Advancements and prospects of novel biologicals for myasthenia gravis: toward personalized treatment based on autoantibody specificities.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease with a prevalence of 150-250 cases per million individuals. Autoantibodies include long-lived antibodies against the acetylcholine receptor (AChR), mainly of the IgG1 subclass, and IgG4, produced almost exclusively by short-lived plasmablasts, which are prevalent in muscle-specific tyrosine kinase (MuSK) myasthenia gravis. Numerous investigations have demonstrated that MG patients receiving conventional medication today still do not possess satisfactory symptom control, indicating a substantial disease burden. Subsequently, based on the type of the autoantibody and the pathogenesis, we synthesized the published material to date and reached a conclusion regarding the literature related to personalized targeted therapy for MG. Novel agents for AChR MG have shown their efficacy in clinical research, such as complement inhibitors, FcRn receptor antagonists, and B-cell activating factor (BAFF) inhibitors. Rituximab, a representative drug of anti-CD20 therapy, has demonstrated benefits in treatment of MuSK MG patients. Due to the existence of low-affinity antibodies or unidentified antibodies that are inaccessible by existing methods, the treatment for seronegative MG remains complicated; thus, special testing and therapy considerations are necessary. It may be advantageous to initiate the application of novel biologicals at an early stage of the disease. Currently, therapies can also be combined and individualized according to different types of antibodies. With such a wide range of drugs, how to tailor treatment strategies to patients with various conditions and find the most suitable solution for each MG profile are our necessary and urgent aims.

The intricate dance of non-coding RNAs in myasthenia gravis pathogenesis and treatment.

Myasthenia gravis (MG) stands as a perplexing autoimmune disorder affecting the neuromuscular junction, driven by a multitude of antibodies targeting postsynaptic elements. However, the mystery of MG pathogenesis has yet to be completely uncovered, and its heterogeneity also challenges diagnosis and treatment. Growing evidence shows the differential expression of non-coding RNAs (ncRNAs) in MG has played an essential role in the development of MG in recent years. Remarkably, these aberrantly expressed ncRNAs exhibit distinct profiles within diverse clinical subgroups and among patients harboring various antibody types. Furthermore, they have been implicated in orchestrating the production of inflammatory cytokines, perturbing the equilibrium of T helper 1 cells (Th1), T helper 17 cells (Th17), and regulatory T cells (Tregs), and inciting B cells to generate antibodies. Studies have elucidated that certain ncRNAs mirror the clinical severity of MG, while others may hold therapeutic significance, showcasing a propensity to return to normal levels following appropriate treatments or potentially foretelling the responsiveness to immunosuppressive therapies. Notably, the intricate interplay among these ncRNAs does not follow a linear trajectory but rather assembles into a complex network, with competing endogenous RNA (ceRNA) emerging as a prominent hub in some cases. This comprehensive review consolidates the landscape of dysregulated ncRNAs in MG, briefly delineating their pivotal role in MG pathogenesis. Furthermore, it explores their promise as prospective biomarkers, aiding in the elucidation of disease subtypes, assessment of disease severity, monitoring therapeutic responses, and as novel therapeutic targets.

Analysis of damage-associated molecular patterns in amyotrophic lateral sclerosis based on ScRNA-seq and bulk RNA-seq data.

Background: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite extensive research, the exact etiology of ALS remains elusive. Emerging evidence highlights the critical role of the immune system in ALS pathogenesis and progression. Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules released by stressed or damaged cells, acting as danger signals and activating immune responses. However, their specific involvement in ALS remains unclear. Methods: We obtained single-cell RNA sequencing (scRNA-seq) data of ALS from the primary motor cortex in the Gene Expression Omnibus (GEO) database. To better understand genes associated with DAMPs, we performed analyses on cell-cell communication and trajectory. The abundance of immune-infiltrating cells was assessed using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. We performed univariate Cox analysis to construct the risk model and utilized the least absolute shrinkage and selection operator (LASSO) analysis. Finally, we identified potential small molecule drugs targeting ALS by screening the Connectivity Map database (CMap) and confirmed their potential through molecular docking analysis. Results: Our study annotated 10 cell types, with the expression of genes related to DAMPs predominantly observed in microglia. Analysis of intercellular communication revealed 12 ligand-receptor pairs in the pathways associated with DAMPs, where microglial cells acted as ligands. Among these pairs, the SPP1-CD44 pair demonstrated the greatest contribution. Furthermore, trajectory analysis demonstrated distinct differentiation fates of different microglial states. Additionally, we constructed a risk model incorporating four genes (TRPM2, ROCK1, HSP90AA1, and HSPA4). The validity of the risk model was supported by multivariate analysis. Moreover, external validation from dataset GSE112681 confirmed the predictive power of the model, which yielded consistent results with datasets GSE112676 and GSE112680. Lastly, the molecular docking analysis suggested that five compounds, namely mead-acid, nifedipine, nifekalant, androstenol, and hydrastine, hold promise as potential candidates for the treatment of ALS. Conclusion: Taken together, our study demonstrated that DAMP entities were predominantly observed in microglial cells within the context of ALS. The utilization of a prognostic risk model can accurately predict ALS patient survival. Additionally, genes related to DAMPs may present viable drug targets for ALS therapy.

