Cathepsin B as a key regulator of ferroptosis in microglia following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a subtype of stroke marked by elevated mortality and disability rates. Recently, mounting evidence suggests a significant role of ferroptosis in the pathogenesis of ICH. Through a combination of bioinformatics analysis and basic experiments, our goal is to identify the primary cell types and key molecules implicated in ferroptosis post-ICH. This aims to propel the advancement of ferroptosis research, offering potential therapeutic targets for ICH treatment. Our study reveals pronounced ferroptosis in microglia and identifies the target gene, cathepsin B (Ctsb), by analyzing differentially expressed genes following ICH. Ctsb, a cysteine protease primarily located in lysosomes, becomes a focal point in our investigation. Utilizing in vitro and in vivo models, we explore the correlation between Ctsb and ferroptosis in microglia post-ICH. Results demonstrate that ICH and hemin-induced ferroptosis in microglia coincide with elevated levels and activity of Ctsb protein. Effective alleviation of ferroptosis in microglia after ICH is achieved through the inhibition of Ctsb protease activity and protein levels using inhibitors and shRNA. Additionally, a notable increase in m6A methylation levels of Ctsb mRNA post-ICH is observed, suggesting a pivotal role of m6A methylation in regulating Ctsb translation. These research insights deepen our comprehension of the molecular pathways involved in ferroptosis after ICH, underscoring the potential of Ctsb as a promising target for mitigating brain damage resulting from ICH.

Evaluation of the antiwear-ability/scratch-resistance efficacy of makeup products by in vitro test method application.

OBJECTIVE: The objective of this study is to propose a method for assessing the antiwear-ability (AW) or surface scratch-resistance (SR) efficacy of makeup products through in vitro experiments. MATERIALS AND METHOD: The method primarily involves measuring the change in weight as a means of evaluating the overall effectiveness. AW/SR effects are evaluated by applying a fixed amount of makeup product on artificial fake skin and comparing the weight difference after simulated friction/scratch. RESULTS: The in vitro results indicate that this method is easy to operate and yields repeatable data. It consistently reflects differences between samples when compared to clinical studies. CONCLUSIONS: This method effectively compares the AW/SR effects of makeup products and demonstrates utility in evaluating product efficacy and difference. It holds great scientific and practical value.

Comparative study of instrumental measurement and sensory evaluation methods for the repairing effect of mildly damaged hair bundles.

OBJECTIVE: This study explores the applicability and scientific accuracy of instrument measurements in repairing hair products on slightly damaged hair bundles. MATERIALS AND METHOD: Sixty hair bundles mildly damaged with hydrogen peroxide and ammonia standards were divided into two groups: the treatment and control groups (30 hair bundles each). The treatment group used commercial hair care essential oil, whereas the control group used tap water to treat the damage. The two groups were measured using an instrument before and after the product application. The objective indicators included the gloss of hair, along with hair cuticle dynamic friction coefficient, and against hair cuticle dynamic friction coefficient. At the same time, two evaluators conducted sensory evaluations on the gloss and frizz levels of the hair bundles. Therefore, data comparison and verification were carried out together with instrumental measurement data. RESULTS: We verified that the instrumental measurement methods could obtain data trends that are consistent with sensory assessment methods; hence, they have the advantages of accuracy, convenience, and quantifiability. CONCLUSION: Thus, the instrumental measurement methods we verified can provide objective evidence for the efficacy of hair care products in repairing hair.

Oestrogen ameliorates blood-brain barrier damage after experimental subarachnoid haemorrhage via the SHH pathway in male rats.

