Association of exposure to multiple heavy metals during pregnancy with the risk of gestational diabetes mellitus and insulin secretion phase after glucose stimulation.

BACKGROUND: Epidemiological evidence for the association between heavy metals exposure during pregnancy and gestational diabetes mellitus (GDM) is still inconsistent. Additionally, that is poorly understood about the potential cause behind the association, for instance, whether heavy metal exposure is related to the change of insulin secretion phase is unknown. OBJECTIVES: We aimed to explore the relationships of blood levels of arsenic (As), lead (Pb), thallium (Tl), nickel (Ni), cadmium (Cd), cobalt (Co), barium (Ba), chromium (Cr), mercury (Hg) and copper (Cu) during early pregnancy with the odds of GDM, either as an individual or a mixture, as well as the association of the metals with insulin secretion phase after glucose stimulation. METHODS: We performed a nested case-control study consisting of 302 pregnant women with GDM and 302 controls at the First Affiliated Hospital of Anhui Medical University in Hefei, China. Around the 12th week of pregnancy, blood samples of pregnant women were collected and levels of As, Pb, Tl, Ni, Cd, Co, Ba, Cr, Hg and Cu in blood were measured. An oral glucose tolerance test (OGTT) was done in each pregnant woman during the 24-28th week of pregnancy to diagnose GDM and C-peptide (CP) levels during OGTT were measured simultaneously. The four metals (As, Pb, Tl and Ni) with the highest effect on odds of GDM were selected for the subsequent analyses via the random forest model. Conditional logistic regression models were performed to analyze the relationships of blood As, Pb, Tl and Ni levels with the odds of GDM. The weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR) were used to assess the joint effects of levels of As, Pb, Tl and Ni on the odds of GDM as well as to evaluate which metal level contributed most to the association. Latent profile analysis (LPA) was conducted to identify profiles of glycemic and C-peptide levels at different time points. Multiple linear regression models were employed to explore the relationships of metals with glycaemia-related indices (fasting blood glucose (FBG), 1-hour blood glucose (1h BG), 2-hour blood glucose (2h BG), fasting C-peptide (FCP), 1-hour C-peptide (1h CP), 2-hour C-peptide (2h CP), FCP/FBG, 1h CP/1h BG, 2h CP/2h BG, area under the curve of C-peptide (AUCP), area under the curve of glucose (AUCG), AUCP/AUCG and profiles of BGs and CPs, respectively. Mixed-effects models with repeated measures data were used to explore the relationship between As (the ultimately selected metal) level and glucose-stimulated insulin secretion phase. The mediation effects of AUCP and AUCG on the association of As exposure with odds of GDM were investigated using mediation models. RESULTS: The odds of GDM in pregnant women increased with every ln unit increase in blood As concentration (odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.04-2.05). The joint effects of As, Pb, Tl and Ni levels on the odds of GDM was statistically significant when blood levels of four metals were exceeded their 50th percentile, with As level being a major contributor. Blood As level was positively associated with AUCG and the category of glucose latent profile, the values of AUCG were much higher in GDM group than those in non-GDM group, which suggested that As exposure associated with the odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance among pregnant women. The significant and positive relationships of As level with AUCP, CP latent profile category, 2h CP and 2h CP/2h BG were observed, respectively; and the values of 1h CP/1h BG and AUCP/AUCG were much lower in GDM group than those in non-GDM group, which suggested that As exposure may not relate to the impairment of insulin secretion (pancreatic ß-cell function) among pregnant women. The relationships between As level and 2h CP as well as 2h CP/2h BG were positive and significant; additionally, the values of 2h CP/2h BG in GDM group were comparable with those in non-GDM group; the peak value of CP occurred at 2h in GDM group, as well as the values of 2h CP/2h BG in high As exposure group were much higher than those in low As exposure group, which suggested that As exposure associated with the increased odds of GDM may be due to that As exposure was related to the change of insulin secretion phase (delayment of the peak of insulin secretion) among pregnant women. In addition, AUCP mediated 11% (p < 0.05) and AUCG mediated 43% (p < 0.05) of the association between As exposure and the odds of GDM. CONCLUSION: Our results suggested that joint exposure to As, Pb, Tl and Ni during early pregnancy was positively associated with the odds of GDM, As was a major contributor; and the association of environmental As exposure with the increased odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance and change of insulin secretion phase after glucose stimulation (delayment of the peak of insulin secretion) among pregnant women.

Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation.

BACKGROUND/AIMS: The activation of the complement system and subsequent inflammatory responses are important features of myocardial ischemia/reperfusion (I/R) injury. Exosomes are nanoscale extracellular vesicles that play a significant role in remote ischemic preconditioning (RIPC) cardioprotection. The present study aimed to test whether RIPC-induced plasma exosomes (RIPC-Exo) exert protective effects on myocardial I/R injury by inhibiting complement activation and inflammation and whether exosomal heat shock protein 90 (HSP90) mediates these effects. METHODS: Rat hearts underwent 30 min of coronary ligation followed by 2 h of reperfusion. Plasma exosomes were isolated from RIPC rats and injected into the infarcted myocardium immediately after ligation. Sixty rats were randomly divided into Sham, I/R, I/R + RIPC-Exo (50 µg/µl), and RIPC-Exo + GA (geldanamycin, 1 mg/kg, administration 30 min before ligation) groups. Cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB), infarct size, the expression of HSP90, complement component (C)3, C5a, c-Jun N-terminal kinase (JNK), interleukin (IL)-1ß, tumor necrosis factor (TNF)-alpha and intercellular adhesion molecule -1 (ICAM-1) were assessed. RESULTS: RIPC-Exo treatment significantly reduced I/R-induced cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB) and infarct size. These beneficial effects were accompanied by decreased C3 and C5a expression, decreased inflammatory factor levels (IL-1ß, TNF-α, and ICAM-1), decreased JNK and Bax, and increased Bcl-2 expression. Meanwhile, the expression of HSP90 in the exosomes from rat plasma increased significantly after RIPC. However, treatment with HSP90 inhibitor GA significantly reversed the cardioprotection of RIPC-Exo, as well as activated complement component, JNK signalling and inflammation, indicating that HSP90 in exosomes isolated from the RIPC was important in mediating the cardioprotective effects during I/R. CONCLUSION: Exosomal HSP90 induced by RIPC played a significant role in cardioprotection against I/R injury, and its function was in part linked to the inhibition of the complement system, JNK signalling and local and systemic inflammation, ultimately alleviating I/R-induced myocardial injury and apoptosis by the upregulation of Bcl-2 expression and the downregulation of proapoptotic Bax.

Polymorphisms of mtDNA in the D-loop region moderate the associations of BMI with HOMA-IR and HOMA-ß among women with polycystic ovary syndrome: a cross-sectional study.

PURPOSE: Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility in women of childbearing age, and many patients with PCOS have obesity and insulin resistance (IR). Although obesity is related to an increased risk of IR, in clinical practice, PCOS patients exhibit different effects on improving insulin sensitivity after weight loss. Therefore, in the present study, we aimed to examine the moderating effect of polymorphisms of mtDNA in the D-loop region on the associations of body mass index (BMI) with the homeostasis model assessment of insulin resistance index (HOMA-IR) and pancreatic ß cell function index (HOMA-ß) among women with PCOS. METHODS: Based on a cross-sectional study, women with PCOS were recruited from the Reproductive Center of the First Affiliated Hospital of Anhui Medical University from 2015 to 2018. A total of 520 women who were diagnosed with PCOS based on the revised 2003 Rotterdam criteria were included in the study. Peripheral blood was collected from these patients, followed by DNA extraction, PCR amplification, and sequencing at baseline. HOMA-IR and HOMA-ß were calculated according to blood glucose-related indices. Moderating effect models were performed with BMI as an independent variable, polymorphisms of mtDNA in the D-loop region as moderators, and ln (HOMA-IR) and ln (HOMA-ß) as dependent variables. To verify the stability of moderating effect, sensitivity analysis was performed with the quantitative insulin sensitivity check index (QUICKI), fasting plasma glucose/fasting insulin (G/I), and fasting insulin as dependent variables. RESULTS: BMI was positively associated with ln (HOMA-IR) and ln (HOMA-ß) (ß = 0.090, p < 0.001; ß = 0.059, p < 0.001, respectively), and the relationship between BMI and ln (HOMA-IR) or ln (HOMA-ß) was moderated by the polymorphisms of mtDNA in the D-loop region. Compared with the respective wild-type, the variant -type of m.16217 T > C enhanced the association between BMI and HOMA-IR, while the variant-type of m.16316 A > G weakened the association. On the other hand, the variant-type of m.16316 A > G and m.16203 A > G weakened the association between BMI and HOMA-ß, respectively. The results of QUICKI and fasting insulin as dependent variables were generally consistent with HOMA-IR, and the results of G/I as dependent variables were generally consistent with HOMA-ß. CONCLUSION: Polymorphisms of mtDNA in the D-loop region moderate the associations of BMI with HOMA-IR and HOMA-ß among women with PCOS.

