mTOR pathway is known to promote cancer malignancy and influence cancer immunity but is unknown for its role in immune checkpoint inhibitors (ICI) therapy. Using Memorial Sloan-Kettering Cancer Center Show more
mTOR pathway is known to promote cancer malignancy and influence cancer immunity but is unknown for its role in immune checkpoint inhibitors (ICI) therapy. Using Memorial Sloan-Kettering Cancer Center dataset (MSKCC), we extracted mTOR pathway gene mutations for stepwise Cox regression in 1661 cancer patients received ICI. We associated the mutation of the gene signature resulted from the stepwise Cox regression with the 1661 patients' survival. Other 553 ICI-treated patients were collected from 6 cohorts for validation. We also performed this survival association in patients without ICI treatment from MSKCC as discovery (n = 2244) and The Cancer Genome Atlas (TCGA) as validation (n = 763). Pathway enrichment analysis were performed using transcriptome profiles from TCGA and IMvigor210 trial to investigate the potential mechanism. We identified 8 genes involved in mTOR pathway, including FGFR2, PIK3C3, FGFR4, FGFR1, FGF3, AKT1, mTOR, and RPTOR, resulted from stepwise Cox regression in discovery (n = 1661). In both discovery (n = 1661) and validation (n = 553), the mutation of the 8-gene signature was associated with better survival of the patients treated with ICI, which was independent of tumor mutation burden (TMB) and mainly attributed to the missense mutations. This survival association was not observed in patients without ICI therapy. Intriguingly, the mutation of the 8-gene signature was associated with increased TMB and PD1/PD-L1 expression. Immunologically, pathways involved in anti-tumor immune response were enriched in presence of this mutational signature in mTOR pathway, leading to increased infiltration of immune effector cells (e.g., CD8 + T cells, NK cells, and M1 macrophages), but decreased infiltration of immune inhibitory M2 macrophages. These results suggested that mTOR pathway gene mutations were predictive of better survival upon ICI treatment in multiple cancers, likely by its association with enhanced anti-tumor immunity. Larger studies are warranted to validate our findings. Show less
Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. How Show more
Many studies show that genetics play a major contribution to the onset of obesity. Human genome-wide association studies (GWASs) have identified hundreds of genes that are associated with obesity. However, the majority of them have not been functionally validated. Show less
Yu Zhang, Yuming Zhu, Mo Zhang+9 more · 2022 · European heart journal. Quality of care & clinical outcomes · Oxford University Press · added 2026-04-24
In the clinical practice, the right ventricular (RV) manifestations have received less attention in hypertrophic cardiomyopathy (HCM). This paper aimed to evaluate the risk prediction value and geneti Show more
In the clinical practice, the right ventricular (RV) manifestations have received less attention in hypertrophic cardiomyopathy (HCM). This paper aimed to evaluate the risk prediction value and genetic characteristics of RV involvement in HCM patients. A total of 893 patients with HCM were recruited. RV hypertrophy, RV obstruction, and RV late gadolinium enhancement were evaluated by echocardiography and/or cardiac magnetic resonance. Patients with any of the above structural abnormalities were identified as having RV involvement. All patients were followed with a median follow-up time of 3.0 years. The primary endpoint was cardiovascular death; the secondary endpoints were all-cause death and heart failure (HF)-related death. Survival analyses were conducted to evaluate the associations between RV involvement and the endpoints. Genetic testing was performed on 669 patients. RV involvement was recognized in 114 of 893 patients (12.8%). Survival analyses demonstrated that RV involvement was an independent risk factor for cardiovascular death (P = 0.002), all-cause death (P = 0.011), and HF-related death (P = 0.004). These outcome results were then confirmed by a sensitivity analysis. Genetic testing revealed a higher frequency of genotype-positive in patients with RV involvement (57.0% vs. 31.0%, P < 0.001), and the P/LP variants of MYBPC3 were more frequently identified in patients with RV involvement (30.4% vs. 12.0%, P < 0.001). Logistic analyses indicated the independent correlation between RV involvement and these genetic factors. RV involvement was an independent risk factor for cardiovascular death, all-cause death and HF-related death in HCM patients. Genetic factors might contribute to RV involvement in HCM. Show less
