Gut microbiota mediate melatonin signalling in association with type 2 diabetes.

AIMS/HYPOTHESIS: It has been shown that melatonin plays a general beneficial role in type 2 diabetes in rodents but its role in humans is controversial. In the present study, we investigated the association between serum melatonin and type 2 diabetes risk in a southern Chinese population in a case-control study. We also examined the role of gut microbiota in this relationship. METHODS: Individuals with type 2 diabetes (cases) and healthy individuals (controls) (n=2034) were recruited from a cross-sectional study and were matched for age and sex in a case-control study. The levels of serum melatonin were measured and the association between serum melatonin and type 2 diabetes risk was examined using a multivariable logistic regression model. We further conducted a rigorously matched case-control study (n=120) in which gut microbial 16S rRNA was sequenced and metabolites were profiled using an untargeted LC-MS/MS approach. RESULTS: Higher levels of serum melatonin were significantly associated with a lower risk of type 2 diabetes (OR 0.82 [95% CI 0.74, 0.92]) and with lower levels of fasting glucose after adjustment for covariates (ß -0.25 [95% CI -0.38, -0.12]). Gut microbiota exhibited alteration in the individuals with type 2 diabetes, in whom lower levels of serum melatonin, lower α- and ß-diversity of gut microbiota (p<0.05), greater abundance of Bifidobacterium and lower abundance of Coprococcus (linear discriminant analysis [LDA] >2.0) were found. Seven genera were correlated with melatonin and type 2 diabetes-related traits; among them Bifidobacterium was positively correlated with serum lipopolysaccharide (LPS) and IL-10, whereas Coprococcus was negatively correlated with serum IL-1ß, IL-6, IL-10, IL-17, TNF-α and LPS (Benjamini-Hochberg-adjusted p value [false discovery rate (FDR)] <0.05). Moreover, altered metabolites were detected in the participants with type 2 diabetes and there was a significant correlation between tryptophan (Trp) metabolites and the melatonin-correlated genera including Bifidobacterium and Coprococcus (FDR<0.05). Similarly, a significant correlation was found between Trp metabolites and inflammation factors, such as IL-1ß, IL-6, IL-10, IL-17, TNF-α and LPS (FDR<0.05). Further, we showed that Trp metabolites may serve as a biomarker to predict type 2 diabetes status (AUC=0.804). CONCLUSIONS/INTERPRETATION: A higher level of serum melatonin was associated with a lower risk of type 2 diabetes. Gut microbiota-mediated melatonin signalling was involved in this association; especially, Bifidobacterium- and Coprococcus-mediated Trp metabolites may be involved in the process. These findings uncover the importance of melatonin and melatonin-related bacteria and metabolites as potential therapeutic targets for type 2 diabetes.

Increased oxidative stress and plasma Hsp70 levels among gasoline filling station attendants.

OBJECTIVES: Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic derivative of manganese (Mn) and is used as an antiknock agent and octane enhancer in gasoline. In this article, we tested the oxidative stress and heat stress protein (Hsp) 70 levels of gasoline station attendants to explore potential plasma biomarkers. Furthermore, the dose-response relationship was also identified. METHODS: A total of 144 workers, including 96 petrol fillers and 48 cashiers, participated in the study. Ambient concentrations of benzene, toluene, ethylbenzene, and xylene (BTEX) and Mn were monitored at nine filling stations. During the measuring process, the individual cumulative exposure index was calculated. Plasma oxidative stress and Hsp70 levels were also analysed using enzyme-linked immunosorbent assay. RESULTS: The BTEX time-weighted average in office areas was significantly lower than in refuelling areas ( p < 0.05). In refuelling areas, the content of Mn ranged from 6.44 µg/m3 to 127.34 µg/m3, which was much higher than that in office areas (3.16-7.22 µg/m3; p < 0.05). Exposed workers had significantly different plasma oxidative stress indicators compared with the control group, respectively: superoxide dismutase (SOD), 39.18 ± 6.05 U/mL versus 52.84 ± 3.87 U/mL; glutathione peroxidase (GSH-Px), 186.07 ± 15.63 U versus 194.38 ± 10.42 U; and malondialdehyde (MDA), 1.68 ± 0.52 nmol/L versus 1.43 ± 0.64 nmol/L (in all comparisons, p < 0.05). Plasma Hsp70 level in the exposed group (2.77 ± 0.64 ng/mL) was significantly higher than in the control group (2.32 ± 0.87 ng/mL; p < 0.05). Furthermore, Hsp70 levels were inversely correlated with the activities of SOD ( r = -0.305) and GSH-Px ( r = -0.302) in the exposed group ( p < 0.05). Moreover, a positive correlation ( r = 0.653) was found between plasma Hsp70 levels and plasma MDA levels ( p < 0.05). CONCLUSION: Exposure to MMT-containing gasoline may result in increasing reactive oxygen stress among filling station attendants. Plasma Hsp70 levels could be used as a sensitive responsive biomarker for exposed workers.

