Assessing tobacco-related ischemic stroke in Pakistan (1990-2019): Insights from the Global Burden of Disease Study.

INTRODUCTION: This study analyzes the impact of active smoking and secondhand smoke on the ischemic stroke burden of Pakistan, 1990-2019. METHODS: We used data from the Global Burden of Disease (GBD) database to conduct a comprehensive evaluation of ischemic stroke-related indicators in Pakistan, including the number of deaths, mortality rates, disability-adjusted life years (DALYs), DALY rates, and the estimated annual percentage change (EAPC). Joinpoint analysis was applied to assess sex-specific temporal trends in the burden of active smoking and secondhand smoke in Pakistan and regions of Pakistan. These assessments incorporated the Socio-Demographic Index (SDI) and we have made comparative analyses of epidemiological differences between active smoking and secondhand smoke exposure. RESULTS: The burden of ischemic stroke related to tobacco use is presented in terms of the age-standardized mortality rate (ASMR) and the age-standardized disability-adjusted life year rate (ASDR) per 100000 population. The results (ASMR/ASDR) for Pakistan were 6.04/130.81, in the middle SDI region 7.69/176.54, and low-middle SDI region 5.64/124.22. Pakistan's ASMR is higher than the global average of 5.85, while ASDR is lower than the global average of 140.23. From 1990 to 2019, a downward trend in both ASMR and ASDR was observed, indicating progress in controlling tobacco-related stroke burdens. Individuals aged ≥70 years experienced the highest rates of stroke (ASMR: 66.31; ASDR: 1091.20). Gender disparities were evident: men were more affected by active smoking (ASMR: 3.08; ASDR: 78.47) than women (ASMR: 0.79; ASDR: 20.76), while women faced a higher burden from secondhand smoke (ASMR: 0.66; ASDR: 16.33) compared to men (ASMR: 0.79; ASDR: 9.93). Regional differences within Pakistan show fluctuating death and DALY rates. Notably, an increasing trend in female ASDR due to secondhand smoke in the Khyber Pakhtunkhwa Region (annual percentage change, APC=0.17 from 2010 to 2019) calls for focused health interventions. CONCLUSIONS: The study finds ASMR for tobacco-related ischemic stroke in Pakistan exceeds global averages, with significant gender and age disparities in exposure to smoke, highlighting the need for targeted health interventions.

Genetic insights into the relationship between immune cell characteristics and ischemic stroke: A bidirectional Mendelian randomization study.

BACKGROUND AND PURPOSE: Ischemic stroke, a major contributor to global disability and mortality, is underpinned by intricate pathophysiological mechanisms, notably neuroinflammation and immune cell dynamics. Prior research has identified a nuanced and often paradoxical link between immune cell phenotypes and ischemic stroke susceptibility. The aim of this study was to elucidate the potential causal links between the median fluorescence intensity (MFI) and morphological parameters (MP) of 731 immune cell types and ischemic stroke risk. METHODS: By analyzing extensive genetic datasets, we conducted comprehensive Mendelian randomization (MR) analyses to discern the genetic correlations between diverse immune cell attributes (MFI and MP) and ischemic stroke risk. RESULTS: Our study identified key immune cell signatures linked to ischemic stroke risk. Both B cells and T cells, among other immune cell types, have a bidirectional influence on stroke risk. Notably, the regulatory T-cell phenotype demonstrates significant neuroprotective properties, with all odds ratio (OR) values and confidence intervals (CIs) being less than 1. Furthermore, CD39 phenotype immune cells, particularly CD39+ CD8+ T cells (inverse variance weighting [IVW] OR 0.92, 95% CI 0.87-0.97; p = 0.002) and CD39+ activated CD4 regulatory T cells (IVW OR 0.93, 95% CI 0.90-0.97; p < 0.001), show notable neuroprotection against ischemic stroke. CONCLUSION: This investigation provides new genetic insights into the interplay between various immune cells and ischemic stroke, underscoring the complex role of immune processes in stroke pathogenesis. These findings lay a foundation for future research, which may confirm and expand upon these links, potentially leading to innovative immune-targeted therapies for stroke prevention and management.

