Risk factors for prostate cancer: An umbrella review of prospective observational studies and mendelian randomization analyses.

BACKGROUND: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. CONCLUSIONS: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.

The activation impact of lactobacillus-derived extracellular vesicles on lipopolysaccharide-induced microglial cell.

Perioperative neurocognitive dysfunction (PND) emerges as a common postoperative complication among elderly patients. Currently, the mechanism of PND remains unclear, but there exists a tendency to believe that inflammation plays a significant role in PND. Alterations in the abundance of intestinal microbiota can increase the permeability of the intestinal mucosal barrier and incite extraintestinal inflammatory responses. Metabolites from these microbiota can be absorbed by the intestinal mucosa into the bloodstream, exerting influence upon the central nervous system (CNS). Lactobacillus (Lac), serving as an intestinal probiotic bacterium, possesses the capacity to modulate emotional behavior and cognitive functions. Extracellular vesicles (EVs) are recognized as novel therapeutic carriers for targeted delivery to regulate physiology and pathogenesis. While the mechanism governing the primary function of Lac-EVs in the CNS remains uncertain. Therefore, we established an in vitro neuroinflammation model to induce PND and then treated the mice with Lac-EVs to observe the effect of these EVs on neuroinflammation, particularly on microglial (MG) polarization. Our research unveils that Lac-EVs reduced inflammation induced by LPS in microglia and the activation of related proteins, including the mRNA expression of M1 labeled protein (iNOS). Moreover, the mRNA expression of M2-labeled protein (Arg1) increased. In addition, flow cytometry revealed that the ratio of M1/M2 microglia also changed significantly. Therefore, Lac-EVs promoted the differentiation of M2 microglia by inducing the preferential expression of specific markers related to M2 macrophages and inflammation. In terms of inflammatory cytokine expression, Lac-EVs decreased the secretion of proinflammatory cytokines (IL-1ß and IL-6) and increased IL-10 production after lipopolysaccharide (LPS) stimulation. Therefore, Lac-EVs induce the activation of M2 microglial cells without inducing cellular harm in vitro, and they demonstrate anti-inflammatory effects against lipopolysaccharide-induced neuroinflammation. This finding suggested that it is an effective anti-inflammatory strategy for alleviating inflammation-driven PNDs.

SUMOylation of annexin A6 retards cell migration and tumor growth by suppressing RHOU/AKT1-involved EMT in hepatocellular carcinoma.

BACKGROUND: The protein annexin A6 (AnxA6) is involved in numerous membrane-related biological processes including cell migration and invasion by interacting with other proteins. The dysfunction of AnxA6, including protein expression abundance change and imbalance of post-translational modification, is tightly related to multiple cancers. Herein we focus on the biological function of AnxA6 SUMOylation in hepatocellular carcinoma (HCC) progression. METHODS: The modification sites of AnxA6 SUMOylation were identified by LC-MS/MS and amino acid site mutation. AnxA6 expression was assessed by immunohistochemistry and immunofluorescence. HCC cells were induced into the epithelial-mesenchymal transition (EMT)-featured cells by 100 ng/mL 12-O-tetradecanoylphorbol-13-acetate exposure. The ability of cell migration was evaluated under AnxA6 overexpression by transwell assay. The SUMO1 modified AnxA6 proteins were enriched from total cellular proteins by immunoprecipitation with anti-SUMO1 antibody, then the SUMOylated AnxA6 was detected by Western blot using anti-AnxA6 antibody. The nude mouse xenograft and orthotopic hepatoma models were established to determine HCC growth and tumorigenicity in vivo. The HCC patient's overall survival versus AnxA6 expression level was evaluated by the Kaplan-Meier method. RESULTS: Lys579 is a major SUMO1 modification site of AnxA6 in HCC cells, and SUMOylation protects AnxA6 from degradation via the ubiquitin-proteasome pathway. Compared to the wild-type AnxA6, its SUMO site mutant AnxA6K579R leads to disassociation of the binding of AnxA6 with RHOU, subsequently RHOU-mediated p-AKT1ser473 is upregulated to facilitate cell migration and EMT progression in HCC. Moreover, the SENP1 deSUMOylates AnxA6, and AnxA6 expression is negatively correlated with SENP1 protein expression level in HCC tissues, and a high gene expression ratio of ANXA6/SENP1 indicates a poor overall survival of patients. CONCLUSIONS: AnxA6 deSUMOylation contributes to HCC progression and EMT phenotype, and the combination of AnxA6 and SENP1 is a better tumor biomarker for diagnosis of HCC grade malignancy and prognosis.

