Search Results (2,041)

Although cardiac metabolic adaptation has been observed in response to the ischemia–reperfusion, the specific temporal and spatial changes occurring in the main regulators of myocardial glucolipid metabolism in the infarcted heart have not been fully characterized. Myocardial infarction (MI) was induced in female swine by transient coronary occlusion. The study design consisted of one control and four MI groups (no reperfusion, 1 min, 1 week, and 1 month after reperfusion). Metabolites obtained from the coronary sinus were determined at baseline, during ischemia, and after coronary reperfusion. mRNA expression of genes related to beta-oxidation and glucose transport were quantified in the five experimental groups and in three myocardial regions (infarcted, adjacent, and remote). In the coronary sinus, reduced glucose and increased lactate levels were detected during ischemia and soon after reperfusion. However, non-esterified fatty acids increased during reperfusion. A general upregulation of genes implicated in glycolysis and beta-oxidation occurred during ischemia and few minutes after reperfusion. Contrarily, heightened mRNA expression of glucose transporters and decay in regulators of beta-oxidation were observed one week after coronary reperfusion. Glycolysis and beta-oxidation are activated during ischemia and few minutes after coronary reopening, while a shift from beta-oxidation to glycolysis is evidenced a few days afterwards. Full article

Ischemic stroke is a neurological disorder resulting from localized brain injury due to focal cerebral ischemia, typically caused by the blockage of one or, in some cases, a few cerebral arteries. This arterial obstruction leads to hypoxia and energy failure, culminating in primary brain damage. Although reperfusion is critical to salvage viable tissue, it often intensifies injury through oxidative stress, inflammation, and cell death—a phenomenon called ischemia–reperfusion (I/R) injury. Milk fat globule-EGF factor 8 (MFG-E8), a multifunctional glycoprotein secreted by stem and immune cells, is a key regulator of inflammation and tissue repair. By modulating microglial activation, attenuating proinflammatory cytokine releases, and preserving neuronal integrity, MFG-E8 mitigates ischemia–reperfusion injury and emerges as a novel therapeutic target for ischemic stroke. Full article

Acute kidney injury is a common complication in the perioperative setting, especially among patients undergoing high-risk surgeries such as cardiac, abdominal, or orthopedic procedures. Characterized by a sudden decline in renal function, perioperative acute kidney injury is typically diagnosed based on rising serum creatinine or reduced urine output. Its incidence varies depending on the surgical type and patient risk factors, but even mild cases are linked to significant consequences, including prolonged hospital stays, enhanced healthcare costs, and higher mortality rates. Despite advances in surgical and anesthetic care, acute kidney injury remains a major cause of morbidity. The development of acute kidney injury in the perioperative period often results from a complex interplay of hypoperfusion, ischemia–reperfusion injury, inflammation, and exposure to nephrotoxic agents. While some predictive models and biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), have shown promise in identifying patients at risk, widespread adoption remains inconsistent, and standardized prevention protocols are lacking. This narrative review synthesizes current evidence on the pathophysiology, risk factors, and prevention strategies for perioperative acute kidney injury. It explores emerging tools for risk stratification and early diagnosis, including novel biomarkers and learning-based models. Additionally, it highlights pharmacologic and non-pharmacologic measures to reduce acute kidney injury incidence, such as balanced fluid management, renal-protective anesthetic strategies, and bundle-based care approaches. Emphasizing a multidisciplinary and personalized model of care, this review highlights the need for coordinated efforts between anesthesiologists, surgeons, and nephrologists to identify modifiable risks and improve outcomes. Reducing the incidence of perioperative acute kidney injury has the potential to enhance recovery, preserve long-term kidney function, and ultimately improve surgical safety. Full article

