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Gong F, Wei Y. LncRNA PVT1 promotes neuroinflammation after intracerebral hemorrhage by regulating the miR-128-3p/TXNIP axis. Int J Neurosci 2025; 135:573-587. [PMID: 38294729 DOI: 10.1080/00207454.2024.2312998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/24/2024] [Accepted: 01/27/2024] [Indexed: 02/01/2024]
Abstract
OBJECTIVE Intracerebral hemorrhage (ICH) has significant morbidity and mortality. TXNIP and the competing endogenous RNA (ceRNA) regulatory mechanism involved in long non-coding RNA (lncRNA) play roles in ICH. We probed the upstream microRNAs (miRNAs)/lncRNAs that regulated TXNIP expression in the ceRNA mechanism. METHODS ICH mouse model was established, and ICH secondary injury was simulated in BV2 microglia by hemin treatment. TXNIP was silenced 48 h before ICH modeling. The ICH mouse brain water content (BWC) and brain lesion volume after ICH were recorded. Neuronal apoptosis and neurological deficits were evaluated by double staining of NeuN and TUNEL/modified Garcia/corner turn/forelimb placement tests. Iba1 + microglia number and tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/IL-10/TXNIP/PVT1/miR-128-3p levels were assessed by immunohistochemistry, Western blot, ELISA, and RT-qPCR. Cell viability/death of BV2 cells conditioned medium-treated neuron HT22 cells were assessed by CCK-8/LDH assays. miRNA that had a targeted binding relationship with TXNIP was screened. The targeted bindings of miR-128-3p to TXNIP/PVT1 to miR-128-3p were verified by dual-luciferase reporter gene assay. RESULTS TXNIP knockdown reduced post-ICH microglial activation/release of pro-inflammatory factors/brain edema/brain lesion volume/neurological deficits in mice and increased releases of anti-inflammatory factors. TXNIP/PVT1 knockdown inhibited hemin-induced inflammatory responses in BV2 cells and protected in vitro co-cultured HT22 cells. PVT1 was a sponge of miR-128-3p to repress TXNIP expression. miR-128-3p knockdown diminished PVT1 knockdown-inhibited hemin-induced BV2 cell inflammatory responses/neurotoxicity. CONCLUSIONS PVT1 silencing reduced hemin-induced neuroinflammation and had a protective effect on neurons by increasing the targeted inhibition of TXNIP by miR-128-3p.
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Affiliation(s)
- Fanyong Gong
- Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Yiting Wei
- Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
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Yuan X, Xia Y, Jiang P, Chen J, Wang C. Neuroinflammation Targeting Pyroptosis: Molecular Mechanisms and Therapeutic Perspectives in Stroke. Mol Neurobiol 2024; 61:7448-7465. [PMID: 38383921 DOI: 10.1007/s12035-024-04050-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/06/2024] [Indexed: 02/23/2024]
Abstract
Pyroptosis is a recently identified type of pro-inflammatory programmed cell death (PCD) mediated by inflammasomes and nucleotide oligomerization domain-like receptors (NLs) and dependent on members of the caspase family. Pyroptosis has been widely reported to participate in the occurrence and progression of various inflammatory diseases, including stroke, a frequently lethal disease with high prevalence and many complications. To date, there have been no effectively therapeutic strategies and methods for treating stroke. Pyroptosis is thought to be closely related to the occurrence and development of stroke. Understanding inflammatory responses induced by the activation of pyroptosis would be hopeful to provide feasible approaches and strategies. Targeting on molecules in the upstream or downstream of pyroptosis pathway has shown promise in the treatment of stroke. The present review summarizes current research on the characteristics of pyroptosis, the function and pathological phenomena of pyroptosis in stroke, the molecule mechanisms related to inflammatory pathways, and the drugs and other molecules that can affect outcomes after stroke. These findings may help identify possible targets or new strategies for the diagnosis and treatment of stroke.
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Affiliation(s)
- Xiwen Yuan
- Neurobiology Key Laboratory of Jining Medical University, Jining, 272067, China
| | - Yiwen Xia
- Neurobiology Key Laboratory of Jining Medical University, Jining, 272067, China
| | - Pei Jiang
- Institute of Clinical Pharmacy & Pharmacology, Jining First People's Hospital, Jining Medical University, Jining, 272011, China
| | - Jing Chen
- Neurobiology Key Laboratory of Jining Medical University, Jining, 272067, China.
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
| | - Chunmei Wang
- Neurobiology Key Laboratory of Jining Medical University, Jining, 272067, China.
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Xu X, Zhang L, He Y, Qi C, Li F. Progress in Research on the Role of the Thioredoxin System in Chemical Nerve Injury. TOXICS 2024; 12:510. [PMID: 39058162 PMCID: PMC11280602 DOI: 10.3390/toxics12070510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/30/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024]
Abstract
(1) Background: Various factors, such as oxidative stress, mitochondrial dysfunction, tumors, inflammation, trauma, immune disorders, and neuronal toxicity, can cause nerve damage. Chemical nerve injury, which results from exposure to toxic chemicals, has garnered increasing research attention. The thioredoxin (Trx) system, comprising Trx, Trx reductase, nicotinamide adenine dinucleotide phosphate, and Trx-interacting protein (TXNIP; endogenous Trx inhibitor), helps maintain redox homeostasis in the central nervous system. The dysregulation of this system can cause dementia, cognitive impairment, nerve conduction disorders, movement disorders, and other neurological disorders. Thus, maintaining Trx system homeostasis is crucial for preventing or treating nerve damage. (2) Objective: In this review study, we explored factors influencing the homeostasis of the Trx system and the involvement of its homeostatic imbalance in chemical nerve injury. In addition, we investigated the therapeutic potential of the Trx system-targeting active substances against chemical nerve injury. (3) Conclusions: Chemicals such as morphine, metals, and methylglyoxal interfere with the activity of TXNIP, Trx, and Trx reductase, disrupting Trx system homeostasis by affecting the phosphatidylinositol-3-kinase/protein kinase B, extracellular signal-regulated kinase, and apoptotic signaling-regulated kinase 1/p38 mitogen-activated protein kinase pathways, thereby leading to neurological disorders. Active substances such as resveratrol and lysergic acid sulfide mitigate the symptoms of chemical nerve injury by regulating the Ras/Raf1/extracellular signal-regulated kinase pathway and the miR-146a-5p/TXNIP axis. This study may guide the development of Trx-targeting modulators for treating neurological disorders and chemical nerve injuries.
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Affiliation(s)
- Xinwei Xu
- School of Medicine, Jiangsu University, Zhenjiang 212013, China; (X.X.); (L.Z.); (Y.H.)
| | - Lan Zhang
- School of Medicine, Jiangsu University, Zhenjiang 212013, China; (X.X.); (L.Z.); (Y.H.)
| | - Yuyun He
- School of Medicine, Jiangsu University, Zhenjiang 212013, China; (X.X.); (L.Z.); (Y.H.)
| | - Cong Qi
- Department of Pharmacy, Jurong People’s Hospital, Jurong 212400, China;
| | - Fang Li
- School of Medicine, Jiangsu University, Zhenjiang 212013, China; (X.X.); (L.Z.); (Y.H.)
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Yang K, Zeng L, He Q, Wang S, Xu H, Ge J. Advancements in research on the immune-inflammatory mechanisms mediated by NLRP3 inflammasome in ischemic stroke and the regulatory role of natural plant products. Front Pharmacol 2024; 15:1250918. [PMID: 38601463 PMCID: PMC11004298 DOI: 10.3389/fphar.2024.1250918] [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: 06/30/2023] [Accepted: 01/11/2024] [Indexed: 04/12/2024] Open
Abstract
Ischemic stroke (IS) is a major cause of mortality and disability among adults. Recanalization of blood vessels to facilitate timely reperfusion is the primary clinical approach; however, reperfusion itself may trigger cerebral ischemia-reperfusion injury. Emerging evidence strongly implicates the NLRP3 inflammasome as a potential therapeutic target, playing a key role in cerebral ischemia and reperfusion injury. The aberrant expression and function of NLRP3 inflammasome-mediated inflammation in cerebral ischemia have garnered considerable attention as a recent research focus. Accordingly, this review provides a comprehensive summary of the signaling pathways, pathological mechanisms, and intricate interactions involving NLRP3 inflammasomes in cerebral ischemia-reperfusion injury. Moreover, notable progress has been made in investigating the impact of natural plant products (e.g., Proanthocyanidins, methylliensinine, salidroside, α-asarone, acacia, curcumin, morin, ginsenoside Rd, paeoniflorin, breviscapine, sulforaphane, etc.) on regulating cerebral ischemia and reperfusion by modulating the NLRP3 inflammasome and mitigating the release of inflammatory cytokines. These findings aim to present novel insights that could contribute to the prevention and treatment of cerebral ischemia and reperfusion injury.
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Affiliation(s)
- Kailin Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Academy of Chinese Medicine, Changsha, Hunan, China
| | - Liuting Zeng
- Graduate School, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi He
- Department of Critical Care Medicine, People’s Hospital of Ningxiang City, Ningxiang, China
| | - Shanshan Wang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Hao Xu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Jinwen Ge
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Academy of Chinese Medicine, Changsha, Hunan, China
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Duan WL, Wang XJ, Ma YP, Sheng ZM, Dong H, Zhang LY, Zhang BG, He MT. Therapeutic strategies targeting the NLRP3‑mediated inflammatory response and pyroptosis in cerebral ischemia/reperfusion injury (Review). Mol Med Rep 2024; 29:46. [PMID: 38275110 PMCID: PMC10835666 DOI: 10.3892/mmr.2024.13170] [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: 07/28/2023] [Accepted: 01/12/2024] [Indexed: 01/27/2024] Open
Abstract
Ischemic stroke poses a major threat to human health. Therefore, the molecular mechanisms of cerebral ischemia/reperfusion injury (CIRI) need to be further clarified, and the associated treatment approaches require exploration. The NOD‑like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome serves an important role in causing CIRI, and its activation exacerbates the underlying injury. Activation of the NLRP3 inflammasome triggers the maturation and production of the inflammatory molecules IL‑1β and IL‑18, as well as gasdermin‑D‑mediated pyroptosis and CIRI damage. Thus, the NLRP3 inflammasome may be a viable target for the treatment of CIRI. In the present review, the mechanisms of the NLRP3 inflammasome in the intense inflammatory response and pyroptosis induced by CIRI are discussed, and the therapeutic strategies that target the NLRP3‑mediated inflammatory response and pyroptosis in CIRI are summarized. At present, certain drugs have already been studied, highlighting future therapeutic perspectives.
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Affiliation(s)
- Wan-Li Duan
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
| | - Xue-Jie Wang
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
| | - Ya-Ping Ma
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
| | - Zhi-Mei Sheng
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
| | - Hao Dong
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
| | - Li-Ying Zhang
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
| | - Bao-Gang Zhang
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261041, P.R. China
| | - Mao-Tao He
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, Shandong 261041, P.R. China
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261041, P.R. China
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Luo L, Wang S, Liu W, Zhang Z, Zhao M, Liu A. Narirutin Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing the TXNIP/NLRP3 Pathway. Neurochem Res 2024; 49:692-705. [PMID: 38047987 DOI: 10.1007/s11064-023-04062-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/07/2023] [Accepted: 11/07/2023] [Indexed: 12/05/2023]
Abstract
Narirutin (Nar) is a flavonoid that is abundantly present in citrus fruits and has attracted considerable attention because of its diverse pharmacological activities and low toxicity. Here, we evaluated the preventive effects of Nar in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen-glucose deprivation/reperfusion (OGD/R)-injured bEnd.3 cells. Pretreatment with Nar (150 mg/kg) for 7 days effectively reduced infarct volume, improved neurological deficits, and significantly inhibited neuronal death in the hippocampus and cortex in MCAO/R-injured mice. Moreover, anti-apoptotic effects of Nar (50 µM) were observed in OGD/R-injured bEnd.3 cells. In addition, Nar pre-administration regulated blood-brain barrier function by increasing tight junction-related protein expression after MCAO/R and OGD/R injury. Nar also inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation by reducing the expression of thioredoxin-interacting protein (TXNIP) in vivo and in vitro. Taken together, these results provide new evidence for the use of Nar in the prevention and treatment of ischemic stroke.
