Search Results (138)

Hypoxic–ischemic brain injury remains the leading cause of death and neurological disability after cardiac arrest. Although targeted temperature management (TTM) and other neuroprotective strategies have demonstrated promising results in preclinical studies, large randomized controlled trials have largely failed to show consistent clinical benefit. This review examines two major limitations that may contribute to these translational failures: delayed initiation of therapy beyond a time-limited therapeutic window and the lack of baseline injury severity stratification. Evidence from both experimental and clinical studies suggests that the opportunity to modify neurological injury may be confined to the first few hours after return of spontaneous circulation (ROSC). Delayed intervention may occur after irreversible neuronal injury, microvascular dysfunction, and impaired cerebrovascular autoregulation have already become established. In addition, cardiac arrest survivors represent a heterogeneous population. Patients with minimal injury may recover with standard supportive care, whereas those with severe irreversible injury are unlikely to benefit from neuroprotective interventions. Patients with moderate-severity brain injury may represent the subgroup most likely to respond to targeted therapies. Ultra-early stratification using neuroimaging, electroencephalography, circulating biomarkers, and clinical risk scores may help identify patients with therapeutic potential. This review proposes that future post-cardiac arrest research should integrate both time-sensitive intervention strategies and early injury severity stratification. Large prospective studies and randomized controlled trials are needed to determine not only whether interventions are effective, but also when they should be initiated and which patients are most likely to benefit. Full article

Background/Objectives: Shenfu Decoction (SFD) is a traditional Chinese herbal formula composed of Panax ginseng and Aconitum carmichaelii that can revive and counteract shock. However, how SFD can mitigate hypothermia caused by seawater immersion is poorly understood. Methods: Three commonly used ratios of SFD (Panax ginseng:Aconitum carmichaelii = 1:1, 1:2, 2:1) were prepared, and their chemical properties were analyzed with UPLC-Q-TOF-MS. A rat model of hypothermia caused by seawater immersion at 15 °C was utilized. Survival analysis was used to evaluate the prophylactic effect of single intragastric administration of SFD with different ratios and doses on the survival time of rats, and to identify the optimal intervention conditions. Network pharmacology analysis based on the absorbed constituents of SFD was performed to preliminarily predict the underlying mechanisms, which were subsequently validated using RT-PCR, Western blotting, ELISA, and H&E staining. Results: SFD contained 54 compounds, including ginsenosides and aconitine alkaloids, whose relative concentrations varied across different ratios of SFD. Animal studies showed that pretreatment of SFD (1:1) administered at a dose of 1.35 g/kg was very effective in increasing rats’ survival time in hypothermia and slowed down core body temperature decline. Based on the 28 plasma-absorbed compounds of SFD, network pharmacology identified 503 targets, enriched in cAMP and MAPK signaling pathways. SFD (1:1, 1.35 g/kg) resulted in larger lipid droplets in brown adipose tissue (BAT) and enhanced the respiratory metabolic rate in seawater-immersion-induced hypothermia rats. Furthermore, its thermogenic effect is likely associated with the upregulation of uncoupling protein 1 (UCP1) via activating p38 MAPK/PGC1α/PPARγ and NE-(β3-AR)-cAMP-PKA pathways. Conclusions: The results of this study demonstrate that a single prophylactic administration of the traditional Chinese medicine formula SFD prior to cold seawater exposure significantly prolongs the survival time of rats. This effect is associated with the upregulation of UCP1 and the subsequent enhancement of thermogenesis in BAT. These findings highlight the great potential of SFD as a promising intervention for the management of hypothermia. Full article

Venom-mediated systemic toxicity is not fully understood. This study explored the dose-dependent effects of Vespa mandarinia venom (VMV) on mice via integrated transcriptomic and metabolomic analyses. Subcutaneous VMV injection induced dose-dependent hypothermia: 80 μg caused severe transient hypothermia and partial mortality, while 40/60 μg led to reversible hypothermia within 24 h. Whole-blood sequencing identified 2400–3281 differentially expressed genes (DEGs) per group, including 1764 shared DEGs. Immune-related pathways were significantly activated, with hub genes validated by qRT-PCR. Serum metabolomics revealed alterations in organic acids, alkaloids, and other metabolites. Integrative transcriptome–metabolome analysis predicted the potential involvement of various pathways in VMV-induced toxicity, including ferroptosis (shared in low-dose VMV groups) and apoptosis. Cumulatively, this study confirms that VMV induces immunometabolic reprogramming, providing a molecular framework for understanding venom-induced systemic toxicity. Full article