Antitumor immunity and prognosis value elicited by FAT3 and LRP1B co-mutation in endometrial cancer.

OBJECTIVE: FAT3 and LRP1B are two tumor suppressor genes with high mutation frequency in multiple cancer types, we sought to investigate the prognostic and immunological significance of these two genes in EC. METHODS: Based on a cohort of 502 EC samples, we conducted a comprehensive analysis of its multidimensional data types including genomic, transcriptomic, and clinical information, the potential impact of FAT3 and LRP1B co-mutation on antitumor immune response and prognosis were systematically discussed. RESULTS: We observed that FAT3 and LRP1B co-mutation was not only defined a dataset with prominently increased TMB, decreased tumor aneuploidy, and specially enriched in MSI-H subtype, but also manifested increased expression of immune-related markers, especially exclusive upregulation of PD-L1 levels and higher PD-L1+/CD8A+ proportion. Further analysis focused on lymphocyte infiltration and pathway enrichment explored the immune cell composition of the microenvironment and underlying molecular mechanisms affecting tumor development. Furthermore, EC patients with FAT3 and LRP1B co-mutation possessed significantly prolonged PFS and OS, and the co-mutation status was proved to be an independent prognostic factor. And a nomogram with high predictive performance was constructed by incorporating co-mutation with clinical features. More strikingly, the prognosis of MSI-H patients in EC with co-mutation was significantly improved, and their survival reached a level consistent with the POLE subtype. CONCLUSIONS: In endometrial cancer, co-mutation of FAT3 and LRP1B not only leads to activation of the immune state, but also represents a subgroup with an improved prognosis, particularly in the MSI-H subtype.

Inhibition of high-fat diet-induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms.

Obesity is a risk factor for insulin resistance, type 2 diabetes, and cardiovascular diseases. Reticulon-4 (Nogo) is an endoplasmic reticulum-resident protein with unclear functions in obesity. Herein, we investigated the effect of Nogo on obesity and associated metabolic disorders. Human serum samples were collected to explore the relationship between circulating Nogo-B and body mass index value. Nogo-deficient and WT littermate control mice were fed normal chow or high-fat diet (HFD) for 14 weeks, and HFD-induced obese C57BL/6J mice were injected scrambled or Nogo siRNA for 2 weeks. We found that in human and mouse serum, Nogo-B was positively correlated to body mass index/bodyweight and lipid profiles. Reduced Nogo (by genetic deletion or siRNA transfection) protected mice against HFD-induced obesity and related metabolic disorders. We demonstrate that Nogo deficiency reversed HFD-induced whitening of brown adipose tissue, thereby increasing thermogenesis. It also ameliorated lipid accumulation in tissues by activating the adiponectin-adiponectin receptor 1-AMP-activated kinase α signaling axis. Finally, Nogo deficiency potently reduced HFD-induced serum proinflammatory cytokines and infiltration of macrophages into metabolic organs, which is related to enhanced NF-κB p65 degradation via the lysosome pathway. Collectively, our study suggests that reduced levels of Nogo protect mice against HFD-induced obesity by increasing thermogenesis and energy metabolism while inhibiting NF-κB-mediated inflammation. Our results indicate that inhibition of Nogo may be a potential strategy for obesity treatment.

Transcriptome comparison analyses in UV-B induced AsA accumulation of Lactuca sativa L.

