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Aksu M, Kaschke K, Podojil JR, Chiang M, Steckler I, Bruce K, Cogswell AC, Schulz G, Kelly J, Wiseman RL, Miller S, Popko B, Chen Y. AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss. Glia 2025; 73:1241-1257. [PMID: 39928347 PMCID: PMC12014361 DOI: 10.1002/glia.70001] [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: 07/25/2024] [Revised: 01/05/2025] [Accepted: 01/28/2025] [Indexed: 02/11/2025]
Abstract
Inflammation-induced oligodendrocyte death and CNS demyelination are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions of Grp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels of Grp78 as well as Ho-1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.
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Affiliation(s)
- Metin Aksu
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Kevin Kaschke
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Joseph R. Podojil
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - MingYi Chiang
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - Ian Steckler
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Kody Bruce
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Andrew C. Cogswell
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - Gwen Schulz
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Jeffery Kelly
- The Scripps Research Institute, Department of Chemistry, La Jolla, CA 92037, USA
| | - R. Luke Wiseman
- The Scripps Research Institute, Department of Molecular and Cellular Biology, La Jolla, CA 92037, USA
| | - Stephen Miller
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - Brian Popko
- Northwestern University, Department of Neurology, Chicago, IL 60611, USA
| | - Yanan Chen
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
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Giroud J, Combémorel E, Pourtier A, Abbadie C, Pluquet O. Unraveling the functional and molecular interplay between cellular senescence and the unfolded protein response. Am J Physiol Cell Physiol 2025; 328:C1764-C1782. [PMID: 40257464 DOI: 10.1152/ajpcell.00091.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/12/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025]
Abstract
Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.
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Affiliation(s)
- Joëlle Giroud
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Emilie Combémorel
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Albin Pourtier
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Corinne Abbadie
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Olivier Pluquet
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
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3
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Zhang K, Yang K, Zeng L, Xiao Y, Yu J. Rab32 protects mitochondrial function by anchoring Fancd2 and mediates the protective effect of penehyclidine hydrochloride against myocardial ischemia-reperfusion injury. Int Immunopharmacol 2025; 156:114697. [PMID: 40286784 DOI: 10.1016/j.intimp.2025.114697] [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: 12/02/2024] [Revised: 03/14/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025]
Abstract
Myocardial cell injury resulting from myocardial ischemia and reperfusion is one of the primary drivers behind the onset and progression of heart disease. Penehyclidine hydrochloride (PHC), a novel selective anti-cholinergic agent, exerts a protective effect against myocardial ischemia-reperfusion injury (MIRI). Rab32 belongs to the family of small GTPase proteins. The present study aimed to investigate whether PHC improved MIRI by regulating Rab32 and to explore the underlying mechanisms. Oxygen-glucose deprivation/reoxygenation (OGD/R) and left anterior descending coronary artery ligation were used to establish MIRI models in vitro and in vivo. Here, we showed that PHC upregulated the expression of Rab32 in OGD/R treated HL-1 cells. PHC alleviated OGD/R-induced cell apoptosis and intracellular and mitochondrial ROS levels, while the downregulation of Rab32 exacerbated cell injury. Rab32 was upregulated in MIRI mice and downregulated in OGD/R-induced HL-1 cells. Rab32 overexpression improved cardiac function, reduced the myocardial infarct size, and inhibited cell apoptosis and mitochondrial dysfunction, either in MIRI mice or OGD/R-induced HL-1 cells. On the mechanism, Rab32 interacted with Fancd2 in HL-1 cells. Rab32 downregulation decreased Fancd2 protein expression in mitochondria. Rab32 anchored Fancd2 to mitochondria in OGD/R treated HL-1 cells. Fancd2 knockdown reversed the protective effect of Rab32 on OGD/R-induced HL-1 cells and aggravated cardiomyocyte injury. Finally, the protective role of PHC on MIRI-caused cardiomyocyte injury was confirmed in MIRI mice. Overall, we demonstrated that Rab32 protects mitochondrial function by anchoring Fancd2 and mediates the protective effect of PHC against MIRI.
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Affiliation(s)
- Kun Zhang
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China; Department of Anesthesiology, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, PR China
| | - Kehui Yang
- Department of Anesthesiology, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, PR China
| | - Lingyuan Zeng
- Department of Anesthesiology, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, PR China
| | - Yang Xiao
- Department of Anesthesiology, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, PR China
| | - JinGui Yu
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
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Guan Y, Li L, Yang R, Lu Y, Tang J. Targeting mitochondria with natural polyphenols for treating Neurodegenerative Diseases: a comprehensive scoping review from oxidative stress perspective. J Transl Med 2025; 23:572. [PMID: 40410831 PMCID: PMC12100838 DOI: 10.1186/s12967-025-06605-0] [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: 02/05/2025] [Accepted: 05/12/2025] [Indexed: 05/25/2025] Open
Abstract
Neurodegenerative diseases are a class of conditions with widespread detrimental impacts, currently lacking effective therapeutic drugs. Recent studies have identified mitochondrial dysfunction and the resultant oxidative stress as crucial contributors to the pathogenesis of neurodegenerative diseases. Polyphenols, naturally occurring compounds with inherent antioxidant properties, have demonstrated the potential to target mitochondria and mitigate oxidative stress. This therapeutic potential has garnered significant attention in recent years. Investigating the mitochondrial targeting capacity of polyphenols, their role in functional regulation, and their ability to modulate oxidative stress, along with exploring novel technologies and strategies for modifying polyphenol compounds and their formulations, holds promise for providing new avenues for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Yueyue Guan
- Department of Encephalopathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
| | - Lei Li
- Department of Anorectal Surgery, Hospital of Chengdu University of Traditional Chinese Medicine and Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Rui Yang
- Department of Encephalopathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
| | - Yun Lu
- Department of Emergency Medicine, Hospital of Chengdu University of Traditional Chinese Medicine and Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Jun Tang
- Department of Encephalopathy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
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Liu Y, Zheng J, Zhong L, Wang Z, Zhao D, Lin H, Zhang X, Meng K, Yang X, Zhang D, Lin L, Qiao L. Vessel-On-A-Chip Coupled Proteomics Reveal Pressure-Overload-Induced Vascular Remodeling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2415024. [PMID: 40126137 PMCID: PMC12097099 DOI: 10.1002/advs.202415024] [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] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 03/01/2025] [Indexed: 03/25/2025]
Abstract
Hypertension, the leading cause of cardiovascular disease and premature mortality, is characterized by increased vessel stretch and alterations in vascular smooth muscle cells (VSMCs). In this study, a vessel-on-a-chip model is developed to simulate both physiological and pathological stretch conditions alongside a mouse model of hypertension. Proteomics analysis is applied to investigate changes in VSMCs using the vessel-on-a-chip system and compared these findings with data from the mouse model. The results demonstrates that physiological stretch enhances the expression of contractile markers in VSMCs. Additionally, the chip effectively replicates cellular responses to pathological stretch and stress, including the upregulation of ERK signaling, calcium ion transport pathway, integrin signaling pathway, endoplasmic reticulum stress, toll-like receptor activation, oxidative stress, and synthesis of sphingolipids and ceramides. These findings indicate that the vessel chip successfully mimics in vivo biological events associated with hypertension. The vessel-on-a-chip system holds promise for advancing the study of vessel-related diseases and facilitating the development of novel hypertension therapeutics.
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Affiliation(s)
- Yanjun Liu
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Jianxujie Zheng
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Lingyan Zhong
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Zengyu Wang
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Dan Zhao
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Hong Lin
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Xiaoxue Zhang
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Ke Meng
- Department of NeurosurgeryZhongshan Hospital (Xiamen)Fudan UniversityXiamenFujian361015China
| | - Xiaoxia Yang
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Dongxue Zhang
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Ling Lin
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
| | - Liang Qiao
- Department of ChemistryZhongshan HospitalFudan UniversityShanghai200000China
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6
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Cruz-Rodríguez M, Chevet E, Muñoz-Pinedo C. Glucose sensing and the unfolded protein response. FEBS J 2025. [PMID: 40272086 DOI: 10.1111/febs.70113] [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: 01/07/2025] [Revised: 03/17/2025] [Accepted: 04/14/2025] [Indexed: 04/25/2025]
Abstract
The unfolded protein response (UPR) is activated primarily upon alteration of protein folding in the endoplasmic reticulum (ER). This occurs under physiological situations that cause an abrupt increase in protein synthesis, or under redox and metabolic stresses. Among the latter, hyperglycemia and glucose scarcity have been identified as major modulators of UPR signaling. Indeed, the first mammalian UPR effector, the glucose-regulated protein 78, also known as BiP, was identified in response to glucose deprivation. Tunicamycin, arguably the most commonly used drug to induce ER stress responses in vitro and in vivo, is an inhibitor of N-glycosylation. We compile here evidence that the UPR is activated upon physiological and pathological conditions that alter glucose levels and that this is mostly mediated by alterations of protein N-glycosylation, ATP levels, or redox balance. The three branches of the UPR transduced by PERK/ATF4, IRE1/XBP1s, and ATF6, as well as non-canonical ER sensors such as SCAP/SREBP, sense ER protein glycosylation status driven by glucose and other glucose-derived metabolites. The outcomes of UPR activation range from restoring protein N-glycosylation and protein folding flux to stimulating autophagy, organelle recycling, and mitochondrial respiration, and in some cases, cell death. Anabolic responses to glucose levels are also stimulated by glucose through components of the UPR. Therefore, the UPR should be further studied as a potential biomarker and mediator of glucose-associated diseases.
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Affiliation(s)
- Mabel Cruz-Rodríguez
- Preclinical and Experimental Research in Thoracic Tumors (PRETT) Group, IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Eric Chevet
- INSERM U1242, Univ Rennes, Centre de Lutte contre le Cancer Eugène Marquis, France
| | - Cristina Muñoz-Pinedo
- Preclinical and Experimental Research in Thoracic Tumors (PRETT) Group, IDIBELL, L'Hospitalet de Llobregat, Spain
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7
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Yu X, Dang L, Dhar A, Zhang R, Xu F, Spasojevic I, Sheng H, Yang W. Activation of ATF6 Signaling Confers Long-Term Beneficial Effects in Young and Aged Mice After Permanent Stroke. Transl Stroke Res 2025:10.1007/s12975-025-01351-3. [PMID: 40259100 DOI: 10.1007/s12975-025-01351-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/29/2025] [Accepted: 04/14/2025] [Indexed: 04/23/2025]
Abstract
Ischemic stroke disrupts protein homeostasis in brain cells, causes endoplasmic reticulum (ER) stress, and consequently activates the unfolded protein response (UPR). The primary function of UPR activation is to help cells restore ER function, thereby promoting cell survival. A major adaptive UPR branch is mediated by activating transcription factor 6 (ATF6). We previously provided experimental evidence that activation of ATF6 signaling in neurons improves short-term outcome after both transient and permanent stroke. However, the effect of ATF6 activation in astrocytes on stroke outcome remains undetermined, and critically, the long-term therapeutic potential of targeting this UPR branch in permanent stroke has not been evaluated. The current study aimed to address these two critical unknowns. First, using conditional knock-in mice in which functional short-form ATF6 (sATF6) is specifically expressed in astrocytes, we demonstrated that astrocytic ATF6 activation modestly improved outcome after permanent stroke. Then, our pharmacokinetic analysis indicated that compound AA147, an ATF6-specific activator, can cross the blood-brain barrier. Lastly, we found that post-stroke treatment with AA147 had no significant beneficial effect on short-term outcome, but improved long-term functional recovery in both young and aged mice after permanent stroke. Together with previous findings, our data support the notion that the ATF6 pathway is a promising target for stroke therapy.
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Affiliation(s)
- Xinyuan Yu
- Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Lihong Dang
- Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Ashis Dhar
- Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Ran Zhang
- Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Feng Xu
- Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Ivan Spasojevic
- Department of Medicine - Oncology, Duke University Medical Center, Durham, NC, USA
- PK/PD Core Laboratory, Duke Cancer Institute, Duke School of Medicine, Durham, NC, USA
| | - Huaxin Sheng
- Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Wei Yang
- Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
- Department of Neurology, Duke University Medical Center, Durham, NC, USA.
