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Scavenger receptor class B type I (SR-BI) is abundant in adult mouse and human brains, but its function in the central nervous system (CNS) remains unclear. This study explored the role of SR-BI in epilepsy and its possible underlying mechanism. Expression patterns of SR-BI in the brains of mice with kainic acid (KA)-induced epilepsy were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction (qPCR), and Western blotting(WB). Behavioral analysis was performed by 24-hour video monitoring and hippocampal local field potential (LFP) recordings were employed to verify the role of SR-BI in epileptogenesis. RNA sequencing (RNA-seq) was used to obtain biological information on SR-BI in the CNS. WB, qPCR, and co-immunoprecipitation (Co-IP) were performed to identify the relationship between SR-BI and the gabapentin receptor α2δ-1.The results showed that SR-BI was primarily co-localized with astrocytes and its expression was down-regulated in the hippocampus of KA mice. Notably, overexpressing SR-BI alleviated the epileptic behavioral phenotype in KA mice. Hippocampal transcriptomic analysis revealed 1043 differentially expressed genes (DEGs) in the SR-BI-overexpressing group. Most DEGs confirmed by RNA-seq analysis were associated with synapses, neuronal projections, neuron development, and ion binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the DEGs were enriched in the glutamatergic synapse pathway. Furthermore, the gabapentin receptor α2δ-1 decreased with SR-BI overexpression in epileptic mice. Overall, these findings highlight the important role of SR-BI in regulating epileptogenesis and that the gabapentin receptor α2δ-1 is a potential downstream target of SR-BI.
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BACKGROUND: Favorable venous outflow (VO) has been recognized as an independent predictor of excellent clinical outcomes in acute ischemic stroke caused by anterior circulation large vessel occlusion (AIS-LVO) patients who received endovascular treatment (EVT). However, the reasons why VO affects clinical outcomes have not been fully explained. In this study, we aimed to identify the potential mediators of VO affecting prognosis. METHODS: We conducted a multicenter retrospective cohort study of consecutive patients with AIS-LVO who underwent EVT. Baseline computed tomographic angiography (CTA) was applied to assess VO by the Cortical Vein Opacification Score (COVES). The primary outcome was functional independence at 90 days (modified Rankin Scale (mRS) score of 0-2). Classifying subtypes of intracranial hemorrhage (ICH) to explore the relationship between ICH subtypes and VO. Multivariate logistic regression and causal mediation analyses were used to evaluate the relationship among VO, functional independence, and potential mediators. RESULTS: Among 860 AIS-LVO patients undergoing EVT, a total of 515 patients were included in the present study after strict screening. In multivariate logistic regression analysis, favorable VO profiles (defined as COVES 3-6) were significantly associated with a lower incidence of ICH (24.2% vs 46.9%, adjusted odds ratio (aOR) 0.48, 95% confidence interval (CI) 0.30 to 0.77, P=0.002) and a higher proportion of functional independence (58.9% vs 15.0%, aOR 4.07, 95% CI 2.41 to 6.88, P<0.001). Mediation analysis showed that favorable VO profiles significantly reduced the incidence of parencuymal hematoma (PH) 2 accounting for 8.0% (95% CI 0.9% to 19.0%) of its beneficial effect on functional independence. CONCLUSION: This study demonstrated the potential mediating effects of severe ICH for the beneficial effect of favorable VO on clinical prognosis among patients with AIS-LVO who underwent EVT.
