Search

The damaged organ may experience severe pathological alterations as a result of tissue ischemia–reperfusion (I/R). The study of stem cell-based repair therapies is actively being conducted, and the outcomes and therapeutic potential of these cells are both promising. Autophagy checks protein homeostasis by breaking down huge damaged proteins or organelles. The study’s objective was to assess how ADSCs impact the autophagic process after testicular ischemia/reperfusion. In our investigation, 30 male rats were divided into five groups: control, ADSC, ischemia, I/R, and I/R + ADSC (n = 6). Hematoxylin–eosin (HE) was used to stain the testes, and histological changes were assessed. The immunoexpression of androgen receptor (AR), Beclin1, protein light chain 3B (LC3B), and p62 were examined. The seminiferous epithelium in the testis from the ischemia and I/R groups revealed significant degeneration with disorganized morphology, damaged spermatogenic cells, and interstitial space congestion, according to HE stain results. Johnsen’s score were significantly better in I/R + ADSC group than in ischemia and I/R groups. We demonstrated that in rat testes from the I/R groups, immunostaining of Beclin 1 (p = 0.042) and LC3B (p = 0.011) were raised, and p62 (p = 0.047) and AR (p = 0.049) were decreased. Ischemia and I/R promoted testicular autophagy, therefore we can conclude that ADSCs prevent excessive autophagy. Additionally, these results show that the use of ADSCs cures testicular injury and dysfunction associated with I/R injury in rats even a little. [ABSTRACT FROM AUTHOR]

There has been growing interest in using quantitative magnetic resonance imaging (MRI) to describe and understand the pathophysiology of acute kidney injury (AKI). The ability to assess kidney blood flow, perfusion, oxygenation, and changes in tissue microstructure at repeated timepoints is hugely appealing, as this offers new possibilities to describe nature and severity of AKI, track the time‐course to recovery or progression to chronic kidney disease (CKD), and may ultimately provide a method to noninvasively assess response to new therapies. This could have significant clinical implications considering that AKI is common (affecting more than 13 million people globally every year), harmful (associated with short and long‐term morbidity and mortality), and currently lacks specific treatments. However, this is also a challenging area to study. After the kidney has been affected by an initial insult that leads to AKI, complex coexisting processes ensue, which may recover or can progress to CKD. There are various preclinical models of AKI (from which most of our current understanding derives), and these differ from each other but more importantly from clinical AKI. These aspects are fundamental to interpreting the results of the different AKI studies in which renal MRI has been used, which encompass different settings of AKI and a variety of MRI measures acquired at different timepoints. This review aims to provide a comprehensive description and interpretation of current studies (both preclinical and clinical) in which MRI has been used to assess AKI, and discuss future directions in the field. Level of Evidence: 1 Technical Efficacy: Stage 3 [ABSTRACT FROM AUTHOR]

Hemorrhagic shock is a significant cause of trauma-related mortality. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a less-invasive aortic occlusion maneuver for severe hemorrhagic shock but potentially inducing oxidative stress injuries. In an animal model, this study investigated hydrogen gas inhalation therapy's potential to mitigate post-REBOA ischemia-reperfusion injuries (IRIs). Ten healthy female swine underwent REBOA placement after induced 40% hemorrhagic shock. They were observed during the IRI phase after a 60-minute Zone 1 occlusion for 180 minutes until euthanasia. 2% hydrogen gas inhalation was started simultaneously with REBOA inflation in the hydrogen group. We evaluated survival time, lactate, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) biomarkers, gross findings, and pathological grades. One swine in the control group died at 90 min, and the remaining animals survived throughout the experiment. Survival analysis showed no significant differences between the two groups (control vs. hydrogen, 4/5 vs. 5/5; Log-rank, P = 0.317). Lactate levels during and after REBOA suggested a tendency towards lower levels in the hydrogen group (10.5 ± 4.2 vs. 7.6 ± 2.3 mmol/L, peak, T = 90). Serum 8-OHdG concentrations showed a lower trend in the hydrogen group (Range: 0.12–0.32 vs. 0.11–0.19 ng/mL). The villi of the ileum were destroyed during REBOA inflation and after reperfusion. Changes in the pathological grade of the ileum demonstrated no significant differences in both groups (2.8 ± 1.0 vs. 2.0 ± 1.0, proximal ileum, T = 240). Hydrogen gas inhalation therapy exhibited no significant difference compared to the control group in survival, lactate level, 8-OHdG, and intestinal mucosal injury following REBOA in a hemorrhagic shock model. Although it may slightly reduce mortality, biomarkers, and intestinal pathology, hydrogen gas inhalation therapy was not shown to have sufficient evidence to mitigate REBOA-IRI. [ABSTRACT FROM AUTHOR]

Organ transplantation is a vital intervention for end-stage organ failure; however, ischemia-reperfusion injury is a complication of transplantation, affecting the prognosis and survival of transplant recipients. As a complex ecosystem, recent research has highlighted the role of the intestinal microecology in transplantation, revealing its significant interplay with ischemia-reperfusion injury. This review explores the interaction between ischemia-reperfusion injury and intestinal microecology, with a special focus on how ischemia-reperfusion injury affects intestinal microecology and how these microecological changes contribute to complications after organ transplantation, such as infection and rejection. Based on a comprehensive analysis of current research advances, this study proposes potential strategies to improve transplant outcomes, offering guidance for future research and clinical practice. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury (IRI) is a common and clinically significant form of tissue damage encountered in medical practice. This pathological process has been thoroughly investigated across a variety of clinical settings, including, but not limited to, sepsis, organ transplantation, shock, myocardial infarction, cerebral ischemia, and stroke. Intestinal IRI, in particular, is increasingly recognized as a significant clinical entity due to marked changes in the gut microbiota and their metabolic products, often described as the body's "second genome." These changes in intestinal IRI lead to profound alterations in the gut microbiota and their metabolic outputs, impacting not only the pathology of intestinal IRI itself but also influencing the function of other organs through various mechanisms. Notable among these are brain, liver, and kidney injuries, with acute lung injury being especially significant. This review seeks to explore in depth the roles and mechanisms of the gut microbiota and their metabolic products in the progression of acute lung injury initiated by intestinal IRI, aiming to provide a theoretical basis and directions for future research into the treatment of related conditions. [ABSTRACT FROM AUTHOR]

Ischemic heart disease (IHD) remains one of the most prominent causes of mortality and morbidity globally, and the risk of ischemia–reperfusion injury is becoming more severe and constant. This underscores the need to develop new methods to protect the heart from damage. DJ‐1 is a multifunctional intracellular protein encoded by the PARK7 gene that plays roles in processes including the control of autophagy, the preservation of mitochondrial integrity, the prevention of apoptosis, and the elimination of oxidative stress. DJ‐1 has recently been the focus of growing interest as a target molecule relevant to treating myocardial ischemia–reperfusion injury due to its protective properties and its role in cellular response mechanisms. Consistently, DJ‐1‐related interventions, such as its exogenous administration or the use of pharmacological agents, have been demonstrated to help protect the myocardium from ischemia–reperfusion injury and associated adverse outcomes. This review provides an overview of DJ‐1 and its therapeutic relevance in the myocardium in the setting of ischemia and reperfusion. [ABSTRACT FROM AUTHOR]