Clinical features of myasthenia gravis with neurological and systemic autoimmune diseases.

Multiple reports on the co-existence of autoimmune diseases and myasthenia gravis (MG) have raised considerable concern. Therefore, we reviewed autoimmune diseases in MG to explore their clinical presentations and determine whether the presence of autoimmune diseases affects the disease severity and treatment strategies for MG. We reviewed all the major immune-mediated coexisting autoimmune conditions associated with MG. PubMed, Embase and Web of Science were searched for relevant studies from their inception to January 2023. There is a higher frequency of concomitant autoimmune diseases in patients with MG than in the general population with a marked risk in women. Most autoimmune comorbidities are linked to AChR-MG; however, there are few reports of MuSK-MG. Thyroid disorders, systemic lupus erythematosus, and vitiligo are the most common system autoimmune diseases associated with MG. In addition, MG can coexist with neurological autoimmune diseases, such as neuromyelitis optica (NMO), inflammatory myopathy (IM), multiple sclerosis (MS), and autoimmune encephalitis (AE), with NMO being the most common. Autoimmune diseases appear to develop more often in early-onset MG (EOMG). MS coexists more commonly with EOMG, while IM coexists with LOMG. In addition, MG complicated by autoimmune diseases tends to have mild clinical manifestations, and the coexistence of autoimmune diseases does not influence the clinical course of MG. The clinical course of neurological autoimmune diseases is typically severe. Autoimmune diseases occur most often after MG or as a combined abnormality; therefore, timely thymectomy followed by immunotherapy could be effective. In addition, thymoma-associated AChR MG is associated with an increased risk of AE and IM, whereas NMO and MS are associated with thymic hyperplasia. The co-occurrence of MG and autoimmune diseases could be attributed to similar immunological mechanisms with different targets and common genetic factor predisposition. This review provides evidence of the association between MG and several comorbid autoimmune diseases.

Long-term effects of air pollution on hospital admissions and mortality for chronic obstructive pulmonary disease in Beijing, China.

OBJECTIVE: We aimed to clarify the association between air pollution and hospital admissions for chronic obstructive pulmonary disease (COPD) and mortality in Beijing, China. METHODS: In this retrospective study, we recruited 510 COPD patients from 1 January 2006 to 31 December 2009. The patient data were obtained from the electronic medical records of Peking University Third Hospital in Beijing. Air pollution and meteorological data were obtained from the Institute of Atmospheric Physics of the Chinese Academy of Sciences. Monthly COPD hospital admissions, mortality and air pollution data were analysed using Poisson regression in generalised additive models adjusted for mean temperature, pressure and relative humidity. RESULTS: There were positive correlations between sulfur dioxide (SO2 ), particulate matter with an aerodynamic diameter ≤ 10 µm (PM10 ) and COPD hospital admissions in the single-pollutant model. An increase of 10 µg/m3 in SO2 and PM10 were associated with an increase of 4.053% (95% CI: 1.470-5.179%) and 1.401% (95%CI: 0.6656-1.850%) in COPD hospital admissions. In the multiple-pollutant model [SO2 and nitrogen dioxide (NO2 ) combinations], there was only a positive correlation between SO2 and COPD hospital admissions. An increase of 10 µg/m3 in SO2 were associated with an increase of 1.916% (95% CI: 1.118-4.286%) in COPD hospital admissions. There was no correlation between three pollutant combinations and COPD hospital admissions. We did not find correlations between air pollution and COPD mortality in either single- or multiple-pollutant models. CONCLUSIONS: SO2 and PM10 may be important factors for the increase in COPD hospital admissions in Beijing, China.

Moderate coffee or tea consumption decreased the risk of cognitive disorders: an updated dose-response meta-analysis.