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BACKGROUND: Valvular diseases are widely recognized as important etiologies for large vessel occlusion stroke (LVO) but their impact on outcomes among patients with LVO receiving endovascular treatment (EVT) are less well delineated. METHODS: This study was a post hoc exploratory analysis of the RESCUE-BT trial, DEVT trial and BASILAR prospective registry. Outcome measures included the modified Rankin Scale (mRS) score at 90 days, symptomatic intracranial hemorrhage, and post-stroke early acute heart failure (EAHF). Chronic significant mitral regurgitation (csMR) was defined as a long-existing mitral regurgitation (MR) with moderate-to-severe MR grade examined by the transthoracic echocardiography. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were obtained by logistic regression models. RESULTS: Among 2011 patients in these three studies, 837 individuals receiving EVT with available information for valvular status were included in this study. In all categories of chronic valvular disorders, only csMR was related to very poor outcomes (mRS 5-6, aOR 2.76 (95% CI 1.59 to 4.78), P<0.001). CsMR (aOR 7.65 (95% CI 4.33 to 13.49), P<0.001) was an independent predictor of post-stroke EAHF. Mediation analysis showed that csMR increased EAHF instead of reocclusion events or venous thrombosis mediated its effects on functional outcome (49.50% (95% CI 24.83% to 90.00%)). Identical results of csMR on clinical outcomes and post-stroke EAHF were detected in novel cohorts constructed by propensity score matching and sensitivity analysis. CONCLUSION: Our study demonstrated that csMR was a mediator of heart-brain interaction associated with poor outcomes of LVO after EVT by increasing the frequency of post-stroke EAHF. Replication of these findings in a larger cohort is warranted.
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OBJECTIVES: To investigate the association between venous outflow (VO) profiles and outcomes among acute ischemic stroke caused by anterior circulation large vessel occlusion (AIS-LVO) patients who had undergone endovascular treatment (EVT) in the late window of 6-24 h from stroke onset. METHODS: This was a post-hoc analysis of our preceding RESCUE-BT trial, with findings validated in an external cohort. Baseline computed tomographic angiography (CTA) was performed to assess VO using the Cortical Vein Opacification Score (COVES). The primary clinical outcome was functional independence at 90 days (modified Rankin Scale score of 0-2). The adjusted odd ratio (aOR) and confidence interval (CI) were obtained from multivariable logistic regressions. RESULTS: A total of 440 patients were included in the present study. After identifying the cutoff of COVES by marginal effects approach, enrolled patients were divided into the favorable VO group (COVES 4-6) and the poor VO (COVES 0-3) group. Multivariable logistic regression analysis showed that favorable VO (aOR 2.25; 95% CI 1.31-3.86; p = 0.003) was associated with functional independence. Similar results were detected in the external validation cohort. Among those with poor arterial collateralization, favorable VO was still an independent predictor of functional independence (aOR 2.09; 95% CI 1.06-4.10; p = 0.032). CONCLUSION: The robust VO profile indicated by COVES 4-6 could promote the frequency of functional independence among AIS-LVO patients receiving EVT in the late window, and the prognostic value of VO was independent of the arterial collateral status. CLINICAL RELEVANCE STATEMENT: The robust venous outflow profile was a valid predictor for functional independence among AIS-LVO patients receiving EVT in the late window (6-24 h) and the predictive role of venous outflow did not rely on the status of arterial collateral circulation.
