CD8 + CD103 + iTregs protect against ischemia-reperfusion-induced acute kidney Injury by inhibiting pyroptosis.

The occurrence of acute kidney injury (AKI) is elevated, one of the main causes is ischemia-reperfusion (I/R). However, no specific therapy is currently available to treat I/R-induced AKI (I/R-AKI). Treg cells have been demonstrated to perform an anti-inflammatory role in a range of autoimmune and inflammatory illnesses. However, there is limited available information about the possible functions of CD8 + CD103 + iTregs in I/R-AKI. We utilized renal tubular epithelial cells (RTECs) subjected to hypoxia-reoxygenation (H/R) and I/R-AKI mouse model to investigate whether CD8 + CD103 + iTregs could attenuate AKI and the underlying mechanism. In vitro, co-cultured with CD8 + CD103 + iTregs alleviated H/R-induced cell injury. After treatment of CD8 + CD103 + iTregs rather than control cells, a significant improvement of I/R-AKI was observed in vivo, including decreased serum creatinine (sCr) and blood urea nitrogen (BUN) levels, reduced renal pathological injury, lowered tubular apoptosis and inhibition of the transition from AKI to chronic kidney disease (CKD). Mechanically, CD8 + CD103 + iTregs alleviated H/R-induced cell injury and I/R-AKI partly by suppressing RTECs pyroptosis via inhibiting the NLRP3/Caspase-1 axis. Our study provides a novel perspective on the possibility of CD8 + CD103 + iTregs for the treatment of I/R-AKI.

Lactate contributes to remote ischemic preconditioning-mediated protection against myocardial ischemia reperfusion injury by facilitating autophagy via AMPK-mTOR-TFEB-CX43 axis.

Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 (MCT1) inhibitor and 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia reoxygenation (H/R) model, lactate markedly mitigated H/R-induced cell damage in H9c2 cells. Meanwhile, further studies suggested that lactate contributed to RIPC rescuing I/R-induced autophagy deficiency by promoting TFEB translocation to the nucleus through activating the AMPK-mTOR pathway without influencing the PI3K-Akt pathway, thus reducing cardiomyocytes damage. Interestingly, we also found that lactate upregulated the mRNA and protein expression of CX43 by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested lactate facilitated CX43-regulated autophagy via AMPK-mTOR-TFEB signaling pathway. Collectively, our research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via AMPK-mTOR-TFEB-CX43 axis.

Diagnosis and Molecular Characterization of Potential RNA Binding Protein Involved in the Pathogenesis of Liver Ischemia Reperfusion Injury.

Background: Liver ischemia-reperfusion is one of the common complications after liver surgery. Uncontrolled liver ischemia-reperfusion will lead to many serious consequences such as surgical failure. It is an urgent clinical problem to search for diagnostic markers and explore its potential pathogenesis. Methods: In this study, we focus on 1411 candidate RNA binding protein. Through several GEO (Gene Expression Omnibus) online datasets, we construct a diagnostic model and perform interactive validation. We evaluate the efficacy of the prognostic model. Using bioinformatics methods, we predicted the relevant signaling pathways of liver ischemia-reperfusion and key genes. We also evaluated the association of RNA binding protein with immune cell infiltration. Single cell sequencing datasets were used to explore the expression profiles of key genes at the single cell level. Machine learning algorithm is used to predict key gene RNA binding domains. Results: ROC (Receiver Operating Characteristic) and DCA (Decision Curve Analysis) curves showed that the above diagnostic model had good and stable diagnostic efficacy and clinical practicability. We identified three key genes (BTG2, CCNL1 and DNAJB1) in liver ischemia-reperfusion. DNAJB1, BTG2 and CCNL1 are mainly expressed in immune cells such as macrophages and T cells, and are closely related to inflammatory pathways such as TNF-α, highlighting their importance in hepatic ischemia reperfusion. We identified RNA-binding domains of the above three genes. We found that the expression of DNAJB1, CCNL1 and BTG2 in the ischemia-reperfusion group were significantly higher than those in the sham operation group. Conclusion: Our study revealed the importance of the candidate RNA binding protein in liver ischemia reperfusion injury and provided new insights into the therapeutic of hepatic ischemia-reperfusion injury.