BACKGROUND: Sex differences affect the occurrence, progression and regression of subarachnoid haemorrhage (SAH). Oestrogen plays a protective role in alleviating the vasospasm and neuronal apoptosis induced by SAH. However, whether oestrogen affects blood‒brain barrier (BBB) integrity has not been fully studied. Oestrogen has been found to regulate the sonic hedgehog (SHH) signalling pathway through the oestrogen receptor in gastric cancer and adrenal glands, and the SHH signalling pathway has an important role in maintaining the BBB by upregulating the expression of tight junction proteins. In this study, we investigated the relationship between oestrogen and the SHH signalling pathway using clinical data and established an experimental SAH model to explore whether oestrogen could ameliorate BBB damage after SAH through the SHH pathway. METHODS: Correlations between oestrogen and the SHH pathway were analysed by patients' cerebrospinal fluid (CSF) samples and the Genotype-Tissue Expression database (GTEx). Then, an experimental rat SAH model was established using the endovascular perforation method and treated with oestrogen, oestrogen inhibitors and SHH signalling pathway inhibitors. Then, the effects of oestrogen on BBB damage were analysed by western blot, immunofluorescence and neurobehavioural experiments. RESULTS: ESLIA detection and correlation analysis showed that oestrogen levels in patients' CSF were positively correlated with the SHH pathway, which was further verified by GTEx gene-correlation analysis. SHH was found to be mainly expressed in neurons and astrocytes in rats under physiological conditions and was upregulated by oestrogen pretreatment. In the SAH model, oestrogen pretreatment was found to reverse SAH-induced decreases in the SHH pathway, which were counteracted by oestrogen receptor inhibitors. Furthermore, oestrogen pretreatment reduced SAH-induced BBB damage, brain oedema and neurological dysfunction, which were eliminated by SHH pathway inhibitors. CONCLUSION: In conclusion, we demonstrate here that oestrogen pretreatment ameliorates brain injury after SAH, at least in part through SHH pathway-mediated BBB protection.

Therapeutic applications of hydrogen sulfide and novel donors for cerebral ischemic stroke: a narrative review.

Ischemic stroke happens when the blood supply to the brain is obstructed and it is associated with numerous complex mechanisms, such as activated apoptosis genes, oxidative stress and reaction of inflammation, which finally result in neurological deficits. Several gases have been proved to have neuroprotective roles, even the classic gases that are thought to be toxic such as hydrogen sulfide (H2S). H2S is the third identified endogenous gas signaling molecule following carbon monoxide and nitric oxide. H2S plays a significant role in stroke. Inhalation of H2S can attenuate cerebral infarct volume and promote neurological function in a rat model of middle cerebral artery occlusion to reduce ischemic stroke-induced injury in vivo and in vitro as a result. Therefore, H2S can be clinically used to reduce ischemic stroke-induced injury. This review introduces the toxic mechanisms and effects of H2S on cerebral ischemic stroke.

Unbalanced regulation of Sec22b and Ykt6 blocks autophagosome axonal retrograde flux in neuronal ischemia-reperfusion injury.

Cerebral ischemia-reperfusion injury in ischemic penumbra is accountable for poor outcome of ischemic stroke patients receiving recanalization therapy. Compelling evidence previously demonstrated a dual role of autophagy in stroke. This study aimed to understand the traits of autophagy in the ischemic penumbra and the potential mechanism that switches the dual role of autophagy. We found that autophagy induction by rapamycin and lithium carbonate performed before ischemia reduced neurological deficits and infarction, while autophagy induction after reperfusion had the opposite effect in the male murine middle cerebral artery occlusion/reperfusion model, both of which were eliminated in mice lacking autophagy (Atg7flox/flox; Nestin-Cre). Autophagic flux determination showed that reperfusion led to a blockage of axonal autophagosome retrograde transport in neurons, which then led to autophagic flux damage. Then, we found that ischemia-reperfusion induced changes in the protein levels of Sec22b and Ykt6 in neurons, two autophagosome transport-related factors, in which Sec22b significantly increased and Ykt6 significantly decreased. In the absence of exogenous autophagy induction, Sec22b knockdown and Ykt6 overexpression significantly alleviated autophagic flux damage, infarction, and neurological deficits in neurons or murine exposed to cerebral ischemia-reperfusion in an autophagy-dependent manner. Furthermore, Sec22b knockdown and Ykt6 overexpression switched the outcome of rapamycin post-treatment from deterioration to neuroprotection. Thus, Sec22b and Ykt6 play key roles in neuronal autophagic flux, and modest regulation of Sec22b and Ykt6 may help to reverse the failure of targeting autophagy induction to improve the prognosis of ischemic stroke.Significance Statement:The highly polarized architecture of neurons with neurites presents challenges for material transport, such as autophagosomes, which form at the neurite tip and need to be transported to the cell soma for degradation. Here, we demonstrate that Sec22b and Ykt6 act as autophagosome porters and play an important role in maintaining the integrity of neuronal autophagic flux. Ischemia-reperfusion-induced excess Sec22b and loss of Ykt6 in neurons lead to axonal autophagosome retrograde trafficking failure, autophagic flux damage, and finally neuronal injury. Facilitated axonal autophagosome retrograde transport by Sec22b knockdown and Ykt6 overexpression may reduce ischemia-reperfusion-induced neuron injury and extend the therapeutic window of pharmacological autophagy induction for neuroprotection.

