Long noncoding RNA as a potential diagnostic tool for prostate cancer: a systematic review and meta-analysis.

PURPOSE: To identify consistently expressed lncRNAs and suitable lncRNAs with high sensitivity and specificity from multiple independent studies as potential biomarkers for PCa diagnostics. METHODS: We searched multiple electronic databases including PubMed, Web of Science, EMBASE, Cochrane Library, CNKI, CQVIP, Wanfang, and CBMdisc for studies published up to July 2022. The quality of the included studies was assessed by two independent reviewers based on the QUADAS-2 tool using Review Manager 5.3. A vote-counting method was used based on the ranking of potential molecular biomarkers. The top-ranked lncRNAs were further assessed for diagnostic value using Meta-disc version 1.4 software. RESULTS: Among the 26 included studies, 2 circulating lncRNAs (PCA3 and MALAT-1) were reported 3 or more times in PCa patients versus non-PCa patients. In further analysis, the areas under the curve of the summary receiver operating characteristic curves for PCA3 and MALAT-1 distinguishing PCa patients were 0.775 and 0.771, respectively. CONCLUSIONS: Based on the current evidence, PCA3 and MALAT-1 are reliable lncRNAs for the diagnosis of PCa.

GRID2 aberration leads to disturbance in neuroactive ligand-receptor interactions via changes to the species richness and composition of gut microbes.

OBJECTIVE: To explore the association between phenotype and the gut microbiome following damage to the GRID2 gene. METHODS: Ten wild-type (WT) mice and 11 GRID2 knockout heterozygous mice (GRID2(±)) of a similar age and weight were randomly selected. Fresh feces were collected from both groups of mice under specified pathogen-free (SPF) conditions. The bacterial genomes were extracted from the feces, the 16S rRNA genes were sequenced, and the data were analyzed to determine clustering, diversity, abundance, LEfSe, and functional differences. Differential expression and enrichment analyses of the RNA-seq and protein levels of the GRID2 gene were also performed using data in the GENE database and the new version of the Human Protein Atlas portal (www.proteinatlas.org). RESULTS: The diversity analysis showed differences in species composition between the two groups at different levels. At phylum level, compared with the WT group, the distribution was more bacteriophages but showed a lower content of Tenericutes in the GRID2(±) group. At the order level, compared with the WT group, a higher content of Actinomycetales and Bacteriophages were found in the GRID2(±) group. The species difference analysis showed that 17 species, including E. faecalis and Paracoccus spp., showed differences in content between the two groups. LEfSe analysis showed that the abundance of Clostridiaceae, Allobaculum, and other groups decreased in the GRID2(±) group compared with the WT group, while Mycoplasma, Sphingomonas, and Alphaproteobacteria increased in abundance. Functional analysis revealed eight differential functions between the WT and GRID2(±) group (P < 0.05). The most significantly disrupted were neuroactive ligand-receptor interactions (P < 9.99e-4). In addition, the differential expression and enrichment analyses performed at RNA-seq and protein levels revealed that the GRID2 gene showed organ-specific expression and was mainly enriched in the brain tissue. CONCLUSIONS: Compared with the WT group, the defective GRID2 gene affected the species richness and composition of gut microbes in the GRID2(±) mice, which in turn affected the function of gut microbes, leading to the disruption of neuroactive ligand-receptor interactions. Our findings indicate that the host gene, GRID2, can influence the abundance of a subset of gut microbes but the exact mechanisms still need further investigation.

Association of both prenatal and early childhood multiple metals exposure with neurodevelopment in infant: A prospective cohort study.

