open
Abstract
The primary challenge in today's world of neuroscience is the search for new therapeutic possibilities for neurodegenerative disease. Central to these disorders lies among other factors, the aberrant folding, aggregation, and accumulation of proteins, resulting in the formation of toxic entities that contribute to neuronal degeneration. This review concentrates on the key proteins such as β-amyloid (Aβ), tau, and α-synuclein, elucidating the intricate molecular events underlying their misfolding and aggregation. We critically evaluate the molecular mechanisms governing the elimination of misfolded proteins, shedding light on potential therapeutic strategies. We specifically examine pathways such as the endoplasmic reticulum (ER) and unfolded protein response (UPR), chaperones, chaperone-mediated autophagy (CMA), and the intersecting signaling of Keap1-Nrf2-ARE, along with autophagy connected through p62. Above all, we emphasize the significance of these pathways as protein quality control mechanisms, encompassing interventions targeting protein aggregation, regulation of post-translational modifications, and enhancement of molecular chaperones and clearance. Additionally, we focus on current therapeutic possibilities and new, multi-target approaches. In conclusion, this review systematically consolidates insights into emerging therapeutic strategies predicated on protein aggregates clearance.
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Affiliation(s)
- Oliwia Koszła
- Department of Biopharmacy, Medical University of Lublin, 4A Chodzki St., Lublin, 20-093, Poland.
| | - Przemysław Sołek
- Department of Biopharmacy, Medical University of Lublin, 4A Chodzki St., Lublin, 20-093, Poland
- Department of Biochemistry and Toxicology, University of Life Sciences, 13 Akademicka St, Lublin, 20-950, Poland
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Wang X, Song Y, Lu X, Zhang H, Wang T. Microcystin-LR Regulates Interaction between Tumor Cells and Macrophages via the IRE1α/XBP1 Signaling Pathway to Promote the Progression of Colorectal Cancer. Cells 2024; 13:1439. [PMID: 39273011 PMCID: PMC11394429 DOI: 10.3390/cells13171439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Microcystin-LR (MC-LR), a cyanobacterial toxin, is a potent carcinogen implicated in colorectal cancer (CRC) progression. However, its impact on the tumor microenvironment (TME) during CRC development remains poorly understood. This study investigates the interaction between tumor cells and macrophages mediated by MC-LR within the TME and its influence on CRC progression. CRC mice exposed to MC-LR demonstrated a significant transformation from adenoma to adenocarcinoma. The infiltration of macrophages increased, and the IRE1α/XBP1 pathway was activated in CRC cells after MC-LR exposure, influencing macrophage M2 polarization under co-culture conditions. Additionally, hexokinase 2 (HK2), a downstream target of the IRE1α/XBP1 pathway, was identified, regulating glycolysis and lactate production. The MC-LR-induced IRE1α/XBP1/HK2 axis enhanced lactate production in CRC cells, promoting M2 macrophage polarization. Furthermore, co-culturing MC-LR-exposed CRC cells with macrophages, along with the IRE1α/XBP1 pathway inhibitor 4μ8C and the hexokinase inhibitor 2-DG, suppressed M2 macrophage-induced CRC cell migration, clonogenicity, and M2 macrophage polarization. This study elucidates the mechanism by which MC-LR-mediated interactions through the IRE1α/XBP1 pathway promote CRC progression, highlighting potential therapeutic targets.
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Affiliation(s)
| | | | | | | | - Ting Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China; (X.W.); (Y.S.); (X.L.); (H.Z.)