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8
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Wang H, Yang X, Deng L, Zhou X, Tao J, Wu Z, Chen H. ATF6α inhibits ΔNp63α expression to promote breast cancer metastasis by the GRP78-AKT1-FOXO3a signaling. Cell Death Dis 2025; 16:289. [PMID: 40223122 PMCID: PMC11994819 DOI: 10.1038/s41419-025-07619-8] [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: 11/14/2024] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Endoplasmic reticulum (ER) stress is increasingly recognized as a driver of cancer progression; however, the precise molecular mechanisms by which ER stress facilitates tumor metastasis remain incompletely understood. In this study, we demonstrate that ER stress-activated ATF6α promotes breast cancer cell migration and metastasis by downregulating the expression of ΔNp63α, a key metastasis suppressor. Mechanistically, ATF6α reduces ΔNp63α expression through GRP78, which interacts with and activates AKT1. Activated AKT1 subsequently phosphorylates FOXO3a, leading to its degradation. Since FOXO3a directly transactivates ΔNp63α expression, its degradation results in reduced ΔNp63α levels. Furthermore, pharmacological inhibition or genetic knockdown of AKT1 upregulates ΔNp63α in vitro and suppresses tumor metastasis in vivo. Clinical analyses reveal that TP63 and FOXO3a expression are significantly reduced in breast cancer tissues compared to normal tissues, whereas ATF6 and GRP78 expression are elevated. Moreover, low TP63 and high GRP78 expression are associated with a poor prognosis in breast cancer patients. Collectively, these findings elucidate the pivotal role of the ATF6α-GRP78-AKT1-FOXO3a axis in chronic ER stress-mediated downregulation of ΔNp63α, establishing a molecular framework for targeting this pathway as a potential therapeutic strategy against breast cancer metastasis.
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Affiliation(s)
- Hong Wang
- Department of Cardiothoracic Surgery, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xin Yang
- Department of Pediatrics, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Liyuan Deng
- Department of Cardiothoracic Surgery, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xuanyu Zhou
- Department of Cardiothoracic Surgery, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jin Tao
- Department of Cardiothoracic Surgery, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Zhiqiang Wu
- Department of Cardiothoracic Surgery, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
| | - Hu Chen
- Department of Cardiothoracic Surgery, School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
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Li H, Xiao F, Zhou C, Zhu T, Wang S. Metabolic Adaptations and Therapies in Cardiac Hypoxia: Mechanisms and Clinical Implications/ Potential Strategies. JACC Basic Transl Sci 2025:S2452-302X(24)00458-3. [PMID: 40265246 DOI: 10.1016/j.jacbts.2024.12.008] [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: 09/10/2024] [Revised: 12/06/2024] [Accepted: 12/11/2024] [Indexed: 04/24/2025]
Abstract
Cardiac hypoxia triggers a cascade of responses and functional changes in myocardial and non-myocardial cells, profoundly affecting cellular metabolism, oxygen-sensing mechanisms, and immune responses. Myocardial cells, being the primary cell type in cardiac tissue, undergo significant alterations in energy metabolism, including glycolysis, fatty acid metabolism, ketone body utilization, and branched-chain amino acid metabolism, to maintain cardiac function under hypoxic conditions. Non-myocardial cells, such as fibroblasts, endothelial cells, and immune cells, although fewer in number, play crucial roles in regulating cardiac homeostasis, maintaining structural integrity, and responding to injury. This review discusses the metabolic reprogramming of immune cells, particularly macrophages, during ischemia-reperfusion injury and explores various therapeutic strategies that modulate these metabolic pathways to protect the heart during hypoxia. Understanding these interactions provides valuable insights and potential therapeutic targets for heart disease treatment.
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Affiliation(s)
- Huili Li
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; Emergency Department, The State Key Laboratory for Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Fei Xiao
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Chenghui Zhou
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China; Research Unit for Perioperative Stress Assessment and Clinical Decision, Chinese Academy of Medical Sciences (2018RU012, West China Hospital, Sichuan University, Chengdu, China.
| | - Sheng Wang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; Linzhi People's Hospital, Linzhi, Tibet, China.
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10
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Jin Z, Xu H, Zhao W, Zhang K, Wu S, Shu C, Zhu L, Wang Y, Wang L, Zhang H, Yan B. Macrophage ATF6 accelerates corticotomy-assisted orthodontic tooth movement through promoting Tnfα transcription. Int J Oral Sci 2025; 17:28. [PMID: 40164575 PMCID: PMC11958779 DOI: 10.1038/s41368-025-00359-7] [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: 08/29/2024] [Revised: 02/15/2025] [Accepted: 02/26/2025] [Indexed: 04/02/2025] Open
Abstract
Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon (RAP). Despite its therapeutic effects, the surgical risk and unclear mechanism hamper the clinical application. Numerous evidences support macrophages as the key immune cells during bone remodeling. Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2; R26GFP lineage tracing system. Fluorescence staining, flow cytometry analysis, and western blot determined the significantly enhanced expression of binding immunoglobulin protein (BiP) and emphasized the activation of sensor activating transcription factor 6 (ATF6) in macrophages. Then, we verified that macrophage specific ATF6 deletion (ATF6f/f; CX3CR1CreERT2 mice) decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy. In contrast, macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement. In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6. At the mechanism level, RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfα promotor and augmenting its transcription. Additionally, molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element (ERSE). Taken together, ATF6 may aggravate orthodontic bone remodeling by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
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Affiliation(s)
- Zhichun Jin
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Hao Xu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Weiye Zhao
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Kejia Zhang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Shengnan Wu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Chuanjun Shu
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Linlin Zhu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Yan Wang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Lin Wang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
| | - Hanwen Zhang
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
| | - Bin Yan
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
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11
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Zi C, Wei Y, Zhu Y, Fan J. RGS12 is a target of penehyclidine hydrochloride that enhances oxidative stress and ferroptosis in a model of myocardial ischemia/reperfusion injury by inhibiting the Nrf2 pathway. Int J Mol Med 2025; 55:52. [PMID: 39930821 PMCID: PMC11781519 DOI: 10.3892/ijmm.2025.5493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 12/13/2024] [Indexed: 02/14/2025] Open
Abstract
Regulator of G‑protein signaling 12 (RGS12) is a regulatory factor that is involved in various physiological processes. However, the role of RGS12 in myocardial ischemia/reperfusion injury (MIRI) currently remains unclear. The present study established a mouse model of MIRI by ligating the left main coronary artery followed by reperfusion. In addition, mouse HL‑1 cells were cultured in a hypoxic and serum‑free medium, followed by reoxygenation to establish an in vitro cell model of hypoxia/reoxygenation (H/R). Adenoviruses targeting RGS12 were subsequently used to either overexpress or silence RGS12 expression. RGS12 was highly expressed in both the myocardial tissues of mice with MIRI and HL‑1 cells subjected to H/R. The results from the in vitro experiments demonstrated that the knockdown of RGS12 reduced oxidative stress under a pathological environment, as indicated by decreased reactive oxygen species (ROS) levels and malondialdehyde activity and increased activities of superoxide dismutase and catalase. Furthermore, mice with MIRI and HL‑1 cells that underwent H/R stimulation exhibited increased ferroptosis, whereas RGS12 knockdown reversed these changes. These results showed that post‑RGS12 silencing the levels of Fe2+ and lipid ROS were decreased, the expression levels of glutathione peroxidase 4 and cystine transporter solute carrier family 7 member 11 were increased and mitochondrial structure was improved by preventing the loss of the mitochondrial crest. Mechanistically, the nuclear factor erythroid 2‑related factor 2 (Nrf2) pathway with anti‑ferroptosis and anti‑oxidative stress capacities was activated by RGS12 knockdown. Conversely, RGS12 overexpression exerted the opposite effects both in vivo and in vitro. Notably, it was demonstrated that penehyclidine hydrochloride (PHC), known to block the MIRI process, decreased RGS12 expression levels both in vivo and in vitro, and RGS12 overexpression inhibited the therapeutic effects of PHC on MIRI. In conclusion, the present study demonstrated that RGS12, a target of PHC, potentially enhanced the progression of MIRI by promoting oxidative stress and ferroptosis, and this effect may involve the regulation of the Nrf2 pathway.
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Affiliation(s)
- Congna Zi
- Department of Anesthesiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075000, P.R. China
| | - Yulei Wei
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075000, P.R. China Received June 26, 2024; Accepted December 13, 2024
| | - Ying Zhu
- Department of Anesthesiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075000, P.R. China
| | - Juan Fan
- Department of Anesthesiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075000, P.R. China
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12
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Lucas D, Sarkar T, Niemeyer CY, Harnoss JC, Schneider M, Strowitzki MJ, Harnoss JM. IRE1 is a promising therapeutic target in pancreatic cancer. Am J Physiol Cell Physiol 2025; 328:C806-C824. [PMID: 39819023 DOI: 10.1152/ajpcell.00551.2024] [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: 07/31/2024] [Revised: 08/13/2024] [Accepted: 01/14/2025] [Indexed: 01/19/2025]
Abstract
[Figure: see text].
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Affiliation(s)
- Denise Lucas
- Department of General, Visceral, and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Tamal Sarkar
- Department of General, Visceral, Thoracic, and Transplant Surgery, University Hospital Giessen, Giessen, Germany
| | - Clara Y Niemeyer
- Department of General, Visceral, and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Julian C Harnoss
- Department of General, Visceral, and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral, Thoracic, and Transplant Surgery, University Hospital Giessen, Giessen, Germany
| | - Moritz J Strowitzki
- Department of General, Visceral, Thoracic, and Transplant Surgery, University Hospital Giessen, Giessen, Germany
| | - Jonathan M Harnoss
- Department of General, Visceral, and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany
- Department of General, Visceral, Thoracic, and Transplant Surgery, University Hospital Giessen, Giessen, Germany
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13
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Zhou X, Li Z, Ren F, Deng H, Wen J, Xiang Q, Zhou Z, Yang X, Rao C. Endoplasmic reticulum stress and unfolded protein response in renal lipid metabolism. Exp Cell Res 2025; 446:114463. [PMID: 39971174 DOI: 10.1016/j.yexcr.2025.114463] [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: 12/15/2024] [Revised: 02/06/2025] [Accepted: 02/16/2025] [Indexed: 02/21/2025]
Abstract
The endoplasmic reticulum (ER) is a crucial cellular organelle involved in protein synthesis, folding, modification, and transport. Exposure to internal and external stressors can induce endoplasmic reticulum stress (ERS), leading to abnormal protein folding and ER malfunction. This stress can disrupt lipid synthesis, metabolism, and transport processes. Fatty acid oxidation is the primary energy source for the renal system. When energy intake exceeds the storage capacity of adipose tissue, lipids accumulate abnormally in non-adipose tissues, including kidneys, liver, and pancreas. Lipids accumulate in the kidneys of nearly all cell types, including thylakoid membranous, pedunculated, and proximal renal tubular epithelial cells. Intracellular free fatty acids can significantly disrupt renal lipid metabolism, contributing to ischemia-reperfusion acute kidney injury, diabetic nephropathy, renal fibrosis, and lupus nephritis. Consequently, this study delineated the primary signaling pathways and mechanisms of the ERS-induced unfolded protein response, explored the mechanistic link between ERS and lipid metabolism, and elucidated its role in renal lipid metabolism. This study aimed to offer new perspectives on managing and treating renal disorders.
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Affiliation(s)
- Xinyi Zhou
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Ziyi Li
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Fajian Ren
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Hua Deng
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Jiayu Wen
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Qiwen Xiang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Zhihui Zhou
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Xiyun Yang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Chaolong Rao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China.
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14
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Fonseka O, Gare SR, Chen X, Zhang J, Alatawi NH, Ross C, Liu W. Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential. Cells 2025; 14:324. [PMID: 40072053 PMCID: PMC11899429 DOI: 10.3390/cells14050324] [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: 01/15/2025] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 03/15/2025] Open
Abstract
Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.
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Affiliation(s)
| | | | | | | | | | | | - Wei Liu
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK; (O.F.); (S.R.G.); (X.C.); (J.Z.); (N.H.A.)
