Hypoxic-ischemic brain damage (HIBD) is one of the main causes of disability in middle-aged and elderly people, as well as high mortality rates and long-term physical impairments in newborns. The pathological manifestations of HIBD include neuronal damage and loss of myelin sheaths. Tau protein is an important microtubule-associated protein in brain, exists in neurons and oligodendrocytes, and regulates various cellular activities such as cell differentiation and maturation, axonal transport, and maintenance of cellular cytoskeleton structure. Phosphorylation is a common chemical modification of Tau. In physiological condition, it maintains normal cell cytoskeleton and biological functions by regulating Tau structure and function. In pathological conditions, it leads to abnormal Tau phosphorylation and influences its structure and functions, resulting in Tauopathies. Studies have shown that brain hypoxia-ischemia could cause abnormal alteration in Tau phosphorylation, then participating in the pathological process of HIBD. Meanwhile, brain hypoxia-ischemia can induce oxidative stress and inflammation, and multiple Tau protein kinases are activated and involved in Tau abnormal phosphorylation. Therefore, exploring specific molecular mechanisms by which HIBD activates Tau protein kinases, and elucidating their relationship with abnormal Tau phosphorylation are crucial for future researches on HIBD related treatments. This review aims to focus on the mechanisms of the role of Tau phosphorylation in HIBD, and the potential relationships between Tau protein kinases and Tau phosphorylation, providing a basis for intervention and treatment of HIBD.
Humans ; tau Proteins/physiology* ; Phosphorylation ; Hypoxia-Ischemia, Brain/physiopathology* ; Animals ; Oxidative Stress

As a common neurological disease in China, stroke has an extremely high rate of death and disability, of which 80% is ischemic stroke (IS), causing a serious burden to individuals and society. Neuronal death is an important factor in the pathogenesis of stroke. Studies have shown that mitochondrial dynamics, as a key mechanism regulating intracellular energy metabolism and cell death, plays an important role in the pathogenesis of IS. In recent years, targeting mitochondrial dynamics has become an emerging therapeutic tool to improve neurological impairment after stroke. This paper reviews the research advance in recent years in IS mitochondrial dynamics, summarizing and discussing the overview of mitochondrial dynamics, the role of mitochondrial dynamics in IS, and the studies on mitochondrial dynamics-based treatment of IS. This paper helps to explore the mechanism of the role of mitochondrial dynamics in IS and effective interventions, and provides a theoretical strategy for targeting mitochondrial dynamics to treat IS in the clinic.
Humans ; Mitochondrial Dynamics/physiology* ; Ischemic Stroke/metabolism* ; Mitochondria/physiology* ; Animals ; Brain Ischemia/physiopathology* ; Energy Metabolism

This study aims to explore the synergistic effects of the main components in salvianolic acids for Injection(SAFI) on key pathological events in cerebral ischemia, elucidating the pharmacological characteristics of SAFI in neuroprotection. Two major pathological gene modules related to endothelial injury and neuroinflammation in cerebral ischemia were mined from single-cell data. According to the topological distance calculated in network medicine, potential synergistic component combinations of SAFI were screened out. The results showed that the combination of caffeic acid and salvianolic acid B scored the highest in addressing both endothelial injury and neuroinflammation, demonstrating potential synergistic effects. The cell experiments confirmed that the combination of these two components at a ratio of 1∶1 significantly protected brain microvascular endothelial cells(bEnd.3) from oxygen-glucose deprivation/reoxygenation(OGD/R)-induced reperfusion injury and effectively suppressed lipopolysaccharide(LPS)-induced neuroinflammatory responses in microglial cells(BV-2). This study provides a new method for uncovering synergistic effects among active components in traditional Chinese medicine(TCM) and offers novel insights into the multi-component, multi-target acting mechanisms of TCM.
Brain Ischemia/metabolism* ; Neuroprotective Agents/pharmacology* ; Animals ; Drugs, Chinese Herbal/administration & dosage* ; Benzofurans/pharmacology* ; Mice ; Drug Synergism ; Caffeic Acids/pharmacology* ; Polyphenols/pharmacology* ; Humans ; Alkenes/pharmacology* ; Endothelial Cells/drug effects* ; Depsides