First report of a p.Cys484Tyr Notch3 mutation in a CADASIL patient with acute bilateral multiple subcortical infarcts-case report and brief review.

BACKGROUND: CADASIL(Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)is an inherited small vessel disease caused by mutations in NOTCH3 gene. Although NOTCH3 has numerous hotspots of gene mutations, mutations in exons 9 are rare. The p.C484T gene mutation type associated with it has not been reported in any relevant cases yet. Furthermore, CADASIL patients rarely present with acute bilateral multiple subcortical infarcts. CASE PRESENTATION: We report the case of a Chinese female patient with CADASIL who experienced "an acute bilateral subcortical infarction" because of"hemodynamic changes and hypercoagulability". In genetic testing, we discovered a new Cys484Tyr mutation in exon 9, which has also been found in the patient's two daughters. CONCLUSIONS: It is important to note that this discovery not only expands the mutation spectrum of Notch3 mutations in CADASIL patients, but also examines the mechanism behind acute bilateral subcortical infarction in CADASIL patients via case reviews and literature reviews, in order to provide some clinical recommendations for early intervention, diagnosis, and treatment in similar cases in the future.

Influence of the brain­gut axis on neuroinflammation in cerebral ischemia­reperfusion injury (Review).

Stroke, a debilitating cerebrovascular ailment, poses significant threats to human life and health. The intricate interplay between the gut­brain­microbiota axis (GBMA) and cerebral ischemia­reperfusion has increasingly become a focal point of scientific exploration, emerging as a pivotal research avenue in stroke pathophysiology. In the present review, the authors delved into the nexus between the GBMA and neuroinflammation observed post­stroke. The analysis underscored the pivotal roles of histone deacetylase 3 and neutrophil extracellular traps subsequent to stroke incidents. The influence of gut microbial compositions and their metabolites, notably short­chain fatty acids and trimethylamine N­oxide, on neuroinflammatory processes, was further elucidated. The involvement of immune cells, especially regulatory T­cells, and the intricate signaling cascades including cyclic GMP­AMP synthase/stimulator of interferon genes/Toll­like receptor, further emphasized the complex regulatory mechanisms of GBMA in cerebral ischemia/reperfusion injury (CI/RI). Collectively, the present review offered a comprehensive perspective on the metabolic, immune and inflammatory modulations orchestrated by GBMA, augmenting the understanding of its role in neuroinflammation following CI/RI.

Exploring the Neuroprotective Effects of Lithium in Ischemic Stroke: A literature review.

Ischemic stroke ranks among the foremost clinical causes of mortality and disability, instigating neuronal degeneration, fatalities, and various sequelae. While standard treatments, such as intravenous thrombolysis and endovascular thrombectomy, prove effective, they come with limitations. Hence, there is a compelling need to develop neuroprotective agents capable of improving the functional outcomes of the nervous system. Numerous preclinical studies have demonstrated that lithium can act in multiple molecular pathways, including glycogen synthase kinase 3(GSK-3), the Wnt signaling pathway, the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) signaling pathway, brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and glutamate receptors. Through these pathways, lithium has been shown to affect inflammation, autophagy, apoptosis, ferroptosis, excitotoxicity, and other pathological processes, thereby improving central nervous system (CNS) damage caused by ischemic stroke. Despite these promising preclinical findings, the number of clinical trials exploring lithium's efficacy remains limited. Additional trials are imperative to thoroughly ascertain the effectiveness and safety of lithium in clinical settings. This review delineates the mechanisms underpinning lithium's neuroprotective capabilities in the context of ischemic stroke. It elucidates the intricate interplay between these mechanisms and sheds light on the involvement of mitochondrial dysfunction and inflammatory markers in the pathophysiology of ischemic stroke. Furthermore, the review offers directions for future research, thereby advancing the understanding of the potential therapeutic utility of lithium and establishing a theoretical foundation for its clinical application.