Inhibition of the cholesteryl ester transfer protein (CETP) has been considered as a promising way for the treatment of cardiovascular disease (CVD) for three decades. However, clinical trials of seve Show more
Inhibition of the cholesteryl ester transfer protein (CETP) has been considered as a promising way for the treatment of cardiovascular disease (CVD) for three decades. However, clinical trials of several CETP inhibitors with various potencies have been marginally successful at best, raising doubts on the target drugability of CETP. The in-depth understanding of the glycosylated CETP structure could be beneficial to more definitive descriptions of the CETP function and the underlying mechanism. In this work, large-scale molecular dynamics simulations were performed to thoroughly explore the mechanism of glycans modulating CETP. Here, the extensive simulation results intensely suggest that glycan88 tends to assist CETP in forming a continuous tunnel throughout interacting with the upper-right region of the N-barrel, while it also could prevent the formation of a continuous tunnel by swinging toward the right-rear of the N-barrel. Furthermore, glycan240 formed stable H-bonds with Helix-B and might further stabilize the central cavity of CETP. Furthermore, the nonspecific involvement of the hydroxyl groups from the various glycans with protein core interactions and the similar influence of different glycans trapped at similar regions on the protein structure suggest that physiological glycan may lead to a similar effect. This study would provide valuable insights into devising novel methods for CVD treatment targeting CETP and functional studies about glycosylation for other systems. Show less
Jiaxin Li, Minhan Yi, Binbin Li+5 more · 2022 · Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · Springer · added 2026-04-24
Neurodegenerative genes are critical in neuronal loss in Parkinson's disease (PD). We performed a systematic meta-analysis including all the studies published on PD risk related to genes encoding enzy Show more
Neurodegenerative genes are critical in neuronal loss in Parkinson's disease (PD). We performed a systematic meta-analysis including all the studies published on PD risk related to genes encoding enzymes vital for dopamine metabolism and neuron survival. We included neurodegeneration-related genes which were divided into four groups according to their functions: main enzymes in dopamine metabolism, receptors and transporters for dopamine or other metabolites, neuroprotective factors for dopaminergic neurons, and genes associated with dopaminergic neurons survival reported in other neurological diseases. We collected original articles from PubMed, Embase, and Web of Science databases. Revman 5.3 software was used to analyze data. The allele model (AM) was used to test the effect size of the effect allele between the case group and the control group and secondary analysis using the dominant model (DM) and recessive model (RM) to analyze the contributions from heterozygote and homozygote to the allele risk. Odds ratio (OR) and 95% confidence interval (CI) were used to present the pooled results. We included 31 variants in 20 genes for the final pooled analysis. Consequently, SLC6A4/5-HTT HTTLPR, BDNF rs56164415, FGF20 rs1721100, PARK16 rs823128, rs823156, rs947211, APOE e2, A2M rs669, RIT2 rs12456492, MAPT intron 9 H1H2, and STH rs62063857 variants were statistically associated with PD risk while researched variants in COMT, DBH, MAO, DAT/SLC6A3, DRD2, GRIN2B, GSK3β, ATP13A2, LINGO1, PICALM, and GRN were not related to PD risk. Several variants from neurodegeneration-related genes are associated with PD risk, which may help deepen the understanding of PD pathogenesis and improve clinical treatment strategies. Show less
Accumulated studies have pointed out the striking association between variants in or near This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD b Show more
Accumulated studies have pointed out the striking association between variants in or near This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis. Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: Our results identified a prominent relationship between Show less
Delta-5 desaturase (D5D), encoded by the fatty acid desaturase 1 (FADS1) gene, is a rate-limiting enzyme in polyunsaturated fatty acid (PUFA) synthesis that influences the PUFA levels in milk fat. How Show more
Delta-5 desaturase (D5D), encoded by the fatty acid desaturase 1 (FADS1) gene, is a rate-limiting enzyme in polyunsaturated fatty acid (PUFA) synthesis that influences the PUFA levels in milk fat. However, the function and molecular mechanism of FADS1 in milk fat metabolism remain largely unknown. The Show less
Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their i Show more
Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their interactions with clinical and lifestyle risk factors on ischemic stroke are limited. Methods and Results We sequenced functional regions of 740 previously identified genes associated with atherosclerotic disease among 999 ischemic stroke cases and 1001 controls of Chinese ancestry. Multiple logistic regression models were used to examine the associations between variants and ischemic stroke and test interactions between variants and clinical and lifestyle risk factors. Functional variants achieving suggestive significance were replicated in an independent sample of 4724 ischemic stroke cases and 5029 controls. Driven by variant main effects, each minor allele of the correlated rs174535, rs174545, and rs3834458 variants at Show less
Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classic Show more
Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classical Wnt/β-catenin signaling pathway. Our study was aimed to determine the association between five candidate single nucleotide polymorphisms (SNPs) of LRP5 or AXIN1 and osteoporosis susceptibility in Chinese Han population. A total of 599 osteoporosis patients and 599 healthy individuals were recruited for this case-control study. Agena MassARRAY was used to genotype SNPs. The association between SNPs and osteoporosis susceptibility in different genetic models was analyzed by PLINK software. We used false-positive report probability (FPRP) analysis to detect whether the positive results were just chance or noteworthy observations. Multifactor dimension reduction (MDR) was used to analyze the interaction of SNP-SNP in the osteoporosis risk. Finally, haplotype analysis was performed by plink1.07 and Haploview software. We found that LRP5 rs11228240, AXIN1 rs2301522, and rs9921222 were significantly associated with the osteoporosis susceptibility. The results of subgroup analysis showed that LRP5 rs11228240 (protective factor) and AXIN1 rs2301522 (risk factor) were associated with the susceptibility of osteoporosis among participants who were age >60 years, female or BMI ≤ 24; AXIN1 rs9921222 significantly increased the risk of osteoporosis among participants with BMI ≤ 24. The genotype A The LRP5-rs11228240, AXIN1-rs2301522, and AXIN1- rs9921222 were associated with osteoporosis susceptibility in Chinese Han population. Show less
Osteoarthritis (OA) is a degenerative joint disease that acts as a major cause of early disability in the old population. However, the molecular mechanisms of autophagy in osteoclasts involved in OA r Show more
Osteoarthritis (OA) is a degenerative joint disease that acts as a major cause of early disability in the old population. However, the molecular mechanisms of autophagy in osteoclasts involved in OA remain unclear. The gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) repository. The NCBI GEO2R and ScanGEO analysis tool were used to identify differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was predicted by the STRING website and visualized with Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to enrich GO terms and signaling pathways using Metascape database. To predict LC3-interacting region (LIR) motif among these DEGs, the iLIR database was selected to assess specific short linear sequences. To obtain potential upstream miRNA targets of these DEGs, the mRNA-miRNA interaction networks were predicted by miRWalk database. The knee OA model was performed in mice, and autophagy related mRNAs of osteoclasts were identified. Experimental specimens were further verified with histopathological staining. Our results reveal that the role of autophagy in osteoclasts could be a regulatory mechanism in OA and that these autophagy-related genes might be targets for the intervention of OA disease. Show less
Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibili Show more
Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibility loci and highlight potential risk factors. CAD-associated RNAm-SNPs were identified in the CARDIoGRAMplusC4D and UK Biobank genome-wide association studies. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Cell experiments and Mendelian randomization (MR) methods were applied to test whether the gene expression levels were associated with CAD. We identified 81 RNAm-SNPs that were associated with CAD or acute myocardial infarction (AMI), including m The present study identified RNAm-SNPs in CAD susceptibility genes, gene expression and circulating proteins as risk factors for CAD and suggested that RNA modification may play a role in the pathogenesis of CAD. Show less
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A co Show more
