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Palachai N, Supawat A, Kongsui R, Klimaschewski L, Jittiwat J. Galangin's Neuroprotective Role: Targeting Oxidative Stress, Inflammation, and Apoptosis in Ischemic Stroke in a Rat Model of Permanent Middle Cerebral Artery Occlusion. Int J Mol Sci 2025; 26:1847. [PMID: 40076473 PMCID: PMC11899015 DOI: 10.3390/ijms26051847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
The rising incidence of ischemic stroke poses significant health and healthcare burdens. Given the limitations of current therapeutic options, there is increasing interest in exploring the potential of galangin, a natural flavonoid compound, as a treatment for ischemic stroke. This study aimed to evaluate the neuroprotective effects and underlying mechanisms of galangin in mitigating oxidative stress, inflammation, and apoptosis in a rat model of permanent cerebral ischemia. Sixty male Wistar rats were divided into six groups: control; right middle cerebral artery occlusion (Rt.MCAO) with vehicle; Rt.MCAO with piracetam, a synthetic compound known as a cognitive enhancer; and Rt.MCAO with galangin administered at doses of 25, 50, and 100 mg/kg body weight. Neurological deficit scores, brain edema, neuronal density, and microglial morphology were assessed along with the activity of myeloperoxidase (MPO), a marker of inflammation, and superoxide dismutase (SOD). Additionally, the expression of key markers for inflammation and apoptosis, cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), Bcl-2-associated X protein (Bax), B-cell lymphoma-extra large (Bcl-XL), and caspase-3, was analyzed to elucidate potential mechanisms. The results demonstrated that galangin treatment significantly improved neurological deficit scores, reduced brain edema, enhanced neuronal density, attenuated microglial activation, decreased MPO activity, and increased SOD activity in both the cortex and hippocampus, highlighting its neuroprotective potential. These effects were linked to the modulation of inflammatory and apoptotic pathways. Specifically, galangin significantly reduced the expression of IL-6, COX-2, Bax, and caspase-3 while increasing the levels of the anti-apoptotic protein Bcl-XL. In conclusion, galangin demonstrates significant promise as a neuroprotective agent for ischemic stroke by suppressing inflammation and apoptosis, thereby improving neurological outcomes. However, clinical trials are required to validate these preclinical findings and confirm galangin's therapeutic efficacy in humans.
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Affiliation(s)
- Nut Palachai
- Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand; (N.P.); (A.S.)
| | - Araya Supawat
- Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand; (N.P.); (A.S.)
| | - Ratchaniporn Kongsui
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand;
| | - Lars Klimaschewski
- Department of Anatomy, Histology and Embryology, Institute of Neuroanatomy, Medical University Innsbruck, 6020 Innsbruck, Austria;
| | - Jinatta Jittiwat
- Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand; (N.P.); (A.S.)
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Ling S, Xu JW. Phenotypes and functions of "aged" neutrophils in cardiovascular diseases. Biomed Pharmacother 2024; 179:117324. [PMID: 39216451 DOI: 10.1016/j.biopha.2024.117324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024] Open
Abstract
Neutrophils are important effector cells of innate immunity and undergo several phenotypic changes after release from the bone marrow. Neutrophils with a late life cycle phenotype are often referred to as "aged" neutrophils. These neutrophils undergo functional changes that accompany stimuli of inflammation, tissue senescence and injury, inducing their maturation and senescence in the circulation and locally in damaged tissues, forming a unique late-life neutrophil phenotype. "Aged" neutrophils, although attenuated in antibacterial capacity, are more active in aging and age-related diseases, exhibit high levels of mitochondrial ROS and mitochondrial DNA leakage, promote senescence of neighboring cells, and exacerbate cardiac and vascular tissue damage, including vascular inflammation, myocardial infarction, atherosclerosis, stroke, abdominal aortic aneurysm, and SARS-CoV-2 myocarditis. In this review, we outline the phenotypic changes of "aged" neutrophils characterized by CXCR4high/CD62Llow, investigate the mechanisms driving neutrophil aging and functional transformation, and analyze the damage caused by "aged" neutrophils to various types of heart and blood vessels. Tissue injury and senescence promote neutrophil infiltration and induce neutrophil aging both in the circulation and locally in damaged tissues, resulting in an "aged" neutrophil phenotype characterized by CXCR4high/CD62Llow. We also discuss the effects of certain agents, such as neutralizing mitochondrial ROS, scavenging IsoLGs, blocking VDAC oligomers and mPTP channel activity, activating Nrf2 activity, and inhibiting neutrophil PAD4 activity, to inhibit neutrophil NET formation and ameliorate age-associated cardiovascular disease, providing a new perspective for anti-aging therapy in cardiovascular disease.
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Affiliation(s)
- Shuang Ling
- School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Jin-Wen Xu
- Institute of Interdisciplinary Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Kongsui R, Jittiwat J. In vivo protective effects of 6‑gingerol in cerebral ischemia involve preservation of antioxidant defenses and activation of anti‑apoptotic pathways. Biomed Rep 2024; 20:85. [PMID: 38665422 PMCID: PMC11040226 DOI: 10.3892/br.2024.1773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Stroke is an important medical problem in developing countries, characterized by a sudden disruption of blood supply to the brain, either through occlusion or hemorrhage. It is a major cause of neurological impairment, resulting in high medical costs. The present study examined the effect of 6-gingerol on morphological changes, antioxidant defenses, and the anti-apoptotic factors p38 mitogen-activated protein kinase (MAPK) and mitofusin (Mfn)2, in a rat model of focal cerebral ischemia. A total of 60 healthy male Wistar rats were randomly allocated into six groups: Control, right middle cerebral artery occlusion (Rt.MCAO) + vehicle, Rt.MCAO + piracetam, and Rt.MCAO + 6-Gin 5, 10 and 20 mg/kg BW groups. The results indicated that 6-gingerol treatment for a duration of 7 days reverses morphological alterations, enhances catalase and glutathione peroxidase activities, reduces Bax, caspase-3 and MAPK expression, and increases Bcl-xL and Mfn2 expression in the cortex and hippocampus. In conclusion, 6-gingerol demonstrated significant in vivo effectiveness in mitigating pathological changes induced by cerebral ischemia. This beneficial effect is attributed, at least in part, to preservation of antioxidant defenses and activation of anti-apoptotic pathways.