BACKGROUND: Impaired neurodevelopment of children has become a growing public concern; however, the associations between metals exposure and neurocognitive function have remained largely unknown. OBJECTIVES: We systematically evaluated the associations of multiple metals exposure during pregnancy and childhood on the neurodevelopment of children aged 2-3 years. METHODS: We measured 22 metals in the serum and urine among703 mother-child pairs from the Guangxi Birth Cohort Study. The neurocognitive development of children was assessed by the Gesell Development Diagnosis Scale (GDDS; Chinese version). Multiple linear regression models were used to evaluate the relationship between the metals (selected by elastic net regression) and the outcomes. The Bayesian kernel machine regression (BKMR) was used to evaluate the possible joint effect between the multiple metal mixture and the outcomes. RESULTS: Prenatal aluminum (Al) exposure was negatively associated with the fine motor developmental quotient (DQ) (ß = -1.545, 95%CI: 2.231, -0.859), adaption DQ (ß = -1.182, 95%CI: 1.632, -0.732), language DQ (ß = -1.284, 95% CI: 1.758, -0.809), and social DQ (ß = -1.729, 95% CI: 2.406, -1.052) in the multi-metal model. Prenatal cadmium (Cd) exposure was negatively associated with gross motor DQ (ß = -2.524, 95% CI: 4.060, -0.988), while postpartum Cd exposure was negatively associated with language DQ (ß = -1.678, 95% CI: 3.227, -0.129). In stratified analyses, infants of different sexes had different sensitivities to metal exposure, and neurobehavioral development was more significantly affected by metal exposure in the first and second trimester. BKMR analysis revealed a negative joint effect of the Al, Cd, and selenium (Se) on the language DQ score; postpartum Cd exposure played a major role in this relationship. CONCLUSION: Prenatal exposure to Al, Ba, Cd, molybdenum (Mo), lead (Pb), antimony (Sb), and strontium (Sr), and postpartum exposure to cobalt (Co), Cd, stannum (Sn), iron (Fe), nickel (Ni), and Se are associated with neurological development of infants. The first and second trimester might be the most sensitive period when metal exposure affects neurodevelopment.

Waist-to-height ratio, an optimal anthropometric indicator for metabolic dysfunction associated fatty liver disease in the Western Chinese male population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been entitled as metabolic-dysfunction associated fatty liver disease (MAFLD). Therefore anthropometric indicators of adiposity may provide a non-invasive predictive and diagnostic tool for this disease. This study intended to validate and compare the MAFLD predictive and diagnostic capability of eight anthropometric indicators. METHODS: The study involved a population-based retrospective cross-sectional design. The Fangchenggang area male health and examination survey (FAMHES) was used to collect data of eight anthropometric indicators, involving body mass index (BMI), waist-to-height ratio (WHtR), waist-hip ratio (WHR), body adiposity index (BAI), cardiometabolic index (CMI), lipid accumulation product (LAP), visceral adiposity index (VAI), and abdominal volume index (AVI). Receiver operating characteristics (ROC) curves and the respective areas under the curves (AUCs) were utilized to compare the diagnostic capacity of each indicator for MAFLD and to determine the optimal cutoff points. Binary logistic regression analysis was applied to identify the odds ratios (OR) with 95% confidence intervals (95% CI) for all anthropometric indicators and MAFLD. The Spearman rank correlation coefficients of anthropometric indicators, sex hormones, and MAFLD were also calculated. RESULTS: All selected anthropometric indicators were significantly associated with MAFLD (P < 0.001), with an AUC above 0.79. LAP had the highest AUC [0.868 (95% CI, 0.853-0.883)], followed by WHtR [0.863 (95% CI, 0.848-0.879)] and AVI [0.859 (95% CI, 0.843-0.874)]. The cutoff values for WHtR, LAP and AVI were 0.49, 24.29, and 13.61, respectively. WHtR [OR 22.181 (95% CI, 16.216-30.340)] had the strongest association with MAFLD, regardless of potential confounders. Among all the anthropometric indicators, the strongest association was seen between LAP and sex hormones. CONCLUSION: All anthropometric indicators were associated with MAFLD. WHtR was identified as the strongest predictor of MAFLD in young Chinese males, followed by LAP and AVI. The strongest association was found between LAP and sex hormones.

Elevated C-reactive protein and complement C3 levels are associated with preterm birth: a nested case-control study in Chinese women.

BACKGROUND: Currently, there are many studies researched the associations between maternal serum inflammatory indicators (i.e. ferritin, C-reactive protein [CRP], C3 and C4) and preterm birth (PTB). The results, however, are inconsistent. Therefore, the aim of this study was to estimate the relationship between maternal serum inflammatory indicators and PTB in a nested case-control (NCC)study. METHODS: A NCC study was conducted by Guangxi Birth Cohort Study which enrolled a total of 6203 pregnant women between 50/7 and 346/7 weeks of gestational age (wGA) from six cities in China between 2015 and 2016. There were 206women who delivered preterm (< 370/7 wGA), and 412 women who delivered term birth, those women were matched by maternal age, birth place, gender of infants, and wGA at blood collection. The inflammatory indicators were quantified by immunoturbidimetric methods. RESULTS: Highest quartile concentrations of all inflammatory indicators were determined versus median. After adjusting for maternal age, high levels of CRP (CRP > 16.60 mg/L) are related to the risk of PTB (OR = 2.16, 95% CI: 1.02-4.56, p = 0.044) in the first trimester. The association of C3 was extremely related to those who delivered PTB (OR = 2.53, 95% CI: 1.14-5.64, p = 0.023) in the first trimester. Moreover, no significant associations were found in C4 (p = 0.079) and ferritin (p = 0.067) between PTB. CONCLUSIONS: Elevated concentrations of CRP and C3 in the first trimester were associated with increased risk of PTB. Inflammatory indicators may act a pivotal part in early diagnosis and prognosis of PTB.