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OBJECTIVES: Epilepsy and migraine are common chronic neurological disease. Epidemiologic studies and shared pathophysiology and treatment suggest that these two diseases overlap. However, migraine is often underestimated among patients with epilepsy. This study aimed to evaluate the prevalence of migraine and identify the related influencing factors among adult patients with epilepsy. METHODS: Adult patients with epilepsy were recruited at the outpatient epilepsy clinic of 13 tertiary hospitals in China from February to September 2022. ID Migraine questionnaire was applied to evaluate for migraine. Both univariable and multivariable logistic regression models were used to explore the influencing factors of migraine. RESULTS: A total of 1326 patients with epilepsy were enrolled in this study. The prevalence of migraine among patients with epilepsy was 19.2% (254/1326). In the multivariable analysis, being female (OR = 1.451, 95% CI: 1.068-1.975; p = 0.018), focal and focal to bilateral tonic-clonic seizures (OR = 1.583, 95% CI: 1.090-2.281; p = 0.015), and current seizure attack in the last 3 months (OR = 1.967, 95% CI: 1.282-3.063; p = 0.002) were the influencing factors for migraine. However, <10% of patients with epilepsy received analgesics for migraine. SIGNIFICANCE: Approximately 20% of patients with epilepsy screened positive for migraine. Being female, focal and focal to bilateral tonic-clonic seizures, and current seizure attack in the last 3 months were the influencing factors for migraine. Neurologists should pay more attention to the screening and management of the migraine among patients with epilepsy in China. PLAIN LANGUAGE SUMMARY: Epilepsy and migraine are common chronic neurological disease with shared pathophysiological mechanisms and therapeutic options. However, migraine is often underestimated among patients with epilepsy. This multicenter study aimed to evaluate the prevalence of migraine and current status of treatment. In this study, approximately 20% of patients with epilepsy screened positive for migraine. Female, focal and focal to bilateral tonic-clonic seizures, and current seizure attack in the last 3 months were identified as independent influencing factors for migraine. Despite the high prevalence, the treatment for migraine was not optimistic, neurologists should pay more attention to the screening and management of migraine.
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Epilepsia , Trastornos Migrañosos , Humanos , Trastornos Migrañosos/epidemiología , Femenino , Masculino , Epilepsia/epidemiología , Adulto , Prevalencia , Estudios Transversales , China/epidemiología , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven , Factores de RiesgoRESUMEN
Emerging pollutants are toxic and harmful chemical substances characterized by environmental persistence, bioaccumulation and biotoxicity, which can harm the ecological environment and even threaten human health. There are four categories of emerging pollutants that are causing widespread concern, namely, persistent organic pollutants, endocrine disruptors, antibiotics, and microplastics. The distribution of emerging pollutants has spatial and temporal heterogeneity, which is influenced by factors such as geographical location, climatic conditions, population density, emission amount, etc. Steroidal estrogens (SEs) discussed in this paper belong to the category of endocrine disruptors. There are generally three types of fate for SEs in the soil environment: sorption, degradation and humification. Humification is a promising pathway for the removal of SEs, especially for those that are difficult to degrade. Through humification, these difficult-to-degrade SEs can be effectively transferred or fixed, thus reducing their impact on the environment and organisms. Contrary to the well-studied process of sorption and degradation, the role and promise of the humification process for the removal of SEs has been underestimated. Based on the existing research, this paper reviews the sources, classification, properties, hazards and environmental behaviors of SEs in soil, and focuses on the degradation and humification processes of SEs and the environmental factors affecting their processes, such as temperature, pH, etc. It aims to provide references for the follow-up research of SEs, and advocates further research on the humification of organic pollutants in future studies.
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Disruptores Endocrinos , Estrógenos , Contaminantes del Suelo , Suelo , Estrógenos/química , Estrógenos/análisis , Contaminantes del Suelo/análisis , Contaminantes del Suelo/química , Disruptores Endocrinos/química , Disruptores Endocrinos/análisis , Suelo/química , Sustancias Húmicas/análisis , Biodegradación Ambiental , Contaminantes Orgánicos Persistentes/química , Monitoreo del AmbienteRESUMEN
Background: Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130). Findings: A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400 mg/d was top-ranked, followed by RTG 1200 mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100 mg/d leading, followed by CNB 400 mg/d. Regarding tolerability, LCM 600 mg/d had the lowest ranking, followed by CNB 400 mg/d. For the safety outcome of AEs, ESL 1200 mg/d was ranked lowest, followed by CNB 400 mg/d. Regarding SAEs, LCM 400 mg/d was ranked lowest, followed by RTG 1200 mg/d. Interpretation: ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS. Funding: None.