Short-chain fatty acids regulate erastin-induced cardiomyocyte ferroptosis and ferroptosis-related genes.

Background: Ferroptosis has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury and can be inhibited or promoted by ATF3. Short-chain fatty acids (SCFAs) have shown benefits in various cardiovascular diseases with anti-inflammatory and antioxidant effects. However, the impact of SCFAs on ferroptosis in ischemic-stimulated cardiomyocytes remains unknown. This study aimed to investigate the effect of SCFAs on cardiomyocyte ferroptosis, the expression of ATF3, and its potential upstream regulators. Methods and results: The expression of ATF3, ferroptosis pathway geneset (FPG), and geneset of potential regulators for ATF3 (GPRA, predicted by the PROMO database) was explored in the public human myocardial infarction single-cell RNA-seq (sma) dataset. Cardiomyocyte data was extracted from the dataset and re-clustered to explore the FPG, ATF3, and GPRA expression patterns in cardiomyocyte subclusters. A dose-dependent toxic experiment was run to detect the suitable dose for SCFA treatment. The erastin-induced ferroptosis model and hypoxia-reoxygenation (H/R) model (10 h of hypoxia followed by 6 h of reoxygenation) were adopted to assess the effect of SCFAs via the CCK8 assay. Gene expression was examined via RT-PCR and western blot. Ferroptosis markers, including lipid peroxides and Fe2+, were detected using the liperfluo and ferroOrange probes, respectively. In the sma dataset, upregulated ferroptosis pathway genes were mainly found in the infarction-stimulated cardiac cells (border zone and fibrotic zone), particularly the cardiomyocytes and adipocytes. The ATF3 and some of its potential transcription factors (VDR, EGR3, PAX5, and SP1) can be regulated by SCFA. SCFA can attenuate erastin-induced lipid peroxidation in cardiomyocytes. SCFA treatment can also reverse erastin-induced Fe2+ increase but may strengthen the Fe2+ in the H/R model. We also precisely defined a ferroptosis subcluster of cardiomyocytes (CM09) that highly expressed FPG, ATF3, and GPRA. Conclusion: The ATF3 and the ferroptosis pathway are elevated in cardiomyocytes of injury-related cardiac regions (border zone, ischemic zone, and fibrotic zone). SCFA can attenuate cardiomyocyte ferroptosis and regulate the expression of ATF3. Our study offers novel insights into the potential targets of SCFAs in the cardiovascular system.

Targeting translocator protein protects against myocardial ischemia/reperfusion injury by alleviating mitochondrial dysfunction.

Ischemic heart disease (IHD) remains a leading cause of mortalities worldwide, necessitating timely reperfusion to reduce acute mortality. Paradoxically, reperfusion can induce myocardial ischemia/reperfusion (I/R) injury, which is primarily characterized by mitochondrial dysfunction. Translocator protein (TSPO) participates in multiple cellular events; however, its role in IHD, especially in the process of myocardial I/R injury, has not been well determined. The aim of the present study was to investigate the functional role of TSPO in myocardial I/R injury and dissect the concomitant cellular events involved. This study utilized small interfering RNA (siRNA) technology to knock down TSPO expression. The I/R process was simulated using an anoxia/reoxygenation (A/R) model. The role of TSPO in H9c2 cardiomyocytes was assessed using various techniques, such as Western blotting, Flow cytometry, Reverse transcription-quantitative PCR (RT-qPCR), Immunofluorescence, Co-immunoprecipitation (co-IP) and similar methods. It was found that A/R markedly upregulated the expression of TSPO in cardiomyocytes. Inhibition of TSPO improved myocardial cell apoptosis and damage following A/R stimulation. Additionally, targeting TSPO alleviated mitochondrial damage, reduced mitochondrial ROS release and enhanced ATP synthesis following A/R stimulation. It was further confirmed that A/R stimulation induced a significant increase in the expression of pivotal markers [phosporylated-PKR-like ER kinase (PERK)/PERK, activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1] involved in the adaptive unfolded protein response, which is accompanied by downstream signaling during endoplasmic reticulum (ER) stress. Notably, TSPO knockdown increased the expression of the aforementioned markers and, subsequently, TSPO was confirmed to interact with ATF6, suggesting that TSPO might play a role in ER stress during myocardial I/R injury. Finally, inhibition of TSPO upregulated mitophagy, as indicated by further decreases in P62 and increases in Parkin and PINK1 levels following A/R stimulation. Together, the results suggest that TSPO plays a multifaceted role in myocardial I/R injury. Understanding TSPO-induced cellular responses could inform targeted therapeutic strategies for patients with IHD.

