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Xing Y, Lin X. Challenges and advances in the management of inflammation in atherosclerosis. J Adv Res 2025; 71:317-335. [PMID: 38909884 DOI: 10.1016/j.jare.2024.06.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 06/14/2024] [Accepted: 06/15/2024] [Indexed: 06/25/2024] Open
Abstract
INTRODUCTION Atherosclerosis, traditionally considered a lipid-related disease, is now understood as a chronic inflammatory condition with significant global health implications. OBJECTIVES This review aims to delve into the complex interactions among immune cells, cytokines, and the inflammatory cascade in atherosclerosis, shedding light on how these elements influence both the initiation and progression of the disease. METHODS This review draws on recent clinical research to elucidate the roles of key immune cells, macrophages, T cells, endothelial cells, and clonal hematopoiesis in atherosclerosis development. It focuses on how these cells and process contribute to disease initiation and progression, particularly through inflammation-driven processes that lead to plaque formation and stabilization. Macrophages ingest oxidized low-density lipoprotein (oxLDL), which partially converts to high-density lipoprotein (HDL) or accumulates as lipid droplets, forming foam cells crucial for plaque stability. Additionally, macrophages exhibit diverse phenotypes within plaques, with pro-inflammatory types predominating and others specializing in debris clearance at rupture sites. The involvement of CD4+ T and CD8+ T cells in these processes promotes inflammatory macrophage states, suppresses vascular smooth muscle cell proliferation, and enhances plaque instability. RESULTS The nuanced roles of macrophages, T cells, and the related immune cells within the atherosclerotic microenvironment are explored, revealing insights into the cellular and molecular pathways that fuel inflammation. This review also addresses recent advancements in imaging and biomarker technology that enhance our understanding of disease progression. Moreover, it points out the limitations of current treatment and highlights the potential of emerging anti-inflammatory strategies, including clinical trials for agents such as p38MAPK, tumor necrosis factor α (TNF-α), and IL-1β, their preliminary outcomes, and the promising effects of canakinumab, colchicine, and IL-6R antagonists. CONCLUSION This review explores cutting-edge anti-inflammatory interventions, their potential efficacy in preventing and alleviating atherosclerosis, and the role of nanotechnology in delivering drugs more effectively and safely.
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Affiliation(s)
- Yiming Xing
- Cardiology Department, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, 230022, China
| | - Xianhe Lin
- Cardiology Department, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, 230022, China.
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2
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Mesfin JM, Carrow KP, Chen A, Hopps MP, Holm JJ, Lyons QP, Nguyen MB, Hunter JD, Magassa A, Wong EG, Reimold K, Paleti SN, Gardner E, Thompson MP, Luo CG, Zhang X, Christman KL, Gianneschi NC. Protein-Like Polymers Targeting Keap1/Nrf2 as Therapeutics for Myocardial Infarction. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025:e2417885. [PMID: 40277240 DOI: 10.1002/adma.202417885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 03/13/2025] [Indexed: 04/26/2025]
Abstract
Myocardial infarction (MI) results in oxidative stress to the myocardium and frequently leads to heart failure (HF). There is an unmet clinical need to develop therapeutics that address the inflammatory stress response and prevent negative left ventricular remodeling. Here, the Keap1/Nrf2 protein-protein interaction is specifically targeted, as Nrf2 activation is known to mitigate the inflammatory response following MI. This is achieved using a Nrf2-mimetic protein-like polymer (PLP) to inhibit the Keap1-Nrf2 interaction. The PLP platform technology provides stability in vivo, potent intracellular bioactivity, and multivalency leading to high avidity Keap1 binding. In vitro and in vivo assays to probe cellular activity and MI therapeutic utility are employed. These Keap1-inhibiting PLPs (Keap1i-PLPs) impart cytoprotection from oxidative stress via Nrf2 activation at sub-nanomolar concentrations in primary cardiomyocytes. Single-digit mg kg-1, single-dose, intravenous PLP administration significantly improves cardiac function in rats post-MI through immunomodulatory, anti-apoptotic, and angiogenic mechanisms. Thus Keap1i-PLPs disrupt key intracellular protein-protein interactions following intravenous, systemic administration in vivo. These results have broad implications not only for MI but also for other oxidative stress-driven diseases and conditions.
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Affiliation(s)
- Joshua M Mesfin
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Kendal P Carrow
- Medical Scientist Training Program, Department of Biomedical Engineering, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Alexander Chen
- Program in Materials Science and Engineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Madeline P Hopps
- Department of Chemistry, International Institute for Nanotechnology, Simpson-Querrey Institute, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA
| | - JoJo J Holm
- Department of Chemistry, International Institute for Nanotechnology, Simpson-Querrey Institute, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA
| | - Quincy P Lyons
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Michael B Nguyen
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Jervaughn D Hunter
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Assa Magassa
- Department of Chemistry, Department of Materials Science & Engineering, Department of Pharmacology, International Institute for Nanotechnology, Simpson-Querrey Institute, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA
| | - Elyse G Wong
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Kate Reimold
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Sriya N Paleti
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Emily Gardner
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Matthew P Thompson
- Department of Chemistry, International Institute for Nanotechnology, Simpson-Querrey Institute, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA
| | - Colin G Luo
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, 92037, USA
| | - Xiaoyu Zhang
- Department of Chemistry, Department of Materials Science & Engineering, Department of Pharmacology, International Institute for Nanotechnology, Simpson-Querrey Institute, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA
| | - Karen L Christman
- Shu Chien-Gene Lay Department of Bioengineering, Program in Materials Science and Engineering, Sanford Consortium for Regenerative Medicine, Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, 92037, USA
| | - Nathan C Gianneschi
- Department of Biomedical Engineering, Department of Chemistry, Department of Materials Science & Engineering, Department of Pharmacology, International Institute for Nanotechnology, Simpson-Querrey Institute, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA
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Ubaida‐Mohien C, Moaddel R, Spendiff S, MacMillan NJ, Filion M, Morais JA, Candia J, Fitzgerald LF, Taivassalo T, Coen PM, Ferrucci L, Hepple RT. Serum Proteomic and Metabolomic Signatures of High Versus Low Physical Function in Octogenarians. Aging Cell 2025; 24:e70002. [PMID: 40059508 PMCID: PMC12073904 DOI: 10.1111/acel.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/12/2024] [Accepted: 01/10/2025] [Indexed: 05/15/2025] Open
Abstract
Physical function declines with aging, yet there is considerable heterogeneity, with some individuals declining very slowly while others experience accelerated functional decline. To gain insight into mechanisms promoting high physical function with aging, we performed proteomics, targeted metabolomics, and targeted kynurenine-focused metabolomic analyses on serum specimens from three groups of octogenarians: High-functioning master athletes (HF, n = 16), healthy normal-functioning non-athletes (NF, n = 12), and lower functioning non-athletes (LF, n = 11). Higher performance status was associated with evidence consistent with: Lower levels of circulating proinflammatory markers, as well as unperturbed tryptophan metabolism, with the normal function of the kynurenic pathway; higher circulating levels of lysophosphatidylcholines that have been previously associated with better mitochondrial oxidative capacity; lower activity of the integrated stress response; lower levels of circulating SASP protein members; and lower levels of proteins that reflect neurodegeneration/denervation. Extending the observations of previous studies focused on the biomarkers of aging that predict poor function, our findings show that many of the same biomarkers associated with poor function exhibit attenuated changes in those who maintain a high function. Because of the cross-sectional nature of this study, results should be interpreted with caution, and bidirectional causality, where physical activity behavior is both a cause and outcome of differences in the biomarker changes, remains a possible interpretation.
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Affiliation(s)
- Ceereena Ubaida‐Mohien
- Intramural Research Program, National Institute on AgingNational Institutes of HealthBaltimoreMarylandUSA
| | - Ruin Moaddel
- Intramural Research Program, National Institute on AgingNational Institutes of HealthBaltimoreMarylandUSA
| | - Sally Spendiff
- Children's Hospital of Eastern Ontario Research InstituteOttawaCanada
| | - Norah J. MacMillan
- Research Institute of the McGill University Health CentreMcGill UniversityMontrealCanada
| | - Marie‐Eve Filion
- Research Institute of the McGill University Health CentreMcGill UniversityMontrealCanada
| | - Jose A. Morais
- Research Institute of the McGill University Health CentreMcGill UniversityMontrealCanada
| | - Julián Candia
- Intramural Research Program, National Institute on AgingNational Institutes of HealthBaltimoreMarylandUSA
| | - Liam F. Fitzgerald
- Department of Physical TherapyUniversity of FloridaGainesvilleFloridaUSA
| | - Tanja Taivassalo
- Department of Physiology and AgingUniversity of FloridaGainesvilleFloridaUSA
| | - Paul M. Coen
- Translational Research InstituteAdvent HealthOrlandoFloridaUSA
| | - Luigi Ferrucci
- Intramural Research Program, National Institute on AgingNational Institutes of HealthBaltimoreMarylandUSA
| | - Russell T. Hepple
- Department of Physical TherapyUniversity of FloridaGainesvilleFloridaUSA
- Department of Physiology and AgingUniversity of FloridaGainesvilleFloridaUSA
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Tang X, Mo D, Jiang N, Kou Y, Zhang Z, Peng R, Mao X, Wang R, Wang Y, Yan F. Polysaccharides from maggot extracts suppressed colorectal cancer progression by inducing ferroptosis via HMOX1/GPX4 signaling pathway. Int J Biol Macromol 2025; 296:139734. [PMID: 39798758 DOI: 10.1016/j.ijbiomac.2025.139734] [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: 09/05/2024] [Revised: 11/17/2024] [Accepted: 01/08/2025] [Indexed: 01/15/2025]
Abstract
Maggots contain various kinds of polysaccharides and recent studies mostly concentrated on their anti-inflammatory functions. While the molecule mechanisms related to the polysaccharides inhibiting carcinogenesis remains unclear. Here we characterized the polysaccharides extracted from maggot (MEs) determining their anti-colon cancer potentials. ME in this study were composed of glucose, mannose, galactose, arabinose and xylose. ME dose-and time-dependently inhibited viability and obviously induced G0/G1 phase arrest in human colon cancer cells. Additionally, Proteomics and western blotting proved that ME suppressed the expression of GPX4 and increased the expression of HMOX1 in vivo and vitro. ME promoted ferroptosis in HCT116 and LOVO cells, reversing ROS, lipid peroxidation and GSSG/GSH radio level. In general, the findings stated that the polysaccharides provided effects of inducing colon cancer ferroptosis, uncovering potential function of ME from maggot as a candidate compound.
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Affiliation(s)
- Xun Tang
- Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, 42 Baiziting Road, Xuanwu District, Nanjing 210009, China; State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - Dongping Mo
- Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, 42 Baiziting Road, Xuanwu District, Nanjing 210009, China
| | - Ning Jiang
- Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Yingying Kou
- Good Clinical Practice Office, the Affiliated Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Zhe Zhang
- Department of Pathology, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Rui Peng
- Department of General Surgery, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xuelian Mao
- Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, 42 Baiziting Road, Xuanwu District, Nanjing 210009, China
| | - Rong Wang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210000, Jiangsu, PR China.
| | - Yong Wang
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China.
| | - Feng Yan
- Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, 42 Baiziting Road, Xuanwu District, Nanjing 210009, China.
