Melastoma dodecandrum lour. Protects against cerebral ischemia-reperfusion injury by ameliorating oxidative stress and endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.

Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI. AIM OF THE STUDY: The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation. MATERIALS AND METHODS: Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT. RESULTS: NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI. CONCLUSION: This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.

Preconditioning with ß-hydroxybutyrate attenuates lung ischemia-reperfusion injury by suppressing alveolar macrophage pyroptosis through the SIRT1-FOXO3 signaling pathway.

The complex pathogenesis of lung ischemia-reperfusion injury (LIRI) was examined in a murine model, focusing on the role of pyroptosis and its exacerbation of lung injury. We specifically examined the levels and cellular localization of pyroptosis within the lung, which revealed alveolar macrophages as the primary site. The inhibition of pyroptosis by VX-765 reduced the severity of lung injury, underscoring its significant role in LIRI. Furthermore, the therapeutic potential of ß-hydroxybutyrate (ß-OHB) in ameliorating LIRI was examined. Modulation of ß-OHB levels was evaluated by ketone ester supplementation and 3-hydroxybutyrate dehydrogenase 1 (BDH-1) gene knockout, along with the manipulation of the SIRT1-FOXO3 signaling pathway using EX-527 and pCMV-SIRT1 plasmid transfection. This revealed that ß-OHB exerts lung-protective and anti-pyroptotic effects, which were mediated through the upregulation of SIRT1 and the enhancement of FOXO3 deacetylation, leading to decreased pyroptosis markers and lung injury. In addition, ß-OHB treatment of MH-S cells in vitro showed a concentration-dependent improvement in pyroptosis, linking its therapeutic benefits to specific cell mechanisms. Overall, this study highlights the significance of alveolar macrophage pyroptosis in the exacerbation of LIRI and indicates the potential of ß-OHB in mitigating injury by modulating the SIRT1-FOXO3 signaling pathway.

Electroacupuncture reduces inflammatory damage following cerebral ischemia-reperfusion by enhancing ABCA1-mediated efferocytosis in M2 microglia.

Ischemic stroke (IS) is a severe cerebrovascular disease with high disability and mortality rates, where the inflammatory response is crucial to its progression and prognosis. Efferocytosis, the prompt removal of dead cells, can reduce excessive inflammation after IS injury. While electroacupuncture (EA) has been shown to decrease inflammation post-ischemia/reperfusion (I/R), its link to efferocytosis is unclear. Our research identified ATP-binding cassette transporter A1 (Abca1) as a key regulator of the engulfment process of efferocytosis after IS by analyzing public datasets and validating findings in a mouse model, revealing its close ties to IS progression. We demonstrated that EA can reduce neuronal cell death and excessive inflammation caused by I/R. Furthermore, EA treatment increased Abca1 expression, prevented microglia activation, promoted M2 microglia polarization, and enhanced their ability to phagocytose injured neurons in I/R mice. This suggests that EA's modulation of efferocytosis could be a potential mechanism for reducing cerebral I/R injury, making regulators of efferocytosis steps a promising therapeutic target for EA benefits.

The Use of Identified Hypoxia-related Genes to Generate Models for Predicting the Prognosis of Cerebral Ischemia‒reperfusion Injury and Developing Treatment Strategies.

Cerebral ischemia‒reperfusion injury (CIRI) is a type of secondary brain damage caused by reperfusion after ischemic stroke due to vascular obstruction. In this study, a CIRI diagnostic model was established by identifying hypoxia-related differentially expressed genes (HRDEGs) in patients with CIRI. The ischemia‒reperfusion injury (IRI)-related datasets were downloaded from the Gene Expression Omnibus (GEO) database ( http://www.ncbi.nlm.nih.gov/geo ), and hypoxia-related genes in the Gene Cards database were identified. After the datasets were combined, hypoxia-related differentially expressed genes (HRDEGs) expressed in CIRI patients were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the HRDEGs were performed using online tools. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed with the combined gene dataset. CIRI diagnostic models based on HRDEGs were constructed via least absolute shrinkage and selection operator (LASSO) regression analysis and a support vector machine (SVM) algorithm. The efficacy of the 9 identified hub genes for CIRI diagnosis was evaluated via mRNA‒microRNA (miRNA) interaction, mRNA-RNA-binding protein (RBP) network interaction, immune cell infiltration, and receiver operating characteristic (ROC) curve analyses. We then performed logistic regression analysis and constructed logistic regression models based on the expression of the 9 HRDEGs. We next established a nomogram and calibrated the prediction data. Finally, the clinical utility of the constructed logistic regression model was evaluated via decision curve analysis (DCA). This study revealed 9 critical genes with high diagnostic value, offering new insights into the diagnosis and selection of therapeutic targets for patients with CIRI. : Not applicable.