Serum multiple cytokines for the prediction of spontaneous preterm birth in asymptomatic women: A nested case-control study.

BACKGROUND: Current biomarkers such as fetal fibronectin and cervical length are accurate predictors of spontaneous preterm birth (sPTB) in women with clinically suspected preterm risk; however, these are not effective for predicting the risk of sPTB in asymptomatic women. Therefore, we performed this study with the objective of determining whether the combinations of specific serum cytokines could accurately predict the sPTB risk in asymptomatic women. METHODS: We conducted a nested case-control study with 129 incident sPTB cases and 258 individually matched controls who participated in an ongoing birth cohort study. The maternal serum levels of the selected 35 cytokines were measured. We evaluated the relationship between the multiple cytokines and sPTB risk using conditional logistic regression and elastic net model. RESULTS: A panel of cytokines was significantly associated with an increased risk of sPTB. The odds ratio (OR) of sPTB per standard deviation (SD) increase of the predictive model score was 1.57 (95% CI 1.25-1.97) for the cytokines model. The combination of the selected serum cytokines was substantially more effective in predicting the risk for sPTB, as the receiver-operator characteristic curve (AUC) values were 0.546 and 0.559 in the single cytokine model and it improved to 0.642 in the multiple cytokines model (PAUC difference = 0.02 for TNF-α vs. multiple cytokines; PAUC difference = 0.05 for TRAIL vs. multiple cytokines). Moreover, the prediction was more accurate in overweight pregnant women, with an AUC = 0.879. CONCLUSIONS: The current study suggested that the combination of selected serum cytokines can more effectively predict the risk of sPTB in asymptomatic women compared with the use of single cytokine.

Low serum folate status in the second trimester increase the risk of low birthweight in Chinese women.

AIM: This study aimed to explore the influence of maternal folate and vitamin B12 (B12) status during pregnancy on the incidence of low birthweight (LBW) infants. METHODS: A total of 6203 eligible women registered in seven hospitals in southern China, and 230 cases with singleton live births and 382 controls were matched for further analyses. The concentrations of serum folate and B12 were detected with chemiluminescence microparticle immunoassay on ARCHITECT i2000-1. Conditional logistic regression was used to evaluate the effects of folate and B12 levels on LBW. RESULTS: Maternal serum folate levels increased basically with increasing the period of folic acid supplementation (P trend <0.001). Moreover, maternal serum folate and B12 levels gradually decreased with the increase of gestational age (P < 0.001). Conditional logistic regressions analysis results showed increased odds ratios (OR) for LBW from the fourth to first folate quartiles (P trend <0.01) in the second trimester. Compared with the women in the highest quartile, those in the lowest quartile of serum folate in the second trimester were found with higher risk of LBW (adjusted OR = 1.67, 95% confidence interval [CI]: 1.02-2.73). However, no significant association was observed between serum folate and LBW in the first trimester or third trimester. In addition, serum B12 exhibited no significant association with LBW. CONCLUSIONS: Low serum folate levels in the second trimester significantly increases the risk of LBW amongst Chinese women with singleton pregnancies.

Single cell RNA-Sequencing Reveals Mast Cells Enhance Mononuclear Phagocytes Infiltration in Bladder Cancer Microenvironment.

Objective: Investigating the interaction between Mast cells (MCs) and Mononuclear Phagocytes (MPs) in the tumor microenvironment (TME) of blader cancer (BCa) to uncover potential immunotherapeutic targets. Methods: Single-cell RNA sequencing (scRNA-Seq) was conducted on 12 BCa patients to identify distinct subgroups of MCs and MPs. Transcriptome data was analyzed to characterize the phenotype, gene enrichment, cell-cell communication, and biological processes. The expression levels of cytokines were assessed by enzyme-linked immunosorbent assay (ELISA), while the chemotactic effects of cytokines were evaluated through Transwell assay. Results: In muscle-invasive bladder cancer (MIBC), the proportion of interferon-stimulated MC subtype (Mast-ISG15) increased. Mast-IL13 subgroup and Mast-CCL2 subgroups were functionally enriched in interferon (IFN) and nuclear factor kappa-B (NF-κB) signaling pathways. The Mast-CCL2 subgroup overexpressed the CCL2 gene, which could chemoattract MPs through CCL2. In vitro experiments confirmed that under stimulation, activated MCs activated IFN and NF-κB signaling, increasing the secretion of CCL2 and IL-13, chemoattracted THP-1 monocyte. Conclusion: This study revealed the vital role of MCs in shaping the TME of BCa. And provides new insights for the precise treatment of BCa.