BACKGROUND: Lettuce (Lactuca sativa L.) cultivated in facilities display low vitamin C (L-ascorbic acid (AsA)) contents which require augmentation. Although UV-B irradiation increases the accumulation of AsA in crops, processes underlying the biosynthesis as well as metabolism of AsA induced by UV-B in lettuce remain unclear. RESULTS: UV-B treatment increased the AsA content in lettuce, compared with that in the untreated control. UV-B treatment significantly increased AsA accumulation in a dose-dependent manner up until a certain dose.. Based on optimization experiments, three UV-B dose treatments, no UV-B (C), medium dose 7.2 KJ·m- 2·d- 1 (U1), and high dose 12.96 KJ·m- 2·d- 1 (U2), were selected for transcriptome sequencing (RNA-Seq) in this study. The results showed that C and U1 clustered in one category while U2 clustered in another, suggesting that the effect exerted on AsA by UV-B was dose dependent. MIOX gene in the myo-inositol pathway and APX gene in the recycling pathway in U2 were significantly different from the other two treatments, which was consistent with AsA changes seen in the three treatments, indicating that AsA accumulation caused by UV-B may be associated with these two genes in lettuce. UVR8 and HY5 were not significantly different expressed under UV-B irradiation, however, the genes involved in plant growth hormones and defence hormones significantly decreased and increased in U2, respectively, suggesting that high UV-B dose may regulate photomorphogenesis and response to stress via hormone regulatory pathways, although such regulation was independent of the UVR8 pathway. CONCLUSIONS: Our results demonstrated that studying the application of UV-B irradiation may enhance our understanding of the response of plant growth and AsA metabolism-related genes to UV-B stress, with particular reference to lettuce.

Epidemiological and genetic evidence for the relationship between ABO blood group and human cancer.

To comprehensively evaluate the etiological role of ABO blood group in human cancer, we conducted a large-scale meta-analysis of 127 publications totaling 20 million participants including 231 737 patients of 20 cancers, supplemented by genetic evidence. Effects of A, AB and B groups on cancer risk were investigated by respectively comparing with O group and their combined counterparts, and subgroup analysis by ethnicity was conducted for O-referent models. For cancer categories, A group increased risk of cancers of oral cavity and nasopharynx, digestive and female genital organs, while both AB and B groups showed associations with cancers of digestive and female genital organs. For individual cancers, A group significantly increased the risk of nine cancers including oral cavity (OR = 1.17, P = .013), stomach (OR = 1.19, P = 3.90 × 10-15 ), pancreas (OR = 1.33, P = 9.89 × 10-33 ), colorectum (OR = 1.09, P = .001), liver (OR = 1.23, P = .011), ovary (OR = 1.13, P = .001), cervix (OR = 1.17, P = .025), bladder (OR = 1.12, P = .025) and breast (OR = 1.06, P = .043). AB group showed associations with only three cancers: stomach (OR = 1.10, P = .007), pancreas (OR = 1.21, P = .001) and ovary (OR = 1.28, P = .006). B group, except for shared associations with A group on pancreas (OR = 1.20, P = 2.27 × 10-5 ) and cervix cancers (OR = 1.13, P = .011), had two distinct associations with esophagus (OR = 1.17, P = .002) and nonmelanoma skin cancers (OR = 0.96, P = .017). Ethnicity-specific analyses revealed the notable effects of non-O groups on pancreatic cancer both in Caucasians and Asians. In genetic analysis, four SNPs were associated with the risk of pancreatic cancer, with rs505922 corresponding to O group showing the strongest protective effect (P = 1.16 × 10-23 ). Our study provided comprehensive evidence of ABO blood group associated with cancers and highlighted its carcinogenic role.

Impact of gallstone disease on the risk of stroke and coronary artery disease: evidence from prospective observational studies and genetic analyses.

BACKGROUND: Despite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events - stroke and coronary artery disease (CAD). METHODS: We first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB). RESULTS: An overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19-1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke ([Formula: see text]=0.16, P = 6.00 × 10-4) and CAD ([Formula: see text]=0.27, P = 2.27 × 10-15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97-1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98-1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83-1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91-1.06), further supporting MR findings. CONCLUSIONS: Our work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.