Chronic exposure to manganese sulfate leads to adverse dose-dependent effects on the neurobehavioral ability of rats.

Manganese sulfate is the main combustion product of methylcyclopentadienyl manganese tricarbonyl (MMT). Currently, little is known about the neurobehavioral consequences of chronic manganese sulfate exposure. In this study, rats were treated with 0, 5.0, 10.0, and 20.0 mg/kg MnSO4 ·H2 O for 24 consecutive weeks via intraperitoneal injection. During the treatment period, spatial learning-memory ability was measured using the Morris water maze (MWM). At the end of the exposure period, spontaneous motor behavior and emotional status, hippocampal histologic changes, and Hsp70 mRNA levels were measured using the open-field test (OFT), hematoxylin-eosin staining and real-time quantitative PCR (RT-PCR), respectively. A dose-dependent decrease was noted in the spatial learning-memory ability and the spontaneous activities of rats (P < 0.05), and negative emotions differed significantly between the exposed groups and the control group (P < 0.05). Moreover, overt morphological changes in the hippocampuses of the exposed rats were detected. Cellular degeneration and death were also found. The Hsp70 mRNA levels of the hippocampal areas in the 20.0 mg/kg group (1.567 ± 0.236) were significantly increased compared with the control group (P < 0.05). These results suggest that chronic exposure to manganese sulfate can have adverse dose-dependent effects on rats' neurobehavioral ability, and the mechanism of abnormal hippocampal Hsp70 expression needs to be further explored. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1571-1579, 2016.

Cognitive function and plasma BDNF levels among manganese-exposed smelters.

OBJECTIVES: To explore the potential dose-response relationship between manganese (Mn) exposure and cognitive function and also plasma brain-derived neurotrophic factor (BDNF) levels in occupational Mn exposure workers. METHODS: A total 819 workers were identified from our Mn-exposed workers, and 293 control workers were recruited in the same region. All exposed workers were divided into three groups based on Mn cumulative exposure index. The Montreal Cognitive Assessment (MoCA) test was applied to estimate cognitive function for all subjects. Plasma BDNF levels were determined by ELISA in 248 selected exposed workers and 100 controls. RESULTS: Mn-exposed workers had significantly lower MoCA scores than those in the control group (25.62 ± 0.25): those in high-exposure group had the lowest scores (21.33 ± 0.32), compared with the intermediate-exposure group (23.22 ± 0.30) and low-exposure group (23.57 ± 0.23). Mn exposure levels were inversely associated with MoCA total scores, all p<0.05. A positive correlation was found between plasma BDNF levels and MoCA total scores (r=0.278, p<0.01). Moreover, compared with the control group (288.7 ± 181.7 pg/mL), BDNF levels were lower in the high-exposure group (127.5 ± 99.8 pg/mL), and in the intermediate-exposure (178.2 ± 138.1 pg/mL) and low-exposure groups (223.4 ± 178.3 pg/mL). Additionally, plasma BDNF levels decreased significantly as Mn exposure levels increased (ptrend<0.01). CONCLUSIONS: Mn exposure may be associated with decreased plasma BDNF levels and cognition impairment in this large cross-sectional study.

