Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.

Stroke is a cerebrovascular disease that is the main cause of death and disability worldwide. Hypoxia is a major factor that causes neuronal damage and even cellular death. However, the mechanism and therapeutic drugs for hypoxia are not completely understood.

In this study, PC12 cells (a rat adrenal pheochromocytoma cell line) were exposed to Cobalt chloride (CoCl2) to induce hypoxia. Using this cell model, the impacts of hypoxia on cell viability, proliferation, reactive oxygen species (ROS), and the levels of lysine β-hydroxybutyrylation (Kbhb) and the inflammatory signaling factor P65 were examined. In addition, we explored the ability of resveratrol (RES) to alleviate CoCl2-induced hypoxia damage.

RES attenuated CoCl2-induced decreases of cell viability and cell proliferation and increase of ROS production in PC12 cells. CoCl2 downregulated Kbhb in PC12 cells, but RES alleviated this effect. In addition, upregulated Kbhb by 3-hydroxybutyric acid sodium could partially recover the CoCl2-induced hypoxia damage to PC12 cells, including cell viability, cell proliferation, oxidative stress, and the protein level of the inflammatory signaling factor P65.

Our results indicate that RES protects against CoCl2-induced hypoxia damage in PC12 cells by modulating Kbhb, a novel post-translational modification.

The stress hyperglycemia ratio (SHR), originally proposed in 2015 by Robert et al., is more significantly relevant and predictive of critical illness than absolute hyperglycemia. Several studies have validated the association between stress hyperglycemia ratio and cerebrovascular disease. However, the value of stress hyperglycemia ratio for severe stroke patients admitted to the ICU remains uncertain. The aim of this study was to investigate the relationship between stress hyperglycemia ratio and clinical short- and long-term prognosis of critically ill patients with acute ischemic stroke (AIS).

Clinical data from 893 critically ill patients with ischemic stroke (IS) were extracted from the Medical Information Marketplace for Intensive Care (MIMIC-IV) database and 793 critically ill IS patients with 1 year of follow-up. The SHR is expressed by the formula: SHR = [(admission glucose (mg/dl)) / (28.7 × HbA1c (%) - 46.7)]. The study population was categorized into quartiles based on SHR level. Outcomes included ICU mortality, hospital mortality, and 1-year mortality. Cox proportional risk regression analysis and restricted cubic spline curves were used to elucidate the association between SHR and clinical prognosis in critically ill patients with AIS.

There were 69 ICU deaths and 100 in-hospital deaths in cohort 1, and 229 patients experienced all-cause mortality during the 1-year follow-up in cohort 2. Multivariate Cox proportional risk analysis showed that elevated SHR was significantly associated with an increased risk of hospital and 1-year all-cause mortality. After adjusting for confounders, patients with elevated SHR were significantly associated with hospital mortality (adjusted risk ratio, 1.870; 95 % confidence interval, 1.180-2.962; P = 0.008) and 1-year mortality (adjusted risk ratio, 2.325; 95 % confidence, 1.729-3.127; P < 0.001). Restricted cubic spline bars showed that a progressively increasing risk of all-cause mortality was associated with an elevated SHR.

Stress hyperglycemia ratios were significantly associated with in-hospital and 1-year all-cause mortality in critically ill IS patients. Moreover, we found that non-diabetic and prediabetic patients showed an increased risk of all-cause mortality. It is suggested that SHR may be useful in identifying ischemic stroke patients at high risk of all-cause mortality and providing personalized interventions as early as possible.

Ischemic stroke is a debilitating condition characterized by high morbidity, disability, recurrence, and mortality rates on a global scale, posing a significant threat to public health and economic stability. Extensive research has thoroughly explored the molecular mechanisms underlying ischemic stroke, elucidating a strong association between soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor proteins (SNAREs) and the pathogenesis of this condition. SNAREs, a class of highly conserved proteins involved in membrane fusion, play a crucial role in modulating neuronal information transmission and promoting myelin formation in the central nervous system (CNS). Preventing the SNARE complex formation, malfunctions in SNARE-dependent exocytosis, and altered regulation of SNARE-mediated vesicle fusion are linked to excitotoxicity, endoplasmic reticulum (ER) stress, and programmed cell death (PCD) in ischemic stroke. However, its underlying mechanisms remain unclear. This study conducts a comprehensive review of the existing literature on SNARE proteins, encompassing the structure, classification, and expression of the SNARE protein family, as well as the assembly - disassembly cycle of SNARE complexes and their physiological roles in the CNS. We thoroughly examine the mechanisms by which SNAREs contribute to the pathological progression and associated risk factors of ischemic stroke (hypertension, hyperglycemia, dyslipidemia, and atherosclerosis). Furthermore, our findings highlight the promise of SNAREs as a viable target for pharmacological interventions in the treatment of ischemic stroke.

ApTOLL, a promising therapeutic agent, has demonstrated effectiveness in mitigating stroke-induced neurological damage in clinical settings. Despite this, the detailed molecular mechanisms by which ApTOLL impacts ischemic stroke remain inadequately understood. In the present study, we explored how ApTOLL modulates downstream microRNAs (miRNAs) to alleviate brain damage and cognitive dysfunction associated with ischemic stroke. We established a rat model of ischemic stroke. Administration of ApTOLL upregulated miR-335-5p and suppressed IRAK1 expression in the ischemic brain. ApTOLL treatment significantly reduced infarct size, diminished neuronal apoptosis, and attenuated pathological damage in the brain. Additionally, ApTOLL led to the inhibition of inflammation and oxidative damage while enhancing autophagy. Similar effects were observed when miR-335-5p was overexpressed or IRAK1 was knocked down. Conversely, the beneficial impacts of ApTOLL were negated by miR-335-5p antagomir or IRAK1 overexpression, suggesting that ApTOLL's neuroprotective effects are mediated by the miR-335-5p/IRAK1 pathway. Mechanistically, ApTOLL exerted its protective role by promoting the expression of miR-335-5p, thereby reducing IRAK1 levels, leading to amelioration of ischemic brain damage. ApTOLL effectively mitigates ischemic stroke-induced neuronal damage by modulating the miR-335-5p/IRAK1 axis. These findings reveal a novel mechanistic pathway for ApTOLL's therapeutic effects and highlight its potential as a promising treatment strategy for ischemic stroke.