CONTEXT: Although several epidemiological studies have examined the association between coffee or tea intake and the risk of cognitive disorders, the results to date are inconsistent. OBJECTIVE: An updated systematic review and dose-response meta-analysis was conducted to confirm the association between coffee, tea, and caffeine consumption and the risk of cognitive disorders. DATA SOURCES: PubMed, Embase, and Web of Science were searched from inception to January 2022 for relevant studies, including dementia, Alzheimer disease (AD), and cognitive impairment or decline. DATA EXTRACTION: Two reviewers independently performed data extraction and assessed the study quality. DATA ANALYSIS: Restricted cubic splines were used to conduct the dose-response meta-analysis for coffee and tea intake. RESULTS: Twenty-two prospective studies and 11 case-control studies involving 389 505 participants were eligible for this meta-analysis. Coffee and tea consumption was linked to a lower risk of cognitive disorders, with an overall relative risk (RR) of 0.73 (95% CI: 0.60-0.86) and 0.68 (95% CI: 0.56-0.80), respectively. The subgroup analysis revealed that ethnicity, sex, and outcomes had significant effects on this association. Protection was stronger for men than that for women in both coffee and tea consumption. A nonlinear relationship was found between coffee consumption and AD risk, and the strength of protection peaked at approximately 2.5 cups/day (RR: 0.74; 95% CI: 0.59-0.93). A linear relationship was found between tea consumption and cognitive disorders, and the risk decreased by 11% for every 1-cup/day increment. CONCLUSION: This meta-analysis demonstrated that the consumption of 2.5 cups coffee/day minimizes the risk of AD, and 1 cup/day of tea intake leads to an 11% reduction in cognitive deficits. Effective interventions involving coffee and tea intake might prevent the occurrence of dementia.

Short-term effect of particulate matter on lung function and impulse oscillometry system (IOS) parameters of chronic obstructive pulmonary disease (COPD) in Beijing, China.

OBJECTIVE: This study aimed to evaluate the associations between particulate matter (PM), lung function and Impulse Oscillometry System (IOS) parameters in chronic obstructive pulmonary disease (COPD) patients and identity effects between different regions in Beijing, China. METHODS: In this retrospective study, we recruited 1348 outpatients who visited hospitals between January 2016 and December 2019. Ambient air pollutant data were obtained from the central monitoring stations nearest the participants' residential addresses. We analyzed the effect of particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) exposure on lung function and IOS parameters using a multiple linear regression model, adjusting for sex, smoking history, education level, age, body mass index (BMI), mean temperature, and relative humidity . RESULTS: The results showed a relationship between PM2.5, lung function and IOS parameters. An increase of 10 µg/m3 in PM2.5 was associated with a decline of 2.083% (95% CI: -3.047 to - 1.103) in forced expiratory volume in one second /predict (FEV1%pred), a decline of 193 ml/s (95% CI: -258 to - 43) in peak expiratory flow (PEF), a decline of 0.932% (95% CI: -1.518 to - 0.342) in maximal mid-expiratory flow (MMEF); an increase of 0.732 Hz (95% CI: 0.313 to 1.148) in resonant frequency (Fres), an increase of 36 kpa/(ml/s) (95% CI: 14 to 57) in impedance at 5 Hz (Z5) and an increase of 31 kpa/(ml/s) (95% CI: 2 to 54) in respiratory impedance at 5 Hz (R5). Compared to patients in the central district, those in the southern district had lower FEV1/FVC, FEV1%pred, PEF, FEF75%, MMEF, X5, and higher Fres, Z5 and R5 (p < 0.05). CONCLUSION: Short-term exposure to PM2.5 was associated with reductions in lung function indices and an increase in IOS results in patients with COPD. The heavier the PM2.5, the more severe of COPD.

The relationship between frailty and community-acquired pneumonia in older patients.

