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Objective: miRNA, circRNA, and lncRNA play crucial roles in the pathogenesis and progression of myocardial ischemia-reperfusion injury (MI/RI). This study aims to provide valuable insights into miRNA, circRNA, lncRNA, and MI/RI from a bibliometric standpoint, with the goal of fostering further advancements in this area. Methods: The relevant literature in the field of miRNA, circRNA, lncRNA, and MI/RI was retrieved from the Science Citation Index Expanded (SCI-E) database within Web of Science. The "Analyze Results" and "Citation Report" functions in WOS were utilized to compile the annual publication and citation counts in this field. Microsoft Office Excel 2019 was used to organize and visualize the data. Furthermore, bibliometric and visualization analyses of countries/regions, institutions, authors, keywords, and references were conducted using the bibliometric visualization software CiteSpace. Results: A total of 858 publications were included for further analysis in this field. The literature was published across 297 journals, with Molecular Medicine Reports contributing the highest number of publications. Researchers from 45 countries participated in studies within this field, with those from China contributing the most publications. The research hotspots in this field primarily focus on three areas: the role of miRNA, circRNA, and lncRNA in the pathogenesis of MI/RI, their potential as therapeutic targets, and their role as biomarkers. Among these, circular RNA, therapy target, inflammatory response, and cardiomyocyte ferroptosis are likely to emerge as emerging trends in this field. Conclusion: The overall development of research in this field is on the rise. The compilation of research hotspots and emerging trends in this area may provide researchers with more references and assistance in selecting research directions, ultimately benefiting MI/RI patients. [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]

Background: At present, hepatic ischemia-reperfusion injury (IRI) is an important complication of partial hepatectomy and liver transplantation, and it is an important cause of poor prognosis. Spleen tyrosine kinase(SYK) plays an important role in a variety of signaling pathways in the liver, but its role in hepatic IRI is still unclear. This study aims to investigate the role and mechanism of SYK in hepatic IRI and tumor recurrence. Methods: We first observed the activation of SYK in the liver of mice in response to hepatic IRI. Subsequently, Pharmacological inhibitions of SYK were used to evaluated the effect of SYK on neutrophil recruitment and NETosis, and further explored the effect of SYK on IRI and tumor recurrence. Results: Our study shows that SYK is activated in response to hepatic IRI and aggravates liver injury. On the one hand, neutrophils SYK during the early stage of liver reperfusion increases neutrophil extracellular traps (NETs) production by promoting Pyruvate kinase M2(PKM2) nuclear translocation leading to upregulation of phosphorylated STAT3, thereby exacerbating liver inflammation and tumor recurrence. On the other hand, macrophages SYK can promote the recruitment of neutrophils and increase the activation of NLRP3 inflammasome and IL1β, which further promotes the formation of NETs. Conclusions: Our study demonstrates that neutrophil and macrophage SYK synergistically promote hepatic IRI and tumor recurrence, and SYK may be a potential target to improve postoperative hepatic IRI and tumor recurrence. [ABSTRACT FROM AUTHOR]

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials. [ABSTRACT FROM AUTHOR]

Inflammation plays a critical role in conditions such as acute liver failure, acute-on-chronic liver failure, and ischemia–reperfusion-induced liver injury. Various pathogenic pathways contribute to liver inflammation, involving inflammatory polarization of macrophages and Küpffer cells, neutrophil infiltration, dysregulation of T cell subsets, oxidative stress, and activation of hepatic stellate cells. While mesenchymal stromal cells (MSCs) have demonstrated beneficial properties, their clinical translation is limited by their cellular nature. However, MSC-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach for immunomodulation. MSC-EVs naturally mirror their parental cell properties, overcoming the limitations associated with the use of MSCs. In vitro and in vivo preclinical studies have demonstrated that MSC-EVs replicate the beneficial effects of MSCs in liver injury. This includes the reduction of cell death and oxidative stress, improvement of hepatocyte function, induction of immunomodulatory effects, and mitigation of cytokine storm. Nevertheless, MSC-EVs face challenges regarding the necessity of defining consistent isolation methods, optimizing MSCs culture conditions, and establishing quality control measures for EV characterization and functional assessment. By establishing standardized protocols, guidelines, and affordable cost mass production, clinicians and researchers will have a solid foundation to conduct further studies, validate the therapeutic efficacy of MSC-EVs, and ultimately pave the way for their clinical implementation in acute liver injury. [ABSTRACT FROM AUTHOR]

Background: Brain injury is a leading cause of morbidity and mortality in patients resuscitated from cardiac arrest. Mitochondrial dysfunction contributes to brain injury following cardiac arrest; therefore, therapies that limit mitochondrial dysfunction have the potential to improve neurological outcomes. Generation of reactive oxygen species (ROS) during ischemia–reperfusion injury in the brain is a critical component of mitochondrial injury and is dependent on hyperactivation of mitochondria following resuscitation. Our previous studies have provided evidence that modulating mitochondrial function with specific near-infrared light (NIR) wavelengths can reduce post-ischemic mitochondrial hyperactivity, thereby reducing brain injury during reperfusion in multiple small animal models. Methods: Isolated porcine brain cytochrome c oxidase (COX) was used to investigate the mechanism of NIR-induced mitochondrial modulation. Cultured primary neurons from mice expressing mitoQC were utilized to explore the mitochondrial mechanisms related to protection with NIR following ischemia–reperfusion. Anesthetized pigs were used to optimize the delivery of NIR to the brain by measuring the penetration depth of NIR to deep brain structures and tissue heating. Finally, a model of out-of-hospital cardiac arrest with CPR in adult pigs was used to evaluate the translational potential of NIR as a noninvasive therapeutic approach to protect the brain after resuscitation. Results: Molecular evaluation of enzyme activity during NIR irradiation demonstrated COX function was reduced in an intensity-dependent manner with a threshold of enzyme inhibition leading to a moderate reduction in activity without complete inhibition. Mechanistic interrogation in neurons demonstrated that mitochondrial swelling and upregulation of mitophagy were reduced with NIR treatment. NIR therapy in large animals is feasible, as NIR penetrates deep into the brain without substantial tissue heating. In a translational porcine model of CA/CPR, transcranial NIR treatment for two hours at the onset of return of spontaneous circulation (ROSC) demonstrated significantly improved neurological deficit scores and reduced histologic evidence of brain injury after resuscitation from cardiac arrest. Conclusions: NIR modulates mitochondrial function which improves mitochondrial dynamics and quality control following ischemia/reperfusion. Noninvasive modulation of mitochondria, achieved by transcranial treatment of the brain with NIR, mitigates post-cardiac arrest brain injury and improves neurologic functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Our previous randomized controlled trial (RCT) have demonstrated that intermittent Pringle's maneuver (IPM) with a 25-min ischemic interval can be applied safely and efficiently in open or laparoscopic hepatectomy in patients with hepatocellular carcinoma (HCC) patients. But prolonging the hepatic inflow blocking time will inevitably aggravate the ischemia-reperfusion injury (IRI) caused by systemic response. This RCT aims to evaluate the effect of administration of dexamethasone versus placebo before clamping the hilar pedicle on postoperative liver function, inflammatory response, and perioperative outcomes among HCC patients undergoing liver resection with 25-min hepatic inflow occlusion. Methods and analysis: This will be a randomized, dual-arm, parallel-group, double-blinded trial. All eligible and consecutive patients are coming from a regional medical center who are diagnosed with HCC and underwent radical R0/R1 resection. All participates are randomly allocated in dexamethasone group or placebo group. All surgeons, anesthesiologists, and outcome assessors will be blinded to allocation status. Primary endpoints are transaminase-based postoperative hepatic injury on seven consecutive days after surgery and assessed by their peak values as well as area under the curve (AUC) of the postoperative course of aminotransferases. Secondary endpoints are postoperative total bilirubin (TBil), coagulation function, inflammatory cytokines and their respective peaks, intraoperative blood loss, postoperative hospital stay, morbidity, and mortality. The above parameters will be compared using the corresponding statistical approach. Subgroup analysis will be performed according to the liver cirrhosis and major hepatectomy. Discussion: Based on our previous study, we will explore further the effect of glucocorticoid administration on attenuating the surgical stress response in order to follow securely 25-min hepatic inflow occlusion. Therefore, the trial protocol is reasonable and the results of the trial may be clinically significant. Trial registration: This trial was registered on 3 December 2022, in the Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR2200066381. The protocol version is V1.0 (20221104). [ABSTRACT FROM AUTHOR]