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15
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Zhang Z, Yu X, Li J, Shen X, Fu W, Liu Y, Dong X, Wang Z. Irisin Mitigates Doxorubicin-Induced Cardiotoxicity by Reducing Oxidative Stress and Inflammation via Modulation of the PERK-eIF2α-ATF4 Pathway. Drug Des Devel Ther 2025; 19:1067-1081. [PMID: 39974610 PMCID: PMC11837746 DOI: 10.2147/dddt.s492691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 01/24/2025] [Indexed: 02/21/2025] Open
Abstract
Purpose Doxorubicin (DOX), an anthracycline antibiotic, has limited clinical use due to its pronounced cardiotoxicity. Irisin, a myokine known for its metabolic regulation, has shown therapeutic effects on cardiovascular disease. This study investigates the potential cardioprotective function of irisin in reducing the cardiac injury induced by DOX. Methods In vitro, H9c2 cells were pretreated with irisin (20 nM) for 24 hours before exposure to DOX (1 μM). In vivo, C57BL/6 mice were administered DOX (5 mg/kg/week, i.p.) for 4 weeks, reaching a cumulative dose of 20 mg/kg. Irisin (1 mg/kg/ 3 days, i.p.) was administered to the mice both 7 days prior to and during DOX injection.Cardiac function was evaluated by echocardiography, and cardiac histology was assessed using HE, WGA, and Masson staining. Myocardial injury markers were quantified using ELISA, and apoptosis was analyzed via TUNEL staining. Oxidative stress was determined by measuring antioxidase activity, MDA and GSH levels, and DHE staining, while mitochondrial superoxide production was assessed using MitoSOX Red. Mitochondrial morphology and function evaluated using transmission electron microscopy and Seahorse analysis, respectively Inflammatory cytokines were quantified in serum and cell supernatants. The role of the PERK-eIF2α-ATF4 pathway mediated by irisin was investigated by Western blot. Using adeno-associated virus serotype-9 carrying mouse FNDC5 shRNA (AAV9-shFNDC5) further validated the protective role of irisin in DOX-induced myocardial injury. Results Irisin reduced DOX-induced cardiac dysfunction and fibrosis. Moreover, irisin mitigated oxidative stress and inflammation through inhibiting the PERK-eIF2α-ATF4 pathway activated by DOX, thus preserving mitochondrial function. While cardiac FNDC5 knockdown exacerbated DOX-induced heart injury and PERK-eIF2α-ATF4 activation, which was partially reversed by irisin. Conclusion Irisin mitigates oxidative stress and inflammation by modulating the PERK-eIF2α-ATF4 pathway, highlighting its potential as a prospective approach for combating DOX-induced cardiotoxicity.
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Affiliation(s)
- Zilong Zhang
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
| | - Xiaolin Yu
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
| | - Jie Li
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
| | - Xin Shen
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
| | - Wenbo Fu
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
| | - Yongguo Liu
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
| | - Xiangyu Dong
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
| | - Zhao Wang
- Department of Cardiology, Cardiac and Pan - Vascular Medicine Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang, People’s Republic of China
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16
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Zhu D, Guo J, Deng X, Li M, Wang Y, Wang Z, Sun Z, Cao S, Zhao T, Xu Y, Liu L, Zhang H. Brucella abortus transcriptional regulator ArsR6 inhibits host pyroptosis via BAB_RS28760 by triggering the endoplasmic reticulum stress pathway. Int Immunopharmacol 2025; 147:114001. [PMID: 39787758 DOI: 10.1016/j.intimp.2024.114001] [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: 10/24/2024] [Revised: 12/15/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
Pyroptosis, which is accompanied by inflammatory responses, is critical for pathogen clearance. However, the mechanism through which Brucella evades host pyroptosis remains unclear. The transcriptional regulator ArsR6 maintains bacterial intracellular homeostasis and possibly influences host cell death. However, whether ArsR6 acts on cellular pyroptosis is unknown. Therefore, we investigated pathogen-host interactions within macrophages infected with Brucella abortus (B. abortus), and found that ArsR6 is crucial for inhibiting host cell pyroptosis after B. abortus infection. The downstream target gene, BAB_RS28760 of ArsR6 was screened using chromatin immunoprecipitation sequencing. BAB_RS28760 belongs to the BA14K protein family and is strongly immunoreactive and induces humoral and cellular immune responses in the host during infection. Deleting ArsR6 in B. abortuspromotes pyroptosis and enhancs the intracellular survival of B. abortus. In addition, ArsR6 negatively regulated its target gene BAB_RS28760, whereas BAB_RS28760 deletion downregulated cellular pyroptosis by inhibiting endoplasmic reticulum stress and decreasing the intracellular survival of B. abortus. Our results reveal for the first time that Brucella ArsR6 reduces endoplasmic reticulum stress activation by negatively regulating its downstream target genes, thus inhibiting host cell pyroptosis. Our study provides new insights into the pathogenic mechanisms of Brucella, which can provide potential selectivity for the development of anti-Brucella therapies.
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Affiliation(s)
- Dexin Zhu
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Jia Guo
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Xingmei Deng
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Min Li
- Changji City Communist Youth League Committee, Changji, China.
| | - Yong Wang
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Zhen Wang
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Zhihua Sun
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Shuzhu Cao
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Tianyi Zhao
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Yimei Xu
- The Center for Disease Control and Prevention of Xinjiang Uygur Autonomous Region, Urumqi, China.
| | - Liangbo Liu
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
| | - Hui Zhang
- College of Animal Science and Technology, Shihezi University, Shihezi, China.
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17
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Lee EJ, Kim K, Diaz-Aguilar MS, Min H, Chavez E, Steinbergs KJ, Safarta LA, Zhang G, Ryan AF, Lin JH. Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome. J Clin Invest 2025; 135:e175562. [PMID: 39570676 PMCID: PMC11785932 DOI: 10.1172/jci175562] [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: 09/08/2023] [Accepted: 11/19/2024] [Indexed: 02/04/2025] Open
Abstract
Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR) and is important for ER function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia. The effect of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we report that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both sexes. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomics analysis of Atf6-/- cochleae revealed a marked induction of the UPR, especially through the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they support the idea that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Last, our genetic findings indicate that ER stress is an important pathomechanism underlying cochlear damage and hearing loss, with clinical implications for patient lifestyle modifications that minimize environmental and physiological sources of ER stress to the ear.
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Affiliation(s)
- Eun-Jin Lee
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Kyle Kim
- Departments of Pathology and
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Monica Sophia Diaz-Aguilar
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
- Rush University Medical College, Chicago, Illinois, USA
| | - Hyejung Min
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Eduardo Chavez
- Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA
| | - Korina J. Steinbergs
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
| | - Lance A. Safarta
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
| | - Guirong Zhang
- Departments of Pathology and
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Allen F. Ryan
- Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA
| | - Jonathan H. Lin
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
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18
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Chen S, Yang L, Xue J, Tian X, Hu H, Gao Q, Feng R, Hao L. Effect of estrogen on myocardial ischemia-reperfusion injury in male and female rats and related mechanism. Steroids 2025; 214:109561. [PMID: 39870188 DOI: 10.1016/j.steroids.2025.109561] [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: 12/12/2023] [Revised: 12/06/2024] [Accepted: 01/21/2025] [Indexed: 01/29/2025]
Abstract
Due to the difference of estrogen levels in different phases of estrous cycle, it is necessary to exclude the influence of endogenous estrogen when studying the cardiovascular effects of estrogen and its analogues. In this study, the ischemia/reperfusion (I/R) injury of isolated heart were investigated in female rats during different phases of estrous cycle with male rats as comparison. The results indicated that the estrogen content in blood of rats during metestrus and diestrus (MD) was lower than those during proestrus and estrous (PE). 17β-Estradiol (E2) at 10-8 M did not show significant effects on I/R injury in male rats and female rats during PE. However, E2 exerted an obviously protective effects against I/R injury on heart rate (HR), lactate dehydrogenase (LDH) and creatine kinase (CK) release in female rats during MD. Furthermore, E2 relieved I/R injury in female rats during MD by decreasing the infarct size and the expression level of p-CaMKII. The results suggested estrous cycles may influence on the extent of cardiac I/R injury due to the regulation of E2 on CaMKII expression level, providing an idea that the estrus cycle should be considered for animal model preparation and toxicity studies in estrogen and environmental hormone research.
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Affiliation(s)
- Sichong Chen
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Lijuan Yang
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Jiayao Xue
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Xinmiao Tian
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Huiyuan Hu
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Qinghua Gao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Rui Feng
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China.
| | - Liying Hao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China.
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19
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Yang P, Jin K, Yao Y, Jin L, Shao X, Li C, Lu X, Fan X. Spatial integration of multi-omics single-cell data with SIMO. Nat Commun 2025; 16:1265. [PMID: 39893194 PMCID: PMC11787318 DOI: 10.1038/s41467-025-56523-4] [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: 05/24/2024] [Accepted: 01/16/2025] [Indexed: 02/04/2025] Open
Abstract
Technical limitations in spatial and single-cell omics sequencing pose challenges for capturing and describing multimodal information at the spatial scale. To address this, we develop SIMO, a computational method designed for the Spatial Integration of Multi-Omics datasets through probabilistic alignment. Unlike previous tools, SIMO not only integrates spatial transcriptomics with single-cell RNA-seq but expands beyond, enabling integration across multiple single-cell modalities, such as chromatin accessibility and DNA methylation, which have not been co-profiled spatially before. We benchmark SIMO on simulated datasets, demonstrating its high accuracy and robustness. Further application on biological datasets reveals SIMO's ability to detect topological patterns of cells and their regulatory modes across multiple omics layers. Through comprehensive analysis of real-world data, SIMO uncovers multimodal spatial heterogeneity, offering deeper insights into the spatial organization and regulation of biological molecules. These findings position SIMO as a powerful tool for advancing spatial biology by revealing previously inaccessible multimodal insights.
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Affiliation(s)
- Penghui Yang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314103, China
| | - Kaiyu Jin
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yue Yao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Lijun Jin
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314103, China
| | - Xin Shao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314103, China
| | - Chengyu Li
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314103, China
| | - Xiaoyan Lu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314103, China.
| | - Xiaohui Fan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314103, China.
- The Joint-laboratory of clinical multi-omics research between Zhejiang University and Ningbo Municipal Hospital of TCM, Ningbo Municipal Hospital of TCM, Ningbo, 315012, China.
- College of Chemistry & Chemical Engineering, Shaoxing University, Shaoxing, PR China.
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20
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Fang Q, Yan Q, Liu X, Zhang X, Zha L, Zhang R, Gao Z, Du J, Chen L. Activated AXL Ameliorates Alcohol-associated Steatotic Liver Ischemia-Reperfusion Injury by Inhibiting ER stress and Mitochondria-associated Apoptosis. Int J Biol Sci 2025; 21:1294-1307. [PMID: 39897049 PMCID: PMC11781187 DOI: 10.7150/ijbs.103789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/31/2024] [Indexed: 02/04/2025] Open
Abstract
Hepatic ischemia-reperfusion (I/R) injury can cause poor prognosis of liver transplantation and hepatectomy, especially in patients with alcohol-associated liver disease (ALD). Apoptosis is closely related to different stages of liver injury, and the death of hepatocytes caused by endoplasmic reticulum (ER) and mitochondria homeostasis perturbation may be key to liver injury. The receptor tyrosine kinases AXL encoded by the gene axl, is a member of the TAM (TYRO3, AXL, and MERTK) family, which participates in various biological processes by binding to the ligand of growth arrest-specific protein 6 (Gas6). However, whether AXL is involved in apoptosis pathways, and the detailed mechanism in hepatic I/R injury remains unknown. In the present study, we found that total AXL is up-regulated while phosphorylated AXL (p-AXL, the active form of AXL) was down-regulated after I/R in human liver tissues from liver transplantation. Consistently, total AXL was found up-regulated while p-AXL was down-regulated during hepatic I/R injury in mice. Pretreatment with Gas6 increased p-AXL expression, reduced ER stress-associated cell apoptosis, alleviated liver damage, and restored ER and mitochondria ultrastructure during hepatic I/R in mice. Furthermore, the ALD model was established by chronic-plus-binge ethanol feeding to explore the role of AXL in I/R liver injury with ethanol-associated steatosis. We found that ALD mice had a lower p-AXL level and were more susceptible to hepatic I/R injury. Importantly, activated AXL ameliorated liver injury by inhibiting IRE1 and PERK pathway to reduce ER stress-associated apoptosis. In conclusion, activated AXL protects alcohol-associated steatotic liver against I/R injury by inhibiting ER stress and mitochondria-associated apoptosis, suggesting that targeting AXL serves as a potential strategy for liver I/R injury, particularly for marginal liver donors with alcohol-associated steatosis.