Decoding 11-oxygenated androgen synthesis: insights from enzyme gene expression and LC-MS/MS quantification.

BACKGROUND: Adrenal-origin and peripheral tissue-transformed 11-oxygenated androgens are recognized as significant androgens. However, our current understanding of the synthesis of 11-oxygenated androgens, including the organs and cell types involved, remains limited. METHODS: We performed comprehensive analyses on an extensive dataset of normal human tissues, which included bulk RNA data from 30 tissues, single-cell RNA sequencing (scRNA) data from 16 tissues and proteomics data from 29 tissues, to characterize the expression profiles of enzyme-encoding genes. To validate the findings, immunohistochemical and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques were employed. RESULTS: Our investigation revealed that the gene expression levels of the enzymes HSD11B2 and AKR1C3 were notably elevated in the kidney and intestines. Intriguingly, within these organs, we observed an increasing trend in enzyme expression with age in women, while a decreasing trend was apparent in men. scRNA analysis revealed that HSD11B2 was predominantly expressed in collecting duct principal cells in the kidney, while AKR1C3 was primarily expressed in the proximal tubules. Intriguingly, nearly all epithelial cells in the intestine expressed these key enzymes. Further analysis using LC-MS/MS revealed that the kidney exhibited the highest levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) among the seven tissues examined, and substantial synthesis of 11KA4 and 11KT was also observed in the intestine. Finally, we developed the TransMap website (http://gxmujyzmolab.cn:16245/TransMap/) to provide comprehensive visualization of all currently available transcriptome data. CONCLUSION: This study offers an overarching perspective on tracing the synthesis of 11-oxygenated androgens in peripheral tissues, thereby providing valuable insights into the potential role of these androgens in humans.

Associations of circulation levels of cytokines with birthweight, preterm birth, spontaneous miscarriages, and stillbirth: A Mendelian randomization analysis.

Background: The association between immune imbalances and adverse pregnancy outcomes has been extensive investigated by observational studies, but remain unclear. Thus, this study aimed to establish the causality of the circulation levels of cytokines on adverse pregnancy outcomes, such as offspring's birthweight (BW), preterm birth (PTB), spontaneous miscarriage (SM), and stillbirth (SB). Methods: Two-sample Mendelian randomization (MR) analysis was employed to investigate potential causal relations between 41 cytokines and pregnancy outcomes on the basis of previously published GWAS datasets. Multivariable MR (MVMR) analysis was implemented to investigate the effect of the composition of cytokine networks on the pregnancy outcomes. Potential risk factors were further estimated to explore the potential mediators. Results: Genetic correlation analysis based on large GWAS data sources revealed that genetically predicted MIP1b (ß = -0.027, S.E. = 0.010, p = 0.009) and MCSF (ß = -0.024, S.E. = 0.011, p = 0.029) were associated with reduced offspring's BW, MCP1 (OR: 0.90, 95% CI: 0.83-0.97, p = 0.007) was associated with reduced SM risk, SCF (ß = -0.014, S.E. = 0.005, p = 0.012) associated with decreased number of SB in MVMR. The univariable MR showed that GROa (OR: 0.92, 95% CI: 0.87-0.97, p = 0.004) was associated with decreased PTB risk. Except for the MCSF-BW association, all above associations surpassed the Bonferroni corrected threshold. The MVMR results revealed that MIF, SDF1a, MIP1b, MCSF and IP10 composed cytokine networks, associated with offspring's BW. Risk factors analysis indicated that the above causal associations might be mediated by smoking behaviors. Conclusion: These findings suggest the causal associations of several cytokines with adverse pregnancy outcomes, which were potentially mediated by smoking and obesity. Some of the results did not been corrected through multiple tests and larger samples verification is required in further studies.

Establishment of a risk score model for bladder urothelial carcinoma based on energy metabolism-related genes and their relationships with immune infiltration.