The activation of the HIF-1α-VEGFA-Notch1 signaling pathway by Hydroxysafflor yellow A promotes angiogenesis and reduces myocardial ischemia-reperfusion injury.

Hydroxyl Safflower Yellow A (HSYA) is the primary bioactive compound derived from Safflower, which has been scientifically proven to possess anti-inflammatory, anti-apoptotic, and ameliorative properties against mitochondrial damage during acute myocardial ischemia-reperfusion injury (MIRI); however, its effects during the recovery stage remain unknown. Angiogenesis plays a crucial role in the rehabilitation process. AIM OF THE STUDY: The objective of this study was to investigate the long-term angiogenic effect of HSYA and its contribution to recovery after myocardial ischemia, as well as explore its underlying mechanism using non-targeted metabolomics and network pharmacology. MATERIALS AND METHODS: The MIRI model in rat was established by ligating the left anterior descending branch of the coronary artery. The effect of HSYA was assessed based on myocardial infarction volume and histopathology. Immunofluorescence staining was employed to evaluate angiogenesis, while ELISA was used to detect markers of myocardial injury. Additionally, a rat myocardial microvascular endothelial cell (CMECs) injury model was established using oxygen-glucose deprivation/reoxygenation (OGD/R), followed by scratch assays, migration assays, and tube formation experiments to assess angiogenesis. Western blot analysis was conducted to validate the underlying mechanism. RESULTS: Our findings provide compelling evidence for the therapeutic efficacy of HSYA in reducing myocardial infarction size, facilitating cardiac functional recovery, and reversing pathological alterations within the heart. Furthermore, we elucidate that HSYA exerts its effects on promoting migration and generation of myocardial microvascular endothelial cells through activation of the HIF-1α-VEGFA-Notch1 signaling pathway. CONCLUSION: These results underscore how HSYA enhances cardiac function via angiogenesis promotion and activation of the aforementioned signaling cascade.

CircRNA-Phf21a_0002 promotes pyroptosis to aggravate hepatic ischemia/ reperfusion injury by sponging let-7b-5p.

Hepatic ischemia‒reperfusion injury is a common injury in liver surgery and liver transplantation that can lead to liver function damage, including oxidative stress, apoptosis, autophagy and inflammatory reactions. Pyroptosis is a type of inflammatory programmed cell death that has been implicated in ischemia‒reperfusion injury-associated inflammatory reactions. Although circular RNAs can regulate cell death in hepatic ischemia‒reperfusion injury, their relationship with pyroptosis remains unclear. Therefore, this study aimed to investigate the effect of circular RNA on pyroptosis in hepatic ischemia‒reperfusion injury. We constructed a mouse hepatic ischemia‒reperfusion injury model for circular RNA sequencing and obtained 40 circular RNAs with significant differential expression, of which 39 were upregulated and 1 was downregulated. Subsequently, the endogenous competitive RNA network was constructed using TarBase, miRTarBase, TargetScan, RNAhybrid, and miRanda. Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology functional analyses of downstream target genes revealed that circRNA-Phf21a_0002 might affect pyroptosis by regulating the mTOR signaling pathway and Bach1 by sponging let-7b-5p. The overexpression plasmid upregulated the expression of circRNA-Phf21a_0002 in a hypoxia/reoxygenation model, which aggravated pyroptosis in AML12 cells and apoptosis and necrosis of hepatocytes. Next, we investigated the underlying mechanism and found that circRNA-Phf21a_0002 enabled the expression of Bach1 through sponging of let-7b-5p. The aggravation of pyroptosis via overexpression of circRNA-Phf21a_0002 was reversed by let-7b-5p mimics in hypoxia/reoxygenation-subjected AML12 cells. Collectively, our study clarifies that circRNA-Phf21a_0002 aggravates the pyroptosis of hepatocytes related to ischemia-reperfusion by sponging let-7b-5p. These findings provide new molecular mechanisms and novel biomarkers for follow-up treatment.

Glucose-Stimulated Mucus Secretion by Goblet Cells Mitigates Intestinal Barrier Dysfunction in a Rat Model of Mesenteric Ischemia/Reperfusion Injury.