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Affiliation(s)
- Li Luo
- Department of Pharmacy, Precision Pharmacy & Drug Development Center, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Saiying Wang
- Department of Pharmacy, Precision Pharmacy & Drug Development Center, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Wenna Liu
- Department of Pharmacy, Precision Pharmacy & Drug Development Center, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China
| | - Zimei Zhang
- Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230026, Anhui, China
| | - Minggao Zhao
- Department of Pharmacy, Precision Pharmacy & Drug Development Center, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
| | - An Liu
- Department of Pharmacy, Precision Pharmacy & Drug Development Center, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
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Panbhare K, Pandey R, Chauhan C, Sinha A, Shukla R, Kaundal RK. Role of NLRP3 Inflammasome in Stroke Pathobiology: Current Therapeutic Avenues and Future Perspective. ACS Chem Neurosci 2024; 15:31-55. [PMID: 38118278 DOI: 10.1021/acschemneuro.3c00536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2023] Open
Abstract
Neuroinflammation is a key pathophysiological feature of stroke-associated brain injury. A local innate immune response triggers neuroinflammation following a stroke via activating inflammasomes. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has been heavily implicated in stroke pathobiology. Following a stroke, several stimuli have been suggested to trigger the assembly of the NLRP3 inflammasome. Recent studies have advanced the understanding and revealed several new players regulating NLRP3 inflammasome-mediated neuroinflammation. This article discussed recent advancements in NLRP3 assembly and highlighted stroke-induced mitochondrial dysfunction as a major checkpoint to regulating NLRP3 activation. The NLRP3 inflammasome activation leads to caspase-1-dependent maturation and release of IL-1β, IL-18, and gasdermin D. In addition, genetic or pharmacological inhibition of the NLRP3 inflammasome activation and downstream signaling has been shown to attenuate brain infarction and improve the neurological outcome in experimental models of stroke. Several drug-like small molecules targeting the NLRP3 inflammasome are in different phases of development as novel therapeutics for various inflammatory conditions, including stroke. Understanding how these molecules interfere with NLRP3 inflammasome assembly is paramount for their better optimization and/or development of newer NLRP3 inhibitors. In this review, we summarized the assembly of the NLRP3 inflammasome and discussed the recent advances in understanding the upstream regulators of NLRP3 inflammasome-mediated neuroinflammation following stroke. Additionally, we critically examined the role of the NLRP3 inflammasome-mediated signaling in stroke pathophysiology and the development of therapeutic modalities to target the NLRP3 inflammasome-related signaling for stroke treatment.
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Affiliation(s)
- Kartik Panbhare
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India
| | - Rukmani Pandey
- Department of Psychiatry, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Chandan Chauhan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India
| | - Antarip Sinha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Lucknow, UP 226002, India
| | - Ravinder K Kaundal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India
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Ma ZY, Jiang C, Xu LL. Protein-protein interactions and related inhibitors involved in the NLRP3 inflammasome pathway. Cytokine Growth Factor Rev 2023; 74:14-28. [PMID: 37758629 DOI: 10.1016/j.cytogfr.2023.09.003] [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: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023]
Abstract
NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) receptor serves as the central node of immune sensing in the innate immune system, and plays an important role in the initiation and progression of chronic diseases. Cryo-electron microscopy (cryo-EM) has provided insights into the conformation of various oligomers within the NLRP3 activation pathway, significantly advancing our understanding of the mechanisms underlying NLRP3 inflammasome activation. Despite the extensive network of protein-protein interactions (PPIs) involved in the assembly and activation of NLRP3 inflammasome, the utilization of protein-protein interactions has been relatively overlooked in the development of NLRP3 inhibitors. This review focuses on summarizing PPIs within the NLRP3 inflammasome activation pathway and small molecule inhibitors capable of interfering with PPIs to counteract the NLRP3 overactivation. Small molecule NLRP3 inhibitors have been gained significant attention owing to their remarkable efficacy, excellent safety profiles, and unique mechanisms of action.
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Affiliation(s)
- Zhen-Yu Ma
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Cheng Jiang
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
| | - Li-Li Xu
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
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Lin W, Zhao XY, Cheng JW, Li LT, Jiang Q, Zhang YX, Han F. Signaling pathways in brain ischemia: Mechanisms and therapeutic implications. Pharmacol Ther 2023; 251:108541. [PMID: 37783348 DOI: 10.1016/j.pharmthera.2023.108541] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/04/2023]
Abstract
Ischemic stroke occurs when the arteries supplying blood to the brain are narrowed or blocked, inducing damage to brain tissue due to a lack of blood supply. One effective way to reduce brain damage and alleviate symptoms is to reopen blocked blood vessels in a timely manner and reduce neuronal damage. To achieve this, researchers have focused on identifying key cellular signaling pathways that can be targeted with drugs. These pathways include oxidative/nitrosative stress, excitatory amino acids and their receptors, inflammatory signaling molecules, metabolic pathways, ion channels, and other molecular events involved in stroke pathology. However, evidence suggests that solely focusing on protecting neurons may not yield satisfactory clinical results. Instead, researchers should consider the multifactorial and complex mechanisms underlying stroke pathology, including the interactions between different components of the neurovascular unit. Such an approach is more representative of the actual pathological process observed in clinical settings. This review summarizes recent research on the multiple molecular mechanisms and drug targets in ischemic stroke, as well as recent advances in novel therapeutic strategies. Finally, we discuss the challenges and future prospects of new strategies based on the biological characteristics of stroke.
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Affiliation(s)
- Wen Lin
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Xiang-Yu Zhao
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Jia-Wen Cheng
- Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China
| | - Li-Tao Li
- Department of Neurology, Hebei General Hospital, Shijiazhuang 050051, Hebei, China
| | - Quan Jiang
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Yi-Xuan Zhang
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China.
| | - Feng Han
- Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, China; International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China; Institute of Brain Science, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing 211166, China.
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Cakir-Aktas C, Bodur E, Yemisci M, van Leyen K, Karatas H. 12/15-lipoxygenase inhibition attenuates neuroinflammation by suppressing inflammasomes. Front Cell Neurosci 2023; 17:1277268. [PMID: 37822799 PMCID: PMC10562712 DOI: 10.3389/fncel.2023.1277268] [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: 08/14/2023] [Accepted: 09/07/2023] [Indexed: 10/13/2023] Open
Abstract
Introduction Lipoxygenases (LOXs) have essential roles in stroke, atherosclerosis, diabetes, and hypertension. 12/15-LOX inhibition was shown to reduce infarct size and brain edema in the acute phase of experimental stroke. However, the significance of 12/15-LOX on neuroinflammation, which has an essential role in the pathophysiology of stroke, has not been clarified yet. Methods In this study, ischemia/recanalization (I/R) was performed by occluding the proximal middle cerebral artery (pMCAo) in mice. Either the 12/15-LOX inhibitor (ML351, 50 mg/kg) or its solvent (DMSO) was injected i.p. at recanalization after 1 h of occlusion. Mice were sacrificed at 6, 24, and 72-h after ischemia induction. Infarct volumes were calculated on Nissl-stained sections. Neurological deficit scoring was used for functional analysis. Lipid peroxidation was determined by the MDA assay, and the inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-10, and TGF-beta were quantified by ELISA. The inflammasome proteins NLRP1 and NLRP3, 12/15-LOX, and caspase-1 were detected with immunofluorescence staining. Results Infarct volumes, neurological deficit scores, and lipid peroxidation were significantly attenuated in ML351-treated groups at 6, 24, and 72-h. ELISA results revealed that the pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha were significantly decreased at 6-h and/or 24-h of I/R, while the anti-inflammatory cytokines IL-10 and TNF-alpha were increased at 24-h or 72-h of ML351 treatment. NLRP1 and NLRP3 immunosignaling were enhanced at three time points after I/R, which were significantly diminished by the ML351 application. Interestingly, NLRP3 immunoreactivity was more pronounced than NLRP1. Hence, we proceeded to study the co-localization of NLRP3 immunoreactivity with 12/15-LOX and caspase-1, which indicated that NLRP3 was co-localized with 12/15-LOX and caspase-1 signaling. Additionally, NLRP3 was found in neurons at all time points but in non-neuronal cells 72 h after I/R. Discussion These results suggest that 12/15-LOX inhibition suppresses ischemia-induced inflammation in the acute and subacute phases of stroke via suppressing inflammasome activation. Understanding the mechanisms underlying lipid peroxidation and its associated pathways, like inflammasome activation, may have broader implications for the treatment of stroke and other neurological diseases characterized by neuroinflammation.
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Affiliation(s)
- Canan Cakir-Aktas
- Institute of Neurological Sciences & Psychiatry, Hacettepe University, Ankara, Türkiye
| | - Ebru Bodur
- Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Türkiye
| | - Muge Yemisci
- Institute of Neurological Sciences & Psychiatry, Hacettepe University, Ankara, Türkiye
- Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Türkiye
| | - Klaus van Leyen
- Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
| | - Hulya Karatas
- Institute of Neurological Sciences & Psychiatry, Hacettepe University, Ankara, Türkiye
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Li N, Wang H, Liu H, Zhu L, Lyu Z, Qiu J, Zhao T, Ren H, Huang L, Chen S, Hu X, Zhou L. The effects and mechanisms of acupuncture for post-stroke cognitive impairment: progress and prospects. Front Neurosci 2023; 17:1211044. [PMID: 37397457 PMCID: PMC10309044 DOI: 10.3389/fnins.2023.1211044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 05/30/2023] [Indexed: 07/04/2023] Open
Abstract
Stroke is one of the important causes of both disability and death worldwide, which is very common in older adults. Post-stroke cognitive impairment (PSCI) is a common secondary damage of stroke, which is the main cause of long-term disability and decreased quality of life in stroke patients, which brings a heavy burden to society and families. Acupuncture, as one of the oldest and widely used worldwide techniques in Chinese medicine, is recommended by the World Health Organization (WHO) as an alternative and complementary strategy for improving stroke care. This review comprehensively summarizes literature from the last 25 years, showing that acupuncture can exert strong beneficial effect on PSCI. The mechanisms of acupuncture on PSCI involves anti-neuronal apoptosis, promoting synaptic plasticity, alleviating central and peripheral inflammatory reactions, and regulating brain energy metabolism disorders (including improving cerebral blood flow, glucose utilization and mitochondrial structure and function, etc.), etc. The effects and mechanisms of acupuncture on PSCI reviewed in this study provides scientific and reliable evidence for acupuncture application for PSCI.