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Affiliation(s)
- Ratchaniporn Kongsui
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Jinatta Jittiwat
- Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand
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Zhou S, Cheng R, Zhang Y, Jiang Y, Zhang L, Jiang Z, Yu Q. CHIR-98014, a GSK 3β Inhibitor, Protects Against Triptolide/Lipopolysaccharide-Induced Hepatotoxicity by Mitochondria-Dependent Apoptosis Inhibition. Chem Res Toxicol 2024; 37:407-418. [PMID: 38284557 DOI: 10.1021/acs.chemrestox.3c00367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
Triptolide (TP) is a remarkable anti-inflammatory and immunosuppressive component separated from Tripterygium wilfordii Hook. F. However, its hepatotoxicity limits its application in the clinical. Our group has proposed a new perspective on TP-induced hepatotoxicity, in which TP enhances liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. Because the cause of the disease is unknown, there is currently no uniform treatment available. In this study, we attempted to determine whether the GSK-3β-JNK pathway affects liver damage and its regulatory mechanism in response to TP/LPS costimulation. In addition, we investigated the effect of CsA or the GSK 3β inhibitor CHIR-98014 on TP/LPS-induced hepatotoxicity. The results showed that the TP/LPS cotreatment mice exhibited obvious hepatotoxicity, as indicated by a remarkable increase in the serum ALT and AST levels, glycogen depletion, GSK 3β-JNK upregulation, and increased apoptosis. Instead of the specific knockdown of JNK1, the specific knockdown of JNK2 had a protective effect. Additionally, 40 mg/kg of CsA and 30 mg/kg of CHIR-98014 might provide protection. In summary, CHIR-98014 could protect against TP/LPS- or TP/TNF-α-induced activation of the GSK 3β-JNK pathway and mitochondria-dependent apoptosis, improving the indirect hepatotoxicity induced by TP.
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Affiliation(s)
- Shaoyun Zhou
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Ruohan Cheng
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yue Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Yihan Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Luyong Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhenzhou Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Qinwei Yu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
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Sun Y, Jiang X, Gao J. Stem cell-based ischemic stroke therapy: Novel modifications and clinical challenges. Asian J Pharm Sci 2024; 19:100867. [PMID: 38357525 PMCID: PMC10864855 DOI: 10.1016/j.ajps.2023.100867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/25/2023] [Accepted: 10/07/2023] [Indexed: 02/16/2024] Open
Abstract
Ischemic stroke (IS) causes severe disability and high mortality worldwide. Stem cell (SC) therapy exhibits unique therapeutic potential for IS that differs from current treatments. SC's cell homing, differentiation and paracrine abilities give hope for neuroprotection. Recent studies on SC modification have enhanced therapeutic effects for IS, including gene transfection, nanoparticle modification, biomaterial modification and pretreatment. These methods improve survival rate, homing, neural differentiation, and paracrine abilities in ischemic areas. However, many problems must be resolved before SC therapy can be clinically applied. These issues include production quality and quantity, stability during transportation and storage, as well as usage regulations. Herein, we reviewed the brief pathogenesis of IS, the "multi-mechanism" advantages of SCs for treating IS, various SC modification methods, and SC therapy challenges. We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.
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Affiliation(s)
- Yuankai Sun
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xinchi Jiang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianqing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
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Liu Y, Wang S, Yang W. Inhibiting the Proliferation of Colorectal Cancer Cells by Reducing TSPO/VDAC Expression. IRANIAN JOURNAL OF PUBLIC HEALTH 2023; 52:1378-1389. [PMID: 37593520 PMCID: PMC10430413 DOI: 10.18502/ijph.v52i7.13239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/13/2023] [Indexed: 08/19/2023]
Abstract
Background We aimed to explore the mechanism of the effect of remimazolam (Rem) on the proliferation of colorectal cancer (CRC) cells with CRC as a disease context. Methods Translocation protein (TSPO) expression in CRC was determined by Western blotting and qRT-PCR in the Second Affiliated Hospital of Qiqihar Medical University from March 2019 to February 2022. TSPO-interacting proteins were predicted through string database. The proliferation was measured by CCK-8 and 5-ethynyl-2-deoxyuridine (EDU). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) and clonal colony on cells were formed to screen for the optimal concentration of Rem and to detect the viability. The expression of apoptosis-related proteins, Bcl-2 and P53, was determined by qRT-PCR and Western blotting. The effect of Rem on the expression of tumor markers, CEA and CA19-9, in CRC was examined through ELISA. Results TSPO expression in CRC tissues and cells was higher than that in ANT samples and normal intestinal epithelial cells. Over-expression of TSPO promoted the proliferation of HCT116 and the expression of tumor markers CEA and CA19-9 and inhibited the apoptosis of HCT116. Interference with TSPO inhibited the proliferation of HCT116 and the expression of CEA and CA19-9 and promoted the apoptosis of HCT116. 1 μg/mL Rem could inhibit the viability of HCT116, the proliferation of HCT116 and the expression of CEA and CA19-9, and improve the apoptosis of HCT116. TSPO could interact with VDAC and affect its protein expression, and Rem could inhibit the proliferation and the expression of CEA and CA19-9 through the TSPO/VDAC pathway, to promote its apoptosis. Conclusion Rem affects the proliferation of CRC cells by inhibiting the TSPO/VDAC pathway.
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Affiliation(s)
- Yang Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Shuyue Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
| | - Weining Yang
- Operating Room, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar 161000, China
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Nehlin JO. Senolytic and senomorphic interventions to defy senescence-associated mitochondrial dysfunction. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 136:217-247. [PMID: 37437979 DOI: 10.1016/bs.apcsb.2023.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2023]
Abstract
The accumulation of senescent cells in the aging individual is associated with an increase in the occurrence of age-associated pathologies that contribute to poor health, frailty, and mortality. The number and type of senescent cells is viewed as a contributor to the body's senescence burden. Cellular models of senescence are based on induction of senescence in cultured cells in the laboratory. One type of senescence is triggered by mitochondrial dysfunction. There are several indications that mitochondria defects contribute to body aging. Senotherapeutics, targeting senescent cells, have been shown to induce their lysis by means of senolytics, or repress expression of their secretome, by means of senomorphics, senostatics or gerosuppressors. An outline of the mechanism of action of various senotherapeutics targeting mitochondria and senescence-associated mitochondria dysfunction will be here addressed. The combination of geroprotective interventions together with senotherapeutics will help to strengthen mitochondrial energy metabolism, biogenesis and turnover, and lengthen the mitochondria healthspan, minimizing one of several molecular pathways contributing to the aging phenotype.
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Affiliation(s)
- Jan O Nehlin
- Department of Clinical Research, Copenhagen University Hospital, Amager and Hvidovre, Hvidovre, Denmark.
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Geng J, Khaket TP, Pan J, Li W, Zhang Y, Ping Y, Cobos Sillero MI, Lu B. Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome. Dev Cell 2023; 58:597-615.e10. [PMID: 37040696 PMCID: PMC10113018 DOI: 10.1016/j.devcel.2023.03.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 07/31/2022] [Accepted: 03/06/2023] [Indexed: 04/13/2023]
Abstract
Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.