Background: Alternative splicing is a fundamental mechanism in the post‐transcriptional regulation of genes. The multifunctional transmembrane glycoprotein receptor carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) undergoes extensive alternative splicing to allow for tunable functions in cell signalling, adhesion and modulation of immune and metabolic responses. Splice isoforms that differ in their ectodomain and short or long cytoplasmic tail (CEACAM1‐S/CEACAM1‐L) have distinct functional roles. The mechanisms that regulate CEACAM1 RNA splicing remain elusive. Methods: This narrative review summarizes the current knowledge of the mechanism and function of CEACAM1 splice isoforms. Historical perspectives address the biological significance of the glycosylated Ig domains, the variable exon 7, and phosphorylation events that dictate its signal transduction pathways. The use of small antisense molecules to target mis‐spliced variable exon 7 is discussed. Results: The Ig variable‐like N domain mediates cell adhesion and immune checkpoint inhibitory functions. Gly and Tyr residues in the transmembrane (TM) domain are essential for dimerization. Calmodulin, Calcium/Calmodulin‐dependent protein kinase II delta (CamK2D), Actin and Annexin A2 are binding partners of CEACAM1‐S. Homology studies of the muCEACAM1‐S and huCEACAM1‐S TM predict differences in their signal transduction pathways. Hypoxia‐inducible factor 1‐α (HIF‐1‐α) induces alternative splicing to produce CEACAM1‐S under limited oxygen conditions. Antisense small molecules directed to exon 7 may correct faulty expression of the short and long cytoplasmic tail splicing isoforms. Conclusion: More pre‐clinical and clinical studies are needed to elucidate the precise mechanisms by which CEACAM1 RNA splicing may be exploited to develop targeted interventions towards novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion injury (I/R) for skeletal muscle usually results from vascular injuries or trauma. Sitagliptin (STG) is an effective member of the dipeptidyl peptidase-4 (DPP-4) inhibitors drug family that plays roles in oxidative stress regulation, inflammation, and autophagy control. In this study, we evaluated the protective roles of STG against I/R of gastrocnemius muscle and the underlying mechanisms. Materials and methods: Forty-eight mice were randomly allocated into three groups: Group I (n = 24): control group which was subdivided equally into subgroup IA; negative control, subgroup IB; sitagliptin (STG), Group II (n = 12): ischemia–reperfusion injury (I/R), and Group III (n = 12): sitagliptin pretreatment (300 mg/kg/ day; p.o.) for two weeks followed by ischemia–reperfusion injury (STG + I/R). We measured SOD activity and MDA level to assess oxidative stress. Moreover, GLP-1/p-PI3K/ p-AKT expression levels were investigated. Autophagy was estimated by assessing lncRNA H19, Beclin-1 and ATG7 expression by RT-qPCR analysis. Inflammatory markers were assessed by iNOS and NF‐κB expression using immunohistochemistry. Results: Our results revealed that STG pretreatment significantly attenuated oxidative stress and inflammation and upregulated GLP-1, p-PI3K, and p-AKT protein levels. Also, LnRNA H19, Becline-1, and ATG7 mRNA expression were downregulated as well as decrease the expression of the inflammatory markers iNOS and NF‐κB with STG pretreatment. Conclusion: Our results highlighted the useful effects of Sitagliptin during hind limb I/R that could be mediated by antioxidant, anti-inflammatory effects, and attenuation of excessive autophagy. [ABSTRACT FROM AUTHOR]

Destabilization of heme proteins is recognized to play a role in acute kidney injury (AKI). Hemopexin (Hpx), known for its role in binding heme, mitigates free heme toxicity. Despite this, the potential adverse effects of Hpx deposition in kidney tissues and its impact on kidney function are not fully understood. Deferoxamine (DFO) chelates iron released from heme and mitigates associated kidney damage. Therefore, this study aimed to evaluate whether Hpx contributes to kidney injury in an ischemia-reperfusion injury (IRI) induced AKI model and to investigate if DFO could alleviate this damage. Mice were categorized into five groups: Sham-Vehicle, Sham-Hpx, IRI-Vehicle, IRI-Hpx, and IRI-Hpx-DFO. Decline in kidney function was observed exclusively in the IRI group, independent of Hpx injection. Serum Hpx levels remained comparable across all groups, and administration of Hpx did not alter serum Hpx levels or kidney function after 24 hours. Although increased Hpx deposition in kidneys was noted in both the IRI and Hpx groups, this accumulation did not correlate with impaired kidney function. Additionally, DFO did not exhibit a protective effect against kidney injury. In summary, Hpx does not directly induce kidney injury and cannot be considered a biomarker for kidney damage caused by IRI. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver transplantation (LT) is a key treatment for liver cancers by reducing tumor burden and improving liver function. While LT offers significant improvement in survival, cancer recurrence rates remain high. Ischemia-reperfusion injury (IRI) caused by mitochondria dysfunction drives tumor recurrence by creating a favorable pro-inflammatory microenvironment. Therefore, strategies that decrease IRI may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT and examined the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP ("ischemia free organ transplantation") and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Liver transplantation (LT) is a key treatment for primary and secondary liver cancers, reducing tumor burden with concurrent improvement of liver function. While significant improvement in survival is noted with LT, cancer recurrence rates remain high. Mitochondrial dysfunction caused by ischemia-reperfusion injury (IRI) is known to drive tumor recurrence by creating a favorable microenvironment rich in pro-inflammatory and angiogenic factors. Therefore, strategies that decrease reperfusion injury and mitochondrial dysfunction may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes and increased use of marginal grafts. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT. The current literature was screened for the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP ("ischemia free organ transplantation") and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Three prospective randomized controlled trials are ongoing in Europe to provide robust evidence on the impact of HOPE on cancer recurrence in LT. [ABSTRACT FROM AUTHOR]

The liver plays a crucial role in regulating lipid metabolism. Our study examined the impact of Exosomes derived from adipose mesenchymal stem cells (ADSCs-Exo) on lipid metabolism following liver ischemia-reperfusion injury (IRI) combined with partial hepatectomy. We developed a miniature swine model for a minimally invasive hemi-hepatectomy combined with liver IRI. In this study, we administered PBS, ADSCs-Exo, and adipose-derived stem cells (ADSCs) individually through the portal vein. Before and after surgery, we evaluated various factors including hepatocyte ultrastructure, lipid accumulation in liver tissue, and expression levels of genes and proteins associated with lipid metabolism. In addition, we measured serum and liver tissue levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (CHOL). TEM and oil red O stain indicated a significant reduction in liver steatosis following ADSCs-Exo treatment, which also elevated serum levels of HDL, LDL, TG, and CHOL. Additionally, ADSCs-Exo have been shown to significantly decrease serum concentrations of HDL, LDL, TG, and CHOL in the liver (p < 0.05). Finally, ADSCs-Exo significantly downregulated lipid synthesis-related genes and proteins, including SREBP-1, SREBP-2, ACC1, and FASN (p < 0.05), while upregulating lipid catabolism-related genes and proteins, such as PPAR-α and ACOX1 (p < 0.05). ADSCs-Exo as a cell-free therapy highlights its therapeutic potential in hepatic lipid metabolism abnormalities. [ABSTRACT FROM AUTHOR]

