Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.

Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.

Unraveling the molecular interactions between α7 nicotinic receptor and a RIC3 variant associated with backward speech.

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G > A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation, and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression, and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wild-type RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the endoplasmic reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR.

Congenital myasthenic syndromes: increasingly complex.

PURPOSE OF REVIEW: Congenital myasthenia syndromes (CMS) are treatable, inherited disorders affecting neuromuscular transmission. We highlight that the involvement of an increasing number of proteins is making the understanding of the disease mechanisms and potential treatments progressively more complex. RECENT FINDINGS: Although early studies identified mutations of proteins directly involved in synaptic transmission at the neuromuscular junction, recently, next-generation sequencing has facilitated the identification of many novel mutations in genes that encode proteins that have a far wider expression profile, some even ubiquitously expressed, but whose defective function leads to impaired neuromuscular transmission. Unsurprisingly, mutations in these genes often causes a wider phenotypic disease spectrum where defective neuromuscular transmission forms only one component. This has implications for the management of CMS patients. SUMMARY: Given the widening nonneuromuscular junction phenotypes in the newly identified forms of CMS, new therapies need to include disease-modifying approaches that address not only neuromuscular weakness but also the multisystem involvement. Whilst the current treatments for CMS are highly effective for many subtypes there remains, in a proportion of CMS patients, an unmet need for more efficacious therapies.

Arabidopsis AGAMOUS-LIKE16 and SUPPRESSOR OF CONSTANS1 regulate the genome-wide expression and flowering time.

Flowering transition is tightly coordinated by complex gene regulatory networks, in which AGAMOUS-LIKE 16 (AGL16) plays important roles. Here, we identified the molecular function and binding properties of AGL16 and demonstrated its partial dependency on the SUPPRESSOR OF CONSTANS 1 (SOC1) function in regulating flowering. AGL16 bound to promoters of more than 2,000 genes via CArG-box motifs with high similarity to that of SOC1 in Arabidopsis (Arabidopsis thaliana). Approximately 70 flowering genes involved in multiple pathways were potential targets of AGL16. AGL16 formed a protein complex with SOC1 and shared a common set of targets. Intriguingly, only a limited number of genes were differentially expressed in the agl16-1 loss-of-function mutant. However, in the soc1-2 knockout background, AGL16 repressed and activated the expression of 375 and 182 genes, respectively, with more than a quarter bound by AGL16. Corroborating these findings, AGL16 repressed the flowering time more strongly in soc1-2 than in the Col-0 background. These data identify a partial inter-dependency between AGL16 and SOC1 in regulating genome-wide gene expression and flowering time, while AGL16 provides a feedback regulation on SOC1 expression. Our study sheds light on the complex background dependency of AGL16 in flowering regulation, thus providing additional insights into the molecular coordination of development and environmental adaptation.

Enhanced OER catalytic activity of single metal atoms supported by the pentagonal NiN2 monolayer: insight from density functional theory calculations.

Two-dimensional material-supported single metal atom catalysts have been extensively studied and proved effective in electrocatalytic reactions in recent years. In this work, we systematically investigate the OER catalytic properties of single metal atoms supported by the NiN2 monolayer. Several typical transition metals with high single atom catalytic activity, such as Fe, Co, Ru, Rh, Pd, Ir, and Pt, were selected as catalytic active sites. The energy calculations show that transition metal atoms (Fe, Co, Ru, Rh, Pd, Ir, and Pt) are easily embedded in the NiN2 monolayer with Ni vacancies due to the negative binding energy. The calculated OER overpotentials of Fe, Co, Ru, Rh, Pd, Ir and Pt embedded NiN2 monolayers are 0.92 V, 0.47 V, 1.13 V, 0.66 V, 1.25 V, 0.28 V, and 0.94 V, respectively. Compared to the 0.57 V OER overpotential of typical OER noble metal catalysts IrO2, Co@NiN2 and Ir@NiN2 exhibit high OER catalytic activity due to lower overpotential, especially for Ir@NiN2. The high catalytic activity of the Ir embedded NiN2 monolayer can be explained well by the d-band center model. It is found that the adsorption strength of the embedded TM atoms with intermediates follows a linear relationship with their d-band centers. Besides, the overpotential of the Ir embedded NiN2 monolayer can be further reduced to 0.24 V under -2% biaxial strain. Such findings are expected to be employed in more two-dimensional material-supported single metal atom catalyzed reactions.

Vagus nerve stimulation as a promising neuroprotection for ischemic stroke via α7nAchR-dependent inactivation of microglial NLRP3 inflammasome.