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Affiliation(s)
- Ji Geng
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tejinder Pal Khaket
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jie Pan
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wen Li
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yan Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yong Ping
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | | | - Bingwei Lu
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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The protection impact of tectoridin on PC12 cell preventing OGD/R-caused damage through PI3K/AKT signaling channel. Eur J Pharmacol 2023; 941:175491. [PMID: 36610685 DOI: 10.1016/j.ejphar.2023.175491] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 11/30/2022] [Accepted: 01/04/2023] [Indexed: 01/06/2023]
Abstract
The present work examined the effect exerted by tectoridin preventing oxygen glucose deprivation/reoxygenation (OGD/R) damage within PC12 cell. We incubated PC12 cells with Na2S2O4 (10 mM) for 2 h, and tectoridin at different concentrations was then added; based on methyl-thiazolyl-tetrazolium (MTT) and lactate dehydrogenase (LDH) tests, the protection impact was tested. 2',7'-dicholorofluorescein diacetate (DCFH-DA), Fluo-3AM, and 5, 5', 6, 6' -tetrachloro-1, 1', 3, 3' -tetraethyl-imidacarbocyanine iodide (JC-1) staining, and Western blotting were used for determining reactive oxygen species (ROS) level, intracellular Ca2+ content, mitochondrial membrane potential (MMP) and the related proteins contents. As a result, tectoridin could improve the cell viability and inhibit the release of LDH. In-depth studies demonstrated that tectoridin limited the overproduction of ROS and intracellular Ca2+ content and increased MMP, which showed a close association with ROS-mediated mitochondrial function. Moreover, tectoridin hindered apoptosis based on the up-regulation of the expressions of p-AKT, Bcl-2/Bax and p-mTOR. Furthermore, the level of Nrf2 was also improved by treatment of tectoridin. In addition, the expression of Bcl-2/Bax, p-Akt, p-mTOR, Nrf2, HO-1, NQO1 and GCLM were reduced by LY294002 and the protective role of tectoridin was limited by LY294002. The results unambiguously suggested that tectoridin reduced OGD/R-caused damage to PC12 cells and might ensure neuroprotection by stimulating the PI3K/AKT signaling channel.
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Boyenle ID, Oyedele AK, Ogunlana AT, Adeyemo AF, Oyelere FS, Akinola OB, Adelusi TI, Ehigie LO, Ehigie AF. Targeting the mitochondrial permeability transition pore for drug discovery: Challenges and opportunities. Mitochondrion 2022; 63:57-71. [PMID: 35077882 DOI: 10.1016/j.mito.2022.01.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/22/2021] [Accepted: 01/17/2022] [Indexed: 12/29/2022]
Abstract
Several drug targets have been amenable to drug discovery pursuit not until the characterization of the mitochondrial permeability transition pore (MPTP), a pore with an undefined molecular identity that forms on the inner mitochondrial membrane upon mitochondrial permeability transition (MPT) under the influence of calcium overload and oxidative stress. The opening of the pore which is presumed to cause cell death in certain human diseases also has implications under physiological parlance. Different models for this pore have been postulated following its first identification in the last six decades. The mitochondrial community has witnessed many protein candidates such as; voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), Mitochondrial phosphate carrier (PiC), Spastic Paralegin (SPG7), disordered proteins, and F1Fo ATPase. However, genetic studies have cast out most of these candidates with only F1Fo ATPase currently under intense argument. Cyclophilin D (CyPD) remains the widely accepted positive regulator of the MPTP known to date, but no drug candidate has emerged as its inhibitor, raising concern issues for therapeutics. Thus, in this review, we discuss various models of MPTP reported with the hope of stimulating further research in this field. We went beyond the classical description of the MPTP to ascribe a 'two-edged sword property' to the pore for therapeutic function in human disease because its inhibition and activation have pharmacological relevance. We suggested putative proteins upstream to CyPD that can regulate its activity and prevent cell deaths in neurodegenerative disease and ischemia-reperfusion injury.
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Affiliation(s)
- Ibrahim Damilare Boyenle
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria; Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Abdulquddus Kehinde Oyedele
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Abdeen Tunde Ogunlana
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Aishat Folashade Adeyemo
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | | | - Olateju Balikis Akinola
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Temitope Isaac Adelusi
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Leonard Ona Ehigie
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Adeola Folasade Ehigie
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria.
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Khaksar S, Bigdeli M, Samiee A, Shirazi-zand Z. Antioxidant and Anti-apoptotic Effects of Cannabidiol in Model of Ischemic Stroke in Rats. Brain Res Bull 2022; 180:118-130. [DOI: 10.1016/j.brainresbull.2022.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/27/2021] [Accepted: 01/05/2022] [Indexed: 12/11/2022]
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Yang T, Guo R, Ofengeim D, Hwang JY, Zukin RS, Chen J, Zhang F. Molecular and Cellular Mechanisms of Ischemia-Induced Neuronal Death. Stroke 2022. [DOI: 10.1016/b978-0-323-69424-7.00005-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Long M, Wang Z, Shao L, Bi J, Chen Z, Yin N. Electroacupuncture Pretreatment Attenuates Cerebral Ischemia-Reperfusion Injury in Rats Through Transient Receptor Potential Vanilloid 1-Mediated Anti-apoptosis via Inhibiting NF-κB Signaling Pathway. Neuroscience 2021; 482:100-115. [PMID: 34929338 DOI: 10.1016/j.neuroscience.2021.12.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/12/2022]
Abstract
Our previous study showed that electroacupuncture (EA) pretreatment elicited protective effect on cerebral ischemia-reperfusion injury (CIRI) in rats, at least partly, which was associated with transient receptor potential vanilloid 1 (TRPV1)-regulated anti-oxidant stress and anti-inflammation. In this study, we further investigated the possible contribution of TRPV1-mediated anti-apoptosis in EA pretreatment-evoked neuroprotection in CIRI. After EA pretreatment at Baihui (GV20), bilateral Shenshu (BL23) and Sanyinjiao (SP6) acupoints, transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 6 h in rats. Then, infarct volume, nerve cell injury, neuronal apoptosis, NF-κB signaling activation, and expression of TRPV1 were evaluated by TTC staining, Hematoxylin-Eosin staining, transmission electron microscopy, immunochemistry, immunofluorescence, and Western blot, respectively. The presented data showed that EA pretreatment significantly reduced infarct volume, relieved nerve cell injury, decreased the expression of pro-apoptotic proteins Bax and cleaved caspase-3, increased the level of anti-apoptotic protein Bcl-2, inhibited NF-κB (p65) transcriptional activity, and curbed TRPV1 expression in MCAO rats. By contrast, enhancement of TRPV1 expression accompanying capsaicin application, the specific TRPV1 agonists, markedly accelerated nerve cell damage, aggravated neuronal apoptosis, prompted nuclear translocation of NF-κB (p65), resulting in the reversion of EA pretreatment-evoked neuroprotective effect in MCAO rats. Thus, we conclude that EA pretreatment-induced downregulation of neuronal TRPV1 expression plays an anti-apoptosis role through inhibiting NF-κB signaling pathway, thereby protecting MCAO rats from cerebral ischemia-reperfusion injury.