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Affiliation(s)
- Ningcen Li
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Binhai New Area Hospital of TCM, Fourth Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hui Wang
- Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shanxi, China
| | - Hang Liu
- Acupuncture and Moxibustion Department, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, Jiangxi, China
- Acupuncture and Moxibustion Medical Clinical Research Center of Jiangxi Province, Nanchang, Jiangxi, China
| | - Lina Zhu
- Acupuncture and Moxibustion Department, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, Jiangxi, China
- Acupuncture and Moxibustion Medical Clinical Research Center of Jiangxi Province, Nanchang, Jiangxi, China
| | - Zhongxi Lyu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiwen Qiu
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tianyi Zhao
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Haiyan Ren
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lihong Huang
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shuangli Chen
- Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiuwu Hu
- Acupuncture and Moxibustion Department, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, Jiangxi, China
- Acupuncture and Moxibustion Medical Clinical Research Center of Jiangxi Province, Nanchang, Jiangxi, China
| | - Liang Zhou
- Acupuncture and Moxibustion Department, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, Jiangxi, China
- Acupuncture and Moxibustion Medical Clinical Research Center of Jiangxi Province, Nanchang, Jiangxi, China
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12
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Wang Y, Yang J, Wang Y, Chen Y, Wang Y, Kuang H, Feng X. Upregulation of TXNIP contributes to granulosa cell dysfunction in polycystic ovary syndrome via activation of the NLRP3 inflammasome. Mol Cell Endocrinol 2023; 561:111824. [PMID: 36450326 DOI: 10.1016/j.mce.2022.111824] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/22/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
Polycystic ovary syndrome (PCOS) is a complex endocrine disease. Thioredoxin-interacting protein (TXNIP) promotes oxidative stress and triggers inflammation. Herein, we investigated the role and potential mechanism of TXNIP in PCOS. In a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS, we found that TXNIP was upregulated in the ovaries, especially in granulosa cells (GCs). TXNIP was also upregulated in testosterone (T)-treated GCs in vitro. Knockdown of TXNIP by lentivirus-constructed shRNA attenuated T-induced GC injury and oxidative stress, as well as inflammation and the NLRP3 inflammasome. The mechanism by which TXNIP promotes inflammation may involve TXNIP dissociation from the TXNIP-TRX complex and binding to NLRP3 to form the inflammasome. Additionally, we verified that knockdown of TXNIP ameliorated ovarian injury and inflammation in mice with DHEA-induced PCOS in vivo. Collectively, we demonstrated that TXNIP is involved in GC inflammation by promoting NLRP3 inflammasome activation in PCOS.
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Affiliation(s)
- Ying Wang
- The Second Department of Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jiyu Yang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yu Wang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yao Chen
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yiran Wang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Hongying Kuang
- The Second Department of Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China.
| | - Xiaoling Feng
- The Second Department of Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China.
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13
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Zhou L, Wang B, Xie H, Du C, Tang J, Tang W. Intrauterine exposure to oxidative stress induces caspase-1-dependent enteric nerve cell pyroptosis. Pediatr Surg Int 2022; 38:1555-1567. [PMID: 35995981 DOI: 10.1007/s00383-022-05199-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/10/2022] [Indexed: 11/24/2022]
Abstract
PURPOSE This study determined whether oxidative stress causes the developmental abnormalities of the enteric nervous system during the embryonic period. METHODS Using the test results of tissue specimens of children with Hirschsprung disease (HSCR), we established a pregnant rat model of oxidative stress and a cellular oxidative stress model to conduct related molecular, cellular, and histopathological experiments for exploration and validation. RESULTS The results of the quantitative real-time polymerase chain reaction assay indicated overexpression of pyroptosis markers (NLRP3, ASC, and caspase-1) in HSCR lesions and newborn pups in the oxidative stress group (treated with D-galactose). The expression of cathepsin D was significantly decreased in intestinal tissues of newborn pups in the oxidative stress group compared to the control group. Reactive oxygen species scavengers (N-acetyl-cysteine, NAC), the caspase-1 inhibitor (VX-765), and the NLRP3 siRNA could reverse the release of LDH, decrease the number of propidium iodide stained cells, and reduce the percentage of TUNEL/caspase-3 double-positive cells in the H2O2-treated group. CONCLUSION Oxidative stress can induce the death of enteric nerve cells by activating caspase-1-dependent pyroptosis through NLRP3 inflammasomes, which may contribute to abnormal enteric nervous system development.
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Affiliation(s)
- Lingling Zhou
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.,Department of General Surgery, Children's Hospital of Wujiang District, Suzhou, People's Republic of China
| | - Bingyu Wang
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.,Department of Pediatric Surgery, Huai'an First People's Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hua Xie
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Chunxia Du
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Jie Tang
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
| | - Weibing Tang
- Department of Neonatal Surgery, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
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14
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Weng WT, Kuo PC, Scofield BA, Paraiso HC, Brown DA, Yu IC, Yen JH. 4-Ethylguaiacol Modulates Neuroinflammation and Promotes Heme Oxygenase-1 Expression to Ameliorate Brain Injury in Ischemic Stroke. Front Immunol 2022; 13:887000. [PMID: 35860274 PMCID: PMC9289724 DOI: 10.3389/fimmu.2022.887000] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/12/2022] [Indexed: 12/05/2022] Open
Abstract
Ischemic stroke is caused by a sudden reduction in cerebral blood flow that subsequently induces a complex cascade of pathophysiological responses, leading to brain inflammation and irreversible infarction. 4-ethylguaiacol (4-EG) is reported to suppress inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects in ischemic stroke remains unexplored. We evaluated the therapeutic potential of 4-EG and examined the cellular and molecular mechanisms underlying the protective effects of 4-EG in ischemic stroke. The effect of 4-EG in ischemic stroke was determined by using a transient middle cerebral artery occlusion (MCAO) animal model followed by exploring the infarct size, neurological deficits, microglia activation, inflammatory cytokine production, blood-brain barrier (BBB) disruption, brain endothelial cell adhesion molecule expression, and microglial heme oxygenase-1 (HO-1) expression. Nrf2-/- and HO-1 inhibitor ZnPP-treated mice were also subjected to MCAO to evaluate the role of the Nrf2/HO-1 pathway in 4-EG-mediated protection in ischemic stroke. We found that 4-EG attenuated infarct size and neurological deficits, and lessened BBB disruption in ischemic stroke. Further investigation revealed that 4-EG suppressed microglial activation, peripheral inflammatory immune cell infiltration, and brain endothelial cell adhesion molecule upregulation in the ischemic brain. Finally, we identified that the protective effect of 4-EG in ischemic stroke was abolished in Nrf2-/- and ZnPP-treated MCAO mice. Our results identified that 4-EG confers protection against ischemic stroke and reveal that the protective effect of 4-EG in ischemic stroke is mediated through the induction of the Nrf2/HO1 pathway. Thus, our findings suggest that 4-EG could be developed as a novel therapeutic agent for the treatment of ischemic stroke.
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Affiliation(s)
- Wen-Tsan Weng
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN, United States
| | - Ping-Chang Kuo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN, United States
| | - Barbara A. Scofield
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN, United States
| | - Hallel C. Paraiso
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Fort Wayne, IN, United States
| | - Dennis A. Brown
- Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, United States
| | - I-Chen Yu
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Fort Wayne, IN, United States
| | - Jui-Hung Yen
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN, United States
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15
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Cheng F, Wang N. N-Lobe of TXNIP Is Critical in the Allosteric Regulation of NLRP3 via TXNIP Binding. Front Aging Neurosci 2022; 14:893919. [PMID: 35721021 PMCID: PMC9201253 DOI: 10.3389/fnagi.2022.893919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammasomes are cytoplasmic complexes that form in response to exogenous microbial invasions and endogenous damage signals. Among the known inflammasomes, the activation of the NACHT (NAIP, CIITA, HET-E, and TP1 domain), leucine-rich repeat, and pyrin domain containing protein 3 (NLRP3) inflammasome is also primarily related to neuroinflammation and nerve cell damage. Previous studies reported that under the stimulation of dangerous signals like reactive oxygen species (ROS), the overexpression and interaction of thioredoxin-interacting protein (TXNIP) with NLRP3 may trigger the inflammatory response through the ROS/TXNIP/NLRP3 signaling pathway. This inflammatory response is the pathophysiological basis of some neurological and neurodegenerative diseases. The activation of inflammasome and apoptosis caused by TXNIP are widespread in brain diseases. Previous report has suggested the TXNIP/NLRP3 interaction interface. However, the comprehensive model of the TXNIP/NLRP3 interaction is still unclear. In this study, molecular docking experiments based on the existing crystal model of NLRP3 were performed to investigate the binding of TXNIP and NLRP3. Three in silico models of the TXNIP/NLRP3 complex were selected, and molecular dynamics simulations evaluated the binding stability of the possible interaction between the two proteins. The results revealed that the E690, E693, and D745 residues in NLRP3 and the K212 and R238 residues in TXNIP play a critical role in the TXNIP/NLRP3 interaction. N-terminal of TXNIP is essential in promoting the conformational changes of NLRP3, although it does not directly bind to NLRP3. Our findings reveal the possible binding mechanism between TXNIP and NLRP3 and the associated allosteric regulation of NLRP3. The constructed models may also be useful for inhibitor development targeting the TXNIP/NLRP3 interaction during inflammasome activation via the ROS/TXNIP/NLRP3 pathway.
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16
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Ahmed HA, Ishrat T. Candesartan Effectively Preserves Cognition in Senescence Accelerated Mouse Prone 8 (SAMP8) mice. J Alzheimers Dis Rep 2022; 6:257-269. [PMID: 35891637 PMCID: PMC9277674 DOI: 10.3233/adr-220016] [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: 02/22/2022] [Accepted: 05/06/2022] [Indexed: 11/18/2022] Open
Abstract
Background: Alzheimer’s disease (AD) has become a worldwide crisis with no effective therapeutic options. The medications currently available for AD are only palliative; their effect is temporary, and they are associated with unfavorable side effects. Even the newest medication aducanumab, granted accelerated FDA approval in 2021, failed to show cognitive benefits in clinical trials and continued approval requires verification in subsequent clinical trials. There is an urgent need for safe and effective therapies to preserve cognition and effectively manage AD. Generally, a new drug product takes several years for FDA approval and exceeds 2.5 billion dollars in research and development, with most new drug products never even reaching the market. This has led to a recent shift for repurposing/repositioning existing FDA-approved medications, to new therapeutic indications. Objective: To investigate the effects of long-term treatment with candesartan, an FDA-approved angiotensin-II type-1 receptor blocker (ARB), on the development of cognitive impairment associated with premature aging. Methods: Candesartan was given at a dose of 1 mg/kg/d in an AD model of senescence-accelerated mouse prone-8 (SAMP8) and senescence-accelerated mouse resistant (SAMR1) mice. Oral treatment with candesartan or vehicle was started, in 2-month-old mice and administered continuously for 4-months. Results: Low-dose candesartan prevented the development of cognitive impairment, otherwise associated with accelerated aging, in SAMP8 mice, by reducing inflammation and nitro-oxidative stress. Candesartan did not affect the cognitive function of control SAMR1 mice. Conclusion: Early ARB treatment might be beneficial in preventing age-related cognitive deficits in AD-prone individuals.
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Affiliation(s)
- Heba A. Ahmed
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis TN, USA
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis TN, USA
- Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis TN, USA
- Neuroscience Institute, University of Tennessee Health Science Center, Memphis TN, USA
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17
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TXNIP: A Double-Edged Sword in Disease and Therapeutic Outlook. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7805115. [PMID: 35450411 PMCID: PMC9017576 DOI: 10.1155/2022/7805115] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/17/2022] [Accepted: 03/21/2022] [Indexed: 12/15/2022]
Abstract
Thioredoxin-interacting protein (TXNIP) was originally named vitamin D3 upregulated protein-1 (VDUP1) because of its ability to bind to thioredoxin (TRX) and inhibit TRX function and expression. TXNIP is an alpha-arrestin protein that is essential for redox homeostasis in the human body. TXNIP may act as a double-edged sword in the cell. The balance of TXNIP is crucial. A study has shown that TXNIP can travel between diverse intracellular locations and bind to different proteins to play different roles under oxidative stress. The primary function of TXNIP is to induce apoptosis or pyroptosis under oxidative stress. TXNIP also inhibits proliferation and migration in cancer cells, although TXNIP levels decrease, and function diminishes in various cancers. In this review, we summarized the main structure, binding proteins, pathways, and the role of TXNIP in diseases, aiming to explore the double-edged sword role of TXNIP, and expect it to be helpful for future treatment using TXNIP as a therapeutic target.