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Mishra S, Paul R, Rani V, Ghosh DK, Jain BP. Cadmium toxicity on endoplasmic reticulum functioning. INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY 2024; 15:107-117. [PMID: 39309612 PMCID: PMC11411147 DOI: 10.62347/ouds3732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 08/25/2024] [Indexed: 09/25/2024]
Abstract
Cadmium (Cd) is a heavy metal pollutant widely distributed in the environment due to industrial activities, mining, and agricultural practices. Cadmium-induced Toxicity exerts profound effects on ER functioning through multiple mechanisms, leading to cellular dysfunction and pathological consequences. Cadmium disrupts protein folding and activates the unfolded protein response (UPR). Cd exposure leads to the accumulation of misfolded proteins, triggering UPR pathways mediated by critical ER transmembrane sensors: IRE1, PERK, and ATF6. The subsequent UPR aims to restore ER homeostasis but can also induce apoptosis under severe stress conditions. Cd disrupts ER calcium homeostasis by inhibiting the SERCA pump, further exacerbating ER stress. The generation of reactive oxygen species (ROS also plays a critical role in Cd toxicity, damaging ER-resident proteins and amplifying UPR activation). Cadmium also affects the lipid metabolism. This review examines the mechanisms by which Cd toxicity impairs ER functioning, disruption of protein folding and quality control mechanisms, and dysregulation of calcium signaling and lipid metabolism. The subsequent cellular consequences, including oxidative stress, apoptosis, and inflammation, are discussed in the context of Cd-induced pathogenesis of diseases such as Cancer and neurodegenerative and cardiovascular disorders. Finally, potential therapeutic strategies must be explored to mitigate the adverse effects of Cd on ER functioning and human health.
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Affiliation(s)
- Shivani Mishra
- Gene Expression and Signaling Lab., Department of Zoology, Mahatma Gandhi Central UniversityMotihari, Bihar 845401, India
| | - Ramakrushna Paul
- Gene Expression and Signaling Lab., Department of Zoology, Mahatma Gandhi Central UniversityMotihari, Bihar 845401, India
| | - Vibha Rani
- Department of Biotechnology, Jaypee Institute of Information TechnologyNoida, UP 201309, India
| | - Debasish Kumar Ghosh
- Kasturba Medical College, Manipal Academy of Higher EducationManipal, Karnataka 576104, India
| | - Buddhi Prakash Jain
- Gene Expression and Signaling Lab., Department of Zoology, Mahatma Gandhi Central UniversityMotihari, Bihar 845401, India
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41
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Dutta T, Chakraborty B, Nigam A, Minocha S, Koner AL. A small-molecule probe to decipher stress-induced ER microenvironments and ER-Golgi communication. J Mater Chem B 2024; 12:7848-7857. [PMID: 38808376 DOI: 10.1039/d4tb00572d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2024]
Abstract
Cellular stress is a crucial factor in regulating and maintaining both organismal and microenvironmental homeostasis. It induces a response that also affects the micropolarity of specific cellular compartments, which is essential for early disease diagnosis. In this contribution, we present a quantitative study of micropolarity changes inside the endoplasmic reticulum (ER) during the G1/S and G2/M phases, using a biocompatible small-molecule fluorophore called ER-Oct. This probe is selectively driven to the ER by its hydrophobicity, and it has the fastest diffusion properties among a series of analogous probes. We found that induced ER stress caused cell cycle arrests leading to an increase in ER micropolarity which is well supported by lambda scanning experiments and fluorescence lifetime imaging microscopy (FLIM) as well. ER-Oct is a versatile staining agent that could effectively stain the ER in various living/fixed mammalian cells, isolated ER, Caenorhabditis elegans, and mice tissues. Furthermore, we used this probe to visualize a well-known biological event, ER to Golgi transport, by live-cell fluorescence microscopy. Our exhaustive investigation of micropolarity using ER-staining dye provides a new way to study ER stress, which could provide a deeper understanding of proteostasis in model systems and even in fixed patient samples.
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Affiliation(s)
- Tanoy Dutta
- Bionanotechnology Lab, Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, Madhya Pradesh - 462066, India.