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Chen G, Long J, Zhang Y, Zhou X, Gao B, Qin Z, Zhu Y, Song B, Cui Z, Liu Z, Xu M, Yu Z, Song B, Zhang Z. Fascia-derived stem cells enhance fat graft retention by promoting vascularization through the HMOX1-HIF-1α pathway. Stem Cell Res Ther 2025; 16:92. [PMID: 40001185 PMCID: PMC11863534 DOI: 10.1186/s13287-025-04204-w] [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: 10/03/2024] [Accepted: 01/29/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Adipose tissue is a widely used autologous soft tissue filler in plastic surgery, particularly for volumetric restoration in cases of soft tissue deficiency. However, effectively controlling the retention rate of transplanted fat remains a major challenge. Therefore, this study aims to explore strategies to enhance fat graft retention. We isolated fascia-derived stem cells (FDSCs) from human superficial fascia and compared their gene expression profiles with those of adipose-derived stem cells (ADSCs). Through bioinformatics analysis and functional experiments, we identified significant differences in the angiogenic potential of the two cell types. Based on sequencing results, we further investigated the roles of hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HMOX1). This study highlights the critical potential of FDSCs in improving fat graft retention and promoting angiogenesis, offering new strategies for enhancing graft survival and optimizing tissue regeneration therapies. METHODS We isolated fascia-derived stem cells (FDSCs) from human superficial fascia and compared them with adipose-derived stem cells (ADSCs). RNA sequencing was performed to analyze gene expression profiles, followed by bioinformatics analysis to identify differences in angiogenic potential. Functional experiments were conducted to investigate the roles of HIF-1α and HMOX1 in angiogenesis. RESULTS RNA sequencing revealed significant gene expression differences related to angiogenesis in FDSCs. The expression levels of HMOX1, HIF-1α, and VEGFa were significantly higher in FDSCs than in ADSCs, and HMOX1 positively regulated the expression of HIF-1α and VEGFa. In vitro experiments demonstrated that FDSCs promoted angiogenesis more effectively than ADSCs. In vivo co-transplantation experiments further confirmed that FDSCs improved fat graft retention and vascularization. CONCLUSIONS We demonstrated that FDSCs can more effectively promote vascularization both in vitro and in vivo, and significantly improve graft retention, indicating their broad potential for future applications in tissue repair and regeneration.
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Affiliation(s)
- Guo Chen
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jie Long
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Medical Cosmetic Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 310006, Hangzhou, Zhejiang, China
| | - Yuge Zhang
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xuhua Zhou
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Botao Gao
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zijin Qin
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Craniomaxillofacial Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yuhan Zhu
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Binyu Song
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ziwei Cui
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhangzi Liu
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Man Xu
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhou Yu
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Baoqiang Song
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Ziang Zhang
- Department of Plastic and Reconstruction Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
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Qin W, Nie P, Hui X, Chen F, Hu X, Shi W, Luo M, Li B. Research progress of hypoxia-inducible factor-1α and zinc in the mechanism of diabetic kidney disease. Front Pharmacol 2025; 16:1537749. [PMID: 39995420 PMCID: PMC11847805 DOI: 10.3389/fphar.2025.1537749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 01/16/2025] [Indexed: 02/26/2025] Open
Abstract
Diabetic kidney disease is one of the common complications in diabetic patients and has gradually become an important pathogenic factor in chronic kidney disease. Therefore, studying the mechanisms of its occurrence and development is of great significance for the prevention and treatment of diabetic kidney disease. Some researchers have pointed out that there is a phenomenon of hypoxia in diabetic kidney tissue and believe that hypoxia-inducible factor-1α is closely related to the occurrence and progression of diabetic kidney disease. Additionally, the homeostasis of zinc plays a key role in the body's adaptation to hypoxic environments. However, the specific relationship among these three factors remains unclear. This article provides a detailed review of the multiple roles of hypoxia-inducible factor-1α in the pathogenesis of diabetic kidney disease, including: regulating angiogenesis, increasing the expression of erythropoietin, modulating oxidative stress through the PI3K/AKT and HIF-1α/HO-1 pathways, promoting inflammatory cell infiltration and the release of inflammatory factors to induce inflammatory responses, facilitating epithelial-mesenchymal transition, pathological angiogenesis, and promoting the release of fibrotic factors, ultimately leading to renal fibrosis. Furthermore, HIF-1α also participates in the occurrence and development of diabetic kidney disease through mechanisms such as regulating apoptosis, inducing mitochondrial autophagy, and vascular calcification. At the same time, this article clarifies the regulatory role of the trace element zinc on hypoxia-inducible factor-1α in diabetic kidney disease. This article provides references and insights for further research on the pathogenesis and progression of diabetic kidney disease.
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Affiliation(s)
| | | | | | | | | | | | - Manyu Luo
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Bing Li
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin, China
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Chen Y, Chen H, Li Z. Multifunctional peptide-drug conjugate CORM-401@R9: A novel approach to combat oxidative stress in cataracts. Free Radic Biol Med 2025; 227:570-581. [PMID: 39667589 DOI: 10.1016/j.freeradbiomed.2024.12.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/07/2024] [Accepted: 12/09/2024] [Indexed: 12/14/2024]
Abstract
Cataracts, the leading cause of blindness globally, are primarily driven by oxidative stress and protein aggregation in the lens. Effective pharmacological treatments for cataracts are still elusive. This study developed a novel multifunctional peptide-drug conjugate, CORM-401@R9 (CO-R9), which activates in response to reactive oxygen species (ROS) and releases carbon monoxide (CO). The conjugate combines poly-arginine-9 peptide (R9) with CORM-401 to improve cellular uptake and CO delivery, targeting the elevated ROS levels characteristic of cataract pathology. In vitro, CO-R9 effectively reduced ROS levels and prevented senescence and apoptosis induced by oxidative stress. Further investigation into the molecular mechanisms reveals that CO-R9 restored redox homeostasis by modulating the expression of key genes and proteins involved in antioxidant defense, anti-apoptotic responses, and molecular chaperoning. This study highlights CO-R9 as a promising therapeutic agent with potential for cataract prevention and treatment.
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Affiliation(s)
- Yilin Chen
- School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin, 300071, China; Senior Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Haixu Chen
- Institute of Geriatrics, National Clinical Research Center for Geriatrics Diseases, The Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Zhaohui Li
- School of Medicine, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin, 300071, China; Senior Department of Ophthalmology, The Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China.
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8
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Jiang Q, Du C, Qian L, Shan T, Bao Y, Gu L, Wang S, Yang T, Zhou L, Wang Z, He Y, Wang Q, Wang H, Wang R, Wang L. GPX3 Overexpression Ameliorates Cardiac Injury Post Myocardial Infarction Through Activating LSD1/Hif1α Axis. J Cell Mol Med 2025; 29:e70398. [PMID: 39900557 PMCID: PMC11790353 DOI: 10.1111/jcmm.70398] [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: 09/23/2024] [Revised: 12/21/2024] [Accepted: 01/17/2025] [Indexed: 02/05/2025] Open
Abstract
Myocardial infarction (MI) often results in significant loss of cardiomyocytes (CMs), contributing to adverse ventricular remodelling and heart failure. Therefore, promoting CM survival during the acute stage of MI is crucial. This study aimed to investigate the potential role of GPX3 in cardiac repair following MI. First, plasma GPX3 levels were measured in patients with acute MI (AMI), and myocardial GPX3 expression was assessed in a mouse MI model. Furthermore, the effects of GPX3 on MI were investigated through CM-specific overexpression or knockdown in vitro and in vivo models. RNA sequencing and subsequent experiments were performed to uncover the molecular mechanisms underlying GPX3-related effects. Multi-omics database analysis and experimental verification revealed a significant upregulation of GPX3 expression in ischemic myocardium following MI and in CMs exposed to oxygen-glucose deprivation (OGD). Immunofluorescence results further confirmed elevated cytoplasmic GPX3 expression in CMs under hypoxic conditions. In vitro, GPX3 overexpression mitigated reactive oxygen species (ROS) production and enhanced CM survival during hypoxia, while GPX3 knockdown inhibited these processes. In vivo, CM-specific GPX3 overexpression in the infarct border zone significantly attenuated CM apoptosis and alleviated myocardial injury, promoting cardiac repair and long-term functional recovery. Mechanistically, GPX3 overexpression upregulated LSD1 and Hif1α protein expression, and rescue experiments confirmed the involvement of the LSD1/Hif1α pathway in mediating the protective effects of GPX3. Overall, our findings suggest that GPX3 exerts a protective role in ischemic myocardium post-MI, at least partially through the LSD1/Hif1α axis, highlighting its potential as a therapeutic target for MI treatment.
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Affiliation(s)
- Qi‐Qi Jiang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Chong Du
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ling‐Ling Qian
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical CenterNanjing Medical UniversityWuxiChina
| | - Tian‐Kai Shan
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Yu‐Lin Bao
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ling‐Feng Gu
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Si‐Bo Wang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Tong‐Tong Yang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Liu‐Hua Zhou
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ze‐Mu Wang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ye He
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Qi‐Ming Wang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Hao Wang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ru‐Xing Wang
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical CenterNanjing Medical UniversityWuxiChina
| | - Lian‐Sheng Wang
- Department of CardiologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
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Wang L, Zhao Z, Shu K, Ma M. MPCD Index for Hepatocellular Carcinoma Patients Based on Mitochondrial Function and Cell Death Patterns. Int J Mol Sci 2024; 26:118. [PMID: 39795978 PMCID: PMC11719604 DOI: 10.3390/ijms26010118] [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: 12/03/2024] [Revised: 12/24/2024] [Accepted: 12/24/2024] [Indexed: 01/30/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer with a poor prognosis. During the development of cancer cells, mitochondria influence various cell death patterns by regulating metabolic pathways such as oxidative phosphorylation. However, the relationship between mitochondrial function and cell death patterns in HCC remains unclear. In this study, we used a comprehensive machine learning framework to construct a mitochondrial functional activity-associated programmed cell death index (MPCDI) based on scRNA-seq and RNA-seq data from TCGA, GEO, and ICGC datasets. The index signature was used to classify HCC patients, and studied the multi-omics features, immune microenvironment, and drug sensitivity of the subtypes. Finally, we constructed the MPCDI signature consisting of four genes (S100A9, FYN, LGALS3, and HMOX1), which was one of the independent risk factors for the prognosis of HCC patients. The HCC patients were divided into high- and low-MPCDI groups, and the immune status was different between the two groups. Patients with a high MPCDI had higher TIDE scores and poorer responses to immunotherapy, suggesting that high-MPCDI patients might not be suitable for immunotherapy. By analyzing the drug sensitivity data of CTRP, GDSC, and PRISM databases, it was found that staurosporine has potential therapeutic significance for patients with a high MPCDI. In summary, based on the characteristics of mitochondria function and PCD patterns, we used single-cell and transcriptome data to identify four genes and construct the MPCDI signature, which provided new perspectives and directions for the clinical diagnosis and personalized treatment of HCC patients.
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Affiliation(s)
- Longxing Wang
- Chongqing Key Laboratory of Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China; (L.W.); (Z.Z.); (K.S.)
| | - Zhiming Zhao
- Chongqing Key Laboratory of Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China; (L.W.); (Z.Z.); (K.S.)
| | - Kunxian Shu
- Chongqing Key Laboratory of Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China; (L.W.); (Z.Z.); (K.S.)
| | - Mingyue Ma
- Chongqing Key Laboratory of Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China; (L.W.); (Z.Z.); (K.S.)
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
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10
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Wang J, Guo Y, Huang J, Yan J, Ma J. Using Network Pharmacology and in vivo Experiments to Uncover the Mechanisms of Radix Paeoniae Rubra and Radix Angelicae Sinensis Granules in Treating Diabetes Mellitus-Induced Erectile Dysfunction. Drug Des Devel Ther 2024; 18:6243-6262. [PMID: 39735336 PMCID: PMC11682668 DOI: 10.2147/dddt.s493198] [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: 08/27/2024] [Accepted: 12/10/2024] [Indexed: 12/31/2024] Open
Abstract
Purpose Diabetes mellitus-induced erectile dysfunction (DMED) lacks targeted therapies. This study investigates the mechanisms and targets of Radix Paeoniae Rubra and Radix Angelicae Sinensis Granules (RAG) in treating DMED using network pharmacology and animal models. Methods We identified RAG's active ingredients and potential targets from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. DMED targets were obtained from GeneCards, OMIM, and PharmGKB. Common targets were identified using R, and interaction networks were built. Cytoscape was used to construct a drug-ingredient-disease-target network, and OmicShare tools performed Gene Ontology and KEGG pathway analyses. Molecular Operating Environment software assessed compound-core gene interactions. Additionally, animal models were used for validation. Results Twenty compounds and 25 common targets linked to vasodilation, protein secretion, apoptosis, and hypoxia were selected. Key pathways included HIF-1, MAPK, cAMP, and Ras. Six core genes (INS, CAT, BDNF, CASP3, CRP, HMOX1) were targeted by RAG. Molecular docking showed stable interactions with oleic acid, catechin, and butylated hydroxytoluene. RAG increased NO, intracavernous pressure, and improved penile histology in rats, upregulating eNOS, iNOS, HMOX1, and downregulating HIF-1. Conclusion RAG may treat DMED via the HIF-1α/HMOX1 pathway, offering a potential novel therapy for DMED.