Spinal cord ischemia–reperfusion (SCI/R) injury remains a major clinical challenge with limited therapeutic options. High-mobility group box 1 (HMGB1), a proinflammatory mediator released during cellular stress, has been implicated in the pathogenesis of ischemia–reperfusion-induced neural damage. In this study, we investigated the neuroprotective potential of the anti-HMGB1 monoclonal antibody (mAb) in a rabbit model of SCI/R injury. Male New Zealand White rabbits were anesthetized and subjected to 11 min of abdominal aortic occlusion using a micro-bulldog clamp following heparinization. Anti-HMGB1 mAb or control IgG was administered intravenously immediately after reperfusion and again at 6 h post-reperfusion. Neurological function was assessed at 6, 24, and 48 h after reperfusion using the modified Tarlov scoring system. The rabbits were euthanized 48 h after reperfusion for spinal cord and blood sampling. Treatment with anti-HMGB1 mAb significantly improved neurological outcomes, reduced the extent of spinal cord infarction, preserved motor neuron viability, and decreased the presence of activated microglia and infiltrating neutrophils. Furthermore, it attenuated apoptosis, oxidative stress, and inflammatory responses in the spinal cord, and helped maintain the integrity of the blood–spinal cord barrier. These findings suggest that anti-HMGB1 mAb may serve as a promising therapeutic agent for SCI/R injury. Full article

Brain ischemia-reperfusion (I/R) injury, commonly occurring in ischemic stroke and post-cardiac arrest scenarios, results in complex secondary damage involving oxidative stress, inflammation, apoptosis, and blood-brain barrier (BBB) breakdown. Despite decades of research, no pharmacological agent has yet been clinically approved for post-I/R neuroprotection. Natural compounds have recently gained attention for their multimodal therapeutic potential, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroregenerative effects. This review highlights nine promising candidates—resveratrol, curcumin, quercetin, berberine, ginkgolide B, baicalin, naringin, fucoidan, and astaxanthin—that exhibit efficacy in experimental models of I/R injury when administered after the insult. Their chemical structures, pharmacokinetics, and mechanisms of action are described in detail, focusing on key signaling pathways such as nuclear factor erythroid 2-related (Nrf2), nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and brain-derived neurotrophic factor (BDNF). Importantly, we outline the selection criteria for these compounds, including demonstrated neuroprotective efficacy, mechanistic clarity, and translational feasibility. While several challenges remain—such as limited bioavailability, BBB penetration, and species-specific metabolism—emerging strategies like nanoparticle delivery, synthetic analogs, and drug combinations offer potential solutions. By emphasizing the therapeutic versatility and mechanistic diversity of these natural agents, this review supports their clinical potential and encourages further preclinical optimization and biomarker-guided human trials. Full article

Background/Objectives: To prevent flap failure, adequate tissue perfusion and effective regenerative processes, undisturbed wound healing are essential, among others. To improve wound healing, various locally and systematically administered pharmacons can be used. This study investigated the effect of PACAP 1-38 (pituitary adenylate cyclase activating polypeptide) and BGP-15 (a nicotinic amidoxime derivative) on the healing of epigastric fasciocutaneous flaps exposed to ischemia–reperfusion (I/R). Methods: Wistar rats were randomly divided into control (no substance), PACAP 1-38, and BGP-15 groups. Groin flaps were prepared bilaterally. The left flap was exposed to 120 min of ischemia prior to suturing it back. We applied wound gels containing substances. Laboratory tests (hematology, erythrocyte deformability, and aggregation) were performed before surgery on the 1st, 3rd, and 7th postoperative days. Lastly, flap skin samples were taken for histological and tensile strength measurements. Results: Impaired erythrocyte deformability and enhanced aggregation were found because of flap I/R. The pharmacons were able to reduce the systemic micro-rheological impairment to varying degrees. The tensile strength increased in the areas of better perfusion. Conclusions: The anti-inflammatory effects of PACAP 1-38 and BPG-15, as well as the impact of PACAP 1-38 on collagen and elastic fiber composition, have been demonstrated. Full article