Using human genetics to understand the epidemiological association between obesity, serum urate, and gout.

OBJECTIVES: We aimed to clarify the genetic overlaps underlying obesity-related traits, serum urate, and gout. METHODS: We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci, and causal relationships between obesity (the exposure variable), gout (the primary outcome) and serum urate (the secondary outcome). Summary statistics were collected from the hitherto largest genome-wide association studies conducted for BMI (N = 806 834), waist-to-hip ratio (WHR; N = 697 734), WHR adjusted for BMI (WHRadjBMI; N = 694 649), serum urate (N = 288 649), and gout (Ncases = 13 179 and Ncontrols = 750 634). RESULTS: Positive overall genetic correlations were observed for BMI (rg = 0.27, P = 6.62 × 10-7), WHR (rg = 0.22, P = 6.26 × 10-7) and WHRadjBMI (rg = 0.07, P = 6.08 × 10-3) with gout. Partitioning the whole genome into 1703 LD (linkage disequilibrium)-independent regions, a significant local signal at 4q22 was identified for BMI and gout. The global and local shared genetic basis was further strengthened by the multiple pleiotropic loci identified in the cross-phenotype association study, multiple shared gene-tissue pairs observed by Transcriptome-wide association studies, as well as causal relationships demonstrated by Mendelian randomization [BMI-gout: OR (odds ratio) = 1.66, 95% CI = 1.45, 1.88; WHR-gout: OR = 1.57, 95% CI = 1.37, 1.81]. Replacing the binary disease status of gout with its latent pathological measure, serum urate, a similar pattern of correlation, pleiotropy and causality was observed with even more pronounced magnitude and significance. CONCLUSION: Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis and pleiotropic loci, as well as a causal relationship between obesity, serum urate, and gout, highlighting an intrinsic link underlying these complex traits.

Systematic investigation of simultaneous copper biosorption and nitrogen removal from wastewater by an aerobic denitrifying bacterium of auto-aggregation.

Finding effective methods for simultaneous removal of eutrophic nutrients and heavy metals has attracted increasing concerns for the environmental remediation. Herein, a novel auto-aggregating aerobic denitrifying strain (Aeromonas veronii YL-41) was isolated with capacities for copper tolerance and biosorption. The denitrification efficiency and nitrogen removal pathway of the strain were investigated by nitrogen balance analysis and amplification of key denitrification functional genes. Moreover, the changes in the auto-aggregation properties of the strain caused by extracellular polymeric substances (EPS) production were focused on. The biosorption capacity and mechanisms of copper tolerance during denitrification were further explored by measuring changes in copper tolerance and adsorption indices, as well as by variations in extracellular functional groups. The strain showed extremely strong total nitrogen removal ability, with 67.5%, 82.08% and 78.48% of total nitrogen removal when NH4+-N, NO2--N, and NO3--N were used as the only initial nitrogen source, respectively. The successful amplification of napA, nirK, norR, and nosZ genes further demonstrated that the strain accomplished nitrate removal through a complete aerobic denitrification pathway. The production of protein-rich EPS of up to 23.31 mg/g and an auto-aggregation index of up to 76.42% may confer a strong biofilm-forming potential to the strain. Under the stress of 20 mg/L copper ions, the removal of nitrate-nitrogen was still as high as 71.4%. In addition, the strain could achieve an efficient removal of 96.9% of copper ions at an initial concentration of 80 mg/L. Scanning electron microscopy and deconvolution analysis of characteristic peaks confirmed that the strains encapsulate heavy metals by secreting EPS and, meanwhile, form strong hydrogen bonding structures to enhance intermolecular forces to resist copper ion stress. This study provides an innovative and effective biological approach for the synergistic bioaugmentation removal of eutrophic substances and heavy metals from aquatic environments.

FBXW7 inhibits the progression of ESCC by directly inhibiting the stemness of tumor cells.