Ischemic stroke is a major cause of disability and death worldwide, and its management requires urgent attention. Previous studies have shown that vagus nerve stimulation (VNS) exerts neuroprotection in ischemic stroke by inhibiting neuroinflammation and apoptosis. In this study, we evaluated the timing for VNS intervention in ischemic stroke, and the underlying mechanisms  of VNS-induced neuroprotection. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min. The left vagus nerve at cervical level was exposed and attached to an electrode connected to a low-frequency electrical stimulator. Vagus nerve stimulation (VNS) was given for 60 min before, during and after tMCAO (Pre-VNS, Dur-VNS, Post-VNS). Neurological function was assessed 24 h after reperfusion. We found that all the three VNS significantly protected against the tMCAO-induced injury evidenced by improved neurological function and reduced infarct volume. Moreover, the Pre-VNS was the most effective against the ischemic injury. We found that tMCAO activated microglia in the ischemic core and penumbra regions of the brain, followed by the NLRP3 inflammasome activation-induced neuroinflammation, which finally triggered neuronal death. VNS treatment preserved α7nAChR expression in the penumbra regions, inhibited NLRP3 inflammasome activation and ensuing neuroinflammation, rescuing cerebral neurons. The role of α7nAChR in microglial NLRP3 inflammasome activation in ischemic stroke was further validated using genetic manipulations, including Chrna7 knockout mice and microglial Chrna7 overexpression mice, as well as pharmacological interventions using the α7nAChR inhibitor methyllycaconitine and agonist PNU-282987. Collectively, this study demonstrates the potential of VNS as a safe and effective strategy to treat ischemic stroke, and presents a new approach targeting microglial NLRP3 inflammasome, which might be therapeutic for other inflammation-related diseases.

[Critical influencing factors on quality of traditional Chinese medicine preparations from perspective of process and equipment].

The quality of traditional Chinese medicine preparations is directly related to the safety of patients. Among the various factors, the process and corresponding critical equipment are critical factors influencing the quality of the preparations. To improve the quality of traditional Chinese medicine preparations, this article summarizes and analyzes the problems in the process links and corresponding critical equipment in the manufacturing process of traditional Chinese medicine preparations. Furthermore, a critical quality attribute evaluation system is established based on safety and effectiveness combined with the drug properties, preparation process, and preparation characteristics, providing a basis for the process and equipment improvements aimed at quality enhancement.

Continuous venovenous hemodiafiltration versus standard medical therapy for the prevention of rhabdomyolysis-induced acute kidney injury: a retrospective cohort study.

AIM: To determine whether continuous venovenous hemodiafiltration (CVVHDF) plus standard medical therapy (SMT) vs. SMT alone prevents rhabdomyolysis (RM)-induced acute kidney injury (AKI) and analyze the related health economics. METHODS: This retrospective cohort study involved 9 RM patients without AKI, coronary heart disease, or chronic kidney disease treated with CVVHDF plus SMT (CVVHDF + SMT group). Nine matched RM patients without AKI treated with SMT only served as controls (SMT group). Baseline characteristics, biochemical indexes, renal survival data, and health economic data were compared between groups. In the CVVHDF + SMT group, biochemical data were compared at different time points. RESULTS: At 2 and 7 days after admission, serum biochemical indices (e.g., myoglobin, creatine kinase, creatinine, and blood urea nitrogen) did not differ between the groups. Total (P = 0.011) and daily hospitalization costs (P = 0.002) were higher in the CVVHDF + SMT group than in the SMT group. After 53 months of follow-up, no patient developed increased serum creatinine, except for 1 CVVHDF + SMT-group patient who died of acute myocardial infarction. In the CVVHDF + SMT group, myoglobin levels significantly differed before and after the first CVVHDF treatment (P = 0.008), and serum myoglobin, serum creatinine, and blood urea nitrogen decreased significantly at different time points after CVVHDF. CONCLUSIONS: Although CVVHDF facilitated myoglobin elimination, its addition to SMT did not improve biochemical indices like serum myoglobin, serum creatine kinase, creatinine, blood urea nitrogen, and lactate dehydrogenase or the long-term renal prognosis. Despite similar hospitalization durations, both total and daily hospitalization costs were higher in the CVVHDF + SMT group.

Changing incidence of hepatitis B and persistent infection risk in adults: a population-based follow-up study from 2011 in China.