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Affiliation(s)
- Man Long
- College of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan, China
| | - Zhigang Wang
- Department of Pathogen Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Luyao Shao
- Department of Pathogen Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Jing Bi
- Department of Pathogen Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Zebin Chen
- College of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan, China; Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan, China
| | - Nina Yin
- Department of Anatomy, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China.
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Gu LF, Chen JQ, Lin QY, Yang YZ. Roles of mitochondrial unfolded protein response in mammalian stem cells. World J Stem Cells 2021; 13:737-752. [PMID: 34367475 PMCID: PMC8316864 DOI: 10.4252/wjsc.v13.i7.737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
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Affiliation(s)
- Li-Fang Gu
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Qi Chen
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Qing-Yin Lin
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan-Zhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750001, Ningxia Hui Autonomous Region, China.
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15
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Dihydrocapsaicin effectively mitigates cerebral ischemia-induced pathological changes in vivo, partly via antioxidant and anti-apoptotic pathways. Life Sci 2021; 283:119842. [PMID: 34298038 DOI: 10.1016/j.lfs.2021.119842] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 12/26/2022]
Abstract
AIMS Ischemic stroke occurs when there is a sudden blockage of cerebral blood flow. This condition is a major cause of mortality, especially in low-income countries, and its incidence is dramatically increasing. Therapeutic strategies against stroke are therefore required. The present study explored the effects of dihydrocapsaicin on neuronal loss, brain infarct volume, and antioxidants in a rat model of permanent occlusion of the right middle cerebral artery (Rt.MCAO). MAIN METHODS Male Wistar rats received dihydrocapsaicin intraperitoneally for 7 days after permanent occlusion of their right middle cerebral artery (Rt.MCAO). Then, the brain infarct volume, neuronal density, and antioxidant and anti-apoptotic activities in the cortex and hippocampus were determined at the end of the study. KEY FINDING Dihydrocapsaicin treatment was found to significantly improve neuronal density, decrease infarct volume, reduce MDA elevation, improve CAT and SOD activities, decrease the density ratio of Bax and caspase-3, and increase the density ratio of Bcl-XL to β-actin in the cerebral cortex and hippocampus. SIGNIFICANCE The present study suggests that dihydrocapsaicin effectively mitigates cerebral ischemia-induced pathological changes in vivo, partly via antioxidant and anti-apoptotic pathways.
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Ma xing shi gan decoction eliminates PM2.5-induced lung injury by reducing pulmonary cell apoptosis through Akt/mTOR/p70S6K pathway in rats. Biosci Rep 2021; 40:225703. [PMID: 32627816 PMCID: PMC7350893 DOI: 10.1042/bsr20193738] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 07/02/2020] [Accepted: 07/03/2020] [Indexed: 12/19/2022] Open
Abstract
The present study was designed to investigate the anti-apoptosis effect of Ma xing shi gan decoction (MXD) on PM2.5-induced lung injury via protein kinase B (Akt)/mTOR/p70S6K pathway. A UPLC-MS/MS system was introduced for component analysis of MXD. Rats were instilled with PM2.5 solution suspension intratracheally to induce acute lung injury. The rats were then orally administered with MXD (16, 8, and 4 g/kg) once a day for 7 consecutive days. The therapeutic effects of MXD were evaluated by Hematoxylin and Eosin (HE) staining. The apoptotic cell death was analyzed by terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay. The alterations in cytochrome c (Cytc) and cleaved-caspase-3 (C-caspase-3) were measured by immunohistochemistry (IHC). The expressions of Bax, B-cell lymphoma 2 (Bcl-2), p-Akt, p-mTOR and p-p70S6K were detected by Western blot. In vitro, PM2.5 exposure model was introduced in A549 cell, followed by incubation with MXD-medicated serum. Hoechst staining was used to determine apoptotic rate. The levels of Bax, Bcl-2, p-Akt, p-mTOR and p-p70S6K were detected by Western blot. Our results in vivo indicated that treatment with MXD decreased histopathological changes score, TUNEL-positive cells rate, expressions of Cytc and C-caspase-3. The in vitro results revealed that incubation with MXD-mediated serum decreased apoptotic rate. Both results in vivo and in vitro demonstrated that MXD inhibited pro-apoptotic protein Bax and promoted anti-apoptotic protein Bcl-2 expression. Likewise, MXD activated Akt/mTOR/p70S6K signal pathway, which was also confirmed by Western immunoblotting. In conclusion, MXD attenuates lung injury and the underlying mechanisms may relate to regulating the apoptosis via Akt/mTOR/p70S6K signaling pathway activation.
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Wang H, Hu X, Li M, Pan Z, Li D, Zheng Q. Daphnoretin induces reactive oxygen species-mediated apoptosis in melanoma cells. Oncol Lett 2021; 21:453. [PMID: 33907563 PMCID: PMC8063224 DOI: 10.3892/ol.2021.12714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/25/2021] [Indexed: 12/11/2022] Open
Abstract
Research suggests that daphnoretin exhibits a diverse array of antitumor mechanisms and pharmacological activities. However, there is no definitive explanation for the antitumor mechanisms of daphnoretin in malignant melanoma. In the present study, MTT and colony formation assays demonstrated that daphnoretin significantly inhibited the proliferation of melanoma A375 and B16 cells. Following treatment with daphnoretin, apoptotic bodies were observed in A375 and B16 cells via Hoechst 33258 staining. Furthermore, western blot analysis revealed that the apoptosis-related proteins cleaved caspase-3, cleaved caspase-9, Bax, cytochrome c and apoptotic protease-activating factor 1 were significantly upregulated, while the expression levels of caspase-3, caspase-9 and Bcl-2 were downregulated in A375 and B16 cells. Flow cytometry and fluorescence microscopy revealed that daphnoretin induced higher levels of reactive oxygen species (ROS). Therefore, the results of the present study indicated that daphnoretin induced ROS-mediated mitochondria apoptosis in human (A375) and murine (B16) malignant melanoma cells.
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Affiliation(s)
- Hui Wang
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, Xinjiang 832003, P.R. China
| | - Xue Hu
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Minjing Li
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Zhaohai Pan
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Defang Li
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Qiusheng Zheng
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, Xinjiang 832003, P.R. China.,Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
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Dendrobium nobile Lindl. polysaccharides reduce cerebral ischemia/reperfusion injury in mice by increasing myeloid cell leukemia 1 via the downregulation of miR-134. Neuroreport 2020; 32:177-187. [PMID: 33323840 DOI: 10.1097/wnr.0000000000001562] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The traditional Chinese medicine, Dendrobium nobile Lindl. polysaccharides (DNLP), reportedly has neuroprotective effects. However, its effects following ischemic stroke remain unclear. This study aimed to explore the role and mechanism of DNLP in experimental models of inflammation and apoptosis. METHODS Inflammation and apoptosis were induced by in vivo ischemia/reperfusion and by in vitro oxygen glucose deprivation/reperfusion (OGD/R). In the in vivo model, immediately after the induction of cerebral ischemia, 50, 100, and 200 mg/kg DNLP were injected intraperitoneally. We subsequently detected indicators of neuronal damage. RESULTS Treatment with Dendrobium nobile Lindl. polysaccharide significantly reduced cerebral ischemic injury. After in vivo and in vitro middle cerebral artery occlusion/reperfusion or OGD/R-induced hypoxia injury, miR-134 expression in neurons was significantly increased. Altering the expression of miR-134 induced changes in myeloid cell leukemia 1 (MCL-1), one of its target proteins. In addition, DNLP significantly downregulated the in vivo and in vitro expression of miR-134 after ischemic injury, and influenced inflammation and apoptotic proteins by altering the level of MCL-1 protein. DNLP also had a protective effect on neurons damaged by OGD/R, which could improve cell survival rates and inhibit lactate dehydrogenase release as well as apoptosis. CONCLUSIONS DNLP may protect the brain and neurons from hypoxic damage in mice with ischemic stroke by activating MCL-1 and downregulating miR-134, providing a new therapeutic target for ischemic stroke.