PLK-3-mediated phosphorylation of BAP1 prevents diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus, and its main clinical manifestation is retinal vascular dysfunction. DR causes blindness and is a problem with significant global health implications. However, treating DR is still challenging. In this study, we aimed to explore the role of polo-like kinase-3 (PLK-3) and the potential regulatory mechanism in DR. Sprague-Dawley rats were injected intraperitoneally with streptozotocin (STZ, 60 mg/kg) to induce a rat model of DR, and rat retinal microvascular endothelial cells (RRMECs) were treated with high glucose (HG, 25 mmol/L glucose) to develop a cell model of DR. We found that PLK-3 was significantly downregulated in the retinal tissues of STZ-induced diabetic rats and HG-induced RRMECs. Lentivirus-mediated PLK-3 overexpression alleviated the histological damages in DR rats. After HG stimulation, cell proliferation, migration, and angiogenesis in RRMECs were inhibited after PLK-3 upregulation. By using label-free proteomics, we identified 82 differentially expressed proteins downstream of PLK-3, including BRCA1-associated protein 1 (BAP1), which was significantly upregulated in PLK-3-overexpressed RRMECs compared to control cells under the HG condition. In vivo and in vitro assays indicated that the forced expression of PLK-3 increased the phosphorylation of BAP1 at serine 592 and caspase-8 expression. Detailed evidence showed that BAP1-shRNA-mediated knockdown restored the cell function in HG-treated RRMECs when PLK-3 was overexpressed. Collectively, this study shows that PLK-3 alleviates retinal vascular dysfunction in DR by inhibiting the phosphorylation of BAP1. Thus, PLK-3 may develop as a promising target for the therapy of DR.

Jingzhi Niuhuangjiedu Tablet Ameliorates Oral Mucositis via the AKT/NFκB/NLRP3 Signaling Pathway: A Network Pharmacology and Experimental Validation.

BACKGROUND: Oral Mucositis (OM) is a common and highly symptomatic complication of cancer therapy that affects patient function and quality of life. Jingzhi Niuhuangjiedu Tablet (JNT) is derived from the famous Chinese herbal formulas Huanglian Jiedu and Fangfeng Tongsheng decoctions, which have been widely used to treat heat toxin syndrome diseases, such as acute pharyngitis, periodontitis, oral ulcers, and oral mucositis (OM), but the underlying mechanism remains unclear. OBJECTIVES: This study validated the efficacy and explored the potential mechanisms of JNT in the treatment of OM by integrating network pharmacological analyses and experimental verification. METHODS: Network pharmacology and molecular docking techniques were used to predict the active components, key targets, and potential mechanisms of action of JNT against OM. The rat OM model was established by administering 5-Fluorouracil (5-FU) and acetic acid to the rat oral mucosa. Lipopolysaccharide (LPS)-treated human gingival fibroblasts (HGFs) were used as an inflammatory cell model. The GFP-NFκB HEK293T cell line was transfected to evaluate the anti-NFκB activity of JNT. RESULTS: A total of 236 Chinese herbal components and 201 corresponding targets were predicted for OM treatment using JNT. Bicuculine, luteolin, wogonin, and naringenin were identified as the important active compounds, while AKT1, ALB, IL6, MAPK3, and VEGFA were considered to be the major targets. Molecular docking revealed that these active compounds exhibited strong binding interactions with their targets. In vivo and in vitro experiments demonstrated that the anti-OM effect of JNT might be closely related to AKT1, NFκB, caspase-1, and NLRP3, as well as biological processes, such as inflammatory response and oxidative stress. CONCLUSION: Network pharmacological and experimental evidence indicates that JNT has a potential therapeutic effect on OM by regulating the Akt/NFκB/NLRP3 pathway.

Joint associations among non-essential heavy metal mixtures and nutritional factors on glucose metabolism indexes in US adults: evidence from the NHANES 2011-2016.

Dietary intake can modify the impact of metals on human health, and is also closely related to glucose metabolism in human bodies. However, research on their interaction is limited. We used data based on 1738 adults aged ≥20 years from the National Health and Nutrition Examination Survey 2011-2016. We combined linear regression and restricted cubic splines with Bayesian kernel machine regression (BKMR) to identify metals associated with each glucose metabolism index (P < 0.05 and the posterior inclusion probabilities of BKMR >0.5) in eight non-essential heavy metals (barium, cadmium, antimony, tungsten, uranium, arsenic, lead, and thallium) and glucose metabolism indexes [fasting plasma glucose (FPG), blood hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)]. We identified two pairs of metals associated with glucose metabolism indexes: cadmium and tungsten to HbA1c and barium and thallium to HOMA-IR. Then, the cross-validated kernel ensemble (CVEK) approach was applied to identify the specific nutrient group (nutrients) that interacted with the association. By using the CVEK model, we identified significant interactions between the energy-adjusted diet inflammatory index (E-DII) and cadmium, tungsten and barium (all P < 0.05); macro-nutrients and cadmium, tungsten and barium (all P < 0.05); minerals and cadmium, tungsten, barium and thallium (all P < 0.05); and A vitamins and thallium (P = 0.043). Furthermore, a lower E-DII, a lower intake of carbohydrates and phosphorus, and a higher consumption of magnesium seem to attenuate the positive association between metals and glucose metabolism indexes. Our finding identifying the nutrients that interact with non-essential heavy metals could provide a feasible nutritional guideline for the general population to protect against the adverse effects of non-essential heavy metals on glucose metabolism.

