Neuropeptide substance P attenuates colitis by suppressing inflammation and ferroptosis via the cGAS-STING signaling pathway.

Neuropeptide substance P (SP) belongs to a family of bioactive peptides and regulates many human diseases. This study aims to investigate the role and underlying mechanisms of SP in colitis. Here, activated SP-positive neurons and increased SP expression were observed in dextran sodium sulfate (DSS)-induced colitis lesions in mice. Administration of exogenous SP efficiently ameliorated the clinical symptoms, impaired intestinal barrier function, and inflammatory response. Mechanistically, SP protected mitochondria from damage caused by DSS or TNF-α exposure, preventing mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. SP can also directly prevent STING phosphorylation through the neurokinin-1 receptor (NK1R), thereby inhibiting the activation of the TBK1-IRF3 signaling pathway. Further studies revealed that SP alleviated the DSS or TNF-α-induced ferroptosis process, which was associated with repressing the cGAS-STING signaling pathway. Notably, we identified that the NK1R inhibition reversed the effects of SP on inflammation and ferroptosis via the cGAS-STING pathway. Collectively, we unveil that SP attenuates inflammation and ferroptosis via suppressing the mtDNA-cGAS-STING or directly acting on the STING pathway, contributing to improving colitis in an NK1R-dependent manner. These findings provide a novel mechanism of SP regulating ulcerative colitis (UC) disease.

5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer's Disease.

BACKGROUND: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer's disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. OBJECTIVE: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date. METHODS: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control. RESULTS: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects. CONCLUSION: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.

Joint effect of 25-hydroxyvitamin D and secondhand smoke exposure on hypertension in non-smoking women of childbearing age: NHANES 2007-2014.

BACKGROUND: Vitamin D deficiency (VDD) may increase the risk of hypertension in women of childbearing age, who may be exposed to secondhand smoke (SHS) simultaneously. Till now, few studies have investigated the joint effects of VDD and SHS on hypertension in this population. We evaluated whether exposure to SHS modified the association between VDD and hypertension. METHODS: Data from National Health and Nutrition Examination Surveys (NHANES) 2007-2014 were analyzed. Our research subjects were 2826 nonsmoking and nonpregnant women of childbearing age (20-44 years old). Hypertension was defined based either on systolic blood pressure (SBP) ≥ 130 mmHg and/or diastolic blood pressure (DBP) ≥ 80 mmHg or on now taking prescribed medicine for hypertension. The directed acyclic graphs (DAG) and the back-door criterion were used to select a minimal sufficient adjustment set of variables (MSAs) that would identify the unconfounded effect of 25(OH)D and hypertension. The interactive effect of VDD and SHS on hypertension was evaluated by using logistic regression models, followed by strata-specific analyses. RESULTS: The prevalence of VDD in the hypertension group was significantly higher than that in the non-hypertension group (48.2% vs 41.0%, P = 0.008), as well as the exposure rate of SHS (39.1% vs 33.8%, P = 0.017). VDD was independently associated with nearly 50% increased risk of hypertension [adjusted odds ratio (aOR) = 1.43, 95% confidence interval (CI): 1.01, 2.04], while no significant association was observed between SHS and hypertension. However, SHS showed a significant synergistic effect on VDD with a higher aOR of 1.79 (95% CI: 1.14, 2.80) (Pinteraction = 0.011). This synergistic effect was more obvious when stratified by BMI (in overweight women, aOR, 95% CI =4.74, 1.65-13.60 for interaction vs 2.33, 1.01-5.38 for VDD only) and race (in Non-Hispanic Black women, aOR, 95% CI =5.11, 1.58-16.54 for interaction vs 2.69, 1.10-6.62 for VDD only). CONCLUSION: There exist synergistic effects of SHS and VDD on the prevalence of hypertension in American women of childbearing age, with more significant effects in women who were overweight or Non-Hispanic Black. Further studies are warranted to verify this finding in other populations, and the molecular mechanisms underlying the joint effect of SHS and VDD need to be elucidated.

Risk of having pulmonary tuberculosis in type 2 diabetes: A hospital-based matched case-control study.