BACKGROUND: This study aimed to estimate hepatitis B incidence and chronicity risk in rural adults in China under the background of eliminating viral hepatitis. METHODS: Hepatitis B surface antigen (HBsAg) screening was conducted every 2 years in demonstration areas since 2011. Individuals with baseline HBsAg-negative were included. Incidence was calculated as the number of HBsAg-positive cases divided by the total person-times. HBsAg-positive individuals were followed up to study the persistent infection (> 6 months), chronic infection (> 12 months), and recovery with hepatitis B surface antibody (anti-HBs). The chi-square test and cox proportional regression analysis were performed. RESULTS: There were 8,942 incident cases over 2,138,532 person-years, yielding an average incidence of 0.42 per 100 person-years. HBV incidence decreased rapidly in both genders and all age groups and then kept stable. Male gender, low population density, low gross domestic product per capita, and islanders were associated with higher incidence. Of the positive cases, 4,989 (55.8%) patients were followed up. The persistent infection, chronic infection, and recovery with anti-HBs rates were 32.3%, 31.0%, and 31.4%, respectively. Persistent or chronic infection was more common in younger adults and males, while seroconversion had no concern with gender or age. CONCLUSIONS: HBV incidence in adult rural residents was decreasing and stayed low. The chronicity rate was relatively high and protective antibodies were induced in only one third. The importance of population-based screening and vaccination for susceptible individuals should be addressed.

Transcriptome Analysis Reveals the Effect of Stocking Density on Energy Metabolism in the Gills of Cherax quadricarinatus under Rice-Crayfish Co-Culture.

Stocking density is a crucial factor affecting productivity in aquaculture, and high stocking density is a stressor for aquatic animals. In this study, we aimed to investigate the effects of stocking densities on oxidative stress and energy metabolism in the gills of Cherax quadricarinatus under rice-crayfish farming. The C. quadricarinatus were reared at low density (LD), medium density (MD), and high density (HD) for 90 days. The results showed that the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and malondialdehyde (MDA) levels were higher in the HD group than those in the LD group. Transcriptomic analysis revealed 1944 upregulated and 1157 downregulated genes in the gills of the HD group compared to the LD group. Gene ontology (GO) enrichment analysis indicated that these differentially expressed genes (DEGs) were significantly associated with ATP metabolism. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis also showed that high stocking density resulted in the dysregulation of oxidative phosphorylation. Furthermore, high stocking density upregulated six lipid metabolism-related pathways. Overall, our findings, despite the limited number of samples, suggested that high stocking density led to oxidative stress and dysregulation of energy metabolism in the gills of C. quadricarinatus under rice-crayfish co-culture. Alteration in energy metabolism may be an adaptive response to adverse farming conditions.

Predictors of post-stroke depression: the perspective from the social convoy model.

BACKGROUND: Post-stroke depression (PSD) as one of the most common neuropsychiatric disorders after a stroke and is caused by many factors. However, the relationships among different factors and their potential contributions to PSD remain unclear. METHODS: Two hundred and seventy-six patients were recruited into this study. The general information questionnaire, the Patient Health Questionnaire-9, the Perceived Social Support Scale, the Family Assessment Device, the General Well-Being Scale, the Barthel Index, and the modified Rankin Scale were used to assess the condition of patients. Subsequently, we identify the main causes associated with the PSD and then performed a path analysis to clarify the direct, indirect and total effects among the variables. RESULTS: We found that age, stroke with coronary heart disease, neurological function, family function, social support, and general well-being had a significant impact on PSD (P < 0.05). Of these, neurological function had the largest total effect on PSD (ß = 0.451), social support contributed the most as a direct effect (ß = -0.306), and family function showed the largest indirect effect (ß = -0.264). CONCLUSION: Individual, disease, and social-psychological factors all contributed to the development of PSD. We should pay more attention to comprehensive assessment, especially for those with poor neurological function, and lacking family or social support. In addition, it would be preferable to provide them with necessary support and care strategies to reduce the incidence of PSD.

PM2.5-bound polyhalogenated carbazoles (PHCZs) in urban Beijing, China: Occurrence and the source implication.