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Barsha Chakraborty
- Bionanotechnology Lab, Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, Madhya Pradesh - 462066, India.
| | - Aditya Nigam
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi - 110016, India
| | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi - 110016, India
| | - Apurba Lal Koner
- Bionanotechnology Lab, Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal, Madhya Pradesh - 462066, India.
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Sun M, Zhang X, Tan B, Zhang Q, Zhao X, Dong D. Potential role of endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity-an update. Front Pharmacol 2024; 15:1415108. [PMID: 39188945 PMCID: PMC11345228 DOI: 10.3389/fphar.2024.1415108] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/01/2024] [Indexed: 08/28/2024] Open
Abstract
As a chemotherapy agent, doxorubicin is used to combat cancer. However, cardiotoxicity has limited its use. The existing strategies fail to eliminate doxorubicin-induced cardiotoxicity, and an in-depth exploration of its pathogenesis is in urgent need to address the issue. Endoplasmic reticulum stress (ERS) occurs when Endoplasmic Reticulum (ER) dysfunction results in the accumulation of unfolded or misfolded proteins. Adaptive ERS helps regulate protein synthesis to maintain cellular homeostasis, while prolonged ERS stimulation may induce cell apoptosis, leading to dysfunction and damage to tissue and organs. Numerous studies on doxorubicin-induced cardiotoxicity strongly link excessive activation of the ERS to mechanisms including oxidative stress, calcium imbalance, autophagy, ubiquitination, and apoptosis. The researchers also found several clinical drugs, chemical compounds, phytochemicals, and miRNAs inhibited doxorubicin-induced cardiotoxicity by targeting ERS. The present review aims to outline the interactions between ERS and other mechanisms in doxorubicin-induced cardiotoxicity and summarize ERS's role in this type of cardiotoxicity. Additionally, the review enumerates several clinical drugs, phytochemicals, chemical compounds, and miRNAs targeting ERS for considering therapeutic regimens that address doxorubicin-induced cardiotoxicity.
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Affiliation(s)
- Mingli Sun
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Xin Zhang
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Boxuan Tan
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Qingya Zhang
- Innovation Institute, China Medical University, Shenyang, Liaoning, China
| | - Xiaopeng Zhao
- College of Exercise and Health, Shenyang Sport University, Shenyang, Liaoning, China
| | - Dan Dong
- College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
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Yu Y, Yu J, Pan Z. Endoplasmic reticulum stress-related features predict the prognosis of osteosarcoma and reveal STC2 as a novel risk indicator for disease progression. Front Oncol 2024; 14:1453173. [PMID: 39119088 PMCID: PMC11306184 DOI: 10.3389/fonc.2024.1453173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 07/12/2024] [Indexed: 08/10/2024] Open
Abstract
Endoplasmic reticulum (ER) stress exerts significant effects on cell growth, proliferation, migration, invasion, chemoresistance, and angiogenesis in various cancers. However, the impact of ER stress on the outcomes of osteosarcoma patients remains unclear. In this study, we established an ER stress risk model based on The Cancer Genome Atlas (TARGET) osteosarcoma dataset to reflect immune features and predict the prognosis of osteosarcoma patients. Survival analysis revealed significant differences in overall survival among osteosarcoma patients with different ER stress-related risk scores. Furthermore, ER stress-related risk features were significantly associated with the clinical pathological characteristics of osteosarcoma patients and could serve as independent prognostic indicators. Functional enrichment analysis indicated associations of the risk model with cell chemotaxis, leukocyte migration, and regulation of leukocyte migration. Additionally, the ER stress-related risk model suggested the presence of an immunosuppressive microenvironment and immune checkpoint responses. We validated the significance of 7 ER stress-related genes obtained from LASSO regression analysis through RT-qPCR testing on osteosarcoma samples from a local hospital, and inferred the importance of STC2 based on the literature. Subsequently, IHC experiments using samples from 70 osteosarcoma cases and 21 adjacent tissue samples confirmed differential expression of STC2 between cancer and normal tissues, and explored the gene's expression in pan-cancer and its association with clinical pathological parameters of osteosarcoma. In conclusion, we have proposed an ER stress risk model as an independent prognostic factor and identified STC2 as a novel risk indicator for disease progression, providing a promising direction for further research and treatment of osteosarcoma.
