Associations of serum vitamin B6 status with the risks of cardiovascular, cancer, and all-cause mortality in the elderly.

Background: There are few studies investigating the relationship between serum vitamin B6 and mortality risk in the elderly. This study hereby evaluated the associations between biomarkers of serum vitamin B6 status and cardiovascular, cancer, and all-cause mortality risks in the elderly. Methods: Our study included a total of 4,881 participants aged 60 years or older from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. Serum vitamin B6 status was estimated based on levels of pyridoxal 5'-phosphate (PLP), 4-pyridoxic acid (4-PA), and vitamin B6 turnover rate (4-PA/PLP) detected by high-performance liquid chromatography. Survival status and corresponding causes of death were matched through the National Death Index records through December 31, 2019. Multivariate Cox regression model was adopted to assess the relationships between serum vitamin B6 status and the risk of mortality. Results: During a median follow-up period of 10.33 years, 507 cardiovascular deaths, 426 cancer deaths, and 1995 all-cause deaths were recorded, respectively. In the multivariate-adjusted Cox model, the hazard ratios (HRs) and 95% confidence intervals (CIs) for the highest versus the lowest quartiles of PLP, 4-PA, and 4-PA/PLP were 0.70(0.54-0.90), 1.33(0.88-2.02), and 2.01(1.41-2.79) for cardiovascular mortality, 0.73(0.52-1.02), 1.05(0.71-1.57), and 1.95(1.25-3.05) for cancer mortality, and 0.62(0.53-0.74), 1.05(0.82-1.34), and 2.29(1.87-2.79) for all-cause mortality, respectively. Conclusion: Our study found that lower serum PLP levels were associated with increased risks of cardiovascular and all-cause mortality among the elderly population. And higher vitamin B6 turnover rate was associated with increased risks of cardiovascular, cancer, and all-cause mortality.

Dynamic changes in ambient PM2.5 and body mass index among old adults: a nationwide cohort study.

Outdoor air pollution has been considered as a severe environmental health issue that almost affecting everyone in the world, and intensive actions were launched. However, little is known about the association between dynamic changes in ambient fine particulate matter (PM2.5) exposure and body mass index (BMI) among old adults. To investigate the dynamic changes in ambient PM2.5 and body mass index among the elderly, we included a total of 7204 participants from 28 provinces of China during 2011-2015 in the China Health and Retirement Longitudinal Study (CHARLS). Ambient fine particle matter (PM2.5) was estimated using a well-validated space-time extremely randomized trees model. Change in PM2.5 and BMI (ΔPM2.5 and ΔBMI) were calculated as the value at a follow-up visit minus value at baseline. Linear mixed-effects models were applied to quantify the associations, controlling for sociodemographic factors. We found that per 1 µg/m3 increase in PM2.5 exposure was associated with a 0.031-0.044 kg/m2 increase in BMI among the elderly. We observed an approximate linear concentration-response relationship of PM2.5 and BMI in each visit. Each 1 µg/m3 increase in ΔPM2.5 exposure was associated with an increase in ΔBMI (ß = 0.040, 95% CI 0.030, 0.049), while per 1 µg/m3 decrease in the ΔPM2.5 exposure level was associated with a decrease in ΔBMI (ß = -0.016, 95% CI -0.027, -0.004). Our findings suggest that dynamic changes in ambient PM2.5 was positively associated with changes in BMI among old Chinese population.

The role of MEG3 in the proliferation of palatal mesenchymal cells is related to the TGFß/Smad pathway in TCDD inducing cleft palate.

Cleft palate (CP) is a common birth defect with a high incidence of occurrence in humans. The 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic halogenated aromatic hydrocarbon, with a strong CP effect on mice. Increasing recent evidences have shown that long-noncoding RNAs (lncRNAs) play an important role in several diseases, including CP. However, there is a paucity of studies on the role of lncRNA MEG3 in the occurrence and development of TCDD-induced CP. In this study, the relationship between MEG3 and the proliferation of palatal mesenchymal cells and the underlying molecular mechanism were studied by establishing fetal CP with TCDD (64 µg/kg) in C57BL/6N mice. The results revealed that MEG3 was highly expressed during the critical period of CP formation and that the fetal mesenchymal proliferation was significantly inhibited at certain critical periods in the mice receiving TCDD. In addition, we noted a possibility of a crosstalk between MEG3 and the TGF-ß/Smad pathway, such that the inhibition of the TGF-ß/Smad pathway was induced by TCDD. Cumulatively, our study suggests that TCDD-induced CP may be caused by MEG3 inhibition of the proliferation of palatal mesenchymal cells involving the TGFß/Smad pathway, which may provide a novel perspective to understand the pathogenesis of CP.

Oct4 plays a role in 2, 3, 7, 8 - tetrachlorobenzo-p-dioxin (TCDD) inducing cleft palate and inhibiting mesenchymal proliferation.