This study aims to investigate the ameliorating effect of Corni Fructus(CF) on the myocardial ischemic injury and the pharmacokinetic properties of characteristic components of CF. The mouse model of isoproterenol-induced myocardial ischemia was established and administrated with the aqueous extract of CF. The general efficacy of CF in ameliorating the myocardial ischemic injury was evaluated based on the cardiac histopathology and the levels of myocardial injury markers: creatine kinase isoenzyme(CK-MB) and cardiac troponin I(cTn-I). The metabolomics analysis was carried out for the heart and serum samples of mice to screen the biomarkers of CF in ameliorating the myocardial ischemic injury and then the predicted biomarkers were submitted to metabolic pathway enrichment. The pharmacokinetic analysis was performed for morroniside, loganin, and cornuside Ⅰ in mouse heart and serum samples to obtain the pharmacokinetic parameters of these components. The pharmacokinetic parameters were then integrated on the basis of self-defined weighting coefficients to simulate an integrated pharmacokinetic profile of CF iridoid glycosides in the heart and serum of the mouse model of myocardial ischemia. The results indicated that CF reduced the pathological damage to cardiac cells and tissue(hematoxylin-eosin staining) and lowered the levels of CK-MB and cTn-I in the serum of the mouse model of myocardial ischemia(P<0.01). Metabolomics analysis screed out 31 endogenous metabolites in the heart and 35 in the serum as biomarkers of CF in ameliorating the myocardial ischemic injury. These biomarkers were altered by modeling and restored by CF. Six metabolic pathways in the heart and 5 in the serum were enriched based on these metabolic markers. The main integrated pharmacokinetic parameters of CF iridoid glycosides were T_(max)=1 h, t_(1/2)=(1.52±0.05) h in the heart and T_(max)=1 h, t_(1/2)=(1.56±0.50) h in the serum. Both concentration-time curves showed a double-peak phenomenon. In conclusion, CF demonstrated the cardioprotective effect by regulating metabolic pathways such as taurine and hypotaurine metabolism, and pantothenic acid and coenzyme A biosynthesis. The integrated pharmacokinetics reflect the general pharmacokinetic properties of characteristic components in CF.
Animals ; Cornus/chemistry* ; Mice ; Metabolomics ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Myocardial Ischemia/metabolism* ; Humans ; Troponin I/metabolism* ; Myocardium/pathology* ; Disease Models, Animal ; Biomarkers/metabolism* ; Creatine Kinase, MB Form/metabolism*

