The present study aimed to provide evidence for the genetic heterogeneity of familial autism spectrum disorder (ASD), which might help to improve our understanding of the complex polygenic basis of th Show more
The present study aimed to provide evidence for the genetic heterogeneity of familial autism spectrum disorder (ASD), which might help to improve our understanding of the complex polygenic basis of this disease. Whole‑exome sequencing (WES) was performed on two autistic children in a family pedigree, and reasonable conditions were set for preliminarily screening variant annotations. Sanger sequencing was used to verify the preliminarily screened variants and to determine the possible sources. In addition, autism‑related genes were screened according to autism databases, and their variants were compared between two autistic children. The results showed that there were 21 genes respectively for autistic children Ⅳ2 and Ⅳ4, preliminarily screened from all variants based on the harmfulness (high) and quality (high or medium) of the variants, as well as the association between mutant genes and autism in human gene mutation database. Furthermore, candidate autism‑related genes were screened according to the evidence score of >4 in the Autism KnowledgeBase (AutismKB) database or ≥3 in the AutDB database. A total of 11 and 10 candidate autism‑related genes were identified in the autistic children Ⅳ2 and Ⅳ4, respectively. Candidate genes with an evidence score of >16 in AutismKB were credible autism‑related genes, which included LAMC3, JMJD1C and CACNA1H in child Ⅳ2, as well as SCN1A, SETD5, CHD7 and KCNMA1 in child Ⅳ4. Other than the c.G1499A mutation of SCN1A, which is known to be associated with Dravet syndrome, the specific missense variant loci of other six highly credible putative autism‑related genes were reported for the first time, to the best of the authors' knowledge, in the present study. These credible autism‑related variants were inherited not only from immediate family members but also from extended family members. In summary, the present study established a reasonable and feasible method for screening credible autism‑related genes from WES results, which by be worth extending into clinical practice. The different credible autism‑related genes between the two autistic children indicated a complex polygenic architecture of ASD, which may assist in the early diagnosis of this disease. Show less
Leukemic stem cells (LSCs) comprise a very rare cell population that results in the development of acute myeloid leukemia. The selective targeting of drivers in LSCs with small molecule inhibitors hol Show more
Leukemic stem cells (LSCs) comprise a very rare cell population that results in the development of acute myeloid leukemia. The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of acute myeloid leukemia. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of jumonji domain modulator #7 (JDM-7). Surface plasmon resonance analysis showed that JDM-7 binds to JMJD1C and its family homolog JMJD1B. JDM-7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, although it led to a significant decrease in semi-solid colony formation experiments at lower concentrations. Moreover, low doses of JDM-7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM-7 downregulates the LSC self-renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM-7 is similar to that of tadalafil, a drug approved by the US Food and Drug Administration. Molecular docking and surface plasmon resonance analysis showed that tadalafil binds to JMJD1C. Moreover, similar to JDM-7, tadalafil suppressed colony formation of leukemia cells in semi-solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM-7 and tadalafil as potential JMJD1C modulators that selectively inhibit the growth of LSCs. Show less
In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-L Show more
In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aβ) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future. Show less
Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system. It is mainly expressed by oligodendrocytes. Although previous studies Show more
Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system. It is mainly expressed by oligodendrocytes. Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition, neuronal homeostasis, precursor migration, plasticity, and neurodegeneration, its functions in the process of oxidative injury are largely uncharacterized. In this study, oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats. We used hydrogen peroxide (H Show less