Stroke, a leading cause of disability and mortality globally, often cooccurs with depression or poststroke depression (PSD). The intricate interplay between mitochondrial metabolism and immune-related inflammation in depression and stroke remains a pivotal yet unresolved area. This study harnessed bioinformatics to elucidate the distinct contributions of mitochondrial metabolism and the immune microenvironment, as well as their complex interactions, to the pathogenesis of depression and stroke. By analyzing gene expression profiles from depression and stroke datasets alongside mitochondrial gene data, differentially expressed genes (DEGs) were meticulously identified, with a particular focus on mitochondria-related DEGs (MitoDEGs). Comprehensive functional investigations of common DEGs were conducted through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A robust protein-protein interaction (PPI) network was constructed, pinpointing ten hub-MitoDEGs intricately linked to depression and stroke. Furthermore, leveraging single-cell RNA sequencing analysis has shed light on gene expression across a myriad of cell types. Notably, these findings demonstrated immune cell dysregulation, revealing significant alterations in neutrophil and CD8+ T-cell infiltration within both the depression and stroke contexts. Correlation analyses revealed profound associations of the hub-MitoDEGs with mitochondrial metabolism, immune-related genes, and immunocytes. Importantly, this study also delineated ten potential drugs that target key genes implicated in depression and stroke, identifying promising avenues for innovative therapeutic interventions in these debilitating disorders.

Disulfidptosis is a pathologic process that occurs under conditions of NADPH deficiency and excess disulfide bonds in cells that express high levels of SLC7A11. This process is caused by glucose deprivation-induced disulfide stress and was first described by cancer researchers. Oxidative stress is a hypothesized mechanism underlying diseases of the central nervous system (CNS), and disulfide stress is a specific type of oxidative stress. Proteins linked to disulfidptosis and metabolic pathways involved in disulfidptosis are significantly associated with diseases of the CNS (neurodegenerative disease, neurogliomas and ischemic stroke). However, the specific mechanism responsible for this correlation remains unknown. This review provides a comprehensive overview of the current knowledge regarding the origin elements, genetic factors, and signaling proteins involved in the pathogenesis of disulfidptosis. It demonstrates that the disruption of thiometabolism and disulfide stress play critical roles in CNS diseases, which are associated with the potential role of disulfidptosis. We also summarize disulfidptosis-related drugs and highlight potential therapeutic strategies for treating CNS diseases. Additionally, this paper suggests a testable hypothesis that might be a promising target for treating CNS diseases.

More than 50 ​% of patients undergoing mechanical thrombectomy (MT) for ischemic stroke have a poor functional outcome despite timely and successful angiographic reperfusion, highlighting the need for adjunctive treatments to reperfusion therapy. Mitochondria are key regulators of cell fate, by controlling cell bioenergetics via oxidative phosphorylation (OXPHOS) and cell death through the mitochondrial permeability transition pore (mPTP). Whether these two main mitochondrial functions are altered by reperfusion and could represent a new cytoprotective approach remains to be elucidated in mice. Swiss male mice underwent either permanent or transient middle cerebral artery occlusion (pMCAO or tMCAO), with neuroscore evaluation and multimodal imaging. The area at risk of necrosis was evaluated by per-occlusion dynamic contrast-enhanced ultrasound. Final infarct size was assessed at day 1 by MRI. Cortical mitochondrial isolation was subsequently performed to assess mPTP sensitivity by calcium retention capacity (CRC) and OXPHOS. A cytoprotective treatment targeting mitochondria, ciclosporine A (CsA), was tested in tMCAO, to mimick the clinical situation of patients treated with MT. Reperfusion after 60 ​min of ischemia improves neuroscores but does not significantly reduce infarct size or mitochondrial dysfunction compared to permanent ischemia. CsA treatment at reperfusion mitigates stroke outcome, decreases final infarct size and improves mitochondrial CRC and OXPHOS. Mitochondrial dysfunctions, i.e. reduced mPTP sensitivity and decreased oxygen consumption rates, were observed in pMCAO and tMCAO regardless of the reperfusion status. CsA improved mitochondrial functions when injected at reperfusion. These suggest that both mPTP opening and OXPHOS alterations are thus early but reversible hallmarks of cerebral ischemia/reperfusion.

