Liang Tang

The major facilitator superfamily domain containing 8 (MFSD8) belongs to an orphan transporter protein expressed in a wide range of tissues. Nevertheless, the specific role of MFSD8 in human health and disease remains unknown. This study aimed to evaluate the role of MFSD8 protein on metabolic function using untargeted metabolomics analysis in human umbilical vein endothelial cells (HUVECs). HUVECs overexpressing MFSD8 were subjected to metabolomics analysis to evaluate changes in endogenous small molecules using LC–MS/MS analysis. In the positive scan mode, 634 metabolites from 1583 compounds were identified. In the negative scan mode, 169 metabolites from 405 compounds were identified. According to the established criteria for identifying differential metabolites, 96 metabolites exhibited significant differences between the MFSD8 and Vector groups. Among them, 62 metabolites were found to be up-regulated, whereas 34 metabolites were classified as down-regulated. Bioinformatics pipeline analysis revealed three common metabolic pathways, including arginine biosynthesis, beta-alanine metabolism, and pyrimidine metabolism, were found under the positive and negative scan modes. The semi-quantitative analysis was conducted on the differential metabolites, revealing that overexpression of MFSD8 resulted in increased levels of l-citrulline, l-aspartic acid, ornithine, N-acetyl-l-aspartic acid, l-histidine, beta-alanine metabolites and exhibited decreased levels of cytidine. The findings of our study indicated that MFSD8 had the most significant role in arginine biosynthesis, beta-alanine metabolism, and pyrimidine metabolism pathways within endothelial cells. The metabolomics data provide new insights into studying potential features of MFSD8 protein in the future.

Neuronal ceroid lipofuscinoses (NCLs) belong to a group of inherited neurodegenerative disorders without effective treatments. Though loss-of-function in the MFSD8 gene resulting in a variant late-infantile subtype of NCLs is well documented, its roles remain poorly explored and understood. The results showed an increased cell apoptosis rate after the MFSD8 gene low expression in HUVECs by Flow cytometric analysis. RNA sequencing revealed 367 differentially expressed genes upon the MFSD8 gene overexpression in HUVECs. Bioinformatics analyses revealed that the MFSD8 gene overexpression might be involved in the PI3K/Akt signaling pathway, and interleukin-6 (IL-6), interleukin-1 beta (IL-1B), fibronectin 1 (FN1), fibroblast growth factor 2 (FGF2), toll-like receptor 4 (TLR4), tumor necrosis factor (TNF), and prostaglandin G/H synthase 2 (PTGS2) were the potential hub genes affected by the MFSD8 gene. Gene set enrichment analysis and qRT-PCR assay validation also disclosed that the “Hallmark_Apoptosis” pathway was dramatically enriched in differentially expressed genes. The results revealed that the loss of functional MFSD8 protein indirectly or directly increased the apoptosis of HUVECs, indicating that the expression of the MFSD8 gene was essential for cell survival. The hub genes, including IL-6, IL-1B, FN1, FGF2, TLR4, TNF, and PTGS2, might provide insight into the apoptosis induced by the MFSD8 gene in NCLs. Although many experiments are required to validate these predictions, the results may help investigate the roles of the MFSD8 gene on apoptosis and the corresponding mechanism.

Tripterygium glycosides (TG) have been reported to ameliorate Alzheimer's disease (AD), although the mechanism involved remains to be determined. In the present study, the lncRNA and circRNA expression profiles of an AD mouse model treated with TG were assessed using microarrays. lncRNAs, mRNAs, and circRNAs in the hippocampi of 3 AD+normal saline (NS) mice and 3 AD+TG mice were detected using microarrays. The most differentially expressed lncRNAs, mRNAs, and circRNAs were screened between the AD+NS and AD+TG groups. The differentially expressed lncRNAs and circRNAs were analyzed using GO enrichment and KEGG analyses. Co‑expression analysis of lncRNAs, circRNAs, and mRNAs was performed by calculating the correlation coefficients. Protein‑protein interaction (PPI) network analysis was performed on mRNAs using STRING. The lncRNA‑target‑transcription factor (TF) network was analyzed using the Network software. In total, 661 lncRNAs, 64 circRNAs, and 503 mRNAs were found to be differentially expressed in AD mice treated with TG. Pou4f1, Egr2, Mag, and Nr4a1 were the hub genes in the PPI network. The KEGG results showed that the mRNAs that were co‑expressed with lncRNAs were enriched in the TNF, PI3K‑Akt, and Wnt signaling pathways. LncRNA‑target‑TF network analysis indicated that TFs, including Cebpa, Zic2, and Rxra, were the most likely to regulate the detected lncRNAs. The circRNA‑miRNA interaction network indicated that 275 miRNAs may bind to the 64 circRNAs. In conclusion, these findings provide a novel perspective on AD pathogenesis, and the detected lncRNAs, mRNAs, and circRNAs may serve as novel therapeutic targets for the management of AD.