Comprehensive Long-Read Sequencing Analysis Discloses the Transcriptome Features of Papillary Thyroid Microcarcinoma.

CONTEXT: Papillary thyroid microcarcinoma (PTMC) is the most common type of thyroid cancer. It has been shown that lymph node metastasis is associated with poor prognosis in patients with PTMC. OBJECTIVE: We aim to characterize the PTMC transcriptome landscape and identify the candidate transcripts that are associated with lateral neck lymph node metastasis of PTMC. METHODS: We performed full-length transcriptome sequencing in 64 PTMC samples. Standard bioinformatic pipelines were applied to characterize and annotate the full-length expression profiles of 2 PTMC subtypes. Functional open reading frame (ORF) annotation of the known and novel transcripts were predicted by HMMER, DeepLoc, and DeepTMHMM tools. Candidate transcripts associated with the pN1b subtype were identified after transcript quantification and differential gene expression analyses. RESULTS: We found that skipping exons accounted for the more than 27.82% of the alternative splicing events. At least 42.56% of the discovered transcripts were novel isoforms of annotated genes. A total of 39 193 ORFs in novel transcripts and 18 596 ORFs in known transcripts were identified. Distribution patterns of the characterized transcripts in functional domain, subcellular localization, and transmembrane structure were predicted. In total, 1033 and 1204 differentially expressed genes were identified in the pN0 and pN1b groups, respectively. Moreover, novel isoforms of FRMD3, NOD1, and SHROOM4 were highlighted for their association with pN1b subtype. CONCLUSION: Our data provided the global transcriptome landscape of PTMC and also revealed the novel isoforms that associated with PTMC aggressiveness.

Synaptotagmin 1 Suppresses Colorectal Cancer Metastasis by Inhibiting ERK/MAPK Signaling-Mediated Tumor Cell Pseudopodial Formation and Migration.

Although synaptotagmin 1 (SYT1) has been identified participating in a variety of cancers, its role in colorectal cancer (CRC) remains an enigma. This study aimed to demonstrate the effect of SYT1 on CRC metastasis and the underlying mechanism. We first found that SYT1 expressions in CRC tissues were lower than in normal colorectal tissues from the CRC database and collected CRC patients. In addition to this, SYT1 expression was also lower in CRC cell lines than in the normal colorectal cell line. SYT1 expression was downregulated by TGF-ß (an EMT mediator) in CRC cell lines. In vitro, SYT1 overexpression repressed pseudopodial formation and reduced cell migration and invasion of CRC cells. SYT1 overexpression also suppressed CRC metastasis in tumor-bearing nude mice in vivo. Moreover, SYT1 overexpression promoted the dephosphorylation of ERK1/2 and downregulated the expressions of Slug and Vimentin, two proteins tightly associated with EMT in tumor metastasis. In conclusion, SYT1 expression is downregulated in CRC. Overexpression of SYT1 suppresses CRC cell migration, invasion, and metastasis by inhibiting ERK/MAPK signaling-mediated CRC cell pseudopodial formation. The study suggests that SYT1 is a suppressor of CRC and may have the potential to be a therapeutic target for CRC.

IDH1R132H mutation increases radiotherapy efficacy and a 4-gene radiotherapy-related signature of WHO grade 4 gliomas.