Background/Objectives: Hypoxic–ischemic encephalopathy is the leading cause of infant mortality and disability. Hypothermic therapy is effective in hypoxic–ischemic encephalopathy, albeit in a limited number of cases. Hypothermia requires advanced technologies and significant financial resources, which are difficult to sustain in low-income countries, with devastating consequences. Valid alternatives to hypothermia therapy are therefore needed. Methods: In vitro organotypic cultures of mouse cerebral cortex slices were used to demonstrate the direct protective effect of N-acetylcysteine (NAC) against brain tissue damage induced by oxygen–glucose deprivation (OGD), and to identify the concentrations and time window that maximize the drug’s effectiveness. NAC’s effectiveness was measured by the incorporation of propidium iodide (PI), a marker of cell membrane integrity. Results: Adding 0.1 and 1 mM NAC to the incubation medium before OGD strongly reduced OGD-induced PI incorporation, by 80% (p < 0.0002) and 89% (p < 0.0001), respectively. Administration of 1 mM NAC 1 h after OGD maintained a high degree of protection against OGD-induced damage (80% reduction in PI incorporation; p < 0.0001), while at 0.1 mM, the efficacy of NAC dropped to 44% (p < 0.005). Administration of NAC 4 h after OGD reduced PI incorporation to 52% (p < 0.005) at 1 mM, while at 0.1 mM, the effect was not significant (17%; p > 0.05). Exposure of slices to 0.1 and 1 mM NAC reduced PI incorporation in female cerebral cortex slices (p < 0.006), while only the higher concentration was effective in male slices (p < 0.05). Exposure to 0.1 mM NAC increased tissue levels of total glutathione (p = 0.0185), while no significant effect was observed with 1 mM NAC. Conclusions: This work highlights the direct effect of NAC in protecting cerebral cortex cells from OGD-induced damage and identifies the concentrations and time window that maximize the drug’s effect. The results underscore the need for further studies to verify the in vivo efficacy of NAC at concentrations found to be active in vitro, and for clinical trials to evaluate whether NAC can reduce hypoxia-induced brain damage in newborns. Full article

Cold exposure may influence reproductive health through vascular changes, yet its mechanisms remain underexplored. This study aimed to investigate the impact of cold exposure on uterine blood vessels and the expression of the AMPK/PGC-1α gene and protein in adult female SD rats. A primary dysmenorrhea model was established in female Sprague Dawley rats and subjected to continuous cold exposure. Changes in body weight, ear temperature, and estrous cycle were observed. Superoxide dismutase (SOD) activity and adenosine triphosphate (ATP) levels were measured to assess oxidative stress. Uterine tissue morphology was assessed via small animal ultrasound, microcirculation observed using RFLSI imaging, and vascular morphology along with caspase-3 and AMPK expression evaluated histologically and immunohistochemically. CD31 and TUNEL double immunofluorescence were used to assess vascular endothelial apoptosis levels. Western blot was used to analyze Bax, BCL-2, and pAMPK/AMPK expression levels. In vitro injury models were used to treat human umbilical vein endothelial cells (HUVECs) with cold stimulus using the AMPK inhibitor Compound C. RT-PCR quantified Bax, AMPK, p53, and PGC-1α expression. Hypothermia-exposed rats exhibited significantly reduced body weight and ear temperature (p < 0.05), prolonged estrous cycle (p < 0.01), and decreased uterine index (p < 0.01), accompanied by reduced SOD and ATP levels (p < 0.01, p < 0.05). Ultrasound and flow imaging revealed decreased uterine blood flow velocity in the hypothermia group (p < 0.01). Histomorphology revealed disorganized uterine cell arrangement, reduced uterine vessel count (p < 0.01), and increased mean vessel area (p < 0.01) in cold-exposed uteri. Immunofluorescence detection revealed increased vascular endothelial cell apoptosis (p < 0.05). Western blot results showed that proapoptotic protein Bax was upregulated (p < 0.01), Bcl-2 was downregulated (p < 0.05), p-AMPK and p-AMPK/AMPK ratio were elevated (p < 0.01) after cold exposure; Rt-qPCR results indicated that Bax and P53 mRNA were increased (p < 0.01), while PGC-1α expression was elevated (p < 0.01). Rt-qPCR results showed elevated Bax and p53 mRNA (p < 0.01), along with increased AMPK and PGC-1α expression (p < 0.01) in the cold-exposed group. In human umbilical vein endothelial cells (HUVECs), compound C attenuated cold-induced effects (p < 0.01) and downregulated Bax and AMPK expression (p < 0.01). Cold exposure exacerbates uterine oxidative stress and energy imbalance, disrupts microcirculatory homeostasis, and induces endothelial cell apoptosis. Excessive phosphorylation of AMPK may co-activate PGC-1α, jointly contributing to cold-induced uterine dysfunction and exacerbated dysmenorrhea. This study reveals potential signaling pathways underlying cold-induced uterine vascular abnormalities, providing novel theoretical foundations and targeted intervention strategies for the prevention and treatment of primary dysmenorrhea. Full article

