Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.

INTRODUCTION: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels. METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders. RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings. CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.

The inhibition of ORMDL3 prevents Alzheimer's disease through ferroptosis by PERK/ATF4/HSPA5 pathway.

Alzheimer's disease (AD) is a neurodegenerative disease with high incidence and widespread attention. There is currently no clear clarification of the pathogenesis. However, ORMDL3 causes ferroptosis in AD, and the potential mechanisms remain unclear. So, this study explore the function of ORMDL3 on ferroptosis in AD and its potential regulatory mechanisms. APPswe/PS1dE9 mice and C57BL/6 mice were induced into the mice model. The murine microglial BV-2 cells also were induced into the vitro model. In serum samples of AD patients, ORMDL3 mRNA expression levels were upregulated. The serum ORMDL3 levels expression was positively related to the ADL score or MoCA score in AD patients. The serum ORMDL3 expression level was positively related to MMSE score or Hcy levels in AD patients. The mRNA expression of ORMDL3 in the hippocampal tissue of the mice model of AD was upregulated at one, four and eight months. The protein expression of ORMDL3 was upregulated in the mice model of AD. ORMDL3 promoted Alzheimer's disease, and increased oxidative response and ferroptosis in a model of AD. PERK/ATF4/HSPA5 pathway is one important signal pathway for the effects of ORMDL3 in a model of AD. Collectively, these data suggested that ORMDL3 promoted oxidative response and ferroptosis in a model of AD by the PERK/ATF4/HSPA5 pathway, which might be a novel target spot mechanism of ferroptosis in AD and may serve as a regulator of AD-induced ferroptosis.

Comparative Efficacy and Acceptability of Cholinesterase Inhibitors and Memantine Based on Dosage in Patients with Vascular Cognitive Impairment: A Network Meta-analysis.

BACKGROUND: Considering the lack of direct comparison between cholinesterase inhibitors and memantine in patients with vascular cognitive impairment (VCI), determining how to choose the best treatment plan remains inconclusive. Hence, we conducted the network meta-analysis to compare the efficacy and acceptability of these drugs. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, Embase and Web of Science were searched for double-blind randomized controlled trials (RCTs) for the treatment of VCI, which involved donepezil, galantamine, rivastigmine, and memantine, from database inception to January 1, 2020. Then, a network meta-analysis based on the frequency method was conducted. RESULTS: Eleven RCTs were included. Compared with the placebo, in terms of efficacy, donepezil 5 mg (standardized mean difference = -1.11, 95% confidence interval = -1.88 to -0.34), donepezil 10 mg (-1.44, -2.31 to -0.56), galantamine 24 mg (-1.99, -3.03 to -0.95), and memantine 20 mg (-1.89, -2.93 to -0.86) were more effective for the cognition of ADAS-cog, and donepezil 5 mg (0.46, 0.12 to 0.81), donepezil 10 mg (0.76, 0.34 to 1.17), and rivastigmine 12mg (0.60, 0.10 to 1.10) exhibited superior benefits for the cognition of MMSE. Donepezil 10 mg (-0.25, -0.44 to -0.06; -1.47, -2.79 to -0.15) exhibited improvements for CDR-SB and EXIT25, respectively. In terms of acceptability, memantine was found to be the best. CONCLUSION: Donepezil 5 mg, donepezil 10 mg, galantamine 24 mg, memantine 20 mg, and rivastigmine 12 mg exerted beneficial effects on cognition, and donepezil 10mg provided beneficial effects for executive function and global status. Based on the network meta-analysis, donepezil 10 mg might be the best choice, considering the benefits on cognition function, executive function and global status, but doserelated adverse reactions need to be noted. In the meantime, memantine is a better comprehensive choice in terms of efficacy and safety.

Chaperonin-Containing TCP1 Subunit 6A Is a Prognostic Potential Biomarker That Correlates With the Presence of Immune Infiltrates in Colorectal Cancer.

AIMS: Chaperonin-containing TCP1 subunit (CCT) 6A is an oncogenic 6th subunit of the CCT family. Nevertheless, not much is documented regarding its function in colorectal cancer (COAD). This investigation seeks to explore the role of CCT6A in the prognosis of COAD. MAIN METHODS: Sequencing data from the Gene Expression Omnibus (GEO) and Cancer Genome Atlas database (TCGA) were employed to analyze the expression of CCT6A and its involvement in various regulatory networks behind COAD. Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) analyzed Levels of expression and survival rates, while GEPIA was used to uncover further the functional networks that involved CCT6A. Database for Annotation, Visualization, and Integrated Discovery (DAVID) tools were used to interpret Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Evaluation of the expression levels of CCT6A in COAD samples was also verified via immunohistochemistry. KEY FINDINGS: We found that the expression of CCT6A is up-regulated in COAD. CCT6A correlated with poor prognosis and decreased immune infiltrates such as CD4+ T cells, B cells, and dendritic cells. CCT6A is increased in COAD patients. CCT6A is associated with several gene networks related to the DDX family and mismatch repair pathways. SIGNIFICANCE: Our data showed that data mining was able to uncover data regarding levels of CCT6A and its involvement in genetic regulating pathways in COAD.

Meta-analysis of matrix metalloproteinase (MMP)-9 C1562T polymorphism and susceptibility to ischemic stroke in the Chinese population.

