Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 23(1), P. 14 - 14

Published: Dec. 21, 2021

Its increasing incidence has led stroke to be the second leading cause of death worldwide. Despite significant advances in recanalization strategies, patients are still at risk for ischemia/reperfusion injuries this pathophysiology, which neuroinflammation is significantly involved. Research shown that acute phase, neuroinflammatory cascades lead apoptosis, disruption blood-brain barrier, cerebral edema, and hemorrhagic transformation, while later stages, these pathways support tissue repair functional recovery. The present review discusses various cell types mechanisms through contributes parenchymal injury repair, as well therapeutic attempts made vitro, animal experiments, clinical trials target neuroinflammation, highlighting future perspectives.

Language: Английский

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Quercetin improves cerebral ischemia/reperfusion injury by promoting microglia/macrophages M2 polarization via regulating PI3K/Akt/NF-κB signaling pathway

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115653 - 115653

Published: Oct. 7, 2023

The modulation of microglial polarization from the pro-inflammatory M1 to anti-inflammatory M2 phenotype shows promise as a therapeutic strategy for ischemic stroke. Quercetin, natural flavonoid abundant in various plants, possesses anti-inflammatory, anti-apoptotic, and antioxidant properties. Nevertheless, its effect underlying mechanism on microglia/macrophages M1/M2 treatment cerebral ischemia/reperfusion injury (CI/RI) remain poorly explored. In current study, we observed that quercetin ameliorated neurological deficits, reduced infarct volume, decreased number (CD16/32+/Iba1+), enhanced (CD206+/Iba1+) after establishing CI/RI model rats. Subsequent vivo vitro experiments indicated downregulated markers (CD86, iNOS, TNF-α, IL-1β, IL-6) upregulated (CD206, Arg-1, IL-10, TGF-β). Network pharmacology analysis molecular docking revealed PI3K/Akt/NF-κB signaling pathway emerged core pathway. Western blot confirmed phosphorylation PI3K Akt, while alleviating IκBα NF-κB both vitro. However, inhibitor LY294002 reversed effects expression key proteins primary microglia oxygen-glucose deprivation/reoxygenation (OGD/R) Collectively, our findings demonstrate facilitates by modulating CI/RI. These provide novel insights into mechanisms

Language: Английский

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Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization

Phytomedicine, Journal Year: 2024, Volume and Issue: 129, P. 155635 - 155635

Published: April 20, 2024

Cerebral ischemia-reperfusion (I/R) injury often leads to neuronal death through persistent neuroinflammatory responses. Recent research has unveiled a unique inflammatory programmed cell mode known as PANoptosis. However, direct evidence for PANoptosis in ischemic stroke-induced not been established. Although it is widely thought that modulating the balance of microglial phenotypic polarization cerebral I/R could mitigate neuroinflammation-mediated death, remains unknown whether influences PANoptotic triggered by I/R. Our prior study demonstrated curcumin (CUR) preconditioning boost neuroprotective properties olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) intracerebral hemorrhage. Yet, potential capacity curcumin-pretreated OM-MSCs (CUR-OM-MSCs) on reducing during uncertain. To mimic injury, We established vivo models reversible middle artery occlusion (MCAO) C57BL/6 mice and vitro oxygen-glucose deprivation/reoxygenation (OGD/R) HT22 neurons BV2 microglia. findings indicated caused microglia adopt an M1 (pro-inflammatory) phenotype both vitro. Curcumin pretreatment enhanced proliferation anti-inflammatory OM-MSCs. The CUR-OM-MSCs group experienced more pronounced reduction better recovery neurological function than group. Bioinformatic analysis revealed microRNA-423-5p (miRNA-423-5p) expression was obviously upregulated compared treatment induced switch M2 (anti-inflammatory) releasing miRNA-423-5p, which targeted nucleotide-binding oligomerization domain 2 (NOD2), upstream regulator NF-kappaB (NF-κB) Mitogen-Activated Protein Kinase (MAPK) signaling pathways, attenuate resulting from This results provide first demonstration existence conditions. ameliorating effect neuroinflammation mediated via upregulating abundance miRNA-423-5p. intervention effectively alleviates combination with holds promise potentially efficacious stroke future.