PURPOSES: To explore the relationship between frailty and community-acquired pneumonia (CAP) in older patients. METHODS: A prospective observational study included 109 older patients(≥ 65 years) hospitalized with CAP in respiratory department of Fuxing hospital, Capital Medical University from June 2018 to December 2020. Frailty scores(Frail Scale, range 0-5) and pneumonia severity CURB-65 scale(mild = 1, modest = 2, and severe ≥ 3) were measured. We extracted clinical variables including white blood cell(WBC), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein(CRP), hemoglobin, and albumin. Charlson Comorbidity Index(CCI) was calculated as well. The correlations between the variables and frailty scores were investigated, respectively. After adjusting for covariates, binomial logistic regression analysis was used to assess independent effect of frailty scores on the outcome(discharge or death/progression) in older CAP patients. RESULTS: The subjects had a median age 87(interquartile range,8.5) years, 60.6% male, 45.9% pre-frail, and 32.1% frail. There were positive correlations between frailty scores and CURB-65 scale (p = 0.000, r = 0.542), CCI(p = 0.000, r = 0.359) and NLR(p = 0.005, r = 0.268). Negative correlations were observed between frailty scores and hemoglobin (p = 0.002, r = - 0.298), albumin (p = 0.000, r = - 0.465). In multivariable logistic regression analysis, the factors associated with discharge or death/progression of CAP were frailty scores (OR = 1.623, p = 0.037), NLR (OR = 1.086, p = 0.008) and albumin (OR = 0.869, p = 0.034). CONCLUSIONS: Frailty is correlated with CURB-65 scale, CCI and hemoglobin, and albumin in older patients with CAP. Frailty is also a correlate of increased risk for death or progression in these older people.

Theaflavin-3,3'-Digallate Inhibits Erastin-Induced Chondrocytes Ferroptosis via the Nrf2/GPX4 Signaling Pathway in Osteoarthritis.

There is evidence that osteoarthritis (OA) is associated with ferroptosis which is a kind of lipid peroxidation-related cell death. Theaflavin-3,3'-digallate(TF3), a polyphenol compound extracted from black tea, possesses antioxidative and anti-inflammatory properties, but its effects on chondrocyte ferroptosis in osteoarthritis (OA) remain unclear. Our present study aims at exploring the protective role and underlying mechanisms of TF3 against erastin-induced chondrocyte ferroptosis in OA. In human primary chondrocytes treated with erastin alone or combined with different doses of TF3, cell viability was assessed by MTS. Ferroptosis-related proteins, including Gpx4, HO-1, and FTH1, were detected by western blot. The levels of lipid peroxidation and Fe2+ were determined by fluorescence staining. Meanwhile, the change of related proteins in the Nrf2/Gpx4 signaling pathway was determined by western blot. siRNA-mediated Nrf2 knockdown and the Gpx4 inhibitor RSL3 were used to explore molecular mechanisms for TF3-induced ferroptosis in OA chondrocyte. The magnetic resonance imaging (MRI), HE staining, Masson's staining, and immunohistochemistry were used to evaluate articular cartilage damages in the rat OA model. The results showed that Gpx4 expression was markedly downregulated in the chondrocytes of OA patients. TF3 reversed erastin-induced ferroptosis of human cultured chondrocytes, lipid ROS, and Fe2+ production in mitochondria. Moreover, the expression of Gpx4, HO-1, FTH1, and Nrf2 was markedly induced by TF3 in the erastin-treated chondrocytes. The antiferroptotic effect of TF3 was related to enhance Nrf2/Gpx4 signaling pathway. Finally, TF3 inhibited OA progression by alleviating in vivo cartilage damage related to chondrocyte ferroptosis. Thus, TF3 significantly inhibits chondrocyte ferroptosis by activating the Nrf2/Gpx4 signaling pathway, suggesting that TF3 serves as a potential therapeutic supplement for OA treatment.

Dose-response meta-analysis on urate, gout, and the risk for Parkinson's disease.

The relationship between Parkinson's disease (PD) and urate or gout has attracted significant interest in recent years, but the results were conflicting. This dose-response meta-analysis aimed to estimate the correlation between urate levels or gout and the risk for PD. The Embase, PubMed, and Medline databases were searched for studies that investigated the relationship between the risk for PD and urate levels or gout. Random-effects or fixed-effects models were used to obtain pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs). Fifteen studies, involving 449,816 participants and 14,687 cases in total, were included in the meta-analysis. High serum urate levels were associated with decreased risk for PD (RR 0.44 [95% CI 0.32-0.55]). Subgroup analysis according to sex revealed a neuroprotective effect of high urate levels against PD among females (0.68 [95% CI 0.43-0.93]) and males (0.49 [95% CI 0.34-0.64]). The risk for PD was lowered by 6% (0.94 [95% CI 0.90-0.98]) for each 1 mg/dl increase in serum urate level and reduced by 13% (0.87 [95% CI 0.80-0.95]) with each 2 mg/dl increase in serum urate level. However, gout was not closely correlated with the risk for PD (0.97 [95% CI 0.85-1.09]). Higher serum urate levels reduced the risk for PD, which was decreased by 6% (relative risk reduction) for each 1 mg/dl increase in serum urate levels. And the results indicated that urate may exert protective effects against the development of PD.

