👤 Shuai Xu

Objective- APOA5 variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown. Approach and Results- Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5 Show less

Dyslipidemia is the most common lipid metabolism disorder in humans, and its etiology remains elusive. Hypertriglyceridemia (HTG) is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Previous studies have demonstrated that mutations in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1(LMF1), and glycerol-3 phosphate dehydrogenase 1 (GPD1) are responsible for HTG by using genomic microarrays and next-generation sequencing. The aim of this study was to identify genetic lesions in patients with HTG. Our study included a family of seven members from Jiangsu province across three generations. The proband was diagnosed with severe HTG, with a plasma triglyceride level of 38.70 mmol/L. Polymerase chain reaction (PCR) and Sanger sequencing were performed to explore the possible causative gene mutations for this patient. Furthermore, we measured the post-heparin LPL and hepatic lipase (HL) activities using an antiserum inhibition method. A compound heterozygous mutation in the LMF1 gene (c.257C＞T/p.P86L and c.1184C＞T/p.T395I) was identified and co-segregated with the affected patient in this family. Both mutations were predicted to be deleterious by three bioinformatics programs (Polymorphism Phenotyping-2, Sorting Intolerant From Tolerant, and MutationTaster). The levels of the plasma post-heparin LPL and HL activities in the proband (57 and 177 mU/mL) were reduced to 24% and 75%, respectively, compared with those assayed in the control subject with normal plasma triglycerides. A compound heterozygous mutation of LMF1 was identified in the presenting patient with severe HTG. These findings expand on the spectrum of LMF1 mutations and contribute to the genetic diagnosis and counseling of families with HTG. Show less

Gypenosides (GP) are a type of traditional Chinese medicine (TCM) extracted from plants and commonly applied for treatment of metabolic diseases. This study aims to explore the effects of GP extracts on alleviating non-alcoholic fatty liver disease (NAFLD). In this experiment, C57BL/6 J mice were randomly assigned into normal diet control (ND), HFHC (high-fat and high-cholesterol) and HFHC + GP (GP) groups. Mice in HFHC group were fed HFHC diet combined with fructose drinking water for 12 weeks to induce the animal model of NAFLD, followed by ordinary drinking water until the end of the experiment. In the HFHC + GP group, mice were fed HFHC diet combined with fructose drinking water for 12 weeks, followed by GP-containing drinking water till the end. Mouse body weight was measured weekly. After animal procedures, mouse liver and serum samples were collected. It is shown that GP administration reduced body weight, enhanced the sensitivity to insulin resistance (IR) and decreased serum levels of ALT, AST and TG in NAFLD mice. In addition, GP treatment alleviated steatohepatitis, and downregulated ACC1, PPARγ, CD36, APOC3 and MTTP levels in mice fed with HFHC diet. Furthermore, GP treatment markedly improved intestinal microbiota, and reduced relative abundance ratio of Firmicutes / Bacteroidetes in the feces of NAFLD mice. Our results suggested that GP alleviated NAFLD in mice through improving intestinal microbiota. Show less

Chronic HBV infection (CHB) can lead to acute-on-chronic liver failure (HBV-ACLF) characterized by high mortality. This study aimed to reveal ACLF-related proteomic alterations, from which protein based diagnostic and prognostic scores for HBV-ACLF were developed. Show less

To investigate the proteomic profiling in buffalo spermatozoa before and after capacitation, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with Tandem Mass Tag (TMT) labeling strategy was applied. As a result, 1461 proteins were identified, 93 of them were found to be differentially expressed (>1.5-fold), including 52 up-regulated proteins and 41 down-regulated proteins during sperm capacitation. 88 out of 93 proteins were annotated and classified. Gene ontology (GO) analysis revealed that most of the differently expressed proteins (DEPs) were involved in the Biological Process of transport, cytoskeleton organization, sexual reproduction, and spermatogenesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that DEPs were mainly involved in the pathways of metabolic pathways, PPAR signaling pathway, and oxidative phosphorylation. Western blot (WB) assay confirmed the expressional variation of VAMP4 and APOC3 proteins. Our date provided a foundation for studying the changes in protein expression during sperm capacitation, which contributing to identifying marker proteins that may be associated with sperm capacitation. Show less