Stroke is a leading cause of death and disability globally, particularly in China. Identifying risk factors for stroke at an early stage is critical to improving patient outcomes and reducing the overall disease burden. However, the complexity of stroke risk factors requires advanced approaches for accurate prediction. The objective of this study is to identify key risk factors for stroke and develop a predictive model using machine learning techniques to enhance early detection and improve clinical decision-making. Data from the China Health and Retirement Longitudinal Study (2011-2020) were analyzed, classifying participants based on baseline characteristics. We evaluated correlations among 12 chronic diseases and applied machine learning algorithms to identify stroke-associated parameters. A dose-response relationship between these parameters and stroke was assessed using restricted cubic splines with Cox proportional hazards models. A refined predictive model, incorporating age, sex, and key risk factors, was developed. Stroke patients were significantly older (average age 69.03 years) and had a higher proportion of women (53%) compared to non-stroke individuals. Additionally, stroke patients were more likely to reside in rural areas, be unmarried, smoke, and suffer from various diseases. While the 12 chronic diseases were correlated (p < 0.05), the correlation coefficients were generally weak (r < 0.5). Machine learning identified nine parameters significantly associated with stroke risk: TyG-WC, WHtR, TyG-BMI, TyG, TMO, CysC, CREA, SBP, and HDL-C. Of these, TyG-WC, WHtR, TyG-BMI, TyG, CysC, CREA, and SBP exhibited a positive dose-response relationship with stroke risk. In contrast, TMO and HDL-C were associated with reduced stroke risk. In the fully adjusted model, elevated CysC (HR = 2.606, 95% CI 1.869-3.635), CREA (HR = 1.819, 95% CI 1.240-2.668), and SBP (HR = 1.008, 95% CI 1.003-1.012) were significantly associated with increased stroke risk, while higher HDL-C (HR = 0.989, 95% CI 0.984-0.995) and TMO (HR = 0.99995, 95% CI 0.99994-0.99997) were protective. A nomogram model incorporating age, sex, and the identified parameters demonstrated superior predictive accuracy, with a significantly higher Harrell's C-index compared to individual predictors. This study identifies several significant stroke risk factors and presents a predictive model that can enhance early detection of high-risk individuals. Among them, CREA, CysC, SBP, TyG-BMI, TyG, TyG-WC, and WHtR were positively associated with stroke risk, whereas TMO and HDL-C were opposite. This serves as a valuable decision-support resource for clinicians, facilitating more effective prevention and treatment strategies, ultimately improving patient outcomes.

Mitochondria, as the energy factories of cells, are involved in a wide range of vital activities, including cell differentiation, signal transduction, the cell cycle, and apoptosis, while also regulating cell growth. However, current pharmacological treatments for stroke are challenged by issues such as drug resistance and side effects, necessitating the exploration of new therapeutic strategies.

This review aims to summarize the regulatory effects of natural compounds targeting mitochondria on neuronal mitochondrial function and metabolism, providing new perspectives for stroke treatment.

Numerous in vitro and in vivo studies have shown that natural products such as berberine, ginsenosides, and baicalein protect neuronal mitochondrial function and reduce stroke-induced damage through multiple mechanisms. These compounds reduce neuronal apoptosis by modulating the expression of mitochondrial-associated apoptotic proteins. They inhibit the activation of the mitochondrial permeability transition pore (mPTP), thereby decreasing ROS production and cytochrome C release, which helps preserve mitochondrial function. Additionally, they regulate ferroptosis, mitochondrial fission, and promote mitochondrial autophagy and trafficking, further enhancing neuronal protection.

As multi-target chemical agents, natural products offer high efficacy with fewer side effects and present promising potential for innovative stroke therapies. Future research should further investigate the effectiveness and safety of these natural products in clinical applications, advancing their development as a new therapeutic strategy for stroke.

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.

Existing evidence indicates that exercise training can enhance neural function by regulating mitochondrial quality control (MQC), which can be impaired by cerebral ischemia, and that sirtuin-3 (SIRT3), a protein localized in mitochondria, is crucial in maintaining mitochondrial functions. However, the relationship among exercise training, SIRT3, and MQC after cerebral ischemia remains obscure. This study attempted to elucidate the relationship among exercise training, SIRT3 and MQC after cerebral ischemia in rats. Male adult SD rats received tMCAO after the transfection of adeno-associated virus encoding either sirtuin-3 (AAV-SIRT3) or SIRT3 knockdown (AAV-sh-SIRT3) into the ipsilateral striata and cortex. Subsequently, the animals were randomly selected for exercise training. The index changes were measured by transmission electron microscopy, Western blot analysis, nuclear magnetic resonance imaging, TUNEL staining, and immunofluorescence staining, etc. The results revealed that after cerebral ischemia, exercise training increased SIRT3 expression, significantly improved neural function, alleviated infarct volume and neuronal apoptosis, maintained the mitochondrial structural integrity, and re-established MQC. The latter promoted mitochondrial biogenesis, balanced mitochondrial fission/fusion, and enhanced mitophagy. These favorable benefits were reversed after SIRT3 interference. In addition, a cellular OGD/R model showed that the increased SIRT3 expression alleviates neuronal apoptosis and re-establishes mitochondrial quality control by activating the β-catenin pathway. These findings suggest that exercise training may optimize mitochondrial quality control by increasing the expression of SIRT3, thereby improving neural functions after cerebral ischemia, which illuminates the mechanism underlying the exercise training-conferred neural benefits and indicates SIRT3 as a therapeutic strategy for brain ischemia.

Mitochondria is a subcellular organelle involved in the pathogenesis of cellular stress, immune responses, differentiation, metabolic disorders, aging, and death by regulating process of fission, fusion, mitophagy, and transport. However, an increased interest in mitochondria as powerhouse for ATP production, the mechanisms of mitochondria-mediated cellular dysfunction in response to hormonal interaction remains unknown. Mitochondrial matrix contains chaperones and proteases that regulate intrinsic apoptosis pathway through pro-apoptotic Bcl-2 family's proteins Bax/Bak, and Cyt C release, and induces caspase-dependent and independent cells death. Energy and growth regulators such as thyroid hormones have profound effect on mitochondrial inner membrane protein and lipid compositions, ATP production by regulating oxidative phosphorylation system. Mitochondria contain cholesterol side-chain cleavage enzyme, P450scc, ferredoxin, and ferredoxin reductase providing an essential site for steroid hormones biosynthesis. In line with this, neurohormones such as oxytocin, vasopressin, and melatonin are correlated with mitochondrial integrity, displaying therapeutic implications for inflammatory and immune responses. Melatonin's also displayed protective role against oxidative stress and mitochondrial synthesis of ROS, suggesting a defense mechanism against aging-related diseases. An imbalance in mitochondrial bioenergetics can cause neurodegenerative disorders, cardiovascular diseases, and cancers. Hormone-induced PGC-1α stimulates mitochondrial biogenesis via activation of NRF1 and NRF2, which in turn triggers mtTFA in brown adipose and cardiac myocytes. Mitochondria can be transferred through cells merging, exosome-mediated transfer, and tunneling through nanotubes. By delineating the underlying molecular mechanism of hormonal mitochondrial interaction, this study reviews the dynamics mechanisms of mitochondria and its effects on cellular level, health, diseases, and therapeutic strategies targeting mitochondrial diseases.