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Hu W, Lin C. S100a8 silencing attenuates inflammation, oxidative stress and apoptosis in BV2 cells induced by oxygen‑glucose deprivation and reoxygenation by upregulating GAB1 expression. Mol Med Rep 2020; 23:64. [PMID: 33215218 PMCID: PMC7716398 DOI: 10.3892/mmr.2020.11702] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 08/11/2020] [Indexed: 12/15/2022] Open
Abstract
S100a8 serves an important role in cell differentiation and is abnormally expressed in common tumors, but there are few studies on the association between S100a8 and brain I/R injury. The present study aimed to investigate the role of S100a8 in oxygen-glucose deprivation and reoxygenation (OGD/R)-induced BV2 microglia cell injury, and to elucidate the potential underlying molecular mechanisms. BV2 cells were exposed to OGD/R to mimic ischemia/reperfusion (I/R) injury in vitro. S100a8 expression was detected via reverse transcription-quantitative PCR and western blot analyses. Following transfection with short hairpin RNAs targeting S100a8, the levels of inflammatory cytokines and oxidative stress-related factors were determined using commercial kits. Apoptosis was assessed using flow cytometric analysis and the expression levels of apoptosis-related proteins were determined using western blot analysis. Subsequently, the mRNA and protein levels of Grb2-associated binder 1 (GAB1) were assessed following S100a8 silencing. Immunoprecipitation (IP) was performed to verify the association between S100a8 and GAB1. The levels of inflammation, oxidative stress and apoptosis were assessed following GAB1 silencing, along with S100a8 silencing in BV2 cells subjected to OGD/R. The results indicated that exposure to OGD/R markedly upregulated S100a8 expression in BV2 cells. S100a8 silencing inhibited inflammation, oxidative stress and apoptosis, accompanied by changes in the expression of related proteins. The IP assay revealed a strong interaction between GAB1 and S100a8. In addition, GAB1 silencing reversed the inhibitory effects of S100a8 silencing on inflammation, oxidative stress and apoptosis in OGD/R-stimulated BV2 cells. Taken together, the results of the present study demonstrated that S100a8 silencing alleviated inflammation, oxidative stress and the apoptosis of BV2 cells induced by OGD/R, partly by upregulating the expression of GAB1. Thus, these findings may potentially provide a novel direction to develop therapeutic strategies for cerebral I/R injury.
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Affiliation(s)
- Wenguang Hu
- Pediatric Neurology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610091, P.R. China
| | - Caimei Lin
- Department of Neurology, Xiamen Children's Hospital of Fujian Province, Xiamen, Fujian 361006, P.R. China
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Modulation of the mitochondrial voltage-dependent anion channel (VDAC) by hydrogen peroxide and its recovery by curcumin. EUROPEAN BIOPHYSICS JOURNAL: EBJ 2020; 49:661-672. [DOI: 10.1007/s00249-020-01469-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 09/25/2020] [Accepted: 10/05/2020] [Indexed: 11/26/2022]
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Glycosylation end products mediate damage and apoptosis of periodontal ligament stem cells induced by the JNK-mitochondrial pathway. Aging (Albany NY) 2020; 12:12850-12868. [PMID: 32611833 PMCID: PMC7377852 DOI: 10.18632/aging.103304] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 03/30/2020] [Indexed: 12/11/2022]
Abstract
Background: Recent studies have confirmed the bidirectional relationship between the two and the exacerbation of periodontitis by type II diabetes mellitus (T2DM), the pathogenic mechanism has not yet been clarified, AGEs has been linked to the pathogenesis of both periodontitis and T2DM, JNK signaling pathway might play a important role to explain the inner mechanism. Objectives: To study advanced glycation end products (AGEs) activate the innate immune system of the host by activating oxidative stress and affecting cellular signal transduction in periodontal ligament stem cells (PDLSCs); Results: TNF-α and/or AGEs can induce the formation of endogenous ROS in PDLSCs, thereby activating the downstream JNK signalling pathway, leading to the initiation of the mitochondria-mediated apoptotic pathway and the induction of PDLSC apoptosis. Conclusion: we hypothesized that the JNK pathway is a key link in the apoptosis of PDLSCs mediated by TNF-α and/or AGEs. Materials and Methods: PDLSCs from healthy volunteers were extracted, cultured and stimulated with TNF-a and/or AGEs, Flow cytometry, CCK-8, multidifferential assay, RT-PCR, apoptosis assay, Transmission electron microscopy and Western blotting were recruit to detect the internal relations between AGEs and PDLSCs.
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22
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Wu L, Zeng S, Cao Y, Huang Z, Liu S, Peng H, Zhi C, Ma S, Hu K, Yuan Z. Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7. Front Cell Neurosci 2019; 13:468. [PMID: 31708743 PMCID: PMC6823346 DOI: 10.3389/fncel.2019.00468] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 10/01/2019] [Indexed: 12/31/2022] Open
Abstract
The c-Jun N-terminal kinase (JNK)/c-Jun cascade-dependent neuronal apoptosis has been identified as a central element for early brain injury (EBI) following subarachnoid hemorrhage (SAH), but the molecular mechanisms underlying this process are still thoroughly undefined to date. In this study, we found that pan-histone deacetylase (HDAC) inhibition by TSA, SAHA, VPA, and M344 led to a remarkable decrease in the phosphorylation of JNK and c-Jun, concomitant with a significant abrogation of apoptosis caused by potassium deprivation in cultured cerebellar granule neurons (CGNs). Further investigation showed that these effects resulted from HDAC inhibition-induced transcriptional suppression of MKK7, a well-known upstream kinase of JNK. Using small interference RNAs (siRNAs) to silence the respective HDAC members, HDAC4 was screened to be required for MKK7 transcription and JNK/c-Jun activation. LMK235, a specific HDAC4 inhibitor, dose-dependently suppressed MKK7 transcription and JNK/c-Jun activity. Functionally, HDAC4 inhibition via knockdown or LMK235 significantly rescued CGN apoptosis induced by potassium deprivation. Moreover, administration of LMK235 remarkably ameliorated the EBI process in SAH rats, associated with an obvious reduction in MKK7 transcription, JNK/c-Jun activity, and neuronal apoptosis. Collectively, the findings provide new insights into the molecular mechanism of neuronal apoptosis regarding HDAC4 in the selective regulation of MKK7 transcription and JNK/c-Jun activity. HDAC4 inhibition could be a potential alternative to prevent MKK7/JNK/c-Jun axis-mediated nervous disorders, including SAH-caused EBI.