F-box and WD repeat domain containing 7 (FBXW7) is an aboriginal and high-frequency mutant gene associated with esophageal squamous cell carcinoma (ESCC). This study was designed to determine the clinical value and molecular mechanisms of FBXW7 in the development of ESCC. The clinical significance of FBXW7 was analyzed in ESCC from TCGA data. The effects of FBXW7 on proliferation, colony formation, migration and invasion, angiogenesis, and apoptosis were tested in ESCC cells. PCR-array, sphere formation assay, and quantitative real-time polymerase chain reaction (qPCR) were used to explore the mechanism of FBXW7. FBXW7 was a significantly mutated gene in ESCC. It was an independent and potential predictor for survival in ESCC patients. In addition, FBXW7 overexpression significantly inhibited ESCC cell proliferation, migration, invasion, angiogenesis, and promoted cell apoptosis. PCR array revealed that FBXW7 overexpression leads to a significant change of gene expressions associated with angiogenesis, cell senescence, and DNA damage and repair. Sphere formation assay and qPCR showed FBXW7 was associated with ESCC stem cell formation. Our results suggest that FBXW7 may act as a tumor suppressor by repressing cancer stem cell formation and regulating tumor angiogenesis, cell senescence, DNA damage, and repair in ESCC.

Z-score regression model for coronary artery diameter in healthy Chinese Han children.

BACKGROUND: Coronary artery distension and aneurysm are complications of Kawasaki disease in children. PURPOSE: To develop a Z-score regression model for coronary artery diameter in children that could be used as reference. MATERIAL AND METHODS: This retrospective analysis included children with normal heart structure between March 2013 and April 2017. Body surface area (BSA) was calculated. The diameters of the right coronary, left main coronary, left anterior descending, and circumflex arteries were measured by echocardiography. Pearson correlation analysis was used to establish linear, exponential, logarithmic, power, and square root regression models. RESULTS: The analysis included 509 children (280 boys) aged 1 day to 15.2 years. Coronary artery diameters were significantly correlated with age, height, body mass, BSA, and BSA (r = 0.663-0.826; P < 0.05), with a stronger correlation for BSA than BSA (P < 0.05). The adjusted determination coefficients (Ra2) were higher for the exponential and square root models than for the other models (P < 0.05). The random error term variance was constant for the exponential model (P > 0.05), and processing with the weighted least-square methods eliminated heteroscedasticity in the other models. The Z-scores were normally distributed for the exponential and square root models (P > 0.05). CONCLUSION: Overall, the square root model was the optimal equation for the calculation of coronary artery Z-score in Chinese Han children. This model could be used to facilitate the diagnosis of coronary artery distension in children with suspected Kawasaki disease.

Hypoxia-based classification and prognostic signature for clinical management of hepatocellular carcinoma.

OBJECTIVE: Intratumoral hypoxia is an essential feature of hepatocellular carcinoma (HCC). Herein, we investigated the hypoxia-based heterogeneity and relevant clinical implication in HCC. METHODS: Three HCC cohorts: TCGA-LIHC, LICA-FR, and LIRI-JP were retrospectively gathered. Consensus clustering analysis was utilized for hypoxia-based classification based upon transcriptome of hypoxia genes. Through LASSO algorithm, a hypoxia-relevant prognostic signature was built. Immunotherapeutic response was inferred through analyzing immune checkpoints, T cell inflamed score, TIDE score, and TMB score. RNF145 expression was measured in normoxic or hypoxic HCC cells. In RNF145-knockout cells, CCK-8, TUNEL, and scratch tests were implemented. RESULTS: HCC patients were classified into two hypoxia subtypes, with more advanced stages and poorer prognosis in cluster2 than cluster1. The heterogeneity in tumor infiltrating immune cells and genetic mutation was found between subtypes. The hypoxia-relevant prognostic model was proposed, composed of ANLN, CBX2, DLGAP5, FBLN2, FTCD, HMOX1, IGLV1-44, IL33, LCAT, LPCAT1, MKI67, PFN2, RNF145, S100A9, and SPP1). It was predicted that high-risk patients presented worse prognosis with an independent and reliable manner. Based upon high expression of immune checkpoints (CD209, CTLA4, HAVCR2, SIRPA, TNFRSF18, TNFRSF4, and TNFRSF9), high T cell inflamed score, low TIDE score and high TMB score, high-risk patients might respond to immunotherapy. Experimental validation showed that RNF145 was upregulated in hypoxic HCC cells, RNF145 knockdown attenuated proliferation and migration, but aggravated apoptosis in HCC cells. CONCLUSION: Altogether, the hypoxia-based classification and prognostic signature might be useful for prognostication and guiding treatment of HCC.

