Search Results (422)

Background and Aims: Hypothermic oxygenated machine perfusion (HOPE) improves outcomes in orthotopic liver transplantation (OLT), but reliance on University of Wisconsin machine perfusion solution (UW-MPS) increases costs and logistical burden. Histidine-tryptophan-ketoglutarate (HTK) has potential as a single-solution alternative for HOPE. This study evaluated the safety and efficacy of HTK versus UW-MPS during HOPE. Methods: A retrospective, propensity score-matched cohort study including 46 patients who received donation after brain death (DBD) grafts that were preserved with HOPE at the Medical University of Vienna between May 2018 and October 2024 was conducted. A total of 23 patients received grafts perfused with HTK; another 23 patients transplanted with organs perfused with UW-MPS were matched based on recipient age and sodium model of end-stage liver disease score, donor age and sex, cold ischemia time, and perfusion time. Postoperative outcomes, perfusion parameters, and cost differences were assessed. Results: The HTK and UW-MPS cohorts demonstrated comparable perfusion dynamics and vascular resistance. While arterial pressure and flow were higher in the UW-MPS group, clinical outcomes—including early allograft dysfunction (47.8% each), ICU stay, and comprehensive complication index—were statistically similar. A trend toward fewer biliary complications (13.0% vs. 30.4%) and reduced hemodialysis requirement (17.4% vs. 30.4%) was observed in the HTK group. Use of HTK reduced perfusion-related costs by approximately EUR 560 per procedure. Conclusion: HTK is a viable alternative to UW-MPS during HOPE in OLT of DBD grafts, offering comparable short-term outcomes and relevant cost savings. Prospective studies are warranted to validate these findings and explore broader applications of single-solution perfusion strategies. Full article

Hypoxic–ischemic encephalopathy remains a major cause of neonatal mortality and long-term neurological disability. Therapeutic hypothermia is currently the only available treatment in hospitals, but its efficacy is limited, making the search for alternative neuroprotective strategies essential. Melatonin has shown promising results in other models of hypoxia–ischemia, acting as a potent antioxidant and anti-inflammatory molecule. Here, we studied the effects of hypoxia–ischemia and melatonin treatment in two brain regions that are particularly vulnerable to hypoxic–ischemic injury. Neonatal rat organotypic slice cultures from the corticostriatal and hippocampal regions were subjected to oxygen–glucose deprivation and reperfusion (OGDR) and treated with melatonin (50 μM). Cell death (propidium iodide staining), redox state (GSH/GSSG ratio) and the inflammatory profile (Proteome Profiler) were analyzed. OGDR markedly increased cell death in both regions and melatonin treatment significantly reduced it. The GSH/GSSG ratio decreased only in the hippocampus after OGDR, but melatonin treatment elevated this ratio in both regions. In contrast, the inflammatory profile was more pronounced in the corticostriatal region, where the treatment strongly reduced proinflammatory mediators. These findings reveal region-specific mechanisms involved in the response to hypoxic–ischemic damage and support the potential of melatonin as a promising therapy for neonatal brain injury. Full article

Background/Objectives: We hypothesized that older recipients have a higher rate of kidney graft failure compared to younger recipients. Thus, we assessed 60-month kidney graft failure (KGF) among deceased donor recipients aged 65 years or older and compared it with that of younger recipients. Methods: A single-center, retrospective cohort study was conducted at Son Espases University Hospital in Palma, Spain, including all consecutive deceased donor kidney transplant recipients from 2011 to 2021. The primary outcome was 60-month KGF, analyzed using the cumulative incidence function (CIF). A multivariable semi-parametric Fine and Gray model was used to estimate the subhazard of KGF in older versus younger recipients, adjusting for variables associated with recipients aged 65 years or older, including KGF and overall survival. Results: The study included 618 recipients, with a median age (interquartile range) of 58 years (47–66 years); of these, 187 (30%) were aged 65 years or older, and 498 (81%) received grafts from donors after brain death. The 60-month CIF (95% confidence interval) of KGF for the entire cohort was 12% (9.1–15). Candidate variables for multivariable analysis included recipient sex, body mass index, donor age, presence of hypertension or diabetes, donor sex, length of hospital stay, cold ischemia time, donor type, multiple renal veins, and Clavien-Dindo grade ≥ 3 complications. After adjustment, KGF risk did not significantly differ between age groups (sHR: 0.75; 95% CI: 0.41–1.38; p = 0.36). Conclusions: Despite having worse baseline characteristics, receiving lower-quality grafts, and experiencing a higher incidence of postoperative complications, we observed comparable 60-month kidney graft survival in older recipients relative to younger ones. These findings support the viability of kidney transplantation in well-selected older patients. Full article