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A comparative proteomics analysis was performed on the cerebrospinal fluid (CSF) from 10 patients with GBS and 10 patients with noninflammatory neurological disease (NND) using the tandem mass tags technique. The differentially expressed proteins were analyzed by bioinformatics, and then the candidate proteins were validated by the enzyme-linked immunosorbent assay method in another cohort containing 160 samples (paired CSF and plasma of 40 patients with GBS, CSF of 40 NND patients and plasma of 40 healthy individuals). In all, 298 proteins were successfully identified in the CSF samples, of which 97 differentially expressed proteins were identified in the GBS and NND groups. Three key molecules were identified as candidate molecules for further validation. The CSF levels of TGOLN2 and NCAM1 decreased in GBS patients compared with NND patients, whereas the CSF levels of APOC3 increased. The enzyme-linked immunosorbent assay results were consistent with our proteomics analysis. Interestingly, in the validation cohort, serum APOC3 levels in the GBS group were consistent with those in the CSF samples and significantly higher than those in the healthy control group. Our preliminary data suggest that the CSF protein expression profile of patients with GBS is different from that of patients with NND. Moreover, alterations of TGOLN2, NCAM1and APOC3 may be used as novel biomarkers for identifying patients with GBS. Show less
The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopa Show more
The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopathological features and genomics. We identified hypoxia-related differentially expressed genes (DEGs) between OC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression (GTEx). LASSO Cox regression analysis was applied for building a prognostic model in the TCGA-GTEx cohorts, and its predictive value was validated in the GEO-OC cohort. Functional enrichment analysis was performed to investigate the underlying mechanisms. By constructing a hypoxia model of the SKOV3 cell line and applying qRT-PCR, we investigated the relationship between hypoxia with two novel genes in the prognostic model (ISG20 and ANGPTL4). Twelve prognostic hypoxia-related DEGs were identified, and nine of them were selected to establish a prognostic model. OC patients were stratified into two risk groups, and the high-risk group showed reduced survival time compared to the low-risk group upon survival analysis. Univariate and multivariate Cox regression analysis demonstrated that the risk score was an independent risk factor for overall survival. The biological function of the identified prognostic hypoxia-related gene signature was involved in immune cell infiltration. Low expression of ISG20 was observed in the CoCl Our findings showed that this hypoxia-related gene signature could serve as a satisfactory prognostic classifier for OC and will be beneficial to the research and development of targeted therapeutic strategies. Show less
Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that det Show more
Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that detects bloodborne factors. Here, we use genetic approaches based on an area postrema cell atlas to reveal inhibitory neurons that counteract nausea-associated poison responses. The gut hormone glucose insulinotropic peptide (GIP) activates area postrema inhibitory neurons that project locally and elicit inhibitory currents in nausea-promoting excitatory neurons through γ-aminobutyric acid (GABA) receptors. Moreover, GIP blocks behavioral responses to poisons in wild-type mice, with protection eliminated by targeted area postrema neuron ablation. These findings provide insights into the basic organization of nausea-associated brainstem circuits and reveal that area postrema inhibitory neurons are an effective pharmacological target for nausea intervention. Show less
The chromobox family, a critical component of epigenetic regulators, participates in the tumorigenesis and progression of many malignancies. However, the roles of the CBX family members (CBXs) in glio Show more
The chromobox family, a critical component of epigenetic regulators, participates in the tumorigenesis and progression of many malignancies. However, the roles of the CBX family members (CBXs) in glioblastoma (GBM) remain unclear. The mRNA expression of CBXs was analyzed in tissues and cell lines by Oncomine and Cancer Cell Line Encyclopedia (CCLE). The differential expression of CBXs at the mRNA level was explored in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases with the "beeswarm" R package. The protein expression of CBXs in GBM was further examined on Human Protein Atlas (HPA). The correlations between CBXs and IDH mutation and between CBXs and GBM subtypes were investigated in the TCGA portal and CGGA database with the "survminer" R package. The alteration of CBXs and their prognostic value were further