Polyhalogenated carbazoles (PHCZs) are recently raising much attention due to their toxicity and ubiquitous environmental distribution. However, little knowledge is known about their ambient occurrences and the potential source. In this study, we developed an analytical method based on GC-MS/MS to simultaneously determine 11 PHCZs in PM2.5 from urban Beijing, China. The optimized method provided low method limit of quantifications (MLOQs, 1.45-7.39 fg/m3) and satisfied recoveries (73.4%-109.5%). This method was applied to analyze the PHCZs in the outdoor PM2.5 (n = 46) and fly ash (n = 6) collected from 3 kinds of surrounding incinerator plants (steel plant, medical waste incinerator and domestic waste incinerator). The levels of ∑11PHCZs in PM2.5 ranged from 0.117 to 5.54 pg/m3 (median 1.18 pg/m3). 3-chloro-9H-carbazole (3-CCZ), 3-bromo-9H-carbazole (3-BCZ), and 3,6-dichloro-9H-carbazole (36-CCZ) were the dominant compounds, accounting for 93%. 3-CCZ and 3-BCZ were significantly higher in winter due to the high PM2.5 concentration, while 36-CCZ was higher in spring, which may be related to the resuspending of surface soil. Furthermore, the levels of ∑11PHCZs in fly ash ranged from 338 to 6101 pg/g. 3-CCZ, 3-BCZ and 36-CCZ accounted for 86.0%. The congener profiles of PHCZs between fly ash and PM2.5 were highly similar, indicating that combustion process could be an important source of ambient PHCZs. To the best of our knowledge, this is the first research providing the occurrences of PHCZs in outdoor PM2.5.

The role of short-chain fatty acids in central nervous system diseases.

Previous studies have found that intracorporal short-chain fatty acids (SCFAs), as the main metabolites of the gut microbiota, play important roles in the intestinal physiology and immune function. Along with the in-depth study of the brain-gut axis, the attention to the roles of SCFAs in central nervous system (CNS) has been raised. It has been found that SCFAs function in CNS diseases by regulating inflammatory response, neuronal apoptosis, oxidative stress, the integrity of the blood-brain barrier (BBB) and so on. Here, the changes, the effects and the mechanisms of different SCFA as individual or mixture in different CNS diseases were summarized. It is expected to lead to increased interest in SCFAs studies as an important regulator in CNS diseases and provide feasible suggestions based on SCFAs for the therapy of CNS diseases in the future.

Iptakalim improves cerebral microcirculation in mice after ischemic stroke by inhibiting pericyte contraction.

Pericytes are present tight around the intervals of capillaries, play an essential role in stabilizing the blood-brain barrier, regulating blood flow and immunomodulation, and persistent contraction of pericytes eventually leads to impaired blood flow and poor clinical outcomes in ischemic stroke. We previously show that iptakalim, an ATP-sensitive potassium (K-ATP) channel opener, exerts protective effects in neurons, and glia against ischemia-induced injury. In this study we investigated the impacts of iptakalim on pericytes contraction in stroke. Mice were subjected to cerebral artery occlusion (MCAO), then administered iptakalim (10 mg/kg, ip). We showed that iptakalim administration significantly promoted recovery of cerebral blood flow after cerebral ischemia and reperfusion. Furthermore, we found that iptakalim significantly inhibited pericytes contraction, decreased the number of obstructed capillaries, and improved cerebral microcirculation. Using a collagen gel contraction assay, we demonstrated that cultured pericytes subjected to oxygen-glucose deprivation (OGD) consistently contracted from 3 h till 24 h during reoxygenation, whereas iptakalim treatment (10 µM) notably restrained pericyte contraction from 6 h during reoxygenation. We further showed that iptakalim treatment promoted K-ATP channel opening via suppressing SUR2/EPAC1 complex formation. Consequently, it reduced calcium influx and ET-1 release. Taken together, our results demonstrate that iptakalim, targeted K-ATP channels, can improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke. Our work reveals that iptakalim might be developed as a promising pericyte regulator for treatment of stroke.

The role of fibrosis index FIB-4 in predicting liver fibrosis stage and clinical prognosis: A diagnostic or screening tool?

This review evaluates the ability of the fibrosis index based on four factors (FIB-4) identifying fibrosis stages, long-time prognosis in chronic liver disease, and short-time outcomes in acute liver injury. FIB-4 was accurate in predicting the absence or presence of advanced fibrosis with cut-offs of 1.0 and 2.65 for viral hepatitis B, 1.45 and 3.25 for viral hepatitis C, 1.30 (<65 years), 2.0 (≥65 years), and 2.67 for non-alcoholic fatty liver disease (NAFLD), respectively, but had a low-to-moderate accuracy in alcoholic liver disease (ALD) and autoimmune hepatitis. It performed better in excluding fibrosis, so we built an algorithm for identifying advanced fibrosis by combined methods and giving work-up and follow-up suggestions. High FIB-4 in viral hepatitis, NAFLD, and ALD was associated with significantly high hepatocellular carcinoma incidence and mortality. Additionally, FIB-4 showed the ability to predict high-risk varices with cut-offs of 2.87 and 3.91 in cirrhosis patients and predict long-term survival in hepatocellular carcinoma patients after hepatectomy. In acute liver injury caused by COVID-19, FIB-4 had a predictive value for mechanical ventilation and 30-day mortality. Finally, FIB-4 may act as a screening tool in the secondary prevention of NAFLD in the high-risk population.