Syringin exerts anti-breast cancer effects through PI3K-AKT and EGFR-RAS-RAF pathways.

BACKGROUND: Breast cancer (BC) is one of the most common malignant tumors with the highest mortality in the world. Modern pharmacological studies have shown that Syringin has an inhibitory effect on many tumors, but its anti-BC efficacy and mechanism are still unclear. METHODS: First, Syringin was isolated from Acanthopanax senticosus (Rupr. & Maxim.) Harms (ASH) by systematic solvent extraction and silica gel chromatography column. The plant name is composed of genus epithet, species additive words and the persons' name who give its name. Then, the hub targets of Syringin against BC were revealed by bioinformatics. To provide a more experimental basis for later research, the hub genes which could be candidate biomarkers of BC and a ceRNA network related to them were obtained. And the potential mechanism of Syringin against BC was proved in vitro experiments. RESULTS: Syringin was obtained by liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR), and high-performance liquid chromatography (HPLC). Bioinformatics results showed that MAP2K1, PIK3CA, HRAS, EGFR, Caspase3, and PTGS2 were the hub targets of Syringin against BC. And PIK3CA and HRAS were related to the survival and prognosis of BC patients, the PIK3CA-hsa-mir-139-5p-LINC01278 and PIK3CA-hsa-mir-375 pathways might be closely related to the mechanism of Syringin against BC. In vitro experiments confirmed that Syringin inhibited the proliferation and migration and promoted apoptosis of BC cells through the above hub targets. CONCLUSIONS: Syringin against BC via PI3K-AKT-PTGS2 and EGFR-RAS-RAF-MEK-ERK pathways, and PIK3CA and HRAS are hub genes for adjuvant treatment of BC.

MEK1/2 inhibitors induce class I alcohol dehydrogenase (ADH1) expression by regulating farnesoid X receptor in hepatic cell lines and C57BL/6J mouse.

BACKGROUND: Alcohol is mainly catabolized by class I alcohol dehydrogenase (ADH1) in liver. ADH deficiency can aggravate ethanol-induced tissue injury. Extracellular signal-regulated kinases 1/2 (ERK1/2) is involved in alcohol metabolism. However, the relationship between ERK1/2 and ADH1 remains unclear. METHODS AND RESULTS: To inhibit ERK1/2, HepG2 and BNL cells were treated with mitogen-activated protein kinases 1/2 (MEK1/2) inhibitors (U0126 and PD98059), and C57BL/6J mice were fed U0126. After treatment, the protein and mRNA expression of ADH1 were determined by Western blot and quantitative real time-PCR. The activity of ADH1 promoter was detected using luciferase assay. The results showed MEK1/2 inhibitors significantly increased ADH1 protein expression by inducing its transcription activity. Then we demonstrated a farnesoid X receptor (FXR) response element (FXRE) in ADH1 promoter by ChIP assay. To test whether FXR mediates the induction of MEK1/2 inhibitors on ADH1, HepG2 cells were transfected with FXR siRNA or ADH1 promoters with FXRE mutation. We found both FXR siRNA and FXRE mutation in ADH1 promoter abolished MEK1/2 inhibitors-induced ADH1 expression, indicating the activation of MEK1/2 inhibitors on ADH1 depends on FXR. CONCLUSIONS: Our findings revealed inhibition of ERK1/2 can significantly increase ADH1 expression, indicating MEK1/2 inhibitors may possess potential application in alcohol-related diseases.

Malnutrition in patients with coronary artery disease: Prevalence and mortality in a 46,485 Chinese cohort study.