Recently, studies on competing endogenous RNA (ceRNA) networks have become prevalent, and circular RNAs (circRNAs) have crucial implications for the development and progression of carcinoma. However, Show more
Recently, studies on competing endogenous RNA (ceRNA) networks have become prevalent, and circular RNAs (circRNAs) have crucial implications for the development and progression of carcinoma. However, studies relevant to metastatic prostate cancer (mPCa) are scant. This study aims to discover potential ceRNAs that may be related to the prognosis of mPCa. RNA-Seq data were obtained from the MiOncoCirc database and Gene Expression Omnibus (GEO). Differential expression patterns of RNAs were examined using R packages. Circular RNA Interactome, miRTarBase, miRDB and TargetScan were applied to predict the corresponding relation between circRNAs, miRNAs and mRNAs. The Gene Ontology (GO) annotations were performed to present related GO terms, and Gene Set Enrichment Analysis (GSEA) tools were applied for pathway annotations. Moreover, survival analysis was conducted for the hub genes. We found 820 circRNAs, 81 miRNAs and 179 mRNAs that were distinguishingly expressed between primary prostate cancer (PCa) and mPCa samples. A ceRNA network including 45 circRNAs, 24 miRNAs and 56 mRNAs was constructed. In addition, the protein-protein interaction (PPI) network was built, and 10 hub genes were selected by using the CytoHubba application. Among the 10 hub genes, survival analysis showed that ITGA1, LMOD1, MYH11, MYLK, SORBS1 and TGFBR3 were significantly connected with disease-free survival (DFS). The circRNA-mediated ceRNA network provides potential prognostic biomarkers for metastatic prostate cancer. Show less
Ageing-related osteoporosis is becoming an emerging threat to human health along with the ageing of human population. The decreased rate of osteogenic differentiation and bone formation is the major c Show more
Ageing-related osteoporosis is becoming an emerging threat to human health along with the ageing of human population. The decreased rate of osteogenic differentiation and bone formation is the major cause of ageing-related osteoporosis. Microtubule actin cross-linking factor 1 (MACF1) is an important cytoskeletal factor that promotes osteogenic differentiation and bone formation. However, the relationship between MACF1 expression and ageing-related osteoporosis remains unclear. This study has investigated the expression pattern of MACF1 in bone tissues of ageing-related osteoporosis patients and ageing mice. The study has further elucidated the mechanism of MACF1 promoting bone formation by inhibiting HES1 expression and activity. Moreover, the therapeutic effect of MACF1 on ageing-related osteoporosis and post-menopausal osteoporosis was evaluated through in situ injection of the MACF1 overexpression plasmid. The study supplemented the molecular mechanisms between ageing and bone formation, and provided novel targets and potential therapeutic strategy for ageing-related osteoporosis. Show less
Osteoblast differentiation leading to bone formation requires a coordinated transcriptional program. Osteoblastic cells with low level of microtubule actin crosslinking factor 1 (MACF1) show reduced o Show more
Osteoblast differentiation leading to bone formation requires a coordinated transcriptional program. Osteoblastic cells with low level of microtubule actin crosslinking factor 1 (MACF1) show reduced osteoblast differentiation ability, however, the comprehensive mechanism of MACF1's action remains unexplored. In the current study, we found that MACF1 knockdown suppressed osteoblast differentiation by altering the transcriptome dynamics. We further identified two MACF1-interacted proteins, cyclin-dependent kinase 12 (CDK12) and MYST/Esa1-associated factor 6 (MEAF6), and two MACF1-interacted transcription factors (TFs), transcription factor 12 (TCF12) and E2F transcription factor 6 (E2F6), which repress osteoblast differentiation by altering the expression of osteogenic TFs and genes. Moreover, we found that MACF1 regulated cytoplasmic-nuclear localization of itself, TCF12 and E2F6 in a concentration-dependent manner. MACF1 oppositely regulates the expression of TCF12 and transcription factor 7 (TCF7), two TFs that drive osteoblast differentiation to opposite directions. This study reveals that MACF1, a cytoskeletal protein, acts as a sponge for repressors of osteoblast differentiation to promote osteoblast differentiation and contributes to a novel mechanistic insight of osteoblast differentiation and transcription dynamics. Show less