Exposure to multiple toxic metals and the risk of early embryonic arrest among women undergoing assisted reproductive techniques.

BACKGROUND: Early embryonic arrest is a great challenge for in vitro fertilization. Whether exposure to toxic metals is associated with an increased risk of early embryonic arrest warrants investigation. OBJECTIVES: Here, we conducted a case-control study in infertile women to estimate the associations between blood barium (Ba), arsenic (As), mercury (Hg), and lead (Pb) exposure levels and the risk of early embryonic arrest. METHODS: Ba, As, Hg, and Pb exposure levels in fasting blood collected from 74 infertile women (123 cycles) with early embryonic arrest and 157 infertile women (180 cycles) without early embryonic arrest were measured by ICP-MS. Bayesian kernel machine regression (BKMR) was used to assess the association of exposure level of toxic metals mixture with the risk of early embryonic arrest as well as to evaluate which metal playing a leading role in the association, and then generalized estimating equations (GEEs) were used to evaluate the relationship between the selected harmful metal and the risk of early embryonic arrest. Finally, the potential causes of early embryonic arrest originating from the harmful metal exposure were explored. RESULTS: Blood Ba levels were significantly higher in the case group than that in the control group (p = 0.009) rather than As, Pb and Hg. Results from BKMR showed that exposure to toxic metals mixture increased the risk of early embryonic arrest, with Ba playing a leading role (PIP = 0.9612). GEE analysis showed that high Ba exposure level was related with the increased risk of early embryonic arrest (p < 0.05) and it impacted on the oogenesis significantly. CONCLUSIONS: Our study found that exposure to toxic metals mixture was associated with the increased risk of early embryonic arrest, and Ba contributed most to the increased risk. Higher Ba exposure in whole blood corresponds to a higher risk of early embryonic arrest and impacted on the oogenesis significantly.

The association between levels of samarium, hafnium, tungsten and rhenium in seminal plasma and the risk of idiopathic oligo-astheno-teratozoospermia in men of childbearing age.

Oligo-astheno-teratozoospermia (OAT) is a global public health problem, which affects 30% men of childbearing age. Meanwhile, with the rapid development of industry and economy, the contents of rare earth elements (REEs) in the environment are increasing. However, little is known about the associations between REEs levels and OAT risk. To evaluate the associations between the levels of four REEs (samarium (Sm), hafnium (Hf), tungsten (W), rhenium (Re)) in seminal plasma and OAT risk, from October 2021 to November 2022, semen samples from 924 men of childbearing age (460 controls and 464 cases) were collected from the reproductive center of the First Affiliated Hospital of Anhui Medical University. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to measure the levels of Sm, Hf, Re and W in seminal plasma. Bayesian kernel machine regression (BKMR) was conducted to explore the joint effects of levels of four REEs in seminal plasma on the risk of OAT and select the one exerting a major role; generalized linear regression models (GLM) with log link function were employed to investigate the association of every REE level in seminal plasma and OAT risk; sankey diagram and linear regression models were utilized to describe the associations between the levels of four REEs and the indexes of sperm quality. The levels of four REEs in seminal plasma were higher in the case group than levels in the control group (pSm = 0.011, pHf = 0.040, pW = 0.062, pRe = 0.001, respectively). In BKMR analysis, the OAT risk increased when the overall levels of four REEs were higher than their 55th percentile compared to all of them at their 50th percentile, and Re level played a major role in the association. Additionally, Re level in seminal plasma was positively associated with  the OAT risk in the single element model after adjustment of covariates (medium vs. low: OR (95% CI) = 1.55 (1.10, 2.18); high vs. low: OR (95% CI) = 1.69 (1.18, 2.42)). Lastly, the sankey diagram and linear regression models revealed that Sm level was negatively associated with the PR%, total sperm count and total progressively motile sperm count; Hf level was negatively associated with the PR%; W and Re levels were negatively associated with the PR% and total motility, and Re level was positively associated with abnormal morphology rate. Men of childbearing age with OAT had higher levels of Sm, Hf and Re in seminal plasma than those in the control group. An increasing trend for the OAT risk was observed with an increase in mixture levels of Sm, Hf, W and Re, and Re exposure level played a major role in the association whether in BKMR model or single element model. Additionally, the levels of these four REEs were negatively associated with the indexes of sperm quality.