Bladder urothelial carcinoma (BLCA) is a common malignant tumor of the human urinary system, and a large proportion of BLCA patients have a poor prognosis. Therefore, there is an urgent need to find more efficient and sensitive biomarkers for the prognosis of BLCA patients in clinical practice. RNA sequencing (RNA-seq) data and clinical information were obtained from The Cancer Genome Atlas, and 584 energy metabolism-related genes (EMRGs) were obtained from the Reactome pathway database. Cox regression analysis and least absolute shrinkage and selection operator analysis were applied to assess prognostic genes and build a risk score model. The estimate and cibersort algorithms were used to explore the immune microenvironment, immune infiltration, and checkpoints in BLCA patients. Furthermore, we used the Human Protein Atlas database and our single-cell RNA-seq datasets of BLCA patients to verify the expression of 13 EMRGs at the protein and single-cell levels. We constructed a risk score model; the area under the curve of the model at 5 years was 0.792. The risk score was significantly correlated with the immune markers M0 macrophages, M2 macrophages, CD8 T cells, follicular helper T cells, regulatory T cells, and dendritic activating cells. Furthermore, eight immune checkpoint genes were significantly upregulated in the high-risk group. The risk score model can accurately predict the prognosis of BLCA patients and has clinical application value. In addition, according to the differences in immune infiltration and checkpoints, BLCA patients with the most significant benefit can be selected for immune checkpoint inhibitor therapy.

Predicted Fat Mass, Lean Body Mass, and Risk of Hypertension: Results from a Chinese Male Cohort Study.

INTRODUCTION: Few studies have deciphered whether lean body mass (LBM) or fat mass (FM) is predominantly responsible for the body mass index (BMI)-hypertension association. This study aimed to assess the associations of predicted LBM and FM with hypertension risk among Chinese male adults. METHODS: A prospective cohort study was conducted among 2,812 male participants free of hypertension in the Fangchenggang Area Males Health and Examination Survey in 2009. We performed multivariable Cox models and restricted cubic spline to examine the associations of predicted LBM and FM and BMI with hypertension, and to further explore the mediating roles of lipid and glycemic traits in the relationship between predicted FM and blood pressure. RESULTS: Of 1,238 participants included in the cohort study, 306 (24.8%) hypertension cases were identified during a median follow-up of 3.8 years, with an incidence rate of 7.0 per 100 person-years. A positive linear-shaped association was consistently observed between BMI and hypertension (p for trend <0.001). Multivariable-adjusted Cox models including predicted LBM and FM observed a positive association between predicted FM and hypertension. Compared with those in the lowest quartile of predicted FM, men in the highest quartile had a hazard ratio (HR) of 1.83 (95% confidence interval (CI): 1.13-2.97) for hypertension. The HR per standard deviation increase of BMI and predicted FM was 1.11 (95% CI: 1.04-1.19) above 23.1 kg/m2 and 1.05 (95% CI: 1.02-1.15) above 14.6 kg, respectively. However, predicted LBM was not associated with hypertension. In addition, high-density lipoprotein cholesterol (HDL-c) and fasting blood glucose (FBG) mediated the relationship of predicted FM with systolic blood pressure, with a mediation ratio of 37.1% and 8.2%, respectively. Furthermore, total cholesterol (TC) and triglyceride (TG) positively mediated the association of predicted FM with diastolic blood pressure, with a mediation ratio of 9.5% and 9.9%, respectively. CONCLUSION: Higher predicted FM might play a central role in the positive linear relationship of the BMI-hypertension association in Chinese male adults, and the link from predicted FM to blood pressure was partially mediated by TC, TG, HDL-c, and FBG.

Gender-specific effects of prenatal mixed exposure to serum phthalates on neurodevelopment of children aged 2-3 years:the Guangxi Birth Cohort Study.

Phthalates have been shown to have adverse effects on neurodevelopment, which may be gender-specific. However, the association between prenatal mixed exposure to phthalates and children's neurodevelopment remains inconsistent. We measured 15 prenatal serum phthalate levels and evaluated children's neurodevelopmental indicators using Gesell Developmental Schedule (GDS) (n = 750). Generalized linear regression was fitted to examine the association. Among boys, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) had adverse effects on gross motor [odds ratio (OR): 7.38, 95% confidence interval (CI):1.42, 38.46]. For gross motor in boys, joint effect was discovered between mono-2-ethylhexyl phthalate (MEHP) and MEHHP. Moreover, synergistic effects were found for MEHP with vanadium and cadmium, and antagonistic effects for MEHP with magnesium, calcium, titanium, iron, copper, selenium, rubidium, and strontium. We did not find statistically significant relationships in girls. In the 1st trimester, adverse effects were identified between mono-2-ethyl-5-oxoyhexyl phthalate (MEOHP) and adaptation (P = 0.024), and monomethyl phthalate (MMP) with social area (P = 0.017). In the 2nd trimester, MEHHP had adverse effects on social area (P = 0.035). In summary, we found boys may be more vulnerable to the neurotoxicity than girls in gross motor, and we also discovered the detrimental effects of phthalates on children's neurodevelopment in the 1st and 2nd trimesters. Therefore, the supplementation of appropriate elements in the 1st and 2nd trimesters may help reduce the adverse effects of phthalates on children's neurodevelopment, especially among boys.

