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
Hypoxia can cause Epithelial-mesenchymal transition (EMT) in renal tubular cells, and in turn, renal fibrosis. We tested the expression of TRIM46, a member of tripartite motif-containing (TRIM) family Show more
Hypoxia can cause Epithelial-mesenchymal transition (EMT) in renal tubular cells, and in turn, renal fibrosis. We tested the expression of TRIM46, a member of tripartite motif-containing (TRIM) family proteins, and mesenchymal markers under hypoxia. Our results showed that hypoxia significantly enhanced expression of TRIM46 in HK2 human renal proximal tubular epithelial cells. Our data further showed that hypoxia led to upregulated expression of mesenchymal markers including α-smooth muscle actin, vimentin, and Snail, and downregulated expression of epithelial marker E-cadherin, coupled with an increased abundance of nuclear β-catenin. However, such effects were reversed when TRIM46 expression was knocked down. TRIM46 overexpression had similar effects as hypoxia exposure, and such effects were reversed when cells were treated with XAV-939, a selective inhibitor for β-catenin. Furthermore, we found that TRIM46 promoted ubiquitination and proteasomal degradation of Axin1 protein, a robust negative regulator of Wnt/β-catenin signaling activity. Finally, increased TRIM46 coupled with decreased Axin1 was observed in a rat renal fibrosis model. These data suggest a novel mechanism contributing to EMT that mediates hypoxia-induced renal fibrosis. Our results suggest that selectively inhibiting this pathway that activates fibrosis in human kidney may lead to development of a novel therapeutic approach for managing this disease. 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
Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-o Show more
Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend 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
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
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
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
The dynamic balance between ubiquitination and deubiquitination is a key mechanism that regulates protein degradation and maintains cell protein homeostasis. Ubiquitin-specific peptidase 13 (USP13), a Show more
The dynamic balance between ubiquitination and deubiquitination is a key mechanism that regulates protein degradation and maintains cell protein homeostasis. Ubiquitin-specific peptidase 13 (USP13), a deubiquitinase (DUB), regulates various physiological and pathological processes, including cancer. A previous study reported that high USP13 mRNA expression confers poor prognosis in gastric cancer (GC). However, the biological function of USP13 in GC remains unknown. Here, we revealed that USP13 expression was upregulated in GC tissue samples compared to noncancerous tissues. USP13-positive expression was associated with poor differentiation, high invasiveness, and advanced tumor stage. Notably, upregulated USP13 expression was closely correlated with the reduced survival of GC patients. We also confirmed increased USP13 expression in GC cell lines. USP13 knockdown prominently suppressed MGC-803 cell migration and invasion. Conversely, USP13 overexpression markedly enhanced SGC-7901 cell motility. Furthermore, USP13 positively regulates the epithelial-mesenchymal transition (EMT) of GC cells. Interestingly, USP13 remarkably enhanced Snail protein expression but did not affect its mRNA levels in GC cells. We confirmed a positive correlation between USP13 and Snail expression in GC tissues. Mechanistically, USP13 knockdown promoted Snail degradation, which could be blocked by the proteasome inhibitor MG132. USP13 interacted with Snail to deubiquitinate and stabilize Snail in GC cells. Finally, Snail knockdown significantly blocked USP13-induced SGC-7901 cell migration and invasion. In conclusion, USP13 overexpression was frequently detected in GC and contributed to the EMT and metastasis of GC by stabilizing Snail. 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
Small therapeutic proteins are receiving increased interest as therapeutic drugs; however, their clinical success has been limited due to their rapid elimination. Here, we report a half-life extension Show more
Small therapeutic proteins are receiving increased interest as therapeutic drugs; however, their clinical success has been limited due to their rapid elimination. Here, we report a half-life extension strategy via strategy via red blood cell red blood cell (RBC) hitch-hiking. This manuscript details the development and characterization of novel anti-RBC single-domain antibodies (sdAbs), their genetic fusion to therapeutic antibody fragments (TAF) as bispecific fusion constructs, and their influence on TAF pharmacokinetics and biodistribution. Several sdAbs specific to the band 3 antigen were generated via phage-display technology. Binding affinity to RBCs was assessed via flow cytometry. Affinity maturation via random mutagenesis was carried out to improve the binding affinity of the sdAbs. Bi-specific constructs were generated by fusing the anti-RBC sdAbs with anti-tissue necrosis factor alpha (TNF-α) TAF via the use of a glycine-serine flexible linker, and assessments for binding were performed via enzyme-linked immunosorbent assay and flow cytometry. Pharmacokinetics of anti-RBC sdAbs and fusion constructs were evaluated following intravenous bolus dosing in mice at a 1 mg/kg dose. Two RBC-binding sdAbs, RB12 and RE8, were developed. These two clones showed high binding affinity to human RBC with an estimated K Show less