Background: Superior mesenteric ischemia/reperfusion (I/R) causes barrier dysfunction and facilitates bacterial translocation (BT) in the small intestine, which can even lead to systemic sepsis. Our previous research showed that luminal administration of glucose and its anaerobic glycolytic metabolites exerted cytoprotective effects on epithelial cells and ameliorated I/R-induced BT in the liver and spleen. Notably, the reduction of BT occurs over the whole intestinal tract, not only restricted in the ligated glucose-containing loop. Objectives: In this study, we hypothesized that local jejunal glucose-contacting might confer on the remote intestinal epithelium regeneration potential, fortify their barrier function and goblet cell secretory activity. Methods: Two 10-cm jejunal segments were isolated in Wistar rats. One segment was ligatured at both ends and infused with Krebs buffer containing 0- or 50-mM glucose (local loop), whereas the adjacent segment was left unaltered and not exposed to glucose (remote loop). The rats then underwent either a sham operation or I/R challenge by occlusion of the superior mesenteric artery for 20 min, followed by reperfusion for 1 h. Results: Enteral addition of glucose in the local jejunum loop alleviated ischemia-induced barrier defects, histopathological scores, cell death, and mucosal inflammation (myeloperoxidase and inflammatory cytokine production) in the remote jejunum. After ischemia, goblet cells in the remote jejunum showed cavitation of mucin granules and low MUC2 expression. Local addition of glucose enhanced MUC2 synthesis and stimulated a jet-like mucus secretion in the remote jejunum, which was accompanied by the restoration of crypt activity. Conclusions: Our results showed local enteral glucose effectively mitigates I/R-induced barrier dysfunction, suggesting that local glucose-stimulated mucus secretion by remote goblet cells may serve to mitigate mucosal inflammation and BT. We provide a more precise barrier protection role of enteral glucose upon I/R challenge, presenting new opportunities for future therapeutic potential.

Subpial transplantation of adipose-derived stem cells alleviates paraplegia in a rat model of aortic occlusion/reperfusion-induced spinal cord infarction.

Background: Thoracoabdominal periprocedural occlusion/reperfusion injury of the spinal cord (SCII/R) can lead to devastating paraplegia, underscoring the critical need for effective interventions. However, our knowledge of optimal medical strategies and their efficacy remains limited. Preclinical investigations have shown promise in harnessing adult stem cells, including pluripotent and multipotent stem cells such as mesenchymal stem cells (MSCs), to address SCII/R by enhancing neuro-inflammation, axonal growth, and myelination. Particularly, growth factors derived from adipose tissue-derived MSCs (ADSCs) have been proposed to facilitate recovery. Despite advancements, achieving complete recovery remains a formidable challenge. Therefore, gaining a more profound insight into the role of ADSCs in alleviating SCII/R-induced paraplegia, including optimizing the delivery systems for therapies, is imperative. Materials and methods: In this study, we assessed the impact of subpial allogeneic rat adipose tissue-derived MSCs (rADSCs) transplantation on paraplegia using a rat SCII/R model induced by ephemeral aortic occlusion, known as the Taira-Marsala model. rADSCs were isolated from adipose tissue of male Sprague-Dawley rats, cultured, characterized, and cryopreserved. One week following the induction of paraplegia, rADSCs (n = 6) or physiological saline (n = 6) were transplanted. Hind limb motor function was evaluated before treatment and at 3-, 7-, and 14-days post-treatment using the Basso-Beattie-Bresnahan scoring system. Results: The rADSC-treated group demonstrated a significant improvement in hind limb motor function compared to the saline-treated group (p < 0.05), with 5 out of 6 rats exhibiting enhanced motor function following treatment. Conclusions: Our findings suggest that subpial rADSC engraftment may enhance SCII/R-induced paraplegia recovery. These initial results drive further research to validate this potential, understand the molecular mechanisms, and optimize therapies.