Multi-parametric MRI-based machine learning model for prediction of pathological grade of renal injury in a rat kidney cold ischemia-reperfusion injury model.

BACKGROUND: Renal cold ischemia-reperfusion injury (CIRI), a pathological process during kidney transplantation, may result in delayed graft function and negatively impact graft survival and function. There is a lack of an accurate and non-invasive tool for evaluating the degree of CIRI. Multi-parametric MRI has been widely used to detect and evaluate kidney injury. The machine learning algorithms introduced the opportunity to combine biomarkers from different MRI metrics into a single classifier. OBJECTIVE: To evaluate the performance of multi-parametric magnetic resonance imaging for grading renal injury in a rat model of renal cold ischemia-reperfusion injury using a machine learning approach. METHODS: Eighty male SD rats were selected to establish a renal cold ischemia -reperfusion model, and all performed multiparametric MRI scans (DWI, IVIM, DKI, BOLD, T1mapping and ASL), followed by pathological analysis. A total of 25 parameters of renal cortex and medulla were analyzed as features. The pathology scores were divided into 3 groups using K-means clustering method. Lasso regression was applied for the initial selecting of features. The optimal features and the best techniques for pathological grading were obtained. Multiple classifiers were used to construct models to evaluate the predictive value for pathology grading. RESULTS: All rats were categorized into mild, moderate, and severe injury group according the pathologic scores. The 8 features that correlated better with the pathologic classification were medullary and cortical Dp, cortical T2*, cortical Fp, medullary T2*, ∆T1, cortical RBF, medullary T1. The accuracy(0.83, 0.850, 0.81, respectively) and AUC (0.95, 0.93, 0.90, respectively) for pathologic classification of the logistic regression, SVM, and RF are significantly higher than other classifiers. For the logistic model and combining logistic, RF and SVM model of different techniques for pathology grading, the stable and perform are both well. Based on logistic regression, IVIM has the highest AUC (0.93) for pathological grading, followed by BOLD(0.90). CONCLUSION: The multi-parametric MRI-based machine learning model could be valuable for noninvasive assessment of the degree of renal injury.

Selenium nanoparticles alleviate renal ischemia/reperfusion injury by inhibiting ferritinophagy via the XBP1/NCOA4 pathway.

Acute kidney injury (AKI) is closely related to lysosomal dysfunction and ferroptosis in renal tubular epithelial cells (TECs), for which effective treatments are urgently needed. Although selenium nanoparticles (SeNPs) have emerged as promising candidates for AKI therapy, their underlying mechanisms have not been fully elucidated. Here, we investigated the effect of SeNPs on hypoxia/reoxygenation (H/R)-induced ferroptosis and lysosomal dysfunction in TECs in vitro and evaluated their efficacy in a murine model of ischemia/reperfusion (I/R)-AKI. We observed that H/R-induced ferroptosis was accompanied by lysosomal Fe2+ accumulation and dysfunction in TECs, which was ameliorated by SeNPs administration. Furthermore, SeNPs protected C57BL/6 mice against I/R-induced inflammation and ferroptosis. Mechanistically, we found that lysosomal Fe2+ accumulation and ferroptosis were associated with the excessive activation of NCOA4-mediated ferritinophagy, a process mitigated by SeNPs through the upregulation of X-box binding protein 1 (XBP1). Downregulation of XBP1 promoted ferritinophagy and partially counteracted the protective effects of SeNPs on ferroptosis inhibition in TECs. Overall, our findings revealed a novel role for SeNPs in modulating ferritinophagy, thereby improving lysosomal function and attenuating ferroptosis of TECs in I/R-AKI. These results provide evidence for the potential application of SeNPs as therapeutic agents for the prevention and treatment of AKI.