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice.

The infiltration of blood components into the brain parenchyma through the lymphoid system is an important cause of subarachnoid hemorrhage injury. AQP4, a water channel protein located at the astrocyte foot, has been reported to regulate blood-brain barrier integrity, and its polarization is disrupted after SAH. Neuronal ferroptosis is involved in subarachnoid hemorrhage- (SAH-) induced brain injury, but the inducing factors are not completely clear. Transferrin is one of the inducing factors of ferroptosis. This study is aimed at researching the role and mechanism of AQP4 in brain injury after subarachnoid hemorrhage in mice. An experimental mouse SAH model was established by endovascular perforation. An AAV vector encoding AQP4 with a GFAP-specific promoter was administered to mice to achieve specific overexpression of AQP4 in astrocytes. PI staining, Fer-1 intervention, and transmission electron microscopy were used to detect neuronal ferroptosis, and dextran (40 kD) leakage was used to detect BBB integrity. Western blot analysis of perfused brain tissue protein samples was used to detect transferrin infiltration. First, neuronal ferroptosis 24 h after SAH was observed by PI staining and Fer-1 intervention. Second, a significant increase in transferrin infiltration was found in the brain parenchyma 24 h after SAH modeling, while transferrin content was positively correlated with neuronal ferroptosis. Then, we observed that AQP4 overexpression effectively improved AQP depolarization and BBB injury induced by SAH and significantly reduced transferrin infiltration and neuronal ferroptosis after SAH. Finally, we found that AQP4 overexpression could effectively improve the neurobehavioral ability of SAH mice, and the neurobehavioral ability was negatively correlated with transferrin brain content. Taken together, these data indicate that overexpression of AQP4 in the mouse brain can effectively improve post-SAH neuronal ferroptosis and brain injury, at least partly by inhibiting transferrin infiltration into the brain parenchyma in the glymphatic system.

Ischemia-induced cleavage of OPA1 at S1 site aggravates mitochondrial fragmentation and reperfusion injury in neurons.

Neuronal mitochondrial dynamics are disturbed after ischemic stroke. Optic atrophy 1 (OPA1) and its GTPase activity are involved in maintaining mitochondrial cristae and inner membrane fusion. This study aimed to explore the role of OMA1-mediated OPA1 cleavage (S1-OPA1) in neurons exposed to cerebral ischemia and reperfusion. After oxygen-glucose deprivation (OGD) for 60 min, we found that mitochondrial fragmentation occurred successively in the axon and soma of neurons, accompanied by an increase in S1-OPA1. In addition, S1-OPA1 overexpression significantly aggravated mitochondrial damage in neurons exposed to OGD for 60 min and 24 h after OGD/R, characterized by mitochondrial fragmentation, decreased mitochondrial membrane potential, mitochondrial cristae ultrastructural damage, increased superoxide production, decreased ATP production and increased mitochondrial apoptosis, which was inhibited by the lysine 301 to alanine mutation (K301A). Furthermore, we performed neuron-specific overexpression of S1-OPA1 in the cerebral cortex around ischemia of middle cerebral artery occlusion/reperfusion (MCAO/R) mice. The results further demonstrated in vivo that S1-OPA1 exacerbated neuronal mitochondrial ultrastructural destruction and injury induced by cerebral ischemia-reperfusion, while S1-OPA1-K301 overexpression had no effect. In conclusion, ischemia induced neuronal OMA1-mediated cleavage of OPA1 at the S1 site. S1-OPA1 aggravated neuronal mitochondrial fragmentation and damage in a GTPase-dependent manner, and participated in neuronal ischemia-reperfusion injury.