Lung adenocarcinoma (LUAD) is the most commonly diagnosed type of lung cancer and exhibits a high morbidity. The present study aimed to investigate the long non-coding RNA (lncRNA)-associated competin Show more
Lung adenocarcinoma (LUAD) is the most commonly diagnosed type of lung cancer and exhibits a high morbidity. The present study aimed to investigate the long non-coding RNA (lncRNA)-associated competing endogenous RNA (ceRNA) mechanisms in LUAD. The receptor activity modifying protein 2-antisense RNA 1 (RAMP2-AS1) was identified using GSE113852 and GSE130779 datasets downloaded from the Gene Expression Omnibus database, and the downregulation of RAMP2-AS1 was the most significant in LUAD. In addition, microRNA (miR)-296-5p was identified to bind to RAMP2-AS1 via bioinformatics analysis. Subsequently, CD44, cyclin D3 (CCND3), neurocalcin δ (NCALD), microtubule actin crosslinking factor 1 (MACF1) and potassium channel tetramerization domain containing 15 were obtained by intersecting the predicted target genes of miR-296-5p and 368 differentially expressed mRNAs in LUAD. According to the Gene Expression Profiling Interactive Analysis and UALCAN databases, these five mRNAs were downregulated in LUAD, and their expression levels were positively correlated with those of RAMP2-AS1. CD44, CCND3, NCALD and MACF1 were selected as key mRNAs in LUAD based on prognostic analyses. Furthermore, functional enrichment analyses were performed and an interaction network was constructed to reveal the functions of the RAMP2-AS1-associated ceRNA in LUAD. The results indicated that the functions were mainly enriched in generic transcription pathways, cyclin D-associated events in G Show less
Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammati Show more
Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. Show less
To explore the role and mechanism of miR-125a-3p in rheumatoid arthritis (RA) progression. The RA-tissues and fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) were used in this study. q Show more
To explore the role and mechanism of miR-125a-3p in rheumatoid arthritis (RA) progression. The RA-tissues and fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) were used in this study. qRT-PCR, western blot and ELISA assay were performed to detect the expression levels of IL-6, IL-β and ΤΝF-α. Dual-luciferase reporter gene assay was used to observe the binding effect of miR-125a-3p and MAST3, and CCK-8 was used to observe the effect of miR-125a-3p on the proliferation of RA-FLS. miR-125a-3p was significantly downregulated in the RA-tissues and RA-FLS, and miR-125a-3p could inhibit the proliferation and reduce the inflammation response of RA-FLS. Besides, MAST3 was found as a target of miR-125a-3p, and increased MAST3 could reverse the effects of miR-125a-3p on RA-FLS including decreased proliferation, reduced inflammation level and the inactivation of Wnt/β-catenin and NF-κB pathways. This study suggests that miR-125a-3p could inactivate the Wnt/β-catenin and NF-κB pathways to reduce the proliferation and inflammation response of RA-FLS via targeting MAST3. Show less
Insulin-independent glucose metabolism, including anaerobic glycolysis that is promoted in resistance training, plays critical roles in glucose disposal and systemic metabolic regulation. However, the Show more
Insulin-independent glucose metabolism, including anaerobic glycolysis that is promoted in resistance training, plays critical roles in glucose disposal and systemic metabolic regulation. However, the underlying mechanisms are not completely understood. In this study, through genetically manipulating the glycolytic process by overexpressing human glucose transporter 1 (GLUT1), hexokinase 2 (HK2) and 6-phosphofructo-2-kinase-fructose-2,6-biphosphatase 3 (PFKFB3) in mouse skeletal muscle, we examined the impact of enhanced glycolysis in metabolic homeostasis. Enhanced glycolysis in skeletal muscle promoted accelerated glucose disposal, a lean phenotype and a high metabolic rate in mice despite attenuated lipid metabolism in muscle, even under High-Fat diet (HFD). Further study revealed that the glucose metabolite sensor carbohydrate-response element-binding protein (ChREBP) was activated in the highly glycolytic muscle and stimulated the elevation of plasma fibroblast growth factor 21 (FGF21), possibly mediating enhanced lipid oxidation in adipose tissue and contributing to a systemic effect. PFKFB3 was critically involved in promoting the glucose-sensing mechanism in myocytes. Thus, a high level of glycolysis in skeletal muscle may be intrinsically coupled to distal lipid metabolism through intracellular glucose sensing. This study provides novel insights for the benefit of resistance training and for manipulating insulin-independent glucose metabolism. Show less