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Affiliation(s)
- Liqiang Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, China
| | - Shulian Zeng
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, China
| | - Yali Cao
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, China
| | - Ziyan Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, China
| | - Sisi Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, China
| | - Huaidong Peng
- Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Cheng Zhi
- Department of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shanshan Ma
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China
| | - Kunhua Hu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China
| | - Zhongmin Yuan
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, China
- Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China
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Zhou L, Ao LY, Yan YY, Li WT, Ye AQ, Li CY, Shen WY, Liang BW, Xiong-Zhu, Li YM. JLX001 Ameliorates Ischemia/Reperfusion Injury by Reducing Neuronal Apoptosis via Down-Regulating JNK Signaling Pathway. Neuroscience 2019; 418:189-204. [PMID: 31487541 DOI: 10.1016/j.neuroscience.2019.08.053] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 08/29/2019] [Accepted: 08/30/2019] [Indexed: 01/26/2023]
Abstract
JLX001, a novel compound with similar structure with cyclovirobuxine D (CVB-D), has been proved to exert therapeutical effects on permanent focal cerebral ischemia. However, the protective effects of JLX001 on cerebral ischemia/reperfusion (I/R) injury and its anti-apoptotic effects have not been reported. We investigated the efficacy of JLX001 in two pharmacodynamic tests (pre-treatment test and post-treatment) with rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). The pharmacodynamic tests demonstrated that JLX001 ameliorated I/R injury by reducing infarct sizes and brain edema. The results of Morris water maze, neurological scores, cylinder test and posture reflex test implied that JLX001 improved the learning, memory and motor ability after MCAO/R in the long term. Anti-apoptotic effects of JLX001 and its regulation of cytosolic c-Jun N-terminal Kinases (JNKs) signal pathway were confirmed in vivo by co-immunofluorescence staining and western immunoblotting. Furthermore, primary cortical neuron cultures were prepared and exposed to oxygen glucose deprivation/reoxygenation (OGD/R) for in vitro studies. Cytotoxicity test and mitochondrial membrane potential (MMP) test showed that JLX001 enhanced cell survival rate and maintained MMP. Flow cytometry and TdT-mediated dUTP-X nick end labeling (TUNEL) staining demonstrated the anti-apoptotic effects of JLX001 in vitro. Likewise, JLX001 regulated JNK signal pathway in vivo, which was also confirmed by western immunoblotting. Collectively, this study presents the first evidence that JLX001 exerted protective effects against I/R injury by reducing neuronal apoptosis via down-regulating JNK signaling pathway.
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Affiliation(s)
- Lin Zhou
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Lu-Yao Ao
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yun-Yi Yan
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wan-Ting Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - An-Qi Ye
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Cheng-Yuan Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wei-Yang Shen
- School of Sciences, China Pharmaceutical University, Nanjing 210009, PR China
| | - Bing-Wen Liang
- Jiangsu Jinglixin Pharmaceutical Technology Company Limited, Nanjing 211100, PR China
| | - Xiong-Zhu
- Jiangsu Jinglixin Pharmaceutical Technology Company Limited, Nanjing 211100, PR China; Medicine & Chemical Institute, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Yun-Man Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
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Praveen Kumar P, Sunil Kumar KT, Kavya Nainita M, Sai Tarun A, Raghu Ramudu BG, Deepika K, Pramoda A, Yasmeen C. Cerebroprotective Potential of Hesperidin Nanoparticles Against Bilateral Common Carotid Artery Occlusion Reperfusion Injury in Rats and In silico Approaches. Neurotox Res 2019; 37:264-274. [PMID: 31422568 DOI: 10.1007/s12640-019-00098-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/30/2019] [Accepted: 08/06/2019] [Indexed: 12/13/2022]
Abstract
Cerebral ischemia-reperfusion (C I/R) accelerates neuronal injury through the overproduction of reactive oxygen species due to mitochondrial dysfunction. Hesperidin has cerebroprotective effects due to its antioxidant and anti-apoptotic nature against oxidative damage caused by C I/R. The blood-brain barrier also limits the hesperidin passage into the cerebral region due to its poor bioavailability. Current research included analysis of binding energy, hesperidin inhibitory constant on inflammatory cytokines (TNF α, IL 6) and apoptotic protein (caspase 3), hesperidin nanoparticles prepared, and investigation of their defense against C I/R rats. Binding energy and IC50 of hesperidin on pathological proteins using AutoDoc. 1.5.6 and PyRx in silico tools were compared with thalidomide. The fabrication method was engaged in the preparing of nano-hesperidin, characterized by SEM assessment. Bilateral common carotid artery occlusion technique has been used in experimental rats to cause C I/R. Nano-hesperidin cerebroprotective activity was assessed by differing infarction magnitude, oxidative stress parameters, TNF α and IL 6, and hippocampal histopathology with rats treated with unformulated hesperidin. Hesperidin found stronger binding strength and IC50 was relative to thalidomide on TNF α, IL 6, and caspase 3. Nano-hesperidin with a size of 100-500 nm was shown in a uniform nano-size and spherical form. Nano-hesperidin-treated rats showed significantly increased glutathione (p < 0.00***), catalase (p < 0.01**), and total protein (p < 0.001***), and decreased cerebral infarction size, TNF α (p < 0.01**), IL 6 (p < 0.01**), and malondialdehyde (p < 0.05*), compared with hesperidin-treated ischemic rats. Therefore, hesperidin nanoparticles may confer protection to the neurons against ischemic injury compared with hesperidin treatment.