Role of diet in stroke incidence: an umbrella review of meta-analyses of prospective observational studies.

BACKGROUND: Stroke is one of the major challenges for the global healthcare system, which makes it necessary to explore the relationship between various modifiable factors and stroke risk. Recently, numerous meta-analyses of prospective observational studies have reported that dietary factors played a key role in the occurrence of stroke. However, the conclusions of previous studies have remained controversial and unclear. Accordingly, we conducted an umbrella review synthesizing and recalculating available evidence to assess the certainty of the associations between dietary factors and stroke. METHODS: Relevant meta-analyses examining the associations between dietary factors and stroke were searched in PubMed and Embase databases up to September 1, 2021. For each eligible meta-analysis, two independent reviewers appraised the methodologic quality using the AMSTAR 2 criteria and estimated the summary effect size, 95% confidence intervals, 95% prediction intervals, heterogeneity between studies, and small-study effects. Moreover, we further assessed the associations between dietary factors and ischemic stroke as well as hemorrhagic stroke. Lastly, a set of pre-specified criteria was applied to qualitatively evaluate the epidemiological credibility of each dietary factor. RESULTS: Overall, our umbrella review included 122 qualified meta-analyses for qualitative synthesis, involving 71 dietary factors related to food groups, foods, macronutrients, and micronutrients. Using the AMSTAR 2 criteria, 5 studies were assessed as high quality, 4 studies as moderate quality, and 113 studies as low or critically low quality. We identified 34 dietary factors associated with stroke occurrence, 25 dietary factors related to ischemic stroke, and 11 factors related to hemorrhagic stroke. Among them, high/moderate certainty epidemiological evidence demonstrated an inverse association between intake of fruits (RR: 0.90) and vegetables (RR: 0.92) and stroke incidence, but a detrimental association between red meat (RR: 1.12), especially processed red meat consumption (RR:1.17), and stroke incidence. Besides, the evidence of high/moderate certainty suggested that the intake of processed meat, fruits, coffee, tea, magnesium, and dietary fiber was associated with ischemic stroke risk, while consumption of tea, fruits, and vegetables was relevant to hemorrhagic stroke susceptibility. CONCLUSIONS: Our study has reported that several dietary factors have a significant impact on stroke risk and offered a new insight into the relationship between dietary modification and stroke occurrence. Our results may provide an effective strategy for stroke prevention.

Circulating Non-coding RNAs as Potential Biomarkers for Ischemic Stroke: A Systematic Review.

BACKGROUND: Recent studies have demonstrated that dysregulated non-coding RNAs (ncRNAs) are involved in the pathogenesis of ischemic stroke (IS), including neuroinflammation, apoptosis, atherosclerosis, and angiogenesis. However, discrepant results make it difficult to apply ncRNAs to clinical practice. Therefore, we performed a meta-analysis to evaluate and elucidate the diagnostic value of ncRNAs in IS. METHODS: We searched the literature in four databases-PubMed, Web of Science, EMBASE, and the Cochrane Library-up to December 31, 2020, to identify the relationship between differentially expressed ncRNAs and IS. Pooled sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the diagnostic performance of ncRNAs. RESULTS: Fifteen studies on microRNAs (miRNAs) including 1687 IS patients and eight studies on long non-coding RNAs (lncRNAs) including 741 IS patients were included in our study. Estimates of the identification efficiency of miRNAs from the 15 studies were as follows: 0.76 (95% CI: 0.67-0.84) for sensitivity (SEN), 0.83 (95% CI: 0.77-0.88) for specificity (SPE), 4.5 (95% CI: 3.4-6.1) for PLR, 0.29 (95% CI: 0.20-0.40) for NLR, and 16 (95% CI: 10-26) for DOR. The area under the curve (AUC) of the summary receiver operator characteristic (SROC) curve showed diagnostic accuracy of 0.87 (95% CI: 0.84-0.90); thus the diagnostic value of all the miRNAs was moderate. In addition, the results for lncRNAs were as follows: 0.73 (95% CI: 0.69-0.77) for SEN, 0.75 (95% CI: 0.70-0.79) for SPE, 2.9 (95% CI: 2.4-3.4) for PLR, 0.36 (95% CI: 0.31-0.42) for NLR, 8 (95% CI: 6-11) for DOR, 0.80 (95% CI: 0.76-0.83) for AUC, and a moderate diagnostic value. CONCLUSION: Our study revealed that blood-circulating ncRNAs could be a moderately effective candidate biomarker for the diagnosis of IS. Furthermore, the combined lncRNAs showed more accurate diagnostic properties than single lncRNAs, and some single miRNAs (e.g., miR-107) showed better diagnostic performance, which may contribute to IS clinical practice.