Acute injuries to the central nervous system (CNS) share a rapid disruption of arousal, autonomic stability, and neuroimmune balance. Among the neuromodulatory systems affected, the orexin (hypocretin) network is uniquely positioned at the intersection of wakefulness, autonomic control, and motivated behavior. Experimental evidence across ischemic, hemorrhagic, traumatic, and systemic models shows that orexin signaling is sharply suppressed during the early post-injury collapse and gradually recovers as arousal circuits and homeostatic functions stabilize. Controlled enhancement of orexinergic tone has been found to improve arousal state, modulate inflammatory responses, and support behavioral engagement, although these effects are highly dependent on timing, receptor subtype, and physiological context. This review synthesizes evidence from ischemia, hemorrhagic stroke, traumatic brain and spinal cord injury, and systemic inflammatory states, and examines the conceptual and translational rationale for targeting orexin pathways. We summarize available pharmacological, peptide-based, neuromodulatory, and physiological strategies to boost orexinergic tone, highlighting the growing development of selective OX₂ agonists and experimental approaches to enhance endogenous orexin activity. By integrating findings across etiologies within a timing-aware framework, this review addresses a gap in the current literature, which has largely treated these injuries in isolation. While clinical testing in acute CNS injury has not yet been performed, the mechanistic convergence across etiologies suggests that orexinergic modulation may offer a phase-sensitive means to stabilize arousal and support recovery. Taken together, orexin emerges as a state-dependent integrator whose modulation could complement existing therapies by linking early arousal stabilization with longer-term motivational and functional recovery. Full article

Objective: Ischemic stroke (IS) is an acute neurologic injury in which inflammatory responses play a key role. Yinchen, a common medicinal plant used in Traditional Chinese Medicine (TCM), has been proven to possess strong anti-inflammatory effects. However, its efficacy in treating IS remains unclear. In this study, we aimed to investigate the therapeutic potential of Yinchen for IS and the material basis of this potential. Methods: The main active components in Artemisia scoparia extract (ASE, the extract of Yinchen), were identified by HPLC and MS. The targets of Yinchen and IS were obtained from public databases. Network pharmacology, molecular docking, and experimental investigation were further applied to acquire the core constituents in Yinchen that work against the neuroinflammation that occuring during IS. The neurological outcomes were evaluated in a transient Middle Cerebral Artery Occlusion (tMCAO) rat model. Additionally, the changes in the inflammatory responses in both the ischemic brain and in lipopolysaccharide (LPS)-treated microglial cells were examined using real-time qPCR. Results: Four active compounds of ASE, including isochlorogenic acid C (ICGA-C), isochlorogenic acid B (ICGA-B), isochlorogenic acid A (ICGA-A), and chlorogenic acid (CGA), were identified by HPLC and MS. Network pharmacology predicted that 103 compounds of Yinchen had 198 intersection targets with IS. The top five of these targets were TNF, STAT3, IL1B, AKT1, and SRC. Molecular docking results demonstrated that the abovementioned four compounds detected in ASE showed good interaction with all of the above five core targets. Moreover, both the four compounds and ASE were observed to attenuate NO release and suppress the release of various inflammatory factors (TNF-α, IL-1β, IL-6, and MCP-1) in a dose-dependent manner in LPS-induced BV2 microglial cells. ASE was further found to exert neuroprotective effects against ischemia–reperfusion (I/R) injury and inhibit the production of inflammatory factors in tMCAO rats. Conclusions: Yinchen exerts an anti-neuroinflammatory effect on IS, and its constituents with high scores binding to five core targets contribute to this effect. This supports its potential as an anti-inflammatory agent for the treatment of IS. Full article

Despite the substantial global impact of ischemic stroke, current therapeutic options remain limited and only partially effective. To advance neuroprotective strategies that could improve the safety and efficacy of existing treatments while preserving brain tissue, we synthesized and evaluated seven new nitrones (MC3, MC5, MC7) and oximes (MC1, MC2, MC4, MC6) derived from different neuroactive steroids—ethisterone (MC1–3), mifepristone (MC4–5) and stanolone (MC6–7)—in an in vitro model of cerebral ischemia. Overall, these derivatives exhibited neuroprotective and antioxidant effects superior to those of the reference compounds cholesteronitrone ChN2, α-tert-butyl nitrone (PBN) and N-acetylcysteine (NAC). Notably, nitrones showed greater neuroprotective, anti-necrotic, and antioxidant potency than their corresponding oximes, regardless of the degree of molecular conjugation. Among them, the stanolone-derived nitrone MC7, which lacks conjugated double bonds, displayed the most balanced and robust profile, consistently enhancing cell viability, reducing necrotic cell death, and suppressing superoxide anion production. Consequently, MC7 has been selected as a promising lead compound for further in vivo studies of cerebral ischemia. Full article