Aerobic exercise, which has been shown to have beneficial effects on plasma lipids, has been recommended as an effective measure to improve the prognosis of individuals with coronary heart disease (CHD). Apolipoprotein C3 (apoC3) is associated with hypertriglyceridemia and is therefore closely related to CHD. We measured apoC3 concentration change in patients with CHD before and after long-term aerobic exercise. Thirty-eight patients with coronary heart disease were randomly assigned to a non-exercise group (19 patients) or exercise group (19 patients). Both groups received essential drugs for CHD. The non-exercise group was kept sedentary while the exercise group performed moderate-intensive aerobic exercise for 8 weeks. Lipid levels and apoC3 levels were measured on the first day and 8 weeks later. Exercise for 8 weeks led to a significant decrease in concentration of triglyceride and apoC3 compared with the baseline. Triglyceride concentration changes were positively associated with apoC3 level changes. Aerobic exercise can improve the lipid profile. It is effective in decreasing triglycerides by targeting apoC3 levels in patients with coronary heart disease. Show less

Cell division cycle 20 (CDC20) is frequently overexpressed in malignant tumours and involved in the differentiation process of hematopoietic stem cells. However, the role of CDC20 in prostate cancer stem-like cells (CSCs) remains poorly understood. The expression of CDC20, CD44, β-catenin were examined in prostate cancer specimens by immunohistochemistry assay, the role of CDC20 on the stem-like properties of prostate CSCs was accessed by real-time quantitive PCR, spheroid formation, in vitro and in vivo limiting dilution assay. CDC20 was associated with malignant progression of prostate cancer, the patients with both high expression CDC20 and CD44 or β-catenin were associated with more aggressive clinicopathological features and poor prognosis. CDC20 was usually enriched in CD44 Our results indicated that CDC20 maintains the self-renewal ability of CD44 Show less

Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/β-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/β-catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c-MET activation and AXIN1 mutations occur concomitantly in ~3%-5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9-based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met in the mouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and HCCs induced by c-Met/∆N90-β-Catenin revealed activation of the Wnt/β-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/β-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared with corresponding lesions from c-Met/∆N90-β-Catenin mice. To study whether endogenous β-Catenin is required for c-Met/sgAxin1-driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal-binding protein for immunoglobulin kappa J region (RBP-J) or the ablation of Notch2 did not significantly affect c-Met/sgAxin1-driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c-Met to induce HCC in mice, in a β-Catenin signaling-dependent but Notch cascade-independent way. Show less

Currently, brown adipose tissue (BAT) is a therapeutic target in obesity and diabetes, but the mechanism of BAT activation remains unclear. Because increasing emphasis has been placed on the role of intracellular peptides in biological processes, we conducted a study to gain insight into the mechanism of BAT activation by using a peptidomic approach and then attempted to identify peptides that are capable of activating BAT. In the present study, we generated the peptidomic profile of the intracellular peptides in brown adipocytes treated with forskolin (FSK) using a peptidomic approach. Then, the differentially expressed peptides were evaluated via Gene Ontology (GO) enrichment, KEGG pathway, and protein-protein interaction (PPI) network analysis. Finally, we selected candidate peptides for further validation via assessing the expression levels of UCP-1 and PGC-1α in brown adipocytes exposed to the peptides. A total of 4,370 peptides were identified, of which 951 were upregulated and 379 were downregulated after FSK treatment. Bioinformatic analysis demonstrated that the ECM-receptor interaction GO term was the most enriched and that collagen alpha-related proteins exhibited the highest degree of PPI. Four peptides separately derived from TSC22 domain family protein 1 (T22D1), bromodomain and WD repeat-containing protein 1 (BRWD1), protein piccolo (PCLO), and collagen alpha-1 (III) chain (CO3A1) increased the expression levels of UCP-1 and PGC-1α. ECM-receptor interaction may play an important role in the process of FSK-stimulated BAT activation, and the pT22D1tide, pBRWD1tide, pPCLOtide, and pCO3A1tide peptides potentially promote BAT thermogenesis. Show less