S-Nitroso Human Serum Albumin Enhances Left Ventricle Hemodynamic Performance and Reduces Myocardial Damage after Local Ischemia-Reperfusion Injury.

Endothelial nitric oxide (NO) production is crucial in maintaining vascular homeostasis. However, in the context of ischemia-reperfusion (I/R) injury, uncoupled endothelial nitric oxide synthase (eNOS) can exacerbate reactive oxygen species (ROS) generation. Supplementation with S-nitroso human serum albumin (S-NO-HSA) offers a potential solution by mitigating eNOS uncoupling, thereby enhancing NO bioavailability. In a study conducted at the University of Verona, male rats underwent thoracotomy followed by 30 min left anterior descendant coronary (LAD) occlusion and subsequent reperfusion. Hemodynamic parameters were meticulously assessed using a conductance catheter inserted via the carotid artery. The rats were stratified into two main groups based on reperfusion duration and the timing of drug infusion, with the effects of S-NO-HSA evaluated after 2 or 24 h. Remarkably, intravenous administration of S-NO-HSA, initiated before or during ischemia, exhibited notable benefits. It significantly improved left ventricular function, safeguarded energetic substrates such as phosphocreatine and ATP, and sustained glutathione levels akin to basal conditions, indicative of diminished oxidative stress. The data from this study strongly suggest a protective role for S-NO-HSA in mitigating I/R injury induced by LAD artery occlusion, a phenomenon observed at both 2 and 24 h post-reperfusion. These findings underscore the promising therapeutic potential of NO supplementation in alleviating myocardial damage subsequent to ischemic insult.

Energy Metabolism and Metformin: Effects on Ischemia-Reperfusion Injury in Kidney Transplantation.

Metformin (MTF) is the only biguanide included in the World Health Organization's list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of interest for many trying to find alternative treatments for varied pathologies. Over time, an increasing body of evidence has shown additional roles of MTF, with unexpected interactions of benefit in other diseases. Metformin (MTF) holds significant promise in mitigating ischemia-reperfusion injury (IRI), particularly in the realm of organ transplantation. As acceptance criteria for organ transplants expand, IRI during the preservation phase remain a major concern within the transplant community, prompting a keen interest in MTF's effects. Emerging evidence suggests that administering MTF during reperfusion may activate the reperfusion injury salvage kinase (RISK) pathway. This pathway is pivotal in alleviating IRI in transplant recipients, potentially leading to improved outcomes such as reduced rates of organ rejection. This review aims to contextualize MTF historically, explore its current uses, pharmacokinetics, and pharmacodynamics, and link these aspects to the pathophysiology of IRI to illuminate its potential future role in transplantation. A comprehensive survey of the current literature highlights MTF's potential to recondition and protect against IRI by attenuating free radical damage, activating AMP-activated protein kinase to preserve cellular energy and promote repair, as well as directly reducing inflammation and enhancing microcirculation.

Therapeutic Potential of Hydrogen Sulfide in Ischemia and Reperfusion Injury.

Ischemia-reperfusion (I/R) injury, a prevalent pathological condition in medical practice, presents significant treatment challenges. Hydrogen sulfide (H2S), acknowledged as the third gas signaling molecule, profoundly impacts various physiological and pathophysiological processes. Extensive research has demonstrated that H2S can mitigate I/R damage across multiple organs and tissues. This review investigates the protective effects of H2S in preventing I/R damage in the heart, brain, liver, kidney, intestines, lungs, stomach, spinal cord, testes, eyes, and other tissues. H2S provides protection against I/R damage by alleviating inflammation and endoplasmic reticulum stress; inhibiting apoptosis, oxidative stress, and mitochondrial autophagy and dysfunction; and regulating microRNAs. Significant advancements in understanding the mechanisms by which H2S reduces I/R damage have led to the development and synthesis of H2S-releasing agents such as diallyl trisulfide-loaded mesoporous silica nanoparticles (DATS-MSN), AP39, zofenopril, and ATB-344, offering a new therapeutic avenue for I/R injury.