As a common birth defect, Cleft palate can be caused by the disturbance during the developmental process of the palatal shelves. The 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) is a well-known environmental teratogenic agent for cleft palate and Aryl hydrocarbon receptor (AhR) pathway can be activated by dioxins. Oct4 as a pluripotent stem cell transcription factor is also involved in the process of embryonic development. The AHR and retinoid receptors have cross-talk at CYP1A1 (cytochrome P450, family 1, subfamily A, polypeptide 1) promoter. There are also bidirectional talk between AhR and Oct4. In this study, we used C57/BL6 N mice and TCDD (64 µg/Kg body weight) to establish a model of fetal cleft palate to observe the effects of dioxin on fetal mesenchymal proliferation and apoptosis, and explore the role of Oct4 in inducing cleft palate. The results showed that dioxin inhibited mesenchymal proliferation and promoted apoptosis. In addition, dioxin inhibited Oct4 expression, and preliminary data suggest that hypermethylation of the Oct4 promoter may be a putative mechanism, suggesting that TCDD might induce cleft palate by inhibiting the proliferation of palatal mesenchymal cells mediated by Oct4.

Association Between Folate and Health Outcomes: An Umbrella Review of Meta-Analyses.

Background: There is no study that has systematically investigated the breadth and validity of the associations of folate and multiple health outcomes. We aimed to evaluate the quantity, validity, and credibility of evidence regarding associations between folate and multiple health outcomes by using umbrella review of meta-analysis. Methods: We searched the MEDLINE, EMBASE, and Cochrane Library databases from inception to May 20, 2018, to identify potential meta-analyses that examined the association of folate with any health outcome. For each included meta-analysis, we estimated the summary effect size and their 95% confidence interval using the DerSimonian and Laird random-effects model. We used the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) to assess methodological quality and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation working group classification) to assess the quality of evidence for each outcome included in the umbrella review. Results: Overall, 108 articles reporting 133 meta-analyses of observational studies and 154 meta-analyses of randomized controlled trials (RCTs) were included in the study. Among them, 108 unique exposure-outcome-population triplets (referred to as unique meta-analyses hereafter) of RCTs and 87 unique meta-analyses of observational studies were reanalyzed. Beneficial effects of folate were observed in the all-cause mortality rate and in a number of chronic diseases, including several birth/pregnancy outcomes, several cancers, cardiovascular disease and metabolic-related outcomes, neurological conditions, and several other diseases. However, adverse effects of folate were observed for prostate cancer, colorectal adenomatous lesions, asthma or wheezing, and wheezing as an isolated symptom and depression. Conclusions: Current evidence allows for the conclusion that folate is associated with decreased risk of all-cause mortality and a wide range of chronic diseases. However, folate may be associated with an increased risk of prostate cancer. Further research is warranted to improve the certainty of the estimates.

TCDD inhibited the osteogenic differentiation of human fetal palatal mesenchymal cells through AhR and BMP-2/TGF-ß/Smad signaling.

Exposure to environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes cleft palate at high rates, but little is known about the underlying biological mechanisms. In the present study, we cultured osteoblasts from human fetal palate mesenchymal cells (hFPMCs) to explore the effects of TCDD on osteogenic differentiation. The results showed that TCDD significantly decreased cell proliferation, alkaline phosphatase (ALP) activity and calcium deposition. RNA analyses and protein detection demonstrated that TCDD downregulated a wide array of pro-osteogenic biomarkers. Further investigation of the underlying molecular mechanisms revealed that exposure to TCDD activated aryl hydrocarbon receptor (AhR) signaling and inhibited BMP-2/TGF-ß1/Smad pathway molecules. The inactivation of AhR signaling using CRISPR/Cas9-mediated AhR deletion or by genetic siRNA knockdown significantly blocked the effects induced by TCDD, suggesting a critical role of AhR activation in the TCDD-mediated inhibition of hFPMC osteogenic differentiation. The cotreatment with TGF-ß1 or BMP-2 and TCDD significantly relieved the activation of AhR and rescued the impairment of osteogenesis caused by TCDD. Taken together, our findings indicated that TCDD inhibited the osteogenic differentiation of hFPMCs via crosstalk between AhR and BMP-2/TGF-ß1/Smad signaling pathway.

Transgenerational impairment of ovarian induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) associated with Igf2 and H19 in adult female rat.

2,3,7,8-Tetrachlorobenze-p-dioxin (TCDD), one of representive Endocrine Disrupting Chemicals (EDCs), has potential adverse effects on human health. Direct exposure to TCDD has been implicated in ovarian follicles development and functions deficits in adulthood. However, it is rarely reported whether indirect exposure to TCDD can cause similar negative impact on F3. The aim of our study was to evaluate the effect of ancestral TCDD exposure on ovarian toxicity in offspring rats (F3), focusing on the Igf2/H19 pathway which was important for follicular development. Pregnant Sprague-Dawley female rats (F0) were given with either vehicle or TCDD (100 or 500 ng/kg BW/day) by gavages during days 8-14 of gestation. Ovarian development and functions of F3 generation was assessed using the ovary coefficient, the vaginal opening time, and regularity of estrous cycle, ovarian pathology, follicles counts and apoptosis of granular cells. The level of E2, FSH and LH in the serum was also detected. Results showed that in the F3 generation 500 ng/kg BW/day TCDD group, ovarian coefficient, LH concentration in serum and number of primary follicles were decreased, and the apoptosis of granular cells was significantly increased. The abnormal rate of estrous cycle and advance rate of vaginal opening time displayed a significantly increase in TCDD-treated groups. RT-PCR analysis showed that the expression level of H19 mRNA in ovary of TCDD treated F3 female rats was increased, compared to the control. Our data showed that ancestral TCDD exposure may impair transgenerational adult ovary development and functions, which may be related to an inhibition of the Igf2/H19 pathway in the ovarian.