Background: Intestinal ischemia-reperfusion injury occurs in acute intestinal obstruction, intussusception, acute mesenteric artery embolism, and other diseases and can lead to local intestinal necrosis, distant organ involvement, or systemic reactions, with high morbidity and mortality. Ferroptosis plays a crucial role in intestinal ischemia-reperfusion injury, and inhibition of ferroptosis may provide new approaches for treating the disease. SIRT3 protects cells from oxidative stress and may be involved in the process of ferroptosis. We hypothesized that resveratrol, an agonist of SIRT3, could ameliorate intestinal ischemia-reperfusion injury by compensating the GSH/GPX4 pathway. Methods: Intestinal ischemia-reperfusion (I/R) and Caco-2 hypoxia-reoxygenation models were established. Transmission electron microscopy was used to assess mitochondrial function; the Chiu's score was used to evaluate the degree of intestinal mucosal injury based on HE staining; and Western blot was used to detect the SIRT3/FoxO3a pathway, tight junction proteins and ferroptosis-related protein expression. Sirt3-/- C57, shSIRT3-Caco-2 cells and siFoxO3a-Caco-2 cells were established. C11-BODIPY was used to detect lipid peroxide in cells; FD4 and IFABP were used to detect intestinal permeability; MitoSOX was used to detect ROS levels; and MitoTracker and immunofluorescence colocalization were used to detect SIRT3 levels. Results: In the intestinal I/R model, I/R injury occurs mainly during the reperfusion period and leads to ferroptosis through the GSH/GPX4 pathway. Resveratrol could reduce ferroptosis and ameliorate I/R injury by activating SIRT3. In Sirt3-/- mice, more intestinal mucosal cells underwent ferroptosis, I/R injury was more severe, and resveratrol lost the ability to ameliorate I/R injury. In addition, hypoxia-reoxygenation increased RSL3-induced ferroptosis sensitivity in Caco-2 cells in vitro. In the presence of shSIRT3 or RSL3 alone, resveratrol could ameliorate Caco-2 ferroptosis, but not RSL3-induced shSIRT3-Caco-2 ferroptosis. Furthermore, resveratrol might activate the SIRT3/FoxO3a pathway, increase the expression of SOD2 and catalase, and inhibit ROS generation, thus reducing lipid peroxidation and ferroptosis. Conclusion: To date, this is the first study to show that resveratrol ameliorates intestinal ischemia-reperfusion injury by activating SIRT3 and reducing ferroptosis. Resveratrol can reduce intestinal ischemia-reperfusion injury by activating the SIRT3/FoxO3a pathway, increasing the expression of SOD2 and catalase, reducing ROS and LPO production, compensating for the GSH/GPX4 pathway and inhibiting ferroptosis. [ABSTRACT FROM AUTHOR]

Background: Retinal ischemia–reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although the molecular mechanism underlying the ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part in the mortality of retinal ganglion cells. Methods: Single-cell RNA sequencing (scRNA-seq), molecular docking, and transfection assay were used to explore the effectiveness and pathogenesis of N,N-dimethyl-3β-hydroxycholenamide (DMHCA)-treated mice with RIR injury and DMHCA-treated microglia after oxygen and glucose deprivation/reoxygenation (OGD/R). Results: DMHCA could suppress inflammatory gene expression and attenuate neuronal lesions, restoring the retinal structure in vivo. Using scRNA-seq on the retina of DMHCA-treated mice, we provided novel insights into RIR immunity and demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as a promising treatment target for RIR. Moreover, the expression of Ninj1, which was increased in RIR injury and OGD/R-treated microglia, was downregulated in the DMHCA-treated group. DMHCA suppressed the activation of the nuclear factor kappa B (NF-κB) pathways induced by OGD/R, which was undermined by the NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed the anti-inflammatory and anti-apoptotic function of DMHCA. Molecular docking indicated that for Ninj1, DMHCA had a low binding energy of − 6.6 kcal/mol, suggesting highly stable binding. Conclusion: Ninj1 may play a pivotal role in microglia-mediated inflammation, while DMHCA could be a potential treatment strategy against RIR injury. [ABSTRACT FROM AUTHOR]

Background: Kidney ischemia–reperfusion injury is inevitable in kidney transplantation, and is essential for primary graft dysfunction and delayed graft function. Our previous study has proved that miR-92a could ameliorate kidney ischemia–reperfusion injury, but the mechanism has not been studied. Methods: This study conducted further research on the role of miR-92a in kidney ischemia–reperfusion injury and organ preservation. In vivo, mice models of bilateral kidney ischemia (30 min), cold preservation after ischemia (cold preservation time of 6, 12, and 24 h), and ischemia–reperfusion (reperfusion time of 24, 48, and 72 h) were established. Before or after modeling, the model mice were injected with miR-92a-agomir through the caudal vein. In vitro, the hypoxia–reoxygenation of HK-2 cells was used to simulate ischemia–reperfusion injury. Results: Kidney ischemia and ischemia–reperfusion significantly damaged kidney function, decreased the expression of miR-92a, and increased apoptosis and autophagy in kidneys. miR-92a agomir tail vein injection significantly increased the expression of miR-92a in kidneys, improved kidney function, and alleviated kidney injury, and the intervention before modeling achieved a better effect than after. Moreover, miR-92a agomir significantly reduced the apoptosis and autophagy in HK-2 cells induced by hypoxia, hypoxia–reoxygenation, and rapamycin, while miR-92a antagomir had opposite effects. Furthermore, mitogen-activated protein kinase, c-Jun NH (2) terminal kinase, caspase 3, Beclin 1, and microtubule-associated protein 1 light chain 3B were inhibited by overexpression of miR-92a both in vivo and in vitro, which in turn reduced apoptosis and autophagy. Conclusions: Our results prove that overexpression of miR-92a attenuated kidney ischemia–reperfusion injury and improved kidney preservation, and intervention before ischemia–reperfusion provides better protection than after. [ABSTRACT FROM AUTHOR]

Background: Despite inconsistent evidence, international guidelines underline the importance of perioperative hyperoxygenation in prevention of postoperative infections. Further, data on safety and efficacy of this method in liver transplant setting are lacking. The aim was to evaluate efficacy and safety of postoperative hyperoxygenation in prophylaxis of infections after liver transplantation. Methods: In this randomized controlled trial, patients undergoing liver transplantation were randomly assigned to either 28% or 80% fraction of inspired oxygen (FiO2) for 6 postoperative hours. Infections occurring during 30-day post-transplant period were the primary outcome measure. Secondary outcome measures included 90-day mortality, 90-day severe morbidity, 30-day pulmonary complications, durations of hospital and intensive care unit stay, and 5-day postoperative bilirubin concentration, alanine and aspartate transaminase activity, and international normalized ratio (INR) (clinicatrials.gov NCT02857855). Results: A total of 193 patients were included and randomized to 28% (n = 99) and 80% (n = 94) FiO2. With similar patient, operative, and donor characteristics in both groups, infections occurred in 34.0% (32/94) of patients assigned to 80% FiO2 as compared to 23.2% (23/99) of patients assigned to 28% FiO2 (p = 0.112). Patients randomized to 80% FiO2 more frequently developed severe complications (p = 0.035), stayed longer in the intensive care unit (p = 0.033), and had higher bilirubin concentration over first 5 post-transplant days (p = 0.043). No significant differences were found regarding mortality, duration of hospital stay, pulmonary complications, and 5-day aspartate and alanine transaminase activity and INR. Conclusions: Postoperative hyperoxygenation should not be used for prophylaxis of infections after liver transplantation due to the lack of efficacy. Trial registration: ClinicalTrials.gov NCT02857855. Registered 7 July 2016. [ABSTRACT FROM AUTHOR]

Background: sCD59, as a soluble form of CD59, is observed in multiple types of body fluids and correlated with the cell damage after ischemia/reperfusion injury. This study aims to observe the dynamic changes of serum sCD59 in patients after restoration of spontaneous circulation (ROSC) and explore the association of serum sCD59 with neurological prognosis and all-cause mortality in patients after ROSC. Methods: A total of 68 patients after ROSC were prospectively recruited and divided into survivors (n = 23) and non-survivors (n = 45) groups on the basis of 28-day survival. Twenty healthy volunteers were enrolled as controls. Serum sCD59 and other serum complement components, including sC5b-9, C5a, C3a, C3b, C1q, MBL, Bb, and pro-inflammatory mediators tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), neurological damage biomarkers neuron-specific enolase (NSE) and soluble protein 100β (S100β) were measured by enzyme linked immunosorbent assay on day 1, 3, and 7 after ROSC. Neurologic outcome was assessed using cerebral performance category scores, with poor neurologic outcome defined as 3–5 points. Results: In the first week after ROSC, serum levels of sCD59, sC5b-9, C5a, C3a, C3b, C1q, MBL, Bb, TNF-α, IL-6, NSE and S100β were significantly elevated in patients after ROSC compared to healthy volunteers, with a significant elevation in the non-survivors compared to survivors except serum C1q and MBL. Serum sCD59 levels were positively correlated with serum sC5b-9, TNF-α, IL-6, NSE, S100β, SOFA score and APACHE II score. Moreover, serum sCD59 on day 1, 3, and 7 after ROSC could be used for predicting poor 28-day neurological prognosis and all-cause mortality. Serum sCD59 on day 3 had highest AUCs for predicting poor 28-day neurological prognosis [0.862 (95% CI 0.678–0.960)] and 28-day all-cause mortality [0.891 (95% CI 0.769–0.962)]. In multivariate logistic regression analysis, the serum level of sCD59D1 was independently associated with poor 28-day neurological prognosis and all-cause mortality. Conclusions: The elevated serum level of sCD59 was positively correlated with disease severity after ROSC. Moreover, serum sCD59 could have good predictive values for the poor 28-day neurological prognosis and all-cause mortality in patients after ROSC. [ABSTRACT FROM AUTHOR]