BACKGROUND AND OBJECTIVES: Diabetes mellitus (DM) leads to nearly 3-fold higher risk of pulmonary tuberculosis (TB), indicating an increasing challenge to public health in low-to-middle income countries. Till now, the risk factor is still uncertain. We carried out this study with the main purpose to identify the risk factors of having TB in DM patients. METHODS AND STUDY DESIGN: A hospital-based matched case-control study was conducted in Qingdao, China from March, 2016 to January, 2018. Cases were DM patients with concurrent TB (DM-TB). Each case was matched with two controls, patients with DM only of similar age, sex and DM course. Cox regression of conditional logistic analysis was used to define the risk factors for having TB in DM, and then sensitivity analysis was carried out. RESULTS: We identified 315 patients, including 105 cases and 210 controls. Smokers had a higher risk of having TB with a multivariable adjusted odds ratio (aOR) of 12.45 than non-smokers. Poor glycemic control (aOR=2.66), frequency of DM re-examination <1 time/year (aOR=3.39), as well as TB contact history was also independently related with higher risk, while BMI ≥24 (aOR=0.42), education level ≥ college (aOR=0.11) showed a negative association. CONCLUSIONS: Poor glycemic control, smoking, low frequency of reexamination was associated with higher risk of having TB in DM, while overweight and obesity, high education levels showed a negative association. These findings provide clues to target DM populations prone to TB, which may be of help to halt the epidemic of TB in high burden countries.

Poor Vitamin D Status in Active Pulmonary Tuberculosis Patients and Its Correlation with Leptin and TNF-α.

Vitamin D deficiency (VDD) is common in tuberculosis (TB) and may be implicated in the etiology of the disease and in its clinical course. The aim of this study was to investigate the association between leptin, inflammatory markers and VD status in TB patients, stratified for presence or absence of diabetes mellitus (DM). Two hundred ninety-nine TB patients were recruited from October 2015 to August 2016. Also, 91 normal controls were included. The information including socio-demographics, dietary intake and living habits was obtained by face-to-face interview. Serum concentrations of leptin and TNF-α, CRP and IL-6 were compared between TB patients with and without severe VDD (SVDD). Pearson's correlation was used to analyze the association between TNF-α, leptin and 25-hydroxyvitamin D (25(OH)D). A significantly higher prevalence of VDD and SVDD was observed in TB patients compared with normal controls (93.0% vs 70.3%, 65.9% vs 3.3% respectively). Concentration of leptin was significantly lower, while TNF-α higher in TB patients with SVDD compared to those without (p<0.05). After adjustment for confounders, leptin was positively associated with 25(OH)D (r=0.210, p=0.002) with similar correlation in TB patients with DM (r=0.240, p=0.020). A negative association between TNF-α and 25(OH)D was observed (r=-0.197, p=0.003), which was significant only in the subgroup without DM (r=-0.304, p=0.001). Our findings indicate that a higher VD status in TB patients may be related to higher immune activity and less serious tissue damage, and that this relation is different according to presence or absence of DM co-morbidity.

Corrigendum: Neural Features of Processing the Enforcement Phrases Used during Occupational Health and Safety Inspections: An ERP Study.

[This corrects the article DOI: 10.3389/fnins.2016.00469.].

Poor Sleep Quality Is Associated with a Higher Risk of Pulmonary tuberculosis in Patients with a Type 2 Diabetes Mellitus Course for More than 5 Years.

A case-control study was conducted in Shandong from January to December 2017 to explore the relationship between sleep quality and the risk of active pulmonary tuberculosis (PTB). Seventy-nine patients with type 2 diabetes mellitus coincident with newly diagnosed pulmonary tuberculosis (DM-PTB) and 169 age, sex, and DM course frequency-matched controls (DM alone) were enrolled. Univariate and multivariable unconditional logistic regression analyses were conducted. We further conducted subgroup analyses to explore the relationship between sleep quality and PTB risk, including DM course (≤5 and ＞5 years), age, sex, and the presence of overweight or obesity (body mass index (BMI) ＞ 24 kg/m2). Multivariate logistic regression demonstrated that poor sleep quality had a borderline negative association with the odds of PTB (P ＝ 0.065). Subgroup multivariate analyses showed that poor sleep quality increased the risk of PTB to more than 3 times among patients with a DM course ＞ 5 years (odds ratio 3.31, 95% confidence interval: 1.08-10.13; P ＝ 0.036) after adjusting for potential confounding factors including residential area, educational level, BMI, history of contact with tuberculosis patients, smoking, alcohol consumption, physical exercise, immune status, and frequency of blood glucose monitoring. In conclusion, poor sleep quality is an independent risk factor of PTB among DM patients with a course of ＞ 5 years, which indicates significant epidemiological implications for PTB control.

B Vitamins Can Reduce Body Weight Gain by Increasing Metabolism-related Enzyme Activities in Rats Fed on a High-Fat Diet.