Background: Static cold storage is the standard method of kidney preservation following donation after circulatory death (DCD). A previous study on rodent models demonstrated the efficacy of storing DCD kidneys at 22 °C in an extracellular-type solution (ETK). We evaluated the efficacy of storing warm-ischemic kidneys at 22 °C in MHC-inbred miniature swine. Methods: After 2 h warm ischemia, the kidneys were preserved in ETK for one hour at either 4 °C or 22 °C and then subjected to ex vivo normothermic machine perfusion (NMP) for 2 h (n = 3 in each group). The same warm-ischemic kidneys, preserved in ETK (n = 3 in each group) or intracellular-type solution (UW; n = 2 in each group) at either 4 °C or 22 °C, were transplanted into MHC-matched recipients. Results: Compared with kidneys preserved at 4 °C, those preserved at 22 °C showed significantly better physiological and metabolic indices during ex vivo NMP. Furthermore, renal function was significantly higher in transplanted kidneys, and graft biopsies on postoperative day 4 showed more localized necrosis in the renal tubules when kidneys were stored at 22 °C. In contrast, recipient animals with kidneys stored in UW solution did not survive for more than 7 days. Conclusions: Two-hour warm-ischemic kidneys from miniature swine showed improved preservation at 22 °C than at 4 °C when an extracellular-type solution was used. Full article

Background: Cardiomyocyte death is a key factor in myocardial ischemia–reperfusion injury (MI/RI), and the expression patterns and molecular mechanisms of pyroptosis-related genes (PRGs) in ischemia–reperfusion injury are poorly understood. Methods: The mouse MI/RI injury-related datasets GSE61592 and GSE160516 were obtained from the Gene Expression Omnibus database, and differential expression analysis was performed on each to identify differentially expressed genes (DEGs). The DEGs were intersected with the PRGs obtained from GeneCards to identify differentially expressed PRGs in MI/RI. Enrichment analysis identified key pathways, while PPI network analysis revealed hub genes. The expression patterns and immune cell infiltration of hub genes were also investigated. The molecular docking prediction of key genes was performed using MOE software in conjunction with the ZINC small molecular compounds database. Key gene expression was validated in an external dataset (GSE4105), a mouse MI/RI model, and an HL-1 cell hypoxia/reoxygenation model via RT-qPCR. Results: A total of 29 differentially expressed PRGs were identified, which are primarily associated with pathways such as “immune system process”, “response to stress”, “identical protein binding”, and “extracellular region”. Seven key genes (Fkbp10, Apoe, Col1a2, Ppic, Tlr2, Fstl1, Serpinh1) were screened, all strongly correlated with immune infiltration. Seven FDA-approved small molecule compounds exhibiting the highest docking potential with each key gene were selected based on a comprehensive evaluation of S-scores and hydrogen bond binding energies. Apoe, Tlr2, and Serpinh1 were successfully validated across external datasets, the mouse MI/RI model, and the cardiomyocyte H/R model. Conclusions: Apoe, Tlr2, and Serpinh1 may be key genes involved in MI/RI-related pyroptosis. Targeting these genes may provide new insights into the treatment of MI/RI. Full article

Mitochondrial reverse electron transport (RET) represents a fundamental but potentially hazardous metabolic process in eukaryotic cells. This review systematically examines current understanding of RET mechanisms and their pathophysiological consequences. RET occurs when electrons flow inversely from reduced coenzyme Q (CoQH₂) to complex I, driven by excessive reduction of the CoQ pool and elevated mitochondrial membrane potential, resulting in substantial superoxide production. While moderate RET contributes to physiological redox signaling, sustained RET activation leads to oxidative damage and activates regulated cell death pathways. Notably, RET demonstrates metabolic duality: it facilitates ATP generation through NAD⁺ reduction while simultaneously inducing mitochondrial dysfunction via reactive oxygen species overproduction. Pathologically, RET has been implicated in myocardial ischemia–reperfusion injury, neurodegenerative disorders including Alzheimer’s diseases, and exhibits context-dependent roles in tumor progression. Emerging evidence also suggests RET involvement in microbial pathogenesis through modulation of host immune responses. These findings position RET as a critical regulatory node in cellular metabolism with broad implications for human diseases. Future investigations should focus on developing tissue-specific RET modulators and elucidating the molecular switches governing its activation threshold, which may yield novel therapeutic strategies for diverse pathological conditions. Full article