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Affiliation(s)
- Jie Wang
- Zhejiang Hospital, Hangzhou, Zhejiang, 310000, People’s Republic of China
| | - Yingxue Guo
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China
| | - Jie Huang
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China
| | - Junfeng Yan
- Zhejiang Hospital, Hangzhou, Zhejiang, 310000, People’s Republic of China
| | - Jianxiong Ma
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, People’s Republic of China
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China
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11
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Saber S, Abdelhady R, Elhemely MA, Elmorsy EA, Hamad RS, Abdel-Reheim MA, El-kott AF, AlShehri MA, Morsy K, Negm S, Kira AY. Nanoscale Systems for Local Activation of Hypoxia-Inducible Factor-1 Alpha: A New Approach in Diabetic Wound Management. Int J Nanomedicine 2024; 19:13735-13762. [PMID: 39723173 PMCID: PMC11669355 DOI: 10.2147/ijn.s497041] [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: 09/19/2024] [Accepted: 11/03/2024] [Indexed: 12/28/2024] Open
Abstract
Chronic wounds in diabetic patients experience significant clinical challenges due to compromised healing processes. Hypoxia-inducible factor-1 alpha (HIF-1α) is a critical regulator in the cellular response to hypoxia, enhancing angiogenesis and tissue restoration. Nevertheless, the cellular response to the developed chronic hypoxia within diabetes is impaired, likely due to the destabilization of HIF-1α via degradation by prolyl hydroxylase domain (PHD) enzymes. Researchers have extensively explored HIF-1α activation as a potential pathway for diabetic wound management, focusing mainly on deferoxamine (DFO) as a potent agent to stabilize HIF-1α. This review provides an update of the other recent pharmacological agents managing HIF-1α activation, including novel PHD inhibitors (roxadustat and daprodustat) and Von Hippel-Lindau protein (VHL) antagonists, which could be potential alternatives for the local treatment of diabetic wounds. Furthermore, it highlights how localized delivery via advanced nanostructures can enhance the efficacy of these novel therapies. Importantly, by addressing these points, the current review can offer a promising area for research. Given that, these novel drugs have minimal applications in diabetic wound healing, particularly in the context of local application through nanomaterials. This gap presents an exciting opportunity for further investigation, as combining these drugs with localized nanotechnology could avoid undesired systemic side effects and sustain drug release within wound site, offering a transformative platform for diabetes wound treatment.
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Affiliation(s)
- Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt
| | - Rasha Abdelhady
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, 63514, Egypt
| | - Mai A Elhemely
- School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M20 4BX, UK
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, 62521, Egypt
| | - Elsayed A Elmorsy
- Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, 51452, Saudi Arabia
| | - Rabab S Hamad
- Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, 62521, Egypt
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia
| | - Attalla F El-kott
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Mohammed A AlShehri
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Kareem Morsy
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Sally Negm
- Department of Life Sciences, College of Science and Art Mahyel Aseer, King Khalid University, Abha, 62529, Saudi Arabia
| | - Ahmed Y Kira
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt
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12
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Yi S, Ye B, Wang J, Yi X, Wang Y, Abudukelimu A, Wu H, Meng Q, Zhou Z. Investigation of guanidino acetic acid and rumen-protected methionine induced improvements in longissimus lumborum muscle quality in beef cattle. Meat Sci 2024; 217:109624. [PMID: 39141966 DOI: 10.1016/j.meatsci.2024.109624] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/30/2024] [Accepted: 08/03/2024] [Indexed: 08/16/2024]
Abstract
This study examined the impact of dietary guanidino acetic acid (GAA) and rumen-protected methionine (RPM) on beef quality in Simmental bulls. For 140 days, forty-five bulls (453.43 ± 29.05 kg) were randomly divided into control (CON), 0.1% GAA (GAA), and 0.1% GAA + 0.1% RPM (GAM) groups with 15 bulls in each group and containing 3 pen with 5 bulls in each pen. Significant improvements in eye muscle area, pH48h, redness (a*) value, and crude protein (CP) content of longissimus lumborum (LL) muscles were observed in the GAA and GAM groups (P < 0.05). Conversely, the lightness (L*) value, drip loss, cooking loss, and moisture contents decreased (P < 0.05). Additionally, glutathione (GSH) and glutathione peroxidase (GSH-PX) concentrations of LL muscles in GAM were higher (P < 0.05), while malondialdehyde (MDA) content of LL muscles in GAA and GAM groups were lower (P < 0.05). Polyunsaturated fatty acids (PUFA) profiles were enriched in beef from GAM group (P < 0.05). The addition of GAA and RPM affected the expression of genes in LL muscle, such as HMOX1, EIF4E, SCD5, and NOS2, which are related to hypoxia metabolism, protein synthesis, and unsaturated fatty acid synthesis-related signaling pathways. In addition, GAA and RPM also affected the content of a series of metabolites such as L-tyrosine, L-tryptophan, and PC (O-16:0/0:0) involved in amino acid and lipid metabolism-related signaling pathways. In summary, GAA and RPM can improve the beef quality and its nutritional composition. These changes may be related to changes in gene expression and metabolic pathways related to protein metabolism and lipid metabolism in beef.
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Affiliation(s)
- Simeng Yi
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; College of Grassland Science and Technology, China Agricultural University, Beijing 100193, China; Frontier Technology Research Institute of China Agricultural University in Shenzhen, China Agricultural University, Shenzhen 518119, China
| | - Boping Ye
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Jinze Wang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Xin Yi
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yao Wang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Abudusaimijiang Abudukelimu
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Hao Wu
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Qingxiang Meng
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Zhenming Zhou
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
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13
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Wu B, Xu W, Wu K, Li Y, Hu M, Feng C, Zhu C, Zheng J, Cui X, Li J, Fan D, Zhang F, Liu Y, Chen J, Liu C, Li G, Qiu Q, Qu K, Wang W, Wang K. Single-cell analysis of the amphioxus hepatic caecum and vertebrate liver reveals genetic mechanisms of vertebrate liver evolution. Nat Ecol Evol 2024; 8:1972-1990. [PMID: 39152328 DOI: 10.1038/s41559-024-02510-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 07/19/2024] [Indexed: 08/19/2024]
Abstract
The evolution of the vertebrate liver is a prime example of the evolution of complex organs, yet the driving genetic factors behind it remain unknown. Here we study the evolutionary genetics of liver by comparing the amphioxus hepatic caecum and the vertebrate liver, as well as examining the functional transition within vertebrates. Using in vivo and in vitro experiments, single-cell/nucleus RNA-seq data and gene knockout experiments, we confirm that the amphioxus hepatic caecum and vertebrate liver are homologous organs and show that the emergence of ohnologues from two rounds of whole-genome duplications greatly contributed to the functional complexity of the vertebrate liver. Two ohnologues, kdr and flt4, play an important role in the development of liver sinusoidal endothelial cells. In addition, we found that liver-related functions such as coagulation and bile production evolved in a step-by-step manner, with gene duplicates playing a crucial role. We reconstructed the genetic footprint of the transfer of haem detoxification from the liver to the spleen during vertebrate evolution. Together, these findings challenge the previous hypothesis that organ evolution is primarily driven by regulatory elements, underscoring the importance of gene duplicates in the emergence and diversification of a complex organ.
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Affiliation(s)
- Baosheng Wu
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Wenjie Xu
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Kunjin Wu
- Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
- Department of Hepatobiliary Surgery and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ye Li
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Mingliang Hu
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Chenguang Feng
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Chenglong Zhu
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Jiangmin Zheng
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Xinxin Cui
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Jing Li
- Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
- Department of Hepatobiliary Surgery and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Deqian Fan
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Fenghua Zhang
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Yuxuan Liu
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China
| | - Jinping Chen
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Chang Liu
- Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
- Department of Hepatobiliary Surgery and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Guang Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
| | - Qiang Qiu
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China.
| | - Kai Qu
- Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education, Xi'an, China.
- Department of Hepatobiliary Surgery and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Wen Wang
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China.
- New Cornerstone Science Laboratory, Xi'an, China.
| | - Kun Wang
- Shaanxi Key Laboratory of Qinling Ecological Intelligent Monitoring and Protection, School of Ecology and Environment, Northwestern Polytechnical University, Xi'an, China.
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China.
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14
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Wang Y, Chen Y, Li Z, Tang L, Wen D, Wu Y, Guo Z. Electroacupuncture enhances cerebral blood perfusion by inhibiting HIF-1α in rat subarachnoid hemorrhage. Brain Res 2024; 1839:149010. [PMID: 38763503 DOI: 10.1016/j.brainres.2024.149010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/06/2024] [Accepted: 05/16/2024] [Indexed: 05/21/2024]
Abstract
OBJECTIVE Cerebral blood perfusion (CBP) reduction is a prevalent complication following subarachnoid hemorrhage (SAH) in clinical practice, often associated with long-term cognitive impairment and prognosis. Electroacupuncture (EA), a widely utilized traditional Chinese therapy for central nervous system disorders, has demonstrated promising therapeutic effects. This study aims to investigate the therapeutic potential of EA in restoring CBP in SAH rats and to explore the mechanisms involving HIF-1α in this process. METHODS Rats were randomly assigned to one of five groups, including Sham, SAH, EA, EA + Saline, and EA + dimethyloxallyl glycine (DMOG) groups. EA treatment was administered for 10 min daily, while DMOG were intraperitoneally injected. Behavioral tests, cerebral blood flow monitoring, vascular thickness measurement, western blotting, and immunofluorescence staining were conducted to assess the therapeutic effects of EA on cerebral blood flow. RESULTS SAH resulted in elevated levels of HIF-1α, endothelin (ET), ICAM-1, P-SELECTIN, E-SELECTIN, and decreased level of eNOS in the brain. This led to cerebral vasospasm, decreased CBF, and cognitive deficits in the rat SAH model. EA intervention downregulated the expression of HIF-1α, ET, ICAM-1, P-SELECTIN, and E-SELECTIN, while increasing eNOS expression. This alleviated cerebral vasospasm, restored CBF, and improved cognitive function. However, the administration of the HIF-1α stabilizer (DMOG) counteracted the therapeutic effects of EA. CONCLUSION EA promotes the recovery of cerebral blood flow after SAH injury, attenuates cerebral vasospasm, and accelerates the recovery of cognitive dysfunction, and its mechanism of action may be related to the inhibition of the HIF-1α signaling pathway.
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Affiliation(s)
- Yingwen Wang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yu Chen
- Department of Rehabilitation, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Zhao Li
- Emergency Department, Chengdu First People's Hospital, Chengdu, Sichuan Province, China.
| | - Liuyang Tang
- Department of Neurosurgery, The People's Hospital of Qijiang District, 401420, China
| | - Daochen Wen
- Department of Neurosurgery, Xuanhan County People's Hospital, Dazhou, China.
| | - Yue Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Zongduo Guo
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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15
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Chen J, Qiu S, Liu Y, Sun W, Zhou T, Zhao L, Li Z, Duan Y. Ultrasound targeted microbubble destruction assisted exosomal delivery of siHmox1 effectively inhibits doxorubicin-induced cardiomyocyte ferroptosis. J Nanobiotechnology 2024; 22:531. [PMID: 39218878 PMCID: PMC11367924 DOI: 10.1186/s12951-024-02794-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: 01/11/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Ferroptosis, triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DOX-induced cardiomyopathy (DIC), and thus limits the use of doxorubicin (DOX) in clinic. Here, we further showed that cardiac ferroptosis induced by DOX in mice was attributed to up-regulation of Hmox1, as knockdown of Hmox1 effectively inhibited cardiomyocyte ferroptosis. To targeted delivery of siRNA into cardiomyocytes, siRNA-encapsulated exosomes were injected followed by ultrasound microbubble targeted destruction (UTMD) in the heart region. UTMD greatly facilitated exosome delivery into heart. Consistently, UTMD assisted exosomal delivery of siHomox1 nearly blocked the ferroptosis and the subsequent cardiotoxicity induced by doxorubicin. In summary, our findings reveal that the upregulation of HMOX1 induces ferroptosis in cardiomyocytes and UTMD-assisted exosomal delivery of siHmox1 can be used as a potential therapeutic strategy for DIC.