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18
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Ye X, Song G, Huang S, Liang Q, Fang Y, Lian L, Zhu S. Caspase-1: A Promising Target for Preserving Blood–Brain Barrier Integrity in Acute Stroke. Front Mol Neurosci 2022; 15:856372. [PMID: 35370546 PMCID: PMC8971909 DOI: 10.3389/fnmol.2022.856372] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/18/2022] [Indexed: 12/24/2022] Open
Abstract
The blood–brain barrier (BBB) acts as a physical and biochemical barrier that plays a fundamental role in regulating the blood-to-brain influx of endogenous and exogenous components and maintaining the homeostatic microenvironment of the central nervous system (CNS). Acute stroke leads to BBB disruption, blood substances extravasation into the brain parenchyma, and the consequence of brain edema formation with neurological impairment afterward. Caspase-1, one of the evolutionary conserved families of cysteine proteases, which is upregulated in acute stroke, mainly mediates pyroptosis and compromises BBB integrity via lytic cellular death and inflammatory cytokines release. Nowadays, targeting caspase-1 has been proven to be effective in decreasing the occurrence of hemorrhagic transformation (HT) and in attenuating brain edema and secondary damages during acute stroke. However, the underlying interactions among caspase-1, BBB, and stroke still remain ill-defined. Hence, in this review, we are concerned about the roles of caspase-1 activation and its associated mechanisms in stroke-induced BBB damage, aiming at providing insights into the significance of caspase-1 inhibition on stroke treatment in the near future.
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Acute Hyperglycemia Exacerbates Hemorrhagic Transformation after Embolic Stroke and Reperfusion with tPA: A Possible Role of TXNIP-NLRP3 Inflammasome. J Stroke Cerebrovasc Dis 2022; 31:106226. [PMID: 34847489 PMCID: PMC8792268 DOI: 10.1016/j.jstrokecerebrovasdis.2021.106226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES Acute hyperglycemia (HG) exacerbates reperfusion injury after stroke. Our recent studies showed that acute HG upregulates thioredoxin-interacting protein (TXNIP) expression, which in turn induces inflammation and neurovascular damage in a suture model of ischemic stroke. The aim of the present study was to investigate the effect of acute HG on TXNIP-associated neurovascular damage, in a more clinically relevant murine model of embolic stroke and intravenous tissue plasminogen activator (IV-tPA) reperfusion. MATERIALS AND METHODS HG was induced in adult male mice, by intraperitoneal injection of 20% glucose. This was followed by embolic middle cerebral artery occlusion (eMCAO), with or without IV-tPA (10 mg/kg) given 3 h post embolization. Brain infarction, edema, hemoglobin content, expression of matrix metalloproteinase (MMP-9), vascular endothelial growth factor A (VEGFA), tight junction proteins (claudin-5, occluding, and zonula occludens-1), TXNIP, and NOD-like receptor protein3 (NLRP3)-inflammasome activation were evaluated at 24 h after eMCAO. RESULTS HG alone significantly increased TXNIP in the brain after eMCAO, and this was associated with exacerbated hemorrhagic transformation (HT; as measured by hemoglobin content). IV-tPA in HG conditions showed a trend to decrease infarct volume, but worsened HT after eMCAO, suggesting that HG reduces the therapeutic efficacy of IV-tPA. Further, HG and tPA-reperfusion did not show significant differences in expression of MMP-9, VEGFA, junction proteins, and NLRP3 inflammasome activation between the groups. CONCLUSION The current findings suggest a potential role for TXNIP in the occurrence of HT in hyperglycemic conditions following eMCAO. Further studies are needed to understand the precise role of vascular TXNIP on HG/tPA-induced neurovascular damage after stroke.
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20
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Mohamed IN, Li L, Ismael S, Ishrat T, El-Remessy AB. Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response. World J Diabetes 2021; 12:1979-1999. [PMID: 35047114 PMCID: PMC8696646 DOI: 10.4239/wjd.v12.i12.1979] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/01/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis. Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease (NAFLD), retinopathy, critical limb ischemia, and impaired angiogenesis. Sterile inflammation driven by high-fat diet, increased formation of reactive oxygen species, alteration of intracellular calcium level and associated release of inflammatory mediators, are the main common underlying forces in the pathophysiology of NAFLD, ischemic retinopathy, stroke, and aging brain. This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein (TXNIP) to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states. Finally, the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.
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Affiliation(s)
- Islam N Mohamed
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California North State University, Elk Grove, CA 95758, United States
| | - Luling Li
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California North State University, Elk Grove, CA 95758, United States
| | - Saifudeen Ismael
- Department of Anatomy and Neurobiology, and Neuroscience Institute, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, and Neuroscience Institute, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Azza B El-Remessy
- Department of Pharmacy, Doctors Hospital of Augusta, Augusta, GA 30909, United States
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21
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Ryan F, Khoshnam SE, Khodagholi F, Ashabi G, Ahmadiani A. How cytosolic compartments play safeguard functions against neuroinflammation and cell death in cerebral ischemia. Metab Brain Dis 2021; 36:1445-1467. [PMID: 34173922 DOI: 10.1007/s11011-021-00770-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 06/06/2021] [Indexed: 11/26/2022]
Abstract
Ischemic stroke is the second leading cause of mortality and disability globally. Neuronal damage following ischemic stroke is rapid and irreversible, and eventually results in neuronal death. In addition to activation of cell death signaling, neuroinflammation is also considered as another pathogenesis that can occur within hours after cerebral ischemia. Under physiological conditions, subcellular organelles play a substantial role in neuronal functionality and viability. However, their functions can be remarkably perturbed under neurological disorders, particularly cerebral ischemia. Therefore, their biochemical and structural response has a determining role in the sequel of neuronal cells and the progression of disease. However, their effects on cell death and neuroinflammation, as major underlying mechanisms of ischemic stroke, are still not understood. This review aims to provide a comprehensive overview of the contribution of each organelle on these pathological processes after ischemic stroke.
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Affiliation(s)
- Fari Ryan
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Centre, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghorbangol Ashabi
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, PO Box: 1417613151, Tehran, Iran.
| | - Abolhassan Ahmadiani
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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22
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Salman M, Ismael S, Li L, Ahmed HA, Puchowicz MA, Ishrat T. Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy. Pharmaceuticals (Basel) 2021; 14:ph14100983. [PMID: 34681207 PMCID: PMC8537904 DOI: 10.3390/ph14100983] [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: 08/17/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 12/03/2022] Open
Abstract
We hypothesize that endothelial-specific thioredoxin-interacting protein knock-out (EC-TXNIP KO) mice will be more resistant to the neurovascular damage (hemorrhagic-transformation-HT) associated with hyperglycemia (HG) in embolic stroke. Adult-male EC-TXNIP KO and wild-type (WT) littermate mice were injected with-streptozotocin (40 mg/kg, i.p.) for five consecutive days to induce diabetes. Four-weeks after confirming HG, mice were subjected to embolic middle cerebral artery occlusion (eMCAO) followed by tissue plasminogen activator (tPA)-reperfusion (10 mg/kg at 3 h post-eMCAO). After the neurological assessment, animals were sacrificed at 24 h for neurovascular stroke outcomes. There were no differences in cerebrovascular anatomy between the strains. Infarct size, edema, and HT as indicated by hemoglobin (Hb)-the content was significantly higher in HG-WT mice, with or without tPA-reperfusion, compared to normoglycemic WT mice. Hyperglycemic EC-TXNIP KO mice treated with tPA tended to show lower Hb-content, edema, infarct area, and less hemorrhagic score compared to WT hyperglycemic mice. EC-TXNIP KO mice showed decreased expression of inflammatory mediators, apoptosis-associated proteins, and nitrotyrosine levels. Further, vascular endothelial growth factor-A and matrix-metalloproteinases (MMP-9/MMP-3), which degrade junction proteins and increase blood-brain-barrier permeability, were decreased in EC-TXNIP KO mice. Together, these findings suggest that vascular-TXNIP could be a novel therapeutic target for neurovascular damage after stroke.
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Affiliation(s)
- Mohd. Salman
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.S.); (S.I.); (L.L.); (H.A.A.)
| | - Saifudeen Ismael
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.S.); (S.I.); (L.L.); (H.A.A.)
| | - Lexiao Li
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.S.); (S.I.); (L.L.); (H.A.A.)
| | - Heba A. Ahmed
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.S.); (S.I.); (L.L.); (H.A.A.)
| | - Michelle A. Puchowicz
- Department of Pediatrics, The University of Tennessee Health Science Center, Memphis, TN 38163, USA;
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.S.); (S.I.); (L.L.); (H.A.A.)
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Correspondence: ; Tel.: +901-448-2178; Fax:-901-448-7193
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23
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Sarkaki A, Rashidi M, Ranjbaran M, Asareh Zadegan Dezfuli A, Shabaninejad Z, Behzad E, Adelipour M. Therapeutic Effects of Resveratrol on Ischemia-Reperfusion Injury in the Nervous System. Neurochem Res 2021; 46:3085-3102. [PMID: 34365594 DOI: 10.1007/s11064-021-03412-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/25/2021] [Accepted: 07/27/2021] [Indexed: 01/07/2023]
Abstract
Resveratrol is a phenol compound produced by some plants in response to pathogens, infection, or physical injury. It is well-known that resveratrol has antioxidant and protective roles in damages potentially caused by cancer or other serious disorders. Thus, it is considered as a candidate agent for the prevention and treatment of human diseases. Evidence has confirmed other bioactive impacts of resveratrol, including cardioprotective, anti-tumorigenic, anti-inflammatory, phytoestrogenic, and neuroprotective effects. Ischemia-reperfusion (IR) can result in various disorders, comprising myocardial infarction, stroke, and peripheral vascular disease, which may continue to induce debilitating conditions and even mortality. In virtue of chronic ischemia or hypoxia, cells switch to anaerobic metabolism, giving rise to some dysfunctions in mitochondria. As the result of lactate accumulation, adenosine triphosphate levels and pH decline in cells. This condition leads cells to apoptosis, necrosis, and autophagy. However, restoring oxygen level upon reperfusion after ischemia by producing reactive oxygen species is an outcome of mitochondrial dysfunction. Considering the neuroprotective effect of resveratrol and neuronal injury that comes from IR, we focused on the mechanism(s) involved in IR injury in the nervous system and also on the functions of resveratrol in the protection, inhibition, and treatment of this injury.
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Affiliation(s)
- Alireza Sarkaki
- Department of Physiology, School of Medicine, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Rashidi
- Department of Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mina Ranjbaran
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Aram Asareh Zadegan Dezfuli
- Department of Microbiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Zahra Shabaninejad
- Department of Nanotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ebrahim Behzad
- Neurology Department, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Adelipour
- Department of Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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24
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Liu W, Zhang G, Sun B, Wang S, Lu Y, Xie H. Activation of NLR family, domain of pyrin containing 3 inflammasome by nitrous oxide through thioredoxin-interacting protein to induce nerve cell injury. Bioengineered 2021; 12:4768-4779. [PMID: 34348577 PMCID: PMC8806838 DOI: 10.1080/21655979.2021.1954741] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Nitrous Oxide (N2O) has been shown to be neurotoxic, but its specific mechanism is still unclear. The purpose of this work is to probe into the impact of N2O on nerve cell injury through regulating thioredoxin-interacting protein (TXNIP)/the NOD-like receptor domain of pyrin containing 3 (NLRP3) pathway. The results indicated that, N2O exposure elevated TXNIP/NLRP3 expression in vivo and in vitro, led to declined learning and memory capabilities in mice, reduced apoptosis rate in hippocampal neuron and Nissl bodies, elevated inflammatory factors TNF-α, IL-1β and IL-6 levels, as well as cleaved caspase-3 and Bax expressions, and reduced Bcl-2 expression. Overexpressing TXNIP or NLRP3 further aggravated these injuries, but knocking down TXNIP or NLRP3 improved them. CO-IP indicated that TXNIP and NLRP3 can be combined, with interaction relationship. All in all, the results manifested that N2O is available to promote nerve cell inflammation and apoptosis through activating the TXNIP/NLRP3 pathway that can be used as a potential target for N2O-induced nerve damage in the future.