Glutathione peroxidase-1 (GPx1) and cAMP/Ca2+ responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics.

Myelin damage is frequently associated with central nervous system (CNS) diseases and is a critical factor influencing neurological function and disease prognosis. Nevertheless, the majority of current treatments for the CNS concentrate on gray matter injury and repair strategies, while clinical interventions specifically targeting myelin repair remain unavailable. In recent years, natural products and herbal medicine have achieved considerable progress in the domain of myelin repair, given their remarkable curative effect and low toxic side effects, demonstrating significant therapeutic potential. In this review, we present a rather comprehensive account of the mechanisms underlying myelin formation, injury, and repair, with a particular emphasis on the interactions between oligodendrocytes and other glial cells. Furthermore, we summarize the natural products and herbal medicine currently employed in remyelination along with their mechanisms of action, highlighting the potential and challenges of certain natural compounds to enhance myelin repair. This review aims to facilitate the expedited development of innovative therapeutics derived from natural products and herbal medicine and furnish novel insights into myelin repair in the CNS.

Ischemic stroke is a high-mortality disease that urgently requires new therapeutic strategies. Insufficient cerebral blood supply can induce poly (ADP-ribose) polymerase (PARP) activation and mitochondrial dysfunction, leading to tissue damage and motor dysfunction. We demonstrate that the expression of TCDD inducible PARP (TIPARP) is elevated in ischemic stroke patients and mice. Knockdown of Tiparp reduces brain infarction and promotes recovery of motor function in ischemic stroke mice. A rationally designed TIPARP inhibitor, XG-04-B1, promotes repair of brain injury and recovery of motor function in ischemic stroke mice. Mechanistically, XG-04-B1 increases neuronal plasticity and inhibits astrocyte activation in ischemic stroke mice. In addition, eukaryotic translation initiation factor 3 subunit B (EIF3B) is a direct target of TIPARP. TIPARP interacts with EIF3B through nucleoplasmic redistribution, leading to mitochondrial dysfunction. Knockdown of Tiparp and inhibition of TIPARP via XG-04-B1 restore mitochondrial homeostasis in ischemic stroke mice. Taken together, TIPARP activation contributes to mitochondrial dysfunction and subsequent brain injury, and is therefore a promising therapeutic target for stroke.

Mitochondria are dynamic organelles that continuously undergo fusion/fission to maintain normal cell physiological activities and energy metabolism. When mitochondrial dynamics is unbalanced, mitochondrial homeostasis is broken, thus damaging mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to lung tissue injury and pulmonary disease progression in a variety of disease models, including inflammatory responses, apoptosis, and barrier breakdown, and that the role of mitochondrial dynamics varies among pulmonary diseases. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in pulmonary diseases. In this review, we discuss the current evidence on the role of mitochondrial dynamics in pulmonary diseases, with a particular focus on its underlying mechanisms in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis (PF), pulmonary arterial hypertension (PAH), lung cancer and bronchopulmonary dysplasia (BPD), and outline effective drugs targeting mitochondrial dynamics-related proteins, highlighting the great potential of targeting mitochondrial dynamics in the treatment of pulmonary disease.

Development of functional recovery therapies is critical to reduce the global impact of stroke as the leading cause of long-term disability. Our previous studies found that acute-phase protein orosomucoid (ORM) could provide an up to 6 h therapeutic time window to reduce infarct volume in acute ischemic stroke by improving endothelial function. However, its role in neurons and functional recovery post-stroke remains largely unknown. Here, we showed that exogenous ORM administration with initial injection at 0.5 h (early) or 12 h (delayed) post-MCAO daily for consecutive 7 days significantly decreased infarct area, improved motor and cognitive functional recovery, and promoted mitochondrial biogenesis after MCAO. While neuron-specific knockout of ORM2, a dominant subtype of ORM in the brain, produced opposite effects which could be rescued by exogenous ORM. In vitro, exogenous ORM protected SH-SY5Y cells from OGD-induced damage and promoted mitochondrial biogenesis, while endogenous ORM2 deficiency worsened these processes. Mechanistically, inactivation of CCR5 or AMPK eliminated the protective effects of ORM on neuronal damage and mitochondrial biogenesis. Taken together, our findings demonstrate that ORM, mainly ORM2, is an endogenous regulator of neuronal mitochondrial biogenesis by activating CCR5/AMPK signaling pathway, and might act as a potential therapeutic target for the functional recovery post-stroke.

Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that occurs when blood supply is restored to ischemic brain tissue and is one of the leading causes of adult disability and mortality. Multiple pathological mechanisms are involved in the progression of CIRI, including neuronal oxidative stress and mitochondrial dysfunction. Isoliquiritigenin (ISL) has been preliminarily reported to have potential neuroprotective effects on rats subjected to cerebral ischemic insult. However, the protective mechanisms of ISL have not been elucidated. This study aims to further investigate the effects of ISL-mediated neuroprotection and elucidate the underlying molecular mechanism. The findings indicate that ISL treatment significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral infarction, neurological deficits, histopathological damage, and neuronal apoptosis in mice. In vitro, ISL effectively mitigated the reduction of cell viability, Na+-K+-ATPase, and MnSOD activities, as well as the degree of DNA damage induced by oxygen-glucose deprivation (OGD) injury in PC12 cells. Mechanistic studies revealed that administration of ISL evidently improved redox homeostasis and restored mitochondrial function via inhibiting oxidative stress injury and ameliorating mitochondrial biogenesis, mitochondrial fusion-fission balance, and mitophagy. Moreover, ISL facilitated the dissociation of Keap1/Nrf2, enhanced the nuclear transfer of Nrf2, and promoted the binding activity of Nrf2 with ARE. Finally, ISL obviously inhibited neuronal apoptosis by activating the Nrf2 pathway and ameliorating mitochondrial dysfunction in mice. Nevertheless, Nrf2 inhibitor brusatol reversed the mitochondrial protective properties and anti-apoptotic effects of ISL both in vivo and in vitro. Overall, our findings revealed that ISL exhibited a profound neuroprotective effect on mice following CIRI insult by reducing oxidative stress and ameliorating mitochondrial dysfunction, which was closely related to the activation of the Nrf2 pathway.

Brain damage caused by acute hypoxia is associated with the physiological activities of mitochondria. Although mitochondria being dynamically regulated, our comprehensive understanding of the response of specific brain cell types to acute hypoxia remains ambiguous. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial-based molecular chaperone, plays a role in controlling mitochondrial movements. Herein, we demonstrated that acute hypoxia significantly alters mitochondria morphology and functionality in both in vivo and in vitro brain injury experiments. Summary-data-based Mendelian Randomization (SMR) analyses revealed possible causative links between mitochondria-related genes and hypoxia injury. Advancing the protein-protein interaction network and molecular docking further elucidated the associations between TRAP1 and mitochondrial dynamics. Furthermore, it was shown that TRAP1 knockdown levels variably affected the expression of key mitochondrial dynamics proteins (DRP1, FIS1, and MFN1/2) in primary hippocampal neurons, astrocytes, and BV-2 cell, leading to changes in mitochondrial structure and function. Understanding the function of TRAP1 in altering mitochondrial physiological activity during hypoxia-induced acute brain injury could help serve as a potential therapeutic target to mitigate neurological damage.

Ischemic stroke is a brain injury caused by cerebral blood circulation disorders and is closely related to oxidative stress. Aldose reductase (AR) is a critical enzyme involved in oxidative stress. Autophagy has previously been found to play a key role in cerebral ischemia‒reperfusion injury. However, it is still unclear how autophagy molecules change after cerebral ischemia‒reperfusion injury in AR knockout mice (AR-/-). A transient middle cerebral artery occlusion (tMCAO) model was generated in AR-/- mice, and the neurological deficit scores of the mice were observed and recorded on Days 1, 3 and 5 after tMCAO. Neuronal damage in the ischemic penumbra was observed by TTC, HE, and Nissl staining. The expression of the autophagy-related molecules Beclin-1, LC3II/I, and P62 as well as that of molecules related to inflammation, oxidative stress, and neurological damage was detected by RT‒qPCR, western blotting, and immunofluorescence. Autophagosomes were observed using a transmission electron microscope. Cerebral ischemia‒reperfusion injury caused neurological deficits and ischemic infarction in tMCAO mice (P < 0.01). Beclin-1, Bcl2/Bax, SOD, GSH-px, P62, PSD95, and TOM20 levels decreased (P < 0.05), while IL-6, LC3II/I, and GFAP levels increased (P < 0.01) in the AR-/- tMCAO-1d group and the AR-/- tMCAO-3d group, compared to those in the sham group. Beclin-1, Bcl2/Bax, NOX4, GSH-px, P62, and PSD95 levels increased (P < 0.01), while IL-6, LC3II/I, and GFAP levels decreased (P < 0.01) in the AR-/- tMCAO-5d group compared to those in the AR-/- tMCAO-1d group. Autophagosome formation was observed in tMCAO mice. In summary, the changes in autophagy proteins in the brain tissue of the AR-/- mice after tMCAO were more obvious on Days 1 and 3 after tMCAO. The expression of Beclin-1 and P62 decreased, and the expression of LC3B increased after cerebral ischemia‒reperfusion injury in AR-/- mouse brain tissue.

LncRNA is a major factor in the occurrence and development of many diseases. However, its mechanism in cerebral ischemia/reperfusion injury (CIRI) is yet unknown. In this study, the transcriptional level and methylation modification level of LncRNAs before and after mechanical thrombectomy were compared by high-throughput sequencing. Venn diagram, Spearman correlation analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, TargetScan, and miRanda were used to analyze the experimental data. The results showed that four key LncRNAs changed at both transcription and methylation levels. Specifically, LncRNA FAR2, LINC02431, and AL357060.1 were downregulated and hypomethylated, while LncRNA FOXD2-AS1 was upregulated and hypomethylated. Moreover, positive regulation of angiogenesis, protein domain-specific binding, autophagy pathway, PPAR signaling pathway, and MAPK signaling pathway were co-enriched between LncRNAs with different expression levels and different methylation levels. Finally, a LncRNA-miRNA-mRNA network was constructed. Therefore, this study explored the potential key LncRNAs and regulatory mechanisms of CIRI.

Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.

To identify the risk factors for pulmonary infection in acute ischemic stroke patients treated with intravenous thrombolysis using alteplase.

A retrospective analysis was conducted on 110 acute ischemic stroke patients who received intravenous alteplase thrombolysis between January 2019 and November 2022. The patients were categorized into a pulmonary infection group (40 cases) and a non-infection group (70 cases).