Role of Specificity Protein 1 (SP1) in Cardiovascular Diseases: Pathological Mechanisms and Therapeutic Potentials.

In mammals, specificity protein 1 (SP1) was the first Cys2-His2 zinc finger transcription factor to be isolated within the specificity protein and Krüppel-like factor (Sp/KLF) gene family. SP1 regulates gene expression by binding to Guanine-Cytosine (GC)-rich sequences on promoter regions of target genes, affecting various cellular processes. Additionally, the activity of SP1 is markedly influenced by posttranslational modifications, such as phosphorylation, acetylation, glycosylation, and proteolysis. SP1 is implicated in the regulation of apoptosis, cell hypertrophy, inflammation, oxidative stress, lipid metabolism, plaque stabilization, endothelial dysfunction, fibrosis, calcification, and other pathological processes. These processes impact the onset and progression of numerous cardiovascular disorders, including coronary heart disease, ischemia-reperfusion injury, cardiomyopathy, arrhythmia, and vascular disease. SP1 emerges as a potential target for the prevention and therapeutic intervention of cardiac ailments. In this review, we delve into the biological functions, pathophysiological mechanisms, and potential clinical implications of SP1 in cardiac pathology to offer valuable insights into the regulatory functions of SP1 in heart diseases and unveil novel avenues for the prevention and treatment of cardiovascular conditions.

Molecular Insight into Acute Limb Ischemia.

Acute limb ischemia (ALI) is defined as a sudden reduction in blood flow to a limb, resulting in cessation of blood flow and, therefore, cessation of the delivery of nutrients and oxygen to the tissues of the lower limb. Despite optimal treatment to restore blood flow to ischemic tissues, some patients may suffer from ischemia/reperfusion (I/R) syndrome, the most severe complication after a revascularization procedure used to restore blood flow. There are multiple molecular and cellular factors that are involved in each phase of ALI. This review focuses firstly on molecular and cellular factors of arterial thrombosis, highlighting the role of atherosclerotic plaques, smooth muscle cells (SMCs), and cytokine which may alter key components of the extracellular matrix (ECM). Then, molecular and cellular factors of arterial embolism will be discussed, highlighting the importance of thrombi composition. Molecular and cellular factors of ischemia/reperfusion syndrome are analyzed in depth, highlighting several important mechanisms related to tissue damage, such as inflammation, apoptosis, autophagy, necrosis, and necroptosis. Furthermore, local and general complications of ALI are discussed in the context of molecular alterations. Ultimately, the role of novel biomarkers and targeted therapies is discussed.

Ferritin Light Chain Alleviates Cerebral Ischemic-Reperfusion Injury-Induced Neuroinflammation via the HIF1α Mediated NF-κB Signaling Pathways.

Ferritin light chain (FtL) is a complex formed by apoferritin and iron core and is one of the main storage forms of iron. Currently, the precise role of FtL in cerebral ischemia/reperfusion injury (CIRI) remains undetermined. This investigation aimed to elucidate the roles and underlying mechanisms of FtL in CIRI. To induce CIRI, an oxygen-glucose deprivation (OGD) model in microglia and middle cerebral artery occlusion (MCAO) model were established using C57BL/6 J mice. The in vivo and in vitro FtL expression patterns were assessed. Furthermore, the potential regulatory mechanism of FtL at the upstream level was also explored. In addition, the in vivo and in vitro role of FtL in post-ischemic inflammation was also clarified. The results indicated that FtL was up-regulated in OGD-induced microglia and CIRI mice. Moreover, OGD activated HIF1α, which interacted with the FtL promoter region as an activator, thereby increasing FtL expression. Furthermore, FtL attenuated the release of pro-inflammatory cytokines (TNFα, IL6) and decreased levels of COX2 and iNOS in microglia; however, FtL knockdown had the opposite effects. Up-regulated FtL was observed to inhibit OGD-induced NF-κB activation in microglia, decreased IκBα degradation, and reduced NF-κB/p65 nuclear translocation. In summary, this study revealed an underlying mechanism of FtL upregulation via HIF1α and highlighted its protective role against post-ischemic neuroinflammation, indicating the potential of FtL as a target for CIRI treatment.