Background: Although marginal donor livers expand the donor pool, an ideal method for quantitatively evaluating the quality of donor livers has not been developed. This study aimed to explore the feasibility of indocyanine green (ICG) fluorescence imaging for estimating liver function in an ischemia–reperfusion model. Methods: Forty-eight rats were randomly and evenly divided into 8 groups: the control group and the experimental groups (I-VII). The portal vein blocking period was 0 min, 10 min, 20 min, 30 min, 40 min, 50 min and 60 min. After blood flow was reestablished and the hemodynamics stabilized, ICG was injected through the dorsal penile vein as a bolus, and the fluorescence signal was recorded for 30 min in real time. The fluorescence intensity (FI) curve of the liver was fitted with an asymptotic regression model. Fresh liver tissues and serum were obtained from the middle lobe of the liver on postoperative day (POD) 1 and POD 7 for histopathological evaluation and liver function tests. Results: The growth rate of the FI curve, parameter b3, decreased from groups I to VII. According to the two sudden changes in b3 (20 min, 50 min), the experimental groups could be classified into 3 groups (A, B and C). Hepatocytes in groups I-II showed slight edema, group III began to show obvious hepatocyte edema and vacuolar degeneration, and in groups VI-VII, severe hepatocyte degeneration, necrosis and large inflammatory cell infiltration were observed. Suzuki's scores in the 3 groups were also significantly different (P < 0.01). At the same time, the serum liver function in the experimental groups showed a significant increase on POD 1 and a decrease on POD 7. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels of groups A, B, and C were significantly different on POD 1 (P < 0.05), and the ALT and direct bilirubin (DB) levels were significantly different on POD 7 (P < 0.05); the lactic dehydrogenase (LDH) level of the group C was significantly higher than that of the groups A and B on POD 1 and POD 7. Meanwhile, the 7-day survival rate of the rats in group C was poor compared to that of the rats in groups A and B (58.3% vs. 100% vs. 100%). Conclusion: ICG fluorescence imaging is effective for estimating the degree of liver damage and grading in an ischemia–reperfusion model. It probably has the potential for use in assessing the quality of the donor liver in liver transplantation. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion injury (IRI) is the pathophysiological hallmark of hepatic dysfunction after orthotopic liver transplantation (OLT). Related to IRI, early allograft dysfunction (EAD) after OLT affects short- and long-term outcome. During inflammatory states, the liver seems to be the main source of procalcitonin (PCT), which has been shown to increase independently of bacterial infection. This study investigates the association of PCT, IRI and EAD as well as the predictive value of PCT during the first postoperative week in terms of short- and long-term outcome after OLT.Methods: Patients ≥ 18 years undergoing OLT between January 2016 and April 2020 at the University Hospital of Zurich were eligible for this retrospective study. Patients with incomplete PCT data on postoperative days (POD) 1 + 2 or combined liver-kidney transplantation were excluded. The PCT course during the first postoperative week, its association with EAD, defined by the criteria of Olthoff, and IRI, defined as aminotransferase level > 2000 IU/L within 2 PODs, were analysed. Finally, 90-day as well as 12-month graft and patient survival were assessed.Results: Of 234 patients undergoing OLT, 110 patients were included. Overall, EAD and IRI patients had significantly higher median PCT values on POD 2 [31.3 (9.7-53.8) mcg/l vs. 11.1 (5.3-25.0) mcg/l; p < 0.001 and 27.7 (9.7-51.9) mcg/l vs. 11.5 (5.5-25.2) mcg/l; p < 0.001] and impaired 90-day graft survival (79.2% vs. 95.2%; p = 0.01 and 80.4% vs. 93.8%; p = 0.033). IRI patients with PCT < 15 mcg/l on POD 2 had reduced 90-day graft and patient survival (57.9% vs. 93.8%; p = 0.001 and 68.4% vs. 93.8%; p = 0.008) as well as impaired 12-month graft and patient survival (57.9% vs. 96.3%; p = 0.001 and 68.4% vs. 96.3%; p = 0.008), while the outcome of IRI patients with PCT > 15 mcg/l on POD 2 was comparable to that of patients without IRI/EAD.Conclusion: Generally, PCT is increased in the early postoperative phase after OLT. Patients with EAD and IRI have a significantly increased PCT maximum on POD 2, and impaired 90-day graft survival. PCT measurement may have potential as an additional outcome predictor in the early phase after OLT, as in our subanalysis of IRI patients, PCT values < 15 mcg/l were associated with impaired outcome. [ABSTRACT FROM AUTHOR]

Background: Despite advances in surgical and postoperative care, myocardial injury or infarction (MI) is still a common complication in patients undergoing coronary artery bypass surgery (CABG). Several studies that aimed to reduce postoperative myocardial injury, including those investigating statin loading, have been conducted but did not indicate any clear benefits. Evolocumab, a PCSK9 inhibitor, has been reported to lower lipids and prevent ischemic events in various medical conditions. However, the effect of evolocumab in cardiovascular surgery has not been evaluated. The objective of this trial is to evaluate the cardioprotective effects of evolocumab in elective CABG patients with multivessel coronary artery disease.Methods: EVOCABG is a prospective, randomized, open, controlled, multicenter, superiority, phase III clinical trial. Patients with multivessel coronary artery disease without initial cardiac enzyme elevation will be recruited (n=100). Participants will be randomly allocated into two groups: a test group (evolocumab (140mg) administration once within 72 h before CABG) and a control group (no administration). The primary outcome is the change in peak levels of serum cardiac marker (troponin-I) within 3 days of CABG surgery compared to the baseline. Secondary outcomes include post-operative clinical events including death, myocardial infarction, heart failure, stroke, and atrial fibrillation.Discussion: This trial is the first prospective randomized controlled trial to demonstrate the efficacy of evolocumab in reducing ischemic-reperfusion injury in patients undergoing CABG. This trial will provide the first high-quality evidence for preoperative use of evolocumab in mitigating or preventing ischemic-reperfusion-related myocardial injury during the surgery.Trial Registration: Clinical Research Information Service (CRIS) of the Republic of Korea KCT0005577 . Registered on 4 November 2020. [ABSTRACT FROM AUTHOR]

Background: Steatotic livers tolerate ischemia–reperfusion injury (IRI) poorly, increasing the risk of organ dysfunction. Ferroptosis is considered the initiating factor of organ IRI. Heme oxygenase oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) (HO-1/BMMSCs) can reduce hepatic IRI; however, the role of ferroptosis in IRI of steatotic grafts and the effect of HO-1/BMMSCs-derived exosomes (HM-exos) on ferroptosis remain unknown. Methods: A model of rat liver transplantation (LT) with a severe steatotic donor liver and a model of hypoxia and reoxygenation (H/R) of steatotic hepatocytes were established. Exosomes were obtained by differential centrifugation, and the differentially expressed genes (DEGs) in liver after HM-exo treatment were detected using RNA sequencing. The expression of ferroptosis markers was analyzed. microRNA (miRNA) sequencing was used to analyze the miRNA profiles in HM-exos. Results: We verified the effect of a candidate miRNA on ferroptosis of H/R treated hepatocytes, and observed the effect of exosomes knockout of the candidate miRNA on hepatocytes ferroptosis. In vitro, HM-exo treatment reduced the IRI in steatotic grafts, and enrichment analysis of DEGs suggested that HM-exos were involved in the regulation of the ferroptosis pathway. In vitro, inhibition of ferroptosis by HM-exos reduced hepatocyte injury. HM-exos contained more abundant miR-124-3p, which reduced ferroptosis of H/R-treated cells by inhibiting prostate six transmembrane epithelial antigen 3 (STEAP3), while overexpression of Steap3 reversed the effect of mir-124-3p. In addition, HM-exos from cell knocked out for miR-124-3p showed a weakened inhibitory effect on ferroptosis. Similarly, HM-exo treatment increased the content of miR-124-3p in grafts, while decreasing the level of STEAP3 and reducing the degree of hepatic ferroptosis. Conclusion: Ferroptosis is involved in the IRI during LT with a severe steatotic donor liver. miR-124-3p in HM-exos downregulates Steap3 expression to inhibit ferroptosis, thereby attenuating graft IRI, which might be a promising strategy to treat IRI in steatotic grafts. [ABSTRACT FROM AUTHOR]