Introduction: Selective brain hypothermia has been investigated to improve neurological outcomes in patients with cardiac arrest; however, an optimal clinical method has not yet been established. This study aimed to evaluate the feasibility of a technique combining transnasal evaporative cooling with simultaneous endovascular temperature management to achieve selective brain hypothermia while preventing systemic hypothermia. Methods: Three adult male Göttingen swine were anesthetized and mechanically ventilated. Transnasal cooling was initiated at maximum output while endovascular warming preserved systemic temperature. Brain parenchymal and rectal temperatures, mean arterial pressure (MAP), heart rate (HR), and cardiac output (CO) were continuously monitored for 60 min. Temperature differences between brain and rectum at 60 min were analyzed. Results: A brain–rectal gradient ≥1.0 °C was achieved in all swine at 25, 40, and 30 min, respectively, and maintained at 1.0–1.5 °C thereafter. Brain temperature (34.5 ± 0.34 °C) was significantly lower than rectal temperature (35.8 ± 0.35 °C) at 60 min after initiation of the selective cooling procedure (p = 0.0048). MAP, HR, and CO showed no deviations from baseline. Conclusions: The combination of transnasal cooling and endovascular warming reliably induced selective brain hypothermia of 1–1.5 °C without adverse effects on hemodynamic parameters in swine. Full article

Background/Objectives: Cardiopulmonary bypass (CPB) facilitates complex cardiac surgery but can damage erythrocyte membranes, impairing microcirculation and oxygen transport. Standard rheological tests assess overall blood properties but fail to define specific cellular mechanisms. In this study, atomic force microscopy (AFM) was employed to characterize morphological, nanostructural, and mechanical changes in erythrocytes following CPB and CPB combined with hypothermic circulatory arrest (HCA). Methods: The study included 14 patients who underwent cardiac surgery with CPB. Patients were divided into two groups. Group 1 underwent heart valve surgery with normothermic CPB (n = 7), and Group 2 underwent aortic arch surgery with CPB combined with HCA and moderate hypothermia (28 °C) (n = 7). Arterial blood samples were collected before the induction of anesthesia and immediately after CPB. The morphology and surface roughness (Rtm) of the erythrocyte membrane were evaluated on air-dried blood smears. Young’s modulus (E) was estimated from force-distance curves on living cells; measurements were performed at 24 °C in PBS. Results: Following CPB, both groups exhibited a decrease in the proportion of discocytes and an increase in echinocytes. In the CPB+HCA group, discocytes were absent after surgery. The mean Rtm increased 1.4-fold in Group 1 and 1.6-fold in Group 2, indicating greater nanostructural membrane damage in the latter. In Group 1, Young’s modulus increased by an average of 1.6 times, indicating increased cell stiffness. In Group 2, the increase was smaller (mean: 1.1 times) and was not statistically significant in some patients. Conclusions: Normothermic CPB primarily affects the nanomechanical properties of erythrocytes, whereas CPB+HCA induces more severe morphological and membrane surface damage while relatively preserving cytoskeletal elasticity. AFM-derived parameters of membrane roughness and cell elasticity may serve as sensitive indicators of erythrocyte biophysical integrity. Full article