The natural compound sinometumine E derived from Corydalis decumbens promotes angiogenesis by regulating HIF-1/ VEGF pathway in vivo and in vitro.

The rhizome of Corydalis decumbens is a traditional Chinese medicine commonly utilized in the clinical treatment of acute ischemic stroke. Numerous phytochemical and biological investigations have demonstrated that protoberberine alkaloids from C. decumbens exhibit diverse pharmaceutical activities against various diseases. Sinometumine E (SE), a protoberberine alkaloid isolated from C. decumbens for the first time, is characterized by a complex 6/6/6/6/6/6 hexacyclic skeleton. In the current study, we investigated the protective effects of SE on endothelial cell injury and its angiogenesis effects in zebrafish. The results suggested that SE showed significant anti-ischemic effects on OGD/R-induced HBEC-5i and HUVECs cell ischemia/reperfusion injury model. Furthermore, it promoted angiogenesis in PTK787-induced, MPTP-induced, and atorvastatin-induced vessel injury models of zebrafish, while also suppressing hypoxia-induced locomotor impairment in zebrafish. Transcriptome sequencing analysis provided a sign that SE likely to promotes angiogenesis through the HIF-1/VEGF signaling pathway to exert anti-ischemic effects. Consistently, SE modulated several genes related to HIF-1/VEGF signal pathway, such as hif-1, vegf, vegfr-2, pi3k, erk, akt and plcγ. Molecular docking analysis revealed that VEGFR-2 exhibited high binding affinity with SE, and western blot analysis confirmed that SE treatment enhanced the expression of VEGFR-2. In conclusion, our study profiled the angiogenic activities of SE in vitro and in vivo. The key targets and related pathways involved in anti-ischemic effects of SE, shedding light on the pharmacodynamic components and mechanisms of Corydalis decumbens, and provides valuable insights for identifying effective substances for the treatment of ischemic stroke.

Irisin preserves mitochondrial integrity and function in tubular epithelial cells after ischemia-reperfusion-induced acute kidney injury.

AIMS: A myokine secreted by skeletal muscles during exercise called irisin mitigates ischemia-reperfusion (I/R) injury in epithelial cells of various organs by limiting damage to mitochondria. We test whether irisin may preserve the mitochondrial integrity and function in renal tubular epithelial cells and protect against ischemia-reperfusion-induced acute kidney injury (AKI). METHODS: We correlated serum irisin levels with serum creatinine and BUN levels from both AKI patients and healthy individuals. In mice with irisin administration, various renal injury markers such as serum creatinine, BUN, kidney injury molecule-1 (Kim-1), and neutrophil gelatinase-associated lipocalin (NGAL), and renal histopathology were assessed after I/R. To identify the potential mechanisms of the protective of irisin's protective effect, we perfused proximal tubules under confocal microscopy and analyzed kidney tissues by qPCR, western blot, and immunohistochemistry. RESULTS: Serum irisin correlated inversely with serum creatinine and BUN levels were significantly lower in AKI patients than in healthy subjects. Administering irisin to mice after I/R decreased biomarker levels for AKI including serum creatinine, BUN, Kim-1, NAGL and lessened histological changes. In kidney tissues of mice, irisin upregulated the mitochondrial autophagy marker protein microtubule-associated protein 1 light chain 3 (LC3), the mitochondrial autophagy pathway-related proteins PTEN-induced putative kinase 1 (PINK1) and Parkinson's disease 2 parkin (PARK2) and downregulated the reactive substrate protein sequestosome 1 (P62) and mitochondrial membrane proteins translocase of outer mitochondrial membrane 20 (TOM20) and translocase of inner mitochondrial membrane 23 (TIM23). CONCLUSION: Irisin protects against renal I/R injury, which may involve the preservation of mitochondrial integrity and function.