Thioredoxin-interacting protein (TXNIP) overexpression is implicated in the pathogenesis of type 2 diabetes. Previous studies have shown that a small molecule compound (W2476) was able to improve β-ce Show more
Thioredoxin-interacting protein (TXNIP) overexpression is implicated in the pathogenesis of type 2 diabetes. Previous studies have shown that a small molecule compound (W2476) was able to improve β-cell dysfunction and exert therapeutic effects in diabetic mice via repression of TXNIP signaling pathway. The impact of W2476 on TXNIP transcription was thus investigated using the chromatin immunoprecipitation method. It was found that W2476 promotes competitive binding of forkhead box O1 transcription factor (FOXO1) to the carbohydrate response element (ChoRE) sequence associated with ChoRE-binding protein (ChREBP)/Mlx interacting protein-like(Mlx) complexes. This interaction hinders the attachment of histone acetyltransferase p300 and reduces histone H4 acetylation on the TXNIP promoter, leading to decreasing TXNIP transcription. Show less
Heart failure (HF) leads to a progressive increase in morbidity and mortality rates. This study aimed to explore the transcriptional landscape during HF and identify differentially expressed transcrip Show more
Heart failure (HF) leads to a progressive increase in morbidity and mortality rates. This study aimed to explore the transcriptional landscape during HF and identify differentially expressed transcripts (DETs) and alternative splicing events associated with HF. We generated a dog model of HF ( Show less
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease. An induced pluripotent stem cell line (EHTJUi003-A) was generated from umbilical cord blood mononuclear cells (UCBMCs) of a fe Show more
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease. An induced pluripotent stem cell line (EHTJUi003-A) was generated from umbilical cord blood mononuclear cells (UCBMCs) of a female neonate with heterozygous mutation of p.L460Wfs (c.1377delC) in the MYBPC3 gene. This iPSC model offers a very valuable resource to study the pathological mechanism of HCM in vitro. Show less
Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death, but exhibits heterogeneous clinical features. A major research focus is to identify specific ultrasonic phenotype Show more
Familial hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death, but exhibits heterogeneous clinical features. A major research focus is to identify specific ultrasonic phenotypes, and causal gene mutations, as well as to elucidate the possible metabolic pathogenic effects in familial HCM through multi-omics study. Nine members of two familial HCM pedigrees were enrolled in this study. Their clinical data were collected, and the data of multiparameter ultrasound, whole-exome sequencing, and untargeted metabolomics were analyzed. We identified three novel pathogenic sarcomere gene mutations, TNNT2-rs397516484, MYH6-rs372446459 and MYBPC3-rs786204339 in two familial HCM pedigrees. The proband of Family 1 and his father carried TNNT2-rs397516484 and MYH6-rs372446459 missense mutations, while the proband of Family 2 and her brother carried MYBPC3-rs786204339 frameshift mutation. They presented with heart failure and abnormal electrocardiogram, accompanied by diastolic and systolic dysfunction and impaired myocardial work. They also showed disturbances of carbohydrate metabolism, including the citrate cycle (TCA cycle), glycolysis/gluconeogenesis, fructose and mannose metabolism, pentose and glucuronate interconversions and amino sugar and nucleotide sugar metabolism. Novel TNNT2-rs397516484, MYH6-rs372446459, and MYBPC3-rs786204339 are pathogenic sarcomere gene mutations in familial HCM, leading to decreased cardiac function and metabolic disturbances of carbohydrate metabolism, which have important implications for biologically defined diagnoses and precision medicine. Show less
The mutation MYBPC3-E334K is a culprit mutation of hypertrophic cardiomyopathy (HCM). The pathogenicity of MYBPC3-E334K is conflicting in ClinVar because of the limited segregation data and the relati Show more