Case report: Head lice in the eyelashes.

Purpose: Head lice infection of the eyelashes and adjacent eyelids is extremely rare. In this case report we present a child with head lice infection of the eyelashes. Observations: A 3-year-old boy presented to the ophthalmology department with a chief complaint of itching and visible abnormal secretions of the upper eyelashes in the right eye for more than 1 week. On ocular examination, a large number of nits and brown secretions were tightly adhered to the root of the upper eyelashes of the right eye, and translucent parasites crept slowly along the eyelashes, without impairment of vision. A few of the parasites and nits were further viewed with a microscope and were identified as head lice. Conclusions and Importance: This case suggests that ophthalmologists should not only consider common inflammation and allergies, but also be alert to parasitic infections when treating patients with ocular itching and abnormal secretions.

Co-exposure of serum calcium, selenium and vanadium is nonlinearly associated with increased risk of type 2 diabetes mellitus in a Chinese population.

BACKGROUND: Metals play an important role in type 2 diabetes mellitus (T2DM). This study aimed to explore the association of T2DM risk with single metal exposure and multi-metal co-exposure. METHODS: A case-control study with 223 T2DM patients and 302 controls was conducted. Serum concentrations of 19 metals were determined by inductively coupled plasma mass spectrometry (ICP-MS). Those metals with greater effects were screened out and co-exposure effects of metals were assessed by least absolute shrinkage and selection operator (LASSO) regression. RESULTS: Serum calcium (Ca), selenium (Se) and vanadium (V) were found with greater effects. Higher levels of Ca and Se were associated with increased T2DM risk (OR = 2.23, 95%CI: 1.38-3.62, Ptrend = 0.002; OR = 3.16, 95%CI: 1.82-5.50, Ptrend < 0.001), but higher V level was associated with decreased T2DM risk (OR = 0.58, 95%CI: 0.34-0.97, Ptrend < 0.001). Serum Ca and V concentrations were nonlinearly associated with T2DM risk (Poverall < 0.001, Pnonliearity < 0.001); however, Se concentration was linearly associated with T2DM risk (Poverall < 0.001, Pnonliearity = 0.389). High co-exposure score of serum Ca, Se and V was associated with increased T2DM risk (OR = 3.50, 95%CI: 2.08-5.89, Ptrend < 0.001) as a non-linear relationship (Poverall < 0.001, Pnonliearity = 0.003). CONCLUSIONS: This study suggest that higher levels of serum Ca and Se were associated with increased T2DM risk, but higher serum V level was associated with decreased T2DM risk. Moreover, co-exposure of serum Ca, Se and V was nonlinearly associated with T2DM risk, and high co-exposure score was positively associated with T2DM risk.

Sex-specific associations of plasma metals and metal mixtures with glucose metabolism: An occupational population-based study in China.

Studies with multi-pollutant approach on the relationships between multiple metals and fasting plasma glucose (FPG) are limited. Few studies are available on the potential sex-specific associations between metal exposures and glucose metabolism. We explored the associations between 22 plasma metals and FPG level among the 769 participants from the manganese-exposed workers healthy cohort in China. We applied a sparse partial least squares (sPLS) regression followed by ordinary least-squares regression to evaluate multi-pollutant association. Bayesian kernel machine regression (BKMR) model was used to deal with metal mixtures and evaluate their joint effects on FPG level. In the sPLS model, negative associations on FPG levels were observed for plasma iron (belta = -0.066), cobalt (belta = -0.075), barium (belta = -0.109), and positive associations for strontium (belta = 0.082), and selenium (belta = 0.057) in men, which overlapped with the results among the overall participants. Among women, plasma copper (belta = 0.112) and antimony (belta = 0.137) were positively associated with elevated FPG level. Plasma magnesium was negatively associated with FPG level in both sexes (belta = -0.071 in men and belta = -0.144 in women). The results of overlapped for plasma magnesium was selected as the significant contributor to decreasing FPG level in the multi-pollutant, single-metal, and multi-metal models. BKMR model showed a significantly negative over-all effect of six metal mixtures (magnesium, iron, cobalt, selenium, strontium and barium) on FPG level among the overall participants from all the metals fixed at 50th percentile. In summary, our findings underline the probable role of metals in glucose homeostasis with potential sex-dependent heterogeneities, and suggest more researches are needed to explore the sex-specific associations of metal exposures with risk of diabetes.