Language: Английский

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The role of AMPK in macrophage metabolism, function and polarisation

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Dec. 8, 2023

AMP-activated protein kinase (AMPK) is a ubiquitous sensor of energy and nutritional status in eukaryotic cells. It plays key role regulating cellular homeostasis multiple aspects cell metabolism. During macrophage polarisation, AMPK not only guides the metabolic programming macrophages, but also counter-regulates inflammatory function macrophages promotes their polarisation toward anti-inflammatory phenotype. located at intersection metabolism inflammation. The characteristics are closely related to immune-related diseases, infectious cancer progression immunotherapy. This review discusses structure its metabolism, macrophages. In addition, it summarises important pathway activators development macrophage-related diseases.

Language: Английский

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Blood–Brain Barrier‐Penetrating and Lesion‐Targeting Nanoplatforms Inspired by the Pathophysiological Features for Synergistic Ischemic Stroke Therapy

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(21)

Published: Feb. 12, 2024

Abstract Ischemic stroke is a dreadful vascular disorder that poses enormous threats to the public health. Due its complicated pathophysiological features, current treatment options after ischemic attack remains unsatisfactory. Insufficient drug delivery lesions impeded by blood–brain barrier (BBB) largely limits therapeutic efficacy of most anti‐stroke agents. Herein, inspired rapid BBB penetrability 4T1 tumor cells upon their brain metastasis and natural roles platelet in targeting injured vasculatures, bio‐derived nanojacket developed fusing cell membrane with membrane, which further clothes on surface paeonol polymetformin‐loaded liposome obtain biomimetic nanoplatforms (PP@PCL) for treatment. The designed PP@PCL could remarkably alleviate ischemia‐reperfusion injury efficiently lesion, preventing neuroinflammation, scavenging excess reactive oxygen species (ROS), reprogramming microglia phenotypes, promoting angiogenesis due synergistic mechanisms anchor characteristics stroke. As result, exerts desirable PC12 neuronal rat model stroke, significantly attenuates apoptosis, reduces infarct volume, recovers neurological functions, bringing new insights into exploiting promising strategies cerebral management.

Language: Английский

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Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies

Orthopaedic Surgery, Journal Year: 2024, Volume and Issue: 16(3), P. 532 - 550

Published: Jan. 31, 2024

Osteoarthritis (OA) is the most common chronic degenerative joint disease in middle‐aged and elderly people, characterized by pain dysfunction. Macrophages are key players OA pathology, their activation state has been studied extensively. Various studies have suggested that macrophages might respond to stimuli microenvironment changing phenotypes pro‐inflammatory or anti‐inflammatory phenotypes, which called macrophage polarization. accumulate become polarized (M1 M2) many tissues, such as synovium, adipose tissue, bone marrow, mesenchymal tissues joints, while resident well other stromal cells, including fibroblasts, chondrocytes, osteoblasts, form function an integrated unit. In this study, we focus exclusively on synovial macrophages, tissue osteoclasts, investigate roles development of OA. We review recent findings related polarization OA, pathogenesis, molecular pathways, therapeutics. summarize several signaling pathways reprogramming NF‐κB, MAPK, TGF‐β, JAK/STAT, PI3K/Akt/mTOR, NLRP3. Of note, despite increasing availability treatments for osteoarthritis, like intra‐articular injections, surgery, cellular therapy, demand more effective clinical therapies remained steady. Therefore, also describe current prospective therapeutic methods deem be a target, physical stimulus, chemical compounds, biological molecules, enhance cartilage repair alleviate progression

Language: Английский

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Bone marrow mesenchymal stem cell-derived extracellular vesicles alleviate diabetes-exacerbated atherosclerosis via AMPK/mTOR pathway-mediated autophagy-related macrophage polarization

Cardiovascular Diabetology, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 29, 2025