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Affiliation(s)
- Jianmei Chen
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China
- Department of Health Medicine, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Shuo Qiu
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China
| | - Yang Liu
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China
| | - Wenqi Sun
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China
| | - Tian Zhou
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China
| | - Lianbi Zhao
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China.
| | - Zhelong Li
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China.
| | - Yunyou Duan
- Department of Ultrasound Diagnostics, Tangdu Hospital, The Fourth Military Medical University, NO. 569th Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China.
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Zhang M, Li J, Hu W. The complex interplay between ferroptosis and atherosclerosis. Biomed Pharmacother 2024; 178:117183. [PMID: 39079265 DOI: 10.1016/j.biopha.2024.117183] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/25/2024] Open
Abstract
Atherosclerosis, characterized by the accumulation of plaque within the arterial walls, is an intricate cardiovascular disease that often results in severe health issues. Recent studies have emphasized the importance of ferroptosis, a controlled type of cell death dependent on iron, as a critical factor in this disease state. Ferroptosis, distinguished by its reliance on iron and the accumulation of lipid hydroperoxides, offers a unique insight into the pathology of atherosclerotic lesions. This summary encapsulates the current knowledge of the intricate role ferroptosis plays in the onset and progression of atherosclerosis. It explores the molecular processes through which lipid peroxidation and iron metabolism contribute to the development of atheromatous plaques and evaluates the possibility of utilizing ferroptosis as a novel treatment approach for atherosclerosis. By illuminating the intricate relationship between ferroptosis-related processes and atherosclerosis, this review paves the way for future clinical applications and personalized medicine approaches aimed at alleviating the effects of atherosclerosis.
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Affiliation(s)
- Mao Zhang
- Department of Vascular Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiangping Li
- Department of Oncological Radiotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Hu
- Department of Vascular Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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17
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Chai Z, Zheng J, Shen J. Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke. CNS Neurosci Ther 2024; 30:e14865. [PMID: 39042604 PMCID: PMC11265528 DOI: 10.1111/cns.14865] [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: 04/11/2024] [Revised: 06/27/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
Ferroptosis is a newly discovered form of programmed cell death that is non-caspase-dependent and is characterized by the production of lethal levels of iron-dependent lipid reactive oxygen species (ROS). In recent years, ferroptosis has attracted great interest in the field of cerebral infarction because it differs morphologically, physiologically, and genetically from other forms of cell death such as necrosis, apoptosis, autophagy, and pyroptosis. In addition, ROS is considered to be an important prognostic factor for ischemic stroke, making it a promising target for stroke treatment. This paper summarizes the induction and defense mechanisms associated with ferroptosis, and explores potential treatment strategies for ischemic stroke in order to lay the groundwork for the development of new neuroprotective drugs.
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Affiliation(s)
- Zhaohui Chai
- Department of NeurosurgeryFirst Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhou CityChina
| | - Jiesheng Zheng
- Department of NeurosurgeryFirst Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhou CityChina
| | - Jian Shen
- Department of NeurosurgeryFirst Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhou CityChina
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Huang Y, Li L, Li Y, Lu N, Qin H, Wang R, Li W, Cheng Z, Li Z, Kang P, Ye H, Gao Q. Knockdown of LncRNA Lcn2-204 alleviates sepsis-induced myocardial injury by regulation of iron overload and ferroptosis. J Mol Cell Cardiol 2024; 192:79-93. [PMID: 38761990 DOI: 10.1016/j.yjmcc.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 05/09/2024] [Accepted: 05/15/2024] [Indexed: 05/20/2024]
Abstract
Ferroptosis is an iron-dependent programmed cell death form resulting from lipid peroxidation damage, it plays a key role in organ damage and tumor development from various causes. Sepsis leads to severe host response after infection with high mortality. The long non-coding RNAs (LncRNAs) are involved in different pathophysiological mechanisms of multiple diseases. Here, we used cecal ligation and puncture (CLP) operation to mimic sepsis induced myocardial injury (SIMI) in mouse model, and LncRNAs and mRNAs were profiled by Arraystar mouse LncRNA Array V3.0. Based on the microarray results, 552 LncRNAs and 520 mRNAs were differentially expressed in the sham and CLP groups, among them, LncRNA Lcn2-204 was the highest differentially expressed up-regulated LncRNA. Iron metabolism disorder was involved in SIMI by bioinformatics analysis, meanwhile, myocardial iron content and lipocalin-2 (Lcn2) protein expressions were increased. The CNC network comprised 137 positive interactions and 138 negative interactions. Bioinformatics analysis showed several iron-related terms were enriched and six genes (Scara5, Tfrc, Lcn2, Cp, Clic5, Ank1) were closely associated with iron metabolism. Then, we constructed knockdown LncRNA Lcn2-204 targeting myocardium and found that it ameliorated cardiac injury in mouse sepsis model through modulating iron overload and ferroptosis. In addition, we found that LncRNA Lcn2-204 was involved in the regulation of Lcn2 expression in septic myocardial injury. Based on these findings, we conclude that iron overload and ferroptosis are the key mechanisms leading to myocardial injury in sepsis, knockdown of LncRNA Lcn2-204 plays the cardioprotective effect through inhibition of iron overload, ferroptosis and Lcn2 expression. It may provide a novel therapeutic approach to ameliorate sepsis-induced myocardial injury.
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Affiliation(s)
- Yuhui Huang
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Lu Li
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Yuping Li
- Department of Life Sciences, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Na Lu
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - Hongqian Qin
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - Rui Wang
- Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Wentao Li
- Department of Clinical Medicine, Bengbu Medical University, Bengbu 233000, China
| | - Zhipeng Cheng
- Department of Clinical Medicine, Bengbu Medical University, Bengbu 233000, China
| | - Zhenghong Li
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China
| | - Pinfang Kang
- Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China; Department of Cardiovascular Medicine, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233000, China
| | - Hongwei Ye
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China.
| | - Qin Gao
- Department of Physiology, Bengbu Medical University, Bengbu 233030, China; Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China.
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Zhou J, Sheng Y, Chen Z, Ding H, Zheng X. RNA-seq reveals differentially expressed lncRNAs and circRNAs and their associated functional network in HTR-8/Svneo cells under hypoxic conditions. BMC Med Genomics 2024; 17:172. [PMID: 38943134 PMCID: PMC11212387 DOI: 10.1186/s12920-024-01933-4] [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: 01/04/2024] [Accepted: 06/13/2024] [Indexed: 07/01/2024] Open
Abstract
Placental hypoxia is hazardous to maternal health as well as fetal growth and development. Preeclampsia and intrauterine growth restriction are common pregnancy problems, and one of the causes is placental hypoxia. Placental hypoxia is linked to a number of pregnancy illnessesv. To investigate their potential function in anoxic circumstances, we mimicked the anoxic environment of HTR-8/Svneo cells and performed lncRNA and circRNA studies on anoxic HTR-8/Svneo cells using high-throughput RNA sequencing. The miRNA target genes were predicted by integrating the aberrant expression of miRNAs in the placenta of preeclampsia and intrauterine growth restriction, and a ceRNA network map was developed to conduct a complete transcriptomic and bioinformatics investigation of circRNAs and lncRNAs. The signaling pathways in which the genes were primarily engaged were predicted using GO and KEGG analyses. To propose a novel explanation for trophoblastic organism failure caused by lncRNAs and circRNAs in an anoxic environment.
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Affiliation(s)
- Jiaqing Zhou
- Obstetrics and Gynecology, Ningbo University, Ningbo, China
- Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - YueHua Sheng
- Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Zhezhan Chen
- Obstetrics and Gynecology, Ningbo University, Ningbo, China
- Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Huiqing Ding
- Obstetrics and Gynecology, Ningbo University, Ningbo, China.
- Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China.
| | - Xiaojiao Zheng
- Obstetrics and Gynecology, Ningbo University, Ningbo, China.
- Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China.
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20
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Phelps J, Hart DA, Mitha AP, Duncan NA, Sen A. Extracellular Vesicles Generated by Mesenchymal Stem Cells in Stirred Suspension Bioreactors Promote Angiogenesis in Human-Brain-Derived Endothelial Cells. Int J Mol Sci 2024; 25:5219. [PMID: 38791256 PMCID: PMC11121007 DOI: 10.3390/ijms25105219] [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: 04/03/2024] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
Interrupted blood flow in the brain due to ischemic injuries such as ischemic stroke or traumatic brain injury results in irreversible brain damage, leading to cognitive impairment associated with inflammation, disruption of the blood-brain barrier (BBB), and cell death. Since the BBB only allows entry to a small class of drugs, many drugs used to treat ischemia in other tissues have failed in brain-related disorders. The administration of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) has shown promise in improving the functional recovery of the brain following cerebral ischemia by inducing blood vessel formation. To facilitate such a treatment approach, it is necessary to develop bioprocesses that can produce therapeutically relevant MSC-EVs in a reproducible and scalable manner. This study evaluated the feasibility of using stirred suspension bioreactors (SSBs) to scale-up the serum-free production of pro-angiogenic MSC-EVs under clinically relevant physioxic conditions. It was found that MSCs grown in SSBs generated EVs that stimulated angiogenesis in cerebral microvascular endothelial cells, supporting the use of SSBs to produce MSC-EVs for application in cerebral ischemia. These properties were impaired at higher cell confluency, outlining the importance of considering the time of harvest when developing bioprocesses to manufacture EV populations.
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Affiliation(s)
- Jolene Phelps
- Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada;
- Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada; (D.A.H.); (A.P.M.)
- McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB T2N 4Z6, Canada;
| | - David A. Hart
- Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada; (D.A.H.); (A.P.M.)
- McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB T2N 4Z6, Canada;
- Department of Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada
- Faculty of Kinesiology, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada
| | - Alim P. Mitha
- Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada; (D.A.H.); (A.P.M.)
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, 1403 29 Street N.W., Calgary, AB T2N 2T9, Canada
| | - Neil A. Duncan
- McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB T2N 4Z6, Canada;
- Department of Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada
- Department of Civil Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada
| | - Arindom Sen
- Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada;
- Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada; (D.A.H.); (A.P.M.)
- McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive N.W., Calgary, AB T2N 4Z6, Canada;
- Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Drive N.W., Calgary, AB T2N 1N4, Canada
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21
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Wang Y, Wang R, Zhu J, Chen L. Identification of mitophagy and ferroptosis-related hub genes associated with intracerebral haemorrhage through bioinformatics analysis. Ann Hum Biol 2024; 51:2334719. [PMID: 38863372 DOI: 10.1080/03014460.2024.2334719] [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: 11/07/2023] [Accepted: 03/21/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Mitophagy and ferroptosis occur in intracerebral haemorrhage (ICH) but our understanding of mitophagy and ferroptosis-related genes remains incomplete. AIM This study aims to identify shared ICH genes for both processes. METHODS ICH differentially expressed mitophagy and ferroptosis-related genes (DEMFRGs) were sourced from the GEO database and literature. Enrichment analysis elucidated functions. Hub genes were selected via STRING, MCODE, and MCC algorithms in Cytoscape. miRNAs targeting hubs were predicted using miRWalk 3.0, forming a miRNA-hub gene network. Immune microenvironment variances were assessed with MCP and TIMER. Potential small molecules for ICH were forecasted via CMap database. RESULTS 64 DEMFRGs and ten hub genes potentially involved in various processes like ferroptosis, TNF signalling pathway, MAPK signalling pathway, and NF-kappa B signalling pathway were discovered. Several miRNAs were identified as shared targets of hub genes. The ICH group showed increased infiltration of monocytic lineage and myeloid dendritic cells compared to the Healthy group. Ten potential small molecule drugs (e.g. Zebularine, TWS-119, CG-930) were predicted via CMap. CONCLUSION Several shared genes between mitophagy and ferroptosis potentially drive ICH progression via TNF, MAPK, and NF-kappa B pathways. These results offer valuable insights for further exploring the connection between mitophagy, ferroptosis, and ICH.