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Affiliation(s)
- WenJuan Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China.,Department of Anesthesiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai City, China
| | - GuangMing Zhang
- Department of Anesthesiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai City, China
| | - Bo Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China
| | - ShuYan Wang
- Department of Anesthesiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai City, China
| | - YinZhong Lu
- Department of Anesthesiology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai City, China
| | - Hong Xie
- Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China
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25
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Ismael S, Nasoohi S, Li L, Aslam KS, Khan MM, El-Remessy AB, McDonald MP, Liao FF, Ishrat T. Thioredoxin interacting protein regulates age-associated neuroinflammation. Neurobiol Dis 2021; 156:105399. [PMID: 34029695 PMCID: PMC8277763 DOI: 10.1016/j.nbd.2021.105399] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/07/2021] [Accepted: 05/16/2021] [Indexed: 12/15/2022] Open
Abstract
Immune system hypersensitivity is believed to contribute to mental frailty in the elderly. Solid evidence indicates NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation intimately connects aging-associated chronic inflammation (inflammaging) to senile cognitive decline. Thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NLRP3 inflammasome activity. This study aims to find whether TXNIP/NLRP3 inflammasome pathway is involved in senile dementia. According to our studies on sex-matched mice, TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity leading to enhanced caspase-1 cleavage and IL-1β maturation, in both sexes. This was closely associated with depletion of the anti-aging and cognition enhancing protein klotho, in aged males. Txnip knockout reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels. Further, TXNIP inhibition along with verapamil replicated TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Together, these findings substantiate the pivotal role of TXNIP to drive inflammaging in parallel with klotho depletion and functional decline, and delineate thioredoxin system as a potential target to decelerate senile dementia.
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Affiliation(s)
- Saifudeen Ismael
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Sanaz Nasoohi
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA; Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Lexiao Li
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA; Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States of America.
| | - Khurram S Aslam
- Center for Earthquake Research and Information, University of Memphis, Memphis, TN, United States of America
| | - Mohammad Moshahid Khan
- Department of Neurology, The University of Tennessee Health Science Center, Memphis, TN, United States of America; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Azza B El-Remessy
- Department of Pharmacy, Doctors Hospital of Augusta, GA, United States of America.
| | - Michael P McDonald
- Department of Neurology, The University of Tennessee Health Science Center, Memphis, TN, United States of America; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Francesca-Fang Liao
- Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN, United States of America; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA; Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States of America; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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26
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Xu Q, Zhao B, Ye Y, Li Y, Zhang Y, Xiong X, Gu L. Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke. J Neuroinflammation 2021; 18:123. [PMID: 34059091 PMCID: PMC8166383 DOI: 10.1186/s12974-021-02137-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/24/2021] [Indexed: 12/14/2022] Open
Abstract
The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a member of the NLR family of inherent immune cell sensors. The NLRP3 inflammasome can detect tissue damage and pathogen invasion through innate immune cell sensor components commonly known as pattern recognition receptors (PRRs). PRRs promote activation of nuclear factor kappa B (NF-κB) pathways and the mitogen-activated protein kinase (MAPK) pathway, thus increasing the transcription of genes encoding proteins related to the NLRP3 inflammasome. The NLRP3 inflammasome is a complex with multiple components, including an NAIP, CIITA, HET-E, and TP1 (NACHT) domain; apoptosis-associated speck-like protein containing a CARD (ASC); and a leucine-rich repeat (LRR) domain. After ischemic stroke, the NLRP3 inflammasome can produce numerous proinflammatory cytokines, mediating nerve cell dysfunction and brain edema and ultimately leading to nerve cell death once activated. Ischemic stroke is a disease with high rates of mortality and disability worldwide and is being observed in increasingly younger populations. To date, there are no clearly effective therapeutic strategies for the clinical treatment of ischemic stroke. Understanding the NLRP3 inflammasome may provide novel ideas and approaches because targeting of upstream and downstream molecules in the NLRP3 pathway shows promise for ischemic stroke therapy. In this manuscript, we summarize the existing evidence regarding the composition and activation of the NLRP3 inflammasome, the molecules involved in inflammatory pathways, and corresponding drugs or molecules that exert effects after cerebral ischemia. This evidence may provide possible targets or new strategies for ischemic stroke therapy.
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Affiliation(s)
- Qingxue Xu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Bo Zhao
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yingze Ye
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yina Li
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yonggang Zhang
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaoxing Xiong
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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27
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Han M, Li S, Li L. Verapamil inhibits early acute liver failure through suppressing the NLRP3 inflammasome pathway. J Cell Mol Med 2021; 25:5963-5975. [PMID: 34031983 PMCID: PMC8256349 DOI: 10.1111/jcmm.16357] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 01/18/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
Acute liver failure (ALF) is a rare disease characterized by the sudden onset of serious hepatic injury, as manifested by a profound liver dysfunction and hepatic encephalopathy in patients without prior liver disease. In this paper, we aim to investigate whether verapamil, an antagonist of TXNIP, inhibits early ALF through suppressing the NLRP3 inflammasome pathway. Firstly, an ALF mouse model was induced by lipopolysaccharide (LPS)/D-galactosamine (GalN) treatment. The optimal concentration of verapamil in treating early ALF mice was determined followed by investigation on its mechanism in LPS/GalN-induced liver injury. Western blot analysis and co-immunoprecipitation were performed to determine the activation of the TXNIP/NLRP3 inflammasome pathway. Subsequently, overexpression of NLRP3 in mouse liver was induced by transfection with AAV-NRLP3 in vivo and in vitro to identity whether verapamil inhibited early ALF through suppressing the activation of NLRP3 inflammasome. We found that ALF was induced by LPS/GalN in mice but was alleviated by verapamil through a mechanism that correlated with suppression of the NLRP3 inflammasome pathway. Oxidative stress and inflammatory response were induced by intraperitoneal injection of LPS/GalN, but alleviated with injection of verapamil. Overexpression of NLRP3 via AAV in mouse liver in vivo and in vitro reduced the therapeutic effect of verapamil on LPS/GalN-induced ALF. Taken together, the TXNIP antagonist verapamil could inhibit activation of the NLRP3 inflammasome, inflammatory responses and oxidative stress to alleviate LPS/GalN-induced ALF.
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Affiliation(s)
- Mingying Han
- Pediatric Intensive Care UnitLinyi People’s HospitalLinyiChina
| | - Shouzhou Li
- Nutrition DepartmentChinese Medicine Hospital in Linyi CityLinyiChina
| | - Lanrong Li
- Emergency DepartmentLinyi People’s HospitalLinyiChina
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28
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Yang D, Tan Y, Li H, Zhang X, Li X, Zhou F. Upregulation of miR-20b Protects Against Cerebral Ischemic Stroke by Targeting Thioredoxin Interacting Protein (TXNIP). Exp Neurobiol 2021; 30:170-182. [PMID: 33972468 PMCID: PMC8118756 DOI: 10.5607/en20046] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 02/26/2021] [Accepted: 03/16/2021] [Indexed: 12/23/2022] Open
Abstract
Dysregulation of microRNAs (miRNAs) is involved in abnormal development and pathophysiology in the brain. Although miR-20b plays essential roles in various human diseases, its function in cerebral ischemic stroke remains unclear. A cell model of oxygen glucose deprivation/reoxygenation (OGD/R) and A rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) were constructed. qRT-PCR and western blot were used to evaluate the expression of miR-20b and TXNIP. Cell viability was detected by MTT assay, and cell apoptosis was evaluated by flow cytometry. Targetscan and Starbase were used to predict the potential targets of miR-20b. Luciferase reporter assay was applied to determine the interaction between miR-20b and TXNIP. Rescue experiments were conducted to confirm the functions of miR-20b/TXNIP axis in cerebral ischemic stroke. MiR-20b was significantly downregulated after I/R both in vitro and in vivo. Upregulation of miR-20b inhibited OGD/R-induced neurons apoptosis and attenuated ischemic brain injury in rat model. Bioinformatic prediction suggested that TXNIP might be a target of miR-20b, and luciferase reporter assay revealed that miR-20b negatively regulated TXNIP expression by directly binding to the 3’-UTR of TXNIP. Downregulation of TXNIP inhibited OGD/R-induced neurons apoptosis in vitro and ischemic brain injury in vivo. Rescue experiments indicated that downregulation of TXNIP effectively reversed the effect of miR-20b inhibitor in neurons apoptosis after OGD/R-treatment and ischemic brain injury in a mouse model after MCAO/R-treatment. Our study demonstrated that upregulation of miR-20b protected the brain from ischemic brain injury by targeting TXNIP, extending our understanding of miRNAs in cerebral ischemic stroke.
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Affiliation(s)
- Dejiang Yang
- Department of Neurology, the Third Affiliated Hospital of Nanchang University, Nanchang 330008, PR. China
| | - Yu Tan
- Department of Neurology, the Third Affiliated Hospital of Nanchang University, Nanchang 330008, PR. China
| | - Huanhuan Li
- Department of Neurology, the Third Affiliated Hospital of Nanchang University, Nanchang 330008, PR. China
| | - Xiaowei Zhang
- Department of Neurology, the Third Affiliated Hospital of Nanchang University, Nanchang 330008, PR. China
| | - Xinming Li
- Department of Neurology, the Third Affiliated Hospital of Nanchang University, Nanchang 330008, PR. China
| | - Feng Zhou
- Department of Neurology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, PR. China
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29
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Ismael S, Nasoohi S, Yoo A, Mirzahosseini G, Ahmed HA, Ishrat T. Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome. Mol Neurobiol 2021; 58:3792-3804. [PMID: 33847912 DOI: 10.1007/s12035-021-02384-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 04/05/2021] [Indexed: 12/23/2022]
Abstract
Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose, 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were assessed for neurobehavioral deficits followed by sacrifice and evaluation of brain infarct volume, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. As adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metalloproteinase 9 (MMP-9) upregulation, and tight junction protein deregulation, which resulted in lesser hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation and reduced infarct volume. This concurred with a remarkable decrease in high-mobility group box protein 1 (HMGB-1) and nuclear factor kappa B (NF-κB) stimulation, leading to less priming of NLRP3 inflammasome. This preclinical study supports verapamil as a safe adjuvant that may complement thrombolytic therapy by inhibiting TXNIP's detrimental role in hyperglycemic stroke.
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Affiliation(s)
- Saifudeen Ismael
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Sanaz Nasoohi
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arum Yoo
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Golnoush Mirzahosseini
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Heba A Ahmed
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA. .,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA. .,Department of Neuroscience Institute, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
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30
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Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook. Int J Mol Sci 2021; 22:ijms22052754. [PMID: 33803178 PMCID: PMC7963165 DOI: 10.3390/ijms22052754] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.
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31
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Carinci M, Vezzani B, Patergnani S, Ludewig P, Lessmann K, Magnus T, Casetta I, Pugliatti M, Pinton P, Giorgi C. Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion. Biomedicines 2021; 9:biomedicines9020169. [PMID: 33572080 PMCID: PMC7914955 DOI: 10.3390/biomedicines9020169] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.
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Affiliation(s)
- Marianna Carinci
- Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (M.C.); (B.V.); (S.P.); (P.P.)
| | - Bianca Vezzani
- Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (M.C.); (B.V.); (S.P.); (P.P.)
| | - Simone Patergnani
- Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (M.C.); (B.V.); (S.P.); (P.P.)
| | - Peter Ludewig
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany; (P.L.); (K.L.); (T.M.)
| | - Katrin Lessmann
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany; (P.L.); (K.L.); (T.M.)
| | - Tim Magnus
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany; (P.L.); (K.L.); (T.M.)
| | - Ilaria Casetta
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy; (I.C.); (M.P.)
| | - Maura Pugliatti
- Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy; (I.C.); (M.P.)
| | - Paolo Pinton
- Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (M.C.); (B.V.); (S.P.); (P.P.)