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Affiliation(s)
- P Praveen Kumar
- Department of Pharmacology, Creative Educational Society's College of Pharmacy, Kurnool, Andhra Pradesh, India.
| | - K T Sunil Kumar
- Shri Vishnu College of Pharmacy, Bhimavaram, Andhra Pradesh, India
| | - M Kavya Nainita
- Department of Pharmacology, Creative Educational Society's College of Pharmacy, Kurnool, Andhra Pradesh, India
| | - A Sai Tarun
- Department of Pharmacology, Creative Educational Society's College of Pharmacy, Kurnool, Andhra Pradesh, India
| | - B G Raghu Ramudu
- Department of Pharmacology, Creative Educational Society's College of Pharmacy, Kurnool, Andhra Pradesh, India
| | - K Deepika
- Department of Pharmacology, Creative Educational Society's College of Pharmacy, Kurnool, Andhra Pradesh, India
| | - A Pramoda
- Department of Pharmacology, Creative Educational Society's College of Pharmacy, Kurnool, Andhra Pradesh, India
| | - C Yasmeen
- Department of Pharmacology, Creative Educational Society's College of Pharmacy, Kurnool, Andhra Pradesh, India
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25
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He J, Li H, Li G, Yang L. Hyperoside protects against cerebral ischemia-reperfusion injury by alleviating oxidative stress, inflammation and apoptosis in rats. BIOTECHNOL BIOTEC EQ 2019. [DOI: 10.1080/13102818.2019.1620633] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Jinting He
- Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, PR China
| | - Haiqi Li
- Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, PR China
| | - Gaofeng Li
- Department of Orthopedics, The People’s Hospital of Jilin Province, Changchun, Jilin, PR China
| | - Le Yang
- Department of Endocrinology, The People’s Hospital of Jilin Province, Changchun, Jilin, PR China
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26
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Zhang H, Chen H, Wang W, Zhang B, Yu L. Sevoflurane reduces ischemic brain injury in rats with diet and streptozotocin-induced diabetes. J Recept Signal Transduct Res 2019; 38:448-454. [PMID: 31038022 DOI: 10.1080/10799893.2019.1585451] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Huapeng Zhang
- Department of Pain Management, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
- Department of Anesthesiology, Yidu Central Hospital of Weifang, Weifang, Shandong, China
| | - Huayong Chen
- Department of Anesthesiology, Yidu Central Hospital of Weifang, Weifang, Shandong, China
| | - Wei Wang
- Department of Anesthesiology, Yidu Central Hospital of Weifang, Weifang, Shandong, China
| | - Baoze Zhang
- Qingzhou Center for Disease Control and Prevention in Shandong, Qingzhou, China
| | - Lingzhi Yu
- Department of Pain Management, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
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27
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Wang RR, Li CF, Wang DZ, Zhang CW, Liu GX. c-Jun N-terminal kinase 3 deficiency protects axotomized retinal ganglion cells via affecting mitochondria involved apoptosis pathway. Int J Ophthalmol 2019; 12:30-37. [PMID: 30662837 PMCID: PMC6326936 DOI: 10.18240/ijo.2019.01.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 11/05/2018] [Indexed: 11/23/2022] Open
Abstract
AIM To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases (JNKs) in mouse optic nerve axotomy induced neurotrauma. METHODS We firstly investigated the expression of JNK1, JNK2, and JNK3 in the retinal ganglion cells (RGCs) by double-immunofluorescent staining. Then we created optic nerve axotomy model in wild type as well as JNK1, JNK2, JNK3, isoform specific gene deficiency mice. With that, we checked the protein expression profile of JNKs and its active form, and quantified the survival RGCs number by immunofluorescence staining. We further explored the molecules underlying isoform specific protective effect by real-time polymerase chain reaction (PCR) and Western blotting assay. RESULTS We found that all the three isoforms of JNKs were expressed in the RGCs. Deficiency of JNK3, but not JNK1 or JNK2, significantly alleviated optic nerve axotomy induced RGCs apoptosis. We further established that expression of Noxa, a pro-apoptotic member of BH3 family, was significantly suppressed only in JNK3 gene deficiency mice. But tumor necrosis factor receptor 1 (TNFR1) and Fas, two key modulators of death receptor mediated apoptosis pathway, did not display obvious change in the expression. CONCLUSION It is suggested that mitochondria mediated apoptosis, but not death receptor mediated apoptosis got involved in the JNK3 gene deficiency induced RGCs protection. Our study provides a novel insight into the isoform-specific role of JNKs in neurotrauma and indicates some cues for its therapeutics.
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Affiliation(s)
- Rong-Rong Wang
- Qingdao University, Qingdao 266000, Shandong Province, China
- Department of Ophthalmology, Jimo Traditional Chinese Medicine Hospital, Qingdao 266200, Shandong Province, China
| | - Cheng-Fang Li
- Department of Ophthalmology, Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - De-Zu Wang
- Department of Ophthalmology, Jimo Traditional Chinese Medicine Hospital, Qingdao 266200, Shandong Province, China
| | - Cheng-Wu Zhang
- Institute of Advanced Materials, Nanjing Tech University, Nanjing 211800, Jiangsu Province, China
| | - Gui-Xiang Liu
- Department of Ophthalmology, Affiliated Hospital of the Medical College of Qingdao University, Qingdao 266000, Shandong Province, China
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28
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Xu H, Hua Y, Zhong J, Li X, Xu W, Cai Y, Mao Y, Lu X. Resveratrol Delivery by Albumin Nanoparticles Improved Neurological Function and Neuronal Damage in Transient Middle Cerebral Artery Occlusion Rats. Front Pharmacol 2018; 9:1403. [PMID: 30564121 PMCID: PMC6288361 DOI: 10.3389/fphar.2018.01403] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/15/2018] [Indexed: 01/27/2023] Open
Abstract
Human serum albumin (HSA) is an intrinsic protein and important carrier that transports endogenous as well as exogenous substances. It is demonstrated in this study that the regional accumulation of albumin in the ischemia-reperfusion (I/R) brain may lead in the application of HSA based nanoparticles in the study of cerebral I/R injury. Resveratrol (RES) is potential in the treatment of cerebral I/R injury but is restricted for its water insolubility and short half-life in vivo. In our study, RES loaded HSA nanoparticles (RES-HSA-NPs) were prepared to facilitate the application of RES in protection from cerebral I/R injury. RES-HSA-NPs demonstrated spherical shape, a diameter about 100 nm, a highest RES encapsulation efficiency of 60.9 ± 5.07%, and controlled release pattern with the maximum release ratio of 50.2 ± 4.91% [in pH = 5.0 phosphate buffered saline (PBS)] and 26. 2 ± 2.73% (in pH = 7.4 PBS), respectively, after 90 h incubation at 37°C. After intravenous injection into transient middle cerebral artery occlusion (tMCAO) rats, RES-HSA-NPs improved neurological score and decreased infarct volume at 24 h after tMCAO in a dose dependent manner. A single dose of 20 mg/kg RES-HSA-NPs via tail vein improved neurological outcomes and decreased infarct volume at 24 and 72 h in tMCAO rats. I/R increased oxidative stress (indicated by products of lipid peroxidation, MDA) and neuronal apoptosis (indicated by yellow-brown TUNEL-positive cells), RES-HSA-NPs significantly attenuated oxidative stress and neuronal apoptosis. These results demonstrated the potential of RES-HSA-NPs in the therapy of cerebral I/R injury.