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: Show more
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: We aimed to screen the effective constituent of N. nucifera alkaloids and elucidated the potential mechanism for treating hyperlipidemia. A triple combination strategy of UHPLC-MS We comprehensively investigated the characterization of N. nucifera alkaloids by using UHPLC-LTQ-Orbitrap MS 35 compounds were identified from N. nucifera alkaloid extraction by UHPLC-LTQ-Orbitrap MS O-nornuciferine and N. nucifera alkaloids had exibited significant effects in hyperlipidemia. The candidate genes were LDLR, LPL and ANGPTL4, etc. It was most likely that they adjusted lipid metabolism by modulating expression levels of various key factors which were involved in bile secretion, glycerolipid metabolism, sphingolipid metabolism and PPAR signaling pathway, and so on. This study clarified the hypolipidemic mechanism of the alkaloids in N. nucifera, and laid a foundation for the subsequent development of clinical application and better quality of N. nucifera. 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
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can Show more
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety. Show less
Childhood overweight and obesity (OW/OB) is a worldwide public health problem, and its genetic risks remain unclear. To investigate risks of OW/OB associated with genetic variances in We conducted a c Show more
Childhood overweight and obesity (OW/OB) is a worldwide public health problem, and its genetic risks remain unclear. To investigate risks of OW/OB associated with genetic variances in We conducted a case-control study with 734 infants included at delivery and followed up to 12-month old. The classification and regression tree analysis were used to generate the structure of the gene-gene interactions, while the unconditional multivariate logistic regression models were applied to analyze the single SNP, gene-gene interactions, and cumulative effects of the genotypes on OW/OB, adjusted for potential confounders. There were 219 (29.84%) OW/OB infants. Rs543874 G allele and rs11030104 AA genotype increased the risk of OW/OB in 12-month-old infants ( Rs543874, rs11030104, and rs11191580 were associated with OW/OB in 12-month-old Chinese infants, and the three SNPs together with rs10913469 and rs11165675 had a combined effect on OW/OB. 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
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
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
Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to i Show more
Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to identify 27 unique chemical components of YZD. Analyzing these using network pharmacology and molecular docking models identified 34 potential interacting molecular targets involved in 26 biochemical pathways. When tested in an animal model of AD, the APP/PS1 transgenic mice showed measurable improvements in spatial orientation and memory after the administration of YZD. These improvements coincided with significantly reduced deposition of Aβ plaques and tau protein in the hippocampi in the treated animals. In addition, a decreased BACE1 and beta-amyloid levels, a downregulation of the p-GSK-3β/GSK-3β, and an upregulation of the PI3K and p-AKT/AKT pathway was seen in YZD treated animals. These 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
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, with high incidence and mortality rates and low survival rates. However, the detailed molecular mechanism of ESCC Show more
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, with high incidence and mortality rates and low survival rates. However, the detailed molecular mechanism of ESCC progression remains unclear. Here, we first showed significantly higher WNT5A and SNAIL expression in ESCC samples than in corresponding paracancerous samples. High WNT5A and SNAIL expression levels correlated positively with lymphatic metastasis and poor prognosis for patients with ESCC based on immunohistochemical (IHC) staining of 145 paired ESCC samples. Spearman's correlation analyses confirmed the strong positive correlation between WNT5A and SNAIL expression, and patients with ESCC presenting coexpression of WNT5A and SNAIL had the worst prognosis. Then, we verified that the upregulation of WNT5A promoted ESCC cell metastasis in vivo and in vitro, suggesting that WNT5A might be a promising therapeutic target for the prevention of ESCC. Furthermore, WNT5A overexpression induced the epithelial-mesenchymal transition via histone deacetylase 7 (HDAC7) upregulation, and HDAC7 silencing significantly reversed WNT5A-induced SNAIL upregulation and ESCC cell metastasis. In addition, we used HDAC7 inhibitors (SAHA and TMP269) to further confirm that HDAC7 participates in WNT5A-mediated carcinogenesis. Based on these results, HDAC7 is involved in WNT5A-mediated ESCC progression, and approaches targeting WNT5A and HDAC7 might be potential therapeutic strategies for ESCC. Show less