The mutation MYBPC3-E334K is a culprit mutation of hypertrophic cardiomyopathy (HCM). The pathogenicity of MYBPC3-E334K is conflicting in ClinVar because of the limited segregation data and the relatively high frequency in gnomAD (0.03% overall, with 0.3% in East Asians and 0.8% in Japanese). The main aim is to clarify the clinical importance and phenotype-genotype correlations in subjects with or without MYBPC3-E334K alone. The prevalence of MYBPC3-E334K was sequenced in 1017 HCM unrelated probands. The clinical features, morphology phenotypes, and electrical phenotypes were further analyzed according to the phenotype and genotype status in families with single-mutation MYBPC3-E334K. Nine of 1017 (0.88%) unrelated HCM probands were detected harboring MYBPC3-E334K, and three of them harbored a second variant in sarcomere protein gene. Family study and co-segregation analyses indicated that patients with single-mutation MYBPC3-E334K showed autosomal dominant mode of inheritance with incomplete penetrance. The overall disease penetrance was 52.6%, and the disease penetrance was higher in males than in females (100% in men vs 25% in women, p = 0.003). The mean age at diagnosis of males was approximately 25 years younger than females (36.57 ± 18.65 vs 62.33 ± 12.10, p = 0.062). The variant MYBPC3-E334K was classified as a likely pathogenic variant, and a second sarcomere variant did not reveal obvious cumulative effects. The patients harboring single-mutation MYBPC3-E334K had incomplete penetrance, and males demonstrated higher penetrance and early onset HCM than females. A second sarcomere variant did not reveal obvious cumulative effects. Show less
Mesenchymal stem cell (MSC) therapy has potential applications in treating atherosclerosis and coronary heart disease (CAD). Previous studies have demonstrated that MSCs are the most preferable source Show more
Mesenchymal stem cell (MSC) therapy has potential applications in treating atherosclerosis and coronary heart disease (CAD). Previous studies have demonstrated that MSCs are the most preferable sources of therapeutic exosomes, which carry long non‑coding RNAs and participate in the progression of atherosclerosis. The results of our previous bioinformatics study demonstrated that the levels of LOC100129516 were significantly upregulated in peripheral blood mononuclear cells obtained from patients with CAD. However, the biological role of LOC100129516 in the development of atherosclerosis remains to be elucidated. In the present study, THP‑1 cells were treated with oxidized low‑density lipoproteins to induce foam cell formation Show less
Liver X receptor α (LXRα; NR1H3) is an important transcription factor that can facilitate milk fat synthesis by regulating the transcription of FASN in mice and goats. Nevertheless, the lipid synthesi Show more
Liver X receptor α (LXRα; NR1H3) is an important transcription factor that can facilitate milk fat synthesis by regulating the transcription of FASN in mice and goats. Nevertheless, the lipid synthesis related to LXRα and its regulation on FASN in the buffalo mammary gland remain elusive. Here, we demonstrated that the mRNA and protein expression of LXRα in buffalo mammary tissue increased in lactation compared with that in the dry-off period. Overexpression of NR1H3 enhanced the lipid droplet formation and triacylglycerol concentration in buffalo mammary epithelial cells (BuMEC), whereas the knockdown of NR1H3 resulted in a decrease in the number of lipid droplets. At the same time, NR1H3 also affected the expression of regulatory factors (INSIG1, INSIG2, SREBF1, and PPARG) related to milk fat synthesis and that of genes involved in de novo synthesis (FASN, ACACA, and SCD), and uptake and transport (LPL, CD36, and FABP3) of fatty acids as well as triacylglycerol synthesis (GPAM, APGAT6, and DGAT1). Luciferase reporter assays indicated that overexpression of NR1H3 resulted in an increase in the activity of FASN promoter, whereas the knockdown of NR1H3 had an opposite effect. When NR1H3 was overexpressed, mutations in LXRE or SRE could decrease the promoter activity of FASN. Furthermore, mutagenesis of both LXRE and SRE within the FASN promoter completely eliminated the induced activity of LXRα. Our results reveal that buffalo LXRα promotes milk fat synthesis through regulating the expression of FASN by directly interacting with FASN promoter and affecting the SREBF1 expression. This study underscores a crucial role of LXRα in regulating lipid synthesis of the buffalo mammary gland. Show less
