N-acetyl-L-leucine protects MPTP-treated Parkinson's disease mouse models by suppressing Desulfobacterota via the gut-brain axis.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and communication between the gut and brain (the gut-brain axis) has been found to be essential in behavior and cognitive function. However, the exact mechanisms underlying microbiota dysbiosis in PD progression have not yet been elucidated. Our study aimed to investigate the correlation between gut microbiota disturbances and feces metabolic disorders in PD. We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD models and observed mice's motor symptoms, dopaminergic (DA) neuron death, and gastrointestinal dysfunction. To identify alterations in microbiota and metabolome, feces were collected from mice and analyzed using 16 S ribosomal RNA sequencing feces metabolomics. Pearson analysis was utilized to investigate correlations between the abundances of gut microbiota components and the levels of gut microbiota metabolites, displaying their interaction networks. Our findings revealed a significant increase in Desulfobacterota in the PD mouse model and 151 differentially expressed fecal metabolites between PD and vehicle mice. Moreover, Pearson correlation analysis suggested that the protective factor N-acetyl-L-leucine (NALL) may be associated with neuroinflammation in the striatum and substantia nigra, which also had a negative relationship with the concentration of Desulfobacterota. Additionally, we found that oral administration of NALL alleviated MPTP-induced Motor Impairments and DA neuronal deficits. All in all, we concluded that the decrease of NALL might lead to a significant increase of Desulfobacterota in the MPTP model mouse and subsequently result in the damage of DA neurons via the gut-brain aix pathway.

Retracted Article: LncRNA MALAT1 aggravates MPP-induced neuronal injury by regulating miR-212 in SH-SY5Y cells.

Parkinson's disease (PD) is the most common neurodegenerative disease and its incidence is rising. Long noncoding RNAs (lncRNAs) have been reported to have essential roles in development of PD. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is dysregulated in PD, while the role of MALAT1 and its mechanism in PD remain poorly understood. In this study, SH-SY5Y cells were exposed to 1-methyl-4-phenylpyridinium (MPP+) to induce a PD model in vitro. Then we explored the effect of MALAT1 on cell viability, apoptosis and inflammatory response as well as its interaction with miR-212 in MPP+-treated SH-SY5Y cells. The results showed that MALAT1 was up-regulated in MPP+-treated SH-SY5Y cells compared with that in the normal group. Overexpression of MALAT1 exacerbated MPP+-induced neuronal injury, uncovered by inhibition of cell viability and increase of cell apoptosis as well as inflammatory cytokine expressions in SH-SY5Y cells. However, knockdown of MALAT1 exerted the opposite effect in MPP+-treated SH-SY5Y cells. Moreover, MALAT1 was bound to miR-212 and negatively regulated the miR-212 level. Furthermore, addition of miR-212 ablated the regulatory effect of MALAT1 on MPP+-induced neuronal injury, as indicated by restoration of cell viability and lower apoptotic rate along with inflammatory cytokine levels in SH-SY5Y cells. Therefore, we concluded that MALAT1 exacerbated MPP+-induced neuronal injury through regulating cell viability, apoptosis and inflammatory cytokines by sponging miR-212, providing a novel theoretical foundation for application of MALAT1 in PD.

[Influence of CYP2C19 gene polymorphisms on the efficacy of clopidogrel treatment for the prevention of ischemic stroke following coronary stent implantation].

OBJECTIVE: To assess the association of CYP2C19 gene polymorphisms with the incidence of ischemic stroke among patients receiving clopidogrel therapy following coronary stenting for coronary artery disease. METHODS: Clinical data of patients receiving clopidogrel therapy after coronary stenting were retrospectively studied. For a case-control study, 137 patients with acute cerebral infarction and 122 non-stroke patients were selected. Based on the variants of the CYP2C19 gene detected by a DNA microarray assay, the patients were further divided into the wild-type group(CYP2C19*1/*1) and mutant group(defined by the presence of at least one loss-of-function allele, including CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*2, CYP2C19*2/*3 and CYP2C19*3/*3). The incidences of ischemic stroke in the two groups were compared through a chi-square analysis. The influence of CYP2C19 gene polymorphisms and clopidogrel therapy on the incidence of ischemic stroke was analyzed through multivariable logistic regression. RESULTS: A total of 259 patients were enrolled. The case and control groups showed no difference in terms of gender and age. There were 123 cases (47.5%) in the CYP2C19 wild-type group and 136 cases (52.5%) in the mutant group. The incidence of ischemic stroke of mutant group was significantly higher than that of wild-type group (59.9% vs. 44.3%, X2=6.398, P=0.042). Multivariate analysis revealed that loss-of-function polymorphisms of the CYP2C19 gene carried a 1.13 times greater risk for ischemic stroke compared to wild-type genotype (OR=2.13, 95%CI: 1.23-3.71). CONCLUSION: The efficacy of clopidogrel for the prevention of ischemic stroke in post-coronary stent patients may be reduced by the insufficiency of the CYP2C19 gene. The dosage of clopidogrel therapy should be adjusted based on its polymorphisms.