To investigate the association of systemic, serum lipids and genetic variants in the high-density lipoprotein (HDL) metabolic pathway with polypoidal choroidal vasculopathy (PCV) in China. The case-control study was included 150 controls and 66 cases with PCV. Serum levels of total cholesterol (TC), low-density lipoprotein (LDL), HDL, triglycerides (TG), apolipoprotein A1 (APOA1), apolipoprotein B (APOB) together with systemic risk factors including gender, hyperlipidemia, diabetes mellitus (DM), hypertension, coronary artery disease (CAD) and asthma were identified. All subjects were genotyped for four single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway: rs10468017 of hepatic lipase (LIPC), rs12678919 of lipoprotein lipase (LPL), rs3764261 and rs173539 of cholesterol ester transfer protein (CETP) with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Student's t-tests, chi-square tests, anova and logistic regression were used to evaluate associations. Hyperlipidemia was a risk factor (odds ratio (OR) = 1.19, P = 0.001) for PCV. HDL, LDL and APOB levels were associated with PCV (OR = 0.001, P = 0.004; OR = 0.099, P = 0.010; OR = 0.839, P = 0.018). Higher level of TC was potently associated with increased risk of PCV (OR = 109.8, P = 0.000). LIPC rs10468017 was a risk factor for PCV (OR = 11.68, P = 0.000). CETP rs3764261 conferred a decreased risk for PCV (OR = 0.08, P = 0.000). No associations of LPL rs12678919 or CETP rs173539 with PCV were found. Mean level of HDL increased with T allele of the CETP gene (p = 0.026): 1.24 mmol/L (±0.31) for the GG genotype and 1.66 mmol/L (±0.54) for the TT genotype. Additionally, T allele was associated with the following increase in APOA1: 136.78 mg/dl (±20.53) for the CC genotype and 149.57 mg/dl (±22.67) for the TT genotype of LIPC and 137.91 mg/dl (±20.36) for the GG genotype and 162.67 mg/dl (±22.50) for the TT genotype of CETP gene. Our study suggested that the significant association was found between hyperlipidemia, the serum levels of TC, HDL, LDL and APOB and PCV. The result of present study also showed that the association of LIPC rs10468017 and CETP rs3764261 with PCV. Show less

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) previously under development as a lipid-modifying agent that reduces LDL-cholesterol and increases HDL-cholesterol in hypercholesterolemic patients. Anacetrapib demonstrates a long terminal half-life and accumulates in adipose tissue, which contributes to a long residence time of anacetrapib. Given our previous report that anacetrapib distributes into the lipid droplet of adipose tissue, we sought to understand whether anacetrapib affected adipose function, using a diet-induced obese (DIO) mouse model. Following 20 weeks of treatment with anacetrapib (100 mg/kg/day), levels of the drug increased to approximately 0.6 mmol/L in white adipose tissue. This level of anacetrapib was not associated with any impairment in adipose functionality as evidenced by a lack of any reduction in biomarkers of adipose functionality (plasma adiponectin, leptin, insulin; adipose adiponectin, leptin mRNA). In DIO wild-type (WT) mice treated with anacetrapib for 2 weeks and then subjected to 30% food restriction during washout to induce weight loss (18%) and fat mass loss (7%), levels of anacetrapib in adipose and plasma were not different between food restricted and ad lib-fed mice. These data indicate that despite deposition and long-term residence of ~0.6 mmol/L levels of anacetrapib in adipose tissue, adipose tissue function appears to be unaffected in mice. In addition, these data also indicate that even with severe caloric restriction and acute loss of fat mass, anacetrapib does not appear to be mobilized from the fat depot, thereby solidifying the role of adipose as a long-term storage site of anacetrapib. Show less

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug candidates targeting the PCSK9/LDLR pathway, that are translatable to humans. Here, by using our recently generated LDLR heterozygote ( Show less

Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL cholesterol and increase in HDL cholesterol in hypercholesterolemic patients. Anacetrapib was not taken forward into filing/registration as a new drug for coronary artery diease, despite the observation of a ∼9% reduction in cardiovascular risk in a large phase III cardiovascular outcomes trial (REVEAL). Anacetrapib displayed no adverse effects throughout extensive preclinical safety evaluation, and no major safety signals were observed in clinical trials studying anacetrapib, including REVEAL. However, anacetrapib demonstrated a long terminal half-life in all species, thought to be due, in part, to distribution into adipose tissue. We sought to understand the dependence of anacetrapib's long half-life on adipose tissue and to explore potential mechanisms that might contribute to the phenomenon. In mice, anacetrapib localized primarily to the lipid droplet of adipocytes in white adipose tissue; in vitro, anacetrapib entry into cultured human adipocytes depended on the presence of a mature adipocyte and lipid droplet but did not require active transport. In vivo, the entry of anacetrapib into adipose tissue did not require lipase activity, as the distribution of anacetrapib into adipose was-not affected by systemic lipase inhibition using poloaxamer-407, a systemic lipase inhibitor. The data from these studies support the notion that the entry of anacetrapib into adipose tissue/lipid droplets does not require active transport, nor does it require mobilization or entry of fat into adipose via lipolysis. Show less