Myeloid-derived suppressor cells (MDSCs) emerge as a promising candidate for the immunotherapy of autoimmune hepatitis (AIH). However, targets for modulating MDSC in AIH are still being searched. Live Show more
Myeloid-derived suppressor cells (MDSCs) emerge as a promising candidate for the immunotherapy of autoimmune hepatitis (AIH). However, targets for modulating MDSC in AIH are still being searched. Liver X receptors (LXRs) are important nuclear receptors linking lipid metabolism and immune responses. Despite the extensive studies of LXR in myeloid compartment, its role in MDSCs is currently less understood. Herein, expression of LXRα was found to be upregulated in AIH patients and colocalized with hepatic MDSCs. In ConA-induced hepatitis, deletion of LXRα led to increased expansion of MDSCs in the liver and alleviated the hepatic injury. MDSCs in LXRα We reported that abrogation of LXRα facilitated the expansion of MDSCs Show less
In recent years, the incidence of lipid metabolism disorders in adolescents has gradually increased, and the effects of DEHP on lipid metabolism have received widespread attention. In this study, 463 Show more
In recent years, the incidence of lipid metabolism disorders in adolescents has gradually increased, and the effects of DEHP on lipid metabolism have received widespread attention. In this study, 463 adolescents aged 16-19 years were enrolled as subjects. This study analyzed the associations between the urinary levels of DEHP metabolites (MEHP, MEOHP, MEHHP, MECPP, MCMHP, and ∑DEHP) and BMI, WHR, WtHR, VAI, LAP, the plasma levels of lipids (TC, TG, HDL-C, and LDL-C), and the peripheral blood leukocyte mRNA levels of SREBP-2, SR-BI, LDLR, and NR1H3. Animal experiments were performed to confirm and expand findings. Wistar rats were administered DEHP at 0, 5, 50, and 500 mg/kg/d for 8 weeks. The serum and liver levels of TC, TG, HDL-C, and LDL-C, and the liver mRNA and protein levels of SREBP-2, SR-BI, LDLR, and NR1H3 were measured. The results showed that WHR, VAI, and LAP were significantly positively associated with the urinary levels of MECPP and ∑DEHP; the plasma HDL-C level was significantly negatively associated with the levels of MECPP, MCMHP and ∑DEHP; the peripheral blood leukocyte mRNA levels of SREBP-2, NR1H3, and LDLR were significantly positively correlated with the MCMHP level; and the SR-BI mRNA level was significantly positively correlated with the levels of MECPP and MCMHP in adolescents. Moreover, the results of animal experiments showed that DEHP exposure significantly increased the serum levels of TC, HDL-C, and LDL-C in 500 mg/kg/d group, as well as the liver levels of TC and HDL-C, up-regulated SREBP-2 mRNA and protein expression in 50 and 500 mg/kg/d groups. DEHP exposure significantly down-regulated SR-BI and NR1H3 protein expression in the liver of the 500 mg/kg/d group rats. Our findings indicate that DEHP exposure can affect lipid metabolism in adolescents by regulating the expression of lipid metabolism-related genes. Show less
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. However, because of shared complications between DKD and chronic kidney disease (CKD), the description and characterizati Show more
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. However, because of shared complications between DKD and chronic kidney disease (CKD), the description and characterization of DKD remain ambiguous in the clinic, hindering the diagnosis and treatment of early-stage DKD patients. Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of DKD, early-stage DKD is rarely accompanied by a high estimated glomerular filtration rate, and thus there is a need for new sensitive biomarkers. Transcriptome profiling of kidney tissue has been reported previously, although RNA sequencing (RNA-Seq) analysis of the venous blood platelets in DKD patients has not yet been described. In the present study, we performed RNA-Seq analysis of venous blood platelets from three patients with CKD, five patients with DKD and 10 healthy controls, and compared the results with a CKD-related microarray dataset. In total, 2097 genes with differential transcript levels were identified in platelets of DKD patients and healthy controls, and 462 genes with differential transcript levels were identified in platelets of DKD patients and CKD patients. Through Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, we selected 11 pathways, from which nine potential biomarkers (IL-1B, CD-38, CSF1R, PPARG, NR1H3, DDO, HDC, DPYS and CAD) were identified. Furthermore, by comparing the RNA-Seq results with the GSE30566 dataset, we found that the biomarker KCND3 was the only up-regulated gene in DKD patients. These biomarkers may have potential application for the therapy and diagnosis of DKD, as well aid in determining the mechanisms underlying DKD. Show less