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Affiliation(s)
- Qi Fang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Qi Yan
- Department of Biochemistry and Molecular Biology, Research Center for Infectious Diseases, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Xingyun Liu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Xiaolu Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Lixia Zha
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Ruixin Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Zhixin Gao
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Jian Du
- Department of Biochemistry and Molecular Biology, Research Center for Infectious Diseases, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
- Provincial Key Laboratory of Zoonoses of High Institutions in Anhui, Anhui Medical University, Hefei 230032, China
| | - Lijian Chen
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
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21
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Zi C, Ma X, Zheng M, Zhu Y. VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via calmodulin/CaMKK2/AMPK pathway. Eur J Pharmacol 2025; 987:177158. [PMID: 39613175 DOI: 10.1016/j.ejphar.2024.177158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/05/2024] [Accepted: 11/27/2024] [Indexed: 12/01/2024]
Abstract
Myocardial injury triggers intense inflammatory reactions and oxidative stress responses. S100 calcium-binding protein A16 (S100A16), a multi-functional calcium (Ca2+)-binding protein, participates in inflammatory responses and contributes to ischemia/reperfusion (I/R) injury. Nevertheless, the precise mechanism by which S100A16 operates in myocardial I/R injury remains uncertain. Cardiac I/R injury was produced by ligation/release of the left anterior descending artery, and mouse cardiac cells were subjected to hypoxia/reoxygenation (H/R) to determine the biological effects in vitro. We demonstrated that S100A16 was upregulated in the ischemic hearts and cardiac cells after I/R and H/R injury. Adenovirus-mediated S100A16 inhibition led to a considerable improvement in cardiac function with a reduced infarct size, accompanied by a reduction in cardiomyocyte apoptosis. Similar effects of S100A16 inhibition on inflammation and reactive oxygen species (ROS) production were observed in cultured cardiomyocytes. Importantly, we showed that I/R and H/R treatment upregulated the expression of voltage-dependent anion channel 1 (VDAC1), which subsequently activated NF-κB/p65 to facilitate the binding of NF-κB/p65 to the S100A16 promoter, thereby activating the transcription and expression of S100A16. Mechanically, S100A16 responded to increasing Ca2+ and interacted with calmodulin (CaM) to regulate the activation of calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMPK pathway. In conclusion, VDAC1 sustained the NF-κB p65 pathway activation to elicit increased S100A16 expression, contributing to myocardial damage and heart failure post-I/R via the CaM/CaMKK2/AMPK pathway. This study revealed a crucial role of the VDAC1-S100A16 axis in the process of myocardial I/R injury, providing novel molecular targets for the treatment of cardiac conditions associated with I/R injury.
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Affiliation(s)
- Congna Zi
- Department of Anesthesiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China.
| | - Xian Ma
- Department of Blood Transfusion, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China.
| | - Maodong Zheng
- Department of Pharmacy, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China
| | - Ying Zhu
- Department of Anesthesiology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, China
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22
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Bassiouni W, Mahmud Z, Simmen T, Seubert JM, Schulz R. MMP-2 inhibition attenuates ER stress-mediated cell death during myocardial ischemia-reperfusion injury by preserving IRE1α. J Mol Cell Cardiol 2025; 198:74-88. [PMID: 39622369 DOI: 10.1016/j.yjmcc.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 09/23/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
Endoplasmic reticulum (ER) stress is one of the major events accompanying myocardial ischemia-reperfusion (IR) injury, as hypoxia and oxidative stress disrupt protein folding in the ER. As a result, the unfolded protein response (UPR) is activated through different sensors including inositol-requiring enzyme 1α (IRE1α) and protein kinase R-like ER kinase (PERK). Failure of the UPR to reduce ER stress induces cellular dysfunction. Matrix metalloproteinase-2 (MMP-2) is a ubiquitous protease that is activated intracellularly in response to oxidative stress and partially localizes near the ER. However, its role in ER homeostasis is unknown. We hypothesized that MMP-2 is involved in the regulation of the UPR and ER stress-mediated apoptosis during IR injury. Isolated mouse hearts subjected to IR injury showed impaired recovery of post-ischemic contractile function compared to aerobically perfused controls. Ventricular extracts from IR hearts had higher levels of glucose-regulated protein-78 and protein disulfide isomerase and lower levels of IRE1α and PERK compared to aerobic controls. MMP-2 inhibitors, ARP-100 or ONO-4817, given 10 min before ischemia, improved cardiac post-ischemic recovery and preserved IRE1α level in hearts subjected to 30 min ischemia/40 min reperfusion. IR also increased the levels of CHOP and mitochondrial Bax and caspase-3 and -9 activities, indicating induction of apoptosis, all of which were attenuated by MMP-2 inhibitors, regardless of the reperfusion time. Immunoprecipitation showed an association between MMP-2 and IRE1α in aerobic and IR hearts. During myocardial IR injury MMP-2 may impair the UPR and induce apoptosis by proteolysis of IRE1α. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in part by preserving IRE1α and preventing the progression to myocardial cell death.
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Affiliation(s)
- Wesam Bassiouni
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Alexandria University, Egypt
| | - Zabed Mahmud
- Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Thomas Simmen
- Department of Cell Biology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
| | - John M Seubert
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada; Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Richard Schulz
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
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23
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Kaniuka O, Deregowska A, Bandura Y, Sabadashka M, Chala D, Kulachkovskyi O, Kubis H, Adamczyk-Grochala J, Sybirna N. Upregulation of GRP78 is accompanied by decreased antioxidant response and mitophagy promotion in streptozotocin-induced type 1 diabetes in rats. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167531. [PMID: 39353543 DOI: 10.1016/j.bbadis.2024.167531] [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: 03/19/2024] [Revised: 09/11/2024] [Accepted: 09/25/2024] [Indexed: 10/04/2024]
Abstract
Endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction are interconnected processes involved in the pathogenesis of diabetes mellitus (DM). In the present study, we demonstrate a distinct unfolded protein response (UPR) signaling pathways in two mammalian models of DM: β-TC-6 cell line and streptozotocin-induced type 1 diabetes model in rats. However, a feature common to both systems was the upregulation of the GRP78 protein. Moreover, in vivo studies showed the disruption of the antioxidant system and an escalation of mitophagy against the background of a depletion of the level of ATP in pancreatic cells. In conclusion, we suggest that glucotoxic conditions induced GRP78 upregulation, and next cause depletion of the antioxidant pool and disruption of the functioning of antioxidant defense enzymes and in consequence promote mitophagy in pancreatic cells. Therefore, GRP78 may be considered as a potential therapeutic factor in patients with diabetes.
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Affiliation(s)
- O Kaniuka
- Department of Biochemistry, Ivan Franko National University of Lviv, 1, Universytetska St., 79000 Lviv, Ukraine.
| | - A Deregowska
- Institute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, Poland.
| | - Yu Bandura
- Department of Biochemistry, Ivan Franko National University of Lviv, 1, Universytetska St., 79000 Lviv, Ukraine.
| | - M Sabadashka
- Department of Biochemistry, Ivan Franko National University of Lviv, 1, Universytetska St., 79000 Lviv, Ukraine.
| | - D Chala
- Department of Biochemistry, Ivan Franko National University of Lviv, 1, Universytetska St., 79000 Lviv, Ukraine.
| | - O Kulachkovskyi
- Department of Biochemistry, Ivan Franko National University of Lviv, 1, Universytetska St., 79000 Lviv, Ukraine.
| | - H Kubis
- Institute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, Poland.
| | - J Adamczyk-Grochala
- Institute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, Poland.
| | - N Sybirna
- Department of Biochemistry, Ivan Franko National University of Lviv, 1, Universytetska St., 79000 Lviv, Ukraine.
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24
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Qian X, Yao M, Xu J, Dong N, Chen S. From cancer therapy to cardiac safety: the role of proteostasis in drug-induced cardiotoxicity. Front Pharmacol 2024; 15:1472387. [PMID: 39611175 PMCID: PMC11602306 DOI: 10.3389/fphar.2024.1472387] [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: 07/29/2024] [Accepted: 11/04/2024] [Indexed: 11/30/2024] Open
Abstract
Drug-induced cardiotoxicity (DICT) poses a significant challenge in the prognosis of cancer patients, particularly with the use of antineoplastic agents like anthracyclines and targeted therapies such as trastuzumab. This review delves into the intricate interplay between drugs and proteins within cardiac cells, focusing on the role of proteostasis as a therapeutic target for mitigating cardiotoxicity. We explore the in vivo modeling of proteostasis, highlighting the complex intracellular environment and the emerging techniques for monitoring proteostasis. Additionally, we discuss how cardiotoxic drugs disrupt protein homeostasis through direct chemical denaturation, endoplasmic reticulum stress, unfolded protein response, chaperone dysfunction, impairment of the proteasome system, and dysregulation of autophagy. Finally, we provide insights into the applications of cardioprotective drugs targeting proteostasis to prevent cardiotoxicity and the adoption of structural proteomics to evaluate potential cardiotoxicity. By gaining a deeper understanding of the role of proteostasis underlying DICT, we can pave the way for the development of targeted therapeutic strategies to safeguard cardiac function while maximizing the therapeutic potential of antineoplastic drugs.
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Affiliation(s)
- Xingyu Qian
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengdong Yao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jingyu Xu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Nianguo Dong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Si Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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25
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Huang CY, Liu YH. Sex difference, proteostasis and mitochondrial function impact stroke-related sarcopenia-A systematic review and meta-analysis. Ageing Res Rev 2024; 101:102484. [PMID: 39218079 DOI: 10.1016/j.arr.2024.102484] [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: 10/14/2023] [Revised: 08/11/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND The prevalence of stroke-related sarcopenia has been noted; however, epidemiological data and interventions that increase or reduce the incidence of stroke-related sarcopenia remain lacking. METHODS Studies on stroke-related sarcopenia were included in association or interventional analyses. All analyses were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two evaluators independently extracted the data. RESULTS Female stroke patients had a higher preference for sarcopenia than male patients (pooled odds ratio [OR] = 0.670, 95 % CI 0.533-0.842, p = 0.001). Although stroke patients without drug use have improved skeletal muscle mass index (SMI) (MD = 0.272, 95 % CI 0.087-0.457, p = 0.004), handgrip strength (HGS) was not significantly altered (MD = -0.068, 95 % CI -0.221-0.076, p = 0.354). Stroke patients with nutrient interventions have improved SMI (MD = -0.354, 95 % CI -0.635- -0.073, p = 0.014) and HGS (MD = -0.394, 95 % CI -0.678- -0.111, p = 0.006); the synergistic effect of rehabilitation exercise has not been ruled out. Whether a sex difference exists in these interventions remains to be investigated. The underlying pathological mechanisms and potential therapeutic strategies for this disease are discussed. CONCLUSION Sex difference, proteostasis, and mitochondrial function may impact the incidence of stroke-related sarcopenia. Understanding the underlying pathological mechanisms and potential therapeutic targets for this disease will provide new insights into disease treatment, prevention, and drug development.
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Affiliation(s)
- Chien-Yu Huang
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung 404328, Taiwan; Department of Chinese Medicine, China Medical University Hospital, Taichung 404333, Taiwan
| | - Yu-Huei Liu
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 404333, Taiwan; Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 404328, Taiwan; Drug Development Center, China Medical University, Taichung 404333, Taiwan.
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26
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Jin Y, Tan M, Yin Y, Lin C, Zhao Y, Zhang J, Jiang T, Li H, He M. Oroxylin A alleviates myocardial ischemia-reperfusion injury by quelling ferroptosis via activating the DUSP10/MAPK-Nrf2 pathway. Phytother Res 2024; 38:5290-5308. [PMID: 39225191 DOI: 10.1002/ptr.8315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/30/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024]
Abstract
Reperfusion therapy is the primary treatment strategy for acute myocardial infarction (AMI). Paradoxically, it can lead to myocardial damage, namely myocardial ischemia/reperfusion injury (MIRI). This study explored whether oroxylin A (OA) protects the myocardium after MIRI by inhibiting ferroptosis and the underlying mechanism. In vivo, we established an MIRI model to investigate the protective effect of OA. In vitro, H9C2 cells were used to explore the regulation of ferroptosis by OA through immunofluorescence staining, western blotting, assay kits, etc. Additionally, RNA sequencing analysis (RNA-seq) and network pharmacology analyses were conducted to elucidate the molecular mechanisms. Our results showed that MIRI caused cardiac structural and functional damage in rats. MIRI promoted ferroptosis, which was consistently observed in vitro. However, pretreatment with OA reversed these effects. The mitogen-activated protein kinases (MAPK) signaling pathway participated in the MIRI process, with dual-specificity phosphatase 10 (DUSP10) found to regulate it. Further confirmation was provided by knocking down DUSP10 using small interfering RNA (siRNA), demonstrating the activation of the DUSP10/MAPK-Nrf2 pathway by OA to protect H9C2 cells from ferroptosis. Our research has demonstrated the mitigating effect of OA on MIRI and the improvement of myocardial function for the first time. The inhibition of ferroptosis has been identified as one of the mechanisms through which OA exerts its myocardial protective effects. Moreover, we have first unveiled that DUSP10 serves as an upstream target involved in mediating ferroptosis, and the regulation of the DUSP10/MAPK-Nrf2 pathway by OA is crucial in inhibiting ferroptosis to protect the myocardium.