The prognosis for the WHO grade 4 IDH-mutant astrocytoma is better than IDH-wildtype glioblastoma (GBM) patients. The purpose of this study is to explore the potential mechanism of how IDH1 mutation can increase the efficacy of radiotherapy and to establish a risk-score model to predict the efficacy of radiotherapy in WHO grade 4 gliomas. First, we conducted experimental study on the effect of IDH1R132H mutation on glioma cells in vitro. Radiosensitivity of glioma cells was detected by γ-H2AX after 5 Gy radiation. Cell proliferation, migration and invasion were determined respectively by CCK-8, EDU, monolayer cell migration scratch assay and Transwell assay. Then we analyzed IDH1 gene status and the survival of WHO grade 4 glioma patients received radiotherapy in our center and verified our results by analyzing CGGA and TCGA database. For the risk-score model, we use CGGA data to find genetic differences between WHO grade 4 IDH-mutant astrocytoma and IDH-wildtype GBM patients, and determined a 4-gene radiotherapy-related signature through survival analysis by R software. Evaluation and verification through different glioma validation sets and different statistical methods. For in vitro experiments, we established glioma cells stably overexpressing IDH1 wild-type and IDH1-mutant proteins. γ-H2AX assay showed that IDH1-mutant glioma cells had higher radiosensitivity than wild-type. CCK-8 and EDU assay showed that proliferation capacity of IDH1-mutant glioma cells declined. Transwell assay and monolayer cell migration scratch assay also showed that IDH1-mutant glioma cells reduced migration and invasion capabilities. Among the 83 WHO grade 4 glioma patients who received radiotherapy in our center, WHO grade 4 IDH-mutant astrocytoma patients had longer OS and PFS versus IDH-wildtype GBM (P = 0.0336, P = 0.0324, respectively). TCGA and CGGA database analysis had the similar results. Through complex analysis of CGGA and TCGA databases, we established a risk-model that can predict the efficacy of radiotherapy for WHO grade 4 glioma patients. The 4-gene radiotherapy-related signature including ADD3, GRHPR, RHBDL1 and SLC9A9. Patients in the high-risk group had worse OS compared to low-risk group (P = 0.0001). High- and low-risk groups of patients receiving radiotherapy have significant survival differences, while patients who did not receive radiotherapy have no survival difference both in CGGA and TCGA databases. WHO grade 4 IDH-mutant astrocytoma is more radiosensitive than IDH-wildtype GBM patients. Our 4-gene radiotherapy-related signature can predict the radiation efficacy of WHO grade 4 glioma patients, and it may provide some reference for clinical treatment options.

Static wind imaging Michelson interferometer for the measurement of stratospheric wind fields.

The stratospheric wind field provides significant information on the dynamics, constituent, and energy transport in the Earth's atmosphere. The measurement of the atmospheric wind field on a global basis at these heights is still lacking because few wind imaging interferometers have been developed that can measure wind in this region. In this paper, we describe an advanced compact static wind imaging Michelson interferometer (SWIMI) developed to measure the stratospheric wind field using near-infrared airglow emissions. The instrument contains a field widened and thermal compensated interferometer with a segmented reflective mirror in one arm, which replace the moving mirror in a conventional Michelson interferometer, to provide interference phase steps. The field widened, achromatic, temperature compensated scheme has been designed and manufactured. The characterization, calibration, inversion software, and test of the instrument have been completed. The capacity of two-dimensional wind, temperature, and ozone measurement of the instrument has been verified in the lab experiment and model simulation. What we believe to be the novel principle, modeling, design, and experiment demonstrated in this paper will offer a significant reference to the static, simultaneous and real-time detection and inversion of the global wind field, temperature, and ozone.

Safety and efficacy of brivaracetam in children epilepsy: a systematic review and meta-analysis.

Background: Epilepsy is one of the most common neurological diseases, affecting people of any age. Although the treatments of epilepsy are more and more diverse, the uncertainty regarding efficacy and adverse events still exists, especially in the control of childhood epilepsy. Methods: We performed a systematic review and meta- analysis following the Cochrane Handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Four databases including PubMed, Embase, Web of Science and Cochrane library were searched. Studies reporting the use of brivaracetam monotherapy or adjuvant therapy in children (aged ≤18 years) were eligible for inclusion. Each stage of the review was conducted by two authors independently. Random-effects models were used to combine effect sizes for the estimation of efficacy and safety. Results: A total of 1884 articles were retrieved, and finally 9 articles were included, enrolling 503 children with epilepsy. The retention rate of BRV treatment was 78% (95% CI: 0.64-0.91), the responder rate (reduction of seizure frequency ≥ 50%) was 35% (95% CI: 0.24-0.47), the freedom seizure rate (no seizure) was 18% (95% CI: 0.10-0.25), and the incidence rate of any treatment-emergent adverse events (TEAE) was 39% (95% CI: 0.09-0.68). The most common TEAE was somnolence, which had an incidence rate of 9% (95% CI: 0.07-0.12). And the incidence rate of mental or behavioral disorders was 12% (95% CI: 0.06-0.17). Conclusion: Our systematic review and meta-analysis showed that BRV seemed to be safe and effective in the treatment of childhood epilepsy.