Bone marrow-derived mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are widely used for therapeutic purposes in preclinical studies. However, their utility treating diabetes-associated atherosclerosis remains largely unexplored. Here, we aimed to characterize BMSC-EV-mediated regulation of autophagy and macrophage polarization. EVs were isolated from the supernatant cultured BMSCs characterized with transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), western blotting. A diabetes-related atherosclerotic ApoE−/− mouse model was established through feeding a high-fat diet (HFD) streptozotocin (STZ). Histopathological analyses carried out using Oil Red O, H&E, Masson staining aorta. TEM immunohistochemistry (IHC) applied evaluate autophagy, immunofluorescence (IF) identify RAW264.7 macrophages induced oxidized low-density lipoprotein (ox-LDL) high glucose (HG), co-cultured BMSC-EVs, analyzed proliferation, migration, foam cell formation. cells transduced marker mRFP-GFP-LC3 lentivirus IF Diabetic mice (DA group) had larger aortic plaque areas lower collagen content than HFD mice. BMSC-EV treatment significantly reduced blood glucose, LDL levels, while increasing content. BMSC-EV-treated aortas contained higher number autophagosomes/autolysosomes, increased expression LC3BII correlating decreased P62 levels proportion M1 macrophages. In vitro, BMSC-EVs inhibited formation ox-LDL HG-induced activated cells. These effects reversed by blocker bafilomycin A1. Consistent vivo findings, elevated autophagy-related protein LC3BII/I also expressed markers CD86 iNOS, but showed M2 Arg-1. Further, AMPKα mTOR phosphorylation which blocked AMPK inhibitor compound C. attenuate diabetes-exacerbated inhibiting vascular via AMPK/mTOR signaling-regulated thus hold promise as agents atherosclerosis. Extracellular derived bone marrow may mitigate diabetes-aggravated regulating AMPK/mTOR-mediated polarization formation, cholesterol transport.

Language: Английский

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Microglia-mediated neuroinflammation and neuroplasticity after stroke

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Aug. 16, 2022

Stroke remains a major cause of long-term disability and mortality worldwide. The immune system plays an important role in determining the condition brain following stroke. As resident innate cells central nervous system, microglia are primary responders defense network covering entire parenchyma, exert various functions depending on dynamic communications with neurons, astrocytes, other neighboring under both physiological or pathological conditions. Microglia activation polarization is crucial for damage repair ischemic stroke, considered double-edged sword neurological recovery. can exist pro-inflammatory states promote secondary damage, but they also secrete anti-inflammatory cytokines neurotrophic factors facilitate recovery In this review, we focus mechanisms microglia-mediated neuroinflammation neuroplasticity after ischemia relevant potential microglia-based interventions stroke therapy.

Language: Английский

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The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: June 20, 2022

The immune response to ischemic stroke is an area of study that at the forefront research and presents promising new avenues for treatment development. Upon cerebral vessel occlusion, innate system activated by danger-associated molecular signals from stressed dying neurons. Microglia, cell population within central nervous which phagocytose debris modulate via cytokine signaling, are first become activated. Soon after, monocytes arrive peripheral system, differentiate into macrophages, further aid in response. activation, both microglia monocyte-derived macrophages capable polarizing phenotypes can either promote or attenuate inflammatory Phenotypes hypothesized increase neuronal damage impair recovery function during later phases stroke. Therefore, modulating neuroimmune cells adopt anti-inflammatory post current interest potential In this review, we outline biology explain their roles acute, subacute, chronic stages stroke, highlight development efforts target these context

Language: Английский

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An RNA-sequencing transcriptome of the rodent Schwann cell response to peripheral nerve injury

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: April 30, 2022

The important contribution of glia to mechanisms injury and repair the nervous system is increasingly recognized. In stark contrast central (CNS), peripheral (PNS) has a remarkable capacity for regeneration after injury. Schwann cells are recognized as key contributors PNS regeneration, but molecular underpinnings cell response how they interact with inflammatory remain incompletely understood.We completed bulk RNA-sequencing purified acutely using immunopanning from naïve injured rodent sciatic nerve at 3, 5, 7 days post-injury. We used qRT-PCR in situ hybridization assess purity probe dataset integrity. Finally, we bioinformatic analysis cell-specific injury-induced modulation cellular pathways.Our data confirm validate RNAseq Bioinformatic identifies discrete modules genes that follow distinct patterns regulation 1st their corresponding pathways. These findings enable improved differentiation myeloid glial components neuroinflammation highlight novel aspects such acute downregulation AGE/RAGE pathway secreted molecules Sparcl1 Sema5a.We provide helpful resource further deciphering depth transcriptional can complement recent single sequencing approaches. As more become available on CNS injury, anticipate this will valuable platform understanding differences responses designing approaches ameliorate regeneration.

Language: Английский

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