Sphingosine-1-phosphate receptor modulators versus interferon beta for the treatment of relapsing-remitting multiple sclerosis: findings from randomized controlled trials.

BACKGROUND: As one kind of disease-modifying therapies, sphingosine-1-phosphate receptor (S1PR) modulators such as fingolimod, ozanimod, and siponimod have been approved or are being developed to treat multiple sclerosis (MS). Several randomized controlled trials (RCT) have been implemented to compare the efficacy and safety of S1PR modulators versus interferon beta in the treatment of people with relapsing-remitting multiple sclerosis (RRMS). METHOD: We searched RCTs which were implemented from January 2010 to June 2020 by searching PubMed, Embase, Cochrane Library databases, and the Central Register of Controlled Trials. Finally, five RCTs were included in our study after carefully choosing. RESULT: We pooled 4304 patients from 5 RCTs. The primary outcome was the annualized relapse rate. We found that the annualized relapse rate in the S1PR modulator group is 20% less than that in the interferon beta group (95%CI, - 0.32 to - 0.07, P = 0.002). S1PR modulators led to a significant reduction in number of new or enlarging T2 lesions per scan and number of gadolinium-enhancing lesions compared with interferon beta. Moreover, S1PR modulators can also improve 54-item multiple sclerosis quality of life (MSQOL-54) physical health composite score (P = 0.0005). CONCLUSION: S1PR modulators exhibited good efficacy and safety for the treatment of RRMS compared with interferon beta. According to follow-up trials, S1PR modulators can improve MSQOL-54 physical health composite score so that it may be beneficial to neurological recovery which need more research to confirm.

Adverse Effects of Esketamine for the Treatment of Major Depression Disorder: Findings from Randomized Controlled Trials.

Esketamine is a promising drug which can induce antidepressant effects in Major Depression Disorder (MDD). Several randomized controlled trials (RCTs) have been implemented to assess the efficacy and safety of esketamine for the treatment of MDD. Therefore, we carried out a meta-analysis to assess adverse effect profiles of esketamine for the treatment of MDD. We searched RCTs which were implemented from January 2010 to June 2020 by searching PubMed, Embase and Cochrane Library databases. Finally, four RCTs with 551 patients were included in our study. We pooled 551 patients from 4 RCTs. Compared with placebo, an increased risk of adverse effects was observed in our analysis. After using esketamine, the risk of nausea (RR = 2.34, 95% CI, 1.04 to 5.25, P = 0.04), dissociation (RR = 4.54, 95% CI, 2.36 to 8.73, P < 0.00001), dizziness (RR = 3.00, 95% CI, 1.80 to 5.00, P < 0.0001), vertigo (RR = 7.47, 95% CI, 2.55 to 21.86, P = 0.0002), hypoesthesia (RR = 5.68, 95% CI, 2.06 to 15.63, P = 0.0008), sedation (RR = 3.96, 95% CI, 1.29 to 12.15, P = 0.02) and paresthesia(RR = 3.05, 95% CI, 1.07 to 8.65, P = 0.04)were significantly increased compared with placebo. Our synthesized data analysis revealed drug specific risk profiles. The most frequent adverse effects under treatment with esketamine were nausea, dissociation, dizziness, vertigo, hypoesthesia,sedation and paresthesia.