Alzheimer’s disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5–2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke. Full article

Brain damage caused by hypoxia-ischemia is a serious complication for a newborn with possible life-long sequelae. To develop targeted neuroprotective strategies, it is essential to understand the mechanisms of injury, particularly the role of microglial phagocytosis, which may contribute to neuronal loss after hypoxia-ischemia. The aim was to evaluate neuronal cell death by phagocytosis in neonatal hypoxia-ischemia by investigating key signaling molecules and the effect of gene deletion of the phagocytic receptor Myeloid-epithelial-reproductive tyrosine kinase (MerTK) in a neonatal mouse model. MerTK, growth arrest–specific 6, and genes related to phagoptosis were regulated in the brain 6–72 h after hypoxic ischemia. Brain injury was reduced in MerTK knock-out vs. wild-type mice by 48% in gray matter (p = 0.002) and by 32% in white matter (p = 0.04). There was a near 40% reduction in NeuN immunoreactivity in microglia in MerTK knock-out mice vs. wild-type (p = 0.03) indicating attenuation of neuronal phagocytosis by microglia. In summary, the reduction in microglial neuronal engulfment and brain injury in MerTK-deficient mice strongly indicates that phagoptosis contributes to neuronal loss after neonatal hypoxia-ischemia. This insight suggests that targeting MerTK-mediated phagocytosis may represent a potential therapeutic approach in neonatal hypoxia-ischemic brain injury. Full article

Cerebral ischemia represents a major mortality and disability cause; oxidative stress is the main intensifier mechanism of excitotoxicity, neuroinflammation, blood–brain barrier failure, and neuronal loss; under these circumstances, firm, mechanism-anchored neuroprotection is an absolute necessity. The work includes a exhaustive, PRISMA (Preferred reporting items for systematic review and meta-analysis)-adherent presentation of the effects of antioxidant peptides and small molecules on tissues, unifying disparate readouts into a coherent tissue-level narrative. A systematic interrogation was performed across major databases over a prespecified interval, applying transparent eligibility criteria to studies that quantified canonical endpoints—infarct volume, neuronal integrity (NeuN/MAP2), apoptosis (TUNEL/cleaved caspase-3), gliosis (GFAP/Iba1), and ultrastructural preservation. The evidence coalesces around a strikingly consistent signal: antioxidant strategies converge on smaller infarcts, robust preservation of neuronal markers, attenuation of apoptotic burden, dampened astroglial–microglial reactivity, and stabilization of mitochondrial and axonal architecture—patterns that align with antioxidative, anti-apoptotic, anti-inflammatory, and ferroptosis-modulating mechanisms. While early clinical data echo these benefits, translation is tempered by heterogeneity in models, timing and dosing windows, and outcome batteries. By consolidating the histological landscape and pinpointing where effects are durable versus contingent, this work elevates antioxidant peptide and small-molecule neuroprotection from promising fragments to an integrated framework and sets an actionable agenda—standardized histological endpoints, protocol harmonization, head-to-head comparisons of peptide versus small-molecule strategies, and adequately powered randomized trials embedded with mechanistic biomarkers to decisively test efficacy and accelerate clinical adoption. Full article

Ischemic stroke initiates a complex cascade of pathophysiological events—including energy failure, excitotoxicity, oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction—that together lead to extensive neuronal damage. Effectively targeting these interconnected mechanisms is crucial for achieving neuroprotection. Alpinetin, known for its antioxidant, anti-inflammatory, and cytoprotective properties, has shown promise as a potential therapeutic agent for cerebral ischemia in preliminary studies. However, the exact molecular mechanisms underlying its neuroprotective effects remain unclear. Therefore, this study aimed to investigate the multifaceted actions of alpinetin in a preclinically relevant right middle cerebral artery occlusion (Rt.MCAO) rat model, focusing on its impact on neuronal survival, inflammation, oxidative stress, apoptosis, and mitochondrial function. Forty male Wistar rats were randomly assigned to four groups: sham operation, Rt.MCAO + vehicle, Rt.MCAO + piracetam (250 mg/kg BW), and Rt.MCAO + alpinetin (100 mg/kg BW). We examined glial cell morphology, protein kinase B (Akt) expression, mitochondrial superoxide dismutase (MnSOD), myeloperoxidase (MPO), anti-apoptotic proteins, mitogen-activated protein kinase (p38 MAPK) and mitofusin-2 (Mfn2). Treatment with alpinetin for 3 days exerted robust neuroprotective effects by significantly reducing astrocytic and microglial activation through the downregulation of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba-1), restoring Akt expression, decreasing MPO activity, and enhancing MnSOD activity. Additionally, alpinetin modulated apoptotic signaling by lowering pro-apoptotic markers Bcl-2 Associated X-protein (Bax) and caspase-3 while increasing the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL). It also attenuated p38 MAPK activation and preserved mitochondrial integrity by mitigating the decline in Mfn2 levels. Overall, these findings highlight the therapeutic potential of alpinetin in targeting multiple pathological processes involved in ischemic brain injury, supporting its promise as an effective treatment for stroke. Full article