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Temporal lobe epilepsy (TLE), the most common type of drug-resistant epilepsy, severely affects quality of life. However, the underlying mechanism of TLE remains unclear and deserves further exploration. Sorbs2, a key synaptic regulatory protein, plays an important role in the regulation of synaptic transmission in the mammalian brain. In this study, we aimed to investigate the expression pattern of Sorbs2 in a kainic acid (KA)-induced TLE mouse model and in patients with TLE to further determine whether Sorbs2 is involved in seizure activity and to explore the potential mechanism by which Sorbs2 affects seizures in this TLE mouse model. First, we found that the expression of Sorbs2 was obviously increased in the hippocampus and cortex of a TLE mouse model and in the temporal cortex of TLE patients, indicating an abnormal expression pattern of Sorbs2 in TLE. Importantly, subsequent behavioral analyses and local field potential (LFP) analyses of a TLE mouse model demonstrated that the downregulation of hippocampal Sorbs2 could prolong the latency to spontaneous recurrent seizures (SRSs) and protect against SRSs. We also found that the knockdown of Sorbs2 in the hippocampus could decrease excitatory synaptic transmission in pyramidal neurons (PNs) in the hippocampal CA1 region and reduce the expression levels of the AMPAR subunits GluA1 and GluA2. Thus, we speculated that Sorbs2 may promote epileptogenesis and the development of TLE by affecting AMPAR-mediated excitatory synaptic transmission in PNs in the CA1 region. Therefore, reducing the expression of hippocampal Sorbs2 could restrain epileptogenesis and the development of TLE.
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Epilepsia del Lóbulo Temporal , Proteínas de Unión al ARN , Receptores AMPA , Convulsiones , Transmisión Sináptica , Animales , Femenino , Humanos , Masculino , Ratones , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/inducido químicamente , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ácido Kaínico/farmacología , Ácido Kaínico/toxicidad , Ratones Endogámicos C57BL , Receptores AMPA/metabolismo , Convulsiones/metabolismo , Convulsiones/inducido químicamente , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genética , Transmisión Sináptica/fisiología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
BACKGROUND: Numerous anti-seizure medications (ASMs) have been developed to treat Dravet syndrome (DS). This network meta-analysis aimed to comprehensively analyse the efficacy of ASMs in DS patients, especially in non-seizure-free patients after treatment. METHODS: PubMed, EMBASE, Cochrane Library, and Chinese National Knowledge Infrastructure databases were searched. The treatment efficacy was assessed by the percentage reduction in monthly convulsive seizure frequency (MCSF) from baseline or individuals who achieved at least a 50 % or 75 % reduction from baseline in convulsive seizure frequency (CSF). RESULTS: Six randomised controlled trials with 633 participants and seven regimens based on four add-on ASMs-fenfluramine (FFA), stiripentol (STP), cannabidiol (CBD), and soticlestat-were included. All drug regimens were superior to the placebo at achieving at least 50 % and 75 % reductions in CSF, but only STP, 0.4 mg/kg/d FFA (FFA0.4), and 0.7 mg/kg/d FFA (FFA0.7) reduced MCSF. STP (50 mg/kg/d) had the highest correlation with reducing MCSF and achieving at least a 50 % reduction from baseline in CSF, followed by FFA0.4 and FFA0.7. Soticlestat and CBD may also be effective in reducing seizures in DS patients. CONCLUSION: STP can be recommended as the first choice among the included drug regimens for reducing seizures in DS patients, while FFA0.4 may be considered the second choice. Other drug regimens can be used as alternative treatments. STP, FFA0.4, and FFA0.7 may consistently present favourable efficacy in most DS patients, while other regimens may present prominent inter-individual variability. Appropriate dose selection and intense monitoring are necessary when treating DS using these drugs.