Objective: Corynoline has displayed pharmacological effects in reducing oxidative stress and inflammatory responses in many disorders. However, its effects on hepatic ischemia–reperfusion (I/R) injury remain unclear. This study aimed to investigate the protective effects of corynoline against hepatic I/R injury and the underlying mechanisms. Methods: Rat models with hepatic I/R injury and BRL-3A cell models with hypoxia/reoxygenation (H/R) insult were constructed. Models were pretreated with corynoline and/or other inhibitors for functional and mechanistic examination. Results: Corynoline pretreatment effectively mitigated hepatic I/R injury verified by reduced serum transaminase levels, improved histological damage scores, and decreased apoptosis rates. Additionally, corynoline pretreatment significantly inhibited I/R-triggered oxidative stress and inflammatory responses, as indicated by enhanced mitochondrial function, reduced levels of ROS and MDA, reduced neutrophil infiltration and suppressed proinflammatory cytokine release. In vitro experiments further showed that corynoline pretreatment increased cellular viability, decreased LDH activity, reduced cellular apoptosis, and inhibited oxidative stress and inflammatory injury in H/R-induced BRL-3A cells. Mechanistically, corynoline significantly increased Nrf2 nuclear translocation and expression levels of its target gene, HO-1. It also blocked NLRP3 inflammasome activation both in vivo and in vitro. Furthermore, pretreatment with Nrf2 inhibitor ML-385 counteracted the protective effect of corynoline on hepatic I/R injury. Ultimately, in vitro studies revealed that the NLRP3 activator nigericin could also nullified the protective effects of corynoline in BRL-3A cells, but had minimal impact on Nrf2 nuclear translocation. Conclusions: Corynoline can exert protective effects against hepatic I/R injury by inhibiting oxidative stress, inflammatory responses, and apoptosis. These effects may be associated with inhibiting ROS-induced NLRP3 inflammasome activation by enhancing Nrf2/HO-1 signaling. These data provide new understanding about the mechanism of corynoline action, suggesting it is a potential drug applied for the treatment and prevention of hepatic I/R injury. [ABSTRACT FROM AUTHOR]

Background: CKD currently affects 8.2% to 9.1% of the global population and the CKD mortality rate has increased during recent decades, making it necessary to identify new therapeutic targets. This study investigated the role of nicotinamide N-methyltransferase (NNMT) in renal fibrosis following ischemia–reperfusion injury (IRI), a key factor in chronic kidney disease (CKD) progression. Methods: We established a mouse model with a knockdown of NNMT to investigate the impact of this enzyme on renal fibrosis after unilateral IRI. We then utilized histology, immunohistochemistry, and metabolomic analyses to investigate fibrosis markers and sphingolipid metabolism in NNMT-deficient mice. We also utilized an Nnmt lentivirus interference vector or an Nnmt overexpression plasmid to transfect mouse kidney proximal tubule cells, stimulated these cells with TGF-β1, and then measured the pro-fibrotic response and the expression of the methylated and unmethylated forms of Sphk1. Results: The results demonstrated that reducing NNMT expression mitigated fibrosis, inflammation, and lipid deposition, potentially through the modulation of sphingolipid metabolism. Histology, immunohistochemistry, and metabolomic analyses provided evidence of decreased fibrosis and enhanced sphingolipid metabolism in NNMT-deficient mice. NNMT mediated the TGF-β1-induced pro-fibrotic response, knockdown of Nnmt decreased the level of unmethylated Sphk1 and increased the level of methylated Sphk1 in renal tubular epithelial cells. Conclusions: Our findings suggest that NNMT functions in sphingolipid metabolism and has potential as a therapeutic target for CKD. Further research is needed to elucidate the mechanisms linking NNMT to sphingolipid metabolism and renal fibrosis. [ABSTRACT FROM AUTHOR]

The preclinical efficacy of mesenchymal stem cell (MSC) therapy after intravenous infusion has been promising, but clinical studies have yielded only modest results. Although most preclinical studies have focused solely on the ischemic lung, it is crucial to evaluate both lungs after ischemia-reperfusion injury, considering the various mechanisms involved. This study aimed to bridge this gap by assessing the acute effects of bone marrow MSC(BM) infusion before ischemic insult and evaluating both ischemic and non-ischemic lungs after reperfusion. Eighteen male Wistar rats (403 ± 23 g) were anesthetized and mechanically ventilated using a protective strategy. After baseline data collection, the animals were randomized to 3 groups (n = 6/group): (1) SHAM; (2) ischemia-reperfusion (IR), and (3) intravenous MSC(BM) infusion followed by IR. Ischemia was induced by complete clamping of the left hilum, followed by 1 h of reperfusion after clamp removal. At the end of the experiment, the right and left lungs (non-ischemic and ischemic, respectively) were collected for immunohistochemistry and molecular biology analysis. MSC(BM)s reduced endothelial cell damage and apoptosis markers and improved markers associated with endothelial cell integrity in both lungs. In addition, gene expression of catalase and nuclear factor erythroid 2-related factor 2 increased after MSC(BM) therapy. In the ischemic lung, MSC(BM) therapy mitigated endothelial cell damage and apoptosis and increased gene expression associated with endothelial cell integrity. Conversely, in the non-ischemic lung, apoptosis gene expression increased in the IR group but not after MSC(BM) therapy. This study demonstrates distinct effects of MSC(BM) therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury. The findings underscore the importance of evaluating both lung types in ischemia-reperfusion studies, offering insights into the therapeutic potential of MSC(BM) therapy in the context of lung injury. [Display omitted] • MSC therapy in the contralateral lung with IRI is an emerging area of research. • Markers of endothelial cell integrity increased after MSC(BM) therapy. • Levels of antioxidative enzyme increased after MSC(BM) therapy. • MSC(BM) therapy prevented lung IRI in ischemic and non-ischemic lungs. [ABSTRACT FROM AUTHOR]

Background/Objectives: Exsanguination is a leading cause of preventable death in military and civilian settings due to extensive blood loss and hemorrhagic shock, which trigger systemic effects such as impaired tissue perfusion, hypoxia, inflammation, and multi-organ dysfunction. Standard resuscitation restores blood volume but fails to address critical aspects of hemorrhagic shock, including inflammation, coagulopathy, and reperfusion injury. To address these limitations, novel phospholipid nanoparticle (PNP)-based resuscitative fluids, VBI-S and VBI-1, were developed to modulate nitric oxide (NO) levels, improving hemodynamic stability, tissue oxygenation, and reducing inflammatory injury. This study assessed the potential of novel phospholipid nanoparticle fluids, VBI-S and VBI-1, as resuscitative agents for severe hemorrhagic shock by evaluating their ability to regulate nitric oxide, restore blood pressure, and mitigate ischemia–reperfusion injury. Methods: This study involved two phases with Sprague Dawley rats (n = 6 per group). Phase one, lasting 4 h, included four groups: blood, Ringer's lactate, VBI-S, and VBI-1. Phase two, lasting 12 h, comprised sham, blood, and VBI-1 groups. Under anesthesia, one femoral artery was catheterized for blood pressure monitoring, and blood withdrawal from the other induced apnea. Reanimation was performed using an intra-arterial infusion of shed blood, Ringer's lactate, VBI-S, or VBI-1. Tissue samples were analyzed histologically and for oxidative DNA damage via immunofluorescence. Chemiluminescence and rheology assessed nitric oxide interactions and viscosity. Data were analyzed using ANOVA. Results: VBI-1 and shed blood increased mean arterial pressure (MAP) from <10 mmHg to survivable levels sustained for 12 h, with VBI-1 showing significantly higher MAP at 3–4 h. Rats treated with Ringer's lactate died within 30 min. Histology revealed reduced organ damage in VBI-1-treated rats compared to shed blood. Immunohistochemistry indicated significantly less oxidative DNA damage (p < 0.001) in VBI-1-treated rats. VBI-1 exhibited superior viscosity and nitric oxide binding. Conclusions: VBI-1 demonstrates strong potential as a resuscitative fluid, offering blood pressure restoration, reduced oxidative damage, and enhanced tissue perfusion, with significant implications for use in resource-limited and pre-hospital settings. [ABSTRACT FROM AUTHOR]