INSR and ISR‑1 may be candidate genes for essential hypertension (EH). However, the genetic association between the INSR and ISR‑1 gene polymorphisms and EH risk remains contradictory. To determine a more precise association of the INSR and ISR‑1 gene polymorphisms and EH, the present study performed a meta‑analysis. Eligible studies up to Jan 2021 were retrieved from multiple databases including PubMed, Embase, Web of Science and China National Knowledge Infrastructure. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the genetic associations between the allele, dominant and recessive models of INSR Nsil, RsaI and ISR‑1 G972R polymorphisms and EH susceptibility. A total of 10 case‑control studies encompassing 2,782 subjects including 1,289 cases and 1,493 controls were evaluated for the present meta‑analysis. Neither of the allele, dominant and recessive models of INSR Nsil and ISR‑1 G972R polymorphisms was associated with EH risk (P>0.05). While the allele [P=0.0008, OR=0.58, (95% CI)=(0.42, 0.80)], dominant [P=0.02, OR=0.59, (95% CI)=(0.38, 0.92)] and recessive models [P=0.003, OR=0.38, (95% CI)=(0.20, 0.72)] of INSR Rsal polymorphism were associated with decreased risk of EH. Subgroup analysis according to ethnicity showed that the significant associations between the allele, dominant and recessive models of INSR Rsal polymorphism and EH risk were observed in Caucasian populations, but not in Asian populations (P>0.05). In conclusion, the INSR Rsal polymorphism is probably a protective factor for EH. To identify the result, additional case‑control designed research with larger numbers of subjects are required.

The nonstructured abstract were supplied as following: Estrogen receptor is involved in the pathogenesis of recurrent spontaneous abortion (RSA). The ESR1 and ESR2 genes can mediate nongenomic estrogen responses. This study aimed to assess the genetic association between the ESR1 and ESR2 genes polymorphisms and RSA susceptibility in a Chinese Han population. A total of 258 women who had experienced RSA and 264 unrelated healthy women were recruited. Genotypes of the 6 polymorphisms in the ESR1 (rs9340799, rs2234693, and rs3798759) and ESR2 genes (rs207764, rs4986938, and rs1256049) were analyzed using Snapshot technology. No association was detected between the alleles and genotypes of ESR1 rs9340799, rs2234693, and rs3798759 polymorphims and RSA risk (P > .05). Subjects carrying the haplotype of rs9340799A-rs2234693C-rs3798759A had a significantly increased RSA risk in the case group compared with the control group (P = .0005, Padj = .003, odds ratios [95% CI] = 0.35 [0.19–0.65]). However, subjects carrying the haplotype of rs9340799G-rs2234693C-rs3798759A had a significantly decreased RSA risk in the case group compared with the control group (P = .0005, Padj = .003, odds ratios [95% CI] = 2.99 [1.57–5.70]). In addition, no association was found between the alleles, genotypes, and haplotypes of ESR2 rs207764, rs4986938, rs1256049 polymorphisms and RSA risk (P > .05). In conclusion, the haplotype rs9340799A-rs2234693C-rs3798759A of ESR1 might be a risk factor. And the haplotype rs9340799G-rs2234693C-rs3798759A of ESR1 might be a protective factor for RSA in a Chinese Han population.

Objective: Schizophrenia is a complex mental disorder with high heritability. The hypothalamic–pituitary–adrenal (HPA) axis, which is the stress system of the neuroendocrine system, is considered to impact psychotic disorders. We hypothesized that polymorphisms of HPA axis genes might be involved in the development of schizophrenia. Methods: A case–control study comprising 234 patients with schizophrenia and 399 matched healthy controls was conducted to investigate the association between the human melanocortin 2 receptor (MC2R) gene and schizophrenia risk. Seven tag single nucleotide polymorphisms (SNPs) (rs16941303, rs16941314, rs2186944, rs28926188, rs7230126, rs948322, and rs948331) of MC2R were genotyped by direct sequencing. Results: No significant associations were observed between any of the alleles, genotypes, or haplotypes examined within the MC2R gene and the risk of schizophrenia in the total group or in subgroups stratified by smoking or alcoholism. However, a subgroup analysis stratified by sex revealed that under the additive model, the C allele of the MC2R rs948331 SNP significantly decreased the risk of schizophrenia in females (odds ratio=0.18). Conclusion: The C allele of the MC2R rs948331 locus may be a protective factor, reducing the risk of schizophrenia in the female Han Chinese population.