Endovascular Therapy Versus Anticoagulation for Treatment of Cerebral Venous Sinus Thrombosis: A Meta-Analysis.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke that mainly affects the young. Anticoagulation (AC) with heparin is the mainstay of treatment for CVST. Although highly anticipated, endovascular therapy (ET) including local thrombolysis and mechanical thrombectomy has been controversial. REVIEW SUMMARY: To compare the effectiveness and safety of ET with AC for patients with confirmed CVST, we systematically searched PubMed, Embase, and Cochrane Library from the earliest date to February 2020. Data on the total number of patients in each treatment group and the exact number of patients for each outcome were separately extracted from 10 studies with 891 patients.Our Results show that ET has a higher mortality rate compared with AC [odds ratio (OR)=1.95; 95% confidence interval (CI), 1.19-3.18; P=0.008<0.01] and has lower probability of good outcome (OR=0.48; 95% CI, 0.23-1.02; P=0.056). ET leads to a higher risk of complications than AC (OR=5.29; 95% CI, 1.17-23.95; P=0.030<0.05). No difference was found in recurrence rate between 2 treatments (OR=0.85; 95% CI, 0.31-2.35; P=0.761). CONCLUSIONS: ET is related to a higher mortality, fewer good outcome and possibly more complications compared with AC. The risks of ET should be weighed in every individualized therapeutic decision.

Pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea: A meta-analysis from randomized controlled trials.

Excessive daytime sleepiness is considered as the prominent symptom in narcolepsy and Obstructive Sleep Apnea (OSA). Pitolisant is a novel selective histamine H3 receptor antagonist approved for improving excessive daytime sleepiness. The meta-analysis is conducted to assess the efficacy and safety of pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and OSA. PubMed, Embase and Cochrane Library databases were searched from earliest date to November 2020 for randomized controlled trials (RCTs). The primary outcomes were mean changes in Epworth Sleepiness Scale (ESS), mean sleep latency, European quality-of-life questionnaire (EQ-5D), and risk ratio of treatment-emergent adverse events (TEAEs). We pooled 678 patients from four RCTs and found pitolisant significantly decreased ESS by mean difference (MD) of - 2.86 points (95% CI: -3.75 to -1.96), increased mean sleep latency by MD of 3.14 min (95% CI: 2.18-4.11), and increased EQ-5D by MD of 3.32 points (95% CI: 0.26-6.39) compared with placebo. The risk ratio of TEAE was 1.37 (95% CI: 1.08-1.74). Insomnia was the only TEAE significantly associated with pitolisant treatment. In conclusion, pitolisant showed great efficacy and controllable security versus placebo for excessive daytime sleepiness in narcolepsy and OSA. Compared with narcolepsy, patients with OSA were deemed to benefit more from pitolisant especially in terms of improving mobility and quality of life of patients without continuous positive airway pressure therapy.

Neurovascular Units and Neural-Glia Networks in Intracerebral Hemorrhage: from Mechanisms to Translation.

Intracerebral hemorrhage (ICH), the most lethal type of stroke, often leads to poor outcomes in the clinic. Due to the complex mechanisms and cell-cell crosstalk during ICH, the neurovascular unit (NVU) was proposed to serve as a promising therapeutic target for ICH research. This review aims to summarize the development of pathophysiological shifts in the NVU and neural-glia networks after ICH. In addition, potential targets for ICH therapy are discussed in this review. Beyond cerebral blood flow, the NVU also plays an important role in protecting neurons, maintaining central nervous system (CNS) homeostasis, coordinating neuronal activity among supporting cells, forming and maintaining the blood-brain barrier (BBB), and regulating neuroimmune responses. During ICH, NVU dysfunction is induced, along with neuronal cell death, microglia and astrocyte activation, endothelial cell (EC) and tight junction (TJ) protein damage, and BBB disruption. In addition, it has been shown that certain targets and candidates can improve ICH-induced secondary brain injury based on an NVU and neural-glia framework. Moreover, therapeutic approaches and strategies for ICH are discussed.