The Disease Burden and Clinical Characteristics of Inflammatory Bowel Disease in the Chinese Population: A Systematic Review and Meta-Analysis.

The temporal trend of inflammatory bowel disease (IBD) incidence is reported to be increasing in worldwide regions; however, reports focusing on China are sparse. The aim of this study was to provide an overview of the disease burden and clinical features of IBD in the Chinese population. We searched Medline, EMBASE, and another two Chinese databases. A parallel literature review and data extraction were conducted. Meta-analysis was performed to estimate the summary incidence rate of Crohn's disease (CD) and ulcerative colitis (UC). The constituent ratios with 95% CI were calculated for clinical phenotypes and classifications. The literature review included 47 publications. The summary incidence rate of IBD was 1.74 (95% CI: 1.08; 2.40) per 100,000 person years, and the corresponding incidence rates of CD and UC were 0.40 (95% CI: 0.23; 0.57) and 1.18 (95% CI: 0.81; 1.56) per 100,000 person years, respectively. The sex distribution analysis indicated a male predominance in both CD (sex ratio: 1.64; 95% CI: 1.47-1.84) and UC (sex ratio: 1.29; 95% CI: 1.21-1.38). The clinical characteristics were summarized using data from 2283 CD cases and 17,958 UC cases; in which the majority of CD patients were diagnosed between 17-40 years of age, with non-stricturing and non-penetrating disease, varied disease locations, and less extra-intestinal manifestation. UC cases were featured with later disease diagnosis, a more severe disease course, more segmental lesions, and less extra-intestinal manifestations. Our study provided an estimated disease burden of IBD and demonstrated distinct clinical features in the Chinese population. Large-scale population-based studies are needed to further evaluate these findings.

Excessive retinoic acid inhibit mouse embryonic palate mesenchymal cell growth through involvement of Smad signaling.

All-trans retinoic acid (atRA), the oxidative metabolite of retinoic acid (RA), is essential for palatogenesis. Overdose RA is capable of inducing cleft palate in mice and humans. Normal embryonic palatal mesenchymal (EPM) cell growth is crucial for shelf growth. Smad signaling is involved in many biological processes. However, it is not much clear if atRA could affect Smad signaling during EPM cells growth. In this study, the timed pregnant mice with maternal administration of 100 mg/kg body weight of RA by gastric intubation were cervical dislocation executed to evaluate growth changes of palatal shelves by hematoxylin and eosin (H&E) staining. At the same time, a primary mouse EPM (MEPM) cell culture model was also established. MEPM cells were treated with atRA (0.1, 0.5, 1, 5 and 10 µM) for 24, 48 and 72 h. The results indicated that the sizes of the shelves were smaller than those in control. AtRA inhibited MEPM cell growth with both increasing concentration and increasing incubation time, especially at 72 h in vitro. Moreover, atRA significantly increased the mRNA and protein expression levels of Smad7 (P < .05), but the mRNA and protein expression levels of PCNA were reduced (P < .05). We also found atRA inhibited phosphorylation of Smad2 compared with untreated group (P < .05). However, the protein and mRNA levels of Smad2 did not change both in atRA-treated and untreated group (P > .05). We demonstrated that RA induced inhibition of MEPM cell growth that could cause cleft palate partly by down-regulation of Smad pathway.

Correlation of proliferation, TGF-ß3 promoter methylation, and Smad signaling in MEPM cells during the development of ATRA-induced cleft palate.

Mesenchymal cell proliferation is one of the processes in shelf outgrowth. Both all-trans retinoic acid (atRA) and transforming growth factor-ß3 (TGF-ß3) play an important role in mouse embryonic palate mesenchymal (MEPM) cell proliferation. The cellular effects of TGF-ß are mediated by Smad-dependent or Smad-independent pathways. In the present study, we demonstrate that atRA promotes TGF-ß3 promoter demethylation and protein expression, but can cause depression of mesenchymal cell proliferation, especially at embryonic day 14 (E14). Moreover, the inhibition of MEPM cell proliferation by atRA results in the downregulation of Smad signaling mediated by transforming growth interacting factor (TGIF). We speculate that the effects of atRA on MEPM cell proliferation may be mediated by Smad pathways, which are regulated by TGIF but are not related to TGF-ß3 expression. Finally, the cellular effects of TGF-ß3 on MEPM cell proliferation may be mediated by Smad-independent pathways.