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Affiliation(s)
- Yifeng Jin
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
- Department of General Practice, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
| | - Mingyue Tan
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
- Department of Geriatrics, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Yunfei Yin
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
| | - Chen Lin
- Jinjihu Business District Squadron, Suzhou Industrial Park Food and Drug Safety Inspection Team, Suzhou, Jiangsu, P. R. China
| | - Yongjian Zhao
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
| | - Jun Zhang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
| | - Tingbo Jiang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
| | - Hongxia Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
| | - Mingqing He
- Department of Gerontology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
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27
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Nordström J, Badia-I-Mompel P, Witasp A, Schwarz A, Evenepoel P, Moor MB, Wennberg L, Saez-Rodriguez J, Wernerson A, Olauson H. Defining the molecular response to ischemia-reperfusion injury and remote ischemic preconditioning in human kidney transplantation. PLoS One 2024; 19:e0311613. [PMID: 39471208 PMCID: PMC11521294 DOI: 10.1371/journal.pone.0311613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 09/22/2024] [Indexed: 11/01/2024] Open
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC. METHODS First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects. RESULTS There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites. CONCLUSIONS The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI.
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Affiliation(s)
- Johan Nordström
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Pau Badia-I-Mompel
- Institute for Computational Biomedicine, Bioquant, Faculty of Medicine, and Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
| | - Anna Witasp
- Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Angelina Schwarz
- Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Pieter Evenepoel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Belgium
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, KU Leuven, Belgium
| | - Matthias B. Moor
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lars Wennberg
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Julio Saez-Rodriguez
- Institute for Computational Biomedicine, Bioquant, Faculty of Medicine, and Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
| | - Annika Wernerson
- Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Olauson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
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28
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Guo Z, Chi R, Peng Y, Sun K, Liu H, Guo F, Guo J. The Role and Interactive Mechanism of Endoplasmic Reticulum Stress and Ferroptosis in Musculoskeletal Disorders. Biomolecules 2024; 14:1369. [PMID: 39595546 PMCID: PMC11591632 DOI: 10.3390/biom14111369] [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] [Revised: 08/27/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
Endoplasmic reticulum (ER) stress is a cellular phenomenon that arises in response to the accumulation of misfolded proteins within the ER. This process triggers the activation of a signalling pathway known as the unfolded protein response (UPR), which aims to restore ER homeostasis by reducing protein synthesis, increasing protein degradation, and promoting proper protein folding. However, excessive ER stress can perturb regular cellular function and contribute to the development of diverse pathological conditions. As is well known, ferroptosis is a kind of programmed cell death characterized by the accumulation of lipid peroxides and iron-dependent reactive oxygen species (ROS), resulting in oxidative harm to cellular structures. In recent years, there has been increasing evidence indicating that ferroptosis occurs in musculoskeletal disorders (MSDs), with emerging recognition of the complex relationship between ER stress and ferroptosis. This review presents a summary of ER stress and the ferroptosis pathway. Most importantly, it delves into the significance of ER stress in the ferroptosis process within diverse skeletal or muscle cell types. Furthermore, we highlight the potential benefits of targeting the correlation between ER stress and ferroptosis in treating degenerative MSDs.
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Affiliation(s)
- Zhou Guo
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Z.G.); (K.S.); (H.L.)
| | - Ruimin Chi
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Yawen Peng
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
- State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Kai Sun
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Z.G.); (K.S.); (H.L.)
| | - Haigang Liu
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Z.G.); (K.S.); (H.L.)
| | - Fengjing Guo
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Z.G.); (K.S.); (H.L.)
| | - Jiachao Guo
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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29
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Splichal RC, Chen K, Walton SP, Chan C. The Role of Endoplasmic Reticulum Stress on Reducing Recombinant Protein Production in Mammalian Cells. Biochem Eng J 2024; 210:109434. [PMID: 39220803 PMCID: PMC11360842 DOI: 10.1016/j.bej.2024.109434] [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] [Indexed: 09/04/2024]
Abstract
Therapeutic recombinant protein production relies on industrial scale culture of mammalian cells to produce active proteins in quantities sufficient for clinical use. The combination of stresses from industrial cell culture environment and recombinant protein production can overwhelm the protein synthesis machinery in the endoplasmic reticulum (ER). This leads to a buildup of improperly folded proteins which induces ER stress. Cells respond to ER stress by activating the Unfolded Protein Response (UPR). To restore proteostasis, ER sensor proteins reduce global protein synthesis and increase chaperone protein synthesis, and if that is insufficient the proteins are degraded. If proteostasis is still not restored, apoptosis is initiated. Increasing evidence suggests crosstalk between ER proteostasis and DNA damage repair (DDR) pathways. External factors (e.g., metabolites) from the cellular environment as well as internal factors (e.g., transgene copy number) can impact genome stability. Failure to maintain genome integrity reduces cell viability and in turn protein production. This review focuses on the association between ER stress and processes that affect protein production and secretion. The processes mediated by ER stress, including inhibition of global protein translation, chaperone protein production, degradation of misfolded proteins, DNA repair, and protein secretion, impact recombinant protein production. Recombinant protein production can be reduced by ER stress through increased autophagy and protein degradation, reduced protein secretion, and reduced DDR response.
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Affiliation(s)
- R. Chauncey Splichal
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - Kevin Chen
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - S. Patrick Walton
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - Christina Chan
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
- Department of Biochemistry and Molecular Biology, Michigan State University, MI, USA
- Department of Computer Science and Engineering, Michigan State University, MI, USA
- Institute for Quantitative Health Science and Engineering, Division of Medical Devices, Michigan State University, MI, USA
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Tepebaşı MY, Savran M, Coşan S, Taştan ŞA, Aydın B. The protective role of selenium against high-fructose corn syrup-induced kidney damage: a histopathological and molecular analysis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7829-7837. [PMID: 38734838 PMCID: PMC11450133 DOI: 10.1007/s00210-024-03149-w] [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: 02/26/2024] [Accepted: 05/05/2024] [Indexed: 05/13/2024]
Abstract
With the growth of the food industry, fructose, the intake of which increases with food, causes obesity and metabolic syndrome. Kidney damage may develop from metabolic syndrome. Selenium (Se) participates in the structure of antioxidant enzymes and has a medicinal effect. In this work, the protective impact of Se on kidney damage produced by high-fructose corn syrup (HFCS) via endoplasmic reticulum (ER) stress was examined. The study comprised four groups, each consisting of ten experimental animals: control, HFCS (20%-HFCS), HFCS (20%-HFCS), + Se (0.3 mg/kg/day/po), and Se (0.3 mg/kg/day/po) alone. The duration of the experiment was 6 weeks. Kidney tissues were stained with hematoxylin and eosin for histological examination. Immunohistochemical analysis was conducted to assess TNF-α and caspase-3 levels. The spectrophotometric evaluation was performed to measure TOS (total oxidant status), TAS (total antioxidant status), and OSI (oxidative stress index) levels. The PERK, ATF4, CHOP, BCL-2, and caspase-9 gene expression levels were assessed by the RT-qPCR method. After Se treatment, histopathological abnormalities and TNF-α and caspase-3 levels in the HFCS+Se group decreased (p < 0.001). While TOS and OSI levels increased dramatically in the HFCS group, TAS values decreased significantly but improved after Se application (p < 0.001). The expression levels of the genes PERK, ATF4, CHOP, and caspase-9 were significantly lower in the HFCS group when compared to the HFCS+Se group (p < 0.05). Our findings suggest that Se may protect against ER stress, oxidative stress, apoptosis, and kidney damage caused by high-dose fructose consumption.
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Affiliation(s)
| | - Mehtap Savran
- Department of Medical Pharmacology, University of Süleyman Demirel, Isparta, Turkey
| | - Samet Coşan
- Department of Medical Pharmacology, University of Süleyman Demirel, Isparta, Turkey
| | | | - Bünyamin Aydın
- Department of Internal Medicine, Kütahya University of Health Sciences, Kütahya, Turkey
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Li C, Li S, Zhang G, Li Q, Song W, Wang X, Cook JA, van der Stoel M, Wright BW, Altamirano F, Niewold EL, Han J, Kimble G, Zhang P, Luo X, Urra H, May HI, Ferdous A, Sun XN, Deng Y, Ikonen E, Hetz C, Kaufman RJ, Zhang K, Gillette TG, Scherer PE, Hill JA, Chen J, Wang ZV. IRE1α Mediates the Hypertrophic Growth of Cardiomyocytes Through Facilitating the Formation of Initiation Complex to Promote the Translation of TOP-Motif Transcripts. Circulation 2024; 150:1010-1029. [PMID: 38836349 PMCID: PMC11427172 DOI: 10.1161/circulationaha.123.067606] [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: 10/17/2023] [Accepted: 05/14/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms. METHODS Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control. RESULTS We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5' terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5' untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo. CONCLUSIONS These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.
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Affiliation(s)
- Chao Li
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shiqian Li
- Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland
- Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland
| | - Guangyu Zhang
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Qinfeng Li
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Weidan Song
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiaoding Wang
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jane A. Cook
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Miesje van der Stoel
- Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland
- Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland
| | - Bradley W. Wright
- Laboratory of Functional Genomics and Translational Control, Cecil H. and Ida Green Center for Reproductive Biology Sciences, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pharmacology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, the University of Texas Southwestern Medical Center, TX 75390, USA
| | - Francisco Altamirano
- Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Erica L. Niewold
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jungsoo Han
- Department of Molecular Biology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Garrett Kimble
- Department of Molecular Biology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Pengfei Zhang
- Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Xiang Luo
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hery Urra
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Bellavista, Santiago, Chile
| | - Herman I. May
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Anwarul Ferdous
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xue-Nan Sun
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yingfeng Deng
- Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Elina Ikonen
- Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland
- Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland
| | - Claudio Hetz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago 8380453, Chile
| | - Randal J. Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
| | - Thomas G. Gillette
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Philipp E. Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Joseph A. Hill
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Biology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jin Chen
- Laboratory of Functional Genomics and Translational Control, Cecil H. and Ida Green Center for Reproductive Biology Sciences, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pharmacology, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, the University of Texas Southwestern Medical Center, TX 75390, USA
| | - Zhao V. Wang
- Division of Cardiology, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
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Wang Y, Li S, Li W, Wu J, Hu X, Tang T, Liu X. Cardiac-targeted and ROS-responsive liposomes containing puerarin for attenuating myocardial ischemia-reperfusion injury. Nanomedicine (Lond) 2024; 19:2335-2355. [PMID: 39316570 PMCID: PMC11492708 DOI: 10.1080/17435889.2024.2402678] [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: 09/06/2024] [Indexed: 09/26/2024] Open
Abstract
Aim: This study aimed to construct an ischemic cardiomyocyte-targeted and ROS-responsive drug release system to reduce myocardial ischemia-reperfusion injury (MI/RI).Methods: We constructed thioketal (TK) and cardiac homing peptide (CHP) dual-modified liposomes loaded with puerarin (PUE@TK/CHP-L), which were expected to deliver drugs precisely into ischemic cardiomyocytes and release drugs in response to the presence of high intracellular ROS levels. The advantages of PUE@TK/CHP-L were assessed by cellular pharmacodynamics, in vivo fluorescence imaging and animal pharmacodynamics.Results: PUE@TK/CHP-L significantly inhibited apoptosis and ferroptosis in H/R-injured cardiomyocytes and also actively targeted ischemic myocardium. Based on these advantages, PUE@TK/CHP-L could significantly enhance the drug's ability to attenuate MI/RI.Conclusion: PUE@TK/CHP-L had potential clinical value in the precise treatment of MI/RI.
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Affiliation(s)
- Yan Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Institution of Clinical Pharmacy, Central South University, Changsha, 410011, China
| | - Shengnan Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Institution of Clinical Pharmacy, Central South University, Changsha, 410011, China
| | - Wenqun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Institution of Clinical Pharmacy, Central South University, Changsha, 410011, China
| | - Junyong Wu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Institution of Clinical Pharmacy, Central South University, Changsha, 410011, China
| | - Xiongbin Hu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Institution of Clinical Pharmacy, Central South University, Changsha, 410011, China
| | - Tiantian Tang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Institution of Clinical Pharmacy, Central South University, Changsha, 410011, China
| | - Xinyi Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Institution of Clinical Pharmacy, Central South University, Changsha, 410011, China
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Wen C, Jiang Y, Chen W, Xu Y, Chen G, Zhou Q, Liu Q, Jiang H, Liu Y, Cao X, Yao Y, Zhang R, Qiu Z, Liu S. Targeting translocator protein protects against myocardial ischemia/reperfusion injury by alleviating mitochondrial dysfunction. Exp Ther Med 2024; 28:349. [PMID: 39071907 PMCID: PMC11273255 DOI: 10.3892/etm.2024.12638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 06/11/2024] [Indexed: 07/30/2024] Open
Abstract
Ischemic heart disease (IHD) remains a leading cause of mortalities worldwide, necessitating timely reperfusion to reduce acute mortality. Paradoxically, reperfusion can induce myocardial ischemia/reperfusion (I/R) injury, which is primarily characterized by mitochondrial dysfunction. Translocator protein (TSPO) participates in multiple cellular events; however, its role in IHD, especially in the process of myocardial I/R injury, has not been well determined. The aim of the present study was to investigate the functional role of TSPO in myocardial I/R injury and dissect the concomitant cellular events involved. This study utilized small interfering RNA (siRNA) technology to knock down TSPO expression. The I/R process was simulated using an anoxia/reoxygenation (A/R) model. The role of TSPO in H9c2 cardiomyocytes was assessed using various techniques, such as Western blotting, Flow cytometry, Reverse transcription-quantitative PCR (RT-qPCR), Immunofluorescence, Co-immunoprecipitation (co-IP) and similar methods. It was found that A/R markedly upregulated the expression of TSPO in cardiomyocytes. Inhibition of TSPO improved myocardial cell apoptosis and damage following A/R stimulation. Additionally, targeting TSPO alleviated mitochondrial damage, reduced mitochondrial ROS release and enhanced ATP synthesis following A/R stimulation. It was further confirmed that A/R stimulation induced a significant increase in the expression of pivotal markers [phosporylated-PKR-like ER kinase (PERK)/PERK, activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1] involved in the adaptive unfolded protein response, which is accompanied by downstream signaling during endoplasmic reticulum (ER) stress. Notably, TSPO knockdown increased the expression of the aforementioned markers and, subsequently, TSPO was confirmed to interact with ATF6, suggesting that TSPO might play a role in ER stress during myocardial I/R injury. Finally, inhibition of TSPO upregulated mitophagy, as indicated by further decreases in P62 and increases in Parkin and PINK1 levels following A/R stimulation. Together, the results suggest that TSPO plays a multifaceted role in myocardial I/R injury. Understanding TSPO-induced cellular responses could inform targeted therapeutic strategies for patients with IHD.