Using Bayesian and weighted regression to evaluate the association of idiopathic oligoastenoteratozoospermia with seminal plasma metal mixtures.

Idiopathic oligoastenoteratozoospermia (iOAT) affects 30% of infertile men of reproductive age. However, the associations between Cr, Fe, Cu, Se or Co levels and iOAT risk have not been determined. This research aimed to assess the associations between Cr, Fe, Cu, Se and Co levels as well as their mixtures in seminal plasma and the risk of iOAT and severe iOAT. Therefore, a case‒control study including 823 participants (416 iOAT patients and 407 controls) recruited from October 2021 to August 2022 at the reproductive medicine center of the First Affiliated Hospital of Anhui Medical University was conducted in Anhui, China. The concentrations of Cr, Fe, Cu, Se and Co in seminal plasma were detected via inductively coupled plasma‒mass spectrometry. Binary logistic regression models were used to assess the associations between the levels of Cr, Fe, Cu, Se and Co and the risk of iOAT and severe iOAT; additionally, Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regressions were performed to evaluate the joint effect of seminal plasma levels of Cr, Fe, Cu, Se and Co on the risk of iOAT and explore which elements contributed most to the relationship. We found significant associations between the concentrations of Fe, Cu and Se in seminal plasma and iOAT risk after adjusting for covariates (Fe, lowest tertile vs. second tertile: aOR = 1.86, 95% CI = 1.31, 2.64; Cu, lowest tertile vs. second tertile: aOR = 1.95, 95% CI = 1.37, 2.76; Se, lowest tertile vs. second tertile: aOR = 1.65, 95% CI = 1.17, 2.35). A lower Se concentration in seminal plasma (lowest tertile vs. second tertile: aOR = 1.84, 95% CI = 1.10, 3.10) was positively associated with the risk of severe iOAT. Additionally, we also observed an association between the concentration of Cr in seminal plasma and the risk of iOAT before adjusting for covariates (Cr, third tertile vs. lowest tertile: OR=1.44, 95% CI: 1.03, 2.02). According to the BKMR analyses, the risk of iOAT increased when the overall concentrations were less than the 25th percentile. The results from the WQS regression indicated that a negative WQS index was significantly associated with the iOAT risk, while a positive WQS index was not. Se and Fe had significant weights in the negative direction. In conclusion, lower Cu, Fe and Se levels in seminal plasma were positively associated with iOAT risk, while higher Cr levels in seminal plasma were positively associated with iOAT risk according to the single element model, and lower levels of Se were related to a greater risk of severe iOAT; when comprehensively considering all the results from BKMR and WQS regression, Fe, Se and Cr levels contributed most to this relationship.

Association Between Exposure to Multiple Toxic Metals in Follicular Fluid and the Risk of PCOS Among Infertile Women: The Mediating Effect of Metabolic Markers.