Our objective was to determine the role of acetyl-Hsp90 and its relationship with the NF-κB p65 signaling pathway in CVDs. We investigated the effect of acetyl-Hsp90 on cardiac inflammation and apoptosis after ischemia–reperfusion injury (I/RI). The results showed that the induction of acetyl-Hsp90 occurred in the heart during I/R and in primary cardiomyocytes during oxygen–glucose deprivation/reoxygenation (OGD/R). Moreover, the nonacetylated mutant of Hsp90 (Hsp90-K284R), through the regulation of ATPase activities within its N-terminal domain (NTD), indirectly or directly increases its interaction with NF-κB p65. This led to a reduction in the activation of the NF-κB p65 pathway, thereby attenuating inflammation, apoptosis, and fibrosis, ultimately leading to an improvement in cardiac function. Furthermore, we demonstrated that recombinant human interleukin-37 (rIL-37) exerts a similar cardioprotective effect by reducing acetylation at K284 of Hsp90 after inhibiting the expression of KAT2A. Hsp90 is acetylated by KAT and can be deacetylated by KDAC, which is in balance in the steady state. Moreover, Hsp90 interacts with NF-κB p65 in the cytosol and inhibits p65 translocation into the nucleus. However, Hsp90-K284 can be acetylated by KAT2A after ischemia–reperfusion treatment. Subsequently, the protein–protein interaction between Hsp90 and NF-κB p65 was disturbed, which induced NF-κB p65 to translocate into the nucleus. However, rIL-37 disturbs this phenotype by inhibiting KAT2A activity. [ABSTRACT FROM AUTHOR]

The article discusses the importance of parenchymal colonization of mesenchymal stem/stromal cells (MSCs) within injured/inflamed tissues for optimal therapeutic effects. The study by Yi et al focuses on enforcing HCELL expression on MSCs to enhance their homing and efficacy in treating cerebral ischemia-reperfusion injury. By increasing MSC tissue colonization through HCELL expression, the study shows promising results in reducing injury severity, decreasing inflammation, and improving outcomes, particularly in stroke therapy. The findings suggest potential applications of HCELL+ MSC therapy in various medical conditions, emphasizing the need for further preclinical studies and clinical trials to optimize MSC-based regenerative medicine efforts. [Extracted from the article]

Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18 h of static cold storage (SCS) followed by 4 h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4 h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 (p < 0.001; p = 0.002, respectively), and tissue IL-1β (p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Liver transplantation (LT) is still limited by organ shortage and post‐transplant monitoring issues. While machine perfusion techniques allow for improving organ preservation, biomarkers like donor‐derived cell‐free DNA (dd‐cfDNA) and mitochondrial cfDNA (mt‐cfDNA) may provide insights into graft injury and viability pre‐ and post‐LT.A prospective observational cohort study was conducted on LT recipients (n = 45) to evaluate dd‐cfDNA as a biomarker of graft dysfunction during the first 6 months after LT. Dd‐cfDNA was quantified on blood samples collected pre‐LT and post‐LT using droplet digital PCR. In livers undergoing dual hypothermic oxygenated machine perfusion (D‐HOPE), total cfDNA and mt‐cfDNA levels were measured on perfusate samples collected at 30‐min intervals. Correlations with graft function and clinical outcomes were assessed.Dd‐cfDNA levels peaked post‐LT and correlated with transaminase levels and histological injury severity. The longitudinal assessment showed that postoperative complications and rejection were associated with an increase in dd‐cfDNA levels. Mt‐cfDNA levels in D‐HOPE perfusate correlated with graft function parameters post‐LT and were higher in patients with early allograft dysfunction and severe complications.This study confirms dd‐cfDNA as a marker of graft injury after LT and suggests that perfusate mt‐cfDNA levels during D‐HOPE correlate with graft function and post‐transplant clinical outcome. Integration of these tests into clinical practice may improve transplant management and viability assessment during hypothermic perfusion. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have explored the effects of L-arginine, whether administered in the form of a supplement or through infusion during cardioplegia, on cardiac and inflammatory markers in individuals undergoing coronary artery bypass grafting (CABG). However, these studies presented contradictory findings. Consequently, the objective of this study was to investigate the impact of l-arginine on these markers by analyzing available randomized controlled trials (RCTs). Methods: We performed an extensive search across various databases, including Embase, Medline/PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar, covering research published until December 2023. To analyze the mean changes in inflammatory and cardiac markers between the L-arginine and control groups, we calculated the weighted mean difference (WMD) along with the corresponding 95% confidence interval (CI) using a random-effects model. Results: A total of 393 RCTs were identified during the initial search. After screening and selection, 7 trials were included. In a meta-analysis of three trials that reported troponin T levels, we found a significant impact of L-arginine on reducing troponin T levels (WMD = -0.61 ng/ml; 95% CI: -1.07, -0.15). Our analysis also showed that L-arginine had a noticeable impact on decreasing interleukin-6 (IL-6) levels (WMD = -7.72 pg/ml; 95% CI: -15.05, -0.39). However, we found no considerable impact of L-arginine treatment on creatine phosphokinase-MB (CPK-MB), tumor necrosis factor-alpha (TNF-α), and troponin I compared to the placebo groups. Conclusions: Our findings suggest that L-arginine may benefit patients undergoing CABG, as it helps reduce inflammatory reactions and limits myocardial ischemia. This study registered in the PROSPERO database (Registration No. CRD42024508341). [ABSTRACT FROM AUTHOR]