Genetically Predicted Levels of Circulating Inflammatory Cytokines and the Risk and Age at Onset of Parkinson's Disease: A Two-Sample Mendelian Randomization Study.

Parkinson's disease (PD) is widely considered to be a disabling neurodegenerative disorder, which has been ranked second worldwide just after Alzheimer's disease. Until present, a wide range of studies has focused on the role of circulating inflammatory cytokines in the development of PD. However, the causal relationship between circulating inflammatory cytokines and the risk and age at the onset of PD has not been elucidated. Hence, to evaluate the effects of circulating inflammatory cytokines on the risk or age at the onset of PD more accurately, we conducted this two-sample Mendelian randomization (MR) study involving summary statistics from genome-wide association studies (GWASs). Totally, we included a GWAS for inflammatory cytokines (8,293 participants), a meta-analysis of GWASs for PD risk (482,730 participants), and a GWAS dataset for age at the onset of PD (17,996 patients with PD). A total of 149 and 131 polymorphisms for exploring relationships between 19 inflammatory cytokines and the risk and age at the onset of PD were obtained as instrumental variants. Then, we used a total of five MR methods, including inverse-variance weighted (IVW), Wald ratio, MR Egger regression, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Finally, we found a causal association between circulating levels of macrophage inflammatory protein-1 beta (MIP1b) and PD risk in the IVW method (OR: 1.06; 95% CI: 1.02-1.10; P = 0.001). Meanwhile, other MR estimates by weighted median and MR-PRESSO methods yielded similar effect estimates. Besides, we identified a suggestive association of interleukin-16 (IL-16) levels with PD risk (OR: 1.08; 95% CI: 1.00-1.17; P = 0.037). For age at PD onset, there was no evidence supporting its correlation with inflammatory cytokines. Our findings implied that MIP1b and IL-16 may be novel biomarkers and promising therapeutic targets for PD development.

Role of N6-methyladenosine modification in pathogenesis of ischemic stroke.

INTRODUCTION: N6-Methyladenosine (m6A), the most common and reversible mRNA modification, has attracted considerable attention recently, and accumulating evidence indicates it has an important role in the progression of ischemic stroke (IS). AREAS COVERED: We first reviewed m6A methylation modification enzymes, including m6A methyltransferases (METTL3, METTL14, and WTAP), demethylases (FTO and ALKBH5), m6A-binding proteins (YTH domain containing 1/2 [YTHDC1/2], YTHDF1/2/3, and insulin like growth factor 2 mRNA binding protein 1/2/3 [IGF2BP1/2/3]), and their-related functions. An alteration in the m6A methylation profile of IS has been reported and m6A is differentially expressed in IS. Thus, we then focused on the underlying mechanism of m6A methylation in IS and the involvement of atherosclerosis (AS), cerebral ischemia/reperfusion (IR) injury, inflammation, oxidative stress, and apoptosis. Furthermore, we also elucidated the effect of m6A-associated single-nucleotide polymorphisms (SNPs) on stroke and uncovered new causal variants for IS. The clinical application of m6A targeting drugs is still in its infancy and will be available in the future. EXPERT OPINION: Collectively, the information in the present review is a summary of the latest developments in m6A modification and highlights the mechanisms underlying IS pathogenesis, which may provide novel insights into the mechanisms and therapeutic targets for IS.

Lipid levels and the risk of dementia: A dose-response meta-analysis of prospective cohort studies.

OBJECTIVES: We performed a dose-response meta-analysis to estimate the association between lipid profiles with the risk of dementia and the potential differences according to the subtype of dementia based on prospective studies. METHODS: We searched PubMed, Embase and Web of Science for relevant articles and performed a meta-analysis. We applied fixed or random-effects models to calculate pooled relative risk (RR) with their 95% confidence intervals (CI). The dose-response relationship was assessed by restricted cubic spline. RESULTS: Twenty-five prospective studies comprising 362,443 participants and 20,121 cases were included in the final analysis. We found that increased risk of all-cause dementia could be predicted by elevated total cholesterol (TC) (RR = 1.13, 95% CI 1.04-1.22). When looking at dementia subtypes, we also observed high TC and triglycerides (TG) may increase the future risk of Alzheimer's disease (AD), with a pooled RR of 1.13 (95% CI: 1.06-1.21) and 1.10 (95% CI: 1.04-1.15) respectively. Moreover, a dose-response analysis revealed a linear association between TC or TG and the risk of AD, with a pooled RR of 1.09 (95% CI: 1.02-1.16) and 1.12 (95% CI: 1.05-1.21) for per 3-mmol/L increment in TC and TG, respectively. CONCLUSIONS: Current evidence suggest that every 3-mmol/L increase in blood TC or TG is linearly associated with a 9% or 12% increase in RR of AD, supporting the notion that high TC and TG levels appear to play a causal role in the development of AD.