Polycystic ovary syndrome (PCOS) severely affects women's fertility and accompanies serious metabolic disturbances, affecting 5%-20% of women of reproductive age globally. We previously found that exposure to toxic metals in the blood raised the risk of PCOS, but the association between exposure to toxic metals and the risk of PCOS in the follicular fluid, the microenvironment for oocyte growth and development in females, and its effect on metabolism has not been reported. This study aimed to evaluate the associations between the concentrations of cadmium (Cd), mercury (Hg), barium (Ba) and arsenic (As) in FF and the risk of PCOS, and to explore the mediating effect of metabolic markers in FF on the above relationship. We conducted a case-control study, including 557 women with PCOS and 651 controls. Ba, Cd, Hg and As levels in FF were measured by ICP-MS, metabolites levels in FF was measured by LC-MS/MS among 168 participants randomly selected from all the participants. Logistic regression models were used to assess the association of a single metal level with the PCOS risk, and linear regression models were used to assess the relationships of a single metal level with clinical phenotype parameters and metabolites levels. Combined effect of metals mixture levels on the risk of PCOS were assessed via weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR). Medication analysis was performed to explore the role of metabolic markers on the relationship of toxic metals levels with the risk of PCOS. The exposure levels of Cd, Hg, Ba and As in FF were all positively and significantly associated with the PCOS risk (with respect to the highest vs. lowest tertile group: OR = 1.57, 95% CI = 1.17 ~ 2.12 for Cd, OR = 1.69, 95% CI = 1.22 ~ 2.34 for Hg, OR = 1.76, 95% CI = 1.32 ~ 2.34 for Ba, OR = 1.42, 95% CI = 1.05 ~ 1.91 for As). In addition, levels of metal mixture also significantly correlated with the risk of PCOS, Cd level contributed most to it. Moreover, we observed significant positive relationships between Cd level and LH (ß = 0.048, 95% CI = 0.002 ~ 0.094), T (ß = 0.077, 95% CI = 0.029 ~ 0.125) and HOMA-IR value (ß = 0.060, 95% CI = 0.012 ~ 0.107), as well as Hg level with LH, FSH/LH ratio and TC. Furthermore, we revealed that estrone sulfate, LysoPE 22:6 and N-Undecanoylglycine were significantly and positively mediating the association between Cd level and the risk of PCOS (with mediated proportion of 0.39, 0.24 and 0.35, respectively), and between Hg level and the risk of PCOS (with mediated proportion of 0.29, 0.20 and 0.46, respectively). These highly expressed metabolites significantly enriched in the fatty acid oxidation, steroid hormone biosynthesis and glycerophospholipids metabolism, which may explain the reason why the levels of Cd and Hg in FF associated with the phenotype of PCOS. Ba and As in FF was not found the above phenomenon. Our results suggested that exposure to multiple toxic metals (Cd, Hg, Ba and As) in FF associated with the increased risk of PCOS, Cd was a major contributor. Levels of Cd and Hg in FF significantly associated with the phenotype of PCOS. The above association may result from that Cd and Hg in FF related with the disturbance of fatty acid oxidation, steroid hormone biosynthesis and the glycerophospholipids metabolism.

Effects of heat shock protein 90 on complement activation in myocardial ischemia/reperfusion injury after pioglitazone preconditioning.

BACKGROUND: Heat shock protein 90 (HSP90) appears to have a pivotal function in ischemic preconditioning. Pioglitazone preconditioning (PioC) attenuates myocardial ischemia/reperfusion (I/R) injuries. OBJECTIVES: The current study aims to investigate the role of HSP90, complement C3 and C5a, and nuclear factor kappa-B (NF-κB) in PioC-induced cardioprotection. MATERIAL AND METHODS: A total of 80 rats were randomly categorized into 4 groups, as follows: sham, I/R, PioC, and PioC+HSP90 inhibitor geldanamycin (PioC+GA). The sham group rats had a thoracotomy, in which the ligature was passed by the heart with no ligation (150 min). The other 3 groups were exposed to ischemia (30 min) followed by reperfusion (2 h). In the PioC group, pioglitazone (3 mg/kg) was administered intravenously 24 h before ischemia. In the PioC+GA group, after being pretreated with pioglitazone, GA was administered (intraperitoneally, 1 mg/kg) 30 min before ischemia. Myocardial infarct sizes (ISs), apoptosis rates, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin I (cTnI) serum levels were determined. The HSP90, C3, NF-κB, C5a, B-cell lymphoma-2 (Bcl-2), and Bax expression levels, as well as interleukin (IL)-1ß, IL-6, intercellular cell adhesion molecule-1 (ICAM-1), and tumor necrosis factor alpha (TNF-α) mRNA levels were measured. RESULTS: The myocardial ISs, serum CK-MB, cTnI and LDH levels, apoptosis rates, IL-1ß, IL-6, TNF-α, ICAM-1 release, as well as Bax, C5a, C3, and NF-κB protein expression were considerably lower in the PioC group than in the I/R group (p < 0.05). The Bcl-2 and HSP90 expression was higher in the PioC group than in the I/R group (p < 0.05). Geldanamycin inhibited the effects of PioC. These data strongly demonstrate that the PioC-induced is dependent upon HSP90 activity. CONCLUSIONS: The HSP90 is indispensable for PioC-mediated cardioprotection. The HSP90 attenuates I/R-induced ISs, apoptosis of cardiomyocytes and myocardial inflammation through C3, C5a and NF-κB activation inhibition.