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Affiliation(s)
| | | | - Zhenyu Pan
- Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
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44
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Wen B, Zhang P, Xie J, Zhou Z, Zhang G, Zhang L, Zhang Z. Deciphering the prognostic role of endoplasmic reticulum stress in lung adenocarcinoma: integrating prognostic prediction and immunotherapy strategies. Clin Exp Med 2024; 24:169. [PMID: 39052154 PMCID: PMC11272744 DOI: 10.1007/s10238-024-01439-4] [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: 06/09/2024] [Accepted: 07/16/2024] [Indexed: 07/27/2024]
Abstract
Endoplasmic reticulum stress (ERS) is a critical factor influencing lung adenocarcinoma (LUAD) progression and patient outcomes. In this study, we analyzed gene expression data from LUAD samples sourced from The Cancer Genomic Atlas and Gene Expression Omnibus databases. Utilizing advanced statistical methods including LASSO and Cox regression, we developed a ERS-associated signature (ERAS) based on ten ERS-related genes. This model stratified patients into high- and low-risk groups, with the high-risk group exhibiting decreased survival rates, elevated tumor mutational burden, and heightened chemotherapy sensitivity. Additionally, we observed lower immune and ESTIMATE scores in the high-ERAS group, indicating a potentially compromised immune response. Experimental validation through quantitative real-time polymerase chain reaction confirmed the utility of our model. Furthermore, we constructed a nomogram to predict 1-, 3-, and 5-year survival rates, providing clinicians with a valuable tool for personalized patient management. In conclusion, our study demonstrates the efficacy of the ERAS in identifying high-ERAS LUAD patients, offering promising implications for improved prognostication and treatment strategies.
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Affiliation(s)
- Bing Wen
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Department of Cardiothoracic Surgery, The Second People's Hospital of Yibin, Yibin, Sichuan, China
| | - Pengpeng Zhang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jiping Xie
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhaokai Zhou
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ge Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lianmin Zhang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
| | - Zhenfa Zhang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
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45
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Ma C, Liu Y, Fu Z. Implications of endoplasmic reticulum stress and autophagy in aging and cardiovascular diseases. Front Pharmacol 2024; 15:1413853. [PMID: 39119608 PMCID: PMC11306071 DOI: 10.3389/fphar.2024.1413853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/24/2024] [Indexed: 08/10/2024] Open
Abstract
The average lifespan of humans has been increasing, resulting in a rapidly rising percentage of older individuals and high morbidity of aging-associated diseases, especially cardiovascular diseases (CVDs). Diverse intracellular and extracellular factors that interrupt homeostatic functions in the endoplasmic reticulum (ER) induce ER stress. Cells employ a dynamic signaling pathway of unfolded protein response (UPR) to buffer ER stress. Recent studies have demonstrated that ER stress triggers various cellular processes associated with aging and many aging-associated diseases, including CVDs. Autophagy is a conserved process involving lysosomal degradation and recycling of cytoplasmic components, proteins, organelles, and pathogens that invade the cytoplasm. Autophagy is vital for combating the adverse influence of aging on the heart. The present report summarizes recent studies on the mechanism of ER stress and autophagy and their overlap in aging and on CVD pathogenesis in the context of aging. It also discusses possible therapeutic interventions targeting ER stress and autophagy that might delay aging and prevent or treat CVDs.