determined CBXs presented significantly differential expressions in pan-cancers. CBX2/3/5/8 were upregulated, whereas CBX6/7 were downregulated at mRNA level in GBM of TCGA and CGGA databases. Similarly, high expression of CBX2/3/5 and low expression of CBX6/8 were further confirmed at the protein level in the HPA. CBX2/6/7 were positively correlated with IDH mutation and CBX1/2/4/5/8 were closely related to GBM subtypes. CBX7 and CBX8 presented the independent prognostic factors for GBM patient survival. GO and KEGG analyses indicated that CBXs were closely related to the histone H3-K36, PcG protein complex, ATPase, and Wnt pathway. The overexpression of CBX7 and underexpression of CBX8 significantly inhibited the proliferation and invasion of glioma cells Our results suggested that CBX7 and CBX8 served as independent prognostic indicators that promoted the proliferation and invasion of glioma cells, providing a promising strategy for diagnosing and treating GBM. Show less
This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and cli Show more
This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and clinical phenotype. Peripheral blood was collected from a family with hypertrophic cardiomyopathy, and deoxyribonucleic acid was extracted. The possible pathogenic genes were detected by whole-exome sequencing, and the variant was verified by Sanger sequencing. Functional change in the variant was predicted by bioinformatics software. Clinical data of the family members are analysed simultaneously. The proband carries a novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X). The analysis of amino acid conservation suggests that the variation is highly conserved. The three-dimensional protein structure shows that the variant in MYBPC3 results in the incompleteness of the fibronectintype-III2 (p872-967) domain and deletion of Ig-like C2-type 6 (p971-1065) and fibronectin type-III 3 and Ig-like C2-type 7 (p1181-1274) domains, in which p1253-1268 is predicted to have a transmembrane helix structure. Clinical data indicate that the phenotypes of variant carriers with hypertrophic cardiomyopathy are diverse, suggesting the functional damages to the protein of MYBPC3. The phenotypes of variant carriers with hypertrophic cardiomyopathy caused by the novel variant in MYBPC3: c.2731G > T (p.E911X) exhibit variable severity and clinical manifestations. Whole-exome sequencing can be used to comprehensive screen hypertrophic cardiomyopathy genes and provide a strong basis for early screening and accurate diagnosis and treatment of hypertrophic cardiomyopathy in children. Show less
Ying Wang, Jun Liu, Chizuru Akatsu+18 more · 2022 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains Show more
Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance. Show less
Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study Show more
Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study, we aimed to clarify the effects of oridonin (Ori), an active diterpenoid extracted from Rabdosia rubescens, on hyperbilirubinemia and revealed the underlying molecular mechanism in vivo and in vitro. Here, we showed that liver X receptor alpha (LXRα) deletion eliminated the protective effect of Ori on phenylhydrazine hydrochloride-induced hyperbilirubinemia mice, indicating that LXRα acted as a key target for Ori treatment of hyperbilirubinemia. Ori significantly increased the expression of LXRα and UDP-glucuronosyltransferase 1A1 (UGT1A1) in the liver of wild-type (WT) mice, which were lost in LXRα Show less
The role of the dynein light chain Tctex-type 3 (DYNLT3) protein in the biological behavior of cervical cancer and its relative molecular mechanisms were investigated. Immunohistochemical staining was Show more
The role of the dynein light chain Tctex-type 3 (DYNLT3) protein in the biological behavior of cervical cancer and its relative molecular mechanisms were investigated. Immunohistochemical staining was used to detect DYNLT3 protein expression in cervical cancer tissues. Cell proliferation and apoptosis rates and invasiveness and migratory capacities were determined by CCK-8 assays, BrdU staining assays and colony formation assays, fluorescence activated cell sorting (FACS), wound healing assays, and Transwell invasion assays of cervical cancer cells after DYNLT3 modulation. The expression levels of Wnt signaling pathway- and EMT-related proteins were examined by Western blotting. Furthermore, the effects of DYNLT3 on the tumorigenicity and metastasis of cervical cancer in nude mice were analyzed by performing immunohistochemistry, and we found that the expression level of the DYNLT3 protein was higher in human normal cervical tissues than in cervical cancer tissues. Overexpression of DYNLT3 obviously attenuated the proliferation, migration