This study aims to investigate the protective effects and mechanisms of polysaccharide extract PCP1 from Polygonatum cyrtonema in ameliorating cerebral ischemia-reperfusion(I/R) injury in rats through modulation of the Toll-like receptor 4(TLR4)/NOD-like receptor protein 3(NLRP3) signaling pathway. In vivo, SD rats were randomly divided into the sham group, model group, PCP1 group, nimodipine(NMDP) group, and TLR4 signaling inhibitor(TAK-242) group. A middle cerebral artery occlusion/reperfusion(MCAO/R) model was established, and neurological deficit scores and infarct size were evaluated 24 hours after reperfusion. Hematoxylin-eosin(HE) and Nissl staining were used to observe pathological changes in ischemic brain tissue. Transmission electron microscopy(TEM) assessed ultrastructural damage in cortical neurons. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-18(IL-18), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and nitric oxide(NO) in serum. Immunofluorescence was used to analyze the expression of TLR4 and NLRP3 proteins. In vitro, a BV2 microglial cell oxygen-glucose deprivation/reperfusion(OGD/R) model was established, and cells were divided into the control, OGD/R, PCP1, TAK-242, and PCP1 + TLR4 activator lipopolysaccharide(LPS) groups. The CCK-8 assay evaluated BV2 cell viability, and ELISA determined NO release. Western blot was used to analyze the expression of TLR4, NLRP3, and downstream pathway-related proteins. The results indicated that, compared with the model group, PCP1 significantly reduced neurological deficit scores, infarct size, ischemic tissue pathology, cortical cell damage, and the levels of inflammatory factors IL-1β, IL-6, IL-18, TNF-α, and NO(P<0.01). It also elevated IL-10 levels(P<0.01) and decreased the expression of TLR4 and NLRP3 proteins(P<0.05, P<0.01). Moreover, in vitro results showed that, compared with the OGD/R group, PCP1 significantly improved BV2 cell viability(P<0.05, P<0.01), reduced cell NO levels induced by OGD/R(P<0.01), and inhibited the expression of TLR4-related inflammatory pathway proteins, including TLR4, myeloid differentiation factor 88(MyD88), tumor necrosis factor receptor-associated factor 6(TRAF6), phosphorylated nuclear factor-kappaB dimer RelA(p-p65)/nuclear factor-kappaB dimer RelA(p65), NLRP3, cleaved-caspase-1, apoptosis-associated speck-like protein(ASC), GSDMD-N, IL-1β, and IL-18(P<0.05, P<0.01). The protective effects of PCP1 were reversed by LPS stimulation. In conclusion, PCP1 ameliorates cerebral I/R injury by modulating the TLR4/NLRP3 signaling pathway, exerting anti-inflammatory and anti-pyroptotic effects.
Animals ; Toll-Like Receptor 4/genetics* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Rats, Sprague-Dawley ; Rats ; Reperfusion Injury/genetics* ; Male ; Signal Transduction/drug effects* ; Polysaccharides/isolation & purification* ; Polygonatum/chemistry* ; Brain Ischemia/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Humans

This study aims to investigate the molecular mechanism by which naringin alleviates cerebral ischemia/reperfusion(CI/R) injury through DRP1/LRRK2/MCU signaling axis. A total of 60 SD rats were randomly divided into the sham group, the model group, the sodium Danshensu group, and low-, medium-, and high-dose(50, 100, and 200 mg·kg~(-1)) naringin groups, with 10 rats in each group. Except for the sham group, a transient middle cerebral artery occlusion/reperfusion(tMCAO/R) model was established in SD rats using the suture method. Longa 5-point scale was used to assess neurological deficits. 2,3,5-Triphenyl tetrazolium chloride(TTC) staining was used to detect the volume percentage of cerebral infarction in rats. Hematoxylin-eosin(HE) staining and Nissl staining were employed to assess neuronal structural alterations and the number of Nissl bodies in cortex, respectively. Western blot was used to determine the protein expression levels of B-cell lymphoma-2 gene(Bcl-2), Bcl-2-associated X protein(Bax), cleaved cysteine-aspartate protease-3(cleaved caspase-3), mitochondrial calcium uniporter(MCU), microtubule-associated protein 1 light chain 3(LC3), and P62. Mitochondrial structure and autophagy in cortical neurons were observed by transmission electron microscopy. Immunofluorescence assay was used to quantify the fluorescence intensities of MCU and mitochondrial calcium ion, as well as the co-localization of dynamin-related protein 1(DRP1) with leucine-rich repeat kinase 2(LRRK2) and translocase of outer mitochondrial membrane 20(TOMM20) with LC3 in cortical mitochondria. The results showed that compared with the model group, naringin significantly decreased the volume percentage of cerebral infarction and neurological deficit score in tMCAO/R rats, alleviated the structural damage and Nissl body loss of cortical neurons in tMCAO/R rats, inhibited autophagosomes in cortical neurons, and increased the average diameter of cortical mitochondria. The Western blot results showed that compared to the sham group, the model group exhibited increased levels of cleaved caspase-3, Bax, MCU, and the LC3Ⅱ/LC3Ⅰ ratio in the cortex and reduced protein levels of Bcl-2 and P62. However, naringin down-regulated the protein expression of cleaved caspase-3, Bax, MCU and the ratio of LC3Ⅱ/LC3Ⅰ ratio and up-regulated the expression of Bcl-2 and P62 proteins in cortical area. In addition, immunofluorescence analysis showed that compared with the model group, naringin and positive drug treatments significantly decreased the fluorescence intensities of MCU and mitochondrial calcium ion. Meanwhile, the co-localization of DRP1 with LRRK2 and TOMM20 with LC3 in cortical mitochondria was also decreased significantly after the intervention. These findings suggest that naringin can alleviate cortical neuronal damage in tMCAO/R rats by inhibiting DRP1/LRRK2/MCU-mediated mitochondrial fragmentation and the resultant excessive mitophagy.
Animals ; Rats, Sprague-Dawley ; Reperfusion Injury/genetics* ; Flavanones/administration & dosage* ; Rats ; Dynamins/genetics* ; Male ; Brain Ischemia/genetics* ; Protein Serine-Threonine Kinases/genetics* ; Signal Transduction/drug effects* ; Humans ; Drugs, Chinese Herbal/administration & dosage*

