Search Results (1,991)

Background/Objectives: Ischemic stroke (IS) induces substantial phenotypic remodeling within the neurovascular unit, and pericytes have been implicated in the cellular responses to ischemic injury. However, the molecular characteristics and regulatory mechanisms underlying pericyte phenotypic remodeling after ischemic stroke remain incompletely understood. Methods: In this study, we used PDGFR-β-CreERT2; ZsGreen lineage-tracing mice and a middle cerebral artery occlusion (MCAO) model to characterize the temporal changes in PDGFR-β-lineage cells following ischemic injury. In vitro, human brain vascular pericytes (HBVPs) exposed to oxygen–glucose deprivation/reperfusion (OGD/R) and subsequently maintained in neurobasal medium to examine ischemia-related phenotypic changes. The involvement of KLF2-associated signaling was further investigated using KLF2 knockdown approaches. Results: We observed increased expression of Nestin in PDGFR-β-lineage cells during the early post-ischemic period, followed by the emergence of subsets co-expressing GFAP or DCX during the subacute stage. These findings indicate the acquisition of neuroglial- and neuronal-associated molecular features, rather than providing definitive evidence of lineage conversion or functional differentiation. The expression of these markers declined at later stages, whereas PDGFR-β-lineage cells were also associated with vascular remodeling during the recovery phase. In vitro, OGD/R-treated HBVPs exhibited increased expression of DCX, MAP2, and NeuN. KLF2 knockdown attenuated these molecular changes. Consistently, OGD/R was associated with increased KLF2, phosphorylated ERK1/2, and MAP2 expression, whereas KLF2 knockdown reduced ERK1/2 phosphorylation and MAP2 expression. These findings suggest that KLF2 is associated with ERK1/2 activation and MAP2 expression during ischemia-related phenotypic remodeling of PDGFR-β-lineage cells. Conclusions: Overall, our results identify transient neuroglial- and neuronal-associated molecular changes in pericytes after ischemic injury and provide evidence for an association between KLF2 and ERK1/2–MAP2 signaling in this process, while further studies are required to determine whether these changes represent stable lineage conversion or functional neuronal differentiation. Full article

Background: Early post-transplant albuminuria is associated with adverse graft and cardiovascular outcomes and may reflect ischemia–reperfusion injury-induced damage to the glomerular filtration barrier. However, evidence for safe adjunctive interventions targeting these early pathophysiological processes remains limited. Methods: In this single-center prospective cohort study with historical controls, adult kidney transplant recipients transplanted between January 2020 and September 2022 served as controls, while consecutive recipients transplanted from October 2022 onward received adjunctive silymarin (900 mg/day for 30 days) in addition to standard immunosuppression. The principal renal outcome was UACR assessed during the first 3 months post-transplant. A ≥25% reduction in UACR between Months 1 and 3 was additionally evaluated as an exploratory responder outcome. Secondary outcomes included estimated glomerular filtration rate (eGFR), lipid profile parameters, tacrolimus exposure, and safety. Results: A total of 136 patients (78 silymarin-treated and 58 controls) were included. UACR was consistently lower in the silymarin group at months 1–3. In multivariable analysis, silymarin treatment was independently associated with lower UACR at month 3. In an exploratory responder analysis, a ≥25% reduction in UACR between Months 1 and 3 occurred more frequently in silymarin-treated patients (OR 3.28, 95% CI 1.38–7.79; p = 0.007). eGFR trajectories were similar between groups. No consistent independent effects on lipid parameters were observed after adjustment. Tacrolimus exposure and adverse event rates were comparable between groups. Conclusions: Short-term silymarin exposure initiated early after kidney transplantation was associated with lower UACR during the first three post-transplant months. These findings support a potential targeted effect on early glomerular injury and suggest that silymarin may represent a safe adjunctive strategy to modulate early post-transplant risk. Full article