Neurodegeneration and Glial Activation Related CSF Biomarker as the Diagnosis of Alzheimer's Disease: A Systematic Review and an Updated Meta- analysis.

OBJECTIVE: Recently, neuron specific enolase (NSE), Visinin-like protein-1 (VLP-1), neurogranin (Ng), and YKL-40 have been identified as candidates for neuronal degeneration and glial activation biomarkers. Therefore, we perform a comprehensive meta-analysis to assess the diagnostic value of CSF NSE, VLP-1, Ng and YKL-40 in Alzheimer's disease (AD). METHODS: We searched Pubmed, MEDLINE, EMBASE databases for research about the levels of CSF NSE, VLP-1, Ng and YKL-40 in AD patients compared with controls or other dementia diseases until Dec 2020. RESULTS: The present meta-analysis contained a total of 51 studies comprising 6248 patients with dementia disorders and 3861 controls. Among them, there were 3262 patients with AD, 2456 patients with mild cognitive impairment (MCI), 173 patients with vascular dementia (VaD), 221 patients with frontotemporal dementia (FTD), and 136 with Lewy bodies dementia (DLB). Our study demonstrated that CSF NSE, VLP-1, Ng and YKL-40 levels were increased in AD as compared to healthy controls. We also observed that the CSF NSE level was higher in AD than VaD, suggesting CSF NSE might act as a key role in distinguishing between AD and VaD. Interestingly, there was a higher VLP-1 expression in AD, and a lower expression in DLB patients. Moreover, we found the CSF Ng level was increased in AD than MCI, implying CSF Ng might be a biomarker for identifying the progression of AD. Additionally, a significantly higher CSF YKL-40 level was detected not only in AD, but also in FTD, DLB, VaD, signifying YKL-40 was not sensitive in the diagnosis of AD. CONCLUSION: Our study confirmed that CSF levels of NSE, VLP-1, and Ng could be valuable biomarkers for identifying patients who are more susceptible to AD and distinguishing AD from other neurodegenerative dementia disorders.

Investigating the causality of metabolites involved in one-carbon metabolism with the risk and age at onset of Parkinson's disease: A two-sample mendelian randomization study.

With the aging population and increasing life expectancy, Parkinson's disease (PD), a neurological disorder rapidly increasing in morbidity and mortality, is causing a huge burden on society and the economy. Several studies have suggested that one-carbon metabolites, including homocysteine, vitamin B6, vitamin B12 and folate acid, are associated with PD risk. However, the results remain inconsistent and controversial. Thus, we performed a two-sample Mendelian randomization (MR) study to detect the causality between one-carbon metabolites and PD susceptibility as well as age at PD onset. We collected several genetic variants as instrumental variables from large genome-wide association studies of one-carbon metabolites (homocysteine: N = 14, vitamin B6: N = 1, vitamin B12: N = 10, folate acid: N = 2). We then conducted MR analyses using the inverse variance-weighted (IVW) approach and additional MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods to further test causality. The results showed no causal association between circulating homocysteine levels and PD risk (p = 0.868) or age at PD onset (p = 0.222) with the IVW method. Meanwhile, similar results were obtained by three complementary analyses. In addition, we did not observe any evidence that the circulating levels of vitamin B6, vitamin B12 and folate acid affected the risk of PD or age at onset of PD. Our findings implied that lowering homocysteine levels through vitamin B6, vitamin B12 or folate acid supplementation may not be clinically helpful in preventing PD or delaying the age at PD onset.

Inflammation-Related circRNA Polymorphism and Ischemic Stroke Prognosis.