Lesion patterns and mechanism analysis of acute contralateral ischemic stroke accompanying stenosis of unilateral extracranial internal carotid artery.

BACKGROUND: Previous studies on unilateral internal carotid artery occlusive disease have focused on the mechanisms of ipsilateral hemispheric stroke, and contralateral stroke is considered to be an accidental phenomenon. Little is known about the relationship between severe stenosis (including occlusion) of the unilateral extracranial segment of the internal carotid artery and contralateral cerebral stroke, and the infarct patterns and pathogenesis require further study. The purpose of this study was to investigate the clinical characteristics and pathogenesis of contralateral acute stroke with unilateral extracranial internal carotid artery stenosis (including occlusion). METHODS: Thirty-four patients were enrolled in this study, and all patients underwent routine clinical evaluation, including medical history, physical examination, laboratory tests, and various imaging evaluations. The morphological characteristics of diffusion-weighted magnetic resonance imaging were applied to determine infarct patterns. The etiological classification was confirmed according to the TOAST classification. RESULTS: There were six distinctive lesion patterns: small subcortical infarcts (six patients), large subcortical infarcts (one patient), diffuse infarcts (eight patients), multiple anterior circulation infarcts (eight patients), multiple posterior circulation infarcts (two patients), and multiple anterior and posterior circulation infarcts (nine patients). CONCLUSION: Diffuse and multiple infarcts were the most common topographic patterns in ischemic stroke contralateral to internal carotid artery stenosis or occlusion. Hemodynamic impairment of the contralateral hemisphere due to hypoperfusion and blood theft is regarded as the basis of stroke occurrence. Low ischemic tolerance and embolism are the main causes of acute ischemic stroke.

Characteristics of annual NH3 emissions from a conventional vegetable field under various nitrogen management strategies.

High N-fertilizer applications to conventional vegetable production systems are associated with substantial emissions of NH3, a key substance that triggers haze pollution and ecosystem eutrophication and thus, causing considerable damage to human and ecosystem health. While N fertilization effects on NH3 volatilization from cereal crops have been relatively well studied, little is known about the magnitude and yield-scaled emissions of NH3 from vegetable systems. Here we report on a 2-year field study investigating the effect of various types and rates of fertilizer application on NH3 emissions and crop yields for a pepper-lettuce-cabbage rotation system in southwest China. Our results show that both NH3 emissions and direct emission factors of applied N varied largely across seasons over the 2-year period, highlighting the importance of measurements spanning entire cropping years. Across all treatments varying from solely applying urea fertilizers to only using organic manures, annual NH3 emissions ranged from 0.64 to 92.4 kg N ha-1 yr-1 (or 0.07-6.84 g N kg-1 dry matter), equivalent to 0.05-5.99% of the applied N. At annual scale, NH3 emissions correlated positively with soil δ15N values, indicating that soil δ15N may be used as an indicator for NH3 losses. NH3 emissions from treatments fertilized partially or fully with manure were significantly lower compared with the urea fertilized treatment, while vegetable yields remained unaffected. Moreover, full substitution of urea by manure as compared to the partial substitution further reduced the yield-scaled annual NH3 emissions by 79.0-92.4%. Across all vegetable seasons, there is a significant negative relationship between yield-scaled NH3 emissions and crop N use efficiency. Overall, our results suggest that substituting urea by manure and reducing total N inputs by 30-50% allows to reduce NH3 emissions without jeopardizing yields. Such a change in management provides a feasible option to achieve environmental sustainability and food security in conventional vegetable systems.