Endovascular thrombectomy [EVT] has revolutionized acute ischemic stroke care by restoring macrovascular reperfusion in large vessel occlusion; however, a persistent “reperfusion–outcome gap” remains, leaving nearly half of successfully recanalized patients without functional independence. This review aims to bridge this translational gap by establishing a mechanistic and procedural framework for adjunctive pharmacotherapy designed to target the microvascular, thromboinflammatory, and reperfusion-related injuries left unaddressed by purely mechanical models. Synthesis of recent literature reveals that futile recanalization is driven by three distinct anatomical and biological bottlenecks: distal microembolization, microcirculatory no-reflow, and ischemia–reperfusion injury. Furthermore, the inconsistency of clinical trial results reflects a critical precision deficit, including dilution of treatment effects across heterogeneous reperfusion grades, inadequate stroke etiology stratification, delayed pharmacologic intervention relative to evolving microvascular injury, and reliance on functional endpoints that inadequately capture tissue-level reperfusion. To address these limitations, this review outlines a tri-axial clinical decision framework integrating reperfusion status, stroke etiology and hemorrhagic risk, which maps specific patient phenotypes, such as incomplete macrovascular reperfusion or underlying intracranial atherosclerotic disease, to targeted pharmacologic strategies including microcatheter-directed intra-arterial thrombolytics and glycoprotein IIb/IIIa inhibitors. The review further argues that future progress will require imaging-guided identification of residual hypoperfusion, mechanistically enriched patient enrolment, and incorporation of biological and tissue-level reperfusion endpoints alongside conventional functional outcomes. Ultimately, closing the reperfusion–outcome gap will require moving beyond empirical, universal drug administration toward a precision, pharmacologically augmented EVT paradigm that aligns adjunctive therapy with mechanism-specific procedural phenotypes and prioritizes true tissue-level recovery over angiographic success alone. Full article

Although the underlying mechanisms of renal IRI have been extensively studied, the corresponding effective treatments are still lacking. HMGB1, an important nuclear factor that is secreted outside cells when experiencing stress conditions, acts as a DAMP and exerts crucial effects on renal IRI. Many studies have suggested that the effect of HMGB1 on kidney damage is mediated mainly through the interaction of HMGB1 with pattern recognition receptors such as TLR4 and RAGE, which then results in the aggravation of local inflammatory response, increased infiltration of leukocytes, and finally renal tubular damage. Preclinical studies using animal models have demonstrated that inhibition of HMGB1 and downstream signal pathways can attenuate renal injury. This review critically evaluates HMGB1 in renal IRI across redox state, subcellular localization, temporal and cell-specific release, receptor usage, integrated stress pathways, autophagy, and regulated cell death. It also compares direct neutralization, inhibition of release or translocation, epigenetic/RNA-based regulation, and receptor-directed strategies. The evidence is predominantly derived from short-term rodent studies, with one large-animal antibody study and no therapeutic human trials. Accordingly, HMGB1 is best regarded as a biologically compelling but clinically unvalidated target whose therapeutic value will depend on redox- and phase-selective inhibition, kidney-directed delivery, and rigorous pharmacokinetic and safety evaluation. Full article

Background/Objectives: Cerebral ischemia–reperfusion injury (CIRI) poses therapeutic challenges because of oxidative stress, blood–brain barrier disruption, and neuronal apoptosis, limiting current treatments. Paeoniflorin (PF) from Paeonia lactiflora has neuroprotective potential, but its multi-target mechanisms remain unclear. This study investigated the role and mechanisms of PF in CIRI, focusing on neuron–endothelial crosstalk. Methods: Oxygen–glucose deprivation/reoxygenation (OGD/R) models were established using SH-SY5Y (human neuroblastoma) and HCMEC/D3 cells (human cerebral microvascular endothelial). Network pharmacology was used to predict potential PF targets and pathways. RNA sequencing, molecular docking, and molecular dynamics simulation were performed to screen and evaluate PF binding characteristics with key targets, and MTT, flow cytometry, Western blotting, and co-cultures were employed to detect paracrine interactions. Results: Network pharmacology and transcriptomics identified VEGF/PI3K-AKT/mTOR pathway enrichment. Molecular docking confirmed stable PF binding to VEGF-A (−8.4 kcal/mol), AKT (−5.5 kcal/mol), and mTOR (−9.6 kcal/mol). PF (10–80 μM) showed no cytotoxicity and reduced OGD/R injury in a concentration-dependent manner (maximal at 40 μM). PF activated VEGF/PI3K-AKT/mTOR signaling, reducing apoptosis by 57% (SH-SY5Y) and 33% (HCMEC/D3); PI3K inhibitor LY294002 abolished these effects. PF-treated HCMEC/D3-conditioned media enhanced OGD/R neuronal viability, verifying paracrine crosstalk. Conclusions: PF alleviated CIRI by directly protecting neurons and indirectly modulating neuron–endothelial crosstalk through VEGF/PI3K-AKT/mTOR activation, supporting its multi-target therapeutic potential. Full article