Background: One of the main effectors on the quality of life of living-kidney donors is postoperative fatigue. Caloric restriction (CR) and short-term fasting (STF) are associated with improved fitness and increased resistance to acute stress. CR/STF increases the expression of cytoprotective genes, increases immunomodulation via increased anti-inflammatory cytokine production, and decreases the expression of pro-inflammatory markers. As such, nutritional preconditioning by CR or STF represents a non-invasive and cost-effective method that could mitigate the effects of acute surgery-induced stress and postoperative fatigue. To investigate whether preoperative STF contributes to a reduction in fatigue after living-kidney donation, a randomized clinical trial is indicated.Methods: We aim to determine whether 2.5 days of fasting reduces postoperative fatigue score in subjects undergoing living-kidney donation. In this randomized study, the intervention group will follow a preoperative fasting regime for 2.5 days with a low-dose laxative, while the control group will receive standard care. The main study endpoint is postoperative fatigue, 4 weeks after living-kidney donation. Secondary endpoints include the effect of preoperative fasting on postoperative hospital admission time, the feasibility of STF, and the postoperative recovery of donor and recipient kidney function. This study will provide us with knowledge of the feasibility of STF and confirm its effect on postoperative recovery.Discussion: Our study will provide clinically relevant information on the merits of caloric restriction for living-kidney donors and recipients. We expect to reduce the postoperative fatigue in living-kidney donors and improve the postoperative recovery of living-kidney recipients. It will provide evidence on the clinical merits and potential caveats of preoperative dietary interventions.Trial Registration: Netherlands Trial Register NL9262 . EudraCT 2020-005445-16 . MEC Erasmus MC MEC-2020-0778. CCMO NL74623.078.21. [ABSTRACT FROM AUTHOR]

Background: Empagliflozin is a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor used to lower blood sugar in adults with type 2 diabetes. Empagliflozin also exerts cardioprotective effects independent from glucose control, but its benefits on arrhythmogenesis and sudden cardiac death are not known. The purpose of this study was to examine the effect of empagliflozin on myocardial ischemia/reperfusion-provoked cardiac arrhythmia and sudden cardiac death in vivo. Methods: Male Sprague Dawley rats were randomly assigned to sham-operated, control or empagliflozin groups. All except for the sham-operated rats were subjected to 5-min left main coronary artery ligation followed by 20-min reperfusion. A standard limb lead II electrocardiogram was continuously measured throughout the experiment. Coronary artery reperfusion-induced ventricular arrhythmogenesis and empagliflozin therapy were evaluated. The hearts were used for protein phosphorylation analysis and immunohistological assessment. Results: Empagliflozin did not alter baseline cardiac normal conduction activity. However, empagliflozin eliminated myocardial vulnerability to sudden cardiac death (from 69.2% mortality rate in the control group to 0% in the empagliflozin group) and reduced the susceptibility to reperfusion-induced arrhythmias post I/R injury. Empagliflozin increased phosphorylation of cardiac ERK1/2 after reperfusion injury. Furthermore, inhibition of ERK1/2 using U0126 abolished the anti-arrhythmic action of empagliflozin and ERK1/2 phosphorylation. Conclusions: Pretreatment with empagliflozin protects the heart from subsequent severe lethal ventricular arrhythmia induced by myocardial ischemia and reperfusion injury. These protective benefits may occur as a consequence of activation of the ERK1/2-dependent cell-survival signaling pathway in a glucose-independent manner. [ABSTRACT FROM AUTHOR]

Background: Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments that trigger resolution of inflammation may also promote iBRB restoration.Methods: Using the mouse retinal ischemia-reperfusion (IR) injury model, we followed the time course of neurodegeneration, inflammation, and iBRB disruption and repair to examine the relationship between resolution of inflammation and iBRB restoration and to determine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes.Results: A 90-min ischemic insult followed by reperfusion in the retina induced cell apoptosis and inner retina thinning that progressed for approximately 2 weeks. IR increased vascular permeability within hours, which resolved between 3 and 4 weeks after injury. Increased vascular permeability coincided with alteration and loss of endothelial cell tight junction (TJ) protein content and disorganization of TJ protein complexes. Shunting of blood flow away from leaky vessels and dropout of leaky capillaries were eliminated as possible mechanisms for restoring the iBRB. Repletion of TJ protein contents occurred within 2 days after injury, long before restoration of the iBRB. In contrast, the eventual re-organization of TJ complexes at the cell border coincided with restoration of the barrier. A robust inflammatory response was evident a 1 day after IR and progressed to resolution over the 4-week time course. The inflammatory response included a rapid and transient infiltration of granulocytes and Ly6C+ classical inflammatory monocytes, a slow accumulation of Ly6Cneg monocyte/macrophages, and activation, proliferation, and mobilization of resident microglia. Extravasation of the majority of CD45+ leukocytes occurred from the superficial plexus. The presence of monocyte/macrophages and increased numbers of microglia were sustained until the iBRB was eventually restored. Intervention with minocycline to reverse microglial activation at 1 week after injury promoted early restoration of the iBRB coinciding with decreased expression of mRNAs for the microglial M1 markers TNF-α, IL-1β, and Ptgs2 (Cox-2) and increased expression of secreted serine protease inhibitor Serpina3n mRNA.Conclusions: These results suggest that iBRB restoration occurs as TJ complexes are reorganized and that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the role of mesenchymal stromal cells (MSCs)-derived exosomes (MSCs-Exo) in the cerebral ischemia–reperfusion (I/R) injury. Methods: Exosomes were isolated from MSCs of adult C57BL/6J mice by the gradient centrifugation method. The expression of miR-26a-5p and CDK6 in MSCs-Exo and mice brain tissues were evaluated by qRT-PCR and western blot. miR-26a-5p mimics and miR-NC were transfected into MSCs, and exosomes were isolated from the MSCs stably expressing miR-26a-5p. Then MSCs-Exo-miR-26a-5p mimics or MSCs-Exo-miR-NC was injected into mice through the tail vein, or added into medium to stimulate BV-2 cells. Cell viability was evaluated by CCK-8 assay. Cell apoptosis was detected by flow cytometry. The apoptosis in brain tissues was evaluated by TUNEL staining assay. Bioinformatics analysis and luciferase reporter assay were performed to determine the binding relationship between miR-26a-5p and CDK6. Results: miR-26a-5p was downregulated and CDK6 was upregulated in MSCs-Exo of MCAO-mice and OGD-induced MSCs. MSCs-Exo-miR-26a-5p mimics significantly reduced cell apoptosis of OGD-injured BV-2 cells. MSCs-Exo-miR-26a-5p mimics significantly reduced the infarct volume of MCAO-induced mice. Luciferase reporter assay revealed that CDK-6 was a target of miR-26a-5p. In addition, MSCs-Exo-miR-26a-5p mimics significantly decreased the expression of CDK6 in both OGD-induced BV-2 cells and the brain tissues of MCAO-treated mice. Conclusion: Our results indicated that MSCs‑Exo attenuated I/R injury in mice by inhibiting microglia apoptosis might via exosomal miR-26a-5p mediated suppression of CDK6. Our study shed light on the application of MSC-Exo as a potential therapeutic tool for cerebral I/R injury. [ABSTRACT FROM AUTHOR]