Apelin-13-Loaded Macrophage Membrane-Encapsulated Nanoparticles for Targeted Ischemic Stroke Therapy via Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

Purpose: Ischemic stroke is a refractory disease wherein the reperfusion injury caused by sudden restoration of blood supply is the main cause of increased mortality and disability. However, current therapeutic strategies for the inflammatory response induced by cerebral ischemia-reperfusion (I/R) injury are unsatisfactory. This study aimed to develop a functional nanoparticle (MM/ANPs) comprising apelin-13 (APNs) encapsulated in macrophage membranes (MM) modified with distearoyl phosphatidylethanolamine-polyethylene glycol-RVG29 (DSPE-PEG-RVG29) to achieve targeted therapy against ischemic stroke. Methods: MM were extracted from RAW264.7. PLGA was dissolved in dichloromethane, while Apelin-13 was dissolved in water, and CY5.5 was dissolved in dichloromethane. The precipitate was washed twice with ultrapure water and then resuspended in 10 mL to obtain an aqueous solution of PLGA nanoparticles. Subsequently, the cell membrane was evenly dispersed homogeneously and mixed with PLGA-COOH at a mass ratio of 1:1 for the hybrid ultrasound. DSPE-PEG-RVG29 was added and incubated for 1 h to obtain MM/ANPs. Results: In this study, we developed a functional nanoparticle delivery system (MM/ANPs) that utilizes macrophage membranes coated with DSPE-PEG-RVG29 peptide to efficiently deliver Apelin-13 to inflammatory areas using ischemic stroke therapy. MM/ANPs effectively cross the blood-brain barrier and selectively accumulate in ischemic and inflamed areas. In a mouse I/R injury model, these nanoparticles significantly improved neurological scores and reduced infarct volume. Apelin-13 is gradually released from the MM/ANPs, inhibiting NLRP3 inflammasome assembly by enhancing sirtuin 3 (SIRT3) activity, which suppresses the inflammatory response and pyroptosis. The positive regulation of SIRT3 further inhibits the NLRP3-mediated inflammation, showing the clinical potential of these nanoparticles for ischemic stroke treatment. The biocompatibility and safety of MM/ANPs were confirmed through in vitro cytotoxicity tests, blood-brain barrier permeability tests, biosafety evaluations, and blood compatibility studies. Conclusion: MM/ANPs offer a highly promising approach to achieve ischemic stroke-targeted therapy inhibiting NLRP3 inflammasome-mediated pyroptosis.

Synbiotic supplementation ameliorates anxiety and myocardial ischaemia-reperfusion injury in hyperglycaemic rats by modulating gut microbiota.

Hyperglycaemia, hyperlipidaemia, hypertension and obesity are the main risk factors affecting the development and prognosis of ischaemic heart disease, which is still an important cause of death today. In our study, male Sprague-Dawley rats were fed either a standard diet (SD) or a high fat and high carbohydrate diet (HF-HCD) for 8 weeks and streptozotocin (STZ) was injected at the seventh week of the feeding period. In one set of rats, a mixture of a prebiotic and probiotics (synbiotic, SYN) was administered by gavage starting from the beginning of the feeding period. Experimental myocardial ischaemia-reperfusion (30 min/60 min) was induced at the end of 8 weeks. Hyperglycaemia, hypertension and increased serum low-density lipoprotein levels occurred in SD- and HF-HCD-fed and STZ-treated rats followed for 8 weeks. Increased density of the Proteobacteria phylum was observed in rats with increased blood glucose levels, indicating intestinal dysbiosis. The severity of cardiac damage was highest in the dysbiotic HF-HCD-fed hyperglycaemic rats, which was evident with increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), tumour necrosis factor-α, and interleukin-6 levels, along with a decrease in ST-segment resolution index. SYN supplementation to either a normal or a high-fat high-carbohydrate diet improved gut dysbiosis, reduced anxiety, decreased CK-MB and cTnI levels, and alleviated myocardial ischaemia-reperfusion injury in hyperglycaemic rats.

Engineered Macrophage Membrane-Coated S100A9-siRNA for Ameliorating Myocardial Ischemia-Reperfusion Injury.

Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion-induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)- and RAGE (receptor for advanced glycation end products)- comodified macrophage membrane-coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9-siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia-reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane-coated nanoparticles may represent a new therapeutic intervention for MIRI.

Enhancing Cardioprotection Through Neutrophil-Mediated Delivery of 18ß-Glycyrrhetinic Acid in Myocardial Ischemia/Reperfusion Injury.