Cardiac surgery-associated acute kidney injury (CS-AKI) increases short- and long-term mortality, progression to chronic kidney disease (CKD), and healthcare costs. Its pathogenesis is multifactorial—combining renal hypoperfusion, impaired oxygen delivery, hemodilution, inflammation, ischemia–reperfusion injury, and nephrotoxin exposure—so no single intervention confers universal protection. This narrative review appraises fourteen perioperative prevention strategies, grading each by study design, reproducibility, and concordance with contemporary guidelines. The strongest actionable evidence supports the preservation of renal oxygen delivery during cardiopulmonary bypass through goal-directed perfusion, perioperative amino acid infusion, and biomarker-guided Kidney Disease: Improving Global Outcomes (KDIGO) care bundles. Remote ischemic preconditioning, pulsatile flow, minimally invasive extracorporeal circulation, dexmedetomidine, N-acetylcysteine, levosimendan, hemoadsorption with the oXiris membrane, and natriuretic peptides show variable or subgroup-dependent signals limited by heterogeneous trial design and acute kidney injury (AKI) definitions. Prevention of CS-AKI is, therefore, best conceived as a multimodal, patient-centered process integrating preoperative risk stratification, intraoperative oxygen delivery optimization, patient blood management (PBM), and postoperative nephrotoxin avoidance and surveillance. Full article

A standardized extract of cultured Lentinula edodes mycelia (ECLM), commercially known as AHCC^®, shows anti-inflammatory, immunomodulatory, and organ-protective properties. Experimental studies have indicated that ECLM modulates innate and adaptive immunity, including natural killer (NK) cell activity, antigen-presenting cell function, T-cell responses, and cytokine balance. These effects are particularly relevant in oncology because surgical stress and ischemia–reperfusion injury (IRI) generate a transient perioperative environment characterized by immune suppression, inflammation, and conditions favorable for metastatic progression. Recent animal studies have demonstrated the protective effects of ECLM in intestinal and hepatic IRI models, providing a potential mechanistic rationale for improving the perioperative host microenvironment. Clinical studies on hepatocellular carcinoma, pancreatic cancer, and gynecological malignancies suggest that ECLM may offer potential benefits in immune preservation, nutritional support, symptom management, and recurrence prevention, although most studies are small and hypothesis-generating. Emerging evidence from patient-derived xenograft and spontaneous carcinogenesis models further suggests that ECLM may influence tumor biology beyond host immune activation, although the underlying mechanisms require elucidation. This review summarizes the mechanistic, preclinical, translational, and clinical evidence supporting the use of ECLM as a candidate for perioperative immunonutritional strategies. We propose the hypothesis that ECLM may function as a perioperative microenvironmental stabilizer that integrates immune preservation and intestinal barrier protection. Full article

Testicular torsion is a urological emergency that causes ischemia–reperfusion (I/R) injury and may result in irreversible germ cell loss and impaired fertility. Oxidative stress, inflammation, and apoptotic pathways play central roles in its pathogenesis. Transient Receptor Potential Melastatin-7 (TRPM7), a bifunctional ion channel/kinase, has recently been implicated in I/R-related cellular injury. Iloprost, a prostacyclin analogue with vasodilatory and antioxidant properties, may offer protective effects; however, its impact on TRPM7-mediated pathways in testicular I/R injury remains unclear. This study aimed to investigate the effects of iloprost on oxidative stress, apoptosis, and TRPM7 expression in an experimental testicular torsion–detorsion model. Thirty-five male Sprague Dawley rats were randomized into five groups: control, sham, iloprost, torsion–detorsion (T/D), and T/D + iloprost. After 60 min of torsion and subsequent detorsion, iloprost (2 µg/kg, intraperitoneal) was administered in the treatment group. Testicular tissues and serum samples were analyzed after 48 h. Histopathology (H&E), apoptosis (TUNEL assay), TRPM7 immunohistochemistry and mRNA expression (RT-qPCR), and serum total antioxidant status (TAS) and total oxidant status (TOS) were evaluated. Torsion–detorsion significantly increased TOS levels, apoptotic cell ratio (ACR), TRPM7 expression, and Bax mRNA expression, while reducing TAS levels (p < 0.05). Iloprost administration significantly improved oxidative stress parameters, restoring TAS and reducing TOS compared with the untreated T/D group. However, it did not significantly reduce histopathological damage, ACR, TRPM7 expression, or Bax mRNA expression. Bcl-2 expression remained largely unchanged across groups. Iloprost improved systemic oxidative status in testicular I/R injury but did not significantly attenuate TRPM7 expression, apoptotic changes, or structural damage under the experimental conditions used. The concurrent increase in TRPM7 expression and apoptotic indices following torsion–detorsion suggests an association between these alterations; however, the present study does not establish a causal relationship between TRPM7 and apoptosis. As TRPM7 activity was not directly assessed or experimentally manipulated, further studies involving TRPM7 inhibition or genetic silencing are required to determine its mechanistic role in testicular I/R-induced apoptosis. Full article