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Affiliation(s)
- Chenguang Ma
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yang Liu
- 32295 Troops of P.L.A, Liaoyang, China
| | - Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
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46
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Gou F, Cai F, Li X, Lin Q, Zhu J, Yu M, Chen S, Lu J, Hu C. Mitochondria-associated endoplasmic reticulum membranes involve in oxidative stress-induced intestinal barrier injury and mitochondrial dysfunction under diquat exposing. ENVIRONMENTAL TOXICOLOGY 2024; 39:3906-3919. [PMID: 38567716 DOI: 10.1002/tox.24232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/04/2024] [Accepted: 02/18/2024] [Indexed: 06/12/2024]
Abstract
Many factors induced by environmental toxicants have made oxidative stress a risk factor for the intestinal barrier injury and growth restriction, which is serious health threat for human and livestock and induces significant economic loss. It is well-known that diquat-induced oxidative stress is implicated in the intestinal barrier injury. Although some studies have shown that mitochondria are the primary target organelle of diquat, the underlying mechanism remains incompletely understood. Recently, mitochondria-associated endoplasmic reticulum membranes (MAMs) have aroused increasing concerns among scholars, which participate in mitochondrial dynamics and signal transduction. In this study, we investigated whether MAMs involved in intestinal barrier injury and mitochondrial dysfunction induced by diquat-induced oxidative stress in piglets and porcine intestinal epithelial cells (IPEC-J2 cells). The results showed that diquat induced growth restriction and impaired intestinal barrier. The mitochondrial reactive oxygen species (ROS) was increased and mitochondrial membrane potential was decreased following diquat exposure. The ultrastructure of mitochondria and MAMs was also disturbed. Meanwhile, diquat upregulated endoplasmic reticulum stress marker protein and activated PERK pathway. Furthermore, loosening MAMs alleviated intestinal barrier injury, decrease of antioxidant enzyme activity and mitochondrial dysfunction induced by diquat in IPEC-J2 cells, while tightening MAMs exacerbated diquat-induced mitochondrial dysfunction. These results suggested that MAMs may be associated with the intestinal barrier injury and mitochondrial dysfunction induced by diquat in the jejunum of piglets.
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Affiliation(s)
- Feiyang Gou
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Fengzhou Cai
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Xin Li
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Qian Lin
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Jiang Zhu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Minjie Yu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Shaokui Chen
- School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan, China
| | - Jianjun Lu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
| | - Caihong Hu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China
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Zhang R, Yao B, Li R, Limesand SW, Zhao Y, Chen X. Chronic Epinephrine-Induced Endoplasmic Reticulum and Oxidative Stress Impairs Pancreatic β-Cells Function and Fate. Int J Mol Sci 2024; 25:7029. [PMID: 39000139 PMCID: PMC11241606 DOI: 10.3390/ijms25137029] [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: 05/08/2024] [Revised: 06/13/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Epinephrine influences the function of pancreatic β-cells, primarily through the α2A-adrenergic receptor (α2A-AR) on their plasma membrane. Previous studies indicate that epinephrine transiently suppresses insulin secretion, whereas prolonged exposure induces its compensatory secretion. Nonetheless, the impact of epinephrine-induced α2A-AR signaling on the survival and function of pancreatic β-cells, particularly the impact of reprogramming after their removal from sustained epinephrine stimulation, remains elusive. In the present study, we applied MIN6, a murine insulinoma cell line, with 3 days of high concentration epinephrine incubation and 2 days of standard incubation, explored cell function and activity, and analyzed relevant regulatory pathways. The results showed that chronic epinephrine incubation led to the desensitization of α2A-AR and enhanced insulin secretion. An increased number of docked insulin granules and impaired Syntaxin-2 was found after chronic epinephrine exposure. Growth curve and cell cycle analyses showed the inhibition of cell proliferation. Transcriptome analysis showed the occurrence of endoplasmic reticulum stress (ER stress) and oxidative stress, such as the presence of BiP, CHOP, IRE1, ATF4, and XBP, affecting cellular endoplasmic reticulum function and survival, along with UCP2, OPA1, PINK, and PRKN, associated with mitochondrial dysfunction. Consequently, we conclude that chronic exposure to epinephrine induces α2A-AR desensitization and leads to ER and oxidative stress, impairing protein processing and mitochondrial function, leading to modified pancreatic β-cell secretory function and cell fate.