The role of age at menarche and age at menopause in Alzheimer's disease: evidence from a bidirectional mendelian randomization study.

The association between endogenous estrogen exposure and Alzheimer's disease (AD) remains inconclusive in previous observational studies, and few Mendelian randomization (MR) studies have focused on their causality thus far. We performed a bidirectional MR study to clarify the causality and causal direction of age at menarche and age at menopause, which are indicators of endogenous estrogen exposure, on AD risk. We obtained all genetic datasets for the MR analyses using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. The MR analyses indicated no significant causal relationship between the genetically determined age at menarche (outlier-adjusted inverse variance weighted odds ratio [IVWOR] = 0.926; 95% confidence interval [CI], 0.803-1.066) or age at menopause (outlier-adjusted IVWOR = 0.981; 95% CI, 0.941-1.022) and AD risk. Similarly, AD did not show any causal association with age at menarche or age at menopause. The sensitivity analyses yielded similar results. In contrast, an inverse association was detected between age at menarche and body mass index (BMI, outlier-adjusted IVW ß = -0.043; 95% CI, -0.077 to -0.009). Our bidirectional MR study provides no evidence for a causal relationship between the genetically determined age at menarche or age at menopause and AD susceptibility, or vice versa. However, earlier menarche might be associated with higher adult BMI.

Assessment Causality in Associations Between Serum Uric Acid and Risk of Schizophrenia: A Two-Sample Bidirectional Mendelian Randomization Study.

PURPOSE: Although increasing lines of evidence showed associations between serum uric acid (UA) levels and schizophrenia, the causality and the direction of the associations remain uncertain. Thus, we aimed to assess whether the relationships between serum UA levels and schizophrenia are causal and to determine the direction of the association. PATIENTS AND METHODS: Two-sample bidirectional Mendelian randomization (MR) analyses and various sensitivity analyses were performed utilizing the summary data from genome-wide association studies within the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium. Secondary MR analyses in both directions were conducted within summary data using genetic risk scores (GRSs) as instrumental variables. RESULTS: Three MR methods provided no causal relationship between serum UA and schizophrenia. Furthermore, GRS approach showed similar results in the three MR methods after adjustment for heterogeneity. By contrast, inverse variance weighted method, weighted median and GRS approach suggested a causal effect of schizophrenia risk on serum UA after adjustment for heterogeneity (per 10-symmetric percentage increase in schizophrenia risk, beta: -0.039, standard error (SE): 0.013, P = 0.003; beta: -0.036, SE: 0.018, P = 0.043; beta: -0.039, SE: 0.013, P = 0.002; respectively). Moreover, in both directions' analyses, the heterogeneity and sensitivity tests suggested no strong evidence of bias due to pleiotropy. CONCLUSION: Schizophrenia may causally affect serum UA levels, whereas the causal role of serum UA concentrations in schizophrenia was not supported by our MR analyses. These findings suggest that UA may be a useful potential biomarker for monitoring treatment or diagnosis of schizophrenia rather than a therapeutic target for schizophrenia.

Effects of Adiponectin on T2DM and Glucose Homeostasis: A Mendelian Randomization Study.