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Anticonvulsivantes , Dioxolanos , Epilepsias Mioclónicas , Metaanálisis en Red , Humanos , Epilepsias Mioclónicas/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Cannabidiol/uso terapéuticoRESUMEN
Information exchange between neurons and astrocytes mediated by extracellular vesicles (EVs) is known to play a key role in the pathogenesis of central nervous system diseases. A key driver of epilepsy is the dysregulation of intersynaptic excitatory neurotransmitters mediated by astrocytes. Thus, we investigated the potential association between neuronal EV microRNAs (miRNAs) and astrocyte glutamate uptake ability in epilepsy. Here, we showed that astrocytes were able to engulf epileptogenic neuronal EVs, inducing a significant increase in the glutamate concentration in the extracellular fluid of astrocytes, which was linked to a decrease in glutamate transporter-1 (GLT-1) protein expression. Using sequencing and gene ontology (GO) functional analysis, miR-181c-5p was found to be the most significantly upregulated miRNA in epileptogenic neuronal EVs and was linked to glutamate metabolism. Moreover, we found that neuronal EV-derived miR-181c-5p interacted with protein kinase C-delta (PKCδ), downregulated PKCδ and GLT-1 protein expression and increased glutamate concentrations in astrocytes both in vitro and in vivo. Our findings demonstrated that epileptogenic neuronal EVs carrying miR-181c-5p decrease the glutamate uptake ability of astrocytes, thus promoting susceptibility to epilepsy.
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Epilepsia , Vesículas Extracelulares , MicroARNs , Humanos , Astrocitos/metabolismo , Proteína Quinasa C-delta/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Vesículas Extracelulares/metabolismo , Ácido Glutámico/metabolismo , Sistema de Transporte de Aminoácidos X-AG/metabolismoRESUMEN
Several studies have emphasized the role of DNA methylation in vitiligo. However, its profile in human skin of individuals with vitiligo remains unknown. Here, we aimed to study the DNA methylation profile of vitiligo using pairwise comparisons of lesions, peri-lesions, and healthy skin. We investigated DNA methylation levels in six lesional skin, six peri-lesional skin, and eight healthy skin samples using an Illumina 850 K methylation chip. We then integrated DNA methylation data with transcriptome data to identify differentially methylated and expressed genes (DMEGs) and analyzed their functional enrichment. Subsequently, we compared the methylation and transcriptome characteristics of all skin samples, and the related genes were further studied using scRNA-seq data. Finally, validation was performed using an external dataset. We observed more DNA hypomethylated sites in patients with vitiligo. Further integrated analysis identified 264 DMEGs that were mainly functionally enriched in cell division, pigmentation, circadian rhythm, fatty acid metabolism, peroxidase activity, synapse regulation, and extracellular matrix. In addition, in the peri-lesional skin, we found that methylation levels of 102 DMEGs differed prior to changes in their transcription levels and identified 16 key pre-DMEGs (ANLN, CDCA3, CENPA, DEPDC1, ECT2, DEPDC1B, HMMR, KIF18A, KIF18B, TTK, KIF23, DCT, EDNRB, MITF, OCA2, and TYRP1). Single-cell RNA analysis showed that these genes were associated with cycling keratinocytes and melanocytes. Further analysis of cellular communication indicated the involvement of the extracellular matrix. The expression of related genes was verified using an external dataset. To the best of our knowledge, this is the first study to report a comprehensive DNA methylation profile of clinical vitiligo and peri-lesional skin. These findings would contribute to future research on the pathogenesis of vitiligo and potential therapeutic strategies.
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Vitíligo , Humanos , Vitíligo/genética , Vitíligo/patología , Metilación de ADN , Multiómica , Piel/metabolismo , Piel/patología , ADN , Transcriptoma , China , Proteínas de Ciclo Celular/genética , Cinesinas/genética , Cinesinas/metabolismo , Proteínas de Neoplasias/genética , Proteínas Activadoras de GTPasa/genéticaRESUMEN
BACKGROUND: The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/medium vessel occlusion beyond 4.5-hour time window. METHODS: The CHinese Acute tissue-Based imaging selection for Lysis In Stroke-Tenecteplase was an investigator-initiated, umbrella phase IIa, open-label, blinded-endpoint, Simon's two-stage randomised clinical trial in 13 centres across mainland China. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis. RESULTS: A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon's two-stage design. DISCUSSION: Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04086147, https://clinicaltrials.gov/ct2/show/NCT04086147).