and invasion of CaSki and SiHa cells, and promoted cell apoptosis. Upregulation of DYNLT3 expression markedly decreased the expression of Wnt signaling pathway-related proteins (Dvl2, Dvl3, p-LRP6, Wnt3a, Wnt5a/b, Naked1, Naked2, β-catenin and C-Myc) and EMT-related proteins (N-cadherin, SOX2, OCT4, vimentin and Snail), and increased the expression of E-cadherin and Axin1. However, the opposite results were observed after down-regulation of DYNLT3 expression. Up-regulation of DYNLT3 expression significantly inhibited tumor growth in a nude mouse model, while downregulation of DYNLT3 showed the opposite results. In addition, the major metastatic site of cervical cancer cells in mice was the lung, and downregulation of DYNLT3 expression increased cancer metastasis Show less
Asthma is an airway disease characterized by airflow limitation and various additional clinical manifestations. Repeated inflammatory stimulation of the airways leads to epithelial-mesenchymal transit Show more
Asthma is an airway disease characterized by airflow limitation and various additional clinical manifestations. Repeated inflammatory stimulation of the airways leads to epithelial-mesenchymal transition (EMT) which aggravates subepithelial fibrosis during the process of airway remodelling and enhances resistance to corticosteroids and bronchodilators in refractory asthma. There is growing evidence that IL-27 modulates airway remodelling, however, the molecular mechanisms involving IL-27 and EMT are poorly understood. The objective of this study was to investigate the effects of IL-27 on ovalbumin (OVA)-challenged asthmatic mice in vivo and TGF-β1-induced EMT in 16HBE cells in vitro. Airway inflammation, mucus secretion, and collagen deposition were analysed by conventional pathological techniques. The ratio of Th17 and Th9 cells in the spleen of mice was measured using flow cytometry, ELISA was performed for cytokine analysis to identify EMT-related molecules and signalling pathways, and other molecular and cellular techniques were used to explore the functional mechanism involving IL-27 and EMT. Airway inflammation in asthmatic mice was significantly alleviated by IL-27, with downregulation of RhoA and ROCK, upregulation of E-cadherin, and a decrease of vimentin and α-SMA expression, compared to asthmatic mice. Moreover, the frequency of Th17 and Th9 cells in the spleen of asthmatic mice decreased following treatment with IL-27. In TGF-β1-induced 16HBE cells, the addition of IL-27 was shown to inhibit EMT, based on the expression of E-cadherin, vimentin, and α-SMA. Intranasal administration of IL-27 attenuates airway inflammation and EMT in a murine model of allergic asthma possibly by downregulating the RhoA/ROCK signalling pathway. Show less
Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to im Show more
Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to improve disorders of glucose and lipid metabolism. However, the mechanisms underlying these improvements are largely unclear. Obese ob/ob mice were fed a standard chow, a low fiber diet (LFD) or a high fiber diet (HFD) for 4 weeks, and the body weight, fecal short chain fatty acids (SCFAs) level, and plasma and liver lipid profiles were analyzed. Oral glucose tolerance testing, and gut microbiota sequencing were also conducted. Dietary inulin improved the dysbiosis of the gut microbiota, attenuated the decrease in phylum Bacteroidetes, repressed the increase of phylum Firmicutes, and led to an increase in the ratio of Firmicutes/Bacteroidetes. At the family level, inulin promoted the expansion of SCFAs-producing Ruminococcaceae and Lachnospiraceae bacteria, which increased the fecal SCFAs concentrations. At the genus level, inulin increased the levels of Bacteroides and Bifidobacteria. Furthermore, our results revealed that there was enhanced expression of angiopoietin-like protein 4 (ANGPTL4), which might be induced by the higher production of SCFAs, and this may underlie the improvements in the disorders of glucose and lipid metabolism seen in mice with added dietary inulin. In conclusion, inulin may ameliorate metabolic disorders by remodeling the gut microbiota and increasing the production of SCFAs, which might be mediated by the ANGPTL4-related signaling pathway. Interventions targeting the gut microbiota warrant further investigation as a novel therapy for metabolic diseases. PRACTICAL APPLICATIONS: Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to improve disorders of glucose and lipid metabolism. However, the mechanisms underlying these improvements are largely unclear. In the present study, we investigated the effects of dietary fiber (inulin) on metabolic homeostasis using ob/ob mice. The results of our study demonstrate that inulin-induced remodeling of the gut microbiota resulted in increased production of short chain fatty acids (SCFAs), leading to the enhanced expression of angiopoietin-like protein 4 (ANGPTL4), which improved the glucose and lipid metabolism. Our results suggest that the gut microbiota, SCFAs and ANGPTL4 pathway at least partially mediate the beneficial effects of inulin on metabolic disorders in ob/ob mice. Show less