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Affiliation(s)
- Yan Wang
- Department of Basic Medicine, Cangzhou Medical College, Cangzhou, China
| | - Rufeng Wang
- Department of Basic Medicine, Cangzhou Medical College, Cangzhou, China
| | - Jianzhong Zhu
- Department of Basic Medicine, Cangzhou Medical College, Cangzhou, China
| | - Ling Chen
- Department of Gynaecology, People's Hospital Affiliated to Cangzhou Medical College, Cangzhou, China
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Ke ZP, Tao WQ, Zhao G, Cheng K. Role of PPAR-related genes in chronic heart failure: evidence from large populations. BMC Cardiovasc Disord 2023; 23:552. [PMID: 37950149 PMCID: PMC10638691 DOI: 10.1186/s12872-023-03554-8] [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: 03/27/2023] [Accepted: 10/10/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND The role of PPAR signaling and its associated genes in the pathogenesis and progression of chronic heart failure (CHF) remains elusive. METHODS We accessed the gene expression profile and relevant baseline information of CHF samples from the Gene Expression Omnibus (GEO) database, specifically from the GSE57338 project. RESULTS From GSE57338 project, we derived the expression value of 126 PPAR-related genes. A protein-protein interaction network was then established to illustrate potential protein interactions. ClueGO analysis results revealed that these genes predominantly participate in functions such as export across plasma membrane, regulation of lipid metabolic process, fatty acid metabolism, circulatory system vascular processes, alcohol metabolism, triglyceride metabolism and regulation of lipid localization and response to nutrient. Using the cytohubba plug-in in Cytoscape, we pinpointed ACADM, PPARG and CPT2 as potential central molecules in HF pathogenesis and progression. Subsequent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis delved into the potential biological role of these three genes in CHF. Immune infiltration analysis suggested that the infiltration level of neutrophils and M2 macrophages might be notably influenced by these genes, thereby playing a role in the CHF mechanism. CONCLUSIONS Our research provides a comprehensive insight into the significance of PPAR associated genes in CHF development. Notably, the genes ACADM, PPARG and CPT2 emerged as potential targets for clinical interventions.
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Affiliation(s)
- Zun-Ping Ke
- Department of Geriatrics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Wen-Qi Tao
- Department of Cardiology, Jing'an District Centre Hospital of Shanghai, Fudan University, Shanghai, 200040, China
| | - Gang Zhao
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China
| | - Kuan Cheng
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.
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23
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Kapanadze T, Gamrekelashvili J, Sablotny S, Kijas D, Haller H, Schmidt-Ott K, Limbourg FP. CSF-1 and Notch signaling cooperate in macrophage instruction and tissue repair during peripheral limb ischemia. Front Immunol 2023; 14:1240327. [PMID: 37691936 PMCID: PMC10484478 DOI: 10.3389/fimmu.2023.1240327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/14/2023] [Indexed: 09/12/2023] Open
Abstract
Ischemia causes an inflammatory response featuring monocyte-derived macrophages (MF) involved in angiogenesis and tissue repair. Angiogenesis and ischemic macrophage differentiation are regulated by Notch signaling via Notch ligand Delta-like 1 (Dll1). Colony stimulating factor 1 (CSF-1) is an essential MF lineage factor, but its role in ischemic macrophage development and the interaction with Notch signaling is so far unclear. Using a mouse model of hind limb ischemia with CSF-1 inhibitor studies and Dll1 heterozygous mice we show that CSF-1 is induced in the ischemic niche by a subpopulation of stromal cells expressing podoplanin, which was paralleled by the development of ischemic macrophages. Inhibition of CSF-1 signaling with small molecules or blocking antibodies impaired macrophage differentiation but prolonged the inflammatory response, resulting in impaired perfusion recovery and tissue regeneration. Yet, despite high levels of CSF-1, macrophage maturation and perfusion recovery were impaired in mice with Dll1 haploinsufficiency, while inflammation was exaggerated. In vitro, CSF-1 was not sufficient to induce full MF differentiation from donor monocytes in the absence of recombinant DLL1, while the presence of DLL1 in a dose-dependent manner stimulated MF differentiation in combination with CSF-1. Thus, CSF-1 is an ischemic niche factor that cooperates with Notch signaling in a non-redundant fashion to instruct macrophage cell fate and maturation, which is required for ischemic perfusion recovery and tissue repair.
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Affiliation(s)
- Tamar Kapanadze
- Vascular Medicine Research, Hannover Medical School, Hannover, Germany
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Jaba Gamrekelashvili
- Vascular Medicine Research, Hannover Medical School, Hannover, Germany
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Stefan Sablotny
- Vascular Medicine Research, Hannover Medical School, Hannover, Germany
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Dustin Kijas
- Vascular Medicine Research, Hannover Medical School, Hannover, Germany
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Hermann Haller
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Kai Schmidt-Ott
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Florian P. Limbourg
- Vascular Medicine Research, Hannover Medical School, Hannover, Germany
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
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Zhang X, Jing F, Guo C, Li X, Li J, Liang G. Tumor-suppressive function and mechanism of miR-873-5p in glioblastoma: evidence based on bioinformatics analysis and experimental validation. Aging (Albany NY) 2023; 15:5412-5425. [PMID: 37382594 PMCID: PMC10333085 DOI: 10.18632/aging.204800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/16/2023] [Indexed: 06/30/2023]
Abstract
This study aims to clarify the mechanistic actions of microRNA-873-5p (miR-873-5p) on glioblastoma (GBM) progression. The most differentially expressed miRNAs were retrieved from the GEO database. It was established that miR-873-5p was downregulated in GBM tissues and cells. Based on in silico prediction and experimental data, HMOX1 was demonstrated to be a target gene of miR-873-5p. Further, miR-873-5p was then ectopically expressed in GBM cells to examine its effect on the malignant behaviors of GBM cells. Overexpression of miR-873-5p inhibited GBM cell proliferation and invasion by targeting HMOX1. HMOX1 promoted SPOP expression by increasing HIF1α expression, thus stimulating GBM cell malignant phenotypes. miR-873-5p suppressed the malignant phenotypes of GBM cells and tumorigenesis in vitro and in vivo by inhibiting the HMOX1/HIF1α/SPOP signaling axis. This study uncovers a novel miR-873-5p/HMOX1/HIF1α/SPOP axis in GBM, providing new insights into GBM progression and therapeutic targets for GBM treatment.
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Affiliation(s)
- Xiaobin Zhang
- Department of Neurosurgery, General Hospital of the Northern Theater Command of Chinese People’s Liberation Army, Shenyang 110000, China
| | - Fangkun Jing
- Department of Neurosurgery, Jinqiu Hospital of Liaoning Province, Shenyang 110000, China
| | - Chen Guo
- Department of Neurosurgery, General Hospital of the Northern Theater Command of Chinese People’s Liberation Army, Shenyang 110000, China
| | - Xinning Li
- Department of Neurosurgery, General Hospital of the Northern Theater Command of Chinese People’s Liberation Army, Shenyang 110000, China
| | - Jianan Li
- Department of Neurosurgery, General Hospital of the Northern Theater Command of Chinese People’s Liberation Army, Shenyang 110000, China
| | - Guobiao Liang
- Department of Neurosurgery, General Hospital of the Northern Theater Command of Chinese People’s Liberation Army, Shenyang 110000, China
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Jeong J, Kim D, Choi J. Integrative Data Mining Approach: Case Study with Adverse Outcome Pathway Network Leading to Pulmonary Fibrosis. Chem Res Toxicol 2023. [PMID: 37093963 DOI: 10.1021/acs.chemrestox.2c00325] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
An adverse outcome pathway (AOP) framework can be applied as an efficient tool for the rapid screening of environmental chemicals. For the development of an AOP, a database mining approach can support an expert derivation approach by gathering a wider range of evidence than in a literature review. In this study, data from various databases were integrated and analyzed to supplement the AOP leading to pulmonary fibrosis by analyzing additional evidence using a data mining approach and establishing an application domain for chemicals. First, we collected chemicals, genes, and phenotypes that were studied and related to pulmonary fibrosis through the Comparative Toxicogenomics Database (CTD). CGPD-tetramers constructed by linking each related chemical, gene, phenotype, and disease can provide the basic components for the assembly of putative AOPs. Next, an AOP network was established by connecting eight existing AOPs for pulmonary fibrosis developed by expert derivation from the AOP Wiki. Finally, the pulmonary fibrosis AOP network was proposed by integrating the AOP network from AOP Wiki and the CGPD-tetramers from the CTD. To prioritize potential chemical stressors in the AOP network, 61 chemicals were ranked using the relevance of the chemical to the AOP and chemical exposure information from the CompTox Chemicals Dashboard. The approach proposed in this study can guide the utilization of available evidence from various databases as well as the literature in constructing AOP networks related to specific diseases.
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Affiliation(s)
- Jaeseong Jeong
- School of Environmental Engineering, University of Seoul, 163 Seoulsiripdae-ro, Dongdaemun-gu, Seoul 02504, Republic of Korea
| | - Donghyeon Kim
- School of Environmental Engineering, University of Seoul, 163 Seoulsiripdae-ro, Dongdaemun-gu, Seoul 02504, Republic of Korea
| | - Jinhee Choi
- School of Environmental Engineering, University of Seoul, 163 Seoulsiripdae-ro, Dongdaemun-gu, Seoul 02504, Republic of Korea
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Tang HZ, Yang ZP, Lu S, Wang B, Wang YY, Sun XB, Qu JX, Rao BQ. Network pharmacology-based analysis of heat clearing and detoxifying drug JC724 on the treatment of colorectal cancer. World J Gastrointest Oncol 2023; 15:90-101. [PMID: 36684054 PMCID: PMC9850754 DOI: 10.4251/wjgo.v15.i1.90] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/28/2022] [Accepted: 12/21/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Heat-clearing and detoxifying drugs has protective effect on colorectal cancer (CRC). Given the complicated features of Traditional Chinese medicine formulas, network pharmacology is an effective approach for studying the multiple interactions between drugs and diseases.
AIM To systematically explore the anticancer mechanism of heat-clearing and detoxifying drug JC724.
METHODS This study obtained the active compounds and their targets in JC724 from Traditional Chinese Medicine System Pharmacology Database. In addition, the CRC targets were obtained from Drugbank, TTD, DisGeNET and GeneCards databases. We performed transcriptome analysis of differentially expressed genes in CRC treated with JC724. Venn diagram was used to screen the JC724-CRC intersection targets as candidate targets. Core targets were selected by protein-protein interaction network and herb ingredient-target-disease network analysis. The functional and pathway of core targets were analysed by enrichment analysis.
RESULTS We found 174 active ingredients and 283 compound targets from JC724. 940 CRC-related targets were reserved from the four databases and 304 CRC differentially expressed genes were obtained by transcriptome analysis. We constructed the network and found that the five core ingredients were quercetin, β Beta sitosterol, wogonin, kaempferol and baicalein. The core JC724-CRC targets were CYP1A1, HMOX1, CXCL8, NQO1 and FOSL1. JC724 acts on multiple signaling pathways associated with CRC, including the Nrf2 signaling pathway, oxidative stress, and the IL-17 signaling pathway.
CONCLUSION In this study, we systematically analyzed the active ingredients, core targets and main mechanisms of JC724 in the treatment of CRC. This study could bring a new perspective to the heat-clearing and detoxifying therapy of CRC.