Elevated Plasma Homocysteine Level Increased the Risk of Early Renal Impairment in Acute Ischemic Stroke Patients.

Renal insufficiency is associated with the prognosis of acute ischemic stroke (AIS) and homocysteine (Hcy) levels. This study investigated the association between plasma Hcy levels and renal insufficiency in patients with AIS. A total of 987 patients with AIS who had been treated at the First People's Hospital of Foshan between 2011 and 2014 were retrospectively studied. Based on their cystatin C (Cys C) levels, the patients were divided into the normal renal function group (Cys C ≤ 1.25 mg/L) or the renal impairment group (Cys C > 1.25 mg/L). Multivariate regression analysis was applied to reveal the association between hyperhomocysteinemia (HHcy) and renal impairment. The renal impairment group showed more advanced age of onset, higher percentage of prior stroke and hypertension, higher baseline National Institute of Health Stroke Scale score, lower high-density lipoprotein cholesterol levels, and higher Hcy levels compared with the normal renal function group. A multivariate analysis revealed a relationship between early renal impairment and Hcy levels: an increase of Hcy by 1 µmol/L was associated with an increase of 12-18% of the risk of renal impairment among patients with AIS and HHcy. Patients with AIS and HHcy had a 2.42-3.51 fold increase of the risk of renal impairment compared with patients with normal Hcy level (P < 0.001). In conclusion, patients with stroke and HHcy could be more prone to renal impairment.

Nitric oxide-mediated immunosuppressive effect of human amniotic membrane-derived mesenchymal stem cells on the viability and migration of microglia.

Human amniotic membrane-derived mesenchymal stem cells (AMSCs) are considered a novel and promising source of stem cells for cell replacement-based therapy. Current research is mostly limited to investigating the cellular differentiation potential of AMSCs, while few have focused on their immunosuppressive properties. This study is aimed at exploring and evaluating the immunosuppressive effect of human AMSCs on the viability and migratory properties of microglia. We found, from results of cell viability assays, that AMSCs can reduce the activity of inflammatory cells by secreting nitric oxide (NO). Also, based on results from wound healing and transwell migration assays, we show that AMSCs can inhibit the migration of human microglia as well as the mouse microglial cell line BV2, suggesting that they have the ability to inhibit the recruitment of certain immune cells to injury sites. Furthermore, we found that NO contributes significantly to this inhibitory effect. Our study provides evidence that human AMSCs can have detrimental effects on the viability and migration of microglia, through secretion of NO. This mechanism may contribute to anti-inflammatory processes in the central nervous system.

Relationship between interleukin-10 -1082A/G polymorphism and risk of ischemic stroke: a meta-analysis.

OBJECTIVE: To analyze the association between -1082A/G polymorphism in interleukin-10 (IL-10) gene and ischemic stroke (IS) risk by meta-analysis. METHODS: We carried out a systematic electronic search in PubMed, BIOSIS Previews, Science Direct, Chinese National Knowledge Infrastructure, Chinese Biomedical Database, Weipu database and WANGFANG Database. Pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated to assess the strength of the association. RESULTS: 7 studies were included. There was no significant association between IL-10 -1082A/G polymorphism and IS risk under all genetic models in overall estimates (A vs. G: OR = 1.23,95%CI = 0.85-1.79;AA vs. GG: OR = 1.01,95%CI = 0.47-2.19; AG vs. GG: OR = 0.76, 95%CI = 0.38-1.55; AA+AG vs. GG: OR = 0.89,95%CI = 0.46-1.73; AA vs. AG+GG: OR = 1.39, 95%CI = 0.91-2.13). Similarly, no associations were found in subgroup analysis based on ethnicity and source of controls. However, removing the study deviating from Hardy-Weinberg equilibrium (HWE) produced statistically significant associations for overall estimates under recessive model(AA VS. AG+GG OR 1.58, 95% CI 1.04-2.42) and among Asians in all genetic models (A VS.G OR 1.64, 95% CI 1.07-2.53; AA vs. GG OR1.91, 95% CI 1.31-2.80; AG vs. GG OR1.44, 95% CI 1.09-1.91; AA+AG vs. GG OR 1.54, 95% CI 1.18-2.01;AA VS. AG+GG OR 1.79, 95% CI 1.07-3.00). Even after Bonferroni correction, the associations were observed still significantly in Asians under the two models (AA vs. GG OR1.91, 95% CI 1.31-2.80, P = 0.0008; AA+AG vs. GG OR 1.54, 95% CI 1.18-2.01, P = 0.001). CONCLUSION: This meta-analysis indicates that IL10 -1082 A/G polymorphism is associated with IS susceptibility in Asians and the -1082 A allele may increase risk of IS in Asians. Considering the sample size is small and between-study heterogeneity is remarkable, more studies with subtle design are warranted in future.