Background: This study tested the hypothesis that combined melatonin (Mel) and adipose-derived mesenchymal stem cells (ADMSCs) treatment was superior to either one alone on protecting the testis against acute testicular torsion-induced ischemia-reperfusion (TTIR) injury. Methods and results: Male adult SD rats (n = 30) were equally categorized into group 1 (sham-operated control), group 2 [TTIR/by torsion of right/left testis (i.e., ischemia) with rotated 720° counterclockwise for 2 h, then detorsion (i.e., reperfusion) to the original position for 72 h], group 3 (TTIR + Mel/intraperitoneal administration/50 mg/kg at 30 min after ischemia, followed by 20 mg at 3 h and days 1/2/3 after TTIR), group 4 (TTIR + ADMSCs/1.2 × 106 cells/by tail-vein administration at 30 min after ischemia, followed by days 1/2 TTIR), and group 5 (TTIR + Mel + ADMSCs/tail-vein administration). The result showed that the protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized-protein), apoptotic/mitochondrial-damaged (mitochondrial-Bax/cleaved-caspase3/cleaved-PARP/cytosolic-cytochrome C), and fibrotic (TGF-ß/Smad3) biomarkers as well as testicular damage scores were lowest in group 1, highest in group 2, and significantly higher in groups 3/4 than in group 5, but they showed no difference between groups 3/4, whereas the protein expressions of androgen receptor (AR) and vimentin showed an opposite pattern of oxidative stress (all p < 0.0001). The cellular levels of inflammation (MMP-9/MPO/CD68) exhibited an identical pattern, whereas the numbers of Sertoli cells, α-tubulin, AR and vimentin as well as thickness of seminiferous tubule exhibited an opposite pattern of oxidative stress among the groups (all p < 0.0001). Conclusion: Mel-ADMSCs effectively protected the testis against TTIR injury. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear. Methods: Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI. Result: HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1β, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery. Conclusion: The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion injury (MIRI) is the main pathological manifestation of cardiovascular diseases such as myocardial infarction. The potential therapeutic effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) and the participation of regulatory T cells (Tregs) in MIRI remains to be defined.Methods: We used the experimental acute MIRI that was induced in mice by left ascending coronary ischemia, which were subsequently randomized to receive immunoglobulin G (IgG) or anti-CD25 antibody PC61 with or without intravenously injected BM-MSCs. The splenectomized mice underwent prior to experimental MIRI followed by intravenous administration of BM-MSCs. At 72 h post-MIRI, the hearts and spleens were harvested and subjected to cytometric and histologic analyses.Results: CD25+Foxp3+ regulatory T cells were significantly elevated after MIRI in the hearts and spleens of mice receiving IgG + BM-MSCs and PC61 + BM-MSCs compared to the respective control mice (all p < 0.01). This was accompanied by upregulation of interleukin 10 and transforming growth factor β1 and downregulation of creatinine kinase and lactate dehydrogenase in the serum. The post-MIRI mice receiving BM-MSCs showed attenuated inflammation and cellular apoptosis in the heart. Meanwhile, splenectomy compromised all therapeutic effects of BM-MSCs.Conclusion: Administration of BM-MSCs effectively alleviates MIRI in mice through inducing Treg activation, particularly in the spleen. [ABSTRACT FROM AUTHOR]

Background: Muscle is severely affected by ischemia/reperfusion injury (IRI). Quiescent satellite cells differentiating into myogenic progenitor cells (MPC) possess a remarkable regenerative potential. We herein established a model of local application of MPC in murine hindlimb ischemia/reperfusion to study cell engraftment and differentiation required for muscle regeneration. Methods: A clamping model of murine (C57b/6 J) hindlimb ischemia was established to induce IRI in skeletal muscle. After 2 h (h) warm ischemic time (WIT) and reperfusion, reporter protein expressing MPC (TdTomato or Luci-GFP, 1 × 106 cells) obtained from isolated satellite cells were injected intramuscularly. Surface marker expression and differentiation potential of MPC were analyzed in vitro by flow cytometry and differentiation assay. In vivo bioluminescence imaging and histopathologic evaluation of biopsies were performed to quantify cell fate, engraftment and regeneration. Results: 2h WIT induced severe IRI on muscle, and muscle fiber regeneration as per histopathology within 14 days after injury. Bioluminescence in vivo imaging demonstrated reporter protein signals of MPC in 2h WIT animals and controls over the study period (75 days). Bioluminescence signals were detected at the injection site and increased over time. TdTomato expressing MPC and myofibers were visible in host tissue on postoperative days 2 and 14, respectively, suggesting that injected MPC differentiated into muscle fibers. Higher reporter protein signals were found after 2h WIT compared to controls without ischemia, indicative for enhanced growth and/or engraftment of MPC injected into IRI-affected muscle antagonizing muscle damage caused by IRI. Conclusion: WIT-induced IRI in muscle requests increased numbers of injected MPC to engraft and persist, suggesting a possible rational for cell therapy to antagonize IRI. Further investigations are needed to evaluate the regenerative capacity and therapeutic advantage of MPC in the setting of ischemic limb injury. [ABSTRACT FROM AUTHOR]

Mitochondria play a central role in cellular energy metabolism, and their dysfunction is increasingly recognized as a critical factor in the pathogenesis of diabetes-related cardiac pathophysiology, including vulnerability to ischemic events that culminate in myocardial infarction on the one hand and ventricular arrhythmias on the other. In diabetes, hyperglycemia and altered metabolic substrates lead to excessive production of reactive oxygen species (ROS) by mitochondria, initiating a cascade of oxidative stress that damages mitochondrial DNA, proteins, and lipids. This mitochondrial injury compromises the efficiency of oxidative phosphorylation, leading to impaired ATP production. The resulting energy deficit and oxidative damage contribute to functional abnormalities in cardiac cells, placing the heart at an increased risk of electromechanical dysfunction and irreversible cell death in response to ischemic insults. While cardiac mitochondria are often considered to be relatively autonomous entities in their capacity to produce energy and ROS, their highly dynamic nature within an elaborate network of closely-coupled organelles that occupies 30-40% of the cardiomyocyte volume is fundamental to their ability to exert intricate regulation over global cardiac function. In this article, we review evidence linking the dynamic properties of the mitochondrial network to overall cardiac function and its response to injury. We then highlight select studies linking mitochondrial ultrastructural alterations driven by changes in mitochondrial fission, fusion and mitophagy in promoting cardiac ischemic injury to the diabetic heart., (© 2024. The Author(s).)

Background: Ischemia-reperfusion injury (IRI) is an important factor limiting the success of cardiac reperfusion therapy. Curcumin has a significant cardioprotective effect against IRI, can inhibit ventricular remodeling induced by pressure load or MI, and improve cardiac function. However, the poor water solubility and low bioavailability of curcumin restrict its clinical application. Methods: In this study, we prepared and evaluated a curcumin-hydrogel (cur-hydrogel) to reduce cardiomyocyte apoptosis and reactive oxygen species formation induced by hypoxia-reoxygenation injury, promote autophagy, and reduce mitochondrial damage by maintaining the phosphorylation of Cx43. Results: Meanwhile, cur-hydrogel can restore cardiac function, inhibit myocardial collagen deposition and apoptosis, and activate JAK2/STAT3 pathway to alleviate myocardial ischemia-reperfusion injury in rats. Conclusions: The purpose of this study is to elucidate the protective effects of cur-hydrogel on myocardial ischemia-reperfusion injury by regulating apoptosis, autophagy, and mitochondrial injury in vitro and in vivo, which lays a new theoretical and experimental foundation for the prevention and reduction of IRI. [ABSTRACT FROM AUTHOR]

Background: This study was designed to determine the effect of human umbilical cord multipotent mesenchymal stromal cells (hUC-MSC) on acute ischemia/reperfusion (I/R) injury of spermatogenic cells. Method: The testicular I/R rat model was established through 720° torsion for 1 h. hUC-MSC were intravenously injected 10 min before detorsion. Injury severity of spermatogenic cells was estimated by Johnsen's score. The proliferating of recipient spermatogonia was measured by the immunostaining of antibodies against Ki67, and all germ cells were detected with DDX4 antibody. And recipient spermatogenesis was assessed by staining spermatozoa with lectin PNA. The levels of inflammatory factors were measured by real-time PCR. And the Selectin-E expression, neutrophil infiltration in the testes was detected by immunostaining. Germ cells apoptosis was tested by TUNEL assay and western blot. Furthermore, the oxidative stress was tested by reactive oxidative species (ROS) levels. In vitro, the condition medium (CM) of hUC-MSC was used to culture human umbilical vein endothelial cells (HUVECs), so as to assess the paracrine effect of hUC-MSC on HUVECs. The protein chip was used to measure the relative concentration of the secretory proteins in the CM of hUC-MSC. Result: hUC-MSC greatly alleviated the testicular injury induced by testis I/R. The levels of proinflammatory factors were downregulated by hUC-MSC in vivo and in vitro. Neutrophil infiltration, ROS, and germ cell apoptosis in testicular tissues were greatly reduced in the group of hUC-MSC. Paracrine factors secreted by hUC-MSC including growth factors, cytokines, and anti-inflammatory cytokine were rich. Conclusion: This study demonstrated that intravenously injected hUC-MSC could protect the spermatogenic cells against I/R injury by reducing the inflammatory response, apoptosis, and acute oxidative injury. Paracrine mechanism of hUC-MSC may contribute to the protection of spermatogenic cells against I/R injury. Therefore, the present study provides a method for clinical treatment of attenuate I/R injury of spermatogenic cells. [ABSTRACT FROM AUTHOR]