Lung adenocarcinoma (LUAD) is a common malignant tumor with a poor prognosis. Recent studies have found that angiopoietin-like 4 (ANGPTL4) is abnormally expressed in many tumors, so it can serve as a Show more
Lung adenocarcinoma (LUAD) is a common malignant tumor with a poor prognosis. Recent studies have found that angiopoietin-like 4 (ANGPTL4) is abnormally expressed in many tumors, so it can serve as a potential prognostic marker and therapeutic target. However, its prognostic value in LUAD remains unclear. We downloaded RNA sequence data for LUAD from The Cancer Genome Atlas (TCGA) database, methylation data from the University of California Santa Cruz genome database, and clinical information. R software (version 4.1.1) was applied to analyze the ANGPTL4 expression in LUAD and nontumor samples, and the correlation with clinical characteristics to assess its prognostic and diagnostic value. In addition, we analyzed the relationship between the ANGPTL4 expression and methylation levels. Tumor IMmune Estimation Resource (TIMER) tool was taken for immune infiltration analysis, and two Gene Expression Omnibus (GEO) datasets were combined for meta-analysis. Finally, differentially expressed genes (DEGs) related to ANGPTL4 were analyzed to clarify its function. As shown in our results, ANGPTL4 was upregulated in LUAD and was an independent risk factor for the diagnosis and prognosis of LUAD. The general methylation level and eight ANGPTL4 methylation sites were significantly negatively correlated with the ANGPTL4 expression. Furthermore, we found that B cell infiltration was negatively correlated with ANGPTL4 expression and was an independent risk factor. Meta-analysis showed that the high expression of ANGPTL4 was closely associated with a poor prognosis. 153 DEGs, including the matrix metalloproteinase family, the chemokines subfamily, and the collagen family, were correlated with ANGPTL4. In this study, we found that ANGPTL4 was significantly elevated in LUAD and was closely associated with the development and poor prognosis of LUAD, suggesting that ANGPTL4 may be a prognostic biomarker and a potential therapeutic target for LUAD. Show less
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are majo Show more
Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulated 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
We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methyla Show more
We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10 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
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, pla Show more
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, plasma exosomes were extracted from 3 patients with AF and 3 patients with sinus rhythm (SR), respectively. Differential expression of exosomal miRNAs were screened by high-throughput sequencing analysis and verified by qRT-PCR from 40 patients with AF and 40 patients with SR. The target genes prediction, biological function, and signaling pathways analysis were conducted by miRanda software, gene ontology (GO), and KEGG analysis. The results showed that there were 40 differently expressed exosomal miRNAs from AF patients compared with SR patients, of which 13 miRNAs were upregulated and 27 miRNAs were downregulated. qRT-PCR validation demonstrated that miR-124-3p, miR-378d, miR-2110, and miR-3180-3p were remarkably upregulated, while miR-223-5p, miR-574-3p, miR-125a-3p, and miR-1299 were downregulated. To explore the function of miR-124-3p associated with AF, plasma exosomes derived from AF patients were co-incubated with rat myocardial fibroblasts. The expression of miR-124-3p was upregulated in myocardial fibroblasts. The viability and proliferation of myocardial fibroblasts were elevated by transfecting with miR-124-3p overexpression plasmids using CCK8 and immunofluorescence-staining methods. AXIN1 was verified to be the target of miR-124-3p by luciferase assay in vitro. Expression of AXIN1 was reduced, while β-catenin, Collagen 1, and α-SMA were increased in myocardial fibroblasts with miR-124-3p overexpression. In conclusion, these findings suggested that circulating exosomal miRNAs may serve as novel biomarkers for AF, and miR-124-3p promotes fibroblast activation and proliferation through regulating WNT/β-catenin signaling pathway via AXIN1. Show less