Search Results (1,654)

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

Ischemia-reperfusion (I/R) injury refers to the exacerbation of tissue or organ damage upon the restoration of blood flow after an ischemic event. Despite its widespread clinical occurrence, therapeutic interventions for I/R injury remain limited in efficacy, presenting a significant challenge in modern medicine. Garlic, traditionally consumed as a food, has gained considerable attention for its medicinal properties. Numerous animal studies have shown that garlic-derived organic polysulfides significantly improve nerve function scores post-I/R, reduce infarct size, mitigate inflammatory responses, and inhibit cellular apoptosis. Thus, understanding the role of garlic-derived organic polysulfides in I/R injury may unveil novel therapeutic targets. This review explores the protective effects and mechanisms of garlic-derived organic polysulfides on I/R injury in various organs, including the brain, spinal cord, myocardium, lungs, liver, kidneys, and testes, highlighting their potential in advancing treatment strategies for affected patients. Full article

Background: Freeze tolerance is an uncommon but highly effective strategy that allows certain vertebrates to survive prolonged exposure to subzero temperatures in a frozen, ischemic state. While past studies have characterized the metabolic and biochemical adaptations involved, including cryoprotectant accumulation and metabolic rate suppression, the contribution of post-transcriptional gene regulation by microRNAs (miRNAs) remains largely unexplored. This study investigated freeze-responsive miRNAs in cardiac tissue of the gray tree frog, Dryophytes versicolor, to better understand the molecular mechanisms that support ischemic survival and tissue preservation. Methods: Adult frogs were subjected to controlled freezing at −2.5 °C, and cardiac tissue was collected from frozen and control animals. Total RNA was extracted and analyzed via small RNA sequencing to identify differentially expressed miRNAs, followed by target gene prediction and KEGG pathway enrichment analysis. Results: A total of 3 miRNAs were differentially expressed during freezing, with significant upregulation of miR-93-5p and let-7b-5p and downregulation of miR-4485-3p. Predicted targets of upregulated miRNAs included genes involved in immune signaling pathways (e.g., cytokine–cytokine receptor interaction), steroid hormone biosynthesis, and neuroactive ligand–receptor interaction, suggesting suppression of energetically costly signaling processes. Downregulation of miRNAs targeting cell cycle, insulin signaling, and WNT pathways indicates possible selective preservation of cytoprotective and repair functions. Conclusion: Overall, these results suggest that D. versicolor employs miRNA-mediated regulatory networks to support metabolic suppression, maintain essential signaling, and prevent damage during prolonged cardiac arrest. This work expands our understanding of freeze tolerance at the molecular level and may offer insights into biomedical strategies for cryopreservation and ischemia–reperfusion injury. Full article

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia–reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC. Full article

Acute kidney injury (AKI) is characterized by a sudden rise in serum creatinine levels, a reduction in urine output, or both. Despite its frequent occurrence in clinical settings, AKI remains poorly understood from a pathophysiological standpoint. As a result, management primarily relies on supportive care rather than targeted treatments. Emerging evidence underscores the pivotal role of oxidative stress in both the initiation and progression of AKI, thereby identifying it as a potential therapeutic target. This review aims to comprehensively examine the pharmacological effects and underlying mechanisms of apocynin (APO) in the context of AKI, with a particular focus on ischemia–reperfusion injury (IRI) and nephrotoxic-induced AKI. Experimental preclinical studies have consistently demonstrated that APO offers protective effects primarily through its inhibition of NADPH oxidase-mediated oxidative stress. In renal IRI and drug-induced nephrotoxicity models, APO has been shown to attenuate oxidative damage, reduce inflammatory responses, and preserve renal structure and function. These results suggest that it may serve as an effective treatment for reducing kidney damage caused by acute ischemia or exposure to nephrotoxic agents. Although the results are encouraging, further investigation is required to establish the optimal dosing strategy and treatment protocol, as well as to confirm the translational relevance of these findings in human clinical settings. Full article

Taxifolin is a natural flavonoid found in a variety of plants, including Siberian larch (Larix sibirica) and milk thistle (Silybum marianum), that has attracted attention for its multifaceted pharmacological properties, including cardioprotective effects. Through its antioxidant and anti-inflammatory activities, taxifolin has shown significant therapeutic potential in cardiovascular diseases such as atherosclerosis, myocardial ischemia, and diabetic cardiomyopathy. This review highlights the cardioprotective effects of taxifolin in preclinical models of atherosclerosis, ischemia/reperfusion injury, and diabetic cardiomyopathy. Taxifolin contributes to its cardioprotective effects through key mechanisms such as modulation of pathways such as PI3K/AKT and JAK2/STAT3, inhibition of NADPH oxidase, and modulation of nitric oxide production. Recent studies have shown that taxifolin can affect glucose metabolism by modulating sodium–glucose transporter (SGLT) expression, potentially enhancing the cardioprotective effects of SGLT2 inhibitors. Given the emerging role of SGLT2 inhibitors in the management of cardiovascular disease, further investigation of the interaction of this pathway with taxifolin may provide new therapeutic insights. Although taxifolin has multifaceted potential in the prevention and treatment of cardiovascular disease, further studies are needed to better understand its mechanisms and validate its efficacy in different disease stages. This review aims to provide a rationale for the clinical application of taxifolin-based cardiovascular therapies and suggest directions for future research. Full article