Background: Kidney ischemia–reperfusion injury is a common pathophysiological phenomenon in the clinic. A large number of studies have found that the tyrosine protein kinase/signal transducer and activator of transcription (JAK/STAT) pathway is involved in the development of a variety of kidney diseases and renal protection associated with multiple drugs. Edaravone (EDA) is an effective free radical scavenger that has been used clinically for the treatment of postischemic neuronal injury. This study aimed to identify whether EDA improved kidney function in rats with ischemia–reperfusion injury by regulating the JAK/STAT pathway and clarify the underlying mechanism. Methods: Histomorphological analysis was used to assess pathological kidney injury, and mitochondrial damage was observed by transmission electron microscopy. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining was performed to detect tubular epithelial cell apoptosis. The expression of JAK2, P-JAK2, STAT3, P-STAT3, STAT1, P-STAT1, BAX and Bcl-2 was assessed by western blotting. Mitochondrial function in the kidney was assessed by mitochondrial membrane potential (ΔΨm) measurement. Results: The results showed that EDA inhibited the expression of p-JAK2, p-STAT3 and p-STAT1, accompanied by downregulation of the expression of Bax and caspase-3, and significantly ameliorated kidney damage caused by ischemia–reperfusion injury (IRI). Furthermore, the JC-1 dye assay showed that edaravone attenuated ischemia–reperfusion-induced loss of kidney ΔΨm. Conclusion: Our findings indicate that EDA protects against kidney damage caused by ischemia–reperfusion through JAK/STAT signaling, inhibiting apoptosis and improving mitochondrial injury. [ABSTRACT FROM AUTHOR]

Background: Ten-eleven translocation (Tet) methyl-cytosine dioxygenases (including Tet1/2/3)-mediated 5mC oxidation and DNA demethylation play important roles in embryonic development and adult tissue homeostasis. The expression of Tet2 and Tet3 genes are relatively abundant in the adult murine kidneys while Tet1 gene is expressed at a low level. Although Tet3 has been shown to suppress kidney fibrosis, the role of Tet2 in kidney physiology as well as renal ischemia-reperfusion (IR) injury is still largely unknown. Results: Tet2−/− mice displayed normal kidney morphology and renal function as WT mice while the expression of genes associated with tight junction and adherens junction was impaired. At 24 h post-renal IR, Tet2−/− mice showed higher SCr and BUN levels, more severe tubular damage, and elevated expression of Kim1 and Ngal genes in the kidney in comparison with WT mice. Moreover, the transcriptomic analysis revealed augmented inflammatory response in the kidneys of Tet2−/− mice. Conclusions: Tet2 is dispensable for kidney development and function at baseline condition while protects against renal IR injury possibly through repressing inflammatory response. Our findings suggest that Tet2 may be a potential target for the intervention of IR-induced acute kidney injury (AKI). [ABSTRACT FROM AUTHOR]

Background: A sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established. Methods: The effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function. Results: Dapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy. Conclusions: Acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness. [ABSTRACT FROM AUTHOR]

Background: Kidney ischemia reperfusion injury (IRI) is a common cause of acute kidney injury and an unavoidable consequence of kidney transplantation and still lacks specific therapeutics. Recently, mesenchymal stem cell (MSC) has been emerging as a promising cell-based therapy for IRI in the context of transplantation. MSC negatively regulates the secretion of pro-inflammatory as well as the activation of immune cells during IRI through its unique immunosuppressive property.Methods: We employed mice kidney IRI model and MSC cell line to monitor the IRI related checkpoints. siRNAs were utilized to knock down the potential key factors for mechanistic analysis. Statistical analysis was performed by using one-way ANOVA with Tukey's post hoc procedure by SPSS.Results: The expression of high-mobility group box 1 protein (HMGB1) is increased in the acute phase as well as the recovery stage of IRI. Importantly, the HMGB1 upregulation is correlated with the injury severity. HMGB1 diminishes the MSC induced immunosuppressive capacity in the presence of pro-inflammatory cytokines in vitro. Toll like receptor 4 (TLR4)-mediated inducible nitric oxide synthase (iNOS) inhibition contributes to the negative effect of HMGB1 on MSCs. HMGB1-TLR4 signaling inhibition augments the therapeutic efficacy of MSCs in mice renal IRI model.Conclusions: These findings demonstrate that HMGB1 plays a crucial role in shaping the immunoregulatory property of MSCs within the microenvironments, providing novel insights into the crosstalk between MSCs and microenvironment components, suggesting HMGB1 signals as a promising target to improve MSC-based therapy. [ABSTRACT FROM AUTHOR]

Background: Despite the fact that histone deacetylase (HDAC) inhibitors have been tested to treat various cardiovascular diseases, the effects of selective HDAC6 inhibitor ACY1215 on infarct size during cardiac ischemia-reperfusion (IR) injury still remain unknown. In the present study we aimed to investigate the effects of ACY1215 on infarct size in rats with cardiac IR injury, as well as to examine the association between HDAC6 inhibitors and the gene expression of hypoxia inducible factor-1α (HIF-1α), a key regulator of cellular responses to hypoxia. Methods: By using computational analysis of high-throughput expression profiling dataset, the association between HDAC inhibitors (pan-HDAC inhibitors panobinostat and vorinostat, and HDAC6 inhibitor ISOX) and their effects on HIF-1α gene-expression were evaluated. The male Wistar rats treated with ligation of left coronary artery followed by reperfusion were used as a cardiac IR model. ACY1215 (50 mg/kg), pan-HDAC inhibitor MPT0E028 (25 mg/kg), and vehicle were intraperitoneally injected within 5 min before reperfusion. The infarct size in rat myocardium was determined by 2,3,5-triphenyltetrazolium chloride staining. The serum levels of transforming growth factor-β (TGF-β) and C-reactive protein (CRP) were also determined. Results: The high-throughput gene expression assay showed that treatment of ISOX was associated with a more decreased gene expression of HIF-1α than that of panobinostat and vorinostat. Compared to control rats, ACY1215-treated rats had a smaller infarct size (49.75 ± 9.36% vs. 19.22 ± 1.70%, p < 0.05), while MPT0E028-treated rats had a similar infarct size to control rats. ACY-1215- and MPT0E028-treated rats had a trend in decreased serum TGF-β levels, but not statistically significant. ACY1215-treated rats also had higher serum CRP levels compared to control rats (641.6 μg/mL vs. 961.37 ± 64.94 μg/mL, p < 0.05). Conclusions: Our research indicated that HDAC6 inhibition by ACY1215 might reduce infarct size in rats with cardiac IR injury possibly through modulating HIF-1α expression. TGF-β and CRP should be useful biomarkers to monitor the use of ACY1215 in cardiac IR injury. [ABSTRACT FROM AUTHOR]

Background: Mimicking ischemia-reperfusion injury, oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) applied to endometrial cells produces significant oxidative stress and programmed necrosis, which can be inhibited by nuclear-factor-E2-related factor 2 (Nrf2) signaling. MicroRNA (miRNA)-induced repression of Keap1, a Nrf2 suppressor protein that facilitates Nrf2 degradation, is novel strategy to activate Nrf2 cascade. Methods: MicroRNA-941 (miR-941) was exogenously expressed in HESC and primary human endometrial cells, and the Nrf2 pathway examined by Western blotting and real-time quantitative PCR analysis. The endometrial cells were treated with OGDR, cell programmed necrosis and apoptosis were tested. Results: MiR-941 is a novel Keap1-targeting miRNA that regulates Nrf2 activity. In T-HESC cells and primary human endometrial cells, ectopic overexpression of miR-941 suppressed Keap1 3′-UTR (untranslated region) expression and downregulated its mRNA/protein expression, leading to activation of the Nrf2 cascade. Conversely, inhibition of miR-941 elevated Keap1 expression and activity in endometrial cells, resulting in suppression of Nrf2 activation. MiR-941 overexpression in endometrial cells attenuated OGDR-induced oxidative stress and programmed necrosis, whereas miR-941 inhibition enhanced oxidative stress and programmed necrosis. MiR-941 overexpression and inhibition were completely ineffective in Keap1−/Nrf2-KO T-HESC cells (using CRISPR/Cas9 strategy). Restoring Keap1 expression, using an UTR-depleted Keap1 construct, abolished miR-941-induced anti-OGDR activity in T-HESC cells. Thus Keap1-Nrf2 cascade activation is required for miR-941-induced endometrial cell protection. Conclusions: Targeting Keap1 by miR-941 activates Nrf2 cascade to protect human endometrial cells from OGDR-induced oxidative stress and programmed necrosis. Video Abstract [ABSTRACT FROM AUTHOR]

