ABSTRACT
In this study, we strove to substantiate the ability of linc‐MAF‐4 to act as a regulator of pathogenesis during multiple sclerosis (MS). We recruited 34 patients who were diagnosed with MS ...according to the revised McDonald criteria. Six patients with MS and 5 healthy volunteers contributed peripheral blood mononuclear cells for microarray analysis. Subsequent knockdown and overexpression of linc‐MAF‐4 in naive CD4+ T cells from the additional 28 patients with MS was performed to track changes in CD4+ T‐cell subsets and their function, as well as to confirm results from the prior microarray analysis. Expression of linc‐MAF‐4 increased significantly in peripheral blood mononuclear cells of patients with MS compared with those of control participants. In addition, linc‐MAF‐4 regulated encephalitogenic T helper (Th)1‐cell differentiation in patients with MS. Transfection of synthetic linc‐MAF‐4 into naive CD4+ T cells facilitated Th1‐cell differentiation and inhibited Th2‐cell differentiation by directly inhibiting MAF, which is a Th2‐cell transcription factor. Linc‐MAF‐4 also promoted activation of CD4+ T cells from patients with MS. Expression level of linc‐MAF‐4 correlated with the annual relapse rate in patients with MS. Our results suggest that linc‐MAF‐4 is involved in the pathogenesis of MS, specifically via regulation of encephalitogenic T cells.—Zhang, F., Liu, G., Wei, C., Gao, C., Hao, J. Linc‐MAF‐4 regulates Th1/Th2 differentiation and is associated with the pathogenesis of multiple sclerosis by targeting MAF. FASEB J. 31, 519–525 (2017). http://www.fasebj.org
It has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer's ...disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD.
Here, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer's Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region.
We found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum.
Our comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.
Background
Multiple sclerosis (MS) is a complex neurological disease and chronic inflammatory disease. Until now, observational studies have reported positive association between serum interleukin-6 ...(IL-6) levels and MS risk. In order to develop effective therapies, we should establish the causal link between IL-6 signaling and MS. However, it is currently unknown whether IL-6 signaling is causally associated with the risk of MS.
Methods
Here, we selected the increased soluble IL-6R (s-IL-6R) levels as the indirect markers for reduced IL-6 signaling, and performed a Mendelian randomization (MR) study using the rs2228145 variant as the instrumental variable to evaluate and quantify the effect of IL-6 signaling on the risk of MS. To be a comparison, we also evaluated the causal association of IL-6 signaling with the risk of other three neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).
Results
We found that the increased s-IL-6R levels (per 1 standard deviation) were significantly associated with decreased MS risk (OR = 0.96, 95% CI 0.94–0.98,
P
= 1.69E-04), but not associated with the risk of AD (OR = 1.01, 95% CI 0.92–1.11,
P
= 0.835), PD (OR = 0.94, 95% CI 0.84–1.05,
P
= 0.261), or ALS (OR = 1.00, 95% CI 0.92–1.10,
P
= 0.9411).
Conclusion
Our findings have the similar directional effects to an existing humanized anti-IL-6R monoclonal antibody Tocilizumab which could bind to the IL-6 binding site of human IL-6R and competitively inhibit IL-6 signaling. Hence, we provided genetic evidence that inhibiting the IL-6 signaling such as tocilizumab treatment might represent a novel therapy for MS.
Abstract Alzheimer's disease (AD) is the most common and complex neurodegenerative disease in the elderly individuals. Recently, genome-wide association studies (GWAS) have been used to investigate ...AD pathogenesis. These GWAS have yielded important new insights into the genetic mechanisms of AD. However, these newly identified AD susceptibility loci exert only very small risk effects and cannot fully explain the underlying AD genetic risk. We hypothesize that combining the findings from different AD GWAS may have greater power than genetic analysis alone. To identify new AD risk factors, we integrated findings from 3 previous large-scale AD GWAS (n = 14,138) using a gene-based meta-analysis and subsequently conducted a pathway analysis using the kyoto encyclopedia of genes and genomes and gene ontology databases. Interestingly, we not only confirmed previous findings, but also highlighted, for the first time, the involvement of cardiovascular disease-related pathways in AD. Our results provided the clues as to the link between these diseases using pathway analysis methods. We believe that these findings will be very useful for future genetic studies of AD.
Abstract
Background
Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson’s disease (PD) remains inconsistent. Hence, it is ...necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention.
Methods
We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test.
Results
We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = − 1.134, 95% CI: − 2.515, 0.248,
P
= 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = − 1.750, 95% CI: − 3.396, − 0.105,
P
= 0.037) and MR-Egger (beta = − 2.592, 95% CI: − 4.623, − 0.560,
P
= 0.012).
Conclusions
We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.
Anthracycline dutomycin is a tetracyclic quinone glycoside produced by
NRRL B-5482. SW91 is a C-12 demethylated dutomycin derivative, which was identified in our previous research. In vitro ...cytotoxicity and apoptosis assays of these two compounds were conducted to demonstrate their antiproliferation activities. The results showed that both dutomycin and SW91 block cells at the S phase, whereas dutomycin shows more significant inhibition of cell growth. Their interactions with calf thymus DNA (CT-DNA) were investigated, with dutomycin exhibiting higher binding affinity. The molecular docking demonstrated that the 12-methyl group makes dutomycin attach to the groove of DNA. These findings suggest that dutomycin has binding higher affinity to DNA and impairs DNA replication resulting in more significant antitumor activity.
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