Aim: Cerebral ischemic stroke (IS) is one of the leading causes of morbidity and mortality globally. However, the mechanisms underlying IS injury remain poorly understood. Ring finger protein 2 (RNF2), the member of the polycomb family (PcG), has been implicated in diverse biological and pathological conditions. However, whether RNF2 plays a role in IS progression is not clarified. This study aims to investigate the potential effects of RNF2 on IS. Methods: The effects of RNF2 were studied in human postmortem IS brains, a rat model of IS, tunicamycin (TM)‐induced mouse neuroblastoma neuro2a (N2a) cells, and oxygen–glucose deprivation/reperfusion (OGD/R)‐induced SH‐SY5Y cells. Results: Here, we demonstrated that RNF2 was markedly upregulated both in human postmortem IS brains and ischemic rat brains and RNF2 overexpression alleviated brain injury induced by middle cerebral artery occlusion by reducing neuron apoptosis. Mechanistically, we found that RNF2 is an E3 ubiquitin ligase for the mesencephalic astrocyte‐derived neurotrophic factor (MANF), which confers protection against brain ischemia. RNF2 interacted with MANF and promoted the monoubiquitination of MANF, consequently facilitating its stability and nuclear localization. Conclusion: Collectively, RNF2 is identified as a critical inhibitor of IS injury by stabilizing MANF through monoubiquitination, suggesting that RNF2 is a potential therapeutic target for IS. [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion injury (IRI) is a complex pathophysiological process and a major cause of delayed graft function (DGF) after transplantation. MicroRNA (miRNA) has important roles in the pathogenesis of IRI and may represent promising therapeutic targets for mitigating renal IRI. miRNA sequencing was performed to profile microRNA expression in mouse kidneys after cold storage and transplantation (CST). Lentivirus incorporating a miR-199a-5p modulator was injected into mouse kidney in situ before syngenetic transplantation and unilateral IRI to determine the effect of miR-199a-5p in vivo. miR-199a-5p mimic or inhibitor was transfected cultured tubular cells before ATP depletion recovery treatment to examine the role of miR-199a-5p in vitro. Sequencing data and microarray showed upregulation of miR-199a-5p in mice CST and human DGF samples. Lentivirus incorporating a miR-199a-5p mimic aggravated renal IRI, and protective effects were obtained with a miR-199a-5p inhibitor. Treatment with the miR-199a-5p inhibitor ameliorated graft function loss, tubular injury, and immune response after CST. In vitro experiments revealed exacerbation of mitochondria dysfunction upon ATP depletion and repletion model in the presence of the miR-199a-5p mimic, whereas dysfunction was attenuated when the miR-199a-5p inhibitor was applied. miR-199a-5p was shown to target A-kinase anchoring protein 1 (AKAP1) by double luciferase assay and miR-199a-5p activation reduced dynamin-related protein 1 (Drp1)-s637 phosphorylation and mitochondrial length. Overexpression of AKAP1 preserved Drp1-s637 phosphorylation and reduced mitochondrial fission. miR-199a-5p activation reduced AKAP1 expression, promoted Drp1-s637 dephosphorylation, aggravated the disruption of mitochondrial dynamics, and contributed to renal IRI. NEW & NOTEWORTHY: This study identifies miR-199a-5p as a key regulator in renal ischemia-reperfusion injury through microRNA sequencing in mouse models and human delayed graft function. miR-199a-5p worsens renal IRI by aggravating graft dysfunction, tubular injury, and immune response, while its inhibition shows protective effects. miR-199a-5p downregulates A-kinase anchoring protein 1 (AKAP1), reducing dynamin-related protein 1 (Drp1)-s637 phosphorylation, increasing mitochondrial fission, and causing dysfunction. Targeting the miR-199a-5p/AKAP1/Drp1 axis offers therapeutic potential for renal IRI, as AKAP1 overexpression preserves mitochondrial integrity by maintaining Drp1-s637 phosphorylation. [ABSTRACT FROM AUTHOR]

Interleukin‐33 (IL‐33) is an alarmin released upon epithelial tissue damage. It functions as a nuclear factor for regulating gene expression. We hypothesised that IL‐33 is involved in the formation of decubitus ulcers through damaged epidermis. Therefore, this study aimed to clarify the mechanism of IL‐33 action in decubitus ulcer formation. IL‐33 knockout (KO), soluble stimulation‐2 (ST2) transgenic, and wild‐type (WT) mice were used to construct an ischemia–reperfusion (I/R) injury as a decubitus model. The ulcer area was significantly reduced in IL‐33 KO mice compared to WT mice but was not reduced in ST2 transgenic mice. Anti‐IL‐33 receptor (transmembrane ST2) antibodies effectively prevented ulcer formation; however, an anti‐IL‐33 neutralising antibody was ineffective. The number of infiltrating macrophages was higher, while that of neutrophils and mast cells was lower in IL‐33 KO mice than in WT mice. The number of M2 macrophages increased in IL‐33 KO mice. Characterisation of gene expression levels revealed significantly reduced interleukin‐1 beta (IL‐1β) and increased C‐C motif chemokine ligand 17 expression in IL‐33 KO mice. Macrophages isolated from ulcers in WT or IL‐33 KO mice stimulated with exogenous IL‐33 produced comparable amounts of IL‐1β. In conclusion, our study indicates that IL‐33 is released in response to I/R injury in the skin, contributing to inflammatory macrophage and mast cell infiltration and stimulation, resulting in IL‐1β production and the massive infiltration of effector cells, including neutrophils, which finally induces decubitus ulcer formation. These results suggest that suppressing IL‐33 expression could be beneficial for treating early‐phase decubitus ulcers. [ABSTRACT FROM AUTHOR]

Liver transplantation has evolved into a mature clinical field, but scarcity of usable organs poses a unique challenge. Expanding the donor pool requires novel approaches for protecting hepatic physiology and cellular homeostasis. Here we define hepatocellular injury during transplantation, with an emphasis on modifiable cell death pathways as future therapeutics. [ABSTRACT FROM AUTHOR]

Objective To explore the role and mechanism of tannic acid in renal ischemia-reperfusion injury (IRI) in mice. Methods Male C57BL/6J mice were randomly divided into sham operation group (Sham group), blank control group (Sham+TA group), experimental group (IRI group) and treatment group (IRI+TA group), with 20 mice in each group. The survival of mice after renal IRI was observed 48 h after surgery. Serum and renal tissue samples were collected from mice 24 h after IRI (5 mice per group), and the levels of blood urea nitrogen and serum creatinine were detected. The levels of inflammatory factors and ferroptosis-related indicators in renal tissue were detected. The pathological damage of renal tissue was assessed. The protein expression levels of glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase longchain family 4 (ACSL4) in renal tissue were detected. Molecular docking software was used to explore the binding activity of tannic acid with nuclear factor E2-related factor 2 (Nrf2) and to verify the expression of Nrf2 and heme oxygenase-1 (HO-1). Results Compared with the IRI group, the postoperative survival rate of mice in the IRI+TA group was higher (0 vs. 60%), the levels of serum creatinine and blood urea nitrogen were decreased, the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in renal tissue were decreased, the renal tissue injury was improved, the levels of malondialdehyde and ferrous ions in renal tissue were reduced, the level of glutathione was increased, the expression of GPX4 was increased, and the expression of ACSL4 was decreased (all P<0.05). Tannic acid may form a suitable spatial complement with Nrf2, with a binding energy of −8.7 kcal/mol, indicating a strong binding ability of tannic acid with Nrf2. The protein levels of Nrf2 and HO-1 in the renal tissue of mice in the IRI+TA group were upregulated. Conclusions Tannic acid may bind to Nrf2 protein, activate the Nrf2/HO-1 pathway to inhibit ferroptosis, and alleviate renal IRI in mice. [ABSTRACT FROM AUTHOR]