Background/Objectives: Cerebral ischemia–reperfusion injury (CIRI) remains a major challenge in the treatment of ischemic stroke, characterized by intertwined oxidative stress and neuroinflammation. Existing monotherapies often fail to address this dual pathology effectively. We developed PLSCZ, a biomimetic nanoplatform integrating a catalytic core of imidazolate framework-8 (ZIF-8)-encapsulated superoxide dismutase (SOD) and catalase (CAT) enzymes with a hybrid platelet membrane shell. This design strategically employs metal–organic frameworks (MOFs) to effectively overcome the critical limitations of enzyme instability and provide a cascade catalytic environment, while the biomimetic surface modification enhances targeting capability, thereby enabling dual-pathway intervention against CIRI. Methods: PLSCZ was engineered by co-encapsulating SOD and CAT within a ZIF-8 core to form a cascade antioxidant system (SCZ). The core was further coated with a hybrid membrane composed of rapamycin-loaded phospholipids and natural platelet membranes. The nanoparticle was characterized by size, structure, enzyme activity, and targeting capability. In vitro and in vivo efficacy was evaluated using oxygen–glucose deprivation/reoxygenation (OGD/R) models and a transient middle cerebral artery occlusion/reperfusion (tMCAO/r) rat model. Results: In vitro, PLSCZ exhibited enhanced enzymatic stability and cascade catalytic efficiency, significantly scavenging reactive oxygen species (ROS) and restoring mitochondrial function. The platelet membrane conferred active targeting to ischemic brain regions and promoted immune evasion. PLSCZ effectively polarized microglia toward the anti-inflammatory M2 phenotype, reduced pro-inflammatory cytokine levels, restored autophagic flux, and preserved blood–brain barrier integrity. In vivo, in tMCAO/r rats, PLSCZ markedly targeted the ischemic hemisphere, reduced infarct volume, improved neurological function, and attenuated neuroinflammation. Conclusions: By synergistic ROS scavenging and anti-inflammatory action, the PLSCZ nanozyme overcomes the limitations of conventional monotherapies for CIRI. This biomimetic, multi-functional platform effectively reduces oxidative stress, modulates the phenotype of microglia, decreases infarct volume, and promotes neurological recovery, offering a promising multi-mechanistic nanotherapeutic for CIRI and a rational design model for MOF-based platforms. Full article

Background/Objectives: Cerebral ischemia and reperfusion injury, induced by bilateral common carotid artery occlusion and reperfusion (BCCAO/R), cause extensive neuronal damage and cognitive impairment. Bouvardia ternifolia (BtD), a plant known for its anti-inflammatory and neuroprotective effects, may offer therapeutic benefits against ischemic injury. This study aimed to evaluate the neuroprotective effects of BtD root extract on neuronal integrity, oxidative stress, and p53 protein expression following global cerebral ischemia in rats. Methods: Adult male Sprague Dawley rats were subjected to the BCCAO/R procedure for 60 min, followed by six days of reperfusion. Experimental groups included BCCAO/R+BtD, BCCAO/R+silymarin (reference control), BCCAO/R+vehicle, and sham controls. Neuronal morphology in the cortex, striatum, hippocampus, and cerebellum was assessed histologically. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), reduced glutathione (GSH), and superoxide dismutase (SOD), were measured, along with the expression of p53 protein. Results: Treatment with BtD significantly decreased oxidative stress markers—LPO (82.2%), ROS (88.2%), GSH (66.5%), and SOD (54%)—and reduced p53 expression levels by 75%. Histological evaluation revealed that neurons in the BCCAO/R+BtD and BCCAO/R+silymarin groups maintained normal morphology, characterized by elongated cells and well-defined nuclei. In contrast, the BCCAO/R+vehicle group exhibited marked neuronal damage, including pyknosis, nuclear fragmentation, and interstitial edema, particularly in the hippocampal CA1 and cortical regions. BtD treatment significantly preserved neuronal structure and enhanced antioxidant defenses. Conclusions:Bouvardia ternifolia extract demonstrates neuroprotective potential in cerebral ischemia by maintaining neuronal architecture, reducing oxidative stress, and modulating p53 expression, supporting its therapeutic relevance in ischemia–reperfusion injury. Full article