Aims or objective: To determine the prevalence of neurodevelopmental disorder (NDD) comorbidities and their association with the clinical profile of children with focal epilepsy treated at the Philippine Children’s Medical Center from 2023 to 2024.

Materials and Method: This cross-sectional analytical study was conducted from June 10, 2023 to June 1, 2024 at the Philippine Children's Medical Center. Detailed information was obtained for each case according to protocol. A complete history was taken from the accompanying caretakers. Children aged 0 to 7 years and 11 months, recently diagnosed with focal epilepsy, were evaluated using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5-TR) criteria. The level of early child development was determined based on the total Battelle Developmental Inventory-2 developmental quotient score.

Results: The study examined 246 children with focal epilepsy. Significant findings included those children with NDD had a higher median age (4.67 years) compared to those without NDD (3.37 years) (p < .001). A higher proportion of non-NDD children were under one year old. Children without NDD had mothers with higher educational attainment (p = .015) and came from families with higher incomes (p = .003). Neonatal complications such as hypoxic-ischemic encephalopathy (HIE) and sepsis were more common in children with NDD (p = .005 and p = .006). Phenobarbital use was more frequent in children with NDD (p = .001), who also had more abnormal EEG and neuroimaging findings (p < .001). Neurodevelopmental evaluations were conducted later for children with NDD (p < .001). A significant number (75.20%) of children exhibited neurodevelopmental problems, with global developmental delay being most prevalent. Crude analysis showed associations between age, number of antiseizure medications, and delays in evaluation with increased odds of NDD.

Conclusion: The study offers insights into children with focal epilepsy at a tertiary hospital in the Philippines, emphasizing the impact of low socioeconomic status, age, birth complications and multiple anti-seizure medications. These findings are vital for clinicians to modify care plans through a multidisciplinary approach to enhance outcomes and improve quality of life in this high-risk population.

Human ; Male ; Female ; Infant Newborn: First 28 Days After Birth ; Infant: 1-23 Months ; Child Preschool: 2-5 Yrs Old ; Child: 6-12 Yrs Old ; Neurodevelopmental Disorders ; Sepsis ; Hypoxia-ischemia, Brain ; Epilepsies, Partial ; Educational Status ; Diagnostic And Statistical Manual Of Mental Disorders ; Child Development

INTRODUCTION

While a 600 mg loading dose (LD) of clopidogrel has demonstrated superior inhibition of platelet function compared to 300 mg LD, the clinical evidence supporting this superiority is limited. The debate centers on whether higher clopidogrel LD regimen in percutaneous coronary intervention (PCI) outperforms the standard 300 mg LD, with potential benefits being more pronounced in higher-risk patients. Balancing enhanced platelet inhibition to reduce ischemic events against the associated risk of increased bleeding remains a critical consideration in determining the optimal loading dose of clopidogrel for patients with ischemic heart disease.

METHODS

A systematic literature search for randomized clinical trials (RCTs) was performed comparing 600 mg with 300 mg LD of clopidogrel using PubMed, MEDLINE, Embase, Cochrane, Clinicaltrials.gov and HerdinPH. Studies included those between 2010 and 2023 involving human subjects. The primary efficacy endpoint was a 1-month rate of major adverse cardiac event (MACE) and the primary safety outcome was bleeding adverse effects.