Efficacy and safety of solriamfetol for excessive sleepiness in narcolepsy and obstructive sleep apnea: findings from randomized controlled trials.

BACKGROUND: Solriamfetol is developed for the treatment of excessive sleepiness in adult patients with narcolepsy and obstructive sleep apnea (OSA). No systematic review of existing literature has been investigated before. Therefore, the meta-analysis is conducted to assess the efficacy and safety of solriamfetol for excessive sleepiness in narcolepsy and OSA. METHODS: PubMed, Embase and Cochrane Library databases were searched from earliest date to July 2020 for randomized controlled trials (RCTs) and the primary outcomes were change from baseline in mean sleep latency and Epworth Sleepiness Scale (ESS). RESULTS: We pooled 1177 patients from five RCTs and found solriamfetol led to a significant increment in mean sleep latency (MD = 9.52, 95% CI: 7.60 to 11.44, P < 0.00001) and a reduction in ESS score (MD = -3.74, 95% CI: -4.38 to -3.09, P < 0.00001) compared with placebo. The proportion of patients with at least one adverse event was significantly increased in solriamfetol group (RR = 1.42, 95% CI: 1.24 to 1.64, P < 0.00001), while no statistical differences existed in the risk of at least one serious adverse event between solriamfetol and controlled group (RR = 0.95, 95% CI: 0.24 to 3.77, P = 0.39). CONCLUSIONS: A dose of 150 mg solriamfetol is proved to be the appropriate and stable dose for excessive sleepiness. In addition, solriamfetol showed good efficacy for excessive sleepiness in narcolepsy and OSA but also significantly increases the risk of adverse events.

Clinical laboratory characteristics of severe patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.

OBJECTIVES: To identify clinical characteristics of severe patients with COVID-19. METHODS: The WHO database of publications on COVID-19 and PubMed were searched from inception to March 20, 2020 and all valuable studies were analyzed using Stata 15.0. RESULTS: We selected forty-four studies with 13,497 patients. In the comparison of severe and non-severe groups, age over 50 (OR = 4.090; 95% CI = 2.422-6.907, P = 0.000) and underlying disease (OR = 3.992; 95% CI = 2.631-6.507, P = 0.000) are risk factors. Female gender (OR = 0.740; 95% CI = 0.622-0.881, P = 0.001) is a protective factor. Characteristics like dyspnea (OR = 4.914; 95% CI = 3.069-7.867, P = 0.000), lymphopenia (OR = 5.528; 95% CI = 3.484-8.772, P = 0.000), thrombocytopenia (OR = 3.623; 95% CI = 1.034-12.691, P = 0.044), elevated C-reactive protein (OR = 5.217; 95% CI = 2.459-11.070, P = 0.000) and D-dimer (OR = 3.780; 95% CI = 1.481-9.648, P = 0.005) were more frequently in severe cases. Diffuse lesions and consolidation (OR = 4.680; 95% CI = 3.183-6.881, P = 0.000) in imaging was considered reliable. CONCLUSIONS: Men older than 50 with underlying disease are susceptible to develop severe pneumonia while female gender is protective. The typical symptom of severe pneumonia was dyspnea, but high fever, headache and diarrhea were not significantly different among patients with varying degrees of severity. Lymphopenia, thrombocytopenia, elevated C-reactive protein and D-dimer occurred more frequently in severe patients and yet leukopenia is not a characteristic laboratory indicator. Diffuse lesions and consolidation are important imaging features to distinguish severe pneumonia.

Galectin-9 Promotes Neuronal Restoration via Binding TLR-4 in a Rat Intracerebral Hemorrhage Model.