Objective To explore the effect and mechanism of microRNA (miR)-155-5p on myocardial pyroptosis in rats with myocardial ischemia-reperfusion injury (IRI). Methods Sixty SD rats were randomly divided into sham group, IRI group, agomir-NC group, miR-155-5p agomir group, antagomir-NC group, and miR-155-5p antagomir group, with 10 rats in each group. Echocardiography was used to measure the left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) of rats. Enzyme-linked immune absorbent assay (ELISA) was used to detect the levels of creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin T (cTnT) in serum, as well as the levels of interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor (TNF)-α in myocardial tissue of rats. Hematoxylin-eosin staining was used to observe pathological changes in rat myocardial tissue. Real-time fluorescent quantitative polymerase chain reaction was used to detect the expression levels of miR-155-5p and silent information regulator 1 (SIRT1) messenger RNA (mRNA) in myocardial tissue of rats. Dual-luciferase reporter gene assay was used to verify the targeting relationship between miR-155-5p and SIRT1. Western blot was used to detect the expression levels of SIRT1, NOD-like receptor protein 3 (NLRP3), cleaved cysteine aspartate specific proteinase-1 (Cleaved Caspase-1), and gasdermin D (GSDMD) proteins in myocardial tissue of rats. Results Compared with the sham group, the LVEDD and LVESD of rats in the IRI group were increased, LVEF and LVFS were decreased, serum levels of CK-MB, LDH, and cTnT were increased, IL-1β, IL-6, IL-18 and TNF-α levels in myocardial tissue were increased, myocardial tissue structure was severely damaged, myocardial fibers were disordered, relative expression of NLRP3, Cleaved Caspase-1, and GSDMD proteins were increased, and the relative expression of SIRT1 protein was decreased (all P<0.05/5). Compared with the IRI group, the rats in the miR-155-5p agomir group had increased LVEDD and LVESD, decreased LVEF and LVFS, increased serum levels of CK-MB, LDH, and cTnT, increased myocardial tissue levels of IL-1β, IL-6, IL-18, TNF-α, aggravated myocardial tissue lesions, increased relative expression of NLRP3, Cleaved Caspase-1, and GSDMD proteins, and decreased relative expression of SIRT1 protein, and the rats in the miR-155-5p antagomir group had decreased LVEDD and LVESD, increased LVEF and LVFS, decreased serum levels of CK-MB, LDH, and cTnT, decreased myocardial tissue levels of IL-1β, IL-6, IL-18, TNF-α, reduced myocardial tissue lesions, decreased relative expression of NLRP3, Cleaved Caspase-1, and GSDMD proteins, and increased relative expression of SIRT1 protein (all P<0.05/5). miR-155-5p was negatively correlated with the expression levels of SIRT1 in rat myocardial tissue, and SIRT1 was a target gene of miR-155-5p. Conclusions miR-155-5p may participate in the regulation of myocardial IRI in rats by targeting the downregulation of SIRT1 and promoting NLRP3-mediated myocardial pyroptosis. [ABSTRACT FROM AUTHOR]

Objective To investigate the role and mechanism of silent information regulator 1 (SIRT1)-NOD-like receptor protein 3 (NLRP3) axis in the effect of remifentanil against ischemia-reperfusion injury (IRI) in rat livers. SD rats were randomly divided into sham operation group (sham group), IRI group, IRI+remifentanil pretreatment group (IRI+RPC group), IRI+SIRT1 inhibitor EX-527 group (IRI+EX-527 group) and IRI+RPC+EX-527 group, with 8 rats in each group. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), interleukin (IL)-1β and IL-18 of rats in each group were detected. The liver tissue pathology was observed. The apoptosis rate of hepatocytes in rats was detected. The expressions of SIRT1, NLRP3, cleaved cysteinyl aspartate specific proteinase-1 (Cleaved Caspase-1) and Gasdermin D (GSDMD) proteins in rat liver tissue were detected. Results Compared with the sham group, the liver tissue pathological score and hepatocyte apoptosis rate of rats in the IRI group were increased, the serum ALT, AST, LDH, IL-1β, and IL-18 levels were increased, the relative expression of SIRT1 protein in liver tissue was decreased, and the relative expression of NLRP3, Cleaved Caspase-1, and GSDMD proteins were increased (all P<0.05). Compared with the IRI group, the liver tissue pathological score and hepatocyte apoptosis rate of rats in the IRI+RPC group were decreased, the serum ALT, AST, LDH, IL-1β, and IL-18 levels were decreased, the relative expression of SIRT1 protein in liver tissue was increased, and the relative expression of NLRP3, Cleaved Caspase1, and GSDMD proteins were decreased; the liver tissue pathological score and hepatocyte apoptosis rate of rats in the IRI+EX-527 group were increased, the ALT, AST, LDH, IL-1β, and IL-18 levels were increased, the relative expression of SIRT1 protein in liver tissue was decreased, and the relative expression of NLRP3, Cleaved Caspase-1, and GSDMD proteins were increased (all P<0.05). Compared with the IRI+RPC group, the liver tissue pathological score and hepatocyte apoptosis rate in the IRI+RPC+EX-527 group were increased, the levels of ALT, AST, LDH, IL-1β, and IL-18 were increased, the relative expression of SIRT1 protein in liver tissue was decreased, and the relative expression of NLRP3, Cleaved Caspase-1, and GSDMD proteins were increased (all P<0.05). Conclusions SIRT1 may participate in the regulation of remifentanil against rat liver IRI by inhibiting NLRP3 mediated cell pyroptosis. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress refers to a cellular stress response triggered when cells are stimulated, which is manifested as the disruption of endoplasmic reticulum homeostasis and dysfunction in various pathological conditions, resulting in the accumulation of a large number of misfolded and unfolded proteins within the endoplasmic reticulum and an imbalance of calcium ions. Macrophages are the most abundant immune cells in the liver and play an important role in maintaining liver homeostasis and various liver diseases. Recent studies have confirmed that the unfolded protein response caused by endoplasmic reticulum stress plays an important role in regulating macrophage immune response. This article reviews the mechanisms of endoplasmic reticulum stress regulating macrophage immune response and its role in liver diseases such as ischemia-reperfusion injury during organ transplantation, liver fibrosis, and hepatocellular carcinoma, in order to deepen the understanding of the mechanism of macrophage immune regulation and provide new ideas for research and interventional treatment related to liver diseases. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury (IRI) and rejection are the main factors affecting the long-term survival of transplant kidneys. IRI or rejection reactions can cause endoplasmic reticulum stress (ERS) leading to renal injury. X-box binding protein 1 (XBP1), as the main ERS-related protein regulating cell homeostasis, generates spliced XBP1 after splicing introns by inositol-requiring enzyme 1α (IRE1α), thereby affecting the expression of target genes and reshaping the cell environment. Appropriate ERS can promote cell survival. However, when the threshold is exceeded, excessive expression of XBP1 can lead to cell instability or death, thereby causing an imbalance in the renal internal environment, which is related to the pathogenesis and progression of kidney transplant-related injury. Therefore, the effective activation of XBP1 has a protective effect on stress injury and helps maintain the vitality and integrity of the renal system. This article reviews the ERS pathway IRE1α-XBP1, the role of XBP1 in renal parenchymal cells and immune cells, the role of XBP1 in renal ischemic injury and rejection, and the clinical detection and potential therapies targeting XBP1. It explores the potential value of targeting XBP1 in kidney transplant-related injury, aiming to provide new targets and directions for improving the prognosis of kidney transplantation. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (I/R) injury with severe cell death is a major complication involved in liver transplantation and resection. The identification of key regulators improving hepatocyte activity may provide potential strategies to clinically resolve I/R-induced injury. N6-methyladenosine (m6A) RNA modification is essential for tissue homeostasis and pathogenesis. However, the potential involvement of m6A in the regulation of hepatocyte activity and liver injury has not been fully explored. In the present study, we found that hepatocyte AlkB homolog H5 (ALKBH5) levels were decreased both in vivo and in vitro I/R models. Hepatocyte-specific ALKBH5 overexpression effectively attenuated I/R-induced liver necrosis and improved cell proliferation in mice. Mechanistically, ALKBH5-mediated m6A demethylation improved the mRNA stability of YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). In conclusion, ALKBH5 is a regulator of hepatic I/R injury that improves hepatocyte repair and proliferation by maintaining YTHDF1 stability and YAP content. The ALKBH5–m6A–YTHDF1–YAP axis represents promising therapeutic targets for hepatic I/R injury to improve the prognosis of liver surgery. [ABSTRACT FROM AUTHOR]