The gastrointestinal tract is affected by multiple ailments that manifest with similar chemical, subcellular, and cellular changes, such as those in intestinal ischemia–reperfusion injury (IRI). The main chemical changes that are described under IRI conditions include the depletion of oxygen available for normal metabolism and the abundant production and increase in intracellular and extracellular concentrations of hydrogen peroxide and other reactive oxygen species (ROS). The enzymes causing this accumulation are xanthine dehydrogenase turning into xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, and nitric oxide synthase. The cellular changes revolve around an oxygen-sensing system that is responsive to varying oxygen levels, which has Hypoxia-Inducible Factors (HIFs) at its base. HIFs are transcription factors, the intracellular concentrations of which significantly increase under hypoxic conditions. Upon activation, they alter the expression of gene sets to ensure appropriate cellular adjustment to the hypoxic and IRI environment. Despite the primary regulation of the system involving oxygen, it is interconnected with multiple other subcellular and cellular functions. Thus, it represents a linchpin control mechanism of cellular adaptation. The effect of HIF activation in intestinal cells aims at preserving the structural integrity of the intestinal lining. The effect in different subtypes of leucocytes aims at immune system activation to protect against previously luminally located and subsequently invading pathogens and toxins. All in all, the HIF system is an integral part of cellular and tissue compensation against intestinal IRI. Full article

Red blood cell (RBC), accounting for approximately 45% of total blood volume, are essential for oxygen delivery and carbon dioxide removal. Their unique biconcave morphology, high surface area-to-volume ratio, and remarkable deformability enable them to navigate microvessels narrower than their resting diameter, ensuring efficient microcirculation. RBC deformability is primarily determined by membrane viscoelasticity, cytoplasmic viscosity, and cell geometry, all of which can be altered under various physiological and pathological conditions. Reduced deformability is a hallmark of numerous diseases, including sickle cell disease, malaria, diabetes mellitus, sepsis, ischemia–reperfusion injury, and storage lesions in transfused blood. As these mechanical changes often precede overt clinical symptoms, RBC deformability is increasingly recognized as a sensitive biomarker for disease diagnosis, prognosis, and treatment monitoring. Over the past decades, diverse techniques have been developed to measure RBC deformability. These include single-cell methods such as micropipette aspiration, optical tweezers, atomic force microscopy, magnetic twisting cytometry, and quantitative phase imaging; bulk approaches like blood viscometry, ektacytometry, filtration assays, and erythrocyte sedimentation rate; and emerging microfluidic platforms capable of high-throughput, physiologically relevant measurements. Each method captures distinct aspects of RBC mechanics, offering unique advantages and limitations. This review synthesizes current knowledge on the pathophysiological significance of RBC deformability and the methods for its measurement. We discuss disease contexts in which deformability is altered, outline mechanical models describing RBC viscoelasticity, and provide a comparative analysis of measurement techniques. Our aim is to guide the selection of appropriate approaches for research and clinical applications, and to highlight opportunities for developing robust, clinically translatable diagnostic tools. Full article

Cerebral ischemia–reperfusion injury (CIRI) is a complex pathological process that arises when blood flow is restored to the brain after ischemia, often resulting in significant neuronal damage and triggering secondary inflammatory responses. This review explores the immune mechanisms underlying CIRI, focusing on the activation and polarization of resident central nervous system (CNS) cells—particularly microglia and astrocytes—and the infiltration of peripheral immune cells such as neutrophils, monocytes/macrophages, and T lymphocytes. We discuss the central role of microglia in the neuroinflammatory cascade, their polarization between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, and how this process influences neuronal damage and tissue repair. This review highlights the roles of the complement system, inflammasome activation, and blood–brain barrier disruption as key drivers of inflammation and neuronal injury. Additionally, we elaborate on the dynamic interactions between resident and infiltrating immune cells, which amplify inflammation and impede post-ischemic recovery. Finally, we discuss emerging therapeutic strategies targeting immune modulation, including cytokine regulation, microglial reprogramming, and targeted drug delivery systems, which offer promising avenues for improving outcomes in ischemic stroke. Full article