OBJECTIVE: Many studies have shown that the C1562T polymorphism in the matrix metalloproteinase (MMP)-9 gene promoter is associated with susceptibility to ischemic stroke (IS), but the association between them remains controversial. Our objective was to explore the relationship between MMP9 C1562T polymorphism and susceptibility to IS in the Chinese population. METHODS: We conducted a database search of Wanfang, China Science and Technology Journal database, China National Knowledge Infrastructure, Medline, Embase, PubMed and Springerlink through September 2019. Meta-analysis was performed using Stata15.0 software (StataCorp LP, College Station, TX, USA). RESULTS: Thirteen articles were included, including 3,996 patients and 3,815 controls. Among the Chinese population, the results showed no significant difference for the allele model (T vs. C; odds ratio = 1.05, 95%CI: 0.80-1.37). Significant differences were found in the dominant model (TT+TC vs. CC; odds ratio = 2.94, 95%CI: 1.58-5.45) and in the recessive model (TT vs. TC+CC; pooled OR = 0.81, 95%CI: 0.66-0.99). Neither the homozygous model or heterozygous model was significant. CONCLUSION: We identified a correlation between MMP-9 C1562T polymorphism and IS in the Chinese population; the TT+TC genotype may increase the risk of IS.

Meta-analysis of 5-hydroxytryptamine transporter gene promoter region polymorphism and post-stroke depression.

OBJECTIVE: To investigate the relationship between 5-hydroxytryptamine transporter gene promoter region (5-HTTLPR) gene polymorphism and post-stroke depression (PSD). METHODS: We searched the CNKI, China Science and Technology Journal, China WanFang, PubMed, Embase, and Web of Science databases for studies of the relationship between 5-HTTLPR polymorphism and PSD. Data were evaluated using Stata software. RESULTS: The L allele was significantly related to the S allele (OR = 0.57, 95% confidence interval (CI) 0.49-0.65). The dominant genotype LL + LS was related to SS (OR = 0.48, 95%CI 0.39-0.59), the recessive genotype LL was related to LS + SS (OR = 0.39, 95%CI: 0.30-0.51), the homozygous genotype LL was related to SS (OR = 0.24, 95%CI 0.18-0.33), and the heterozygous genotype LS was related to SS (OR = 0.55, 95 CI 0.44-0.68). All the differences were significant. Ethnicity subgroup analysis showed significant differences among the five genotypes in both Asians and Caucasians. Hardy-Weinberg equilibrium (HWE) subgroup analysis showed that, after removal of a non-HWE-conforming control group, all five genotypes were significant and genotypes LL, LS + LL, and LS and L allele had beneficial effects on recovery from PSD. CONCLUSION: 5-HTTLPR gene polymorphism is strongly associated with PSD, and the LL, LS + LL, and LS genotypes and L allele may protect against this condition.

Resveratrol Activates Autophagy via the AKT/mTOR Signaling Pathway to Improve Cognitive Dysfunction in Rats With Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a main cause of vascular dementia and is also an etiological factor of neurological diseases and mental disorders. However, few treatments are available for CCH, and new medications are needed. In the present study, we employed a rat model of CCH that was based on bilateral common carotid artery occlusion and investigated the therapeutic effects of resveratrol and its detailed mechanism of action. We evaluated neurological deficit scores and performed the Morris water maze test, hematoxylin and eosin staining, TUNEL staining, enzyme-linked immunosorbent assays, and Western blot. Resveratrol reduced neurological deficit scores in CCH rats and reduced pathological damage in the frontal cortex and hippocampus. Resveratrol activated autophagy and inhibited the expression of AKT/mechanistic target of rapamycin (mTOR) signaling pathway-related proteins. Treatment with a phosphoinositide-3 kinase inhibitor reversed the protective effect of resveratrol. These findings suggest that resveratrol improves cognitive function in a rat model of CCH and reduces oxidative stress-induced neuronal damage in the frontal cortex and hippocampus by activating autophagy and inhibiting neuronal apoptosis. These effects may be regulated by the AKT/mTOR signaling pathway.

Effectiveness and safety of warfarin and anti-platelet drugs for the primary prevention of stroke in patients with non-valvular atrial fibrillation: a meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of warfarin and anti-platelet drugs as the primary approach to the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). METHODS: Three English databases (the Cochrane library, Embase, and Medline), and three Chinese databases (the Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, and Chinese Periodical Full-text Database of Science and Technology) were searched to select potentially eligible studies published before May, 2014. The studies were randomized controlled trials (RCTs) that investigated the effectiveness and safety of using warfarin and anti-platelet drugs in preventing stroke in NVAF patients; The statistical analysis was performed using the Review Manager 5.2 software provided by the Cochrane Collaboration. RESULTS: nine articles were finally included. Compared with antiplatelet drugs, warfarin treatment significantly reduced the risk of stroke (OR = 0.62, 95% CI 0.50-05.77), systemic embolism events (OR = 0.49, 95% CI 0.31-0.77), ischemic stroke events (OR = 0.46, 95% CI 0.36-0.59), stroke-related disability or death events (OR = 0.66, 95% CI 0.52-0.84). Warfarin did not increase the incidence of All-cause death events (OR = 0.92, 95% CI 0.78-1.08), intracranial hemorrhage events (OR = 1.28, 95% CI 0.85-1.93), major hemorrhage events (OR = 1.01, 95% CI 0.79-1.29). CONCLUSIONS: This meta-analysis found that compared with antiplatelet drugs, warfarin treatment significantly reduced the risk of stroke, systemic embolism events, ischemic stroke events, stroke-related disability or death events. And warfarin did not increase the incidence of All-cause death events, intracranial hemorrhage events, major hemorrhage events.