Multivariate logistic regression analysis identified the following independent risk factors for pulmonary infection: age, National Institutes of Health Stroke Scale (NIHSS) score at admission, underlying lung disease, hypertension, mechanical ventilation, aspiration, confusion, and elevated C-reactive protein (CRP) levels (all P<0.05). The sensitivity and specificity of CRP ifor predicting pulmonary infection were 88.57% and 75.00%, respectively. The NIHSS score demonstrated a sensitivity of 87.14% and a specificity of 70.00%. Further stratification of patients into a good prognosis group (75 cases) and a poor prognosis group (35 cases) revealed that high NIHSS scores at admission, increased fibrinogen (FIB) levels, a thrombolysis window exceeding 3 hours, and concurrent pulmonary infection were independent risk factors for poor prognosis. The area under the ROC curve for NIHSS in predicting prognosis was 0.890, and for FIB, it was 0.854 (P<0.001). The sensitivity and specificity of NIHSS for predicting poor prognosis were 89.33% and 82.86%, respectively, while for FIB, they were 84.00% and 82.86%.

These findings indicate that factors such as age, NIHSS score, underlying lung disease, hypertension, and elevated CRP levels significantly contribute to the risk of pulmonary infection in acute ischemic stroke patients. Clinicians should closely monitor these values to manage the risk of pulmonary infection effectively.

Low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytic/signaling cell-surface receptor that regulates diverse cellular functions, including cell survival, differentiation, and proliferation. LRP1 has been previously implicated in the pathogenesis of neurodegenerative disorders, but there are inconsistencies in its functions. Therefore, whether and how LRP1 maintains brain homeostasis remains to be clarified. Here, we report that astrocytic LRP1 promotes astrocyte-to-neuron mitochondria transfer by reducing lactate production and ADP-ribosylation factor 1 (ARF1) lactylation. In astrocytes, LRP1 suppressed glucose uptake, glycolysis, and lactate production, leading to reduced lactylation of ARF1. Suppression of astrocytic LRP1 reduced mitochondria transfer into damaged neurons and worsened ischemia-reperfusion injury in a mouse model of ischemic stroke. Furthermore, we examined lactate levels in human patients with stroke. Cerebrospinal fluid (CSF) lactate was elevated in stroke patients and inversely correlated with astrocytic mitochondria. These findings reveal a protective role of LRP1 in brain ischemic stroke by enabling mitochondria-mediated astrocyte-neuron crosstalk.

Oxidative stress is widely involved in the pathological process of ischemic stroke and ischemia-reperfusion. Several research have demonstrated that eliminating or reducing oxidative stress can alleviate the pathological changes of ischemic stroke. However, current clinical antioxidant treatment did not always perform as expected. This bibliometric research aims to identify research trends, topics, hotspots, and evolution on oxidative stress in the field of ischemic stroke, and to find potentially antioxidant strategies in future clinical treatment. Relevant publications were searched from the Web of Science (WOS) Core Collection databases (2001-2022). VOSviewer was used to visualize and analyze the development trends and hotspots. In the field of oxidative stress and ischemic stroke, the number of publications increased significantly from 2001 to 2022. China and the USA were the leading countries for publication output. The most prolific institutions were Stanford University. Journal of Cerebral Blood Flow and Metabolism and Stroke were the most cited journals. The research topics in this field include inflammation with oxidative stress, mitochondrial damage with oxidative stress, oxidative stress in reperfusion injury, oxidative stress in cognitive impairment and basic research and clinical translation of oxidative stress. Moreover, "NLRP3 inflammasome," "autophagy," "mitophagy," "miRNA," "ferroptosis," and "signaling pathway" are the emerging research hotspots in recent years. At present, multi-target regulation focusing on multi-mechanism crosstalk has progressed across this period, while challenges come from the transformation of basic research to clinical application. New detection technology and new nanomaterials are expected to integrate oxidative stress into the clinical treatment of ischemic stroke better.

Pre-clinical trials have demonstrated the neuroprotective effects of transplanted human neural stem cells (hNSCs) during the post-ischemic phase. However, the exact neuroprotective mechanism remains unclear. Tunneling nanotubes (TNTs) are long plasma membrane bridges that physically connect distant cells, enabling the intercellular transfer of mitochondria and contributing to post-ischemic repair processes. Whether hNSCs communicate through TNTs and their role in post-ischemic neuroprotection remains unknown. In this study, non-immortalized hNSC lines derived from fetal human brain tissues were examined to explore these possibilities and assess the post-ischemic neuroprotection potential of these hNSCs. Using Tau-STED super-resolution confocal microscopy, live cell time-lapse fluorescence microscopy, electron microscopy, and direct or non-contact homotypic co-cultures, we demonstrated that hNSCs generate nestin-positive TNTs in both 3D neurospheres and 2D cultures, through which they transfer functional mitochondria. Co-culturing hNSCs with differentiated SH-SY5Y (dSH-SY5Y) revealed heterotypic TNTs allowing mitochondrial transfer from hNSCs to dSH-SY5Y. To investigate the role of heterotypic TNTs in post-ischemic neuroprotection, dSH-SY5Y were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R) with or without hNSCs in direct or non-contact co-cultures. Compared to normoxia, OGD/R dSH-SY5Y became apoptotic with impaired electrical activity. When OGD/R dSH-SY5Y were co-cultured in direct contact with hNSCs, heterotypic TNTs enabled the transfer of functional mitochondria from hNSCs to OGD/R dSH-SY5Y, rescuing them from apoptosis and restoring the bioelectrical profile toward normoxic dSH-SY5Y. This complete neuroprotection did not occur in the non-contact co-culture. In summary, our data reveal the presence of a functional TNTs network containing nestin within hNSCs, demonstrate the involvement of TNTs in post-ischemic neuroprotection mediated by hNSCs, and highlight the strong efficacy of our hNSC lines in post-ischemic neuroprotection. Human neural stem cells (hNSCs) communicate with each other and rescue ischemic neurons through nestin-positive tunneling nanotubes (TNTs). A Functional mitochondria are exchanged via TNTs between hNSCs. B hNSCs transfer functional mitochondria to ischemic neurons through TNTs, rescuing neurons from ischemia/reperfusion ROS-dependent apoptosis.