Background: Excessive formation of neutrophil extracellular traps (NETs) leads to NETosis, accompanied by the release of citrullinated histone H3 (CitH3), a key mediator of septic inflammation. However, the role of CitH3 in sterile inflammation, such as acute myocardial infarction (MI) and post-MI heart failure, remains incompletely understood. Methods and Results: We investigated the role of CitH3, a byproduct of NETosis, in myocardial ischemia/reperfusion (I/R) injury using a murine MI model. C57BL/6J mice were subjected to left coronary artery (LCA) occlusion followed by reperfusion and treated with either a humanized anti-CitH3 monoclonal antibody (hCitH3-mAb) or control human IgG. In mice undergoing 40 min of LCA occlusion and 24 h of reperfusion, hCitH3-mAb administered 10 min before reperfusion significantly reduced infarct size by 36% compared to control (p < 0.05). Plasma levels of CitH3, IL-1β, and interferon-β were significantly elevated following MI but were attenuated by hCitH3-mAb. In addition, plasma and cardiac tissue from treated mice showed significantly lower levels of citrate synthase, a marker of mitochondrial injury, suggesting that hCitH3-mAb preserved mitochondrial integrity after MI. In mice undergoing 50 min of LCA occlusion and 21 days of reperfusion, longitudinal echocardiography revealed preservation of left ventricular ejection fraction (LVEF) in hCitH3-mAb-treated mice, with significant improvement observed on days 7, 14, and 21 post-MI (p < 0.05 vs. control). hCitH3-mAb also mitigated myocardial fibrosis and preserved tissue architecture. Conclusions: These findings demonstrated CitH3 as a critical mediator of myocardial injury and adverse remodeling following acute MI. Neutralization of CitH3 via hCitH3-mAb attenuates I/R injury and preserves cardiac function by mitigating inflammation and protecting mitochondrial integrity. Targeting CitH3 represents a promising therapeutic strategy to prevent heart failure following MI. Full article

Pressure ulcers (PUs) are localized injuries caused by prolonged mechanical loading and ischemia, often leading to delayed healing and high recurrence rates. Although conventional treatments aim to support tissue repair, their efficacy remains limited, prompting interest in noninvasive therapies such as the pulsed electromagnetic field (PEMF). The PEMF has been reported to enhance cellular proliferation, re-epithelialization, and collagen remodeling, but its effects in pressure ulcer models, particularly concerning genetic background, remain unclear. This study investigated the therapeutic effects of the PEMF in a murine pressure ulcer model established by ischemia and reperfusion injury induced with externally attached magnets in two mouse strains, BALB/c and C57BL/6. The PEMF (10 Hz, 24 h per day) was used to treat PU-induced mice from day 4 to day 15 in BALB/c mice and to day 14 in C57BL/6 mice. Wound healing was assessed by gross morphological observation, histological analysis, and digital quantification of epidermal lesion length and collagen-positive area. In BALB/c mice, PEMF-treated wounds showed a modest trend toward improved re-epithelialization and collagen deposition, although the differences were not statistically significant. In contrast, C57BL/6 mice exhibited a significantly shorter length of epidermal lesion in the PEMF group on day 14, indicating enhanced epidermal regeneration. Collagen analysis showed comparable levels between treated and control groups in both strains, with no significant differences observed. To further assess the cellular response to PEMF, a scratch wound assay was conducted using HaCaT cells. Quantitative analysis demonstrated that PEMF treatment accelerated cell migration and wound closure in vitro. These findings suggest that PEMF enhances epidermal regeneration and keratinocyte mobility, with therapeutic responses potentially influenced by genetic background. This study supports the potential application of PEMF in pressure ulcer treatment and underscores the importance of strain selection in preclinical wound healing research. Full article