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Affiliation(s)
- Ran Zhang
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Bingpeng Yao
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Rui Li
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Sean W Limesand
- School of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, AZ 85721, USA
| | - Yongju Zhao
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Xiaochuan Chen
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
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Diane A, Allouch A, Mu-U-Min RBA, Al-Siddiqi HH. Endoplasmic reticulum stress in pancreatic β-cell dysfunctionality and diabetes mellitus: a promising target for generation of functional hPSC-derived β-cells in vitro. Front Endocrinol (Lausanne) 2024; 15:1386471. [PMID: 38966213 PMCID: PMC11222326 DOI: 10.3389/fendo.2024.1386471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 06/10/2024] [Indexed: 07/06/2024] Open
Abstract
Diabetes mellitus (DM), is a chronic disorder characterized by impaired glucose homeostasis that results from the loss or dysfunction of pancreatic β-cells leading to type 1 diabetes (T1DM) and type 2 diabetes (T2DM), respectively. Pancreatic β-cells rely to a great degree on their endoplasmic reticulum (ER) to overcome the increased secretary need for insulin biosynthesis and secretion in response to nutrient demand to maintain glucose homeostasis in the body. As a result, β-cells are potentially under ER stress following nutrient levels rise in the circulation for a proper pro-insulin folding mediated by the unfolded protein response (UPR), underscoring the importance of this process to maintain ER homeostasis for normal β-cell function. However, excessive or prolonged increased influx of nascent proinsulin into the ER lumen can exceed the ER capacity leading to pancreatic β-cells ER stress and subsequently to β-cell dysfunction. In mammalian cells, such as β-cells, the ER stress response is primarily regulated by three canonical ER-resident transmembrane proteins: ATF6, IRE1, and PERK/PEK. Each of these proteins generates a transcription factor (ATF4, XBP1s, and ATF6, respectively), which in turn activates the transcription of ER stress-inducible genes. An increasing number of evidence suggests that unresolved or dysregulated ER stress signaling pathways play a pivotal role in β-cell failure leading to insulin secretion defect and diabetes. In this article we first highlight and summarize recent insights on the role of ER stress and its associated signaling mechanisms on β-cell function and diabetes and second how the ER stress pathways could be targeted in vitro during direct differentiation protocols for generation of hPSC-derived pancreatic β-cells to faithfully phenocopy all features of bona fide human β-cells for diabetes therapy or drug screening.
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Affiliation(s)
- Abdoulaye Diane
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
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49
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Tao Y, Yi X, Gu Y, Yang R, Li Z, Guo X, Zhao D, Zhang Y. Neurotoxicity of dibutyl phthalate in zebrafish larvae: Decreased energy acquisition by neurons. Food Chem Toxicol 2024; 188:114666. [PMID: 38621509 DOI: 10.1016/j.fct.2024.114666] [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: 12/24/2023] [Revised: 01/26/2024] [Accepted: 04/12/2024] [Indexed: 04/17/2024]
Abstract
This work was designed to investigate the neurotoxic effects of the typical plasticizer dibutyl phthalate (DBP) using zebrafish larvae as a model. The results of exhibited that zebrafish larvae exposed to DBP at concentrations of 5 μg/L and 10 μg/L exhibited brain malformations (24 h) and behavioral abnormalities (72 h). After 72 h of exposure to DBP, microglia in the brain were over-activated, reactive oxygen species (ROS) formation was increased, and apoptosis was observed. Meanwhile, it was found that neurons exhibited impaired mitochondrial structure, absent mitochondrial membrane potential and up-regulated autophagy. Further comprehensive biochemical analyses and RNA-Seq, validated by RT-qPCR, glutamate metabolism and PPAR signaling pathway were significantly enriched in the DBP stress group, this may be the main reason for the disruption of glycolysis/gluconeogenesis processes and the reduction of energy substrates for the astrocyte-neuron lactate shuttle (ANLS). In addition, the DBP-exposed group showed aberrant activation of endoplasmic reticulum (ER) stress signaling pathway, which may be related to ROS as well as neuronal apoptosis and autophagy. In conclusion, DBP-induced neurotoxicity may be the combined result of insufficient neuronal energy acquisition, damage to mitochondrial structure, apoptosis and autophagy. These results provide a theoretical basis for understanding the neurotoxic effects of DBP.