Circadian rhythm is a master process observed in nearly every type of cell throughout the body, and it macroscopically regulates daily physiology. Recent clinical trials have revealed the effects of circadian variation on the incidence, pathophysiological processes, and prognosis of acute ischemic stroke. Furthermore, core clock genes, the cell-autonomous pacemakers of the circadian rhythm, affect the neurovascular unit-composing cells in a nonparallel manner after the same pathophysiological processes of ischemia/reperfusion. In this review, we discuss the influence of circadian rhythms and clock genes on each type of neurovascular unit cell in the pathophysiological processes of acute ischemic stroke.

Ischemic stroke is a significant global cause of death and disability. Currently, treatment options for acute ischemic stroke are limited to intravenous thrombolysis and mechanical recanalization. Therefore, novel neuroprotective strategies are imperative. Stem cell transplantation possesses the capabilities of differentiation, proliferation, neuronal replacement, nerve pathway reconstruction, secretion of nerve growth factors, and enhancement of the microenvironment; thus, it is a potential therapeutic approach for ischemic stroke. In addition, the immunomodulatory function of stem cells and the combined treatment of stem cells and exosomes exhibit a favorable protective effect on brain injury and neurological dysfunction following stroke. Meanwhile, the theory of microbiota-gut-brain axis provides us with a novel perspective for comprehending and managing neurological diseases. Lastly, stem cell transplantation has demonstrated promising outcomes not only in treating ischemic stroke but also in dealing with other neurological disorders, such as brain tumors. Furthermore, challenges related to the tissue source, delivery method, immune response, and timing of transplantation still need to be addressed to optimize the treatment.

Ischemic stroke presents a significant threat to human health due to its high disability rate and mortality. Currently, the clinical treatment drug, rt-PA, has a narrow therapeutic window and carries a high risk of bleeding. There is an urgent need to find new effective therapeutic drugs for ischemic stroke. Icariin (ICA), a key ingredient in the traditional Chinese medicine Epimedium, undergoes metabolism in vivo to produce Icaritin (ICT). While ICA has been reported to inhibit neuronal apoptosis after cerebral ischemia-reperfusion (I/R), yet its underlying mechanism remains unclear.

PC-12 cells were treated with 200 µM H2O2 for 8 h to establish a vitro model of oxidative damage. After administration of ICT, cell viability was detected by Thiazolyl blue tetrazolium Bromide (MTT) assay, reactive oxygen species (ROS) and apoptosis level, mPTP status and mitochondrial membrane potential (MMP) were detected by flow cytometry and immunofluorescence. Apoptosis and mitochondrial permeability transition pore (mPTP) related proteins were assessed by Western blotting. Middle cerebral artery occlusion (MCAO) model was used to establish I/R injury in vivo. After the treatment of ICA, the neurological function was scored by ZeaLonga socres; the infarct volume was observed by 2,3,5-Triphenyltetrazolium chloride (TTC) staining; HE and Nissl staining were used to detect the pathological state of the ischemic cortex; the expression changes of mPTP and apoptosis related proteins were detected by Western blotting.

In vitro: ICT effectively improved H2O2-induced oxidative injury through decreasing the ROS level, inhibiting mPTP opening and apoptosis. In addition, the protective effects of ICT were not enhanced when it was co-treated with mPTP inhibitor Cyclosporin A (CsA), but reversed when combined with mPTP activator Lonidamine (LND). In vivo: Rats after MCAO shown cortical infarct volume of 32-40%, severe neurological impairment, while mPTP opening and apoptosis were obviously increased. Those damage caused was improved by the administration of ICA and CsA.

ICA improves cerebral ischemia-reperfusion injury by inhibiting mPTP opening, making it a potential candidate drug for the treatment of ischemic stroke.

Cerebral infarction (CI) is characterized by a high prevalence, disability, and mortality. Timely or improper treatment greatly affects patient prognosis.

To explore the drug efficacy of aspirin plus edaravone and to explore their effect on quality of life (QOL), anxiety and depression in CI patients.

We retrospectively analyzed the records of 124 CI patients treated between June 2019 and February 2021 who were assigned to an observation group (OG) (combination therapy of aspirin and edaravone, 65 patients) or a control group (CG) (aspirin monotherapy, 59 patients). The therapeutic effects, pre- and posttreatment National Institutes of Health Stroke Scale (NIHSS) scores, activities of daily living, degree of cognitive impairment, protein levels of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and S-100B, occurrence of adverse reactions, and serum high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were evaluated, detected and compared between the two groups. Finally, posttreatment QOL, anxiety, and depression were assessed by the Medical Outcomes Study 36- Item Short Form Health Survey Scale, Self-rating Depression Scale (SDS), and Self-rating Anxiety Scale (SAS), respectively.

Compared with the CG, the OG had markedly better therapeutic effects, greater improvements in activities of daily living, and better alleviation in cognitive dysfunction after treatment, as well as lower posttreatment NIHSS scores and serum NSE, GFAP, S-100B, hs-CRP, IL-6, and TNF-α levels; the OG was similar to the CG in terms of adverse reactions but was better than the CG in terms of posttreatment QOL; and the OG also had lower SDS and SAS scores than the CG after treatment.

Aspirin plus edaravone had a good curative effect on CI. It can reverse cranial nerve damage in patients, improve neurological function and prognosis, and alleviate inflammation, anxiety, and depression; thus, it is considered safe and worthy of clinical application.