Background: Acute respiratory distress syndrome (ARDS) occurs in 20–40% of patients following esophagectomy and is associated with substantial postoperative morbidity and mortality. A major contributor to postoperative ARDS is pulmonary ischemia–reperfusion injury (IRI); however, the role of IRI in ARDS following esophagectomy is not adequately addressed in current experimental models. In this study, we established a large animal model of pulmonary IRI that reproduces key physiological, inflammatory, and histopathological features of pulmonary ischemia–reperfusion-induced acute lung injury relevant to postoperative ARDS after esophagectomy. Methods: Sequential pulmonary ischemia–reperfusion injury was induced in ten anesthetized Landrace pigs using unilateral hilar inflow occlusion. Right lung ischemia was achieved by clamping the hilar inflow for three hours, followed by reperfusion. Subsequently, the left lung underwent two hours of ischemia. Hemodynamic, respiratory, and inflammatory parameters were continuously monitored throughout the experiment. Blood samples were collected to assess leukocyte counts and circulating inflammatory cytokines, including tumor necrosis factor-α and interleukin-6. Lung tissue samples were obtained for histopathological evaluation. Results: ARDS-like lung injury was successfully induced in all animals, with PaO₂/FiO₂ ratios falling below 200 mmHg during the predefined reperfusion observation period. Lung compliance decreased by approximately 50% after ischemia and further declined following reperfusion. Progressive leukocyte elevation and elevated tumor necrosis factor-α and interleukin-6 levels were observed, indicating a systemic inflammatory response. Hallmark features of ARDS were histologically confirmed, including intra-alveolar hemorrhage, interstitial and perivascular edema, and neutrophil infiltration. Conclusions: This porcine model reproduces key physiological, inflammatory, and histopathological features consistent with pulmonary ischemia–reperfusion-induced ARDS-like lung injury. Although it does not reproduce the complete clinical syndrome of post-esophagectomy ARDS, it provides a clinically relevant translational platform for investigating pulmonary ischemia–reperfusion injury and evaluating potential preventive and therapeutic strategies. Full article

Background/Objectives: Renal ischemia–reperfusion injury (IRI) and infection-associated renal damage are characterized by persistent inflammation, oxidative stress, microvascular dysfunction, and impaired tissue regeneration, creating a hostile microenvironment that limits effective repair. We developed an injectable, photocrosslinkable methacrylated chitosan (CSMA) hydrogel for the localized co-delivery of cerium oxide nanoparticles (CeO₂NPs) and vascular endothelial growth factor (VEGF), aiming to integrate redox modulation, antibacterial activity, and regenerative support. Methods: Gelation, microstructure, rheology, degradation, and CeO2NP/VEGF were characterized. Tubular epithelial and fibroblast migration and endothelial network formation, angiogenic gene expression, and antibacterial activity against Staphylococcus aureus and Escherichia coli were evaluated in vitro. Theraputic performance was assessed by renal surface application in a rat renal IRI model and catheter-mediated interavsical administration in an ascending urinary tract infection model. Systematic biocompatibility was evaluated separately in a 14-day subcutaneous implantation study. Renal response were further investigated using transcriptomic and targeted molecular analyses. Results: The CSMA/VEGF/CeO₂NPs hydrogel exhibited rapid in situ gelation, interconnected porous architecture, stable viscoelasticity, gradual degradation, and sustained release of both CeO₂NPs and VEGF. The formulation enhanced tubular epithelial and fibroblast migration, promoted endothelial network formation and angiogenic gene expression and effectively inhibited both S. aureus and E. coli. In a surgically controlled rat renal IRI model, direct renal-surface application of the hydrogel reduced tubular injury, inflammatory infiltration, and fibrotic remodeling. In a separate ascending urinary tract infection model, catheter-based intravesical administration reduced the ascending renal bacterial burden and infection-associated inflammatory injury. No detectable adverse systemic effects observed under the tested conditions over the 14-day observation period in the subcutaneous implantation. Transcriptomic analyses further revealed that CSMA/VEGF/CeO₂NPs treatment was associated with marked remodeling of the renal injury microenvironment, characterized by suppression of antigen presentation and immune activation pathways, alongside restoration of metabolic programs associated with amino acid, lipid, and purine metabolism. These molecular changes were accompanied by downregulation of CIITA/CD74/MHC-II signaling, recovery of metabolic regulators AGXT and ACOX1, modulation of Hippo/YAP- and ECM-associated pathways, and preservation of renal structural markers including nephrin and WT1. Conclusions: The localized CSMA-mediated co-delivery of CSMA/VEGF/CeO₂NPs hydrogel promotes renal repair through resolution of maladaptive immune activation, metabolic reprogramming, angiogenic enhancement, and preservation of renal structural integrity, providing a promising biomaterial strategy for the treatment of ischemic and infection-associated renal injuries. Full article