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Affiliation(s)
- Hua-Zhen Tang
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastrointestinal Surgery, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing 100038, China
| | - Zhen-Peng Yang
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastrointestinal Surgery, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing 100038, China
| | - Shuai Lu
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastrointestinal Surgery, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing 100038, China
| | - Bing Wang
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastrointestinal Surgery, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing 100038, China
| | - Yu-Ying Wang
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastrointestinal Surgery, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing 100038, China
| | - Xi-Bo Sun
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Breast Surgery, The Second Affiliated Hospital of Shandong First Medical University, Taian 271000, Shandong Province, China
| | - Jin-Xiu Qu
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastrointestinal Surgery, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing 100038, China
| | - Ben-Qiang Rao
- Department of Gastrointestinal Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastrointestinal Surgery, Key Laboratory of Cancer FSMP for State Market Regulation, Beijing 100038, China
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Zheng T, Huang Z, Ling H, Li J, Cheng H, Chen D, Lu Q, Zhao J, Su W. The mechanism of the Nfe2l2/Hmox1 signaling pathway in ferroptosis regulation in acute compartment syndrome. J Biochem Mol Toxicol 2023; 37:e23228. [PMID: 36193742 PMCID: PMC10078270 DOI: 10.1002/jbt.23228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 07/30/2022] [Accepted: 09/16/2022] [Indexed: 01/18/2023]
Abstract
Acute compartment syndrome (ACS) is a life-threatening orthopedic emergency, which can even result in amputation. Ferroptosis is an iron-dependent form of nonapoptotic cell death. This study investigated the mechanism of ferroptosis in ACS, explored candidate markers, and determined effective treatments. This study identified pathways involved in the development of ACS through gene set enrichment analysis (GSEA), Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA of heme oxygenase 1 (Hmox1). Bioinformatics methods, combined with real-time quantitative polymerase chain reaction, western blot analysis, and iron staining, were applied to determine whether ferroptosis was involved in the progression of ACS and to explore the mechanism of nuclear factor erythroid-2-related factor 2 (Nfe2l2)/Hmox1 in ferroptosis regulation. Optimal drugs for the treatment of ACS were also investigated using Connectivity Map. The ferroptosis pathway was enriched in GSEA, KEGG of DEGs, and GSEA of Hmox1. After ACS, the reactive oxygen species content, tissue iron content, and oxidative stress level increased, whereas glutathione peroxidase 4 protein expression decreased. The skeletal muscle was swollen and necrotized; the number of mitochondrial cristae became fewer or even disappeared, and Nfe2l2/Hmox1 expression increased at the transcriptional and protein levels. Hmox1 was highly expressed in ACS, indicating that Hmox1 is a possible marker for ACS. we could predict 12 potential target drugs for the treatment of ACS. In conclusion, Hmox1 was a potential candidate marker for ACS diagnosis. Ferroptosis was involved in the progression of ACS. It was speculated that ferroptosis is inhibited by the Nfe2l2/Hmox1 signaling pathway.
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Affiliation(s)
- Tiejun Zheng
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
| | - Zhao Huang
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
| | - He Ling
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
| | - Junfeng Li
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
| | - Hong Cheng
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
| | - Dingquan Chen
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
| | - Qinzhen Lu
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
| | - Jinmin Zhao
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Wei Su
- Department of Orthopaedic Traumatology and Hand Surgery, The First Affiliated Hospital to Guangxi Medical University, Nanning, Guangxi, China
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Zhou W, Tao T, Yu W, Wu W, Hui Z, Xu H, Li Y, Zhang Y, Yang X. Recombinant Adenovirus-Mediated HIF-lα Ameliorates Neurological Dysfunction by Improving Energy Metabolism in Ischemic Penumbra After Cerebral Ischemia-Reperfusion in Rats. Neuropsychiatr Dis Treat 2023; 19:775-784. [PMID: 37051416 PMCID: PMC10085005 DOI: 10.2147/ndt.s389022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Background Hypoxia inducible factor-1α (HIF-1α) regulates glucose metabolism during ischemia. This study investigated the effect of recombinant adenovirus HIF-1ɑ on neurological function and energy metabolism in a rat cerebral ischemia-reperfusion model. Methods Rats were divided into four groups: sham-operated (Sham) group, cerebral ischemia-reperfusion (CIR) group, recombinant adenovirus empty vector (Ad) group, and recombinant adenovirus-mediated HIF-1α (AdHIF-1α) group. The AdHIF-1α group and the Ad group were injected with AdHIF-1α and Ad in the lateral ventricle. The mNSS was performed at post-ischemia day 0 (P0) and P1, P14 and P28. At P14, the cerebral infarct volume was compared. At P28, HE staining, Nissl stains and TUNEL staining were performed. The expression of HIF-1α, GLUT1 and PFKFB3 were evaluated by Western Blot and immunohistochemistry. High performance liquid chromatography (HPLC) was used to determine the expression of GLUT1 and PFKFB3, and the level of energy metabolites: ATP, ADP and AMP. Results mNSS scores in the AdHIF-1α group were consistently lower than those in the CIR and Ad groups from P14 (P < 0.05) and Ad groups (P < 0.05). The cerebral infarct volume was reduced in the AdHIF-1α group compared with that in CIR group and Ad group (P < 0.05). At P28, HE showed better pathological changes in AdHIF-1α group. The number of Nissl bodies was increased in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The number of apoptotic cells in the AdHIF-1α group was fewer than that in the CIR and Ad groups (P < 0.05). The expression of HIF-1α, GLUT1 and PFKFB3 was significantly higher in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The ATP, ADP and AMP in the ischemic penumbra were also higher in the AdHIF-1α group (P < 0.05). Conclusion HIF-lα promoted neurological function recovery and decreased cerebral infarct volume in rats after cerebral ischemia-reperfusion injury by improving energy metabolism.
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Affiliation(s)
- Wenmei Zhou
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Tao Tao
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
- Correspondence: Tao Tao, Tel +86 13985162824, Email
| | - Wenfeng Yu
- Department of Human Anatomy, Basic Medical College, Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China
| | - Wanfu Wu
- Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA
| | - Zhirong Hui
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Hongliang Xu
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Yaqi Li
- Emergency Department, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Ying Zhang
- Department of Chinese Traditional Medicine, Zunyi Medical and Pharmaceutical College, Zunyi, Guizhou, 563006, People’s Republic of China
| | - Xiaohui Yang
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
- Department of Rehabilitation Medicine, The Affiliated Hospital Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of China
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Xin K, Tian K, Yu Q, Han L, Zang Z. Effects of altitude on meat quality difference and its relationship with HIF-1α during postmortem maturation of beef. J Food Biochem 2022; 46:e14470. [PMID: 36288466 DOI: 10.1111/jfbc.14470] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 01/14/2023]
Abstract
This study investigated the differences in meat quality during postmortem aging of yak meat from different altitudes as well as the relationship between the release of hypoxic factor HIF-1α and meat quality. The results showed that the HIF-1α increased with altitude but during aging process, there was an initial increase before a subsequent decrease (p < .05). Moreover, significant increases were showed in glycolytic potential, a* value, pH, HIF-1α mRNA expression, HIF-1α protein expression and shear force with altitude (p < .05). Additionally, the b* value, L* value, water holding power and MFI decreased significantly (p < .05). HIF-1α was shown, by PLS-DA method analysis, to be the main protein marker for differences in the quality during aging time of meat from three altitude groups. HIF-1α protein expression was high correlated with glycolytic potential, pH value, meat color, tenderness and water holding capacity during postmortem aging. The results demonstrated that HIF-1α is a novel marker protein that influences meat quality in yak from different altitudes and that HIF-1α-mediated glycolytic pathway was key to the meat quality during postmortem aging. PRACTICAL APPLICATIONS: Yak meat has the advantages of high protein, low fat, good amino acid and fatty acid composition, so the nutritional value of yak meat is in line with the current best-selling beef with less fat in domestic and foreign markets. But consumers often think that the meat tenderness of yak meat is worse than that of beef and improving the quality of yak meat was worthy of attention specifically. This study investigated the differences in meat quality during postmortem aging of yak meat at different altitudes and the relationship between hypoxic factor HIF-1α release and meat quality.
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Affiliation(s)
- Keqi Xin
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, China
| | - Kai Tian
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, China
| | - Qunli Yu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, China
| | - Ling Han
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, China
| | - Zhixuan Zang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, China
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A Three-Gene Signature for Predicting the Prognosis of Patients Treated with Transarterial Chemoembolization (TACE) and Identification of PD-184352 as a Potential Drug to Reverse Nonresponse to TACE. JOURNAL OF ONCOLOGY 2022; 2022:2704862. [PMID: 36213835 PMCID: PMC9534656 DOI: 10.1155/2022/2704862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/08/2022] [Accepted: 07/31/2022] [Indexed: 11/30/2022]
Abstract
Background Transarterial chemoembolization (TACE) is a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Owing to differences in its efficacy across individuals, determining the indicators of patient response to TACE and finding approaches to reversing nonresponse thereto are necessary. Methods Transcriptome data were obtained from the GSE104580 dataset, in which patients were marked as having TACE response or nonresponse. We identified differentially expressed genes (DEGs) and performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We screened genes with a prognostic value for TACE in the HIF-1 signaling pathway by univariate regression analysis. By using least absolute shrinkage and selection operator (LASSO) Cox regression, we established a multigene signature in GSE14520, which we verified using a drug sensitivity test. The Connectivity Map (CMap) database was used to find potential drugs to reverse nonresponse to TACE. Results We constructed a prognostic signature consisting of three genes (erythropoietin (EPO), heme oxygenase 1 (HMOX1), and serine protease inhibitor 1 (SERPINE1)) that we validated by drug sensitivity test. After dividing patients treated with TACE into high- and low-risk groups based on this new signature, we showed that overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group and that the risk score was an independent predictor of OS in patients treated with TACE. Based on our CMap findings, we speculated that PD-184352, an inhibitor of mitogen-activated protein kinase (MEK), had potential as a drug treatment to reverse nonresponse to TACE. We confirmed this speculation by using PD-184352 in a cell promotion experiment in a TACE environment. Conclusion We constructed a TACE-specific three-gene signature that could be used to predict HCC patients' responses to and prognosis after TACE treatment. PD-184352 might have potential as a drug to improve TACE efficacy.
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The Mito-Hormetic Mechanisms of Ozone in the Clearance of SARS-CoV2 and in the COVID-19 Therapy. Biomedicines 2022; 10:biomedicines10092258. [PMID: 36140358 PMCID: PMC9496465 DOI: 10.3390/biomedicines10092258] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
An increasing body of evidence in the literature is reporting the feasibility of using medical ozone as a possible alternative and adjuvant treatment for COVID-19 patients, significantly reducing hospitalization time, pro-inflammatory indicators, and coagulation markers and improving blood oxygenation parameters. In addition to the well-described ability of medical ozone in counteracting oxidative stress through the upregulation of the main anti-oxidant and scavenging enzymes, oxygen–ozone (O2–O3) therapy has also proved effective in reducing chronic inflammation and the occurrence of immune thrombosis, two key players involved in COVID-19 exacerbation and severity. As chronic inflammation and oxidative stress are also reported to be among the main drivers of the long sequelae of SARS-CoV2 infection, a rising number of studies is investigating the potential of O2–O3 therapy to reduce and/or prevent the wide range of post-COVID (or PASC)-related disorders. This narrative review aims to describe the molecular mechanisms through which medical ozone acts, to summarize the clinical evidence on the use of O2–O3 therapy as an alternative and adjuvant COVID-19 treatment, and to discuss the emerging potential of this approach in the context of PASC symptoms, thus offering new insights into effective and safe nonantiviral therapies for the fighting of this devastating pandemic.
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Formal Meta-Analysis of Hypoxic Gene Expression Profiles Reveals a Universal Gene Signature. Biomedicines 2022; 10:biomedicines10092229. [PMID: 36140330 PMCID: PMC9496516 DOI: 10.3390/biomedicines10092229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 08/29/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Integrating transcriptional profiles results in identifying gene expression signatures that are more robust than those obtained for individual datasets. However, a direct comparison of datasets derived from heterogeneous experimental conditions is problematic, hence their integration requires applying of specific meta-analysis techniques. The transcriptional response to hypoxia has been the focus of intense research due to its central role in tissue homeostasis and prevalent diseases. Accordingly, many studies have determined the gene expression profile of hypoxic cells. Yet, despite this wealth of information, little effort has been made to integrate these datasets to produce a robust hypoxic signature. We applied a formal meta-analysis procedure to datasets comprising 430 RNA-seq samples from 43 individual studies including 34 different cell types, to derive a pooled estimate of the effect of hypoxia on gene expression in human cell lines grown ingin vitro. This approach revealed that a large proportion of the transcriptome is significantly regulated by hypoxia (8556 out of 20,888 genes identified across studies). However, only a small fraction of the differentially expressed genes (1265 genes, 15%) show an effect size that, according to comparisons to gene pathways known to be regulated by hypoxia, is likely to be biologically relevant. By focusing on genes ubiquitously expressed, we identified a signature of 291 genes robustly and consistently regulated by hypoxia. Overall, we have developed a robust gene signature that characterizes the transcriptomic response of human cell lines exposed to hypoxia in vitro by applying a formal meta-analysis to gene expression profiles.