Mxene-bpV plays a neuroprotective role in cerebral ischemia-reperfusion injury by activating the Akt and promoting the M2 microglial polarization signaling pathways.

Studies have shown that the inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN)was neuroprotective against ischemia/reperfusion(I/R) injury. Bisperoxovanadium (bpV), a derivative of vanadate, is a well-established inhibitor of PTEN. However, its function islimited due to its general inadequacy in penetrating cell membranes. Mxene(Ti3C2Tx) is a novel two-dimensional lamellar nanomaterial with an excellent ability to penetrate the cell membrane. Yet, the effects of this nanomaterial on nervous system diseases have yet to be scrutinized. Here, Mxene(Ti3C2Tx) was used for the first time to carry bpV(HOpic), creating a new nanocomposite Mxene-bpV that was probed in a cerebral I/R injury model. The findings showed that this synthetic Mxene-bpV was adequately stable and can cross the cell membraneeasily. We observed that Mxene-bpV treatment significantly increased the survival rate of oxygen glucose deprivation/reperfusion(OGD/R)--insulted neurons, reduced infarct sizes and promoted the recovery of brain function after mice cerebral I/R injury. Crucially, Mxene-bpV treatment was more therapeutically efficient than bpV(HOpic) treatment alone over the same period. Mechanistically, Mxene-bpV inhibited the enzyme activity of PTEN in vitro and in vivo. It also promoted the expression of phospho-Akt (Ser473) by repressing PTEN and then activated the Akt pathway to boost cell survival. Additionally, in PTEN transgenic mice, Mxene-bpV suppressed I/R-induced inflammatory response by promoting M2 microglial polarization through PTEN inhibition. Collectively, the nanosynthetic Mxene-bpV inhibited PTEN' enzymatic activity by activating Akt pathway and promoting M2 microglial polarization, and finally exerted neuroprotection against cerebral I/R injury.

Time-Restricted Feeding Protects against Renal Ischemia-Reperfusion Injury in Mice.

Ischemia-reperfusion injury (IRI) in the kidneys is a major cause of acute kidney injury (AKI). Time-restricted feeding (TRF), known for its metabolic health benefits and alleviation of various chronic diseases without calorie restriction, was investigated for its potential protective effects against IRI-induced AKI. Male C57BL/6 mice underwent unilateral IRI, with their kidneys collected after two days. For two weeks before IRI induction, the TRF group had unlimited access to standard chow but within an 8-hour feeding window during the dark cycle. The study groups were Control, TRF, IRI, and TRF + IRI. In the TRF + IRI group, tubular damage scores significantly decreased compared to the IRI group. Furthermore, the TRF + IRI mice had lower levels of phosphorylated NF-κB and fewer F4/80-positive macrophages than the IRI group. Oxidative stress markers for lipids and proteins were also notably lower in the TRF + IRI group. Additionally, TUNEL-positive tubular cells and cleaved caspase-3 expression were reduced in the TRF + IRI group. Without calorie restriction, TRF mitigated renal damage by reducing inflammation, oxidative stress, and tubular apoptosis in renal IRI. This suggests that TRF could be a promising dietary strategy to prevent IRI-induced AKI.

The Protective Role of Molecular Hydrogen in Ischemia/Reperfusion Injury.