RESULTS

Nine RCTs involving 29,827 patients were included in the efficacy analysis. Mean duration of follow-up was 30 days. Only eight studies were eligible for safety analysis. Compared with standard LD clopidogrel, high LD significantly reduced the incidence of overall MACE (OR: 0.82, 95% CI: 0.74-0.91, p = 0.0002), nonfatal myocardial infarction (OR: 0.56; 95% CI: 0.32-0.99, p = 0.15) and target vessel revascularization (OR: 0.63; 95% CI: 0.41-0.95, p = 0.03), without significant difference in terms of cardiac death (OR: 0.89; 95% CI: 0.76-1.04, p = 0.15) and stroke (OR: 0.92; 95% CI: 0.67-1.26, p = 0.61). However, major bleeding risk was higher in the 600 mg LD (1.9%; 261/13288) compared with 300 mg LD (2.4%; 328/13242) [OR: 1.27; 95% CI: 1.08-1.49, p = 0.005] without significant difference in minor bleeding (OR: 1.05; 95% CI: 0.94-1.17, p = 0.35).

CONCLUSION

The administration of 600 mg clopidogrel LD reduces the overall risk of MACE with associated increased risk of major bleeding.

Human ; Clopidogrel ; Ischemic Heart Disease ; Myocardial Ischemia ; Percutaneous Coronary Intervention

We describe an unusual case of hypoxic ischemic encephalopathy in a preterm female of 36 weeks who presented with status epilepticus and atypical abdominal myoclonus. The seizures were confirmed electrographically using video electroencephalography (EEG), while the abdominal myoclonus was demonstrated to be nonepileptic, as it had no EEG correlate. Other possible causes of neonatal seizures were excluded. The infant then responded to a gamut of antiseizure medications but the myoclonus persisted. To the best of our knowledge, this is the first report of atypical myoclonus in a preterm baby caused by hypoxic ischemic encephalopathy.

Human ; Hypoxic Ischemic Encephalopathy ; Hypoxia-ischemia, Brain ; Status Epilepticus ; Myoclonus ; Neonate ; Infant, Newborn

INTRODUCTION: Arrhythmias, especially atrial fibrillation (AF) and ventricular arrhythmias, are independent risk factors of mortality in patients with ischaemic heart disease (IHD). While there is a growing body of evidence that suggests an association between obstructive sleep apnoea (OSA) and cardiac arrhythmias, evidence on this relationship in patients with IHD has been scant and inconsistent. We hypothesised that in patients with IHD, severe OSA is associated with an increased risk of nocturnal arrhythmias. METHODS: We studied 103 consecutive patients with IHD who underwent an overnight polysomnography. Exposed subjects were defined as patients who had an apnoea-hypopnoea index (AHI) ≥30/h (severe OSA), and nonexposed subjects were defined as patients who had an AHI <30/h (nonsevere OSA). All electrocardiograms (ECGs) were interpreted by the Somte ECG analysis software and confirmed by a physician blinded to the presence or absence of exposure. Arrhythmias were categorised as supraventricular and ventricular. Arrhythmia subtypes (ventricular, atrial and conduction delay) were analysed as dichotomous outcomes using multiple logistic regression models. RESULTS: Atrial fibrillation and AF/flutter (odds ratio 13.5, 95% confidence interval 1.66-109.83; P = 0.003) were found to be more common in the severe OSA group than in the nonsevere OSA group. This association remained significant after adjustment for potential confounders. There was no significant difference in the prevalence of ventricular and conduction delay arrhythmias between the two groups. CONCLUSION In patients with IHD, there was a significant association between severe OSA and nocturnal AF/flutter. This underscores the need to evaluate for OSA in patients with IHD, as it may have important implications on clinical outcomes.
Humans ; Sleep Apnea, Obstructive/diagnosis* ; Atrial Fibrillation/diagnosis* ; Male ; Female ; Middle Aged ; Polysomnography ; Electrocardiography ; Myocardial Ischemia/complications* ; Aged ; Risk Factors ; Logistic Models