Background: Tripterygium glycoside (TG) has been suggested to have protective effects on the diseases of the central nervous system including Alzheimer’s disease (AD). The mechanisms involving lncRNA-associated competing endogenous RNAs (ceRNAs) were shown to play important roles in the development of AD. However, the ceRNA mechanism of TG in treating AD is still unknown. Thus, we aimed to explore the ceRNA mechanism in the treatment of AD with TG. Methods: A total of 32 C57BL/6J mice were administered 3 μL of Aβ_25-35 (dual side, 1 mg/mL) by a single stereotactic injection in the brain to conduct AD mouse model. AD mouse models were randomly selected and divided into the AD+normal saline (NS) group (n=16) and the AD+TG group (n=16). The expression data of lncRNAs, mRNAs, and miRNAs in the hippocampus of mice from AD+NS group (n=3) and the AD+TG group (n=3) were obtained by microarray analysis. The MuTaME method was used to predict the ceRNA regulatory network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the DAVID database. A protein–protein interaction (PPI) network was constructed by using STRING software. Results: TG can significantly improve spatial memory and inhibit the production of p-tau in an Aβ_25-35-induced AD mouse model. A total of 661 differentially expressed lncRNAs, 503 mRNAs, and 13 miRNAs were identified. A ceRNA network involving the top 200 mRNA-miRNA-lncRNA pairs with 16 lncRNAs, 11 miRNAs, and 52 mRNAs was visualized. And a PPI network complex filtered 26 gene nodes in DEGs was predicted. Conclusion: We have identified 503 DEGs, 661 DElncRNAs, and 13 DEmiRNAs during treatment with TG in Aβ_25-35-induced AD mouse model. A ceRNA network based on the DElncRNAs, DEmRNAs, and DEmiRNAs was conducted, which provided new insight into the lncRNA-mediated ceRNA regulatory mechanisms underlying the effects of TG in the treatment of AD.

Inflammatory factors play an important role in the pathogenesis of Alzheimer’s disease (AD). Byu d Mar 25 (BM25) has been suggested to have protective effects in the central nervous system. However, the effect of BM25 on AD has not been determined. This study aims to investigate the neuroprotective effect of BM25 in AD. A total of 40 AD model mice were randomly assigned to the following five groups (n = 8 per group): the AD + NS group, the AD + donepezil group, and three AD + BM25 groups treated with either 58.39 mg/kg (AD + BM25-L), 116.77 mg/kg (AD + BM25-M), or 233.54 mg/kg BM25 (AD + BM25-H). The Morris water maze test was performed to assess alterations in spatial learning and memory deficits. Nissl staining was performed to detect Nissl bodies and neuronal damage. The expression of IL-1β and TNF-α was evaluated by ELISA. The protein expression of P-P38, P38, P-IκBα, caspase 1, COX2, and iNOS was determined by western blotting. The expression of Aβ, p-Tau, and CD11b was measured by immunohistochemistry. The mRNA expression levels of IL-1β, TNF-α, COX2, and iNOS were measured by qRT-PCR. Spatial memory significantly improved in the AD + BM25-M and AD + BM25-H groups compared with the AD + NS group ( ). The expression of Aβ and p-Tau significantly decreased in the AD + BM25-M and AD + BM25-H groups ( ). The neuron density and hierarchy and number of pyramidal neurons significantly increased in the AD + BM25-M and AD + BM25-H groups ( ). In addition, the expression levels of CD11b, IL-1β, TNF-α, COX2, iNOS, caspase 1, p-IκBα, and p-P38 significantly decreased in the AD + BM25-M and AD + BM25-H groups ( ). In conclusion, our findings suggest that BM25 may exert anti-inflammatory and neuroprotective effects in AD model mice by suppressing the activity of microglia and inhibiting the phosphorylation of IκBα and p38 MAPK.

Alzheimer’s disease (AD) is acommon neurodegenerative disease in the aged population. Tripterygium glycoside (TG) has been reported to protect the nervous system. However, the effect of TG on AD is still unknown. We aimed to explore the effect of TG on AD. Thirty-two C57BL/6J mice were randomly selected and assigned to the normal control, AD model, AD+donepezil, and AD+TG groups. PC12 cells were assigned to the normal control, AD cell model, and AD+TG groups. The alterations in spatial memory and learning abilities of mice were measured by Morris water maze. Neuronal damage in mice was detected using Nissl staining. The expression levels of Aβ_25-35, p-Tau, and CD11b in brain tissues were detected using immunohistochemistry. The expression levels of IL-1β, TNF-α, NO, p-P38, P38, p-IκBα, Caspase1, COX2, and iNOS were measured using ELISAs, qRT–PCR, and western blotting.TG significantly improved the spatial memory and learning abilities of AD mice. Compared toAD model group, significantly lower expression levels of Aβ_25-35, p-Tau, and CD11b were observed in AD+TG group (p < 0.05). The neuron density significantly increased in AD+TG group (p < 0.05). Significantly lower expression levels of IL-1β, TNF-α, NO, caspase-1, COX2, iNOS, p-IκBα and p-P38 MAPK were detected in AD+TG group (p < 0.05). In summary, TG may exert aneuroprotective effect by suppressing the release of inflammatory factors and microglial activity and inhibiting the phosphorylation of IκBα and p38 MAPK. These findings may improve our understanding of the mechanism of TG intervention in AD.

Purpose . To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods . Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results . Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene ( MFSD8 ) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion . The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.