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Zhang LL, Tang RJ, Yang YJ. The underlying pathological mechanism of ferroptosis in the development of cardiovascular disease. Front Cardiovasc Med 2022; 9:964034. [PMID: 36003910 PMCID: PMC9393259 DOI: 10.3389/fcvm.2022.964034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular diseases (CVDs) have been attracting the attention of academic society for decades. Numerous researchers contributed to figuring out the core mechanisms underlying CVDs. Among those, pathological decompensated cellular loss posed by cell death in different kinds, namely necrosis, apoptosis and necroptosis, was widely regarded to accelerate the pathological development of most heart diseases and deteriorate cardiac function. Recently, apart from programmed cell death revealed previously, ferroptosis, a brand-new cellular death identified by its ferrous-iron-dependent manner, has been demonstrated to govern the occurrence and development of different cardiovascular disorders in many types of research as well. Therefore, clarifying the regulatory function of ferroptosis is conducive to finding out strategies for cardio-protection in different conditions and improving the prognosis of CVDs. Here, molecular mechanisms concerned are summarized systematically and categorized to depict the regulatory network of ferroptosis and point out potential therapeutic targets for diverse cardiovascular disorders.
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Affiliation(s)
- Li-Li Zhang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui-Jie Tang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Yue-Jin Yang,
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Dandapath I, Gupta R, Singh J, Shukla N, Jha P, Sharma V, Suri A, Sharma MC, Suri V, Sarkar C, Kulshreshtha R. Long Non-coding RNA and mRNA Co-expression Network Reveals Novel Players in Pleomorphic Xanthoastrocytoma. Mol Neurobiol 2022; 59:5149-5167. [PMID: 35674862 DOI: 10.1007/s12035-022-02893-5] [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: 11/10/2021] [Accepted: 05/18/2022] [Indexed: 11/25/2022]
Abstract
Histological interpretation of the rare pleomorphic xanthoastrocytoma (PXA) has been the holy grail for treatment options. However, no stand-alone clinical interventions have been developed owing to the lack of gene expression profiling data in PXA/APXA patients. We first time report the comprehensive analyses of the coding as well as long non-coding RNA (lncRNA) signatures of PXA/APXA patients. Several genes such as IGFBP2, NF1, FOS, ERBB2, and lncRNAs such as NEAT1, HOTAIRM1, and GAS5 known to play crucial roles in glioma patients were also deregulated in PXA patients suggesting the commonality in the molecular signatures. PPI network, co-expression, and lncRNA-mRNA interaction studies unraveled hub genes (such as ERBB2, FOS, RPA1) and networks that may play a critical role in PXA biology. The most enriched pathways based on gene profiles were related to TLR, chemokine, MAPK, Rb, and PI3K-Akt signaling pathways. The lncRNA targets were enriched in glucuronidation, adipogenesis, TGF-beta signaling, EGF/EGFR signaling, and cell cycle pathways. Interestingly, several mRNAs like PARVG, and ABI2 were found to be targeted by multiple lncRNAs suggesting a tight control of their levels. Some of the most prominent lncRNA-mRNA pairs were LOC728730: MRPL9, XLOC_l2_011987: ASIC2, lnc-C1QTNF5-1: RNF26. Notably, several lncRNAs such as lnc-CETP-1, lnc-XRCC3-1, lnc-RPL31-1, lnc-USP13-1, and MAPKAPK5-AS1, and genes such as RPA1, NTRK3, and CNRP1 showed strong correlation to the progression-free survival of PXA patients suggesting their potential as novel biomarkers. Overall, the findings of this study may facilitate the development of a new realm of RNA biology in PXA that may have clinical significance in the future.
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Affiliation(s)
- Iman Dandapath
- Neuropathology Laboratory, All India Institute of Medical Sciences, Neurosciences Centre, New Delhi, 110029, India
| | - Rahul Gupta
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, 110016, India
| | - Jyotsna Singh
- Neuropathology Laboratory, All India Institute of Medical Sciences, Neurosciences Centre, New Delhi, 110029, India
| | - Nidhi Shukla
- Neuropathology Laboratory, All India Institute of Medical Sciences, Neurosciences Centre, New Delhi, 110029, India
| | - Prerana Jha
- Neuropathology Laboratory, All India Institute of Medical Sciences, Neurosciences Centre, New Delhi, 110029, India
| | - Vikas Sharma
- All India Institute of Medical Sciences, CCRF, New Delhi, 110029, India
| | - Ashish Suri
- Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - M C Sharma
- Neuropathology Laboratory, All India Institute of Medical Sciences, Neurosciences Centre, New Delhi, 110029, India
| | - Vaishali Suri
- Neuropathology Laboratory, All India Institute of Medical Sciences, Neurosciences Centre, New Delhi, 110029, India.
| | - Chitra Sarkar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India.
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, 110016, India.
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Zeng CY, Wang XF, Hua FZ. HIF-1α in Osteoarthritis: From Pathogenesis to Therapeutic Implications. Front Pharmacol 2022; 13:927126. [PMID: 35865944 PMCID: PMC9294386 DOI: 10.3389/fphar.2022.927126] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoarthritis is a common age-related joint degenerative disease. Pain, swelling, brief morning stiffness, and functional limitations are its main characteristics. There are still no well-established strategies to cure osteoarthritis. Therefore, better clarification of mechanisms associated with the onset and progression of osteoarthritis is critical to provide a theoretical basis for the establishment of novel preventive and therapeutic strategies. Chondrocytes exist in a hypoxic environment, and HIF-1α plays a vital role in regulating hypoxic response. HIF-1α responds to cellular oxygenation decreases in tissue regulating survival and growth arrest of chondrocytes. The activation of HIF-1α could regulate autophagy and apoptosis of chondrocytes, decrease inflammatory cytokine synthesis, and regulate the chondrocyte extracellular matrix environment. Moreover, it could maintain the chondrogenic phenotype that regulates glycolysis and the mitochondrial function of osteoarthritis, resulting in a denser collagen matrix that delays cartilage degradation. Thus, HIF-1α is likely to be a crucial therapeutic target for osteoarthritis via regulating chondrocyte inflammation and metabolism. In this review, we summarize the mechanism of hypoxia in the pathogenic mechanisms of osteoarthritis, and focus on a series of therapeutic treatments targeting HIF-1α for osteoarthritis. Further clarification of the regulatory mechanisms of HIF-1α in osteoarthritis may provide more useful clues to developing novel osteoarthritis treatment strategies.
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Affiliation(s)
- Chu-Yang Zeng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xi-Feng Wang
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Xi-Feng Wang, ; Fu-Zhou Hua,
| | - Fu-Zhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Xi-Feng Wang, ; Fu-Zhou Hua,
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Burczyk G, Cichon I, Kolaczkowska E. Itaconate Suppresses Formation of Neutrophil Extracellular Traps (NETs): Involvement of Hypoxia-Inducible Factor 1α (Hif-1α) and Heme Oxygenase (HO-1). Front Immunol 2022; 13:864638. [PMID: 35837403 PMCID: PMC9273966 DOI: 10.3389/fimmu.2022.864638] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 06/01/2022] [Indexed: 01/01/2023] Open
Abstract
Neutrophil extracellular traps (NETs) immobilize pathogens during early stages of systemic inflammation but as the reaction progresses they become detrimental to endothelial cells and the organ-specific cells. For this reason it would be of importance to control their formation by either physiological or pharmacological means. Endogenously, formation of NETs is under control of cellular and whole organism metabolism as shown previously in the course of bacterial systemic inflammation, obesity or the combination of the two. Numerous leukocytes are subjected to immunometabolic regulation and in macrophages exposure to lipopolysaccharide (LPS) leads to two breaks in the Krebs cycle that impact this cell functioning. As a consequence of the first break, anti-microbial itaconic acid (itaconate) is produced whereas the second break activates hypoxia-inducible factor-1α (Hif-1α). In turn, itaconate activates transcription of the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2) which upregulates cyto-protective heme oxygenase (HO-1). Here we report that exogenously added derivative of the itaconic acid, 4-octyl itaconate (4-OI), diminishes formation of NETs by neutrophils of either normal (lean) or obese mice, and independently of the age of the animals or immunoaging. Elucidating the mechanism of this inhibition we unravel that although Nrf2/HO-1 expression itself is not altered by 4-OI, it is up-regulated when compared against the NET formation while Hif-1α is downregulated in 4-OI-pre-treated LPS-stimulated neutrophils in either way. We further show that blockage of Hif-1α by its specific inhibitor diminishes NET release as does inhibition by 4-OI. Also inhibition of HO-1 activity correlates with diminished LPS-induced NET release upon pre-treatment with 4-OI albeit LPS alone induced NETs are not HO-1-dependent. In summary, we unravel that 4-OI inhibits NET formation by murine neutrophils independently of their origin (health vs. metabolically challenged animals) and the age of individuals/immunosenescence via inhibition of Hif-1α and induction of HO-1.
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Heme Oxygenase-1: An Anti-Inflammatory Effector in Cardiovascular, Lung, and Related Metabolic Disorders. Antioxidants (Basel) 2022; 11:antiox11030555. [PMID: 35326205 PMCID: PMC8944973 DOI: 10.3390/antiox11030555] [Citation(s) in RCA: 131] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/24/2022] [Accepted: 03/10/2022] [Indexed: 12/12/2022] Open
Abstract
The heme oxygenase (HO) enzyme system catabolizes heme to carbon monoxide (CO), ferrous iron, and biliverdin-IXα (BV), which is reduced to bilirubin-IXα (BR) by biliverdin reductase (BVR). HO activity is represented by two distinct isozymes, the inducible form, HO-1, and a constitutive form, HO-2, encoded by distinct genes (HMOX1, HMOX2, respectively). HO-1 responds to transcriptional activation in response to a wide variety of chemical and physical stimuli, including its natural substrate heme, oxidants, and phytochemical antioxidants. The expression of HO-1 is regulated by NF-E2-related factor-2 and counter-regulated by Bach-1, in a heme-sensitive manner. Additionally, HMOX1 promoter polymorphisms have been associated with human disease. The induction of HO-1 can confer protection in inflammatory conditions through removal of heme, a pro-oxidant and potential catalyst of lipid peroxidation, whereas iron released from HO activity may trigger ferritin synthesis or ferroptosis. The production of heme-derived reaction products (i.e., BV, BR) may contribute to HO-dependent cytoprotection via antioxidant and immunomodulatory effects. Additionally, BVR and BR have newly recognized roles in lipid regulation. CO may alter mitochondrial function leading to modulation of downstream signaling pathways that culminate in anti-apoptotic, anti-inflammatory, anti-proliferative and immunomodulatory effects. This review will present evidence for beneficial effects of HO-1 and its reaction products in human diseases, including cardiovascular disease (CVD), metabolic conditions, including diabetes and obesity, as well as acute and chronic diseases of the liver, kidney, or lung. Strategies targeting the HO-1 pathway, including genetic or chemical modulation of HO-1 expression, or application of BR, CO gas, or CO donor compounds show therapeutic potential in inflammatory conditions, including organ ischemia/reperfusion injury. Evidence from human studies indicate that HO-1 expression may represent a biomarker of oxidative stress in various clinical conditions, while increases in serum BR levels have been correlated inversely to risk of CVD and metabolic disease. Ongoing human clinical trials investigate the potential of CO as a therapeutic in human disease.