Docosahexaenoic acid promotes M2 microglia phenotype via activating PPARγ-mediated ERK/AKT pathway against cerebral ischemia-reperfusion injury.

In ischemia-reperfusion stroke, microglia play a dual role in brain injury as well as brain repair, and promoting their switch from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype is considered to be a potential therapeutic strategy. Docosahexaenoic acid (DHA) is an essential long-chain omega-3 polyunsaturated fatty acid that exhibits potent anti-inflammatory properties in the acute phase of ischemic stroke, but its effect on microglia polarization is unknown. Thus, the objective of this study was to investigate the neuroprotective effects of DHA on rat brain following ischemia-reperfusion injury, and to investigate the mechanism by which DHA regulates microglia polarization. We administered DHA 5 mg/kg intraperitoneally daily for 3 d following a transient middle cerebral artery occlusion reperfusion model in rats. The protective effects of DHA on cerebral ischemia-reperfusion injury were detected by TTC staining, HE staining, Nissler staining, and TUNEL staining. Quantitative real-time PCR, immunofluorescence, western blot, and enzyme-linked immunosorbent assay were used to detect the expression of M1 and M2 microglia-associated markers and PPARγ-mediated ERK/AKT signaling pathway proteins. We found that DHA significantly improved brain injury by decreasing the expression of the M1 phenotypic marker (iNOS, CD16) and increasing the expression of the M2 phenotypic marker (Arg-1, CD206). DHA also increased the expression of peroxisome proliferator-activated receptor gamma (PPARγ) mRNA and protein, increased the expression of the pathway protein AKT, and decreased the expression of ERK1/2. In addition, DHA promoted the expression of anti-inflammatory factor IL-10 and decreased the expression of pro-inflammatory factors TNF-α and IL-1ß. However, the PPARγ antagonist GW9662 greatly blocked these beneficial effects. These results suggest that DHA may activate PPARγ to inhibit ERK and activate AKT signaling pathways to regulate microglia polarization, thereby reducing neuroinflammation and promoting neurological recovery to alleviate cerebral ischemia-reperfusion injury.

Clinical features of ischemic stroke in patients with nonvalvular atrial fibrillation combined with intracranial atherosclerotic stenosis.

BACKGROUND: Nonvalvular atrial fibrillation (NVAF) and intracranial atherosclerotic stenosis (ICAS) are major causes of ischemic stroke. Relatively few studies have focused on the risk factors and clinical features of ischemic stroke caused by NVAF combined with ICAS. METHOD: We retrospectively evaluated NVAF and/or ICAS in patients with acute ischemic stroke admitted within 72 h after stroke. All patients with acute ischemic stroke underwent diffusion-weighted magnetic resonance imaging (DWI), magnetic resonance angiography (MRA), computed tomography angiography (CTA), and/or digital subtraction angiography (DSA). NVAF was detected by routine electrocardiogram or 24-h Holter examination, Doppler echocardiography, and contrast echocardiography of the right heart. RESULTS: Among the 635 enrolled patients, NVAF, ICAS, and NVAF+ICAS were diagnosed in 170 (26.77%), 255 (40.16%), and 210 (33.07%) patients, respectively. Patients in the NVAF+ICAS group were older (p < .001), specifically aged ≥75 years (p < .001). The admission time of the NVAF+ICAS group was shorter (p < .001) than that of the ICAS group. The admission NIHSS score of the NVAF group was higher than that of the NVAF+ICAS group (p < .001). HsCRP, NTpro-BNP, and LEVF levels were significantly different among the three groups (p < .001). NVAF+ICAS ischemic stroke occurred mainly in the right hemisphere (52.4%). CONCLUSION: NVAF with ICAS ischemic stroke is more likely to occur in older patients. Infarctions occurred mainly in the right cerebral hemisphere. Neurological deficits in NVAF are more severe than those in NVAF combined with ICAS and in simple ICAS ischemic strokes. HsCRP, LEVF, andNTpro-BNP seem to be closely associated with NVAF+ICAS ischemic stroke.