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Affiliation(s)
- Yue Tao
- School of Resources and Environment, Northeast Agricultural University, Harbin, 150030, China
| | - Xiaodong Yi
- School of Resources and Environment, Northeast Agricultural University, Harbin, 150030, China
| | - Yanyan Gu
- School of Resources and Environment, Northeast Agricultural University, Harbin, 150030, China
| | - Rongyi Yang
- School of Resources and Environment, Northeast Agricultural University, Harbin, 150030, China
| | - Zixu Li
- School of Resources and Environment, Northeast Agricultural University, Harbin, 150030, China
| | - Xiangyong Guo
- Fuyu County Agricultural Technology Extension Center, Qiqihar, 161299, China
| | - Donglin Zhao
- School of Resources and Environment, Northeast Agricultural University, Harbin, 150030, China
| | - Ying Zhang
- School of Resources and Environment, Northeast Agricultural University, Harbin, 150030, China.
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Hemagirri M, Chen Y, Gopinath SCB, Sahreen S, Adnan M, Sasidharan S. Crosstalk between protein misfolding and endoplasmic reticulum stress during ageing and their role in age-related disorders. Biochimie 2024; 221:159-181. [PMID: 37918463 DOI: 10.1016/j.biochi.2023.10.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
Maintaining the proteome is crucial to retaining cell functionality and response to multiple intrinsic and extrinsic stressors. Protein misfolding increased the endoplasmic reticulum (ER) stress and activated the adaptive unfolded protein response (UPR) to restore cell homeostasis. Apoptosis occurs when ER stress is prolonged or the adaptive response fails. In healthy young cells, the ratio of protein folding machinery to quantities of misfolded proteins is balanced under normal circumstances. However, the age-related deterioration of the complex systems for handling protein misfolding is accompanied by ageing-related disruption of protein homeostasis, which results in the build-up of misfolded and aggregated proteins. This ultimately results in decreased cell viability and forms the basis of common age-related diseases called protein misfolding diseases. Proteins or protein fragments convert from their ordinarily soluble forms to insoluble fibrils or plaques in many of these disorders, which build up in various organs such as the liver, brain, or spleen. Alzheimer's, Parkinson's, type II diabetes, and cancer are diseases in this group commonly manifest in later life. Thus, protein misfolding and its prevention by chaperones and different degradation paths are becoming understood from molecular perspectives. Proteodynamics information will likely affect future interventional techniques to combat cellular stress and support healthy ageing by avoiding and treating protein conformational disorders. This review provides an overview of the diverse proteostasis machinery, protein misfolding, and ER stress involvement, which activates the UPR sensors. Here, we will discuss the crosstalk between protein misfolding and ER stress and their role in developing age-related diseases.
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Affiliation(s)
- Manisekaran Hemagirri
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Yeng Chen
- Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Subash C B Gopinath
- Faculty of Chemical Engineering and Technology, Universiti Malaysia Perlis, Arau, 02600, Malaysia
| | - Sumaira Sahreen
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Mohd Adnan
- Department of Biology, College of Science, University of Ha'il, Ha'il, P. O. Box 2440, Saudi Arabia.
| | - Sreenivasan Sasidharan
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia.
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