Background: Because hearts in acute myocardial infarction are often prone to ischemia-reperfusion damage during cardiac surgery, we investigated the influence of intracellular crystalloid cardioplegia solution (CCP) and extracellular blood cardioplegia solution (BCP) on cardiac function, metabolism, and infarct size in a rat heart model of myocardial infarction.Methods: Following euthanasia, the hearts of 50 rats were quickly excised, cannulated, and inserted into a blood-perfused isolated heart apparatus. A regional myocardial infarction was created in the infarction group (18 hearts) for 120 min; the control group (32 hearts) was not subjected to infarction. In each group, either Buckberg BCP or Bretschneider CCP was administered for an aortic clamping time of 90 min. Functional parameters were recorded during reperfusion: coronary blood flow, left ventricular developed pressure (LVDP) and contractility (dp/dt max). Infarct size was determined by planimetry. The results were compared between the groups using analysis of variance or parametric tests, as appropriate.Results: Cardiac function after acute myocardial infarction, 90 min of cardioplegic arrest, and 90 min of reperfusion was better preserved with Buckberg BCP than with Bretschneider CCP relative to baseline (BL) values (LVDP 54 ± 11% vs. 9 ± 2.9% [p = 0.0062]; dp/dt max. 73 ± 11% vs. 23 ± 2.7% [p = 0.0001]), whereas coronary flow was similarly impaired (BCP 55 ± 15%, CCP 63 ± 17% [p = 0.99]). The infarct in BCP-treated hearts was smaller (25% of myocardium) and limited to the area of coronary artery ligation, whereas in CCP hearts the infarct was larger (48% of myocardium; p = 0.029) and myocardial necrosis was distributed unevenly to the left ventricular wall.Conclusions: In a rat model of acute myocardial infarction followed by cardioplegic arrest, application of BCP leads to better myocardial recovery than CCP. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion (IR) injury is a leading cause of death all over the world, so developing practical approaches to promote cardioprotection against IR injury is essential. Exercise training is an effective strategy to improve cardioprotection. Hence, the purpose of this study was to investigate the effect of short-term preconditioning with two types of high-intensity interval training (HIIT) and moderate intensity continuous training (MICT) on klotho and TRPC6 mechanisms in cardioprotection.Methods: Eighty Male Wistar rats (250-300 g) were randomly divided into 7 groups, including Control, HIIT, MICT, Sham, IR, HIIT+IR, and MICT+IR. Training was performed in 5 consecutive days. HIIT protocol consisted of running on the treadmill at intervals 85-90% vo2max that separated by slow intensity periods at 50-60% vo2max. MICT program was performed at 70% VO2max at the same running distance with HIIT groups. The cardiac IR injury was induced by LAD occlusion followed by reperfusion. ELISA kit was used in order to measure the plasma levels of klotho, LDH and CK-MB, and TRPC6 expression was determined using the western blot technique. Data were analyzed using one way ANOVA and Tukey's post hoc tests.Results: The results of this study showed that both types of exercise training programs significantly increase plasma levels of klotho and reduce the infarct size and heart injury. In addition, the exercise training decreased the amount of TRPC6 channels expression during IR. However, the effect of HIIT on increasing the klotho and cardioprotection was greater compared to MICT.Conclusions: Based on the results, even a short-term of aerobic exercise training, especially HIIT, promotes cardioprotection against IR injury and decreases infarct size via an increase in klotho and attenuate of protein expression of myocardial TRPC6 during IR. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation (LT) is considered the standard treatment for end-stage liver disease, but ideal donors remain in limited supply, resulting in an unavoidable increase in the need to use grafts from marginal donors. The attenuation of ischemia-reperfusion injury (IRI) in such marginal donors is therefore crucial for reducing the possibility of the primary non-function of grafts and graft loss. Some reports have found that molecular-hydrogen showed antioxidant and anti-inflammatory effects in preventing IRI in some non-hepatic transplant models. Therefore, we investigated whether or not molecular-hydrogen could attenuate IRI in LT model rats.Methods: We used a hydrogen-rich water bath to dissolve hydrogen into solution and graft tissues and performed isogenic and orthotopic LT in Lewis rats with University of Wisconsin (UW) solution. Blood and tissue samples were collected 6 h after the reperfusion. Hepatic enzymes in serum were measured. Pathological findings including the expressions of cytokines and heme oxygenase (HO)-1 in liver tissues were evaluated.Results: The concentration of hydrogen inside the graft tissues increased depending on the storage time, plateauing after 1 h. Serum liver enzyme levels were significantly lower and the histology score of liver damage markedly attenuated in the group given grafts preserved in hydrogen-rich UW solution than in the control group. The hydrogen-rich UW solution group also showed less oxidative damage and hepatocyte apoptosis than the control group, and the expression of proinflammatory cytokines tended to be lower while the protein levels of HO-1 were significantly increased (n = 3-12 per group, P < 0.05).Conclusions: Storage of liver grafts in hydrogen-rich UW solution resulted in superior functional and morphologic protection against IRI via the up-regulation of HO-1 expression. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion injury (IRI) has become one of the most serious complications after reperfusion therapy in patients with acute myocardial infarction. Small ubiquitin-like modification (SUMOylation) is a reversible process, including SUMO E1-, E2-, and E3-mediated SUMOylation and SUMO-specific protease-mediated deSUMOylation, with the latter having been shown to play a vital role in myocardial IRI previously. However, little is known about the function and regulation of SUMO E3 ligases in myocardial IRI. Results: In this study, we found dramatically decreased expression of PIAS1 after ischemia/reperfusion (I/R) in mouse myocardium and H9C2 cells. PIAS1 deficiency aggravated apoptosis and inflammation of cardiomyocytes via activating the NF-κB pathway after I/R. Mechanistically, we identified PIAS1 as a specific E3 ligase for PPARγ SUMOylation. Moreover, H9C2 cells treated with hypoxia/reoxygenation (H/R) displayed reduced PPARγ SUMOylation as a result of down-regulated PIAS1, and act an anti-apoptotic and anti-inflammatory function through repressing NF-κB activity. Finally, overexpression of PIAS1 in H9C2 cells could remarkably ameliorate I/R injury. Conclusions: Collectively, our findings demonstrate the crucial role of PIAS1-mediated PPARγ SUMOylation in protecting against myocardial IRI. [ABSTRACT FROM AUTHOR]