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OBJECTIVE: Renal function can modify the outcomes of large vessel occlusion (LVO) stroke across stroke etiologies in disparate degrees. The presence of renal function deficit can also impair the pharmacokinetics of tirofiban. Hence, this study aimed to investigate the roles of renal function in determining efficacy and safety of intravenous tirofiban before endovascular treatment (EVT) for acute ischemic stroke patients with large vessel occlusion (LVO). METHODS: This study was a post hoc exploratory analysis of the RESCUE-BT trial. The primary outcome was the proportion of patients achieving functional independence (modified Rankin scale 0-2) at 90 days, and the primary safety outcome was the rate of symptomatic intracranial hemorrhage (sICH). RESULTS: Among 908 individuals with available serum creatinine, decreased estimated glomerular filtration rate (eGFR) status was noted more commonly in patients with cardioembolic stroke (CE), while large artery atherosclerosis (LAA) was predominant in patients with normal renal function. In LAA with normal renal function, tirofiban was associated with higher rates of functional independence at 90 days (41.67% vs 59.80%, p = 0.003). However, for LVO patients with renal dysfunction, tirofiban did not improve functional outcomes for any of the etiologies (LAA, p = 0.876; CE, p = 0.662; others, p = 0.894) and significantly increased the risk of sICH among non-LAA patients (p = 0.020). Mediation analysis showed tirofiban reduced thrombectomy passes (12.27%) and drug/placebo to recanalization time (14.25%) mediated its effects on functional independence. CONCLUSION: This present study demonstrated the importance of evaluating renal function before administering intravenous tirofiban among patients with LVO who are planned to undergo EVT.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Tirofibán/efectos adversos , Accidente Cerebrovascular Isquémico/complicaciones , Isquemia Encefálica/complicaciones , Resultado del Tratamiento , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Hemorragias Intracraneales/inducido químicamente , RiñónRESUMEN
BACKGROUND: The EphB receptor tyrosine kinase family participates in intricate signaling pathways that orchestrate neural networks, guide neuronal axon development, and modulate synaptic plasticity through interactions with surface-bound ephrinB ligands. Additionally, Kalirin, a Rho guanine nucleotide exchange factor, is notably expressed in the postsynaptic membrane of excitatory neurons and plays a role in synaptic morphogenesis. This study postulates that Kalirin may act as a downstream effector of EphB3 in epilepsy. This investigation focuses on understanding the link between EphB3 and epilepsy. MATERIALS AND METHODS: Chronic seizure models using LiCl-pilocarpine (LiCl/Pilo) and pentylenetetrazol were developed in rats. Neuronal excitability was gauged through whole-cell patch clamp recordings on rat hippocampal slices. Real-time PCR determined Kalirin's mRNA expression, and Western blotting was employed to quantify EphB3 and Kalirin protein levels. Moreover, dendritic spine density in epileptic rats was evaluated using Golgi staining. RESULTS: Modulation of EphB3 functionality influenced acute seizure severity, latency duration, and frequency of spontaneous recurrent seizures. Golgi staining disclosed an EphB3-driven alteration in dendritic spine density within the hippocampus of epileptic rats, underscoring its pivotal role in the reconfiguration of hippocampal neural circuits. Furthermore, our data propose Kalirin as a prospective downstream mediator of the EphB3 receptor. CONCLUSIONS: Our findings elucidate that EphB3 impacts the action potential dynamics in isolated rat hippocampal slices and alters dendritic spine density in the inner molecular layer of epileptic rat hippocampi, likely through Kalirin-mediated pathways. This hints at EphB3's significant role in shaping excitatory circuit loops and recurrent seizure activity via Kalirin.