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (M.C.); (B.V.); (S.P.); (P.P.)
- Correspondence:
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32
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Domingues A, Jolibois J, Marquet de Rougé P, Nivet-Antoine V. The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target. Int J Mol Sci 2021; 22:ijms22041693. [PMID: 33567593 PMCID: PMC7914816 DOI: 10.3390/ijms22041693] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 12/17/2022] Open
Abstract
Thioredoxin interacting protein (TXNIP) is a metabolism- oxidative- and inflammation-related marker induced in cardiovascular diseases and is believed to represent a possible link between metabolism and cellular redox status. TXNIP is a potential biomarker in cardiovascular and ischemic diseases but also a novel identified target for preventive and curative medicine. The goal of this review is to focus on the novelties concerning TXNIP. After an overview in TXNIP involvement in oxidative stress, inflammation and metabolism, the remainder of this review presents the clues used to define TXNIP as a new marker at the genetic, blood, or ischemic site level in the context of cardiovascular and ischemic diseases.
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Affiliation(s)
- Alison Domingues
- INSERM 1140, Innovative Therapies in Haemostasis, Faculty of Pharmacy, Université de Paris, 75006 Paris, France; (A.D.); (J.J.); (P.M.d.R.)
| | - Julia Jolibois
- INSERM 1140, Innovative Therapies in Haemostasis, Faculty of Pharmacy, Université de Paris, 75006 Paris, France; (A.D.); (J.J.); (P.M.d.R.)
| | - Perrine Marquet de Rougé
- INSERM 1140, Innovative Therapies in Haemostasis, Faculty of Pharmacy, Université de Paris, 75006 Paris, France; (A.D.); (J.J.); (P.M.d.R.)
| | - Valérie Nivet-Antoine
- INSERM 1140, Innovative Therapies in Haemostasis, Faculty of Pharmacy, Université de Paris, 75006 Paris, France; (A.D.); (J.J.); (P.M.d.R.)
- Clinical Biochemistry Department, Assistance Publique des Hôpitaux de Paris, Necker Hospital, 75015 Paris, France
- Correspondence:
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Al Mamun A, Wu Y, Monalisa I, Jia C, Zhou K, Munir F, Xiao J. Role of pyroptosis in spinal cord injury and its therapeutic implications. J Adv Res 2021; 28:97-109. [PMID: 33364048 PMCID: PMC7753222 DOI: 10.1016/j.jare.2020.08.004] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 08/05/2020] [Accepted: 08/08/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Currently, spinal cord injury (SCI) is a pathological incident that triggers several neuropathological conditions, leading to the initiation of neuronal damage with several pro-inflammatory mediators' release. However, pyroptosis is recognized as a new programmed cell death mechanism regulated by the stimulation of caspase-1 and/or caspase-11/-4/-5 signaling pathways with a series of inflammatory responses. AIM Our current review concisely summarizes the potential role of pyroptosis-regulated programmed cell death in SCI, according to several molecular and pathophysiological mechanisms. This review also highlights the targeting of pyroptosis signaling pathways and inflammasome components and its therapeutic implications for the treatment of SCI. KEY SCIENTIFIC CONCEPTS Multiple pieces of evidence have illustrated that pyroptosis plays significant roles in cell swelling, plasma membrane lysis, chromatin fragmentation and intracellular pro-inflammatory factors including IL-18 and IL-1β release. In addition, pyroptosis is directly mediated by the recently discovered family of pore-forming protein known as GSDMD. Current investigations have documented that pyroptosis-regulated cell death plays a critical role in the pathogenesis of multiple neurological disorders as well as SCI. Our narrative article suggests that inhibiting the pyroptosis-regulated cell death and inflammasome components could be a promising therapeutic approach for the treatment of SCI in the near future.
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Key Words
- AIM2, Absent in melanoma 2
- ASC, apoptosis-associated speck-like protein
- ATP, Adenosine triphosphate
- BBG, Brilliant blue G
- CCK-8, Cell Counting Kit-8
- CNS, central nervous system
- CO, Carbon monoxide
- CORM-3, Carbon monoxide releasing molecle-3
- Caspase-1
- Cx43, Connexin 43
- DAMPs, Damage-associated molecular patterns
- DRD1, Dopamine Receptor D1
- ECH, Echinacoside
- GSDMD, Gasdermin D
- Gal-3, Galectin-3
- H2O2, Hydrogen peroxide
- HO-1, Heme oxygenase-1
- IL-18, Interleukin-18
- IL-1β, Interleukin-1 beta
- IRE1, Inositol requiring enzyme 1
- JOA, Japanese orthopedics association
- LPS, Lipopolysaccharide
- NDI, Neck data index
- NF-κB, Nuclear factor-kappa B
- NLRP1, NOD-like receptor protein 1
- NLRP1b, NOD-like receptor protein 1b
- NLRP3
- NLRP3, Nucleotide-binding domain-like receptor protein 3
- Neuroinflammation
- Nrf2, Nuclear factor erythroid 2-related factor 2
- OPCs, Oligodendrocyte progenitor cells
- PAMPs, Pathogen-associated molecular patterns
- PRRs, Pattern recognition receptors
- Pyroptosis
- ROS, Reactive oxygen species
- Spinal cord injury
- TLR4, Toll-like receptor 4
- TXNIP, Thioredoxin-interacting protein
- Therapeutic implications
- double stranded DNAIR, Ischemia reperfusion
- si-RNA, Small interfering RNA
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Affiliation(s)
- Abdullah Al Mamun
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035 Zhejiang Province, China
| | - Yanqing Wu
- Institute of Life Sciences, Wenzhou University, Wenzhou, 325035 Zhejiang Province, China
| | - Ilma Monalisa
- Department of Pharmacy, Southeast University, Banani, Dhaka 1213, Bangladesh
| | - Chang Jia
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027 Zhejiang Province, China
| | - Kailiang Zhou
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027 Zhejiang Province, China
| | - Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035 Zhejiang Province, China
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Ismael S, Ahmed HA, Adris T, Parveen K, Thakor P, Ishrat T. The NLRP3 inflammasome: a potential therapeutic target for traumatic brain injury. Neural Regen Res 2021; 16:49-57. [PMID: 32788447 PMCID: PMC7818859 DOI: 10.4103/1673-5374.286951] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although the precise mechanisms contributing to secondary brain injury following traumatic brain injury are complex and obscure, a number of studies have demonstrated that inflammatory responses are an obvious and early feature in the pathogenesis of traumatic brain injury. Inflammasomes are multiprotein complexes that prompt the stimulation of caspase-1 and subsequently induce the maturation and secretion of proinflammatory cytokines, such as interleukin-1β and interleukin-18. These cytokines play a pivotal role in facilitating innate immune responses and inflammation. Among various inflammasome complexes, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is the best characterized, a crucial role for NLRP3 has been demonstrated in various brain diseases, including traumatic brain injury. Several recent studies have revealed the contribution of NLRP3 inflammasome in identifying cellular damage and stimulating inflammatory responses to aseptic tissue injury after traumatic brain injury. Even more important, blocking or inhibiting the activation of the NLRP3 inflammasome may have substantial potential to salvage tissue damage during traumatic brain injury. In this review, we summarize recently described mechanisms that are involved in the activation and regulation of the NLRP3 inflammasome. Moreover, we review the recent investigations on the contribution of the NLRP3 inflammasome in the pathophysiology of TBI, and current advances and challenges in potential NLRP3-targeted therapies. A significant contribution of NLRP3 inflammasome activation to traumatic brain injury implies that therapeutic approaches focused on targeting specific inflammasome components could significantly improve the traumatic brain injury outcomes.
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Affiliation(s)
- Saifudeen Ismael
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Heba A Ahmed
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tusita Adris
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | | | - Parth Thakor
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, USA
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Thioredoxin-Interacting Protein (TXNIP) with Focus on Brain and Neurodegenerative Diseases. Int J Mol Sci 2020; 21:ijms21249357. [PMID: 33302545 PMCID: PMC7764580 DOI: 10.3390/ijms21249357] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
The development of new therapeutic approaches to diseases relies on the identification of key molecular targets involved in amplifying disease processes. One such molecule is thioredoxin-interacting protein (TXNIP), also designated thioredoxin-binding protein-2 (TBP-2), a member of the α-arrestin family of proteins and a central regulator of glucose and lipid metabolism, involved in diabetes-associated vascular endothelial dysfunction and inflammation. TXNIP sequesters reduced thioredoxin (TRX), inhibiting its function, resulting in increased oxidative stress. Many different cellular stress factors regulate TXNIP expression, including high glucose, endoplasmic reticulum stress, free radicals, hypoxia, nitric oxide, insulin, and adenosine-containing molecules. TXNIP is also directly involved in inflammatory activation through its interaction with the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome complex. Neurodegenerative diseases such as Alzheimer’s disease have significant pathologies associated with increased oxidative stress, inflammation, and vascular dysfunctions. In addition, as dysfunctions in glucose and cellular metabolism have been associated with such brain diseases, a role for TXNIP in neurodegeneration has actively been investigated. In this review, we will focus on the current state of the understanding of possible normal and pathological functions of TXNIP in the central nervous system from studies of in vitro neural cells and the brains of humans and experimental animals with reference to other studies. As TXNIP can be expressed by neurons, microglia, astrocytes, and endothelial cells, a complex pattern of regulation and function in the brain is suggested. We will examine data suggesting TXNIP as a therapeutic target for neurodegenerative diseases where further research is needed.
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Feng YS, Tan ZX, Wu LY, Dong F, Zhang F. The involvement of NLRP3 inflammasome in the treatment of Alzheimer's disease. Ageing Res Rev 2020; 64:101192. [PMID: 33059089 DOI: 10.1016/j.arr.2020.101192] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/04/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and it is characterised by progressive deterioration in cognitive and memory abilities, which can severely influence the elderly population's daily living abilities. Although researchers have made great efforts in the field of AD, there are still no well-established strategies to prevent and treat this disease. Therefore, better clarification of the molecular mechanisms associated with the onset and progression of AD is critical to provide a theoretical basis for the establishment of novel preventive and therapeutic strategies. Currently, it is generally believed that neuroinflammation plays a key role in the pathogenesis of AD. Inflammasome, a multiprotein complex, is involved in the innate immune system, and it can mediate inflammatory responses and pyroptosis, which lead to neurodegeneration. Among the various types of inflammasomes, the NLRP3 inflammasome is the most characterised in neurodegenerative diseases, especially in AD. The activation of the NLRP3 inflammasome causes the generation of caspase-1-mediated interleukin (IL)-1β and IL-18 in microglia cells, where neuroinflammation is involved in the development and progression of AD. Thus, the NLRP3 inflammasome is likely to be a crucial therapeutic molecular target for AD via regulating neuroinflammation. In this review, we summarise the current knowledge on the role and regulatory mechanisms of the NLRP3 inflammasome in the pathogenic mechanisms of AD. We also focus on a series of potential therapeutic treatments targeting NLRP3 inflammasome for AD. Further clarification of the regulatory mechanisms of the NLRP3 inflammasome in AD may provide more useful clues to develop novel AD treatment strategies.