B vitamins are enzyme cofactors that play an important role in energy metabolism. The aim of this study was to elucidate whether B vitamin administration can reduce body weight (BW) gain by improving energy metabolism-related enzyme activities in rats fed on a highfat diet. Fifty rats were randomly assigned to one of the following five groups: control group (C), including rats fed on standard rat chow; four treatment groups (HO, HI, H2, and H3), in which rats were fed on a high-fat diet. Rats in the HI group were treated daily with 100 mg/kg BW thiamine (VB1), 100 mg/kg BW riboflavin (VB2), and 250 mg/kg BW niacin (VPP); rats in the H2 group were treated daily with 100 mg/kg BW pyridoxine (VB6), 100 mg/kg BW cobalamin (VB12), and 5 mg/kg BW folate (FA); and rats in the H3 group were treated daily with all of the B vitamins administered to the HI and H2 groups. After 12 weeks, the BW gains from the initial value were 154.5±58.4 g and 159.1±53.0 g in the HI and C groups, respectively, which were significantly less than the changes in the HO group (285.2±14.8 g, P<0.05). In the HO group, the plasma total cholesterol (CHO) and triglyceride (TG) levels were 1.59±0.30 mmol/L and 1,55±0.40 mmol/L, respectively, which were significantly greater than those in the HI group (1.19±0.18 mmol/L and 0.76±0.34 mmol/L, respectively, P<0.05). The activities of transketolase (TK), glutathione reductase, and Na+/K+ adenosine triphosphatase were significantly increased in the B vitamin-treated groups and were significantly greater than those in the HO group (P<0.05). Furthermore, the glucose-6-phosphate dehydrogenase, pyruvic acid kinase, and succinate dehydrogenase activities also were increased after treatment with B vitamins. Supplementation with B vitamins could effectively reduce BW gain and plasma levels of lipids by improving energy metabolism-related enzyme activities in rats, thus possibly providing potential benefits to humans.

The NS1 protein of avian influenza virus H9N2 induces oxidative-stress-mediated chicken oviduct epithelial cells apoptosis.

The pathogenesis of H9N2 subtype avian influenza virus infection (AIV) in hens is often related to oviduct tissue damage. The viral non-structural NS1 protein is thought to play a key role in regulating the pathogenicity of AIV, but its exact function in this process remains elusive. In this study, the pro-apoptosis effect of H9N2 NS1 protein was examined on chicken oviduct epithelial cells (COECs) and our data indicated that NS1-induced oxidative stress was a contributing factor in apoptosis. Our data indicate that NS1 protein level was correlated with reactive oxygen species (ROS) in COECs transfected with NS1 expression plasmids. Interestingly, decreased activities of antioxidant enzymes, superoxide dismutase and catalase, were observed in NS1-transfected COECs. Treatment of COECs with antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), significantly inhibited NS1-induced apoptosis. Moreover, although antioxidant treatment has little effect on the activation of caspase-8 in NS1-transfected cells, the activation of caspase-3/9 and Bax/Bcl-2 were significantly downregulated. Taken together, the results of our study demonstrated that expression of H9N2 NS1 alone is sufficient to trigger oxidative stress in COECs. Additionally, NS1 protein can induce cellular apoptosis via activating ROS accumulation and mitochondria-mediated apoptotic signalling in COECs.

Neural Features of Processing the Enforcement Phrases Used during Occupational Health and Safety Inspections: An ERP Study.

The appropriate enforcement phrases used during occupational health and safety (OHS) inspection activities is a crucial factor to guarantee the compliance with OHS regulations in enterprises. However, few researchers have empirically investigated the issue of how enforcement phrases are processed. The present study explored the neural features of processing two types of enforcement phrases (severe-and-deterrent vs. mild-and-polite phrases) used during OHS inspections by applying event-related potentials (ERP) method. Electroencephalogram data were recorded while the participants distinguished between severe-and-deterrent phrases and mild-and-polite phrases depicted in written Chinese words. The ERP results showed that severe-and-deterrent phrases elicited significantly augmented P300 amplitude with a central-parietal scalp distribution compared with mild-and-polite phrases, indicating the allocation of more attention resources to and elaborate processing of the severe-and-deterrent phrases. It reveals that humans may consider the severe-and-deterrent phrases as more motivationally significant and elaborately process the severity and deterrence information contained in the enforcement phrases for the adaptive protection. The current study provides an objective and supplementary way to measure the efficiency of different enforcement phrases at neural level, which may help generate appropriate enforcement phrases and improve the performance of OHS inspections.

Relation of leptin, ghrelin and inflammatory cytokines with body mass index in pulmonary tuberculosis patients with and without type 2 diabetes mellitus.