Testicular torsion is a time-critical urological emergency in which surgical detorsion, the only accepted treatment, simultaneously rescues and injures the gonad. Restoration of blood flow triggers a burst of reactive oxygen and nitrogen species, neutrophil recruitment, inflammasome activation, and regulated germ cell death, so that a substantial proportion of anatomically salvaged testes still undergo atrophy and functional loss. A large experimental literature, running to several hundred reports, has shown that antioxidants of almost every chemical class attenuate this injury in rodent models, yet no antioxidant has entered routine clinical use as an adjunct to detorsion in humans, and we are not aware of any adequately powered randomized trial in this setting. This narrative review integrates the redox pathophysiology of testicular ischemia–reperfusion injury with an appraisal of the agents tested against it, and then asks why the translational gap has proved so durable. We examine model heterogeneity, the dominance of pretreatment designs that cannot be reproduced in an emergency department, the reliance on short-term surrogate biochemistry rather than fertility endpoints, and the sobering precedents of neuroprotection and cardioprotection. We close with a roadmap for first-in-human evaluation, covering candidate prioritization, route and timing of administration, biomarker selection, and a feasible trial architecture. Full article

Purpose: Intestinal ischemia–reperfusion injury (IRI) remains a major clinical challenge associated with substantial morbidity. Although the biological functions of insulin-like growth factor-I (IGF-I) have been extensively investigated, evidence regarding the direct administration of exogenous recombinant IGF-I in experimental intestinal IRI remains limited. This study evaluated the histological effects of recombinant IGF-I administered at different time points in a rat model of intestinal IRI. Methods: Male Wistar rats underwent 45 min of superior mesenteric artery occlusion followed by 3 h of reperfusion. Animals were allocated to five groups: Sham, untreated Control, and three IGF-I-treated groups receiving intraperitoneal recombinant IGF-I before ischemia, during ischemia, or at reperfusion. Histological injury was assessed using the Chiu grading system (0–5). Data were analyzed using non-parametric statistical methods. Results: Forty-five rats were included in the final analysis. Untreated controls demonstrated the greatest mucosal injury (median Chiu score: 4, IQR: 3–4), whereas Sham-operated animals exhibited minimal injury (median: 0, IQR: 0–1). All IGF-I-treated groups demonstrated lower median histological injury scores (median: 2), with the lowest median observed in the reperfusion group (IQR: 1–3). However, none of the individual comparisons with untreated controls remained statistically significant after Bonferroni correction. A post hoc exploratory pooled analysis demonstrated a similar histological pattern but likewise did not show a statistically significant difference between pooled IGF-I-treated animals and controls after adjustment for multiple comparisons. Conclusions: In this experimental rat model, exogenous recombinant IGF-I administration was consistently associated with lower histological injury scores than untreated ischemia–reperfusion controls, although a definitive treatment effect could not be established. These findings provide additional experimental evidence regarding the histological effects of recombinant IGF-I in intestinal ischemia–reperfusion injury and support further investigation in larger experimental studies incorporating quantitative histological, molecular, and functional endpoints. Full article