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Therapeutic Effects of Bee Bread on Obesity-Induced Testicular-Derived Oxidative Stress, Inflammation, and Apoptosis in High-Fat Diet Obese Rat Model. Antioxidants (Basel) 2022; 11:antiox11020255. [PMID: 35204140 PMCID: PMC8868291 DOI: 10.3390/antiox11020255] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/25/2022] [Accepted: 01/25/2022] [Indexed: 12/19/2022] Open
Abstract
Obesity is a debilitating disorder with a variety of problems including oxidative stress, inflammation, and apoptosis. The aim of our study was to investigate the therapeutic role of bee bread on oxidative stress, apoptosis, and inflammation in the testis of obese rats. Thirty-two adult male Sprague Dawley rats, with weights between 230–300 g, were distributed into four groups (n = 8/group), namely normal control (C), obese (Ob), obese + BB or obese + OR [high-fat diet (HFD) for 6 weeks then HFD plus bee bread or orlistat for another 6 weeks] groups. Bee bread (0.5 g/kg) or orlistat (10 mg/kg/day) was diluted with distilled water and administered daily for 6 weeks by oral gavage. There were significant decreases in the activities of antioxidant enzymes [glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GR)], glutathione (GSH)] and total antioxidant capacity (TAC) levels and mRNA expressions of nuclear factor erythroid 2–related factor 2 (Nrf2), superoxide dismutase (Sod), catalase (Cat) and glutathione peroxidase (Gpx) in the obese group relative to the control group. Meanwhile, the mRNA levels of pro-inflammatory markers, namely: inducible nitric oxide synthase (Inos), nuclear factor kappa B (Nf-κβ), tumour necrotic factor α (Tnf-α) and interleukin 1β (Il-1β) were significantly increased while interleukin (Il-10) was decreased in the obese group relative to the control group. Further, proliferating cell nuclear antigen (PCNA) immunoexpressions decreased while cleaved caspase-3 immunohistochemical staining increased significantly in the obese group, in addition to increases in the mRNA levels of p53, Bax, Caspases-8, 9 and 3, relative to the control group. Treatment with bee bread showed increases in antioxidant enzymes and PCNA immunoexpression, as well as decreases in inflammation and apoptosis markers in the testes. This study has shown that bee bread has therapeutic effects against oxidative stress, inflammation, apoptosis in the testis of HFD-induced obese male rats, thereby suggesting its role as a natural supplement capable of treating obesity-induced male reproductive impairment.
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Targeting the Ang2/Tie2 Axis with Tanshinone IIA Elicits Vascular Normalization in Ischemic Injury and Colon Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:7037786. [PMID: 34804370 PMCID: PMC8598375 DOI: 10.1155/2021/7037786] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/04/2021] [Accepted: 10/15/2021] [Indexed: 02/06/2023]
Abstract
Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.
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Costa Silva RCM, Correa LHT. Heme Oxygenase 1 in Vertebrates: Friend and Foe. Cell Biochem Biophys 2021; 80:97-113. [PMID: 34800278 DOI: 10.1007/s12013-021-01047-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/07/2021] [Indexed: 10/19/2022]
Abstract
HO-1 is the inducible form of the enzyme heme-oxygenase. HO-1 catalyzes heme breakdown, reducing the levels of this important oxidant molecule and generating antioxidant, anti-inflammatory, and anti-apoptotic byproducts. Thus, HO-1 has been described as an important stress response mechanism during both physiologic and pathological processes. Interestingly, some findings are demonstrating that uncontrolled levels of HO-1 byproducts can be associated with cell death and tissue destruction as well. Furthermore, HO-1 can be located in the nucleus, influencing gene transcription, cellular proliferation, and DNA repair. Here, we will discuss several studies that approach HO-1 effects as a protective or detrimental mechanism in different pathological conditions. In this sense, as the major organs of vertebrates will deal specifically with distinct types of stresses, we discuss the HO-1 role in each of them, exposing the contradictions associated with HO-1 expression after different insults and circumstances.
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Affiliation(s)
- Rafael Cardoso Maciel Costa Silva
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Leonardo Holanda Travassos Correa
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Plicosepalus acacia Extract and Its Major Constituents, Methyl Gallate and Quercetin, Potentiate Therapeutic Angiogenesis in Diabetic Hind Limb Ischemia: HPTLC Quantification and LC-MS/MS Metabolic Profiling. Antioxidants (Basel) 2021; 10:antiox10111701. [PMID: 34829572 PMCID: PMC8614836 DOI: 10.3390/antiox10111701] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 11/23/2022] Open
Abstract
Plicosepalus acacia (Fam. Loranthaceae) has been reported to possess hypoglycemic, antioxidant, antimicrobial, and anti-inflammatory effects. Liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) analysis revealed the presence of a high content of polyphenolic compounds that are attributed to the therapeutic effects of the crude extract. In addition, methyl gallate and quercetin were detected as major phytomedicinal agents at concentrations of 1.7% and 0.062 g%, respectively, using high-performance thin layer chromatography (HPTLC). The present study investigated the effect of the P. acacia extract and its isolated compounds, methyl gallate and quercetin, on hind limb ischemia induced in type 1 diabetic rats. Histopathological examination revealed that treatment with P. acacia extract, methyl gallate, and quercetin decreased degenerative changes and inflammation in the ischemic muscle. Further biochemical assessment of the hind limb tissue showed decreased oxidative stress, increased levels of nitric oxide and endothelial nitric oxide synthase (eNOS), and enhancement of the levels of heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) in the groups treated with methyl gallate and quercetin. Expression levels of hypoxia inducible factor-1 alpha (HIF-1α), VEGF, fibroblast growth factor-2 (FGF-2), and miR-146a were upregulated in the muscle tissue of methyl gallate- and quercetin-treated groups along with downregulation of nuclear factor kappa B (NF-κB). In conclusion, P. acacia extract and its isolated compounds, methyl gallate and quercetin, mediated therapeutic angiogenesis in diabetic hind limb ischemia.
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Xu L, Zhao Q, Li D, Luo J, Ma W, Jin Y, Li C, Chen J, Zhao K, Zheng Y, Yu D. MicroRNA-760 resists ambient PM 2.5-induced apoptosis in human bronchial epithelial cells through elevating heme-oxygenase 1 expression. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 284:117213. [PMID: 33933780 DOI: 10.1016/j.envpol.2021.117213] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/31/2021] [Accepted: 04/19/2021] [Indexed: 06/12/2023]
Abstract
PM2.5 (particles matter smaller aerodynamic diameter of 2.5 μm) exposure, a major environmental risk factor for the global burden of diseases, is associated with high risks of respiratory diseases. Heme-oxygenase 1 (HMOX1) is one of the major molecular antioxidant defenses to mediate cytoprotective effects against diverse stressors, including PM2.5-induced toxicity; however, the regulatory mechanism of HMOX1 expression still needs to be elucidated. In this study, using PM2.5 as a typical stressor, we explored whether microRNAs (miRNAs) might modulate HMOX1 expression in lung cells. Systematic bioinformatics analysis showed that seven miRNAs have the potentials to target HMOX1 gene. Among these, hsa-miR-760 was identified as the most responsive miRNA to PM2.5 exposure. More importantly, we revealed a "non-conventional" miRNA function in hsa-miR-760 upregulating HMOX1 expression, by targeting the coding region and interacting with YBX1 protein. In addition, we observed that exogenous hsa-miR-760 effectively elevated HMOX1 expression, reduced the reactive oxygen agents (ROS) levels, and rescued the lung cells from PM2.5-induced apoptosis. Our results revealed that hsa-miR-760 might play an important role in protecting lung cells against PM2.5-induced toxicity, by elevating HMOX1 expression, and offered new clues to elucidate the diverse functions of miRNAs.
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Affiliation(s)
- Lin Xu
- School of Public Health, Qingdao University, Qingdao, China
| | - Qianwen Zhao
- School of Public Health, Qingdao University, Qingdao, China
| | - Daochuan Li
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Jiao Luo
- School of Public Health, Qingdao University, Qingdao, China
| | - Wanli Ma
- School of Public Health, Qingdao University, Qingdao, China
| | - Yuan Jin
- School of Public Health, Qingdao University, Qingdao, China
| | - Chuanhai Li
- School of Public Health, Qingdao University, Qingdao, China
| | - Jing Chen
- School of Public Health, Qingdao University, Qingdao, China
| | - Kunming Zhao
- School of Public Health, Qingdao University, Qingdao, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, Qingdao, China
| | - Dianke Yu
- School of Public Health, Qingdao University, Qingdao, China.
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Jassim AH, Inman DM, Mitchell CH. Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration. Front Pharmacol 2021; 12:699623. [PMID: 34366851 PMCID: PMC8334009 DOI: 10.3389/fphar.2021.699623] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/22/2021] [Indexed: 12/11/2022] Open
Abstract
Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial and inflammatory signaling can exacerbate issues in chronic neurodegenerations. This review discusses evidence for the interaction between mitochondrial damage and inflammation, with a focus on glaucomatous neurodegeneration, and proposes that positive feedback resulting from this crosstalk drives pathology. Mitochondrial dysfunction exacerbates inflammatory signaling in multiple ways. Damaged mitochondrial DNA is a damage-associated molecular pattern, which activates the NLRP3 inflammasome; priming and activation of the NLRP3 inflammasome, and the resulting liberation of IL-1β and IL-18 via the gasdermin D pore, is a major pathway to enhance inflammatory responses. The rise in reactive oxygen species induced by mitochondrial damage also activates inflammatory pathways, while blockage of Complex enzymes is sufficient to increase inflammatory signaling. Impaired mitophagy contributes to inflammation as the inability to turnover mitochondria in a timely manner increases levels of ROS and damaged mtDNA, with the latter likely to stimulate the cGAS-STING pathway to increase interferon signaling. Mitochondrial associated ER membrane contacts and the mitochondria-associated adaptor molecule MAVS can activate NLRP3 inflammasome signaling. In addition to dysfunctional mitochondria increasing inflammation, the corollary also occurs, with inflammation reducing mitochondrial function and ATP production; the resulting downward spiral accelerates degeneration. Evidence from several preclinical models including the DBA/2J mouse, microbead injection and transient elevation of IOP, in addition to patient data, implicates both mitochondrial damage and inflammation in glaucomatous neurodegeneration. The pressure-dependent hypoxia and the resulting metabolic vulnerability is associated with mitochondrial damage and IL-1β release. Links between mitochondrial dysfunction and inflammation can occur in retinal ganglion cells, microglia cells and astrocytes. In summary, crosstalk between damaged mitochondria and increased inflammatory signaling enhances pathology in glaucomatous neurodegeneration, with implications for other complex age-dependent neurodegenerations like Alzheimer's and Parkinson's disease.
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Affiliation(s)
- Assraa Hassan Jassim
- Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA, United States
| | - Denise M. Inman
- Department of Pharmaceutical Sciences, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Claire H. Mitchell
- Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA, United States
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, United States
- Department of Physiology, University of Pennsylvania, Philadelphia, PA, United States
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Chirumbolo S, Valdenassi L, Simonetti V, Bertossi D, Ricevuti G, Franzini M, Pandolfi S. Insights on the mechanisms of action of ozone in the medical therapy against COVID-19. Int Immunopharmacol 2021; 96:107777. [PMID: 34020394 PMCID: PMC8112288 DOI: 10.1016/j.intimp.2021.107777] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/28/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023]
Abstract
An increasing amount of reports in the literature is showing that medical ozone (O3) is used, with encouraging results, in treating COVID-19 patients, optimizing pain and symptoms relief, respiratory parameters, inflammatory and coagulation markers and the overall health status, so reducing significantly how much time patients underwent hospitalization and intensive care. To date, aside from mechanisms taking into account the ability of O3 to activate a rapid oxidative stress response, by up-regulating antioxidant and scavenging enzymes, no sound hypothesis was addressed to attempt a synopsis of how O3 should act on COVID-19. The knowledge on how O3 works on inflammation and thrombosis mechanisms is of the utmost importance to make physicians endowed with new guns against SARS-CoV2 pandemic. This review tries to address this issue, so to expand the debate in the scientific community.
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Affiliation(s)
- Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
| | - Luigi Valdenassi
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy
| | - Vincenzo Simonetti
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy
| | - Dario Bertossi
- Department of Surgery, Dentistry, Paediatrics and Gynaecology Unit of Maxillo-Facial Surgery University of Verona, Verona, Italy
| | | | - Marianno Franzini
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy
| | - Sergio Pandolfi
- SIOOT, High School in Oxygen Ozone Therapy, University of Pavia, Italy; SIOOT INTERNATIONAL, Communian Clinic, Gorle Bergamo, Italy; Villa Mafalda Clinics via Monte delle Gioie, Rome, Italy
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