PURPOSE: The associations of adiponectin with type 2 diabetes mellitus (T2DM), glucose homeostasis (including ß-cell function index (HOMA-ß), insulin resistance (HOMA-IR), fasting insulin (FI) and fasting glucose (FG)) have reported in epidemiological studies. However, the previous observational studies are prone to biases, such as reverse causation and residual confounding factors. Herein, a Mendelian Randomization (MR) study was conducted to determine whether causal effects exist among them. MATERIALS AND AND METHODS: Two-sample MR analyses and multiple sensitivity analyses were performed using the summary data from the ADIPOGen consortium, MAGIC Consortium, and a meta-analysis of GWAS with a considerable sample of T2DM (62,892 cases and 596,424 controls of European ancestry). We got eight valid genetic variants to predict the causal effect among adiponectin and T2DM and glucose homeostasis after excluding the probable invalid or pleiotropic variants. RESULTS: Adiponectin was not associated with T2DM (odds ratio (OR) = 1.004; 95% confidence interval (CI): 0.740, 1.363) when using MR Egger after removing the invalid SNPs, and the results were consistent when using the other four methods. Similar results existed among adiponectin and HOMA-ß, HOMA-IR, FI, FG. CONCLUSION: Our MR study revealed that adiponectin had no causal effect on T2DM and glucose homeostasis and that the associations among them in observational studies may be due to confounding factors.

The Endogenous Alterations of the Gut Microbiota and Feces Metabolites Alleviate Oxidative Damage in the Brain of LanCL1 Knockout Mice.

Altered composition of the gut microbiota has been observed in many neurodegenerative diseases. LanCL1 has been proven to protect neurons and reduce oxidative stress. The present study was designed to investigate alterations of the gut microbiota in LanCL1 knockout mice and to study the interactions between gut bacteria and the brain. Wild-type and LanCL1 knockout mice on a normal chow diet were evaluated at 4 and 8-9 weeks of age. 16s rRNA sequence and untargeted metabolomics analyses were performed to investigate changes in the gut microbiota and feces metabolites. Real-time polymerase chain reaction analysis, AB-PAS staining, and a TUNEL assay were performed to detect alterations in the gut and brain of knockout mice. The serum cytokines of 9-week-old knockout mice, which were detected by a multiplex cytokine assay, were significantly increased. In the central nervous system, there was no increase of antioxidant defense genes even though there was only low activity of glutathione S-transferase in the brain of 8-week-old knockout mice. Interestingly, the gut tight junctions, zonula occludens-1 and occludin, also displayed a downregulated expression level in 8-week-old knockout mice. On the contrary, the production of mucus increased in 8-week-old knockout mice. Moreover, the compositions of the gut microbiota and feces metabolites markedly changed in 8-week-old knockout mice but not in 4-week-old mice. Linear discriminant analysis and t-tests identified Akkermansia as a specific abundant bacteria in knockout mice. Quite a few feces metabolites that have protective effects on the brain were reduced in 8-week-old knockout mice. However, N-acetylsphingosine was the most significant downregulated feces metabolite, which may cause the postponement of neuronal apoptosis. To further investigate the effect of the gut microbiota, antibiotics treatment was given to both types of mice from 5 to 11 weeks of age. After treatment, a significant increase of oxidative damage in the brain of knockout mice was observed, which may have been alleviated by the gut microbiota before. In conclusion, alterations of the gut microbiota and feces metabolites alleviated oxidative damage to the brain of LanCL1 knockout mice, revealing that an endogenous feedback loop mechanism of the microbiota-gut-brain axis maintains systemic homeostasis.

HIPK2 polymorphisms rs2058265, rs6464214, and rs7456421 were associated with kidney stone disease in Chinese males not females.

BACKGROUND AND AIM: Recent studies have shown that genetic factors are involved in the development of kidney stone disease (KSD). A case-control association analysis was performed to investigate the association between homeodomain-interacting protein kinase 2 (HIPK2; OMIM *606868) polymorphisms and KSD. METHODS: A total of 890 KSD patients and 920 healthy subjects were analyzed. Polymorphisms were genotyped using SNPscanTM high-throughput SNP classification technology. The genotypic and allelic frequencies in KSD patients and healthy individuals were analyzed using a Chi-square test. RESULTS: The genotype and allele distributions of the three polymorphisms (rs2058265, rs6464214, and rs7456421 in HIPK2) displayed strong associations with KSD in males (rs2058265: odds ratio [OR] 2.480,95%confidence interval [CI] 1.205-5.106, p = 0.014; rs6464214: OR 2.466, 95%CI 1.198-5.078, p = 0.014; rs7456421: OR 2.846, 95%CI 1.362-5.947, p = 0.005; perallele: r2058265T, OR 1.357, 95%CI 1.073-1.715, p = 0.011; rs6464214G, OR 1.340, 95%CI 1.060-1.693, p = 0.014; rs7456421C, OR 1.356, 95%CI 1.073-1.713, p = 0.011). Patients carrying the T allele of rs2058265, the G allele of rs6464214, or the C allele of rs7456421 showed higher systolic blood pressure, creatinine, and uric acid levels compared with wild-genotype individuals after adjusting for age, gender, and body mass index (p < 0.005). CONCLUSION: The association of HIPK2 gene polymorphisms with KSD was only observed in males but not in females. HIPK2 gene polymorphisms were also involved in the changes of KSD-related metabolic traits.