Oridonin prevents oxidative stress-induced endothelial injury via promoting Nrf-2 pathway in ischaemic stroke.

Oridonin, a natural diterpenoid compound extracted from a Chinese herb, has been proved to exert anti-oxidative stress effects in various disease models. The aim of the present study was to investigate the protective effects of oridonin on oxidative stress-induced endothelial injury in ischaemic stroke. We found oridonin repaired blood-brain barrier (BBB) integrity presented with upregulation of tight junction proteins (TJ proteins) expression, inhibited the infiltration of periphery inflammatory cells and neuroinflammation and thereby reduced infarct volume in ischaemic stroke mice. Furthermore, our results showed that oridonin could protect against oxidative stress-induced endothelial injury via promoting nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf-2). The specific mechanism could be the activation of AKT(Ser473)/GSK3ß(Ser9)/Fyn signalling pathway. Our findings revealed the therapeutic effect and mechanism of oridonin in ischaemic stroke, which provided fundamental evidence for developing the extracted compound of Chinese herbal medicine into an innovative drug for ischaemic stroke treatment.

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

Factor analysis approach unveils the influencing factors of dandruff in the normal teenage population.

The aim of this study was to explore the main factors affecting the occurrence of dandruff in healthy people (nondisease-induced scalp desquamation). This study analyzed the fungal microbial diversity of the scalp in Chinese teenage volunteers and measured scalp sebum secretion, the scalp pH value, and scalp transepidermal water loss. The amount and size of dandruff were measured, and the main factors that influence dandruff in the normal population were identified using principal component analysis. The results showed that an increase in Malassezia restricta led to an increased amount of dandruff in the mild and moderate groups. Conversely, this was not found for individuals in the severe group, whose dandruff symptoms were influenced by scalp barrier function. In terms of dandruff area grouping, the pH value and the amount of sebum secretion were the main factors, with the barrier function and microbial diversity being secondary factors. Dandruff cosmetics should emphasize different treatments for different types of dandruff to achieve better antidandruff effects. The results of this study provide a new theoretical basis for the development of multiple targets for antidandruff agents aimed at the normal population.

May Measurement Month 2017: an analysis of blood pressure screening results in China-East Asia.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. In China, several hypertension screening programmes are undertaken in the elderly in the community and in youths at university entrance and graduation. However, most people, especially the middle-aged working population, do not often have their BP measured. The current awareness (46.9%), treatment (40.7%), and control rates (15.3%) of hypertension remain low, while the proportion of screenees with hypertension is high in adult Chinese (23.2%). An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. About 125 236 individuals were screened. After multiple imputation, with 124 623 as denominator, 32 089 (25.7%) had hypertension. Of the 103 981 individuals not on antihypertensive medication, 11 447 (11.0%) were hypertensive. Of the 20 547 individuals on antihypertensive medication, 7392 (36.0%) had uncontrolled BP (≥140/90 mmHg). An opportunistic screening may effectively identify those with high BP regardless of the use of antihypertensive medication and shows similar information on BP as a survey in a randomly selected population sample.

S1PR3 is essential for phosphorylated fingolimod to protect astrocytes against oxygen-glucose deprivation-induced neuroinflammation via inhibiting TLR2/4-NFκB signalling.

Fingolimod (FTY720) is used as an immunosuppressant for multiple sclerosis. Numerous studies indicated its neuroprotective effects in stroke. However, the mechanism remains to be elucidated. This study was intended to investigate the mechanisms of phosphorylated FTY720 (pFTY720), which was the principle active molecule in regulating astrocyte-mediated inflammatory responses induced by oxygen-glucose deprivation (OGD). Results demonstrated that pFTY720 could protect astrocytes against OGD-induced injury and inflammatory responses. It significantly decreased pro-inflammatory cytokines, including high mobility group box 1 (HMGB1) and tumour necrosis factor-α (TNF-α). Further, studies displayed that pFTY720 could prevent up-regulation of Toll-like receptor 2 (TLR2), phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear translocation of nuclear factor kappa B (NFκB) p65 subunit caused by OGD. Sphingosine-1-phosphate receptor 3 (S1PR3) knockdown could reverse the above change. Moreover, administration of TLR2/4 blocker abolished the protective effects of pFTY720. Taken together, this study reveals that pFTY720 depends on S1PR3 to protect astrocytes against OGD-induced neuroinflammation, due to inhibiting TLR2/4-PI3K-NFκB signalling pathway.