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Epilepsia , Neuronas , Ratas , Animales , Ratas Sprague-Dawley , Estudios Prospectivos , Neuronas/metabolismo , Epilepsia/metabolismo , Convulsiones/metabolismoRESUMEN
The regulatory effect of DNA methylation on the pathogenesis of acne vulgaris is completely unknown. Herein we analyzed the DNA methylation profile in skin samples of acne vulgaris and further integrated it with gene expression profiles and single-cell RNA-sequencing data. Finally, 31,134 differentially methylated sites and 770 differentially methylated and expressed genes (DMEGs) were identified. The multi-omics analysis suggested the importance of DNA methylation in inflammation and immunity in acne. And DMEGs were verified in an external dataset and were closely related to early inflammatory acne. Additionally, we conducted experiments to verify the mRNA expression and DNA methylation level of DMEGs. This study supports the significant contribution of epigenetics to the pathogenesis of acne vulgaris and may provide new ideas for the molecular mechanisms of and potential therapeutic strategies for acne vulgaris.
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Background: Depression and anxiety are the most common psychiatric comorbidities in patients with epilepsy (PWE). However, they are often unrecognized and consequently untreated. Objective: The study was conducted to evaluate the prevalence and risk factors of anxiety and depression among Chinese adult PWE. Design: Cross-sectional study. Methods: Adult PWE were recruited from 13 tertiary epilepsy centers from February to September 2022. Generalized Anxiety Disorder-7 and Neurological Disorders Depression Inventory for Epilepsy were applied to evaluate anxiety and depression, respectively. Both univariate and multivariate logistic regression analyses models were performed to explore the risk factors of anxiety and depression. Results: A total of 1326 PWE were enrolled in this study. The prevalence of anxiety and depression was 31.45% and 27.30%, respectively. Being female [odds ratio (OR) = 1.467, 95% CI: 1.134-1.899; p = 0.004], focal and focal to bilateral tonic-clonic seizures (TCSZ) (OR = 1.409, 95% CI: 1.021-1.939; p = 0.036), and seizure occurrence in the last 3 months (OR = 1.445, 95% CI: 1.026-2.044; p = 0.036) were the risk factors for anxiety. Focal and focal to bilateral TCSZ (OR = 1.531, 95% CI: 1.094-2.138; p = 0.013) and seizure occurrence in the last 3 months (OR = 1.644, 95% CI: 1.130-2.411; p = 0.010) were the risk factors for depression. In addition, for every 1-year increment of age, the odds of developing depression were decreased by 3.8% (p = 4.12e-5). Nevertheless, up to 70% of PWE did not receive any treatment for comorbidity. Conclusion: There were approximately 30% of PWE screened positive for anxiety or depression. Both focal and focal to bilateral TCSZ and seizure occurrence in the last 3 months were estimated as risk factors for anxiety and depression. However, the current status of treatment was not optimal.
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Coronavirus disease-2019 (COVID-19) first emerged in late 2019 and has since spread worldwide. More than 600 million people have been diagnosed with COVID-19, and over 6 million have died. Vaccination against COVID-19 is one of the best ways to protect humans. Epilepsy is a common disease, and there are approximately 10 million patients with epilepsy (PWE) in China. However, China has listed "uncontrolled epilepsy" as a contraindication for COVID-19 vaccination, which makes many PWE reluctant to get COVID-19 vaccination, greatly affecting the health of these patients in the COVID-19 epidemic. However, recent clinical practice has shown that although a small percentage of PWE may experience an increased frequency of seizures after COVID-19 vaccination, the benefits of COVID-19 vaccination for PWE far outweigh the risks, suggesting that COVID-19 vaccination is safe and recommended for PWE. Nonetheless, vaccination strategies vary for different PWE, and this consensus provides specific recommendations for PWE to be vaccinated against COVID-19.