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Affiliation(s)
- Chenghao Wen
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Yunfei Jiang
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Wen Chen
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Yueyue Xu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Ganyi Chen
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Qiang Zhou
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Quan Liu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Southeast University, Nanjing, Jiangsu 210006, P.R. China
| | - Hongwei Jiang
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Yafeng Liu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Xu Cao
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Yiwei Yao
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Ruoyu Zhang
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Zhibing Qiu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
| | - Shengchen Liu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
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Chang Y, Chen L, Zhang M, Zhang S, Liu R, Feng S. Pharmacologic activation of activating transcription factor 6 contributes to neuronal survival after spinal cord injury in mice. J Neurochem 2024; 168:3221-3234. [PMID: 39114965 DOI: 10.1111/jnc.16092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 10/04/2024]
Abstract
The impact of primary and secondary injuries of spinal cord injury (SCI) results in the demise of numerous neurons, and there is still no efficacious pharmacological intervention for it. Recently, studies have shown that endoplasmic reticulum stress (ERS) plays a pivotal role in recovery of neurological function after spinal cord injury. As a process to cope with intracellular accumulation of misfolded and unfolded proteins which triggers ERS, the unfolded protein response (UPR) plays an important role in maintaining protein homeostasis. And, a recently disclosed small molecule AA147, which selectively activates activating transcription factor 6 (ATF6), has shown promising pharmacological effects in several disease models. Thus, it seems feasible to protect the neurons after spinal cord injury by modulating UPR. In this study, primary neurons were isolated from E17-19 C57BL/6J mouse embryos and we observed that AA147 effectively promoted the survival of neurons and alleviated neuronal apoptosis after oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. This was evident through a decrease in the proportion of PI-positive and TUNEL-positive cells, an increase in BCL-2 expression, and a decrease in the expression of BAX and C-caspase3. In in-vivo experiments, these findings were corroborated by TUNEL staining and immunohistochemistry. It was also found that AA147 enhanced three arms of the unfolded protein response with reduced CHOP expression. Besides, AA147 mitigated the accumulation of ROS in neurons probably by upregulating catalase expression. Furthermore, spinal cord injury models of C57BL/6J mice were established and behavioral experiments revealed that AA147 facilitated the recovery of motor function following SCI. Thus, pharmacologic activation of ATF6 represents a promise therapeutic approach to ameliorate the prognosis of SCI.
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Affiliation(s)
- Yong Chang
- Orthopaedic Research Center of Shandong University, Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lu Chen
- Orthopaedic Research Center of Shandong University, Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Mingzhe Zhang
- Orthopaedic Research Center of Shandong University, Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Shiji Zhang
- Orthopaedic Research Center of Shandong University, Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Renshuai Liu
- Orthopaedic Research Center of Shandong University, Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Shiqing Feng
- Orthopaedic Research Center of Shandong University, Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Advanced Medical Research Institute, Shandong University, Jinan, Shandong, China
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35
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Liu Y, Xu C, Gu R, Han R, Li Z, Xu X. Endoplasmic reticulum stress in diseases. MedComm (Beijing) 2024; 5:e701. [PMID: 39188936 PMCID: PMC11345536 DOI: 10.1002/mco2.701] [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: 02/21/2023] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/28/2024] Open
Abstract
The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.
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Affiliation(s)
- Yingying Liu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
| | - Chunling Xu
- School of Pharmaceutical SciencesTsinghua UniversityBeijingChina
| | - Renjun Gu
- School of Chinese MedicineNanjing University of Chinese MedicineNanjingChina
- Department of Gastroenterology and HepatologyJinling HospitalMedical School of Nanjing UniversityNanjingChina
| | - Ruiqin Han
- State Key Laboratory of Medical Molecular BiologyDepartment of Biochemistry and Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ziyu Li
- School of Acupuncture and TuinaSchool of Regimen and RehabilitationNanjing University of Chinese MedicineNanjingChina
| | - Xianrong Xu
- Department of Aviation Clinical Medicine, Air Force Medical CenterPLABeijingChina
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Guo Q, Wang J, Ni C, Pan J, Zou J, Shi Y, Sun J, Zhang X, Wang D, Luan F. Research progress on the natural products in the intervention of myocardial infarction. Front Pharmacol 2024; 15:1445349. [PMID: 39239656 PMCID: PMC11374734 DOI: 10.3389/fphar.2024.1445349] [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: 06/07/2024] [Accepted: 08/05/2024] [Indexed: 09/07/2024] Open
Abstract
Coronary heart disease is a prevalent cardiovascular ailment globally, with myocardial infarction (MI) being one of its most severe manifestations. The morbidity and mortality of MI are escalating, showing an increasing trend among younger, highly educated individuals, thereby posing a serious threat to public health. Currently, thrombolysis, percutaneous coronary intervention, and coronary artery bypass grafting are the primary clinical treatments for MI. Although these methods significantly reduce patient mortality, complications often result in poor prognoses. Due to limitations in chemical synthetic drug research, the focus has shifted towards developing herbs based on natural substances. Natural medicines represent a novel approach for safer and more effective MI management and treatment. They can control multiple pathogenic variables by targeting various pathways and systems. This paper investigates the molecular mechanisms of MI and evaluates the application of natural products and medicinal plants in MI treatment over the past 5 years, demonstrating their specific good therapeutic potential and superior tolerance. These natural therapies have been shown to mitigate myocardial cell damage caused by MI through mechanisms such as oxidative stress, inflammation, apoptosis, angiogenesis, myocardial fibrosis, autophagy, endoplasmic reticulum stress, mitophagy, and pyroptosis. This review offers the latest insights into the application of natural products and medicinal plants in MI treatment, elucidating their mechanisms of action and serving as an important reference for MI prevention.
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Affiliation(s)
- Qiuting Guo
- College of Pharmacy, Xianyang Polytechnic Institute, Xianyang, China
| | - Jinhui Wang
- Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, China
| | - Caixia Ni
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, China
| | - Jiaojiao Pan
- Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, China
| | - Junbo Zou
- Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, China
| | - Yajun Shi
- Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, China
| | - Jing Sun
- Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, China
| | - Xiaofei Zhang
- Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, China
| | - Deng Wang
- Department of Pharmacy, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Fei Luan
- Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi, China
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Liu YC, Bai X, Liao B, Chen XB, Li LH, Liu YH, Hu HJ, Xu K. Activating transcription factor 6 contributes to cisplatin‑induced ototoxicity via regulating the unfolded proteins response. Biomed Pharmacother 2024; 177:117025. [PMID: 38941893 DOI: 10.1016/j.biopha.2024.117025] [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: 03/23/2024] [Revised: 06/12/2024] [Accepted: 06/21/2024] [Indexed: 06/30/2024] Open
Abstract
As a broad-spectrum anticancer drug, cisplatin is widely used in the treatment of tumors in various systems. Unfortunately, several serious side effects of cisplatin limit its clinical application, the most common of which are nephrotoxicity and ototoxicity. Studies have shown that cochlear hair cell degeneration is the main cause of cisplatin-induced hearing loss. However, the mechanism of cisplatin-induced hair cell death remains unclear. The present study aimed to explore the potential role of activating transcription factor 6 (ATF6), an endoplasmic reticulum (ER)-localized protein, on cisplatin-induced ototoxicity in vivo and in vitro. In this study, we observed that cisplatin exposure induced apoptosis of mouse auditory OC-1 cells, accompanied by a significant increase in the expression of ATF6 and C/EBP homologous protein (CHOP). In cell or cochlear culture models, treatment with an ATF6 agonist, an ER homeostasis regulator, significantly ameliorated cisplatin-induced cytotoxicity. Further, our in vivo experiments showed that subcutaneous injection of an ATF6 agonist almost completely prevented outer hair cell loss and significantly alleviated cisplatin-induced auditory brainstem response (ABR) threshold elevation in mice. Collectively, our results revealed the underlying mechanism by which activation of ATF6 significantly improved cisplatin-induced hair cell apoptosis, at least in part by inhibiting apoptosis signal-regulating kinase 1 expression, and demonstrated that pharmacological activation of ATF6-mediated unfolded protein response is a potential treatment for cisplatin-induced ototoxicity.
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Affiliation(s)
- Yu-Chen Liu
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China; Queen Mary school, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xue Bai
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Bing Liao
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xu-Bo Chen
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Li-Hua Li
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yue-Hui Liu
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hai-Jun Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China.
| | - Kai Xu
- Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China.
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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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Zhang J, Zhao Y, Gong N. Endoplasmic reticulum stress signaling modulates ischemia/reperfusion injury in the aged heart by regulating mitochondrial maintenance. Mol Med 2024; 30:107. [PMID: 39044180 PMCID: PMC11265325 DOI: 10.1186/s10020-024-00869-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 06/27/2024] [Indexed: 07/25/2024] Open
Abstract
Aging is associated with an increased risk of myocardial ischemia/reperfusion injury (IRI). With an increasing prevalence of cardiovascular diseases such as coronary arteriosclerosis in older people, there has been increasing interest in understanding the mechanisms of myocardial IRI to develop therapeutics that can attenuate its damaging effects. Previous studies identified that abnormal mitochondria, involved in cellar senescence and oxidative stress, are the master subcellular organelle that induces IRI. In addition, endoplasmic reticulum (ER) stress is also associated with IRI. Cellular adaptation to ER stress is achieved by the activation of ER molecular chaperones and folding enzymes, which provide an important link between ER stress and oxidative stress gene programs. In this review, we outline how these ER stress-related molecules affect myocardial IRI via the crosstalk of ER stress and mitochondrial homeostasis and discuss how these may offer promising novel therapeutic targets and strategies against age-related cardiovascular diseases.
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Affiliation(s)
- Ji Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, P.R. China
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology & Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, 230022, P.R. China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, P.R. China
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, 430030, P.R. China.
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40
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Fallah M, Rakhshan K, Nikbakht F, Maleki-Ravasan N, Tahghighi A, Azizi Y. Cardioprotective effects of the aqueous extract of Echinops cephalotes on myocardial ischemia-reperfusion in rats by modulation of MMP-2, MMP-9, TIMP, and oxidative stress. Biomed Pharmacother 2024; 176:116927. [PMID: 38870633 DOI: 10.1016/j.biopha.2024.116927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/29/2024] [Accepted: 06/09/2024] [Indexed: 06/15/2024] Open
Abstract
Echinops plants have received great attention for the treatment of many diseases due to pharmacological properties such as their antidiabetic, antioxidant, and anti-inflammatory characteristics. The major purpose of the present study was to investigate the cardioprotective benefits of Echinops cephalotes (Ech) against myocardial ischemia-reperfusion (MI/R) injury. Male Wistar rats were randomly allocated to three groups: sham, MI, and MI + Ech. The left coronary artery (LAD) was blocked for 30 minutes to induce MI. In the treatment group, rats were given 150 mg/kg/day of Ech extract for 28 days. Aqueous extracts were made from Echinops plants. To study heart function, fibrosis, cardiac damage indicators, and oxidative stress factors, echocardiography, Masson's trichrome staining, and biochemical tests were used. The expression of matrix metalloproteinase 2 and 9 (MMP2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP) was determined using Western blotting. Tissue damage was assessed using hematoxylin and eosin staining. MI group exhibited significantly reduced ejection fraction (EF) and fractional shortening (FS), enhanced levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), cardiac Troponin I (cTnI), and malondialdehyde (MDA), as well as a decrease in the Glutathione (GSH) tissue content, reduced activity of superoxide dismutase (SOD), increasing fibrosis, upregulations of MMP-2 and MMP-9, and reduction of TIMP compared to the sham group. The findings suggest that Ech in particular, could be a promising therapeutic agent to reduce the damage in MI by targeting oxidative stress and modulating the activities of matrix metalloproteinases and their tissue inhibitors.