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Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury. J Neuroinflammation 2020; 17:330. [PMID: 33153475 PMCID: PMC7643474 DOI: 10.1186/s12974-020-01988-x] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 10/07/2020] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemic stroke. NLRP3 inflammasome, involved in the regulation of inflammatory cascade, can simultaneously lead to GSDMD-executed pyroptosis in cerebral ischemia. Low-density lipoprotein receptor (LDLR), responsible for cholesterol uptake, was noted to exert potential anti-inflammatory bioactivities. Nevertheless, the role of LDLR in neuroinflammation mobilized by cerebral ischemia/reperfusion (I/R) has not been investigated. METHODS Ischemic stroke mice model was accomplished by middle cerebral artery occlusion. Oxygen-glucose deprivation was employed after primary cortical neuron was extracted and cultured. A pharmacological inhibitor of NLRP3 (CY-09) was administered to suppress NLPR3 activation. Histological and biochemical analysis were performed to assess the neuronal death both in vitro and in vivo. In addition, neurological deficits and behavioral deterioration were evaluated in mice. RESULTS The expression of LDLR was downregulated following cerebral I/R injury. Genetic knockout of Ldlr enhanced caspase-1-dependent cleavage of GSDMD and resulted in severe neuronal pyroptosis. LDLR deficiency contributed to excessive NLRP3-mediated maturation and release of IL-1β and IL-18 under in vitro and in vivo ischemic conditions. These influences ultimately led to aggravated neurological deficits and long-term cognitive dysfunction. Blockade of NLRP3 substantially retarded neuronal pyroptosis in Ldlr-/- mice and cultured Ldlr-/- neuron after experimental stroke. CONCLUSIONS These results demonstrated that LDLR modulates NLRP3-mediated neuronal pyroptosis and neuroinflammation following ischemic stroke. Our findings characterize a novel role for LDLR as a potential therapeutic target in neuroinflammatory responses to acute cerebral ischemic injury.
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IGF-1R stimulation alters microglial polarization via TLR4/NF-κB pathway after cerebral hemorrhage in mice. Brain Res Bull 2020; 164:221-234. [DOI: 10.1016/j.brainresbull.2020.08.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 08/13/2020] [Accepted: 08/23/2020] [Indexed: 12/17/2022]
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Z-Guggulsterone alleviated oxidative stress and inflammation through inhibiting the TXNIP/NLRP3 axis in ischemic stroke. Int Immunopharmacol 2020; 89:107094. [PMID: 33129097 DOI: 10.1016/j.intimp.2020.107094] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 09/25/2020] [Accepted: 10/09/2020] [Indexed: 01/05/2023]
Abstract
Ischemic stroke is a serious and life-threatening cerebrovascular thrombotic disease; however, the therapeutic strategy is limited for the complicated mechanism and narrow therapeutic window. Our previous study suggested that Z-Guggulsterone (Z-GS), an active component derived from myrrh, is a good candidate for cerebral injury. The object of this study is to investigate the exact mechanisms of Z-GS in cerebral ischemic stroke. Rats were used to conduct middle cerebral artery occlusion (MCAO) model and were treated with different dosage of Z-GS. Morphological results showed that Z-GS significantly alleviated neurological deficits, infarct volume and histopathological damage in MCAO rats. A total of 8276 differentially expressed genes were identified based on microarray analysis. Oxidation-reduction process and inflammatory response were enriched as the significant gene ontology items. TXNIP and NLRP3 were screened as the potential target genes by Series Test of Cluster (STC) analysis. The results were validated by immunohistochemistry and immunofluorescence staining. Besides, Z-GS successfully inhibited oxidative stress and inflammatory response in oxygen-glucose deprivation (OGD) treated neurons. Knockdown of TXNIP significantly decreased the expression of NLRP3 in OGD-induced neurons. In addition, Z-GS treatment scarcely changed the expressions of NLRP3 in siRNA-TXNIP pretreated cells compared with the siRNA-TXNIP alone treatment group, suggesting that the neuroprotective effect of Z-GS was dependent on TXNIP-NLRP3 axis. Taken together, this study revealed that Z-GS exerted neuroprotective property through alleviated oxidative stress and inflammation via inhibiting the TXNIP/NLRP3 axis. Z-GS could be considered as a promising candidate for the treatment of ischemic stroke.
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Gamdzyk M, Doycheva DM, Kang R, Tang H, Travis ZD, Tang J, Zhang JH. GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells. J Cell Mol Med 2020; 24:12318-12330. [PMID: 33034416 PMCID: PMC7686982 DOI: 10.1111/jcmm.15698] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/23/2020] [Accepted: 07/09/2020] [Indexed: 12/19/2022] Open
Abstract
This study aimed to investigate the effects of PPAR‐β/δ receptor agonist GW0742 on neuroinflammation in a rat model of hypoxia‐ischaemia (HI) and in PC12 cells in OGD model. HI was induced by ligating the common carotid artery and inducing hypoxia for 150 minutes. Immunofluorescence was used for quantification of microglia activation and for determining cellular localization of PPAR‐β/δ. Expression of proteins was measured by Western blot. Activation of miR‐17‐5p by GW0742 was assessed in PC12 cells by Dual‐Luciferase Reporter Gene Assay. The endogenous expression of TXNIP, NLRP3, cleaved caspase‐1 and IL‐1β was increased after HI. GW0742 treatment significantly reduced the number of activated pro‐inflammatory microglia in ipsilateral hemisphere after HI. Mechanistically, GW0742 significantly decreased the expression of TXNIP, NLRP3, IL‐6 and TNF‐α. Either PPAR‐β/δ antagonist GSK3787, miR‐17‐5p inhibitor, or TXNIP CRISPR activation abolished the anti‐inflammatory effects of GW0742. Activation of PPAR‐β/δ by GW0742 activated miR‐17‐5p expression in PC12 cells and increased cell viability after OGD, which was accompanied by decreased expression of TXNIP and reduced secretion of IL‐1β and TNF‐α. In conclusion, GW0742 may be a promising neurotherapeutic for the management of HI patients.
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Affiliation(s)
- Marcin Gamdzyk
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Desislava Met Doycheva
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Ruiqing Kang
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Hong Tang
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Zackary D Travis
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Jiping Tang
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - John H Zhang
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.,Department of Anesthesiology, Neurosurgery and Neurology, Loma Linda University School of Medicine, Loma Linda, CA, USA
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Ding R, Ou W, Chen C, Liu Y, Li H, Zhang X, Chai H, Ding X, Wang Q. Endoplasmic reticulum stress and oxidative stress contribute to neuronal pyroptosis caused by cerebral venous sinus thrombosis in rats: Involvement of TXNIP/peroxynitrite-NLRP3 inflammasome activation. Neurochem Int 2020; 141:104856. [PMID: 32980492 DOI: 10.1016/j.neuint.2020.104856] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/06/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023]
Abstract
Cerebral venous sinus thrombosis (CVST) is a rare type of stroke, which is life-threatening in severe cases. However, considerably less attention has been concentrated on the mechanism of neural cell damage after CVST. This study aims to investigate the role of endoplasmic reticulum stress, oxidative stress, and pyroptosis in a well-established rodent model of CVST. Rat brains were harvested at 0 h, 6 h, days 1, days 3, days 7, and days 14 post-CVST for measurement of corresponding indexes. Endoplasmic reticulum stress sensors (including protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme-1α (IRE1α)), oxidative stress markers (thioredoxin-interacting protein (TXNIP) and peroxynitrite), NLRP3, caspase p20, IL-1β, and gasdermin D (GSDMD, an indicator of pyroptosis) were separately evaluated by Western-blot and Immunohistochemistry/Immunofluorescence. Co-immunoprecipitation and Fluorescent double-labeling were employed to probe into the relationship between TXNIP/peroxynitrite and NLRP3 inflammasome. In the damaged cortex region, profuse p-PERK, p-IRE1α, TXNIP were produced and predominantly localized in neurons accompanied by a small amount expressed in microglia and astrocytes. The levels of 3-nitrotyrosine (3-NT, as a footprint of peroxynitrite), NLRP3, caspase p20, IL-1β, and GSDMD were distinctly elevated post-CVST and cellular localization of peroxynitrite, NLRP3, caspase p20, and IL-1β was largely observed in neurons and/or microglia. Importantly, sites of enhanced TXNIP and 3-NT immunoreactivity were colocalized with increased NLRP3 staining, indicating the involvement of TXNIP and peroxynitrite in NLRP3 inflammasome activation and subsequent pyroptosis. Besides, co-immunoprecipitation also hinted that there might be an interaction or causality between TXNIP/peroxynitrite and NLRP3 inflammasome. We concluded that endoplasmic reticulum stress and oxidative stress may jointly lead to neuronal NLRP3 inflammasome activation and pyroptosis after CVST.
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Affiliation(s)
- Rui Ding
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Weiyang Ou
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Chengwei Chen
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Yaqi Liu
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Haiyan Li
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Xifang Zhang
- The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Huihui Chai
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Xiaowen Ding
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Qiujing Wang
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou, 510630, Guangdong, China.
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Du X, Xu Y, Chen S, Fang M. Inhibited CSF1R Alleviates Ischemia Injury via Inhibition of Microglia M1 Polarization and NLRP3 Pathway. Neural Plast 2020; 2020:8825954. [PMID: 32908485 PMCID: PMC7474788 DOI: 10.1155/2020/8825954] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/31/2020] [Accepted: 08/12/2020] [Indexed: 12/16/2022] Open
Abstract
Ischemia cerebral stroke is one of the common neurological diseases with severe inflammatory response and neuron death. The inhibition of colony-stimulating factor 1 receptor (CSF1R) which especially expressed in microglia/macrophage exerted neuroprotection in stroke. However, the underlying neuroinflammatory regulation effects of CSF1R in ischemia stroke are not clear. In this study, cerebral ischemia stroke mice model was established. The C57/B6J mice were administered with Ki20227, a CSF1R inhibitor, by gavage for 7 consecutive days (0.002 mg/kg/day) before modeling. The Rota-Rod test and neurobehavioral score test were investigated to assess neurobehavioral functions. The area of infarction was assessed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The mRNA expressions of M1/M2 microglia markers were evaluated by real-time PCR. Immunofluorescence and Western blot were utilized to detect the changes of Iba1 and NLRP3 pathway proteins. Results showed that neurobehavioral function improvement was demonstrated by an increased stay time on the Rota-Rod test and a decreased neurobehavioral score in the Ki20227 treatment group. The area of infarction reduced in Ki20227 group when compared to the stroke group. Moreover, the mRNA expression of M1 microglia markers (TNF-α and iNOS) decreased while M2 microglia markers (IL-10 and Arg-1) increased. Meanwhile, compared to the stroke and stroke+PBS group, Ki20227 administration downregulated the expression of NLRP3, active caspase 1, and NF-κB protein in the ischemia penumbra of Ki20227 treatment group mice. In short, the CSF1R inhibitor, Ki20227, played vital neuroprotective roles in ischemia cerebral stroke mice, and the mechanisms may be via inhibiting microglia M1 polarization and NLRP3 inflammasome pathway activation. Our study provides a potential new target for the treatment of ischemic stroke injury.