High maternal osteocalcin levels during pregnancy is associated with low birth weight infants: A nested case-control study in China.

BACKGROUND: Low birth weight infants (LBW) are at risk of chronic diseases in later life due to the disorder of energy metabolism during pregnancy. Osteocalcin (OC) has been identified as a hormone that regulate energy metabolism. However, few studies have researched on the associations between maternal serum OC levels and low birth weight infants. OBJECTIONS: To examine the associations between maternal serum OC concentrations and LBW. METHODS: This was a nested case-control study involving a total of 230 pregnant women delivering LBW and 382 control pregnant women (matched for infant gender, gestational age at blood draw, region of Maternity and Child Healthcare Hospital and maternal age in 1: (1-2) ratio). One serum sample was collected from each pregnant woman at 5-35 weeks' gestation. Pregnant women were divided into 3 groups (1st, 2nd and 3rd trimester group). There were 60 and 142 and 28 pregnant women delivering LBW in the first, second and third trimester, respectively. Similarly, there were 101 and 233 and 48 controls in the first, second and third trimester, respectively. Maternal serum OC and 25(OH)D concentrations were categorized into low and high levels, the low level used as reference in analyses. Binary logistic regression model was used to compute odd radio (ORs) for LBW according to levels of maternal serum OC and 25(OH)D. RESULTS: Compared with the subjects in low level in first trimester, LBW was two times as likely to occur among pregnancy women with high serum OC concentrations (OR = 2.04, 95%CI:1.05-3.96). After adjusted for confounding factors, a significant positive relationship still existed (adjusted ORs = 2.29, 95%CI: 1.11-4.72). In second trimester, women in high level of serum OC had nearly 1.6 times the risk of delivering LBW infants as those in the low level (OR = 1.55, 95%CI: 1.01-2.37). After adjusted for confounding factors, the ORs increased (ORs = 1.59, 95%CI:1.03-2.45). No significant associations were found between maternal serum OC levels and LBW in third trimester. In addition, there were no associations between maternal 25(OH)D concentrations and LBW during pregnancy. CONCLUSION: High maternal serum OC levels in the first or the second trimester during pregnancy may be associated with the risk of LBW.

Breast cancer in postmenopausal women is associated with an altered gut metagenome.

BACKGROUND: Increasing evidence suggests that gut microbiota play a role in the pathogenesis of breast cancer. The composition and functional capacity of gut microbiota associated with breast cancer have not been studied systematically. METHODS: We performed a comprehensive shotgun metagenomic analysis of 18 premenopausal breast cancer patients, 25 premenopausal healthy controls, 44 postmenopausal breast cancer patients, and 46 postmenopausal healthy controls. RESULTS: Microbial diversity was higher in breast cancer patients than in controls. Relative species abundance in gut microbiota did not differ significantly between premenopausal breast cancer patients and premenopausal controls. In contrast, relative abundance of 45 species differed significantly between postmenopausal patients and postmenopausal controls: 38 species were enriched in postmenopausal patients, including Escherichia coli, Klebsiella sp_1_1_55, Prevotella amnii, Enterococcus gallinarum, Actinomyces sp. HPA0247, Shewanella putrefaciens, and Erwinia amylovora, and 7 species were less abundant in postmenopausal patients, including Eubacterium eligens and Lactobacillus vaginalis. Acinetobacter radioresistens and Enterococcus gallinarum were positively but weakly associated with expression of high-sensitivity C-reactive protein; Shewanella putrefaciens and Erwinia amylovora were positively but weakly associated with estradiol levels. Actinomyces sp. HPA0247 negatively but weakly correlated with CD3+CD8+ T cell numbers. Further characterization of metagenome functional capacity indicated that the gut metagenomes of postmenopausal breast cancer patients were enriched in genes encoding lipopolysaccharide biosynthesis, iron complex transport system, PTS system, secretion system, and beta-oxidation. CONCLUSION: The composition and functions of the gut microbial community differ between postmenopausal breast cancer patients and healthy controls. The gut microbiota may regulate or respond to host immunity and metabolic balance. Thus, while cause and effect cannot be determined, there is a reproducible change in the microbiota of treatment-naive patients relative to matched controls.