Cold-inducible RNA-binding protein (CIRP) is a critical molecule in the central nervous system (CNS) with functions that depend on its subcellular localization, exhibiting biphasic regulatory roles in both physiological and pathological processes. Under physiological conditions, intracellular cold-inducible RNA-binding protein (iCIRP) contributes to the maintenance of circadian rhythms by regulating the stability of core clock gene mRNAs and exerts neuroprotective effects during mild hypothermia by preserving the blood–brain barrier and inhibiting apoptosis. Pathologically, extracellular cold-inducible RNA-binding protein (eCIRP) functions as a damage-associated molecular pattern (DAMP) that drives neuroinflammation and brain injury. In ischemic stroke (IS), eCIRP promotes neutrophil extracellular trap (NET) formation and increases microglial activity via the Toll-like receptor 4 (TLR4) pathway. In cerebral ischemia–reperfusion (I/R) injury, eCIRP activates oxidative stress and the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome through the TLR4 axis, exacerbating mitochondrial damage. In intracerebral hemorrhage (ICH), eCIRP further amplifies inflammation via the interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. In traumatic brain injury (TBI), eCIRP activates the endoplasmic reticulum stress pathway, intensifying apoptosis. In Alzheimer’s disease (AD), eCIRP regulates tau phosphorylation and β-amyloid (Aβ) metabolism and may mediate the link between alcohol exposure and AD pathology. Preclinical studies indicate that serum eCIRP levels correlate with IS and ICH severity, highlighting its potential as a biomarker. This systematic review elucidates the mechanisms of CIRP in CNS diseases, providing insights for understanding and preventing conditions such as IS, cerebral I/R injury, ICH, TBI, and AD. Full article

Background: Ketamine and magnesium sulfate are commonly used perioperatively to prevent shivering, a frequent and clinically relevant complication of spinal and general anesthesia. Although their hypothermic effects are well documented, the neurotransmitter mechanisms underlying these effects remain insufficiently understood. This study examines whether serotonergic, adrenergic (α₂), and GABAergic (GABA_A) systems contribute to hypothermia induced by ketamine and a ketamine–magnesium sulfate combination. Methods: Body temperature was measured in Wistar rats after administration of ketamine (10 mg/kg) or the ketamine (5 mg/kg)–magnesium sulfate (5 mg/kg) combination. To assess neurotransmitter involvement, animals received yohimbine (α₂ antagonist), methysergide (non-selective 5-HT antagonist), or bicuculline (GABA_A antagonist) prior to ketamine or the drug combination. Data were analyzed using two-way repeated measures ANOVA followed by Tukey’s post hoc test. Results: Yohimbine at 0.5 and 1 mg/kg significantly potentiated ketamine-induced hypothermia, while only 3 mg/kg enhanced the effect of the ketamine–magnesium sulfate combination. Methysergide had a bidirectional influence: 1 mg/kg methysergide deepened ketamine-induced hypothermia, whereas 0.5 mg/kg methysergide attenuated the hypothermic effect of the ketamine–magnesium sulfate combination. Bicuculline (1–2 mg/kg) did not alter the hypothermic responses to ketamine or the combination. Conclusions: These findings indicate that ketamine- and ketamine–magnesium sulfate-induced hypothermia is primarily modulated by serotonergic and adrenergic mechanisms, whereas GABA_A receptor-dependent pathways do not appear to play a major role under the experimental conditions used. These results provide new mechanistic insights into NMDA antagonist–related thermoregulation and may help inform anesthetic strategies for shivering prevention and maintenance of perioperative thermal stability. Full article