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Affiliation(s)
- Xiaoxue Du
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, 310006 Zhejiang, China
- Translational Medicine Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006 Zhejiang, China
| | - Yuzhen Xu
- Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Shijia Chen
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, 310006 Zhejiang, China
| | - Marong Fang
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, 310006 Zhejiang, China
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Wang K, Ru J, Zhang H, Chen J, Lin X, Lin Z, Wen M, Huang L, Ni H, Zhuge Q, Yang S. Melatonin Enhances the Therapeutic Effect of Plasma Exosomes Against Cerebral Ischemia-Induced Pyroptosis Through the TLR4/NF-κB Pathway. Front Neurosci 2020; 14:848. [PMID: 33013286 PMCID: PMC7461850 DOI: 10.3389/fnins.2020.00848] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/21/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Ischemic stroke-induced inflammation and inflammasome-dependent pyroptotic neural death cause serious neurological injury. Nano-sized plasma exosomes have exhibited therapeutic potential against ischemia and reperfusion injury by ameliorating inflammation. To enhance its therapeutic potential in patients with ischemic injury, we isolated exosomes from melatonin-treated rat plasma and assessed the neurological protective effect in a rat model of focal cerebral ischemia. Methods Basal plasma exosomes and melatonin-treated plasma exosomes were isolated and intravenously injected into a rat model of focal cerebral ischemia. Neurological recovery was evaluated by determining the modified neurological severity score (mNSS), infarct volume, and brain water content. Pyroptosis in the ischemic cortex was detected through dUTP nick-end labeling (TUNEL) assay, lactate dehydrogenase (LDH) release, and gasdermin D (GSDMD) cleavage. NLRP3 inflammasome assembly and global inflammatory cytokine secretion were detected by enzyme-linked immunosorbent assay (ELISA) and Western blot assay. In immunized Sprague-Dawley rats, microglia pyroptosis was determined through a positive percentage of IBA1+ and caspase-1 (p20)+ cells. Finally, the microRNA (miRNA) profiles in melatonin-treated plasma exosomes were analyzed by exosome miRNA microarray analysis. Results Melatonin treatment enhanced plasma exosome therapeutic effects against ischemia-induced inflammatory responses and inflammasome-mediated pyroptosis. In addition, we confirmed that ischemic stroke-induced pyroptotic cell death occurred in the microglia and neuron, while the administration of melatonin-treated exosomes further effectively decreased the infarct volume and improved recovery of function via regulation of the TLR4/NF-κB signaling pathway. Finally, the altered miRNA profiles in the melatonin-treated plasma exosomes demonstrated the regulatory mechanisms involved in neurological recovery after ischemic injury. Conclusion This study suggests that nano-sized plasma exosomes with melatonin pretreatment might be a more effective strategy for patients with ischemic brain injury. Further exploration of key molecules in the plasma exosome may provide increased therapeutic value for cerebral ischemic injury.
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Affiliation(s)
- Kankai Wang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Junnan Ru
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hengli Zhang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiayu Chen
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao Lin
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhongxiao Lin
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Min Wen
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lijie Huang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haoqi Ni
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qichuan Zhuge
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Su Yang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Olcum M, Tastan B, Ercan I, Eltutan IB, Genc S. Inhibitory effects of phytochemicals on NLRP3 inflammasome activation: A review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 75:153238. [PMID: 32507349 DOI: 10.1016/j.phymed.2020.153238] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 04/12/2020] [Accepted: 04/27/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND The NLRP3 inflammasome formation and following cytokine secretion is a crucial step in innate immune responses. Internal and external factors may trigger inflammasome activation and result in inflammatory cytokine secretion. Inflammasome formation and activity play critical roles in several disease pathologies such as cardiovascular, metabolic, renal, digestive, and CNS diseases. Underlying pathways are not yet clear, but phytochemicals as alternative therapies have been extensively used for suppression of inflammatory responses. PURPOSE In this review, we aimed to summarize in vivo and in vitro effects on NLRP3 inflammasome activation of selected phytochemicals. METHOD Three phytochemicals; Sulforaphane, Curcumin, and Resveratrol were selected, and studies were reviewed to clarify their intracellular signaling mechanism in NLRP3 inflammasome activity. PubMed and Scopus databases are used for the search. For sulforaphane, 8 articles, for curcumin, 25 articles, and for resveratrol, 41 articles were included in the review. CONCLUSION In vitro and in vivo studies pointed out that the selected phytochemicals have inhibitory properties on NLRP3 inflammasome activity. However, neither the mechanism is clear, nor the study designs and doses are standardized.
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Affiliation(s)
- Melis Olcum
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey
| | - Bora Tastan
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | - Ilkcan Ercan
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | - Irem B Eltutan
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | - Sermin Genc
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; Department of Neuroscience, Health Science Institute, Dokuz Eylul University, Izmir, Turkey.
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Zeng X, Li Y, Ma S, Tang Y, Li H. Phoenixin-20 Ameliorates Lipopolysaccharide-Induced Activation of Microglial NLRP3 Inflammasome. Neurotox Res 2020; 38:785-792. [DOI: 10.1007/s12640-020-00225-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 12/17/2022]
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VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF- κB Pathways to Improve Functional Outcomes in TBI Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7879629. [PMID: 32377306 PMCID: PMC7181015 DOI: 10.1155/2020/7879629] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 02/28/2020] [Accepted: 03/20/2020] [Indexed: 01/12/2023]
Abstract
Background Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.
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Schölwer I, Habib P, Voelz C, Rolfes L, Beyer C, Slowik A. NLRP3 Depletion Fails to Mitigate Inflammation but Restores Diminished Phagocytosis in BV-2 Cells After In Vitro Hypoxia. Mol Neurobiol 2020; 57:2588-2599. [PMID: 32239449 DOI: 10.1007/s12035-020-01909-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/23/2020] [Indexed: 12/30/2022]
Abstract
Post-hypoxic/ischemic neuroinflammation is selectively driven by sterile inflammation, which implies the interplay of brain-intrinsic immune cells with other neural cells and immigrated peripheral immune cells. The resultant inflammatory cascade evolves extra- and intracellular pathogen and danger-associated receptors. The latter interacts with multiprotein complexes termed inflammasomes. The NLRP3 inflammasome is one of the best-described inflammasomes. However, its impact on post-ischemic neuroinflammation and its role in neuroprotection after ischemic stroke are still under debate. Microglial cells are known to be the main source of neuroinflammation; hence, we depleted NLRP3 in BV-2 microglial cells using shRNA to investigate its role in IL-1β maturation and phagocytosis after hypoxia (oxygen-glucose-deprivation (OGD)). We also examined the expression profiles of other inflammasomes (NLRC4, AIM2, ASC) and caspase-1 activity after OGD. OGD triggered caspase-1 activity and increased IL-1β secretion in BV-2 cells with no alteration after NLRP3 depletion. The expression of the AIM2 inflammasome was significantly higher after OGD in NLRP3-depleted cells, whereas NLRC4 was unaltered in all groups. Interestingly, OGD induced a complete inactivation of phagocytic activity in wild-type cells, while in NLRP3-depleted BV-2, this inactivity was restored after hypoxia. Our findings indicate a minor role of NLRP3 in the inflammatory response after hypoxic/ischemic stimulus. However, NLRP3 seems to play a pivotal role in the regulation of post-ischemic phagocytosis. This might be a prerequisite for the putative neuroprotective effect.
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Affiliation(s)
- Isabelle Schölwer
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Pardes Habib
- Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Clara Voelz
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Leoni Rolfes
- Neurology Clinic and Institute for Translational Neurology, University of Muenster, Münster, Germany
| | - Cordian Beyer
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
- JARA-Brain, RWTH Aachen University, Aachen, Germany
| | - Alexander Slowik
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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Ismael S, Nasoohi S, Yoo A, Ahmed HA, Ishrat T. Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice. Mol Neurobiol 2020; 57:2495-2508. [PMID: 32172516 DOI: 10.1007/s12035-020-01893-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/14/2020] [Indexed: 12/23/2022]
Abstract
Hyperglycemia has been shown to counterbalance the beneficial effects of tissue plasminogen activator (tPA) and increase the risk of intracerebral hemorrhage in ischemic stroke. Thioredoxin interacting protein (TXNIP) mediates hyperglycemia-induced oxidative damage and inflammation in the brain and reduces cerebral glucose uptake/utilization. We have recently reported that TXNIP-induced NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation contributes to neuronal damage after ischemic stroke. Here, we tested the hypothesis that tPA induces TXNIP-NLRP3 inflammasome activation after ischemic stroke, in hyperglycemic mice. Acute hyperglycemia was induced in mice by intraperitoneal (IP) administration of a 20% glucose solution. This was followed by transient middle cerebral artery occlusion (t-MCAO), with or without intravenous (IV) tPA administered at reperfusion. The IV-tPA exacerbated hyperglycemia-induced neurological deficits, ipsilateral edema and hemorrhagic transformation, and accentuated peroxisome proliferator activated receptor-γ (PPAR-γ) upregulation and TXNIP/NLRP3 inflammasome activation after ischemic stroke. Higher expression of TXNIP in hyperglycemic t-MCAO animals augmented glucose transporter 1 (GLUT-1) downregulation and increased vascular endothelial growth factor-A (VEGF-A) expression/matrix metallopeptidase 9 (MMP-9) signaling, all of which result in blood brain barrier (BBB) disruption and increased permeability to endogenous immunoglobulin G (IgG). It was also associated with a discernible buildup of nitrotyrosine and accumulation of dysfunctional tight junction proteins: zonula occludens-1 (ZO-1), occludin and claudin-5. Moreover, tPA administration triggered activation of high mobility group box protein 1 (HMGB-1), nuclear factor kappa B (NF-κB), and tumor necrosis factor-α (TNF-α) expression in the ischemic penumbra of hyperglycemic animals. All of these observations suggest a powerful role for TXNIP-NLRP3 inflammasome activation in the tPA-induced toxicity seen with hyperglycemic stroke.
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Affiliation(s)
- Saifudeen Ismael
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Sanaz Nasoohi
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arum Yoo
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Heba A Ahmed
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA. .,Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA. .,Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
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Estrogen protects neuroblastoma cell from amyloid-β 42 (Aβ42)-induced apoptosis via TXNIP/TRX axis and AMPK signaling. Neurochem Int 2020; 135:104685. [PMID: 31931042 DOI: 10.1016/j.neuint.2020.104685] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 12/20/2019] [Accepted: 01/08/2020] [Indexed: 12/26/2022]
Abstract
Alzheimer's disease (AD), a massive challenge to global health, is featured with the extracellular plaques made up of amyloid-β 42 (Aβ42) and the intracellular neurofibrillary pathology composed of the microtubule-associated protein tau. Women seem to have a higher vulnerability to AD. In the present study, we identified Thioredoxin-interacting protein (TXNIP) as a specifically highly-expressed gene in the hippocampus in female AD patients by bioinformatics analysis. Consistently, in the hippocampus in female AD mice, apoptosis and TXNIP expression were enhanced while TRX expression was suppressed. In Aβ42-stimulated SH-SY5Y cells, the administration of estradiol significantly rescued Aβ42-suppressed cell viability and protein level of TRX while inhibited Aβ42-induced increases in ROS production, cell apoptosis, ΔΨm, and the protein levels of PERK, IREα, and TXNIP, further confirming the potential role of estrogen in AD progression and the involvement of TXNIP/TRX axis. Furthermore, the protective effects of estradiol against Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells could be significantly reversed by AMPK inhibitor, Compound C, indicating that estradiol could improve Aβ42-induced AD via TXNIP/TRX and AMPK signaling. In summary, we demonstrated the cellular function of estradiol on Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells and a novel mechanism of TXNIP/TRX axis involved in estradiol function via AMPK signaling.
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Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4717258. [PMID: 31998437 PMCID: PMC6964721 DOI: 10.1155/2020/4717258] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 10/18/2019] [Accepted: 10/31/2019] [Indexed: 12/05/2022]
Abstract
Oxidative stress and neuroinflammation play essential roles in ischemic stroke-induced brain injury. Previous studies have reported that Ezetimibe (Eze) exerts antioxidative stress and anti-inflammatory properties in hepatocytes. In the present study, we investigated the effects of Eze on oxidative stress and neuroinflammation in a rat middle cerebral artery occlusion (MCAO) model. One hundred and ninety-eight male Sprague-Dawley rats were used. Animals assigned to MCAO were given either Eze or its control. To explore the downstream signaling of Eze, the following interventions were given: AMPK inhibitor dorsomorphin and nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA. Intranasal administration of Eze, 1 h post-MCAO, further increased the endogenous p-AMPK expression, reducing brain infarction, neurologic deficits, neutrophil infiltration, microglia/macrophage activation, number of dihydroethidium- (DHE-) positive cells, and malonaldehyde (MDA) levels. Specifically, treatment with Eze increased the expression of p-AMPK, Nrf2, and HO-1; Romo-1, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Cleaved Caspase-1, and IL-1β were reduced. Dorsomorphin and Nrf2 siRNA reversed the protective effects of Eze. In summary, Eze decreases oxidative stress and subsequent neuroinflammation via activation of the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Therefore, Eze may be a potential therapeutic approach for ischemic stroke patients.
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