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Affiliation(s)
- Huae Xu
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Ye Hua
- Department of Neurology, The Affiliated Wuxi Second People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jie Zhong
- School of Foreign Languages, Nanjing University of Finance and Economics, Nanjing, China
| | - Xiaolin Li
- Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Xu
- Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingyuan Cai
- Department of Geriatric Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yukang Mao
- Department of Medical Image Science, Xuzhou Medical University, Xuzhou, China
| | - Xiaowei Lu
- Department of Geriatric Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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29
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Mo XY, Li XM, She CS, Lu XQ, Xiao CG, Wang SH, Huang GQ. Hydrogen-rich saline protects rat from oxygen glucose deprivation and reperusion-induced apoptosis through VDAC1 via Bcl-2. Brain Res 2018; 1706:110-115. [PMID: 30287344 DOI: 10.1016/j.brainres.2018.09.037] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/31/2018] [Accepted: 09/30/2018] [Indexed: 11/17/2022]
Abstract
BACKGROUND Hydrogen is received as an inert gas that thought to be non-functional in vivo previously. Recently, emerging evidences showed that in ischemia/reperfusion (IR) condition, hydrogen reduced cellular reactive oxygen species (ROS) production and ameliorated cell apoptosis. However, the underlying mechanism of hydrogen on IR-induced apoptosis remains elusive. Here we tried to unravel the mode of action of hydrogen with rat adrenal medulla cell line PC-12 in vitro. METHODS The mitochondrial functions before and after oxygen glucose deprivation and reperfusion (OGD/RP) were determined with corresponding dyes. The expression of Bcl-2, Bax, VDAC1, cytochrome c and caspase 9 was detected using qRT-PCR and Western Blotting method. Then Bcl-2 inhibitor, AB-199, was applied to investigate the role of Bcl-2 in OGD/RP-induced cell apoptosis. Finally, we manipulated the expression of VDAC1 with plasmids transfection to understand the effects of VDAC1 on Bcl-2-mediated anti-apoptosis in OGD/RP. RESULTS In this study, we demonstrated that hydrogen-rich saline (HRS) reduced OGD/RP-mediated neuronal loss by stimulating the expression of Bcl-2, which suppressed the activity of VDAC1. Consequently, HRS maintained the mitochondrial functions, restrained the release of cytochrome c and caspase 9 activation, resulting in ameliorated cell viability. CONCLUSIONS HRS ameliorated OGD/RP-induced PC-12 cell apoptosis and provided a novel treatment option for ischemia.
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Affiliation(s)
- Xiao-Ye Mo
- Department of Emergency, Xiangya Hospital of Central South University, Changsha 410008, PR China
| | - Xiang-Min Li
- Department of Emergency, Xiangya Hospital of Central South University, Changsha 410008, PR China
| | - Chang-Shou She
- Department of Emergency, Xiangya Hospital of Central South University, Changsha 410008, PR China
| | - Xiao-Qin Lu
- Department of Emergency, Xiangya Hospital of Central South University, Changsha 410008, PR China
| | - Cheng-Gen Xiao
- Department of Emergency, Xiangya Hospital of Central South University, Changsha 410008, PR China
| | - Shi-Hai Wang
- Department of Emergency, Xiangya Hospital of Central South University, Changsha 410008, PR China
| | - Guo-Qing Huang
- Department of Emergency, Xiangya Hospital of Central South University, Changsha 410008, PR China.
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30
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Immune Cells After Ischemic Stroke Onset: Roles, Migration, and Target Intervention. J Mol Neurosci 2018; 66:342-355. [DOI: 10.1007/s12031-018-1173-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 09/14/2018] [Indexed: 01/09/2023]
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31
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Liu Q, Zhang D, Hu D, Zhou X, Zhou Y. The role of mitochondria in NLRP3 inflammasome activation. Mol Immunol 2018; 103:115-124. [PMID: 30248487 DOI: 10.1016/j.molimm.2018.09.010] [Citation(s) in RCA: 331] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 09/10/2018] [Accepted: 09/13/2018] [Indexed: 12/19/2022]
Abstract
The NLRP3 inflammasome is a multiprotein platform which is activated upon cellular infection or stress. Its activation leads to caspase-1-dependent secretion of proinflammatory cytokines like interleukin-1β (IL-1β) and IL-18, and an inflammatory form of cell death termed as pyroptosis. Recent studies have unveiled the pivotal roles of mitochondria in initiation and regulation of the NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) inflammasome. NLRP3 activators induce mitochondrial destabilization, NLRP3 deubiquitination, linear ubiquitination of ASC, and externalization or release of mitochondria-derived molecules such as cardiolipin and mitochondrial DNA. These molecules bind to NLRP3 that is translocated on mitochondria and activate the NLRP3 inflammasome. Here we review recently described mechanisms by which mitochondria regulate NLRP3 inflammasome activation.
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Affiliation(s)
- Qiuyun Liu
- College of Animal Science, Southwest University, Chongqing 402460, China
| | - Danyan Zhang
- College of Animal Science, Southwest University, Chongqing 402460, China
| | - Diyu Hu
- College of Animal Science, Southwest University, Chongqing 402460, China
| | - Xiangmei Zhou
- State Key Laboratories for Agrobiotechnology, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yang Zhou
- College of Animal Science, Southwest University, Chongqing 402460, China.
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MacDougall G, Anderton RS, Mastaglia FL, Knuckey NW, Meloni BP. Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics. Neurobiol Dis 2018; 121:17-33. [PMID: 30218759 DOI: 10.1016/j.nbd.2018.09.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 08/26/2018] [Accepted: 09/11/2018] [Indexed: 01/11/2023] Open
Abstract
Stroke is the second leading cause of death globally and represents a major cause of devastating long-term disability. Despite sustained efforts to develop clinically effective neuroprotective therapies, presently there is no clinically available neuroprotective agent for stroke. As a central mediator of neurodamaging events in stroke, mitochondria are recognised as a critical neuroprotective target, and as such, provide a focus for developing mitochondrial-targeted therapeutics. In recent years, cationic arginine-rich peptides (CARPs) have been identified as a novel class of neuroprotective agent with several demonstrated mechanisms of action, including their ability to target mitochondria and exert positive effects on the organelle. This review provides an overview on neuronal mitochondrial dysfunction in ischaemic stroke pathophysiology and highlights the potential beneficial effects of CARPs on mitochondria in the ischaemic brain following stroke.
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Affiliation(s)
- Gabriella MacDougall
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Perron Institute for Neurological and Translational Science, Nedlands, Australia; School of Heath Sciences, and Institute for Health Research, The University Notre Dame Australia, Fremantle, Australia.
| | - Ryan S Anderton
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Perron Institute for Neurological and Translational Science, Nedlands, Australia; School of Heath Sciences, and Institute for Health Research, The University Notre Dame Australia, Fremantle, Australia
| | - Frank L Mastaglia
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Perron Institute for Neurological and Translational Science, Nedlands, Australia
| | - Neville W Knuckey
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Perron Institute for Neurological and Translational Science, Nedlands, Australia; Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia
| | - Bruno P Meloni
- Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Perron Institute for Neurological and Translational Science, Nedlands, Australia; Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia
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