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Affiliation(s)
- Masoud Fallah
- Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Kamran Rakhshan
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farnaz Nikbakht
- Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Azar Tahghighi
- Laboratory of Medicinal Chemistry, Department of Clinical Research, Pasteur Institute of Iran, Tehran, Iran
| | - Yaser Azizi
- Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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López-Valverde L, Vázquez-Mosquera ME, Colón-Mejeras C, Bravo SB, Barbosa-Gouveia S, Álvarez JV, Sánchez-Martínez R, López-Mendoza M, López-Rodríguez M, Villacorta-Argüelles E, Goicoechea-Diezhandino MA, Guerrero-Márquez FJ, Ortolano S, Leao-Teles E, Hermida-Ameijeiras Á, Couce ML. Characterization of the plasma proteomic profile of Fabry disease: Potential sex- and clinical phenotype-specific biomarkers. Transl Res 2024; 269:47-63. [PMID: 38395389 DOI: 10.1016/j.trsl.2024.02.006] [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: 11/23/2023] [Revised: 01/25/2024] [Accepted: 02/20/2024] [Indexed: 02/25/2024]
Abstract
Fabry disease (FD) is a X-linked rare lysosomal storage disorder caused by deficient α-galactosidase A (α-GalA) activity. Early diagnosis and the prediction of disease course are complicated by the clinical heterogeneity of FD, as well as by the frequently inconclusive biochemical and genetic test results that do not correlate with clinical course. We sought to identify potential biomarkers of FD to better understand the underlying pathophysiology and clinical phenotypes. We compared the plasma proteomes of 50 FD patients and 50 matched healthy controls using DDA and SWATH-MS. The >30 proteins that were differentially expressed between the 2 groups included proteins implicated in processes such as inflammation, heme and haemoglobin metabolism, oxidative stress, coagulation, complement cascade, glucose and lipid metabolism, and glycocalyx formation. Stratification by sex revealed that certain proteins were differentially expressed in a sex-dependent manner. Apolipoprotein A-IV was upregulated in FD patients with complications, especially those with chronic kidney disease, and apolipoprotein C-III and fetuin-A were identified as possible markers of FD with left ventricular hypertrophy. All these proteins had a greater capacity to identify the presence of complications in FD patients than lyso-GB3, with apolipoprotein A-IV standing out as being more sensitive and effective in differentiating the presence and absence of chronic kidney disease in FD patients than renal markers such as creatinine, glomerular filtration rate and microalbuminuria. Identification of these potential biomarkers can help further our understanding of the pathophysiological processes that underlie the heterogeneous clinical manifestations associated with FD.
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Affiliation(s)
- Laura López-Valverde
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. RICORS-SAMID, CIBERER. University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain
| | - María E Vázquez-Mosquera
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. RICORS-SAMID, CIBERER. University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain
| | - Cristóbal Colón-Mejeras
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. RICORS-SAMID, CIBERER. University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain
| | - Susana B Bravo
- Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Proteomic Platform, University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain
| | - Sofía Barbosa-Gouveia
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. RICORS-SAMID, CIBERER. University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain
| | - J Víctor Álvarez
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. RICORS-SAMID, CIBERER. University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain
| | - Rosario Sánchez-Martínez
- Internal Medicine Department, Alicante General University Hospital-Alicante Institute of Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante 03010, Spain
| | - Manuel López-Mendoza
- Department of Nephrology, Hospital Universitario Virgen del Rocío, Manuel Siurot s/n, Sevilla 41013, Spain
| | - Mónica López-Rodríguez
- Internal Medicine Department, Hospital Universitario Ramón y Cajal, IRYCIS, Colmenar Viejo, Madrid 28034, Spain; Faculty of Medicine and Health Sciences, Universidad de Alcalá (UAH), Av. de Madrid, Alcalá de Henares 28871, Spain
| | - Eduardo Villacorta-Argüelles
- Department of Cardiology, Complejo Asistencial Universitario de Salamanca, P°. de San Vicente 58, Salamanca 37007, Spain
| | | | - Francisco J Guerrero-Márquez
- Department of Cardiology, Internal Medicine Service, Hospital de la Serranía, San Pedro, Ronda, Málaga 29400, Spain
| | - Saida Ortolano
- Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute-SERGAS-UVIGO, Clara Campoamor 341, Vigo 36213, Spain
| | - Elisa Leao-Teles
- Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de São João, Prof. Hernâni Monteiro, Porto 4200-319, Portugal
| | - Álvaro Hermida-Ameijeiras
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. RICORS-SAMID, CIBERER. University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain.
| | - María L Couce
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. RICORS-SAMID, CIBERER. University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain; Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, Choupana s/n, Santiago de Compostela, A Coruña 15706, Spain.
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42
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Rives D, Peak C, Blenner MA. RNASeq highlights ATF6 pathway regulators for CHO cell engineering with different impacts of ATF6β and WFS1 knockdown on fed-batch production of IgG 1. Sci Rep 2024; 14:14141. [PMID: 38898154 PMCID: PMC11187196 DOI: 10.1038/s41598-024-64767-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024] Open
Abstract
Secretion levels required of industrial Chinese hamster ovary (CHO) cell lines can challenge endoplasmic reticulum (ER) homeostasis, and ER stress caused by accumulation of misfolded proteins can be a bottleneck in biomanufacturing. The unfolded protein response (UPR) is initiated to restore homeostasis in response to ER stress, and optimization of the UPR can improve CHO cell production of therapeutic proteins. We compared the fed-batch growth, production characteristics, and transcriptomic response of an immunoglobulin G1 (IgG1) producer to its parental, non-producing host cell line. We conducted differential gene expression analysis using high throughput RNA sequencing (RNASeq) and quantitative polymerase chain reaction (qPCR) to study the ER stress response of each cell line during fed-batch culture. The UPR was activated in the IgG1 producer compared to the host cell line and our analysis of differential expression profiles indicated transient upregulation of ATF6α target mRNAs in the IgG1 producer, suggesting two upstream regulators of the ATF6 arm of the UPR, ATF6β and WFS1, are rational engineering targets. Although both ATF6β and WFS1 have been reported to negatively regulate ATF6α, this study shows knockdown of either target elicits different effects in an IgG1-producing CHO cell line. Stable knockdown of ATF6β decreased cell growth without decreasing titer; however, knockdown of WFS1 decreased titer without affecting growth. Relative expression measured by qPCR indicated no direct relationship between ATF6β and WFS1 expression, but upregulation of WFS1 in one pool was correlated with decreased growth and upregulation of ER chaperone mRNAs. While knockdown of WFS1 had negative impacts on UPR activation and product mRNA expression, knockdown of ATF6β improved the UPR specifically later in fed-batch leading to increased overall productivity.
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Affiliation(s)
- Dyllan Rives
- Department of Chemical & Biomolecular Engineering, Clemson University, 206 S. Palmetto Blvd., Clemson, SC, 29634-0909, USA
| | - Caroline Peak
- Department of Chemical & Biomolecular Engineering, Clemson University, 206 S. Palmetto Blvd., Clemson, SC, 29634-0909, USA
| | - Mark A Blenner
- Department of Chemical & Biomolecular Engineering, Clemson University, 206 S. Palmetto Blvd., Clemson, SC, 29634-0909, USA.
- Department of Chemical & Biomolecular Engineering, University of Delaware, 590 Avenue 1743, Newark, DE, 19713, USA.
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Wu J, Cui Y, Ding W, Zhang J, Wang L. The protective effect of Macrostemonoside T from Allium macrostemon Bunge against Isoproterenol-Induced myocardial injury via the PI3K/Akt/mTOR signaling pathway. Int Immunopharmacol 2024; 133:112086. [PMID: 38642441 DOI: 10.1016/j.intimp.2024.112086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/31/2024] [Accepted: 04/10/2024] [Indexed: 04/22/2024]
Abstract
Myocardial injury (MI) signifies a pathological aspect of cardiovascular diseases (CVDs) such as coronary artery disease, diabetic cardiomyopathy, and myocarditis. Macrostemonoside T (MST) has been isolated from Allium macrostemon Bunge (AMB), a key traditional Chinese medicine (TCM) used for treating chest stuffiness and pains. Although MST has demonstrated considerable antioxidant activity in vitro, its protective effect against MI remains unexplored. To investigate MST's effects in both in vivo and in vitro models of isoproterenol (ISO)-induced MI and elucidate its underlying molecular mechanisms. This study established an ISO-induced MI model in rats and assessed H9c2 cytotoxicity to examine MST's impact on MI. Various assays, including histopathological staining, TUNEL staining, immunohistochemical staining, DCFH-DA staining, JC-1 staining, ELISA technique, and Western blot (WB), were utilized to explore the potential molecular mechanisms of MI protection. In vivo experiments demonstrated that ISO caused myocardial fiber disorders, elevated cardiac enzyme levels, and apoptosis. However, pretreatment with MST significantly mitigated these detrimental changes. In vitro experiments revealed that MST boosted antioxidant enzyme levels and suppressed malondialdehyde (MDA) production in H9c2 cells. Concurrently, MST inhibited ISO-induced reactive oxygen species (ROS) production and mitigated the decline in mitochondrial membrane potential, thereby reducing the apoptosis rate. Moreover, pretreatment with MST elevated the expression levels of p-PI3K, p-Akt, and p-mTOR, indicating activation of the PI3K/Akt/mTOR signaling pathway and consequent protection against MI. MST attenuated ISO-induced MI in rats by impeding apoptosis through activation of the PI3K/Akt/mTOR signaling pathway. This study presents potential avenues for the development of precursor drugs for CVDs.
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Affiliation(s)
- Jianfa Wu
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Ying Cui
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Weixing Ding
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Jing Zhang
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China.
| | - Lulu Wang
- School of Medicine, Changchun Sci-Tech University, Changchun 130600, China.
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Yang K, Gao R, Chen H, Hu J, Zhang P, Wei X, Shi J, Chen Y, Zhang L, Chen J, Lyu Y, Dong Z, Wei W, Hu K, Guo Y, Ge J, Sun A. Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition. Eur Heart J 2024; 45:1662-1680. [PMID: 38666340 PMCID: PMC11089336 DOI: 10.1093/eurheartj/ehae205] [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: 04/09/2023] [Revised: 02/18/2024] [Accepted: 03/19/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND AND AIMS The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.