Intracerebral hemorrhage (ICH) is a devastating disease with high rates of mortality and morbidity. Galactose lectin-9 (Gal-9) belongs to the family of ß-galactoside-binding lectins, which has been shown to play a vital role in immune tolerance and inflammation. However, the function of Gal-9 in ICH has not been fully studied in details. Several experiments were carried out to explore the role of Gal-9 in the late period of ICH. Primarily, ICH models were established in male adult Sprague Dawley (SD) rats. Next, the relative protein levels of Gal-9 at different time points after ICH were examined and the result showed that the level of Gal-9 increased and peaked at the 7th day after ICH. Then we found that when the content of Gal-9 increased, both the number of M2-type microglia and the corresponding anti-inflammatory factors also increased. Through co-immunoprecipitation (CO-IP) analysis, it was found that Gal-9 combines with Toll-like receptor-4 (TLR-4) during the period of the recovery after ICH. TUNEL staining and Fluoro-Jade B staining (FJB) proved that the amount of cell death decreased with the increase of Gal-9 content. Additionally, several behavioral experiments also demonstrated that when the level of Gal-9 increased, the motor, sensory, learning, and memory abilities of the rats recovered better compared to the ICH group. In short, this study illustrated that Gal-9 takes a crucial role after ICH. Enhancing Gal-9 could alleviate brain injury and promote the recovery of ICH-induced injury, so that Gal-9 may exploit a new pathway for clinical treatment of ICH.

Sex-Specific Associations of Smoking with Spontaneous Subarachnoid Hemorrhage: Findings from Observational Studies.

BACKGROUND: Some studies have reported that women are at higher risk for spontaneous subarachnoid hemorrhage (SAH) compared with men, and smoking is the most important lifestyle risk factor for spontaneous SAH. However, it is still unknown whether the risk of SAH from smoking and smoking status is differential for women and men. We performed a meta-analysis to estimate the effect of smoking on SAH in women compared with men. METHODS: PubMed (January 1, 1966 to February 19, 2020) and EMBASE (January 1, 1980 to February 19, 2020) were systematically searched. Studies that estimated sex-specific relative risks (RRs) of SAH were selected. We pooled sex-specific RRs, comparing women with men using random-effects meta-analysis. RESULTS: Data from 20 observational studies that included 1,387,204 participants (563,898 women) and 7,838 SAHs (3,977 women) were analyzed. The combined women-to-men RRs of former smokers versus never smokers for SAH were 1.08 (95% confidence interval [CI] 0.62-1.89, p = 0.78). The pooled women-to-men RRs of current smokers versus never smokers were 1.39 (95% CI 1.05-1.83, p = 0.02). The combined women-to-men RRs of total smokers versus never smokers RRs were 1.15 (95% CI 0.88-1.52, p = 0.30). CONCLUSIONS: Our study shows there is not enough evidence to suggest that women who smoke have a greater risk for SAH than men; however, women who persistently smoke have a greater risk. Smoking seems to be more susceptible in the increased SAH risk in women.

Luteolin alleviates neuroinflammation via downregulating the TLR4/TRAF6/NF-κB pathway after intracerebral hemorrhage.

The activation of microglia and inflammatory responses is essential for the process of intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). In this study, we investigated the effects of luteolin on ICH-induced SBI and the potential mechanisms. Autologous blood was injected to establish the ICH model in vivo, and oxyhemoglobin (OxyHb) was used to mimic the ICH model in vitro. We found that the administration of luteolin significantly improved motor and sensory impairments and inhibited neuronal cell degeneration in vivo. In the in vitro study, the decrease of the neuronal cell viability induced by activated microglia was alleviated by luteolin treatment. Furthermore, by antagonizing the activation of the Toll-like receptor 4 (TLR4)/TNF receptor-associated factor 6 (TRAF6)/nuclear transcription factor-κB (NF-κB) signaling pathway, the ICH-induced elevation of cytokine release was decreased after treatment with luteolin, which was confirmed both in vivo and in vitro. Additionally, we found that luteolin engaged with TRAF6 and inhibited the ubiquitination of TRAF6. Taken together, our findings demonstrate the neuroprotective effects of luteolin after ICH and the potential mechanisms, which suggest that luteolin is a potential therapeutic candidate for ICH treatment.