Glucocorticoids, adrenal-derived steroid hormones, facilitate the physiological response to stress. High-density lipoproteins (HDL) are considered the primary source of cholesterol used for glucocorti Show more
Glucocorticoids, adrenal-derived steroid hormones, facilitate the physiological response to stress. High-density lipoproteins (HDL) are considered the primary source of cholesterol used for glucocorticoid synthesis in mice. Phospholipid transfer protein (PLTP) is a key player in HDL formation. In the current study we tested the hypothesis that HDL deficiency associated with genetic lack of PLTP negatively impacts the adrenal steroid function. We determined the glucocorticoid response to overnight food deprivation stress and the adrenal lipid and genetic phenotype of wild-type and PLTP knockout mice. Basal plasma corticosterone levels, adrenal weights, and adrenocortical neutral lipid stores were not different between wild-type and PLTP knockout mice. Strikingly, plasma corticosterone levels were also equally high in the two groups of mice under fasting conditions (two-way ANOVA genotype effect: P>0.05). However, compensatory mechanisms were active to overcome adrenal lipid depletion, since gene expression levels of cholesterol synthesis, acquisition and mobilization proteins were ~2-fold higher in PLTP knockout adrenals versus wild-type adrenals. In support of an overall similar glucocorticoid stress response, hepatic relative mRNA expression levels of the glucocorticoid receptor target/glucocorticoid-sensitive genes PEPCK, ANGPTL4, FGF21, TDO2 and HMGCS2 were also not different. We have shown that hypocholesterolemic PLTP knockout mice exhibit a normal glucocorticoid response to food deprivation. These novel data (1) highlight that the effect of HDL deficiency on adrenal glucocorticoid output in mice is model dependent and (2) imply that other (lipoprotein) cholesterol sources than HDL can also generate the pool utilized by adrenocortical cells to synthesize glucocorticoids. Show less
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been appli Show more
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been applied to ameliorate cognitive impairment in mild-to-moderate AD patients. However, the overall molecular mechanism of SQYG in treating AD has not been clarified. This study aimed to investigate the molecular mechanism of SQYG on AD using an integration strategy of network pharmacology and molecular docking. The active compounds of SQYG and common targets between SQYG and AD were screened from databases. The herb-compound network, compound-target network, and protein-protein interaction network were constructed. The enrichment analysis of common targets and molecular docking were performed. 816 compounds and 307 common targets between SQYG and AD were screened. KEGG analysis revealed that common targets were mainly enriched in lipid metabolism, metal ion metabolism, IL-17 signaling pathway, GABA receptor signaling, and neuroactive ligand-receptor interaction. Molecular docking analysis showed high binding affinity between ginsenoside Rg1 and A The therapeutic mechanisms of SQYG on AD were associated with regulating lipid metabolism, metal ion metabolism, IL-17 signaling pathway, and GABA receptor signaling. Ginsenoside Rg1, tanshinone IIA, baicalin, astragaloside IV, and folic acid may play an important role in AD treatment. Show less
To explore the diagnosis value of inflammatory markers and cytokines in neonatal sepsis. In this retrospective analysis, 90 cases of neonatal sepsis admitted to our hospital from April 2019 to April 2 Show more
To explore the diagnosis value of inflammatory markers and cytokines in neonatal sepsis. In this retrospective analysis, 90 cases of neonatal sepsis admitted to our hospital from April 2019 to April 2021 were included in the observation group, and 70 healthy neonates who received routine physical examinations in our hospital during the same period were recruited as the control group. Comparison and analysis of inflammatory markers and cytokines levels between the two groups were performed on days 1, 3, and 7 after the onset. Flow cytometry was used to measure the white blood cells (WBCs) and percentage of neutrophils (N%), immunoturbidimetry was used to determine C-reactive protein (CRP), immunochromatographic analysis was used to determine procalcitonin (PCT) in plasma, and the enzyme-linked immunosorbent assay was used to determine interleukin-27 (IL-27), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor- Compared with healthy controls, neonatal sepsis resulted in significantly higher levels of WBC, N%, PCT, and CRP on days 1, 3, and 7 after onset. The levels of WBC, N%, and PCT were continuously decreased from day 1 to day 7, while the levels of CRP were increased on day 1 and day 3 but declined on day 7 ( Neonatal sepsis was associated with fluctuating levels of WBC, N%, PCT, CRP, IL-27, IL-6, IL-10, and TNF- Show less
Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of Wh Show more
Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m Show less
Cardiac dysfunction resulting from sepsis causes high morbidity and mortality. Silibinin (SIL) is a secondary metabolite isolated from the seed extract of the milk thistle plant with various propertie Show more
Cardiac dysfunction resulting from sepsis causes high morbidity and mortality. Silibinin (SIL) is a secondary metabolite isolated from the seed extract of the milk thistle plant with various properties, including anti-inflammatory, anti-fibrotic, and anti-oxidative activities. This study, for the first time, examined the effects and mechanisms of SIL pretreatment, posttreatment and in combination with classical antibiotics in septic myocardial injury. The survival rate, sepsis score, anal temperature, routine blood parameters, blood biochemical parameters, cardiac function indicators, pathological indicators of myocardial injury, NR1H3 signaling pathway, and several sepsis-related signaling pathways were detected 8 h following cecal ligation and puncture (CLP). Our results showed that SIL pretreatment showed a significant protective effect on sepsis and septic myocardial injury, which was explained by the attenuation of inflammation, inhibition of oxidative stress, improvement of mitochondrial function, regulation of endoplasmic reticulum stress (ERS), and activation of the NR1H3 pathway. SIL posttreatment and the combination of SIL and azithromycin (AZI) showed a certain therapeutic effect. RNA-seq detection further clarified the myocardial protective mechanisms of SIL. Taken together, this study provides a theoretical basis for the application strategy and combination of SIL in septic myocardial injury. Show less
Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity o Show more
Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities. Show less
The heterogeneity of hepatocellular carcinoma (HCC) highlights the importance of precision therapy. In recent years, single-cell RNA sequencing has been used to reveal the expression of genes at the s Show more
The heterogeneity of hepatocellular carcinoma (HCC) highlights the importance of precision therapy. In recent years, single-cell RNA sequencing has been used to reveal the expression of genes at the single-cell level and comprehensively study cell heterogeneity. This study combined big data analytics and single-cell data mining to study the influence of genes on HCC prognosis. The cells and genes closely related to the HCC were screened through single-cell RNA sequencing (71,915 cells, including 34,414 tumor cells) and big data analysis. Comprehensive bioinformatics analysis of the key genes of HCC was conducted for molecular classification and multi-dimensional correlation analyses, and a prognostic model for HCC was established. Finally, the correlation between the prognostic model and clinicopathological features was analyzed. 16,880 specific cells, screened from the single-cell expression profile matrix, were divided into 20 sub-clusters. Cell typing revealed that 97% of these cells corresponded to HCC cell lines, demonstrating the high specificity of cells derived from single-cell sequencing. 2,038 genes with high variability were obtained. The 371 HCC samples were divided into two molecular clusters. Cluster 1 (C1) was associated with tumorigenesis, high immune score, immunotherapy targets (PD-L1 and CYLA-4), high pathological stage, and poor prognosis. Cluster 2 (C2) was related to metabolic and immune function, low immune score, low pathological stage, and good prognosis. Seven differentially expressed genes (CYP3A4, NR1I2, CYP2C9, TTR, APOC3, CYP1A2, and AFP) identified between the two molecular clusters were used to construct a prognostic model. We further validated the correlation between the seven key genes and clinical features, and the established prognostic model could effectively predict HCC prognosis. Our study identified seven key genes related to HCC that were used to construct a prognostic model through single-cell sequencing and big data analytics. This study provides new insights for further research on clinical targets of HCC and new biomarkers for clinical application. Show less