Myocardial ischemia/reperfusion injury (MI/RI) generates reactive oxygen species (ROS) and initiates inflammatory responses. Traditional therapies targeting specific cytokines or ROS often prove inadequate. An innovative drug delivery system (DDS) is developed using neutrophil decoys (NDs) that encapsulate 18ß-glycyrrhetinic acid (GA) within a hydrolyzable oxalate polymer (HOP) and neutrophil membrane vesicles (NMVs). These NDs are responsive to hydrogen peroxide (H2O2), enabling controlled GA release. Additionally, NDs adsorb inflammatory factors, thereby reducing inflammation. They exhibit enhanced adhesion to inflamed endothelial cells (ECs) and improved penetration. Once internalized by cardiomyocytes through clathrin-mediated endocytosis, NDs protect against ROS-induced damage and inhibit HMGB1 translocation. In vivo studies show that NDs preferentially accumulate in injured myocardium, reducing infarct size, mitigating adverse remodeling, and enhancing cardiac function, all while maintaining favorable biosafety profiles. This neutrophil-based system offers a promising targeted therapy for MI/RI by addressing both inflammation and ROS, holding potential for future clinical applications.

The Worsening of Myocardial Ischemia-Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology.

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.

Mitochondrial Function and Resistance to Oxidative Stress in the Kidney during Pregnancy.

We demonstrated that the serum of pregnant rats increases viability of kidney epithelial cells and promotes their proliferation. The intensity of oxidative stress in the kidneys was also reduced during pregnancy, but only in rats that were not exposed to acute ischemic kidney injury. This decrease in oxidative stress was not associated with changes in transmembrane mitochondrial potential, the size of mitochondria, time of opening of mitochondrial permeability transition pore (mPTP), mitochondrial respiration rate, antioxidant activity, or nitric oxide level.

Protective effect of rupatadine on testicular ischemia/reperfusion injury in rats: Modulation of IL-6/STAT3, Akt/ mTOR signaling pathways.

BACKGROUNDS & AIM: Spermatic cord rotation is a common problem in the field of urology, that finally results in necrosis of testicular tissue as well as male infertility. Rupatadine (RUP); a second-generation antihistaminic drug; demonstrated to have a possible protective effect in variable ischemia/reperfusion (I/R) rat models, but its role has not been studied yet in testicular I/R model. MATERIAL & METHODS: The present study investigated RUP ability to ameliorate testicular I/R injury. The study includes four groups (6 rats/group); sham group, sham group pretreated with RUP (6 mg/kg/day; orally) for 14 days, I/R group, and RUP-I/R pretreated group. KEY FINDINGS: The results demonstrated that I/R significantly lowered serum testosterone level and testicular tissue content of reduced glutathione. Besides, a significant elevation in malondialdehyde level, hypoxia-inducible factor-1, signal transducers and activators of transcription-3 (STAT-3), interleukin-6 (IL-6), histamine, and platelet activating factor levels along with an inhibition in testicular tissue level of vascular endothelial growth factor-A (VEGF-A) with an evident increase in caspase-3 immunoexpression in germ cells. Also, I/R significantly lowered p-AKT and mTOR testicular expression. While, RUP-I/R pretreated group showed a reversal in the testicular I/R damaging effects in a significant manner in the all the aforementioned parameters. CONCLUSION: Based on these findings; RUP was proved to have a possible protective effect in testicular I/R injury via its antioxidant effect and its ability to modulate IL-6/STAT3, Akt/ mTOR inflammatory signaling pathways with improvement in the testicular VEGF-A level.

Comparing open and robot-assisted partial nephrectomy - a single institution report.

BACKGROUND: Open partial nephrectomy (OPN) has previously been considered the gold standard procedure for treatment of T1 localized renal tumors. After introduction of robot assisted partial nephrectomy (RAPN) as an alternative method to OPN, OPN was gradually abandoned at our department. The aim of the study was to retrospectively compare the results of patients treated with either OPN or RAPN for suspected renal carcinoma. METHODS: Patients who underwent either open or robotic assisted partial nephrectomy between January 1st 2010 and December 31st 2020 were retrospectively included in the study. Each tumor subjected to surgery was scored preoperatively by the RENAL nephrometry score. Complications within 30 days were assessed according to the Clavien-Dindo classification system. RESULTS: A total of 197 patients who underwent partial nephrectomy were identified; 75 were subjected to OPN and 122 were treated with RAPN. There were no significant differences between the groups with respect to age (OPN: 63 years ± 11, RAPN: 62 years ± 10), gender (OPN: 71/29%, RAPN: 67/33%), body mass index (OPN: 28 ± 5, RAPN: 28 ± 5), ASA score (OPN: 2.4 ± 0.6, RAPN: 2.2 ± 0.5), or nephrometry score (OPN: 6.6 ± 1.7, RAPN: 6.9 ± 1.7, p = 0.2). The operative time was significantly shorter in the OPN group (81 min) compared to the RAPN group (144.5 min, p < 0.001). Mean perioperative blood loss was 227 ± 162 ml in the OPN group compared to 189 ± 152 ml in the RAPN group (p = 0.1). Mean length of stay was shorter in the RAPN group (3 days) compared to the OPN group (6, days, p < 0.001). Positive surgical margin rate was significantly higher in the OPN group (21.6%) compared to the RAPN group (4.2%, p < 0.001). There were no differences in the number of Clavien-Dindo graded complications between the groups (p = 0.6). CONCLUSIONS: The introduction of RAPN at our department resulted in shorter length of stay and fewer positive surgical margins, without increasing complications.