A case of acute basilar artery occlusion due to atherosclerotic disease revascularized by drug-coated balloon dilation.

Acute basilar artery occlusion (ABAO) accounts for 1% of all ischemic stroke cases, but has a high rate of severe complications and mortality (75-91%). Intracranial atherosclerosis is an significant cause of ischemic stroke. Revascularization using stents has shown good efficacy. However, intra-stent thrombosis and in-stent restenosis (ISR) are significant complications following stent placement. Drug-coated balloons (DCB), coated with the anti-proliferative drug paclitaxel (an inhibitor of endothelial proliferation), can prevent in-stent restenosis. Successful use of DCB dilation in the coronary and lower extremity vasculature has been reported. In our case, a 68-year-old Chinese male with ABAO was successfully revascularized by DCB dilation and showed dramatic improvement in stroke symptoms. This report may inform future treatment of patients with ABAO.

Neuroprotective effect of Dl-3-n-butylphthalide against ischemia-reperfusion injury is mediated by ferroptosis regulation via the SLC7A11/GSH/GPX4 pathway and the attenuation of blood-brain barrier disruption.

Background: Stroke is one of the most severe diseases worldwide, resulting in physical and mental problems. Dl-3-n-butylphthalide, a compound derived from celery seed, has been approved for treating ischemic stroke in China. No study has evaluated how Dl-3-n-butylphthalide affects the ferroptosis SLC7A11/GSH/GPX4 signal pathway and blood-brain barrier (BBB) PDGFRß/PI3K/Akt signal pathways in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model of ischemic stroke. Methods: Sprague-Dawley rats were used to develop the MCAO/R model. Our study used three incremental doses (10, 20, and 30) of Dl-3-n-butylphthalide injected intraperitoneally 24 h after MCAO/R surgery. The neuroprotective effect and success of the model were evaluated using the neurofunction score, brain water content determination, and triphenyl-tetrazolium chloride-determined infarction area changes. Pathological changes in the brain tissue and the degree of apoptosis were examined by hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, pathway proteins and RNA expression levels were studied to verify the effects of Dl-3-n-butyphthalide on both pathways. At the same time, commercial kits were used to detect glutathione, reactive oxygen species, and malondialdehyde, to detect oxidative stress in brain tissues. Results: The middle dose of Dl-3-n-butylphthalide not only improved MCAO-induced brain dysfunction and alleviated pathological damage, brain inflammatory response, oxidative stress, and apoptosis but also protected against ferroptosis and reduced BBB damage. These changes resulted in improved neurological function in the cerebral cortex. Conclusion: We speculate that Dl-3-n-butylphthalide has a neuroprotective effect on focal cerebral ischemia/reperfusion, which may be mediated through ferroptosis-dependent SLC7A11/GSH/GPX4 signal pathway and PDGFRß/PI3/Akt signal pathway.

Regulation of the p53­mediated ferroptosis signaling pathway in cerebral ischemia stroke (Review).

Stroke is one of the most threatening diseases worldwide, particularly in countries with larger populations; it is associated with high morbidity, mortality and disability rates. As a result, extensive research efforts are being made to address these issues. Stroke can include either hemorrhagic stroke (blood vessel ruptures) or ischemic stroke (blockage of an artery). Whilst the incidence of stroke is higher in the elderly population (≥65), it is also increasing in the younger population. Ischemic stroke accounts for ~85% of all stroke cases. The pathogenesis of cerebral ischemic injury can include inflammation, excitotoxic injury, mitochondrial dysfunction, oxidative stress, ion imbalance and increased vascular permeability. All of the aforementioned processes have been extensively studied, providing insights into the disease. Other clinical consequences observed include brain edema, nerve injury, inflammation, motor deficits and cognitive impairment, which not only cause disabilities obstructing daily life but also increase the mortality rates. Ferroptosis is a type of cell death that is characterized by iron accumulation and increased lipid peroxidation in cells. In particular, ferroptosis has been previously implicated in ischemia-reperfusion injury in the central nervous system. It has also been identified as a mechanism involved in cerebral ischemic injury. The tumor suppressor p53 has been reported to modulate the ferroptotic signaling pathway, which both positively and negatively affects the prognosis of cerebral ischemia injury. The present review summarizes the recent findings on the molecular mechanisms of ferroptosis under the regulation of p53 underlying cerebral ischemia injury. Understanding of the p53/ferroptosis signaling pathway may provide insights into developing methods for improving the diagnosis, treatment and even prevention of stroke.