BACKGROUND: Pulmonary tuberculosis (TB) patients often suffer from anorexia and poor nutrition, causing weight loss. The peptide hormones leptin and its counterpart ghrelin, acting in the regulation of food intake and fat utilization, play an important role in nutritional balance. This study aimed to investigate the association of blood concentrations of leptin, ghrelin and inflammatory cytokines with body mass index (BMI) in TB patients with and without type 2 diabetes mellitus (T2DM). METHODS: BMI, biochemical parameters and plasma levels of leptin, ghrelin and inflammatory cytokines were measured before the start of treatment in 27 incident TB patients with T2DM, 21 TB patients and 23 healthy subjects enrolled in this study. RESULTS: The levels of leptin were significantly higher in TB patients (35.2 ± 19.1 ng/ml) than TB+T2DM (12.6 ± 6.1 ng/ml) and control (16.1 ± 11.1 ng/ml) groups. The level of ghrelin was significantly lower in TB (119.9 ± 46.1 pg/ml) and non-significantly lower in TB+T2DM (127.7 ± 38.6 pg/ml) groups than control (191.6 ± 86.5 pg/ml) group. The levels of TNF-α were higher, while IFN-γ and IL-6 levels were lower in patients than in the control group. Leptin showed a negative correlation with BMI in TB (r=-0.622, p<0.05) and TB+T2DM (r= -0.654, p<0.05) groups, but a positive correlation with BMI in the control group (r=0.521, p<0.05). Contrary ghrelin showed a positive correlation with BMI in TB (r=0.695, p<0.05) and TB+T2DM (r= 0.199, p>0.05) groups, but negative correlation with BMI in the control (r=-0.693, p<0.05) group. Inflammatory cytokines were poorly correlated with BMI in this study. Only IFN-γ showed a significant negative correlation with BMI in the control group (r=-0.545, p<0.05). CONCLUSIONS: This study may suggest that possible abnormalities in ghrelin and leptin regulation (high levels of leptin and low levels of ghrelin) may be associated with low BMI and may account for the poor nutrition associated with TB and TB+T2DM.

Screening and intervention of diabetes mellitus in patients with pulmonary tuberculosis in poverty zones in China: rationale and study design.

BACKGROUND: The merging epidemics of pulmonary tuberculosis (PTB) and diabetes mellitus (DM) have been raised concerns by many experts but no large scale screening and intervention have been launched yet, especially in low-income areas. The current study aims to understand the prevalence of DM in active PTB patients and evaluate the outcomes of diet and living habit intervention in poverty zones in China. METHODS/DESIGN: A cross-sectional investigation and intervention study will be carried out. At least 7000 active PTB patients will be recruited, together with 7000 nonTB persons from the same community. The project will be divided into two stages. The first stage is to train TB workers on DM screening and regular treatment. Screening and related investigation will be carried out afterwards. The second stage is focussed on intervention. A comprehensive strategy will be utilized to conduct health promotion among the patients, the health providers and the lay public. DISCUSSION: To our knowledge, this is the first and largest study which focuses on the prevalence of DM in PTB in China. We hypothesize that the current prevalence of DM in PTB in China will be understood and the results of our study will provide important evidence for preventing and controlling DM and PTB.

Antioxidant micronutrient supplementation increases erythrocyte membrane fluidity in adults from a rural Chinese community.

The objective of the present study was to investigate age-related differences in erythrocyte membrane fluidity (EMF) and changes in antioxidant capacity following supplementation. A total of seventy-four children were randomly divided into two groups: group A1 was the placebo-controlled group and group A2 was supplemented daily with 600 µg retinol, 1·0 mg ß-carotene, 100 mg tocopherol, 300 mg ascorbic acid and 200 µg Se. A total of ninety young people were randomly divided into B1 and B2 groups, and ninety-one elderly subjects were divided into C1 and C2 groups. Groups B1 and C1 were placebo-controlled groups, and groups B2 and C2 were daily supplemented with 900 µg retinol, 1·5 mg ß-carotene, 200 mg tocopherol, 500 mg ascorbic acid and 400 µg Se. Results showed that plasma malondialdehyde (MDA) was 5·35 µmol/l in children, which was lower than in young and elderly people. The MDA levels of the young and elderly individuals in the treated groups were significantly lower compared with the control groups, but the supplementation did not alter MDA levels in children. At baseline, there was a lower value of polarisation (ρ) and microviscosity (η) in children, indicating a higher EMF, than in both the young and elderly subjects. After the 2-month trial, the ρ and η values of young and elderly subjects in the treated groups decreased significantly in comparison with the placebo groups, indicating an increase in EMF. In conclusion, there was a background of higher MDA levels and lower EMF in young and elderly people than in children, which could be improved by antioxidant supplementation.