Background/Objectives: Naringin, a major flavonoid found in citrus fruits, has garnered significant attention over the past two decades for its potential cardiovascular benefits. This systematic review evaluates the effects of naringin on endothelial function and myocardial performance, with particular emphasis on ischemia-reperfusion (I/R) injury, based on the literature published from January 2000 to June 2025. Methods: The review was conducted in accordance with PRISMA 2020 guidelines. A comprehensive search of PubMed, Scopus, EMBASE, and Web of Science databases was performed using key terms including “naringin”, “cardiovascular”, “endothelial function”, “atherosclerosis”, and “ischemia-reperfusion.” A total of 62 studies were included and categorized into three domains: cellular models, animal studies, and human trials. Risk of bias assessments were conducted for each study type using appropriate tools. Results: Naringin consistently exhibited antioxidant, anti-inflammatory, and vasoprotective effects across all study types. Mechanistic studies highlighted the modulation of key signaling pathways, including PI3K/Akt, NF-κB, Nrf2, the renin-angiotensin system (RAS), and enhancement of KATP channel expression, as well as its ability to inhibit apoptosis, autophagy, and ferroptosis. In animal models, naringin improved endothelium-dependent vasorelaxation, reduced infarct size, and preserved myocardial function. Although limited, human trials reported beneficial effects on lipid profiles, arterial stiffness, and adiponectin levels. Conclusions: Naringin demonstrates strong potential as a dietary adjunct for cardiovascular protection, especially in the context of ischemic injury and vascular dysfunction. Further well-designed clinical trials are needed to define optimal dosing strategies and improve its bioavailability in humans. Full article

A new trinor-sesterterpenoid penitalarin D (1), with a 3,6-dioxabicyclo[3.1.0]hexane moiety, as well as two known compounds, penitalarin C (2) and nafuredin A (3), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Their structures were determined by detailed NMR, MS spectroscopic analyses, and ECD calculations. Penitalarin D (1) and nafuredin A (3) showed toxicity or no toxicity against HepG2 cells at a concentration of 200 μM. The transcriptome sequencing and bioinformatics analysis revealed that 3 could be effective by regulating ferroptosis pathways in HepG2 cells, which was subsequently validated by RT-qPCR, demonstrating significant upregulation of ferroptosis-related genes. Pre-treatment with 3 could mitigate hypoxia-reoxygenation-induced damage in the oxygen glucose deprivation/reperfusion (OGD/R) cell model. Given the structural similarity of compounds 1, 2, and 3, we also screened compounds 1 and 2 in an AML12 OGD/R model. As no significant activity was observed, compound 3 was selected for subsequent in vivo studies. Subsequently, in vivo experiments demonstrated that 3 could significantly decrease pro-inflammatory cytokines and display the hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI). These findings identified nafuredin A (3) as a promising hepatoprotective agent for new drug development. Full article

Objective: To evaluate the perioperative outcomes, functional impact, and oncologic efficacy of off-clamp robotic-assisted partial nephrectomy (RAPN) in patients with renal masses across multiple high-volume centers. Materials and Methods: We conducted a retrospective multicenter study including 563 patients (group 1) who underwent clampless RAPN between January 2018 and December 2024. Patients with solitary kidneys, tumors >7 cm, or prior renal surgery were excluded. The standardized surgical technique involved tumor resection without clamping of the renal artery, followed by the use of hemostatic agents and standard/selective suturing of the resection bed on demand. Patients in group 1 were compared to 244 consecutive patients treated in the same centres and treated with RAPN with an on-clamp procedure (group 2). Primary outcomes included operative time, blood loss, and complications, while secondary outcomes assessed renal function preservation and oncologic control at an at least 12-month follow-up. Results: The median operative time was 118 min (IQR: 100–140 min), and median estimated blood loss was 150 mL (range: 50–400 mL). The overall complication rate was 9.2%, with most classified as Clavien–Dindo Grade I–II. No intraoperative conversions to open surgery were recorded. Renal function was well preserved, with a median estimated glomerular filtration rate (eGFR) decline of 4.1% at three months (p > 0.05), and no cases of acute kidney injury. Oncologic outcomes were favorable, with a positive surgical margin rate (PSM) of 2.4% and two cases of tumor recurrences (0.36%) documented at a 12-month follow-up. Conclusions: The off-clamp RAPN is a safe and effective nephron-sparing approach, offering significant renal function preservation while maintaining oncologic efficacy. This technique minimizes ischemia–reperfusion injury and post-surgical fibrosis, providing a viable alternative to on-clamp RAPN. Further prospective trials are warranted to confirm long-term benefits and refine patient selection criteria. Full article

Carbon monoxide (CO) is generally recognized as a toxic gas; however, it has recently been identified as an endogenous gasotransmitter with significant cytoprotective properties. CO modulates key molecular pathways, including anti-inflammatory, anti-apoptotic, antioxidant, and vasodilatory signaling pathways, by targeting heme- and non-heme-containing proteins. These proteins include soluble guanylate cyclase, cytochrome P450 enzymes, MAPKs, and NLRP3. This review summarizes recent advances in understanding the molecular mechanisms associated with the protective effects of CO, particularly in the context of ischemia–reperfusion injury relevant to organ transplantation. We discuss preclinical data from rodent and large animal models, as well as therapeutic delivery strategies, such as inhalation, CO-releasing molecules, and gas-entrapping materials. We also reviewed early-phase clinical trials. The objective of this review is to provide a thorough exploration of CO as a potential therapeutic gas, with special emphasis on its application in transplantation. Full article