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COVID-19 , Epilepsia , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Consenso , Pueblos del Este de Asia , Epilepsia/complicaciones , Epilepsia/epidemiología , VacunaciónRESUMEN
BACKGROUND: Melanoma is of great interest due to its aggressive behavior and less favorable prognosis. The need for the development of novel drugs for the treatment of melanoma is urgent. Considerable evidence indicated that Schisandrin B (Sch B), a bioactive compound extracted from Schisandra chinensis, has numerous anti-tumor properties in multiple malignant tumors. A few studies have reported the effect of Sch B on melanogenesis in the melanoma B16F10 cell line; however, the specific anti-tumor effects and mechanisms need to be further explored. OBJECTIVE: This study aimed to investigate the effects of Sch B on the cell viability, migration, invasion, and cell cycleblocking of melanoma cells and explore its potential anti-tumor mechanism in vitro and in vivo. METHODS: Melanoma cells (A375 and B16) were treated with different concentrations of Sch B (0, 20, 40, 60, or 80 µM), with dimethyl sulfoxide (DMSO) as control. The inhibitory effect of Sch B on A375 and B16 melanoma cells was verified by crystal violet assay and CCK8 assay. The flow cytometry was performed to observe cell cycle blocking. The effect of Sch B on the migration and invasion of melanoma cells was detected by wound healing assay and transwell assay, respectively. Western blot analysis was used to determine protein expression levels. The growth of the A375 melanoma xenograft-treated groups and immunohistochemical staining were conducted to assess the anti-tumor effect of Sch B in vivo. RESULTS: The crystal violet assay and CCK8 assay showed that Sch B significantly inhibited melanoma cell viability in a dose-dependent manner. Meanwhile, the flow cytometry analysis revealed that Sch B induced melanoma cell cycleblocking at the G1/S phase. In addition, the wound healing assay and transwell assay showed that Sch B inhibited the migration and invasion of melanoma cells. Furthermore, by establishing an animal model, we found that Sch B significantly inhibited the growth of melanoma in vivo. The potential mechanism could be that Sch B inhibited the activity of the Wnt/ß-catenin signaling pathway. CONCLUSION: These findings indicated that Sch B inhibits the cell viability and malignant progression of melanoma cells via the Wnt/ß-catenin pathway and induces cell cycle arrest. Our study suggests that Sch B has potential as a bioactive compound for the development of new drugs for melanoma.
Asunto(s)
Melanoma , Vía de Señalización Wnt , Animales , Humanos , Supervivencia Celular , Melanoma/tratamiento farmacológicoRESUMEN
BACKGROUND: While statins have been widely used in patients with large-artery atherosclerotic stroke, their effectiveness in patients with cardioembolic large vessel occlusion (CE-LVO) undergoing endovascular treatment (EVT) remains unclear. This study aimed to evaluate whether combining statin therapy with EVT could improve clinical outcomes in patients with acute ischemic stroke caused by CE-LVO in the anterior circulation. METHODS: We performed a retrospective screening on patients with CE-LVO in the anterior circulation who underwent EVT in 27 hospitals across China between 2018 and 2021. The primary outcome measure was functional independence, defined as a 90-day modified Rankin Scale (mRS) score of 0 to 2. Safety outcomes included 90-day mortality and symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 510 patients with CE-LVO in the anterior circulation undergoing EVT were included in this study. Of these, 404 (79.2%) patients received statin treatment (statin group), while 106 (20.8%) did not (non-statin group). Statin treatment was significantly associated with improved functional independence (adjusted OR (aOR) 2.072, 95% CI 1.197 to 3.586, P=0.009). Moreover, statin use was associated with a lower rate of 90-day mortality (aOR 0.343, 95% CI 0.197 to 0.596, P<0.001) and a lower rate of sICH (aOR 0.153, 95% CI 0.072 to 0.325, P<0.001). CONCLUSION: Statin treatment was associated with improved clinical outcomes and reduced risks of mortality and sICH in patients with CE-LVO in the anterior circulation undergoing EVT.