Ischemia/reperfusion injury (IRI) represents a significant contributor to morbidity and mortality associated with various clinical conditions, including acute coronary syndrome, stroke, and organ transplantation. During ischemia, a profound hypoxic insult develops, resulting in cellular dysfunction and tissue damage. Paradoxically, reperfusion can exacerbate this injury through the generation of reactive oxygen species and the induction of inflammatory cascades. The extensive clinical sequelae of IRI necessitate the development of therapeutic strategies to mitigate its deleterious effects. This has become a cornerstone of ongoing research efforts in both basic and translational science. This review examines the use of molecular hydrogen for IRI in different organs and explores the underlying mechanisms of its action. Molecular hydrogen is a selective antioxidant with anti-inflammatory, cytoprotective, and signal-modulatory properties. It has been shown to be effective at mitigating IRI in different models, including heart failure, cerebral stroke, transplantation, and surgical interventions. Hydrogen reduces IRI via different mechanisms, like the suppression of oxidative stress and inflammation, the enhancement of ATP production, decreasing calcium overload, regulating cell death, etc. Further research is still needed to integrate the use of molecular hydrogen into clinical practice.

Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury.

BACKGROUND: Skeletal muscle ischaemia-reperfusion injury (IRI) is a prevalent condition encountered in clinical practice, characterised by muscular dystrophy. Owing to limited treatment options and poor prognosis, it can lead to movement impairments, tissue damage, and disability. This study aimed to determine and verify the influence of transient receptor potential canonical 6 (TRPC6) on skeletal muscle IRI, and to explore the role of TRPC6 in the occurrence of skeletal muscle IRI and the signal transduction pathways activated by TRPC6 to provide novel insights for the treatment and intervention of skeletal muscle IRI. METHODS: In vivo ischaemia/reperfusion (I/R) and in vitro hypoxia/reoxygenation (H/R) models were established, and data were comprehensively analysed at histopathological, cellular, and molecular levels, along with the evaluation of the exercise capacity in mice. RESULTS: By comparing TRPC6 knockout mice with wild-type mice, we found that TRPC6 knockout of TRPC6 could reduced skeletal muscle injury after I/R or H/R, of skeletal muscle, so as therebyto restoringe some exercise capacity inof mice. TRPC6 knockdown can reduced Ca2+ overload in cells, therebyo reducinge apoptosis. In additionAdditionally, we also found that TRPC6 functionsis not only a key ion channel involved in skeletal muscle I/R injury, but also can affects Ca2+ levels and then phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway. by knocking downTherefore, knockdown of TRPC6, so as to alleviated the injury inducedcaused by skeletal muscle I/R or and H/R. CONCLUSIONS: These findingsdata indicate that the presence of TRPC6 exacerbatescan aggravate the injury of skeletal muscle injury after I/Rischemia/reperfusion, leading towhich not only causes Ca2+ overload and apoptosis., Additionally, it impairsbut also reduces the self- repair ability of cells by inhibiting the expression of the PI3K/Akt/mTOR signalling pathway. ETo exploringe the function and role of TRPC6 in skeletal muscle maycan presentprovide a novelew approachidea for the treatment of skeletal muscle ischemia/reperfusion injury.

Daprodustat reduces skeletal muscle ischemia-reperfusion injury in mice.

PURPOSE: The purpose of the present work was to assess the specific effects and underlying mechanisms of Daprodustat (GSK1278863) on skeletal muscle injury induced by ischemia reperfusion (I/R). METHODS: C57BL/6 mice were randomized into the skeletal muscle I/R injury (I/R), Daprodustat (GSK1278863) pretreatment and I/R (I/R + GSK) and sham operation (Sham) groups. The skeletal muscle I/R injury model was established by placing an orthodontic rubber band at the left hip joint for 3 h and releasing it for 3 h. H&E staining, wet weight/dry weight ratio assessment, TUNEL assay, ELISA, qRT-PCR and immunoblot were utilized to assess the effects of Daprodustat. RESULTS: Daprodustat pretreatment significantly ameliorated apoptosis in skeletal muscle cells, reduced oxidative damage and suppressed inflammatory cytokines. Mechanistically, Daprodustat positively affected NF-κB signaling activation. CONCLUSION: These data demonstrated that Daprodustat may provide a potential clinical approach for preventing or treating skeletal muscle injury induced by I/R.