Serum Cu, Zn and IL-1ß Levels May Predict Fetal Miscarriage Risk After IVF Cycles: A Nested Case-Control Study.

To explore the association between serum-related indicators (levels of inflammatory cytokines and essential trace elements) and miscarriage risk among infertile women undergoing assisted reproductive techniques (ART) on the 14th day after embryo transfer, and to develop and establish a multivariable algorithm model that might predict pregnancy outcome. According to a nested case-control study design, a total of 100 miscarriage cases and 100 live birth controls were included in this study, and women in both groups were infertile and have underwent in vitro fertilization (IVF). Pregnancy tests were performed and serum levels of five essential trace elements (vanadium (V), copper (Cu), zinc (Zn), selenium (Se) and molybdenum (Mo)) and five inflammatory cytokines (interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α)) of the participants were measured on the 14th day after embryo transfer. The serum levels of five inflammatory cytokines were determined by multiple magnetic bead enzyme immunity analyzer; and the serum concentrations of five elements were determined simultaneously by inductively coupled plasma‒mass spectrometry (ICP ‒ MS). The logistic regression was used to evaluate the relationship between these serum indices and miscarriage risk among women undergoing ART, and a predictive model of pregnancy outcome based on these indices was established. The levels of IL-10, IL-1ß and TNF-α of infertile women in the live birth group were significantly higher than those in the miscarriage group (p = 0.009, p < 0.001, p = 0.006), and the levels of V, Cu, Zn and Se of infertile women in the live birth group were also significantly higher than those in the miscarriage group (all p < 0.001). Through logistic regression analyses, we found that serum levels of IL-1ß, TNF-α, V, Cu, Zn and Se were significantly and negatively associated with miscarriage risk. Different combination prediction models were generated according to the results of logistic regression analyses, and the combination of IL-1ß, Cu and Zn had the best prediction performance. The area under the curve (AUC) was 0.776, the sensitivity of the model was 60% and the specificity was 84%. In conclusion, the serum-related indicators of women undergoing ART on the 14th day after embryo transfer, including the inflammatory cytokines such as IL-1ß and TNF-α and the essential trace metal elements such as V, Cu, Zn and Se, were negatively correlated with miscarriage risk. A multivariate algorithm model to predict pregnancy outcome among women undergoing ART was established, which showed that IL-1ß, Cu and Zn might synergistically predict pregnancy outcome.

The Association Between the Levels of Oxidative Stress Indicators (MDA, SOD, and GSH) in Seminal Plasma and the Risk of Idiopathic Oligo-asthenotera-tozoospermia: Does Cu or Se Level Alter the Association?

Epidemiological studies on the associations between the levels of oxidative stress (OS) indicators (MDA, SOD, and GSH) in seminal plasma and the risk of idiopathic oligo-asthenotera-tozoospermia (OAT) are still inconsistent. Additionally, whether the associations can be altered by the status of essential trace elements is still unknown. To investigate the relationship between MDA, SOD, and GSH levels in seminal plasma and the risk of idiopathic OAT, and further to examine whether levels of iron (Fe), copper (Cu), and selenium (Se) in seminal plasma can alter the associations. A total of 148 subjects (75 idiopathic OAT cases and 73 controls) were included in this study. Seminal plasma samples from all the participants were measured for levels of MDA, SOD, GSH, Fe, Cu, and Se. Unconditional logistic regression models were used to examine the associations between three oxidative stress indicators and the risk of idiopathic OAT. Bayesian kernel machine regression was performed to determine the joint effects of levels of three OS indicators on the risk of idiopathic OAT. Subgroup analyses were performed to explore whether the above associations can be different when Fe, Cu, and Se were in different levels. The level of MDA in seminal plasma was positively associated with the risk of idiopathic OAT, with adjusted odds ratio (OR) and 95% confidence interval (CI) of 2.38 (1.17, 4.83), and SOD and GSH levels were not associated with the risk of idiopathic OAT. In BKMR analyses, we found a significant positive association between the mixture of MDA, SOD, and GSH levels and the risk of idiopathic OAT at concentrations below the 65th percentile, while a negative association at concentrations above it. In subgroup analysis, a positive association was observed between MDA levels in seminal plasma and the risk of idiopathic OAT in the high-Cu group (adjusted OR = 3.66, 95%CI = 1.16, 11.57), while no significant association was found in the low-Cu group (adjusted OR = 1.43, 95%CI = 0.44, 4.58). Additionally, a negative association was found between GSH levels in seminal plasma and the risk of idiopathic OAT in the high-Se group (adjusted OR = 0.34, 95%CI = 0.11, 0.99), while no significant association was observed in the low-Se group (adjusted OR = 1.96, 95%CI = 0.46, 8.27). The levels of MDA, SOD, and GSH in seminal plasma were associated with the risk of idiopathic OAT, and the levels of Cu and Se in seminal plasma may alter the associations.