Background: Current options to treat clinical relapse in inflammatory central nervous system (CNS) conditions such as cerebral ischemia-reperfusion injury are limited, and agents that are more effective are required. Disruption of the blood-brain barrier is an early feature of lesion formation that correlates with clinical exacerbation and facilitates the entry of inflammatory medium and inflammatory cells. Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring anti-inflammatory antagonist of the interleukin-1 (IL-1) family. The broad-spectrum anti-inflammatory effects of IL-1RA have been investigated against various forms of neuroinflammation. However, the effect of IL-1RA on blood-brain barrier disruption following ischemia-reperfusion has not been reported.Methods: In this study, we investigated the effects of IL-1RA and a novel protein (IL-1RA-PEP) that was fused to IL-1RA with a cell penetrating peptide, on blood-brain barrier integrity, in male rats subjected to transient middle cerebral artery occlusion.Results: After intravenous administration, IL-1RA-PEP (50 mg/kg) penetrated cerebral tissues more effectively than IL-1RA. Moreover, it preserved blood-brain barrier integrity, attenuated changes in expression and localization of tight junction proteins and matrix metalloproteinases, and enhanced angiogenesis in ischemic brain tissue. Further study suggested that the effects of IL-1RA-PEP on preserving blood-brain barrier integrity might be closely correlated with the p65/NF-κB pathway, as evidenced by the effects of the inhibitor JSH-23.Conclusions: Collectively, our results demonstrated that IL-1RA-PEP could effectively penetrate the brain of rats with middle cerebral artery occlusion and ameliorate blood-brain barrier disruption. This finding might represent its novel therapeutic potential in the treatment of the cerebral ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Lung ischemia-reperfusion (IR) injury after transplantation as well as acute shortage of suitable donor lungs are two critical issues impacting lung transplant patients. This study investigates the anti-inflammatory and immunomodulatory role of human mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) to attenuate lung IR injury and improve of ex-vivo lung perfusion (EVLP)-mediated rehabilitation in donation after circulatory death (DCD) lungs.Methods: C57BL/6 wild-type (WT) mice underwent sham surgery or lung IR using an in vivo hilar-ligation model with or without MSCs or EVs. In vitro studies used primary iNKT cells and macrophages (MH-S cells) were exposed to hypoxia/reoxygenation with/without co-cultures with MSCs or EVs. Also, separate groups of WT mice underwent euthanasia and 1 h of warm ischemia and stored at 4 °C for 1 h followed by 1 h of normothermic EVLP using Steen solution or Steen solution containing MSCs or EVs.Results: Lungs from MSCs or EV-treated mice had significant attenuation of lung dysfunction and injury (decreased edema, neutrophil infiltration and myeloperoxidase levels) compared to IR alone. A significant decrease in proinflammatory cytokines (IL-17, TNF-α, CXCL1 and HMGB1) and upregulation of keratinocyte growth factor, prostaglandin E2 and IL-10 occurred in the BAL fluid from MSC or EV-treated mice after IR compared to IR alone. Furthermore, MSCs or EVs significantly downregulated iNKT cell-produced IL-17 and macrophage-produced HMGB1 and TNF-α after hypoxia/reoxygenation. Finally, EVLP of DCD lungs with Steen solution including MSCs or EVs provided significantly enhanced protection versus Steen solution alone. Co-cultures of MSCs or EVs with lung endothelial cells prevents neutrophil transendothelial migration after exposure to hypoxia/reoxygenation and TNF-α/HMGB1 cytomix.Conclusions: These results suggest that MSC-derived EVs can attenuate lung inflammation and injury after IR as well as enhance EVLP-mediated reconditioning of donor lungs. The therapeutic benefits of EVs are in part mediated through anti-inflammatory promoting mechanisms via attenuation of immune cell activation as well as prevention of endothelial barrier integrity to prevent lung edema. Therefore, MSC-derived EVs offer a potential therapeutic strategy to treat post-transplant IR injury as well as rehabilitation of DCD lungs. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion (IR) affects microRNA (miR) expression and causes substantial inflammation. Multiple roles of the tumor suppressor miR-129-5p in cerebral IR have recently been reported, but its functions in the spinal cord are unclear. Here, we investigated the role of miR-129-5p after spinal cord IR, particularly in regulating high-mobility group box-1 (HMGB1) and the Toll-like receptor (TLR)-3 pathway.Methods: Ischemia was induced via 5-min occlusion of the aortic arch. The relationship between miR-129-5p and HMGB1 was elucidated via RT-PCR, western blotting, and luciferase assays. The cellular distribution of HMGB1 was determined via double immunofluorescence. The effect of miR-129-5p on the expression of HMGB1, TLR3, and downstream cytokines was evaluated using synthetic miRs, rHMGB1, and the TLR3 agonist Poly(I:C). Blood-spinal cord barrier (BSCB) permeability was examined by measuring Evans blue (EB) dye extravasation and the water content.Results: The temporal miR-129-5p and HMGB1 expression profiles and luciferase assay results indicated that miR-129-5p targeted HMGB1. Compared with the Sham group, the IR group had higher HMGB1 immunoreactivity, which was primarily distributed in neurons and microglia. Intrathecal injection of the miR-129-5p mimic significantly decreased the HMGB1, TLR3, interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels and the double-labeled cell count 48 h post-surgery, whereas rHMGB1 and Poly(I:C) reversed these effects. Injection of miR-129-5p mimic preserved motor function and prevented BSCB leakage based on increased Basso Mouse Scale scores and decreased EB extravasation and water content, whereas injection rHMGB1 and Poly(I:C) aggravated these injuries.Conclusions: Increasing miR-129-5p levels protect against IR by ameliorating inflammation-induced neuronal and BCSB damage by inhibiting HMGB1 and TLR3-associated cytokines. [ABSTRACT FROM AUTHOR]

Background: Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. Previous research has indicated that MAPC cell therapy might attenuate this injury by its paracrine effects on the pro-/anti-inflammatory balance. This study aims to investigate the immunoregulatory capacities of MAPC cells in PGD when administered in the airways. Methods: Lungs of domestic pigs (n = 6/group) were subjected to 90 minutes of warm ischemia. Lungs were cold flushed, cannulated on ice and placed on EVLP for 6 hours. At the start of EVLP, 40 ml of an albumin-plasmalyte mixture was distributed in the airways (CONTR group). In the MAPC cell group, 150 million MAPC cells (ReGenesys/Athersys, Cleveland, OH, USA) were added to this mixture. At the end of EVLP, a physiological evaluation (pulmonary vascular resistance, lung compliance, PaO2/FiO2), wet-to-dry weight ratio (W/D) sampling and a multiplex analysis of bronchoalveolar lavage (BAL) (2 x 30 ml) was performed. Results: Pulmonary vascular resistance, lung compliance, PaO2/FiO2 and W/D were not statistically different at the end of EVLP between both groups. BAL neutrophilia was significantly reduced in the MAPC cell group. Moreover, there was a significant decrease in TNF-α, IL-1β and IFN-γ in the BAL, but not in IFN-α; whereas IL-4, IL-10 and IL-8 were below the detection limit. Conclusions: Although no physiologic effect of MAPC cell distribution in the airways was detected during EVLP, we observed a reduction in pro-inflammatory cytokines and neutrophils in BAL in the MAPC cell group. This effect on the innate immune system might play an important role in critically modifying the process of PGD after transplantation. Further experiments will have to elucidate the immunoregulatory effect of MAPC cell administration on graft function after transplantation. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stromal cells (MSCs) and renal stem/progenitors improve the recovery of acute kidney injury (AKI) mainly through the release of paracrine mediators including the extracellular vesicles (EVs). Several studies have reported the existence of a resident population of MSCs within the glomeruli (Gl-MSCs). However, their contribution towards kidney repair still remains to be elucidated. The aimof the present study was to evaluate whether Gl-MSCs and Gl-MSC-EVs promote the recovery of AKI induced by ischemia-reperfusion injury (IRI) in SCID mice. Moreover, the effects of Gl-MSCs and Gl-MSC-EVs were compared with those of CD133+ progenitor cells isolated from human tubules of the renal cortical tissue (T-CD133+ cells) and their EVs (T-CD133+-EVs). Methods: IRI was performed in mice by clamping the left renal pedicle for 35 minutes together with a right nephrectomy. Immediately after reperfusion, the animals were divided in different groups to be treated with: Gl-MSCs, T-CD133+ cells, Gl-MSC-EVs, T-CD133+-EVs or vehicle. To assess the role of vesicular RNA, EVs were either isolated by floating to avoid contamination of non-vesicles-associated RNA or treated with a high dose of RNase. Mice were sacrificed 48 hours after surgery. Results: Gl-MSCs, and Gl-MSC-EVs both ameliorate kidney function and reduce the ischemic damage post IRI by activating tubular epithelial cell proliferation. Furthermore, T-CD133+ cells, but not their EVs, also significantly contributed to the renal recovery after IRI compared to the controls. Floating EVs were effective while RNase-inactivated EVs were ineffective. Analysis of the EV miRnome revealed that Gl-MSC-EVs selectively expressed a group of miRNAs, compared to EVs derived from fibroblasts, which were biologically ineffective in IRI. Conclusions: In this study, we demonstrate that Gl-MSCs may contribute in the recovery of mice with AKI induced by IRI primarily through the release of EVs. [ABSTRACT FROM AUTHOR]

Background: The high prevalence of hepatitis B virus (HBV) imposes a huge burden of hepatocellular carcinoma (HCC) in Asia. Surgical resection remains an important therapeutic strategy for HCC. Hepatic inflow occlusion, known as the Pringle maneuver, is the most commonly used method of reducing blood loss during liver parenchymal transection. A major issue with this maneuver is ischemia-reperfusion injury to the remnant liver, and the hemodynamic disturbance it induces in the tumor-bearing liver raises an oncological concern. Given the technical advances in living donor liver transplantation, vascular occlusion in liver resection can be avoided in experienced hands. The aim of this study is to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with hepatic inflow occlusion. Methods/design: This study will include eligible patients with HBV-related HCC elected for liver resection. Fifty-seven patients will be enrolled in each randomization arm to detect a 20 % difference in the serum level of total bilirubin on postoperative day 5 (80 % power and α = 0.05). The secondary endpoints include procedural parameters, perioperative liver function and inflammatory response, postoperative morbidity and mortality, and long-term outcomes. Patients will be followed for up to 5 years. Data will be statistically analyzed on an intention-to-treat basis. Discussion: This prospective randomized controlled trial is designed to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with vascular occlusion. The clinical implications of these outcomes may change current surgical practice and fill the oncological gaps therein. [ABSTRACT FROM AUTHOR]