Epileptic seizures in the neonatal brain induce oxidative stress and disrupt the blood–brain barrier (BBB), leading to long-term cerebrovascular and neurodevelopmental deficits. This study examined the protective effects of selective head cooling and NADPH oxidase (NOX) inhibition on BBB integrity following seizures. Neonatal seizures were induced in newborn pigs with bicuculline under normothermic or selective head cooling conditions. BBB disruption was assessed by Evans Blue extravasation and quantification of circulating brain-derived endothelial cells (CD45⁻/CD146⁺/GluT1⁺). Seizures under normothermia caused marked BBB leakage, cerebrovascular apoptosis, and elevated endothelial biomarkers, whereas selective head cooling (cortical temperature ~25 °C, body ~35 °C) significantly reduced these effects. Pharmacological inhibition of NOX with setanaxib (5 mg/kg) or sulforaphane (0.4 mg/kg) also prevented BBB disruption during normothermia. In vitro, primary porcine and human brain endothelial cells exposed to glutamate or TNF-α showed increased NOX activity, ROS production, apoptosis, and barrier leakage, all attenuated by NOX inhibitors or moderate hypothermia (<30 °C). These findings identify endothelial NOX as a key mediator of seizure-induced BBB injury and demonstrate that both NOX inhibition and selective head cooling effectively preserve cerebrovascular integrity. Combined hypothermic and antioxidant therapy may offer a promising strategy to prevent cerebrovascular injury and BBB damage in neonatal epilepsy. Full article

3-chloromethcathinone (3-CMC) is a synthetic cathinone that gained relevance, having been involved in a large number of seizures and poisoning reports. Despite this, literature currently lacks information on its pharmaco-toxicological effects. This study aims to investigate the acute sensorimotor and physiological effects of 3-CMC (0.1–30 mg/kg; i.p.) in male and female CD-1 mice and its effects (1 and 10 mg/kg) on Prepulse Inhibition (PPI). Furthermore, we describe a series of 3-CMC (or CMC)-related human intoxications (Italy, 2014–2025) registered by the PCC–National Toxicology Information Centre. Finally, we predicted the ADMET properties of 3-CMC compared to 2-CMC, 4-CMC, 2-MMC, and two 3-CMC metabolites. 3-CMC induced in mice locomotor stimulation in mice, relevant tachypnoea and hypothermia, sensorimotor, and PPI alterations were observed only at high doses, with minor sex differences. All intoxications were non-fatal and involved male patients showing psychomotor agitation, psychosis, aggressiveness, CNS depression, but also cardiac arrhythmias, thoracic pain, and tachypnea. N-dealkylation, N-hydroxylation, and phenyl hydroxylation were the main predicted reactions. Drug–drug interaction potential and cardiotoxicity were suggested for all compounds. This interdisciplinary study elucidates 3-CMC effects and its associated risks, opening new objectives for future studies on CMC compounds to provide critical information to clinicians and the toxicological field. Full article

Neonatal hypoxic–ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term disability, despite therapeutic hypothermia (TH) treatment, underscoring the need for further preclinical research. In the present study, we compared the neuroprotection afforded by TH and inhaled molecular hydrogen (H₂) treatment in a translational newborn pig HIE model. Following 20 min of asphyxia induced by a hypoxic/hypercapnic gas mixture, piglets were reoxygenated and monitored for 48 h. Animals were randomly assigned to normothermia, continuous H₂ ventilation (2.1%), or TH (33.5 °C for 37 h followed by slow rewarming) groups. Physiological parameters, electroencephalography (EEG), visual evoked potentials (VEPs), and neuropathology were assessed. TH eliminated post-asphyxia seizures and improved VEP latency, while H₂ delayed seizure onset and increased quantitative EEG markers of signal complexity. Neuropathology revealed severe thalamic injury in normothermic controls, which was significantly attenuated by both H₂ and TH, while neocortical, hippocampal, and basal ganglia injury was less extensive and not significantly altered by either of the neuroprotective interventions. These findings demonstrate that continuous H₂ inhalation provides neuroprotection in HIE comparable to TH, particularly in the thalamus. H₂ also exerts distinct electrophysiological effects, suggesting its therapeutic potential as a treatment for neonatal HIE. Full article