CircRNAs belong to a novel class of noncoding RNAs that are generated by exons of genes by alternative mRNA splicing and involved in pathophysiological processes of ischemic stroke by regulating neuro-inflammation. A total of 982 patients were enrolled in our study for stroke recovery analysis. The aim of our study was to first explore the association between the inflammation-related circRNA polymorphism and functional outcome 3 months after ischemic stroke by using multivariate logistic regression model. Next, we further investigated the role of circRNA polymorphism in predicting stroke recurrence by using Cox proportional hazard regression model. Five circRNA polymorphisms were genotyped by using polymerase chain reaction and ligation detection reaction method. We identified circ-STAT3 (signal transducer and activator of transcription) rs2293152 GG genotype to be associated with poorer recovery 90 days after stroke (OR = 1.452, 95% CI: 1.165-4.362, p = 0.016). After adjusting for confound factors, the association for rs2293152 with 3 months outcome after IS was stronger, suggesting a mechanism that rs2293152 is an independent risk factor for stroke recovery (OR = 2.255, 95% CI: 1.034-2.038, p = 0.031). However, no other circRNA polymorphisms (circ-DLGAP4 rs41274714, circ-TRAF2 rs10870141, circ-ITCH rs10485505, rs4911154) were associated with functional outcome 3 months after stroke in any genetic models. Subgroup analysis revealed that the negative effect of rs2293152 GG genotype was greater in female and older patients, subjects with history of hypertension. Additionally, all the circRNA polymorphisms were not correlated with recurrent risk of ischemic stroke. Our results indicated that circ-STAT3 might be a novel biomarker for predicting functional outcome after stroke and an important contributor to the ischemic stroke recovery.

GWAS-linked hot loci predict short-term functional outcome and recurrence of ischemic stroke in Chinese population.

In the past decade, an increasing number of genome-wide association studies (GWASs) have been applied to ischemic stroke (IS) susceptibility and recovery. In our study, six GWAS-linked hot loci (ALDH2 rs10744777, HDAC9 rs2107595, ABO rs532436, PATJ rs76221407, LOC105372028 rs1842681 and PTCH1 rs2236406) were selected, genotyped and analyzed in 982 IS patients from northern Chinese population, in order to explore their roles in stroke functional outcome and recurrence risk. We found that PTCH1 rs2236406 was significantly associated with functional outcome after stroke. Further logistic regression analysis revealed the variant genotype TC/CC of rs2236406 as an independent prognostic factor for poor stroke recovery in Chinese population. Meanwhile, we observed that GA/AA genotype of ABO rs532436 was statistically correlated with the increased risk of stroke recurrence, especially for patients with large-artery atherosclerosis. Moreover, multivariate Cox analysis identified ABO rs12342 as an independent predictor for IS recurrence. Further functional annotation analysis demonstrated that rs2236406 and rs2043211 were located in the transcriptionally active region, and could change the regulatory motif, transcription factor binding capacity and expression level of RP11-435O5.5 (antisense to PTCH1) and ABO, respectively. In summary, our results suggested that PTCH1 rs2236406 and ABO rs532436 may be novel genetic markers and potential therapeutic targets for stroke prognosis. More studies are required to confirm our findings and clarify the underlying molecular mechanisms.

Homocysteine and Folic Acid: Risk Factors for Alzheimer's Disease-An Updated Meta-Analysis.

Background: Recent studies have reported that homocysteine (Hcy) may play a vital role in the pathogenesis of vascular dementia (VaD) and Alzheimer's disease (AD). Our study explored the relationship between the plasma Hcy and folate levels and the risk of dementia. Methods: We searched Embase, PubMed, and Web of Science for published literature, including case-control studies and prospective cohort studies, and performed a systematic analysis. Results: The results of our meta-analysis, consisting of case-control studies, showed higher levels of Hcy and lower levels of folate in dementia, AD, and VaD patients than those in non-demented controls (for dementia: SMD = 0.812, 95% CI [0.689, 0.936], p = 0.000 for Hcy; SMD = -0.677, 95% CI [-0.828, -0.525], p = 0.000 for folate). AD patients showed significantly lower plasma Hcy levels compared to VaD patients (SMD = -0.278, 95% CI [-0.466, -0.09], p = 0.000). Subgroup analysis revealed that ethnicity, average age, and dementia type had no significant effect on this association. Furthermore, from the analysis of prospective cohort studies, we identified that elevated plasma Hcy levels were associated with an increased risk of dementia, AD, and VaD (RRdementia = 1.22, 95% CI [1.08, 1.36]; RRAD = 1.07, 95% CI [1.04, 1.11]; RRVaD = 1.13, 95% CI [1.04, 1.23]). In addition, every 5 µmol/L increase in the plasma Hcy level was associated with a 9% increased risk of dementia and a 12% increased risk of AD. Conclusion: Hcy and folic acid are potential predictors of the occurrence and development of AD. A better understanding of their function in dementia could provide evidence for clinicians to rationalize clinical intervention strategies.