The aberrant expression of ceroid-lipofuscinosis 3 (CLN3) has been reported in a variety of human malignancies. However, the role of CLN3 in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, we found that CLN3 was frequently upregulated in HCC clinical samples and HCC-derived cell lines and was significantly correlated with an APF serum level ≥20 μg/L, a tumour size ≥5 cm, multiple tumours, and the absence of encapsulation. Kaplan-Meier showed that CLN3 upregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in HCC patients. Cox regression analysis revealed that CLN3 upregulation was an independent risk factor for RFS and OS. A functional study demonstrated that the knockdown of CLN3 expression profoundly suppressed the growth and metastasis of HCC cells both in vitro and in vivo. Mechanistic investigation revealed that the EGFR/PI3K/AKT pathway was essential for mediating CLN3 function. In conclusion, our results provide the first evidence that CLN3 contributes to tumour progression and metastasis and offer a potential prognostic predictor and therapeutic target for HCC. Show less

Carbamoyl phosphate synthetase-1 (CPS1), the first rate-limiting mitochondrial enzyme in the urea cycle, regulates proliferation and differentiation during tumor progression. However, the detailed function of CPS1 in glioblastoma Multiforme (GBM) is still unclear. Here, we highlight mechanisms for CPS1 upregulation and the effects of upregulated CPS1 on GBM tumorigenesis. The transcriptome data from several public databases, such as Oncomine and GEPIA, revealed that CPS1 transcriptional level was significantly upregulated in GBM tissues and cells. Moreover, CPS1 was hypomethylated in GBM tissues. The Wanderer database, linked to the Cancer Genome Atlas (TCGA), showed the association between CPS1 expression or its methylation values and the clinicopathological parameters in GBM patients. Our work fully demonstrated that CPS1 expression was upregulated in GBM and this gene could be used as a potential diagnostic and prognosis indicator for GBM. Show less

Further analysis has revealed that the signal reported in Extended Data Fig. 1c of this Letter is attributed to phosphorylethanolamine, not carbamoyl phosphate. A newly developed derivatization method revealed that the level of carbamoyl phosphate in these NSCLC extracts is below the detection threshold of approximately 10 nanomoles. These findings do not alter the overall conclusions of the Letter; see associated Amendment for full details. The Letter has not been corrected online. Show less

Metabolic homeostasis of amino acids is essential for human health. Here, we aimed to investigate a potential role for the clock component reverse erythroblastosis virus α (Rev-erbα) in circadian regulation of amino acid metabolism. RNA-seq with Rev-erbα Show less

Microbial fuel cells (MFCs) are eco-friendly bio-electrochemical reactors that use exoelectrogens as biocatalyst for electricity harvest from organic biomass, which could also be used as biosensors for long-term environmental monitoring. Glucose and xylose, as the primary ingredients from cellulose hydrolyzates, is an appealing substrate for MFC. Nevertheless, neither xylose nor glucose can be utilized as carbon source by well-studied exoelectrogens such as Show less

Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed. We searched in PubMed for manuscripts published in English, combining terms such as "Valproic acid", "hepatotoxicity", "liver injury", and "mechanisms". The data of screened papers were analyzed and summarized. The formation of VPA reactive metabolites, inhibition of fatty acid β-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity. Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug. Show less