Association between transforming growth factor-beta 1 T869C polymorphism and ischemic stroke: a meta-analysis.

OBJECTIVE: To explore the association between transforming growth factor-beta1 (TGF-ß1) T869C polymorphism and risk of ischemic stroke (IS) by performing a meta-analysis based on published articles. METHODS: Systematic electronic searches of PubMed, Science Direct, BIOSIS Previews, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, and WANFANG Database were performed. The strength of the association was calculated by pooled odds ratios (ORs) with 95% confidence intervals (95%CIs). Subgroup analysis was conducted to explore potential sources of heterogeneity. Sensitivity analysis was performed to elucidate the stability of the outcomes. Publication bias was evaluated by Begg's funnel plot and Egger's test. RESULTS: A total of 6 studies involving 1701 cases were included. The overall estimates did not show any significant association between TGF-ß1 T869C polymorphism and risk of IS under all genetic models (C vs. T: OR = 1.08,95%CI = 0.88-1.32; CC vs. TT:OR = 1.17,95%CI = 0.79-1.72; CT vs. TT: OR = 0.91, 95%CI = 0.68-1.22; CC+CT vs. TT: OR = 0.99, 95%CI = 0.73-1.35; CC vs. CT+TT: OR = 1.23, 95%CI = 0.95-1.59). Similar lacking associations were observed in subgroup analysis based on ethnicity and source of controls. When stratified by study design, significant increased association of IS risk was found in cohort studies under genetic models except recessive model(C vs. T: OR = 1.18, 95%CI = 1.05-1.32; CC vs. TT: OR = 1.40, 95%CI = 1.10-1.77; CT vs. TT: OR = 1.23, 95%CI = 1.02-1.49; CC+CT vs. TT: OR = 1.27, 95%CI = 1.03-1.57; CC vs. CT+TT, OR = 1.21, 95%CI = 0.99-1.47), whereas in case-control studies a significant decreased risk was detected under heterozygote comparison(CT vs. CC: OR = 0.72, 95%CI = 0.57-0.92). However, after correction for multiple testing, the associations were observed to be null significant in both cohort and case-control subgroups among all genetic models. CONCLUSION: This meta-analysis suggested that current epidemiological studies of TGF-ß1 T869C polymorphism are too inconsistent to draw a conclusion on the association with IS susceptibility. Given the small sample size and remarkable between-study heterogeneity, further well-designed prospective large-scale studies are warranted.

Bone marrow-derived mesenchymal stem cells maintain the resting phenotype of microglia and inhibit microglial activation.

Many studies have shown that microglia in the activated state may be neurotoxic. It has been proven that uncontrolled or over-activated microglia play an important role in many neurodegenerative disorders. Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown in many animal models to have a therapeutic effect on neural damage. Such a therapeutic effect is attributed to the fact that BMSCs have the ability to differentiate into neurons and to produce trophic factors, but there is little information available in the literature concerning whether BMSCs play a therapeutic role by affecting microglial activity. In this study, we triggered an inflammatory response situation in vitro by stimulating microglia with the bacterial endotoxin lipopolysaccharide (LPS), and then culturing these microglia with BMSC-conditioned medium (BMSC-CM). We found that BMSC-CM significantly inhibited proliferation and secretion of pro-inflammatory factors by activated microglia. Furthermore, we found that the phagocytic capacity of microglia was also inhibited by BMSC-CM. Finally, we investigated whether the induction of apoptosis and the production of nitric oxide (NO) were involved in the inhibition of microglial activation. We found that BMSC-CM significantly induced apoptosis of microglia, while no apoptosis was apparent in the LPS-stimulated microglia. Our study also provides evidence that NO participates in the inhibitory effect of BMSCs. Our experimental results provide evidence that BMSCs have the ability to maintain the resting phenotype of microglia or to control microglial activation through their production of several factors, indicating that BMSCs could be a promising therapeutic tool for treatment of diseases associated with microglial activation.