Previous work has shown that mouse models fed a non-obesogenic high-fat diet have preserved cardiac function and no obesity-associated comorbidities such as diabetes. However, they do suffer increased cardiac vulnerability to ischemic reperfusion (I/R) injury, which has been attributed to changes in Ca²⁺ handling, oxidative stress, and mitochondrial transition pore activity. However, there have been no studies investigating the involvement of metabolites. Wild-type mice were fed either a control or a non-obesogenic high-fat diet for ~26 weeks. Key cardiac metabolites were extracted from freshly excised hearts and from hearts exposed to 30 min global ischemia followed by 45 min reperfusion. The extracted metabolites were measured using commercially available kits and HPLC. Hemodynamic cardiac function was monitored in Langendorff perfused hearts. Levels of energy-rich phosphates and related metabolites were similar for both hearts fed a control or a high-fat diet. However, the high-fat diet decreased cardiac glycogen and increased cardiac lactate, hypoxanthine, alanine, and taurine levels. Langendorff perfused hearts from the high-fat diet group suffered more ischemic stress during ischemia, as shown by the significantly shorter time needed for onset and for reaching maximal ischemic (rigor) contracture. Following I/R, there was a significant decrease in myocardial adenine nucleotides and a significant increase in the levels of alanine and purines for both groups. Most of the principal amino acids tended to fall during I/R. Hearts from mice fed a high-fat diet showed more changes during I/R in markers of energetics (phosphorylation potential and energy charge), metabolic stress (lactate), and osmotic stress (taurine). This study suggests that cardiac metabolic changes due to high-fat diet feeding, independent of obesity-related comorbidities, are responsible for the marked metabolic changes and the increased vulnerability to I/R. Full article

Background: Ischemia–reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI). While the precise mechanisms of AKI are still incompletely defined, extensive evidence highlights tubular cell injury and death as key factors in its development. Necroptosis has recently emerged as a critical pathway in the pathogenesis of ischemia–reperfusion-induced AKI (IR-AKI). Although sex differences in susceptibility to IR-AKI have been reported, it remains unclear whether there are sex differences in necroptosis dynamics and whether these differences underlie the observed sexual dimorphism in kidney IRI. This study aimed to address these questions. Methods: male and female C57BL/6 J mice were subjected to AKI via ischemia induced by bilateral renal pedicle clamping for 18 min at 37 °C. Plasma, urine, and kidney samples were collected at 0 h, 3 h, 6 h, 12 h, 24 h, 48 h, and 72 h post-reperfusion. Kidney injury and function were assessed by measuring plasma creatinine (PCr), blood urea nitrogen (BUN) levels, and histological damage (PAS and cleaved caspase3 staining). Necroptosis activation was assessed by quantifying phosphorylated forms of key markers: p-RIPK1 and p-MLKL. To explore the role of sex hormones in regulating necroptosis dynamics, ovariectomized female mice were subjected to the same IR-AKI protocol, and their kidney injury and functional outcomes were compared with those of intact counterparts. Results: The PCr was 0.35 ± 0.04 and 0.32 ± 0.06 mg/dL for males and females, respectively, at 3 h of IR. The levels exponentially increased to 2.05 ± 0.18 at 48 h post-reperfusion in the males but only gradually to 0.94 ± 0.13 mg/dL in females. Necroptosis activation began as early as 3 h post-IR in males but was delayed until ~6 h in females. Males exhibited stronger and more sustained necroptosis activation than females, showing elevated phosphorylation levels of pRIPK1 and pMLKL in Western blot. Female sex hormone deficiency exacerbated the female response to IR-induced injury, which reduced the sex difference in the dynamic of the necroptotic activation and subsequent kidney injury. To our knowledge, this is the first study to characterize sex differences in the initiation and progression of necroptosis and subsequent injury in a mouse model of IR-AKI. Conclusions: Our findings reveal distinct temporal patterns of programmed cell death between sexes. Necroptosis-targeted therapies require early intervention in males, which can be delayed in females after IR-AKI, highlighting the need for sex-specific therapeutic windows. Full article