Skin flaps are tissue transferred from a donor to a recipient site to fill covering defects in the surface of the body. During transfer, skin flaps are severely predisposed to ischemia not only due to ischemia but also to ischemia–reperfusion (I/R) injury, a paradoxical exacerbation of cellular death following blood flow restoration in tissues exposed to ischemic insults. This systematic review aimed to report the in vivo outcomes of the application of stem cell-derived conditioned medium (secretome) or its derivatives toward skin flap following I/R injury in experimental studies. This study was a systematic review with literature searched using Science Direct, PubMed, Directory of Open Access Journal, Cochrane Central, Clinicaltrials.gov, and Europe PMC on January 24, 2024, for studies reporting the effects of stem cell-derived conditioned medium (secretome) or its derivatives in the skin flap I/R injury in animal models. We obtained a total of 318 studies during the search, which were then screened. Ten studies were included in the review. Our study found that stem cell-conditioned medium increases overall flap survivability; promotes vascularization, perfusion, and angiogenesis; reduces inflammation, reduces apoptosis and oxidants; and increases collagen secretion and maturation. The effect was found to be even more profound when the stem cells were set to proliferate under hypoxic conditions. Secretome did not only exhibit prosurvival and proproliferation properties suitable for responding to ischemic insults but also anti-inflammatory and antiapoptotic properties suitable for responding to I/R injury. Furthermore, secretome also assisted native structure recovery. The results from the experimental studies found that secretome is a promising therapy to increase flap survivability when also promoting histology recovery.

Abstract Renal ischemia-reperfusion injury (IRI) is an important cause of acute kidney injury (AKI). However, the pathophysiological changes and mechanisms during IRI-AKI progression remain unclear. This study aims toinvestigate the potential mechanisms in the progression of IRI-AKI by integrating metabolomics and transcriptomics data, providing a reference for the subsequent identification of biomarkers and therapeutic targets. IRI-AKI rat models with 30 min of ischemia and 24–72 h of reperfusion surgery simulating the progression of AKI were established. Compared to the control group underwent sham surgery (NC group), most of the differentially expressed metabolites (DEMs) in IRI-AKI 24 h and IRI-AKI 72 h decreased, mainly including amino acids, organic acids, and carnitines. Additionally, we found that DEMs were mainly enriched in amino acid-related pathways, among which valine, leucine, and isoleucine biosynthesis were dramatically altered in all comparisons. Transcriptomics revealed that differentially expressed genes (DEGs) were primarily involved in amino acid, lipid, and fatty acid metabolism. By integrating metabolomics and transcriptomics, we found valine, leucine, and isoleucine biosynthesis play key roles in IRI-AKI development. Our findings concluded that valine, leucine, and isoleucine pathways are hubs that potentially connect transcriptomes to metabolomes, providing new insights regarding the pathogenesis of IRI-AKI and its potential biomarkers and therapeutic strategies.

Abstract Background Ischemia-reperfusion injury (I/R) for skeletal muscle usually results from vascular injuries or trauma. Sitagliptin (STG) is an effective member of the dipeptidyl peptidase-4 (DPP-4) inhibitors drug family that plays roles in oxidative stress regulation, inflammation, and autophagy control. In this study, we evaluated the protective roles of STG against I/R of gastrocnemius muscle and the underlying mechanisms. Materials and methods Forty-eight mice were randomly allocated into three groups: Group I (n = 24): control group which was subdivided equally into subgroup IA; negative control, subgroup IB; sitagliptin (STG), Group II (n = 12): ischemia–reperfusion injury (I/R), and Group III (n = 12): sitagliptin pretreatment (300 mg/kg/ day; p.o.) for two weeks followed by ischemia–reperfusion injury (STG + I/R). We measured SOD activity and MDA level to assess oxidative stress. Moreover, GLP-1/p-PI3K/ p-AKT expression levels were investigated. Autophagy was estimated by assessing lncRNA H19, Beclin-1 and ATG7 expression by RT-qPCR analysis. Inflammatory markers were assessed by iNOS and NF‐κB expression using immunohistochemistry. Results Our results revealed that STG pretreatment significantly attenuated oxidative stress and inflammation and upregulated GLP-1, p-PI3K, and p-AKT protein levels. Also, LnRNA H19, Becline-1, and ATG7 mRNA expression were downregulated as well as decrease the expression of the inflammatory markers iNOS and NF‐κB with STG pretreatment. Conclusion Our results highlighted the useful effects of Sitagliptin during hind limb I/R that could be mediated by antioxidant, anti-inflammatory effects, and attenuation of excessive autophagy.

Abstract Background Numerous studies have explored the effects of L-arginine, whether administered in the form of a supplement or through infusion during cardioplegia, on cardiac and inflammatory markers in individuals undergoing coronary artery bypass grafting (CABG). However, these studies presented contradictory findings. Consequently, the objective of this study was to investigate the impact of l-arginine on these markers by analyzing available randomized controlled trials (RCTs). Methods We performed an extensive search across various databases, including Embase, Medline/PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar, covering research published until December 2023. To analyze the mean changes in inflammatory and cardiac markers between the L-arginine and control groups, we calculated the weighted mean difference (WMD) along with the corresponding 95% confidence interval (CI) using a random-effects model. Results A total of 393 RCTs were identified during the initial search. After screening and selection, 7 trials were included. In a meta-analysis of three trials that reported troponin T levels, we found a significant impact of L-arginine on reducing troponin T levels (WMD = -0.61 ng/ml; 95% CI: -1.07, -0.15). Our analysis also showed that L-arginine had a noticeable impact on decreasing interleukin-6 (IL-6) levels (WMD = -7.72 pg/ml; 95% CI: -15.05, -0.39). However, we found no considerable impact of L-arginine treatment on creatine phosphokinase-MB (CPK-MB), tumor necrosis factor-alpha (TNF-α), and troponin I compared to the placebo groups. Conclusions Our findings suggest that L-arginine may benefit patients undergoing CABG, as it helps reduce inflammatory reactions and limits myocardial ischemia. This study registered in the PROSPERO database (Registration No. CRD42024508341).