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Affiliation(s)
- Kun Yang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
| | - Rifeng Gao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- Department of Cardiology, The Fifth People’s Hospital of Shanghai, Fudan University, 128 Ruili Road, Shanghai 200240, China
- Department of Cardiac Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China
| | - Hanchuan Chen
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
| | - Jingjing Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310006, China
| | - Peng Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- Department of Cardiology, Minhang Hospital affiliated to Fudan University, 170 Xinsong Road, Shanghai 201100, China
| | - Xiang Wei
- Department of Cardiology, The Fifth People’s Hospital of Shanghai, Fudan University, 128 Ruili Road, Shanghai 200240, China
| | - Jiaran Shi
- Department of Cardiology, Lihuili Hospital Facilitated to Ningbo University, 57 Xingning Road, Ningbo 315040, China
| | - Yinyin Chen
- Department of Radiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
- Department of Medical Imaging, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Liwei Zhang
- Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, 134 Dongjie Road, Fuzhou 350001, China
| | - Juntao Chen
- Department of Urology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
| | - Yang Lyu
- Department of Cardiology, The Fifth People’s Hospital of Shanghai, Fudan University, 128 Ruili Road, Shanghai 200240, China
| | - Zhen Dong
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
| | - Wei Wei
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China
| | - Kai Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
| | - Yansong Guo
- Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, 134 Dongjie Road, Fuzhou 350001, China
- Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases, 134 Dongjie Road, Fuzhou 350001, China
- Fujian Heart Failure Center Alliance, 134 Dongjie Road, Fuzhou 350001, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- Institutes of Biomedical Sciences, Fudan University, 131 Dongan Road, Shanghai 200032, China
- Key Laboratory of Viral Heart Diseases, National Health Commission, 180 Fenglin Road, Shanghai 200032, China
- Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, 180 Fenglin Road, Shanghai 200032, China
| | - Aijun Sun
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China
- Institutes of Biomedical Sciences, Fudan University, 131 Dongan Road, Shanghai 200032, China
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45
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Yao Y, Liu H, Gu Y, Xu X, Zhang X. A causal association between amyotrophic lateral sclerosis and atrial fibrillation: a two-sample Mendelian randomization study. Front Cardiovasc Med 2024; 11:1351495. [PMID: 38665232 PMCID: PMC11043605 DOI: 10.3389/fcvm.2024.1351495] [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: 01/24/2024] [Accepted: 04/01/2024] [Indexed: 04/28/2024] Open
Abstract
Objectives To look into the connection between amyotrophic lateral sclerosis (ALS) and atrial fibrillation (AF) using Mendelian randomization (MR). Methods Two-sample MR was performed using genetic information from genome-wide association studies (GWAS). Genetic variants robustly associated with ALS and AF were used as instrumental variables. GWAS genetic data for ALS (n = 138,086, ncase = 27,205) and AF (n = 1,030,836, ncase = 60,620), publicly available from IEU Open. The specific MR protocols were Inverse variance-weighted (IVW), Simple mode, MR Egger, Weighted mode, and Weight median estimator (WME). Subsequently, the MR-Egger intercept and Cochran Q examine were used to evaluate instrumental variables (IVs)' heterogeneity and multiplicative effects (IVs). In addition, MR-PRESSO analysis was conducted to exclude any potential pleiotropy. Results The IVW method demonstrated that ALS positively affected AF [OR: 1.062, 95% CI (1.004-1.122); P = 0.035]. Indeed, other MR methods were in accordance with the tendency of the IVW method (all OR > 1), and sensitivity testing verified the reliability of this MR result. Conclusions This MR study proves a positive causal connection between ALS and atrial fibrillation. Further studies are warranted to elucidate the mechanisms linking ALS and AF.
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Affiliation(s)
| | | | | | - Xiaojin Xu
- Department of Cardiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Xiwen Zhang
- Department of Cardiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
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Liang T, Xu S, Liu R, Xia X. Activating transcription factor 6 alleviates secondary brain injury by increasing cystathionine γ-lyase expression in a rat model of intracerebral hemorrhage. Aging (Albany NY) 2024; 16:6990-7008. [PMID: 38613810 PMCID: PMC11087128 DOI: 10.18632/aging.205737] [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: 11/14/2023] [Accepted: 03/03/2024] [Indexed: 04/15/2024]
Abstract
BACKGROUND Intracerebral hemorrhage (ICH) comprises primary and secondary injuries, the latter of which induces increased inflammation and apoptosis and is more severe. Activating transcription factor 6 (ATF6) is a type-II transmembrane protein in the endoplasmic reticulum (ER). ATF6 target genes could improve ER homeostasis, which contributes to cryoprotection. Hence, we predict that ATF6 will have a protective effect on brain tissue after ICH. METHOD The ICH rat model was generated through autologous blood injection into the right basal ganglia, the expression of ATF6 after ICH was determined by WB and IF. The expression of ATF6 was effectively controlled by means of intervention, and a series of measures was used to detect cell death, neuroinflammation, brain edema, blood-brain barrier and other indicators after ICH. Finally, the effects on long-term neural function of rats were measured by behavioral means. RESULT ATF6 was significantly increased in the ICH-induced brain tissues. Further, ATF6 was found to modulate the expression of cystathionine γ-lyase (CTH) after ICH. Upregulation of ATF6 attenuated neuronal apoptosis and inflammation in ICH rats, along with mitigation of ICH-induced brain edema, blood-brain barrier deterioration, and cognitive behavior defects. Conversely, ATF6 genetic knockdown induced effects counter to those aforementioned. CONCLUSIONS This study thereby emphasizes the crucial role of ATF6 in secondary brain injury in response to ICH, indicating that ATF6 upregulation may potentially ameliorate ICH-induced secondary brain injury. Consequently, ATF6 could serve as a promising therapeutic target to alleviate clinical ICH-induced secondary brain injuries.
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Affiliation(s)
- Tianyu Liang
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang, China
| | - Sen Xu
- Second Clinical Medical School, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Renyang Liu
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang, China
| | - Xiaoping Xia
- Department of Intensive Care Unit, Taizhou Integrated Traditional Chinese and Western Medicine Hospital, Wenling, Zhejiang Province, China
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47
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Hofmann C, Aghajani M, Alcock CD, Blackwood EA, Sandmann C, Herzog N, Groß J, Plate L, Wiseman RL, Kaufman RJ, Katus HA, Jakobi T, Völkers M, Glembotski CC, Doroudgar S. ATF6 protects against protein misfolding during cardiac hypertrophy. J Mol Cell Cardiol 2024; 189:12-24. [PMID: 38401179 DOI: 10.1016/j.yjmcc.2024.02.001] [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: 07/29/2023] [Revised: 01/11/2024] [Accepted: 02/01/2024] [Indexed: 02/26/2024]
Abstract
Cardiomyocytes activate the unfolded protein response (UPR) transcription factor ATF6 during pressure overload-induced hypertrophic growth. The UPR is thought to increase ER protein folding capacity and maintain proteostasis. ATF6 deficiency during pressure overload leads to heart failure, suggesting that ATF6 protects against myocardial dysfunction by preventing protein misfolding. However, conclusive evidence that ATF6 prevents toxic protein misfolding during cardiac hypertrophy is still pending. Here, we found that activation of the UPR, including ATF6, is a common response to pathological cardiac hypertrophy in mice. ATF6 KO mice failed to induce sufficient levels of UPR target genes in response to chronic isoproterenol infusion or transverse aortic constriction (TAC), resulting in impaired cardiac growth. To investigate the effects of ATF6 on protein folding, the accumulation of poly-ubiquitinated proteins as well as soluble amyloid oligomers were directly quantified in hypertrophied hearts of WT and ATF6 KO mice. Whereas only low levels of protein misfolding was observed in WT hearts after TAC, ATF6 KO mice accumulated increased quantities of misfolded protein, which was associated with impaired myocardial function. Collectively, the data suggest that ATF6 plays a critical adaptive role during cardiac hypertrophy by protecting against protein misfolding.
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Affiliation(s)
- Christoph Hofmann
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; SDSU Heart Institute and Department of Biology, San Diego State University, San Diego, CA, USA
| | - Marjan Aghajani
- Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA
| | - Cecily D Alcock
- Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA
| | - Erik A Blackwood
- Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA
| | - Clara Sandmann
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Nicole Herzog
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Julia Groß
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Lars Plate
- Department of Chemistry, Vanderbilt University, Nashville, TN, USA; Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - R Luke Wiseman
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Hugo A Katus
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Tobias Jakobi
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA
| | - Mirko Völkers
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Christopher C Glembotski
- Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA
| | - Shirin Doroudgar
- Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; Department of Internal Medicine and the Translational Cardiovascular Research Center, University of Arizona College of Medicine - Phoenix, Phoenix, USA.
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48
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Zhang J, Zhang X, Liu Y, Shi Y, Chen F, Leng Y. Recent insights into the effect of endoplasmic reticulum stress in the pathophysiology of intestinal ischaemia‒reperfusion injury. Biochem Biophys Res Commun 2024; 701:149612. [PMID: 38316091 DOI: 10.1016/j.bbrc.2024.149612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/07/2024]
Abstract
Intestinal ischaemia‒reperfusion (I/R) injury is a surgical emergency. This condition is associated with a high mortality rate. At present, there are limited number of efficient therapeutic measures for this injury, and the prognosis is poor. Therefore, the pathophysiological mechanisms of intestinal I/R injury must be elucidated to develop a rapid and specific diagnostic and treatment protocol. Numerous studies have indicated the involvement of endoplasmic reticulum (ER) stress in the development of intestinal I/R injury. Specifically, the levels of unfolded and misfolded proteins in the ER lumen are increased due to unfolded protein response. However, persistent ER stress promotes apoptosis of intestinal mucosal epithelial cells through three signalling pathways in the ER, impairing intestinal mucosal barrier function and leading to the dysfunction of intestinal tissues and distant organ compartments. This review summarises the mechanisms of ER stress in intestinal I/R injury, diagnostic indicators, and related treatment strategies with the objective of providing novel insights into future therapies for this condition.
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Affiliation(s)
- Jianmin Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Xiaohui Zhang
- The Department of Anaesthesiology, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Yongqiang Liu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China; The Department of Anaesthesiology, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Yajing Shi
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Feng Chen
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yufang Leng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China; The Department of Anaesthesiology, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
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49
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Lei Y, Yu H, Ding S, Liu H, Liu C, Fu R. Molecular mechanism of ATF6 in unfolded protein response and its role in disease. Heliyon 2024; 10:e25937. [PMID: 38434326 PMCID: PMC10907738 DOI: 10.1016/j.heliyon.2024.e25937] [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: 11/01/2023] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 03/05/2024] Open
Abstract
Activating transcription factor 6 (ATF6), an important signaling molecule in unfolded protein response (UPR), plays a role in the pathogenesis of several diseases, including diseases such as congenital retinal disease, liver fibrosis and ankylosing spondylitis. After endoplasmic reticulum stress (ERS), ATF6 is activated after separation from binding immunoglobulin protein (GRP78/BiP) in the endoplasmic reticulum (ER) and transported to the Golgi apparatus to be hydrolyzed by site 1 and site 2 proteases into ATF6 fragments, which localize to the nucleus and regulate the transcription and expression of ERS-related genes. In these diseases, ERS leads to the activation of UPR, which ultimately lead to the occurrence and development of diseases by regulating the physiological state of cells through the ATF6 signaling pathway. Here, we discuss the evidence for the pathogenic importance of ATF6 signaling in different diseases and discuss preclinical results.
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Affiliation(s)
| | | | - Shaoxue Ding
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Chunyan Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
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50
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Chi H, Chai Y, Ma L, Wang Y, Wu Q, Wang L, Zhai J, Ma F, Tian Y, Qi N, Peng J, Fu Y, Yang X, Huang H, Ma S. The mechanism by which piR-000699 targets SLC39A14 regulates ferroptosis in aging myocardial ischemia/reperfusion injury. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1352-1364. [PMID: 38439666 PMCID: PMC11532203 DOI: 10.3724/abbs.2024024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 02/25/2024] [Indexed: 03/06/2024] Open
Abstract
Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to different types of cell death. The degree of irreversible myocardial damage is closely related to age, and ferroptosis is involved in cardiomyocyte damage. However, the mechanisms underlying ferroptosis regulation in aging myocardial I/R injury are still unclear. The present study aims to explore the underlying mechanism of piRNA regulation in ferroptosis. Using left anterior descending coronary artery ligation in an aging rat model and a D-galactose-induced rat cardiomyocyte line (H9C2) to construct an aging cardiomyocyte model, we investigate whether ferroptosis occurs after reperfusion injury in vitro and in vivo. This study focuses on the upregulation of piR-000699 after hypoxia/reoxygenation treatment in aging cardiomyocytes by observing hypoxia/reoxygenation (H/R) injury indicators and ferroptosis-related indicators and clarifying the role of piR-000699 in H/R injury caused by ferroptosis in aging cardiomyocytes. Bioinformatics analysis reveals that SLC39A14 is a gene that binds to piR-000699. Our data show that ferroptosis plays an important role in I/R injury both in vivo and in vitro. Furthermore, the results show the potential role of piR-000699 in regulating SLC39A14 in ferroptosis in aging cardiomyocytes under hypoxia/reoxygenation conditions. Together, our results reveal that the mechanism by which piR-000699 binds to SLC39A14 regulates ferroptosis in aging myocardial I/R injury.
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Affiliation(s)
- Hongyang Chi
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
- School of Laboratory MedicineNingxia Medical UniversityYinchuan750004China
| | - Yue’e Chai
- College of PharmacyGuizhou Medical UniversityGuiyang561113China
| | - Lingju Ma
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
- Department of Geriatrics and Special Needs MedicineGeneral Hospital of Ningxia Medical UniversityYinchuan750004China
| | - Yichen Wang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Qianqian Wu
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Lexin Wang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Junjie Zhai
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Fufun Ma
- School of Laboratory MedicineNingxia Medical UniversityYinchuan750004China
| | - Yancheng Tian
- School of Laboratory MedicineNingxia Medical UniversityYinchuan750004China
| | - Ning Qi
- School of Laboratory MedicineNingxia Medical UniversityYinchuan750004China
| | - Jianhong Peng
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Youjuan Fu
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Xiaoling Yang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Hui Huang
- Department of Geriatrics and Special Needs MedicineGeneral Hospital of Ningxia Medical UniversityYinchuan750004China
| | - Shengchao Ma
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
- School of Laboratory MedicineNingxia Medical UniversityYinchuan750004China
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