BACKGROUND AND AIMS: Malnutrition is associated with poor prognosis in a wide range of illnesses. However, its long-term prognostic impact in general coronary artery disease (CAD) patients is not well known. We aim to report the prevalence and long-term mortality of malnutrition in the whole general population. METHODS AND RESULTS: In this retrospective cohort study, the controlling nutritional status (CONUT) score was applied to 46,485 consecutive patients undergoing coronary angiography (CAG) and diagnosed with CAD from January 2007 to July 2018. Patients were stratified as having no malnutrition (n = 19,780), mild (n = 21,092), moderate (n = 5286) and severe malnutrition (n = 327), based on CONUT score. Overall, mean age was 63.1 ± 10.7 years, and 75.8% of patients (n = 35,250) were male. 45.4% of patients were mildly malnourished and 12.1% were moderately or severely malnourished. During a median follow-up of 5.1 years (interquartile range: 3.0-7.7 years), 6093 (17.3%) patients died. After adjusting for confounders, malnutrition risk was associated with significantly increased risk for all-cause death (mild vs. normal, HR = 1.19,95% confidence interval [CI]: 1.12 to 1.28; moderate vs. normal, HR = 1.42,95% CI: 1.30 to 1.55; severe vs. Normal, HR = 1.95, 95% CI: 1.57 to 2.41) (p for trend<0.001). The similar result on all-cause mortality was also found in different subgroups stratified by gender, chronic kidney disease, anemia, percutaneous coronary intervention. CONCLUSIONS: Malnutrition is a common complication among patients with CAD, and is strongly associated with increased mortality. Further studies need to explore the efficacy of nutritional interventions on long-term prognosis among CAD patients. This study was registered at Clinicaltrials.gov as NCT04407936.

Association between living arrangements and cognitive decline in older adults: A nationally representative longitudinal study in China.

BACKGROUND: Living arrangements are critical to the survival and well-being of older people, especially in China where the filial piety culture demands adult children care for and serve their parents. The study aimed to explore the association between living arrangements and cognitive decline among older people in China. METHODS: Participants included 6,074 older adults over 60 years old (49.65% male, mean age 67.2 years [range 60-98]) from four waves (2011-2018) of the China Health and Retirement Longitudinal Study. Two to four assessments were conducted over a follow-up of an average of 5.3 years (range, 2-7). Cognitive function was assessed using an adapted Chinese version of Mini-Mental State Examination (MMSE). Living arrangements were classified as follows: living alone, living with spouse, living with adult children, living with spouse and adult children and living with others. Multilevel models were used to investigate the relationship between living arrangements and cognitive decline, as well as the gender difference. RESULTS: As the main type of living arrangements of the study participants (44.91%), living with spouse was taken as the reference group. Compared to the reference group, living alone (ß=-0.126, P < 0.001), living with adult children (ß=-0.136, P < 0.001), living with spouse and adult children (ß=-0.040, P < 0.05) and living with others (ß=-0.155, P < 0.05) were all related to a faster rate of cognitive decline. Further, the association between living arrangements and cognitive decline varied by gender. Living alone (ß=-0.192, P < 0.001) was associated with a faster cognitive decline only in older men. Living with spouse and adult children (ß=-0.053, P < 0.05) and living with others (ß=-0.179, P < 0.05) were associated with faster cognitive decline only in older women. CONCLUSION: This study suggests that living arrangements in older people in China were associated with cognitive decline, and these associations varied by gender. Greater attention to living arrangements might yield practical implications for preserving the cognitive function of the older population.

Novel physical performance-based models for activities of daily living disability prediction among Chinese older community population: a nationally representative survey in China.