Association of UCP1 polymorphisms with type 2 diabetes mellitus and their interaction with physical activity and sedentary behavior.

BACKGROUND: Uncoupling protein 1 (UCP1) has been reported to be associated with type 2 diabetes mellitus (T2DM) in different populations, however, little is reported in Chinese population. The present study aimed to explore the association between some polymorphisms of UCP1 with T2DM and the interactions between UCP1 and physical activity/sedentary behavior (PA/SB) lifestyle in Chinese population. METHODS: Three polymorphisms (rs1472268, rs3811790 and rs3811791) were genotyped in 929 T2DM patients and 1044 nondiabetic controls. The data of PA and SB were acquired. Logistic regression and linear regression were conducted to assess the association of UCP1 and T2DM and related traits. RESULTS: The CC genotype of rs3811791 was significantly associated with an increased risk of T2DM [odds ratio (OR) = 1.42, P = 0.042] and a higher level of triglyceride (TG) (ß = 0.048, P = 0.034). This association still existed in the group of SB ≥ 3 h/d (OR = 1.66, P = 0.009) and the group of PA ≥ 150 min/week and SB ≥ 3 h/d (OR = 1.60, P = 0.034). In the group of PA < 150 min/week and SB < 3h/d, CC genotype was associated with a higher level of homeostatic model assessment of insulin resistance (HOMA-IR) index, and in the group of PA < 150 min/week and SB ≥ 3 h/d, CC genotype was associated with increased level of TG and decreased high-density lipoprotein cholesterol (HDL-C). CONCLUSION: This study suggests that rs3811791 of UCP1 may be associated with T2DM and TG. Moreover, we demonstrate that SB interacted with rs3811791 of UCP1 was associated with T2DM, and PA interacted with rs3811791 of UCP1 was associated with the level of HOMA-IR, HDL-C, and TG.

Plasma metals and serum bilirubin levels in workers from manganese-exposed workers healthy cohort (MEWHC).

Few studies specifically address the possible associations between multiple-metal exposures and liver damage among the occupational population. This study aimed to explore the cross-sectional relationships of plasma metals with liver function parameters. For 571 on-the-spot workers in the manganese-exposed workers healthy cohort (MEWHC), we determined liver function parameters: total bilirubin (TBILI), direct bilirubin (DBILI), indirect bilirubin (IBILI), alanine transaminase (ALT) and aspartate transaminase (AST). Total concentrations of 22 plasma metals were measured by ICP-MS. The LASSO (least absolute shrinkage and selection operator) penalized regression model was applied for selecting plasma metals independently associated with liver function parameters. Multiple linear regression analyses and restricted cubic spline (RCS) were utilized for identifying the exposure-response relationship of plasma metals with liver function parameters. After adjusting for covariates and selected metals, a 1-SD increase in log-10 transformed levels of iron was associated with increases in the levels of TBILI, DBILI and IBILI by 20.3%, 12.1% and 23.7%, respectively; similar increases in molybdenum for decreases in levels of TBILI, DBILI and IBILI by 6.1%, 2.6% and 8.3%, respectively. The effect of a 1-SD increase in plasma copper corresponded decreases of 3.2%, 3.4% and 5.0% in TBILI, AST and ALT levels, respectively. The spline analyses further clarified the non-linear relationships between plasma iron and bilirubin whilst negative linear relationships for plasma molybdenum and bilirubin. Plasma iron was positively whilst plasma molybdenum was negatively associated with increased serum bilirubin levels. Further studies are needed to validate these associations and uncover the underlying mechanisms.

The association between serum iron status and risk of asthma: a 2-sample Mendelian randomization study in descendants of Europeans.