IntroductionPatients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo.MethodsAdults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts.ResultsLiver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability.DiscussionSerum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

Ischemia-reperfusion injury (IRI) during orthotopic liver transplantation (OLT) contributes to graft rejection and poor clinical outcomes. The disulfide form of high mobility group box 1 (diS-HMGB1), an intracellular protein released during OLT-IRI, induces pro-inflammatory macrophages. How diS-HMGB1 differentiates human monocytes into macrophages capable of activating adaptive immunity remains unknown. We investigated if diS-HMGB1 binds toll-like receptor (TLR) 4 and TLR9 to differentiate monocytes into pro-inflammatory macrophages that activate adaptive immunity and promote graft injury and dysfunction. Assessment of 106 clinical liver tissue and longitudinal blood samples revealed that OLT recipients were more likely to experience IRI and graft dysfunction with increased diS-HMGB1 released during reperfusion. Increased diS-HMGB1 concentration also correlated with TLR4/TLR9 activation, polarization of monocytes into pro-inflammatory macrophages, and production of anti-donor antibodies. In vitro, healthy volunteer monocytes stimulated with purified diS-HMGB1 had increased inflammatory cytokine secretion, antigen presentation machinery, and reactive oxygen species production. TLR4 inhibition primarily impeded cytokine/chemokine and costimulatory molecule programs, whereas TLR9 inhibition decreased HLA-DR and reactive oxygen species production. diS-HMGB1-polarized macrophages also showed increased capacity to present antigens and activate T memory cells. In murine OLT, diS-HMGB1 treatment potentiated ischemia-reperfusion-mediated hepatocellular injury, accompanied by increased serum alanine transaminase levels. This translational study identifies the diS-HMGB1/TLR4/TLR9 axis as potential therapeutic targets in OLT-IRI recipients.

Elevated inflammatory reactions are a significant component in cerebral ischemia–reperfusion injury (CIRI). Activation of α7-Nicotinic Acetylcholine Receptor (α7nAChR) reduces stroke-induced inflammation in rats, but the anti-inflammatory pathway in microglia under CIRI condition remains unclear. This study employed qRT-PCR, protein assays, NanoString analysis, and bioinformatics to examine the effects of PNU282987 treatment (α7nAChR agonist) on BV2 microglial functional differentiation in oxygen–glucose deprivation/reoxygenation (OGDR) condition. OGDR significantly increased the gene expression of pro-inflammatory markers such as TNF-α, IL-6, and IL1β, while α7nAChR agonists reduced these markers. The anti-inflammatory gene marker IL-10 was upregulated by α7nAChR agonist treatment. Downstream pathway marker analysis showed that both gene and protein expression of NFκB was associated with anti-inflammatory effects. Blocking microRNA-21 with antagomir reversed the anti-inflammatory effects. NanoString analysis revealed that microRNA-21 inhibition significantly affected inflammation-related genes, including AL1RAP, TLR9, FLT1, PTGIR, NFκB, TREM2, TNF, SMAD7, FOS, CCL5, IFIT1, CFB, CXCL10, IFI44, DDIT3, IRF7, OASL1, IL1A, IFIT2, C3, CD40, STAT2, IFIT3, IL1RN, OAS1A, CSF1, CCL4, CCL2, CCL3, BCL2L1, and ITGB2. Enrichment analysis of upregulated genes identified Gene Ontology Biological Processes related to cytokine responses and TNF-associated pathways. This study highlights α7nAChR activation as a key regulator of anti-inflammatory responses in BV2 microglia under OGDR conditions, with micro-RNA21 identified as a crucial mediator of receptor-driven neuroprotection via the TNF-α/NFκB signalling pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Flap transplantation technique is a commonly used surgical procedure for the treatment of severe tissue defects, but postoperative flap necrosis is easily triggered by ischemia-reperfusion injury. Therefore, it is still an important research topic to improve the survival rate of transplanted flaps. OBJECTIVE: To review the pathogenesis and latest treatment progress of flap ischemia-reperfusion injury. METHODS: CNKI, WanFang Database and PubMed database were searched for relevant literature published from 2014 to 2024. The search terms used were “flap, ischemia-reperfusion injury, inflammatory response, oxidative stress, Ca2+ overload, apoptosis, mesenchymal stem cells, platelet-rich plasma, signaling pathways, shock wave, pretreatment” in Chinese and English. After elimination of irrelevant literature, poor quality and obsolete literature, 77 documents were finally included for review. RESULTS AND CONCLUSION: Flap ischemia/reperfusion injury may be related to pathological factors such as inflammatory response, oxidative stress response, Ca2+ overload, and apoptosis, which can cause apoptosis of vascular endothelial cells, vascular damage and microcirculation disorders in the flap, and eventually lead to flap necrosis. Studies have found that mesenchymal stem cell transplantation, platelet-rich plasma, signaling pathway modulators, shock waves, and pretreatment can alleviate flap ischemia/reperfusion injuries from different aspects and to varying degrees, and reduce the necrosis rate and necrosis area of the grafted flap. Although there are many therapeutic methods for skin flap ischemia/reperfusion injury, a unified and effective therapeutic method has not yet been developed in the clinic, and the advantages and disadvantages of various therapeutic methods have not yet been compared. Most of the studies remain in the stage of animal experiments, rarely involving clinical observations. Therefore, a lot of research is required in the future to gradually move from animal experiments to the clinic in order to better serve the clinic. [ABSTRACT FROM AUTHOR]

Cerebral ischemia–reperfusion (I/R) injury is a complex pathophysiological process involving multiple mechanisms, including apoptosis and autophagy, which can lead to significant neuronal damage. PIEZO1, a stretch-activated ion channel, has recently emerged as a potential regulator of cellular responses to ischemic conditions. However, its role in neuronal cell survival and death during ischemic events is not well elucidated. This study aimed to ascertain the regulatory function of PIEZO1 in neuronal cell apoptosis and autophagy in an in vitro model of hypoxia-reoxygenation and an in vivo model of brain I/R injury. HT22 hippocampal neuronal cells were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) to simulate ischemic conditions, with subsequent reoxygenation. In vitro, PIEZO1 expression was silenced using small interfering RNA (si-RNA) transfection. The effects on cell viability, apoptosis, and autophagy were assessed using CCK-8 assays, PI-Annexin/V staining combined with flow cytometry, and Western blot analysis. Additionally, intracellular Ca2+ levels in HT22 cells were measured using a Ca2+ probe. The involvement of the AMPK-mTOR pathway was investigated using rapamycin. For in vivo validation, middle cerebral artery occlusion/reperfusion (MCAO/R) in rats was employed. To determine the neuroprotective role of PIEZO1 silencing, sh-PIEZO1 adeno-associated virus was stereotaxically injected into the cerebral ventricle, and neurological and histological outcomes were assessed using neurological scoring, TTC staining, H&E staining, Nissl staining, and immunofluorescence. In HT22 cells, OGD/R injury notably upregulated PIEZO1 expression and intracellular Ca2+ levels. Silencing PIEZO1 significantly diminished OGD/R-induced Ca2+ influx, apoptosis, and autophagy, as indicated by lower levels of pro-apoptotic and autophagy-related proteins and improved cell viability. Additionally, PIEZO1 modulated the AMPK-mTOR signaling pathway, an effect that was counteracted by rapamycin treatment, implying its regulatory role. In vivo, PIEZO1 silencing ameliorated brain I/R injury in MCAO/R rats, demonstrated by improved neurological function scores and reduced neuronal apoptosis and autophagy. However, these neuroprotective effects were reversed through rapamycin treatment. Our findings indicate that PIEZO1 is upregulated following ischemic injury and facilitates Ca2+ influx, apoptosis, and autophagy via the AMPK-mTOR pathway. Silencing PIEZO1 confers neuroprotection against I/R injury both in vitro and in vivo, highlighting its potential as a therapeutic target for stroke management. [ABSTRACT FROM AUTHOR]