Effects of STAT4 on myocardial ischemia­reperfusion injury and the underlying mechanisms.

The regulation of cardiac function by the nuclear transcription factor signal transducer and activator of transcription 4 (STAT4) has been recently recognized. Nevertheless, the role and mechanisms of action of STAT4 in myocardial ischemia­reperfusion (I/R) injury remain unknown. Consequently, the present study constructed a rat model of I/R by ligation of the left anterior descending coronary artery. Following sacrifice, the rat hearts were excised and analyzed to investigated the effects of STAT4 on I/R­induced myocardial injury. Western blotting demonstrated that expression of STAT4 decreased significantly in the rat model of cardiac I/R and in H9C2 cells that were subjected to hypoxia and reoxygenation (H/R). The overexpression of STAT4 in H9C2 cells reduced cell damage and apoptosis induced by H/R. Furthermore, both in vivo and in vitro, the level of PI3K decreased significantly. Although the AKT protein expression levels were not altered, the AKT phosphorylation levels decreased significantly. STAT4 overexpression enhanced the expression of PI3K and AKT in the H9C2 cells. On the whole, the present study demonstrated that STAT4 alleviated I/R­induced myocardial injury through the PI3K/AKT signaling pathway.

[Retracted] Salidroside mitigates hypoxia/reoxygenation injury by alleviating endoplasmic reticulum stress­induced apoptosis in H9c2 cardiomyocytes.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the cell apoptotic assay data shown in Fig. 1D on p. 3763 were strikingly similar to data that had already been submitted for publication in Fig. 3A in different form in another article written by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been submitted for publication prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 3760­3768, 2018; DOI: 10.3892/mmr.2018.9403].

Keap1-independent GSK-3ß/Nrf2 signaling mediates electroacupuncture inhibition of oxidative stress to induce cerebral ischemia-reperfusion tolerance.

PURPOSE: Cerebral ischemia-reperfusion (CIR) injury is a devastating consequence of stroke characterized by oxidative stress-induced neuronal damage. Electroacupuncture (EA) has emerged as a potential therapeutic intervention for ischemic stroke, but its underlying mechanisms remain incompletely understood. This study aimed to elucidate whether EA exerts anti-oxidative stress effects against CIR injury by modulating the GSK-3ß/Nrf2 pathway. METHODS: CIR mouse models were established using the suture-occluded method and underwent EA pretreatment. Cognitive and neurologic function, cerebral infarct volume, and neuronal damage were assessed in mice. Oxidative stress levels and the expression of components of the GSK-3ß/Nrf2 pathway in the cerebral cortex were measured. The regulatory effect of GSK-3ß on Nrf2 and its role in electroacupuncture to alleviate oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury were investigated by modulating GSK-3ß expression in HT22 hippocampal neuronal cells and electroacupuncture serum intervention. Ultimately, Nrf2 knockout mice, GSK-3ß knockout mice, and wild-type mice treated with TBHQ (an Nrf2 activator) were utilized for further validation. RESULTS: EA pretreatment improved cognitive impairment and neuronal damage induced by CIR injury. Mechanistically, EA inhibited oxidative stress in the cerebral cortex, manifested by reduced levels of reactive oxygen species and malondialdehyde, along with increased superoxide dismutase activity. Furthermore, EA upregulated the expression of Nrf2 and its downstream antioxidant enzymes HO-1 and NQO1, while Keap1 expression remained unaffected. In vitro, GSK-3ß overexpression inhibited the protective effects of EA serum on OGD/R-induced neuronal damage. In vivo, knockout of either Nrf2 or Gsk-3ß genes abolished the neuroprotective effects of EA, and TBHQ exerted effects similar to EA, confirming the significant role of GSK-3ß/Nrf2 in mediating EA antioxidative effects. CONCLUSION: EA exerts antioxidative stress effects against CIR injury by activating the GSK-3ß/Nrf2 signaling pathway, independent of Keap1 regulation.