BACKGROUND: Physical performances including upper and lower limb functions have predictive roles in activities of daily living (ADL) disability, but they have rarely been incorporated into prediction models. This study primarily aimed to develop and validate novel physical performance-based models for ADL disability among Chinese older adults. Comparisons of predictive performance across multiple models were performed, and model simplification was further explored. METHODS: Data were obtained from the China Health and Retirement Longitudinal Study in the 2011 and 2015 waves, containing 2192 older adults over 60 years old. Our models were constructed by logistic regression analysis, using a backward stepwise selection. Model performance was internally validated by discrimination, calibration, and clinical utility. Integrated Discrimination Improvement (IDI) and Net Reclassification Improvement (NRI) were used to assess the incremental benefit of the extended models. Moreover, nomograms were built for visualization. RESULTS: We selected gender, age, smoking, self-report health condition, BMI, depressive symptoms, and cognitive function into the fundamental model (Model 1). Based on Model 1, five novel prediction models were constructed by adding handgrip strength (Model 2), Short Physical Performance Battery (SPPB) (Model 3), gait speed (Model 4), handgrip strength plus SPPB (Model 5), and handgrip strength plus gait speed (Model 6), respectively. Significant improvement in predictive values were observed for all five novel models compared with Model 1 (C-index = 0.693). The lower limb model (Model 3 SPPB model: C-index = 0.731) may play a key role in the prediction of ADL disability, reflecting a comparable predictive value to the comprehensive models combining both upper and lower limbs (Model 5 handgrip strength + SPPB model: C-index = 0.732). When we simplified the lower limb models by replacing SPPB with gait speed, the predictive values attenuated slightly (C-index: Model 3 vs Model 4: 0.731 vs 0.714; Model 5 vs Model 6: 0.732 vs 0.718), but still better than the upper limb model (Model 2 handgrip strength model: C-index = 0.701). CONCLUSIONS: Physical performance-based models, especially lower limb model, provided improved prediction for ADL disability among Chinese older adults, which may help guide the targeted intervention.

Current Status and Applications for Hydraulic Pump Fault Diagnosis: A Review.

To implement Prognostics Health Management (PHM) for hydraulic pumps, it is very important to study the faults of hydraulic pumps to ensure the stability and reliability of the whole life cycle. The research on fault diagnosis has been very active, but there is a lack of systematic analysis and summary of the developed methods. To make up for this gap, this paper systematically summarizes the relevant methods from the two aspects of fault diagnosis and health management. In addition, in order to further facilitate researchers and practitioners, statistical and comparative analysis of the reviewed methods is carried out, and a future development direction is prospected.

The Taste-Masking Mechanism of Chitosan at the Molecular Level on Bitter Drugs of Alkaloids and Flavonoid Glycosides from Traditional Chinese Medicine.

Taste masking of traditional Chinese medicines (TCMs) containing multiple bitter components remains an important challenge. In this study, berberine (BER) in alkaloids and phillyrin (PHI) in flavonoid glycosides, which are common bitter components in traditional Chinese medicines, were selected as model drugs. Chitosan (CS) was used to mask their unfriendly taste. Firstly, from the molecular level, we explained the taste-masking mechanism of CS on those two bitter components in detail. Based on those taste-masking mechanisms, the bitter taste of a mixture of BER and PHI was easily masked by CS in this work. The physicochemical characterization results showed the taste-masking compounds formed by CS with BER (named as BER/CS) and PHI (named as PHI/CS) were uneven in appearance. The drug binding efficiency of BER/CS and PHI/CS was 50.15 ± 2.63% and 67.10 ± 2.52%, respectively. The results of DSC, XRD, FTIR and molecular simulation further indicated that CS mainly masks the bitter taste by disturbing the binding site of bitter drugs and bitter receptors in the oral cavity via forming hydrogen bonds between its hydroxyl or amine groups and the nucleophilic groups of BER and PHI. The taste-masking evaluation results by the electronic tongue test confirmed the excellent taste-masking effects on alkaloids, flavonoid glycosides or a mixture of the two kinds of bitter components. The in vitro release as well as in vivo pharmacokinetic results suggested that the taste-masked compounds in this work could achieve rapid drug release in the gastric acid environment and did not influence the in vivo pharmacokinetic results of the drug. The taste-masking method in this work may have potential for the taste masking of traditional Chinese medicine compounds containing multiple bitter components.