Post-stroke cognitive impairment (PSCI) remains the most common consequence of ischemic stroke. In this study, we aimed to investigate the role and mechanisms of melatonin (MT) in improving cognitive dysfunction in stroke mice. We used CoCl2-induced hypoxia-injured SH-SY5Y cells as a cellular model of stroke and photothrombotic-induced ischemic stroke mice as an animal model. We found that the stroke-induced upregulation of mitophagy, apoptosis, and neuronal synaptic plasticity was impaired both in vivo and in vitro. The results of the novel object recognition test and Y-maze showed significant cognitive deficits in the stroke mice, and Nissl staining showed a loss of neurons in the stroke mice. In contrast, MT inhibited excessive mitophagy both in vivo and in vitro and decreased the levels of mitophagy proteins PINK1 and Parkin, and immunofluorescence staining showed reduced co-localization of Tom20 and LC3. A significant inhibition of mitophagy levels could be directly observed under transmission electron microscopy. Furthermore, behavioral experiments and Nissl staining showed that MT ameliorated cognitive deficits and reduced neuronal loss in mice following a stroke. Our results demonstrated that MT inhibits excessive mitophagy and improves PSCI. These findings highlight the potential of MT as a preventive drug for PSCI, offering promising therapeutic implications.

Stroke is an acute cerebrovascular disease in which brain tissue is damaged due to sudden obstruction of blood flow to the brain or the rupture of blood vessels in the brain, which can prompt ischemic or hemorrhagic stroke. After stroke onset, ischemia, hypoxia, infiltration of blood components into the brain parenchyma, and lysed cell fragments, among other factors, invariably increase blood-brain barrier (BBB) permeability, the inflammatory response, and brain edema. These changes lead to neuronal cell death and synaptic dysfunction, the latter of which poses a significant challenge to stroke treatment.

Synaptic dysfunction occurs in various ways after stroke and includes the following: damage to neuronal structures, accumulation of pathologic proteins in the cell body, decreased fluidity and release of synaptic vesicles, disruption of mitochondrial transport in synapses, activation of synaptic phagocytosis by microglia/macrophages and astrocytes, and a reduction in synapse formation.

This review summarizes the cellular and molecular mechanisms related to synapses and the protective effects of drugs or compounds and rehabilitation therapy on synapses in stroke according to recent research. Such an exploration will help to elucidate the relationship between stroke and synaptic damage and provide new insights into protecting synapses and restoring neurologic function.

Vascular cognitive impairment (VCI) encompasses a range of cognitive deficits arising from vascular pathology. The pathophysiological mechanisms underlying VCI remain incompletely understood; however, chronic cerebral hypoperfusion (CCH) is widely acknowledged as a principal pathological contributor. Mitochondria, crucial for cellular energy production and intracellular signaling, can lead to numerous neurological impairments when dysfunctional. Recent evidence indicates that mitochondrial dysfunction-marked by oxidative stress, disturbed calcium homeostasis, compromised mitophagy, and anomalies in mitochondrial dynamics-plays a pivotal role in VCI pathogenesis. This review offers a detailed examination of the latest insights into mitochondrial dysfunction within the VCI context, focusing on both the origins and consequences of compromised mitochondrial health. It aims to lay a robust scientific groundwork for guiding the development and refinement of mitochondrial-targeted interventions for VCI.

Brain ischemia is one of the major causes of chronic disability and death worldwide. It is related to insufficient blood supply to cerebral tissue, which induces irreversible or reversible intracellular effects depending on the time and intensity of the ischemic event. Indeed, neuronal function may be restored in some conditions, such as transient ischemic attack (TIA), which may be responsible for protecting against a subsequent lethal ischemic insult. It is well known that the brain requires high levels of oxygen and glucose to ensure cellular metabolism and energy production and that damage caused by oxygen impairment is tightly related to the brain's low antioxidant capacity. Oxygen is a key player in mitochondrial oxidative phosphorylation (OXPHOS), during which reactive oxygen species (ROS) synthesis can occur as a physiological side-product of the process. Indeed, besides producing adenosine triphosphate (ATP) under normal physiological conditions, mitochondria are the primary source of ROS within the cell. This is because, in 0.2-2% of cases, the escape of electrons from complex I (NADPH-dehydrogenase) and III of the electron transport chain occurring in mitochondria during ATP synthesis leads to the production of the superoxide radical anion (O2•-), which exerts detrimental intracellular effects owing to its high molecular instability. Along with ROS, reactive nitrosative species (RNS) also contribute to the production of free radicals. When the accumulation of ROS and RNS occurs, it can cause membrane lipid peroxidation and DNA damage. Here, we describe the intracellular pathways activated in brain tissue after a lethal/sub lethal ischemic event like stroke or ischemic tolerance, respectively, highlighting the important role played by oxidative stress and mitochondrial dysfunction in the onset of the two different ischemic conditions.

Ischemic stroke has high mortality and morbidity rates and is the second leading cause of death in the world, but there is no definitive medicine. Seventy Flavors Pearl Pill (SFPP) is a classic formula in Tibetan Medicine. Clinical practice has shown the attenuation effect of SFPP on blood pressure disorders, strokes and their sequelae and other neurological symptoms, but its mechanism remains to be elucidated. In this study, we established three animal models in vivo and three cell models to evaluate the anti-hypoxia, anti-ischemia, and reperfusion injury prevention effects of SFPP. Quantitative proteomics revealed that oxidative phosphorylation (OXPHOS) is essential for SFPP's efficacy. Then, cysteine-activity based protein profiling technology, which reflects redox stress at the proteome level, was employed to illustrate that SFPP brought functional differences of critical proteins in OXPHOS. In addition, quantitative metabolomics revealed that SFPP affects whole energy metabolism with OXPHOS as the core. Finally, we performed a compositional identification of SFPP to initially explore the components of potential interventions in OXPHOS. These results provide new perspectives and tools to explore the mechanism of herbal medicine. The study suggests that OXPHOS could be a potential target for further research and intervention of ischemic stroke treatment.

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.