BACKGROUND: Observational studies present conflicting results about a possible association of iron status with asthma risk, pointing to potential modifiable targets for prevention. OBJECTIVE: The aim of this study was to use Mendelian randomization (MR) to estimate associations between iron status and asthma risk. METHODS: We used the Genetics of Iron Status consortium to identify genetic variants that could be used as instrumental variables for the effect of systemic iron status. The following sets of instruments were used: a conservative set (instruments restricted to variants with concordant relations to 4 iron status biomarkers) and a liberal set (instruments selected using variants associated with at least 1 of 4 iron status biomarkers). Associations of these genetic variants with asthma risk were estimated in data from the Trans-National Asthma Genetics Consortium (TAGC) and the GABRIEL consortium (A Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community). Data on the association of genetic variants with iron status and with asthma were combined to assess the influence of iron status on asthma risk. RESULTS: In the conservative approach, the MR OR of asthma was 1.00 (95% CI: 0.91, 1.10) per SD increase in iron, 0.96 (95% CI: 0.78, 1.18) in log-transformed ferritin, 0.99 (95% CI: 0.93, 1.06) in transferrin saturation, and 1.03 (95% CI: 0.93, 1.14) in transferrin in the TAGC dataset (none of the values were statistically significant). An age at onset-stratified analysis in the GABRIEL dataset suggested no effect of iron status in childhood onset, later onset, or unknown age at onset asthma. Findings from the liberal approach were similar, and the results persisted in sensitivity analyses (all P > 0.05). CONCLUSIONS: This MR study does not provide evidence of an effect of iron status on asthma, suggesting that efforts to change iron concentrations will probably not result in decreased risk of asthma.

Exploring the mechanism of clear cell renal cell carcinoma metastasis and key genes based on multi-tool joint analysis.

Clear cell renal cell carcinoma (ccRCC) is a highly invasive urological malignant tumor that results in shorter patient survival. At present, the mechanism of ccRCC metastasis is not clear. We explored the possible mechanisms of ccRCC metastasis by analyzing the transcriptome of ccRCC patients from the Cancer Genome Atlas (TCGA) database. Comparing the differences in transcriptome in patients with and without metastasis, we found 323 differential genes (|log2FoldChange| > 1 and P < 0.001). KEGG and GO enrichment analyses of differentially expressed genes (DEGs) suggest that the transfer mechanism of ccRCC may be related to complement and coagulation cascades and cholesterol metabolism. To explore the key genes affecting tumor metastasis, we analyzed the association of these genes with patient survival time and found that 16 genes were significantly associated (P < 0.05). We compared the differences in expression of these 16 genes between ccRCC patients and the normal population, and the results showed that TF and B4GALNT1 were overexpressed in patients. Co-expression gene analysis indicated that TF may participate in the metastasis of cancer through the complement system and mucopolysaccharide biosynthesis. B4GALNT1 may affect metastasis through focal adhesion, calcium signaling pathways, and Hippo signaling pathways. Our studies suggest that the complement system and the coagulation cascade, cholesterol metabolism, calcium pathway and iron transport may be associated in the mechanism of metastasis. TF and B4GALNT1 may be the key genes for metastasis, and they may be potential diagnostic markers and therapeutic targets for ccRCC.

Association of SERPINE1 rs6092 with type 2 diabetes and related metabolic traits in a Chinese population.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-I), encoded by SERPINE1 gene, is a member of the serine protease inhibitor superfamily, and polymorphisms in SERPINE1 have been reported to be associated with type 2 diabetes (T2D). This study investigated whether the polymorphism in PAI-I contribute to the risk for T2D. METHODS: A 1:1 case-control study was conducted to investigate the association of rs6092 in SERPINE1 with T2D and diabetes-related metabolic traits, including body mass index, waist circumference (WC), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol, low density lipoprotein cholesterol, fasting plasma glucose and glycosylated hemoglobin (HbA1c) in a Chinese population, with a total of 1572 subjects (786 T2D patients and 786 healthy controls). The polymorphism was genotyped based on MassARRAY genotyping system. RESULTS: The AA genotype and A allele of rs6092 exerted a protective effect on T2D risk (odds ratio (OR) = 0.431 and 0.630, respectively). In a recessive model, we also observed the protective association of rs6092 with T2D (OR = 0.195). The above associations were only observed in men. In female patients, there was a significant difference in HbA1c level between the AA homozygotes and GG homozygotes, as well as between the AA homozygotes and combined GG and GA genotypes. In male patients, the WC level in the subjects carrying AA genotype was lower than those in the subjects with GG genotype (P = 0.000), and the association was also significant in a recessive model (P = 0.000). Additionally, there was a significant difference in TG level between the AA homozygotes and GG homozygotes (P = 0.017), as well as the AA homozygotes and combined GG and GA genotypes (P = 0.032). CONCLUSIONS: Our study suggests that the A allele and AA genotype of rs6092 may protect against T2D, and have a protective effect on WC, but a negative effect on TG in men, while may contribute to a lower HbA1c level in women.