Kaemperfol Protects Dopaminergic Neurons by Promoting mTOR-Mediated Autophagy in Parkinson's Disease Models.

We previously showed that kaempferol (KAE) could exert neuroprotective effects against PD. It has been demonstrated that abnormal autophagy plays a key role in the development of PD. Mitochondrial dysfunction, involved in the development of PD, can damage dopaminergic neurons. Whether the protective effects of KAE were exerted via regulating autophagy remains largely undefined, however. This study aimed to investigate whether KAE could protect dopaminergic neurons via autophagy and the underlying mechanisms using a MPTP/MPP+-stimulated PD model. Cell viability was detected by cell counting kit-8 (CCK-8) assay, and protein levels of autophagy mediators along with mTOR signaling pathway molecules were investigated by immunohistochemistry and Western blot analyses. The results showed that KAE could ameliorate the behavioral impairments of mice, reduce the loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta, and reduce α-synuclein (α-syn) levels. Furthermore, KAE upregulated levels of autophagy effector protein of Beclin-1 and autophagy microtubule associated protein of light chain 3 (LC3) in the substantia nigra (SN) while rescuing mitochondrial integrity, and downregulated levels of ubiquitin binding protein p62 and cleaved caspase-3, probably by decreasing the mammalian target of rapamycin (mTOR) signaling pathway. Further in vitro experiments demonstrated similar results. In conclusion, KAE exerts neuroprotective effects against PD potentially by promoting autophagy via inhibiting the mTOR signaling pathway.

Treatment with 1,25-Dihydroxyvitamin D3 Delays Choroid Plexus Infiltration and BCSFB Injury in MRL/lpr Mice Coinciding with Activation of the PPARγ/NF-κB/TNF-α Pathway and Suppression of TGF-ß/Smad Signaling.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication of systemic lupus erythematosus (SLE) involving the nervous system with high morbidity and mortality. A key hypothesis in NPSLE is that a disrupted barrier allows autoantibodies and immune components of peripheral blood to penetrate into the central nervous system (CNS), resulting in inflammation and damage. The blood cerebrospinal fluid barrier (BCSFB), which consists of the choroid plexus and the hypothalamic tanycytes, has long been regarded as an immunological sanctuary site. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] is the active form of vitamin D, which plays multiple roles in inflammation and immunoregulation. In this study, we investigated the possible protective effects of 1,25-dihydroxyvitamin D3 against BCSFB dysfunction in NPSLE in MRL/lpr mice and explored the mechanism by which 1,25-dihydroxyvitamin D3 inhibits the progression of NPSLE. In this study, we found that supplementation with 1,25-dihydroxyvitamin D3 markedly improved serological and immunological indices, delayed inflammatory infiltration, delayed neuronal deformation, and upregulated the expression of brain-derived neurotrophic factor (BDNF) proteins in the brain. Furthermore, 1,25-dihydroxyvitamin D3 downregulated proinflammatory cytokines such as nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) by activating peroxisome proliferator-activated receptor γ (PPARγ), and it reduced the expression of the TGF-ß/Smad signaling pathway. Our findings demonstrate that 1,25-dihydroxyvitamin D3 delayed cell infiltration into the choroid plexus and decreased markers suggestive of cognitive decline in MRL/lpr mice, and the mechanism may be related to protection against BCSFB disruption through activation of the anti-inflammatory PPARγ/NF-κB/TNF-α pathway as well as upregulation of BDNF and inhibition of the TGF-ß/Smad signaling pathway. These findings provide a novel direction for the study of NPSLE.