Hypoxia-ischemia is a serious perinatal complication affecting neonates globally. Animal models have increased the understanding of its pathophysiology and have been used to investigate potential therapies. Exenatide, clinically used for the treatment of type 2 diabetes mellitus, also protects the rodent brain from hypoxia-ischemia. The rabbit brain has an earlier neurodevelopmental maturation than rodents, as well as similar postnatal maturation to humans. We hereby introduce a new, reproducible hypoxia-ischemia model in rabbit kits at postnatal day (P) 3–4. Following hypoxia-ischemia, rabbit kits received different exenatide concentrations: 170 μg/g (2-dose) or 500 μg/g (1- or 2-dose), or vehicle. The brains were collected seven days later for histological assessment showing that 500 μg/g exenatide, either as a 1- or 2-dose regimen, reduced brain tissue loss by 90% in hypoxia-ischemia experiments both at P3 and P4. A second cohort received a 1-dose 500 μg/g of exenatide or vehicle, and were sacrificed at different early time-points for glucose, ketone bodies, body weight, and temperature measurements. Our results showed a transient 2-fold increase in ketone bodies (0.6 to 1.3 mmol/L) at 6 h. Exenatide did not affect glucose, body temperature or weight gain and appears to be safe and well tolerated in the rabbit model of hypoxia-ischemia. Full article

Chronic kidney disease (CKD) affects over 10% of the global population, with end-stage renal disease (ESRD) necessitating renal replacement therapy. Kidney transplantation remains the optimal treatment for ESRD. However, the global donor kidney shortage crisis has led to increased reliance on deceased donor kidneys. Donors are classified as either donation after brain death (DBD) or donation after circulatory death (DCD), each associated with distinct ischemic injuries that impact graft function. Ischemia–reperfusion injury (IRI) plays a pivotal role in transplant outcomes, triggering oxidative stress, inflammation, and endothelial dysfunction. While static cold storage (SCS) remains the gold standard for organ preservation, alternative strategies such as hypothermic or normothermic machine perfusion (HMP and NMP), use of oxygen carriers during storage, and supplemental compounds to storage solutions have emerged, offering potential benefits in preserving graft viability. This review explores the cellular and molecular mechanisms of ischemic injury in deceased donor kidneys, preservation strategies tested in preclinical models, and emerging therapeutic interventions aimed at improving adverse post-transplant outcomes. Full article

Today, hydrogen is already widely regarded as up-and-coming source of energy. It is essential to meet energy needs while reducing environmental pollution, since it has a high energy capacity and does not emit carbon oxide when burned. However, for the widespread application of hydrogen energy, it is necessary to search new technical solutions for both its production and storage. A promising effective and cost-efficient method of hydrogen generation and storage can be the use of solid materials, including nanomaterials in which chemical or physical adsorption of hydrogen occurs. Focusing on the recommendations of the DOE, the search is underway for materials with high gravimetric capacity more than 6.5% wt% and in which sorption and release of hydrogen occurs at temperatures from −20 to +100 °C and normal pressure. This review aims to summarize research on hydrogen generation and storage using silicon nanostructures and silicon composites. Hydrogen generation has been observed in Si nanoparticles, porous Si, and Si nanowires. Regardless of their size and surface chemistry, the silicon nanocrystals interact with water/alcohol solutions, resulting in their complete oxidation, the hydrolysis of water, and the generation of hydrogen. In addition, porous Si nanostructures exhibit a large internal specific surface area covered by SiH_x bonds. A key advantage of porous Si nanostructures is their ability to release molecular hydrogen through the thermal decomposition of SiHx groups or in interaction with water/alkali. The review also covers simulations and theoretical modeling of H₂ generation and storage in silicon nanostructures. Using hydrogen with fuel cells could replace Li-ion batteries in drones and mobile gadgets as more efficient. Finally, some recent applications, including the potential use of Si-based agents as hydrogen sources to address issues associated with new approaches for antioxidative therapy. Hydrogen acts as a powerful antioxidant, specifically targeting harmful ROS such as hydroxyl radicals. Antioxidant therapy using hydrogen (often termed hydrogen medicine) has shown promise in alleviating the pathology of various diseases, including brain ischemia–reperfusion injury, Parkinson’s disease, and hepatitis. Full article