Association of APOB and LIPC polymorphisms with type 2 diabetes in Chinese Han population.

BACKGROUND: Apolipoprotein B (APOB), and hepatic lipase (LIPC) genes have been shown to play a key role in lipid metabolism in type 2 diabetes (T2D). This study aimed to investigate the association of the three polymorphisms (rs679899 in APOB and rs6078 and rs6083 in LIPC) with T2D and related clinical quantitative traits. METHODS: We conducted a case-control study in Chinese Han population, with a total of 929 T2D patients and 1044 healthy subjects in Chinese Han population. Polymorphisms were genotyped by MassARRAY Genotyping System. RESULTS: The risk allele G of the polymorphism rs679899 was related to T2D (odds ratio (OR): 1.207, 95% confidence interval (CL): 1.006-1.448, P = 0.043) and the polymorphism rs679899 was associated with glutamyl transpeptidase (GGT) levels (P = 0.001). We also showed that the polymorphism rs6083 was associated with cholesterol (CHOL) levels (P = 0.012), triglyceride (TG) levels (P = 0.040), and low-density lipoprotein cholesterol (LDL) levels (P = 0.033). No significant difference in genotypic frequencies of rs6078 and rs6083 was observed between T2D patients and controls. CONCLUSION: This study suggests that the APOB polymorphism rs679899 is associated with type 2 diabetes and GGT levels, while the LIPC polymorphism rs6083 may influence CHOL, TG, and LDL levels in Chinese Han population.

Manganese in blood cells as an exposure biomarker in manganese-exposed workers healthy cohort.

Elevated exposure to manganese (Mn) has long been a public health concern. However, there is currently no consensus on the best exposure biomarker. Here we aimed to investigate the exposomic characteristics of plasma metals among Mn-exposed workers and explore the potential biomarkers of Mn exposure in the blood pool. First, total sixteen plasma metals (Calcium, Magnesium, Iron, Zinc, Copper, Selenium, Lead, Chromium, Arsenic, Manganese, Nickel, Molybdenum, Cadmium, Mercury, Thallium, and Cobalt) were determined among 40 occupationally Mn-exposed subjects. Second, Mn levels in both plasma and blood cells were detected among 234 workers from the manganese-exposed workers healthy cohort (MEWHC), respectively. Analysis of plasma metal exposome showed that the plasma Mn concentrations were positively correlated to plasma Fe (r=0.361), Ni (r=0.363), Cr (r=0.486), and Hg (r=0.313) (all p<0.05). Mn concentrations in plasma were not significantly correlated to external exposure levels (ptrend=0.200), and it was further confirmed among the 234 subjects (ptrend=0.452). However, Mn concentrations in blood cells progressively increased as the external exposure dose increased (low-exposure group vs high-exposure group, median 11.53µg/L vs 20.41µg/L, ptrend=0.001). Our results suggest that Mn in blood cells, but not plasma, could serve as a potential internal exposure biomarker. Larger validation studies are needed to establish the utility of this biomarker.

The risk of missed abortion associated with the levels of tobacco, heavy metals and phthalate in hair of pregnant woman: A case control study in Chinese women.

To assess the association between exposure to the tobacco, heavy metals and phthalate on early pregnancy and missed abortion.42 women with missed abortion and 57 matched controls (women with normal pregnancies) were recruited between March and May 2012, from the Department of Gynecology and Obstetrics, First Affiliated Hospital of Guangxi Medical University and the People Hospital of Guangxi Zhuang Autonomous Region. The questionnaire survey was carried on to learn about the basic conditions, as well as smoking history of all participants. The levels of tobacco, heavy metal, and phthalate exposure were compared between the 2 groups by measuring nicotine, cocaine, cadmium (Cd), manganese (Mn), plumbum (Pb) and dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di-2-ethyl hexyl phthalate (DEHP) in the hair samples.Out results showed that significant differences in age (P = .042), premarital examination (P = .041), passive smoking (P = .021), and heavy metal exposure (P = .022) were found in the case group compared to the control. In addition, the concentration of nicotine (P = .037), cotinine (P = .018), Cd (P = .01), Pb (P = .038) and DEHP (P = .001) in the hair were significantly higher in the case group. Furthermore, logistic analysis revealed that age [Odds Ratio (OR) 1.172, 95% confidence interval (CI) 1.036-1.327], Cd (OR 8.931, 95% CI 2.003-39.811), Cotinine (OR 4.376, 95% CI 1.159-16.531), DEHP (OR 1.863, 95% CI 1.103-3.146) were important factors contributing to the missed abortion (P < .05).It was demonstrated that high gestational age, passive smoking, heavy metals, and the phthalate exposure were the risk factors for missed abortion, while the premarital health examination was a protective factor. Avoiding these harmful substances before getting pregnant and during the early stages of pregnancy, might help prevent missed abortions.