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal. Show less

Overall survival of patients with low-grade glioma (LGG) has shown no significant improvement over the past 30 years, with survival averaging approximately 7 years. This study aimed to identify novel promising biomarkers of LGG and reveal its potential molecular mechanisms by integrated bioinformatics analysis. The microarray datasets of GSE68848 and GSE4290 were selected from GEO database for integrated analysis. In total, 293 overlapping differentially expressed genes (DEGs) were detected using the limma package. One hundred and eighty-eight nodes with 603 interactions were obtained from the establishment of protein-protein interaction (PPI) network. Functional and signaling pathway enriched were significantly correlated with the synapse and calcium signaling pathway, respectively. Module analysis revealed eight hub genes with high connectivity, which included CHRM1, DLG2, GABRD, GRIN1, HTR2A, KCNJ3, KCNJ9, and NUSAP1, and they were markedly correlated with patients' prognosis. The mining of the Gene Expression Profiling Interactive Analysis database and qPCR further confirmed the abnormal expression of these key genes with their prognostic value in LGG. We eventually predicted the 20 most vital small molecule drugs, which potentially reverse the carcinogenic state of LGG, as per the CMap (connectivity map) database and these DEGs, and MS-275 (enrichment score = -0.939) was considered as the most promising small molecule to treat LGG. In conclusion, our study provided eight reliable novel molecular biomarkers for diagnosis, prognosis prediction, and treatment targets for LGG. These conclusions will contribute to a better comprehension of molecular mechanisms fundamental to LGG occurrence and progression, and providing new insights for future development of genomic individualized treatment in LGG. Show less

Tripartite Motif Containing 11 (TRIM11), an E3 ubiquitin ligase, is identified as a carcinogen causing certain human cancers. However, the specific role of TRIM11 is still uncovered in human osteosarcoma (OS) cells. To explore the role of TRIM11 in OS cells, TRIM11 was induced by silencing and overexpression in OS cells using RNA interference (RNAi) and lentiviral vector, respectively. qRT-PCR and western blot were used to examine the transcription and translation levels of the target gene. Cell count kit-8 (CCK-8) assays were established to analyze cell proliferation. Cell apoptosis ratio was determined via flow cytometry. In our analyses, TRIM11 was suggested to be upregulated, and it functioned as a pro-proliferation and antiapoptosis factor in OS cells. Moreover, the extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 was used to examine the relationship between TRIM11 and ERK1/2 in OS cells. Results demonstrated that the role of TRIM11 was significantly disrupted by the ERK1/2 inhibitor PD98059. Interestingly, we found TRIM11 overexpression did not affect dual-specificity phosphatase 6 (DUSP6) transcription, but improved its translation in OS cells. Co-immunoprecipitation (Co-IP) analyses revealed that TRIM11 interacted with DUSP6. Importantly, overexpression of TRIM11 enhanced DUSP6 ubiquitination in OS cells. Therefore, TRIM11 might suppress the translation of DUSP6 via improving its ubiquitination. Additionally, TRIM11 silencing in OS cells significantly reduced its tumorigenicity Show less

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neuron loss, inflammation and oxidative stress injury in the substantia nigra pars compacta (SNpc). Tripartite motif 10 (TRIM10) belongs to the TRIM family of proteins and has been implicated to play a role in in PD, although supporting evidence has yet to be established. 1-methyl-4-phenylpyridinium (MPP+), the metabolite of MPTP (Mitochondrial parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine), is often used to generate a cellular model of PD. In this study, we found that MPP + inhibited cell proliferation and induced TRIM10 expression. Knockdown of TRIM10 alleviated cell apoptosis and ROS generation induced by MPP+. Further, MPP + decreased the expression of dual specificity phosphatase 6 (DUSP6) and this effect was reversed by TRIM10 knockdown. Moreover, DUSP6 alleviated cell apoptosis and ROS generation induced by TRIM10. Of note, TRIM10 suppressed DUSP6 by promoting DUSP6 ubiquitination. In conclusion, silencing of TRIM10 reduced cell apoptosis and ROS levels in a cellular model of PD, suggesting a potential role of TRIM10 in PD treatment. Show less

Macrophages play a fundamental role in human chronic diseases such as rheumatoid arthritis, atherosclerosis, and cancer. In the present study, we demonstrated that dual-specificity phosphatase 6 (DUSP6) was upregulated by lipopolysaccharide (LPS) treatment of macrophages. (E/Z)-BCI hydrochloride (BCI) functions as a small molecule inhibitor of DUSP6, and BCI treatment inhibited DUSP6 expression in LPS-activated macrophages. BCI treatment inhibited LPS-triggered inflammatory cytokine production, including IL-1β and IL-6, but not TNF-α, and also affected macrophage polarization to an M1 phenotype. In addition, BCI treatment decreased reactive oxygen species (ROS) production and significantly elevated the levels of Nrf2. Interestingly, pharmacological inhibition of DUSP6 attenuated LPS-induced inflammatory responses was independent of extracellular signal-regulated kinase (ERK) signaling. Furthermore, BCI treatment inhibited phosphorylation of P65 and nuclear P65 expression in LPS-activated macrophages. These results demonstrated that pharmacological inhibition of DUSP6 attenuated LPS-induced inflammatory mediators and ROS production in macrophage cells via activating the Nrf2 signaling axis and inhibiting the NF-κB pathway. These anti-inflammatory effects indicated that BCI may be considered as a therapeutic agent for blocking inflammatory disorders. Show less