Background Liver X receptor (LXR) belongs to the metabolic nuclear receptor superfamily, which plays a critical regulatory role in vascular physiology/pathology. However, effects of systemic LXR activ Show more
Background Liver X receptor (LXR) belongs to the metabolic nuclear receptor superfamily, which plays a critical regulatory role in vascular physiology/pathology. However, effects of systemic LXR activation on established vulnerable plaques and the potential isotype-specific role involved remain unclear. Methods and Results The 8-week-old male apolipoprotein E Show less
X-linked ectodermal dysplasia receptor (XEDAR) is a new member of the tumor necrosis factor receptor (TNFR) family that induces cell death. The purpose of this study is to determine the tumor-suppress Show more
X-linked ectodermal dysplasia receptor (XEDAR) is a new member of the tumor necrosis factor receptor (TNFR) family that induces cell death. The purpose of this study is to determine the tumor-suppressive potential of XEDAR in the development and differentiation of gastric cancer (GC). XEDAR levels were analyzed in human GC tissues and adjacent normal tissues by immunohistochemistry (IHC), quantitative real-time reverse transcription PCR (RT-qPCR), and Western blot analysis. We found that XEDAR expression was significantly downregulated in GC tissues and further decreased in low differentiated GC tissues. Overexpression of XEDAR in MKN45 and MGC803 cells suppressed the ability of cell proliferation and migration, whereas silencing XEDAR showed the opposite effect. Additionally, XEDAR silencing resulted in the upregulation of the differentiation molecular markers β-catenin, CD44 and Cyclin D1 at the protein levels, whereas XEDAR overexpression showed the opposite effect. Notably, XEDAR positively regulated the expression of liver X receptor alpha (LXRα) through upregulating the RELA gene that was characterized as a transcription factor of LXRα in this study. Inhibition of LXRα by GSK2033 or activation of the Wnt/β-catenin pathway by Wnt agonist 1 impaired the effect of XEDAR overexpression on differentiation of MKN45 cells. Moreover, inhibition of RELA mediated by siRNA could promote cell proliferation/migration and rescue the effect of XEDAR overexpression on cell behaviors and expression of genes. Subsequently, overexpression of XEDAR suppressed the growth of GC cells in Show less
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingx Show more
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingxin Recipe IV (DXR IV) was further improved from the DXR according to the traditional use. However, the mechanism of DXR IV in atherosclerosis is unclear. This study aimed to illustrate whether DXR IV improve atherosclerosis through modulating the lipid metabolism and gut microbiota in atherosclerosis mice. 40 male ApoE DXR IV exerted the anti-atherosclerosis effect by inhibiting the excessive cholesterol deposition in aorta and regulating the level of TG, TC, LDL-C and HDL-C. The composition of gut microbiota was changed. Interestingly, the relative abundance of Muribaculaceae and Ruminococcaceae increased after DXR IV administration, whereas the abundance of Erysipelotrichaceae decreased, which have been beneficial to lipid metabolism. Nine potential metabolic biomarkers, including acetate, butyrate, propionate, alanine, succinate, valerate, xylose, choline, glutamate, were identified, which were related to fatty acid metabolism. Further, the pathway of fatty acid was detected by the RT-qPCR and western blotting. Compared with model group, the level of LXR-α and SREBP1 decreased significantly in DXR IV group while LXR-β, SREBP2 showed no statistical significance. It indicated that DXR IV modulated lipid metabolism by LXR-α/SREBP1 but not LXRβ and SREBP2. DXR IV exhibits potential anti-atherosclerosis effect, which is closely related to lipid metabolism and the gut microbiota. This study may provide novel insights into the mechanism of DXR IV on atherosclerosis and a basis for promising clinical usage. Show less