Manganese accumulation in hair and teeth as a biomarker of manganese exposure and neurotoxicity in rats.

Manganese (Mn) is an essential trace element to humans. However, excessive Mn causes cognitive impairment resulting from injury to the central nervous system within the hippocampus. No ideal biomarker is currently available for evaluating Mn exposure and associated neurotoxicity in the body. Hence, this study used Mn levels in the serum (MnS), teeth (MnT), and hair (MnH) as biomarkers for evaluating the association between Mn exposure and cognitive impairment in Mn-treated rats. A total of 32 male Sprague-Dawley rats were randomly divided into four groups, received 0, 5, 10, and 20 mg/(kg day) of MnCl2·4H2O for 5 days a week for 18 weeks, respectively. Lifetime Mn cumulative dose (LMCD) was used to evaluate external Mn exposure. Hippocampus, serum, teeth, and hair specimens were collected from the rats for Mn determination by graphite furnace atomic absorption spectrometry. Learning and memory functions were assessed using the Morris water maze test. Results showed that chronic Mn exposure increased the hippocampus (MnHip), MnS, MnT, and MnH levels, as well as impaired learning and memory function in rats. MnHip, MnT, and MnH levels were positively correlated with LMCD (r = 0.759, r = 0.925, and r = 0.908, respectively; p < 0.05), escape latency (r = 0.862, r = 0.716, and r = 0.814, respectively; p < 0.05), and the number of platform crossings (r = -0.734, r = -0.514, and r = -0.566, respectively; p < 0.05). No association was observed between MnS levels and the number of platform crossings (r = -0.286, p > 0.05). Thus, MnT and MnH detected long-term low-dose Mn exposure. These parameters can be reliable biomarkers for Mn exposure and associated neurotoxicity in Mn-treated rats.

Synergistic impaired effect between smoking and manganese dust exposure on pulmonary ventilation function in Guangxi manganese-exposed workers healthy cohort (GXMEWHC).

PURPOSE: The aims of this study were to investigate the effects of manganese (Mn) dust exposure on lung functions and evaluate the potential synergistic effect between smoking and Mn dust exposure among refinery workers. METHODS: A retrospective study including 1658 workers in a ferromanganese refinery was conducted, with subjects who were from the Guangxi manganese-exposed workers healthy cohort (GXMEWHC). Based on the Mn manganese cumulative exposure index (Mn-CEI), all subjects were divided into the low exposure group (n = 682) and the high exposure group (n = 976). A pulmonary function test was performed using an electronic spirometer, including the values and percentages of FVC, FEV1, FEV1/FVC, MMEF, PEFR, MVV, respectively. RESULTS: No significant effect of Mn dust exposure on the pulmonary function was found in the female workers (all p>0.05). However, there was an obvious decrease in the male workers in the high exposure group compared with those in the low exposure group (FVC -60 ml, FEV1 -120 ml, MMEF -260 ml/s, MVV -5.06 L, all p<0.05). In the high exposure group, the reduction in FVC% predicted, MMEF and MMEF% predicted was 1.0%, 210 mL/s, and 4.9%, respectively. In particular, among the exposed subjects smokers had a statistically significant decrease in lung function compared with non-smokers and the reduction in FVC% predicted, MMEF and MMEF% predicted was 1.0%, 210 mL/s, and 4.9%, respectively (p<0.05). Partial correlation analysis showed that there was also negative correlation between Mn-CEI and decreased changes in MMEF (r = -0.159, p = 0.018) and also MMEF% predicted (r = -0.163, p = 0.015). CONCLUSIONS: Mn dust can impair the pulmonary ventilation function of male workers but not females, and individual smoking habits and manganese exposure had a synergistic effect on the lung function decrease.