HSP90-Mediates Liraglutide Preconditioning-Induced Cardioprotection by Inhibiting C5a and NF-κB.

OBJECTIVE: We previously showed that HSP90 is involved in postconditioning cardioprotection by inhibiting complement C5a. Here, we investigated whether HSP90-mediated C5a/NF-κB inhibition is responsible for the cardioprotection conferred by liraglutide. METHODS: Rat hearts underwent a 30 min occlusion of the anterior descending coronary artery, after which reperfusion was performed for 2 h. A total of 100 rats were randomly assigned to the following groups: ischemia/reperfusion (I/R), sham, liraglutide preconditioning (LP, liraglutide, 0.18 mg/kg, intravenously, 12 h before ischemia), HSP90 inhibitor geldanamycin (GA, 1 mg/kg, intraperitoneally, 30 min before ischemia) plus LP, and C5a receptor antagonist PMX53 (1 mg/kg, intravenously, 30 min before ischemia) plus LP. Cardiac injury, C5a/NF-κB activation, and inflammation were investigated. RESULTS: LP significantly attenuated I/R-induced cardiomyocyte apoptosis, infarct size, and secretion of creatine kinase-MB, lactate dehydrogenase and cardiac troponin I. These effects were complemented by decreased C5a levels, nuclear factor (NF)-κB signaling, inflammatory cytokine expression, and increased HSP90 levels. GA, an HSP90 inhibitor, promotes C5a activation, NF-κB signaling, and inflammation and suppresses cardioprotection by LP. By contrast, PMX53, a C5a inhibitor, suppressed C5a activation, NF-κB signaling, and inflammation, and enhanced cardioprotection by LP. CONCLUSION: HSP90 markedly contributes to LP cardioprotection by inhibiting inflammatory responsesand C5a/NF-κB signaling , ultimately attenuating I/R-induced cardiomyocyte apoptosis by suppressing the proapoptotic factor Bax, and inducing the anti-apoptotic factor Bcl2.

Influence of combined exposure levels of total arsenic and inorganic arsenic on arsenic methylation capacity among university students: findings from Bayesian kernel machine regression analysis.

The arsenic (As) methylation capacity is an important determinant of susceptibility to As-related diseases. Total As (TAs) or inorganic As (iAs) was reported to associated with As methylation capacity. We measured urinary concentrations of iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) by using HPLC-HG-AFS and calculated the primary methylation capacity index (PMI) and secondary methylation capacity index (SMI) in 209 university students in Hefei, China, a non-As endemic area. Volunteers were given a standardized questionnaire asking about their sociodemographic characteristics. Bayesian kernel machine regression (BKMR) analysis was used to estimate the association of lnTAs and lniAs levels with methylation indices (ln%MMA, ln%DMA, lnPMI, lnSMI). The median concentrations of iAs, MMA, and DMA were 1.22, 0.92, and 12.17 µg/L, respectively; the proportions of iAs, MMA, and DMA were 8.76%, 6.13%, and 84.84%, respectively. Females had higher %DMA and lower %MMA than males. The combined levels of lnTAs and lniAs showed a decrease in the changes in ln%DMA and lnSMI. With regard to the single exposure level, the lnTAs showed positive correlations with ln%DMA, lnPMI, and lnSMI when lniAs was set at a specific level, while lniAs showed negative correlations with ln%DMA, lnPMI, and lnSMI when lnTAs was set at a specific level; all the dose-response relationships were nonlinear. Our results suggested that combined levels of TAs and iAs play an important role in reducing As methylation capacity, especially iAs, and the reduction only occurs when TAs and iAs are present up to a certain combined level.