Vitiligo is a potentially serious condition characterized by loss of melanin and death of melanocytes. To identify potential therapeutic targets for vitiligo, we conducted a microarray analysis of three human vitiligo specimens and paired adjacent normal tissues. Because we found that the fatty acid desaturase 1 (FADS1) gene was downregulated in vitiligo specimens, we carried out experiments to assess its role in melanocyte replication and survival. RT-qPCR was used to verify that FADS1 expression was lower in vitiligo-affected tissues and vitiligo melanocyte PIG3V cells than in matched controls or normal human epidermal PIG1 melanocytes. In addition, CCK-8, immunofluorescence, western blot and flow cytometry assay were used to detect the proliferation and apoptosis in PIG1 cells respectively. Overexpression of FADS1 promoted proliferation of PIG3V melanocytes, while FADS1 silencing inhibited proliferation and induced cell death in PIG1 melanocytes. Increased ROS generation; induction of mitochondrial-mediated apoptosis via upregulation of Bax and active caspases 3 and 9 and downregulation of Bcl-2; and cell cycle arrest via downregulation of c-Myc and Cyclin D1 and upregulation of p21 were all enhanced after FADS1 silencing in PIG1 melanocytes. These findings implicate FADS1 downregulation in the pathogenesis of vitiligo and may open new avenues for its treatment. Show less

Estrogen is very important to the differentiation of B lymphocytes; B lymphopoiesis induced by OVX was supposedly involved in osteoporosis. But the effects of B lymphocytes on the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) are not clear. In this study, we detected bone quality and bone loss in a trabecular bone by electronic universal material testing machine and microcomputed tomography (micro-CT) in OVX and splenectomized-ovariectomy (SPX-OVX) rats. Additionally, changes in lymphocytes (B lymphocyte, CD4 Show less

Fatty acids play a key role in cellular bioenergetics, membrane biosynthesis and intracellular signaling processes and thus may be involved in cancer development and progression. In the present study, we comprehensively assessed associations of 14,522 common single-nucleotide polymorphisms (SNPs) in 149 genes of the fatty-acid synthesis pathway with cutaneous melanoma disease-specific survival (CMSS). The dataset of 858 cutaneous melanoma (CM) patients from a published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used as the discovery dataset, and the identified significant SNPs were validated by a dataset of 409 CM patients from another GWAS from the Nurses' Health and Health Professionals Follow-up Studies. We found 40 noteworthy SNPs to be associated with CMSS in both discovery and validation datasets after multiple comparison correction by the false positive report probability method, because more than 85% of the SNPs were imputed. By performing functional prediction, linkage disequilibrium analysis, and stepwise Cox regression selection, we identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted CMSS, with an allelic hazards ratio of 0.66 (95% confidence interval = 0.51-0.84 and p = 8.34 × 10 Show less

Advanced non-small cell lung cancer (NSCLC) leads to a high death rate in patients and is a major threat to human health. NSCLC induces an immune suppressive microenvironment and escapes from immune surveillance Show less

Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neurological alterations associated with white matter injury and demyelination may underlie this link. However, whether disturbances in cerebral myelination contribute to the initiation of depression in epilepsy remains unclear. In the present study, we investigated the connection between demyelination disorders and the development of depression comorbidity in epilepsy. We first induced spontaneous recurrent epilepticus seizure (SRS) in young rats with pilocarpine. We then established depressive behaviors by recurrent forced swimming test and evaluate the depression state by sucrose preference test. The ratio of depression comorbidity in SRS rats was then calculated. Next, myelination in SRS-Depressed (SRS-D) rats was explored via PCR, western blotting, and immunohistochemistry for the key myelin promotion factor, Olig2 and inhibition factor, LINGO-1. Finally, in situ RNA hybridization of NCX3, one of the dominant Ca Show less