Pregnancy-related acute kidney injury (PR-AKI) increases the risk of chronic kidney disease (CKD) in the postpartum period, yet mechanisms driving this transition remain unclear. Uremic toxins, including indoxyl sulfate (IS), are implicated in AKI-to-CKD progression. Using a rat model of PR-AKI induced by ischemia–reperfusion on gestational day (GD) 18, we assessed IS contributions to renal injury in the postpartum. A subset of rats received the oral adsorbent AST-120 in the postpartum period to reduce IS. Additional groups received IS during pregnancy with or without AST-120 treatment in the postpartum period. Renal function, blood pressure, circulating and urinary IS concentrations, and renal histopathology were evaluated. PR-AKI resulted in sustained postpartum elevations in circulating (p = 0.03) and urinary (p < 0.03) IS, reduced urine output (p = 0.03), increased proteinuria (p < 0.0001), increased serum albumin, and increased renal fibrosis (p = 0.008) compared to normal pregnant control rats. Absorption of indole, a precursor for IS, significantly reduced urinary IS (p = 0.03), reduced serum creatinine (p = 0.006), and attenuated renal fibrosis (p = 0.002) in treated PR-AKI rats. While not significant, indole absorption improved urine output (p = 0.06) and reduced proteinuria (p = 0.07) in treated PR-AKI rats. IS administration during pregnancy recapitulated key features of postpartum CKD. Elevated IS contributes to persistent renal injury following PR-AKI. Postpartum reduction in IS with AST-120 dampens the progression of renal injury. These findings highlight uremic toxins as mechanistic drivers and potential therapeutic targets in post partum CKD following PR-AKI. Full article

Background: Myocardial ischemia–reperfusion during cardiac surgery is associated with complex metabolic alterations that reflect both myocardial injury and recovery. This prospective study aimed to characterize intraoperative lactate, pH, and bicarbonate dynamics in paired coronary sinus (CS) and peripheral blood samples and to explore whether these responses could be integrated into a composite marker of reperfusion-related metabolic burden (RMB). Methods: We prospectively studied 101 patients undergoing cardiac surgery with cardiopulmonary bypass. Simultaneous blood samples from the CS and peripheral circulation were obtained before aortic cross-clamping (T0), immediately after declamping (T1), and 10 min after reperfusion (T2). Temporal changes and transmyocardial gradients of lactate, pH, and bicarbonate were analyzed. RMB was calculated from standardized changes in these variables. As an exploratory analysis, associations with in-hospital mortality were evaluated using receiver operating characteristic (ROC) analysis. Results: Significant temporal variations in metabolic parameters were observed, with the most pronounced transmyocardial disturbances occurring at aortic declamping. Lactate demonstrated the largest gradient during early reperfusion, accompanied by transient acidosis and bicarbonate consumption. The RMB framework integrated these coordinated metabolic responses into a single measure of reperfusion stress. In exploratory outcome analyses, higher RMB values were observed among non-survivors, with the largest observed AUC for peripheral RMB measured 10 min after reperfusion (AUC 0.87). However, these estimates were based on only seven deaths and should be considered hypothesis-generating. Conclusions: Paired CS and peripheral sampling revealed dynamic metabolic adaptations during myocardial ischemia–reperfusion. The exploratory RMB framework integrates coordinated metabolic changes into a single descriptive measure of reperfusion-related stress. Its observed associations with in-hospital mortality remain preliminary and require confirmation through external validation and evaluation in larger independent prospective cohorts. Full article

Background and Objectives: Ischemia–reperfusion (IR) injury to skeletal muscle induces both structural and functional impairments, primarily attributed to increased production of reactive oxygen species and subsequent inflammation following reperfusion. Iloprost (ILO), a stable prostacyclin analog, exerts cytoprotective effects through reduction in oxidative stress as well as by improvement of microvascular function. The purpose of the present study was to investigate the influence of iloprost on Isthmin-1 (ISM-1), adropin and transient receptor potential canonical 6 (TRPC6) immunoreactivity in rat lower extremity muscles in an experimental IR model. Materials and Methods: Thirty male Wistar albino rats, were divided into five groups, each with an equal number of rats; Control, Sham, ILO, IR, and IR + ILO. The ILO group received an intravenous infusion of 2 ng/kg/min ILO. After intracardiac blood was collected, muscle tissue samples were rapidly removed. Serum total oxidant status (TOS) and total antioxidant status (TAS) levels were measured. Histopathological examination of the collected muscle tissue samples was performed using hematoxylin-eosin staining, and immunohistochemical staining was used to assess the immunoreactivity of ISM-1, adropin, and TRPC6. Results: The IR group showed increased serum total oxidant status levels and immunoreactivity for ISM-1, adropin, and TRPC6, while total antioxidant status levels decreased. Compared with the IR group, the IR + ILO group showed decreased serum TOS levels and immunoreactivity for ISM-1, adropin, and TRPC6, while TAS levels increased. Conclusions: Treatment with ILO may have a protective effect on the skeletal muscle of lower extremities exposed to ischemia–reperfusion injury. This effect may be due to a reduction in oxidative stress and the regulation of immunoreactivity of ISM-1, adropin, and TRPC6. Full article