Neonatal hypoxic–ischaemic encephalopathy (HIE) remains a leading cause of infant morbidity and mortality worldwide, with therapeutic hypothermia being the only clinically approved treatment. This study investigates the cortical expression pattern of neuroserpin during postnatal brain development and evaluates its neuroprotective potential in hypoxia–ischaemia (HI)-induced brain damage using a modified Rice–Vannucci model. Experiments were conducted in both male and female neuroserpin knockout (KO) mice and through administration of exogenous neuroserpin into the brain. Between postnatal day 4 to 14 (P4–P14), neuroserpin-immunoreactive cell density peaked at P8–P10 in cortical layers 5 and 6b, with a gradual increase in layers 2/3 and minimal changes in layers 4 and 6a. Despite comparable levels of ischaemic brain damage between the KO and wild-type (WT) mice, exogenous neuroserpin administration suppressed the HI-induced oxidative stress. Additionally, it reduced microglial activation and reactive astrogliosis in the cortex in mild HIE, mitigating cortical thinning and preserving neuronal distribution. These findings suggest that endogenous neuroserpin alone is insufficient for neuroprotection against HI-induced damage, but exogenous neuroserpin shows promise as a pharmacological intervention for mild neonatal HIE. Full article

Objective: The objective of this study was to clarify the connection between BTX-A injections and local changes in skin temperature and to assess the correlation between post-BTX-A injection facial vascular hyperthermia and subcutaneous adipose tissue thickness (SAT) in the frontal area using thermography. Methods: The study involved 30 patients (mean age 42 ± 0.5 years; 18 women, 12 men). Facial skin temperature was measured via thermography (Thermo GEAR G30) before, immediately after, and 20 min after subcutaneous injection of BTX-A with hemagglutinin complex, gelatin (6 mg), and maltose monohydrate (12 mg). SAT development was graded by combined visual-palpation assessment. Statistical analysis included Student’s t-test and the Mann–Whitney U-test. Results: Biphasic thermal response: immediately post-injection: Significant decrease in min (−1.1 °C) and mean (−0.3 °C) facial temperatures (p < 0.05); 20 min post-injection: pronounced increase in mean (+1.5 °C), max (+1.3 °C), and min (+1.6 °C) temperatures (p < 0.001), attributed to BTX-A-induced vasodilation and local inflammation. Subjects with pronounced SAT exhibited significantly higher baseline temperatures (Me = 33.1 °C vs. 29.8 °C; p < 0.001) and more intense hyperthermic responses (+1.6 °C mean increase vs. +1.1 °C in low-SAT group; p < 0.001). Pronounced SAT was predominantly female (10/15; p < 0.05) and linked to higher BMI (33.3% overweight vs. 0% in low-SAT; *p = 0.036*). Conclusions: SAT thickness is a key determinant of post-BTX-A vascular hyperthermia, with pronounced SAT predicting stronger reactions. Practical Recommendation: Targeted local hypothermia (+4 °C to +8 °C for 5–7 min post-injection, adjustable by SAT thickness) mitigates hyperemia, edema, hematoma risk, and potential toxin diffusion, especially in high-SAT individuals. Full article

This review explores the maternal gut microbiome’s role in shaping neonatal neurodevelopmental outcomes following perinatal asphyxia (PA), a leading cause of infant mortality and disability with limited therapeutic options beyond hypothermia. We synthesized current evidence on microbiome-mediated neuroprotective mechanisms against hypoxic-ischemic brain injury. The maternal microbiome influences fetal development through bioactive metabolites (short-chain fatty acids, indole derivatives) that cross the placental barrier, bacterial antigen regulation, and infant microbiome colonization. These pathways activate multiple protective mechanisms: anti-inflammatory signaling via NF-κB suppression and regulatory T cell expansion; antioxidant defenses through Nrf2 activation; neural repair via BDNF upregulation and neurogenesis; and oxytocin system modulation. Animal models demonstrate that maternal dysbiosis from high-fat diet or antibiotics exacerbates PA-induced brain damage, increasing inflammatory markers and hippocampal injury. Conversely, probiotic supplementation, dietary fiber, and specific interventions (omega-3, resveratrol) reduce neuroinflammation and oxidative injury. Human studies link maternal dysbiosis-associated conditions (obesity, gestational diabetes) with adverse pregnancy outcomes, though direct clinical evidence for PA severity remains limited. Understanding the maternal microbiome-fetal brain axis opens therapeutic avenues, including prenatal probiotics, dietary modifications, and targeted metabolite supplementation to prevent or mitigate PA-related neurological sequelae, potentially complementing existing neuroprotective strategies. Full article