Involvement of gut-brain communication in arsenite-induced neurobehavioral impairments in adult male mice.

Arsenite is a well-documented neurotoxic metalloid that widely distributes in the natural environment. However, it remains largely unclear how arsenite affects neurological function. Therefore, in this study, the healthy adult male mice were exposed to 0.5 mg/L and 5 mg/L arsenite through drinking water for 30 and 90 days, respectively. Our results showed that there was no significant alteration in the intestine and brain for 30 days exposure, but exposure to arsenite for 90 days significantly induced a reduction of locomotor activity and anxiety-like behavior, caused pathological damage and inflammatory responses in the brain and intestine. We also found that arsenite remarkably disrupted intestinal barrier integrity, decreased the levels of lysozyme and digestive enzymes. Intriguingly, chronic exposure to arsenite significantly changed the levels of gut-brain peptides. Taken together, this study provides meaningful insights that gut-brain communication may involve in the neurobehavioral impairments of arsenite.

Exposure to di (2-ethylhexyl) phthalate causes locomotor increase and anxiety-like behavior via induction of oxidative stress in brain.

Di (2-ethylhexyl) phthalate (DEHP) is one of the most prevalent xenoestrogen endocrine disruptor in daily life. A growing number of studies showed that DEHP could exhibit long-term adverse health effects on the human body, particularly in the liver, kidneys, heart and reproductive systems. However, the impact of oral intake of DEHP on the nervous system is extremely limited. In the present study, the adult C57BL/6J male mice were intragastrically administered with two dosages of DEHP for 35 days. The behavioral parameters were assessed using the elevated plus maze and open-field test. The mRNA expression levels of neuropeptides and the oxidative stress-associated proteins were detected by qPCR and western blot seperately. The histopathologic alterations of the brain were observed by H&E and Nissl staining. The results demonstrated that DEHP exposure could result in neurobehavioral impairments such as locomotor increase and anxiety-like behavior. Furthermore, pathological damages were clearly observed in the cerebral cortex and hippocampus, accompanied by a decrease in neuropeptides and an increase in oxidative stress, which were all positively correlated with the dose of DEHP. Together, these findings provide valuable clues into the DEHP-induced neurotoxicity.

The effects of gestational diabetes mellitus with maternal age between 35 and 40 years on the metabolite profiles of plasma and urine.

BACKGROUND: Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance in pregnancy and without a history of diabetes mellitus. While there are limited metabolomic studies involving advanced maternal age in China, we aim to investigate the metabolomic profiling of plasma and urine in pregnancies complicated with GDM aged at 35-40 years at early and late gestation. METHODS: Twenty normal and 20 GDM pregnant participants (≥ 35 years old) were enlisted from the Complex Lipids in Mothers and Babies (CLIMB) study. Maternal plasma and urine collected at the first and third trimester were detected using gas chromatography-mass spectrometry (GC-MS). RESULTS: One hundred sixty-five metabolites and 192 metabolites were found in plasma and urine respectively. Urine metabolomic profiles were incapable to distinguish GDM from controls, in comparison, there were 14 and 39 significantly different plasma metabolites between the two groups in first and third trimester respectively. Especially, by integrating seven metabolites including cysteine, malonic acid, alanine, 11,14-eicosadienoic acid, stearic acid, arachidic acid, and 2-methyloctadecanoic acid using multivariant receiver operating characteristic models, we were capable of discriminating GDM from normal pregnancies with an area under curve of 0.928 at first trimester. CONCLUSION: This study explores metabolomic profiles between GDM and normal pregnancies at the age of 35-40 years longitudinally. Several compounds have the potential to be biomarkers to predict GDM with advanced maternal age. Moreover, the discordant metabolome profiles between the two groups could be useful to understand the etiology of GDM with advanced maternal age.

Rodents on a high-fat diet born to mothers with gestational diabetes exhibit sex-specific lipidomic changes in reproductive organs.

Maternal gestatonal diabetes mellitus (GDM) and offspring high-fat diet (HFD) have been shown to have sex-specific detrimental effects on the health of the offspring. Maternal GDM combined with an offspring HFD alters the lipidomic profiles of offspring reproductive organs with sex hormones and increases insulin signaling, resulting in offspring obesity and diabetes. The pre-pregnancy maternal GDM mice model is established by feeding maternal C57BL/6 mice and their offspring are fed with either a HFD or a low-fat diet (LFD). Testis, ovary and liver are collected from offspring at 20 weeks of age. The lipidomic profiles of the testis and ovary are characterized using gas chromatography-mass spectrometry. Male offspring following a HFD have elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers have decreased testes weights and testosterone levels, while female offspring from GDM mothers show increased ovary weights and estrogen levels. Maternal GDM aggravates the effects of an offspring HFD in male offspring on the AKT pathway, while increasing the risk of developing inflammation when expose to a HFD in female offspring liver. Testes are prone to the effect of maternal GDM, whereas ovarian metabolite profiles are upregulated in maternal GDM and downregulated in offspring following an HFD. Maternal GDM and an offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in the offspring, such as obesity and diabetes.

Downregulation of beclin 1 restores arsenite-induced impaired autophagic flux by improving the lysosomal function in the brain.

Arsenite is a toxic metalloid that causes various adverse effects in the brain. However, the underlying mechanisms of arsenite-induced neurotoxicity remain poorly understood. In this study, both adult beclin 1+/+ and beclin 1+/- mice were employed to establish a model of chronic arsenite exposure by treating with arsenite via drinking water for 6 months. The results clearly demonstrated that exposure to arsenite profoundly caused damage to the cerebral cortex, induced autophagy and impaired autophagic flux in the cerebral cortex. Heterozygous disruption of beclin 1 in animals remarkably alleviated the neurotoxic effects of arsenite. To verify the results obtained in the animals, a permanent U251 cell line was used. After treating of cells with arsenite, similar phenomenon was also observed, showing the significant elevation in the expression levels of autophagy-related genes. Importantly, lysosomal dysfunction caused by arsenite was observed in vitro and in vivo. Either knockdown of beclin 1 in cells or heterozygous disruption of beclin 1 in animals remarkably alleviated the lysosomal dysfunction induced by arsenite. These findings indicate that downregulation of beclin 1 could restore arsenite-induced impaired autophagic flux possibly through improving lysosomal function, and correct that regulation of autophagy via beclin 1 would be an alternative approach for the treatment of arsenite neurotoxicity.

Polystyrene nanoparticles enhance the adverse effects of di-(2-ethylhexyl) phthalate on male reproductive system in mice.

Coexposure of nanoplastics (NPs) with other pollutants adsorbed from the surroundings has received extensive attention. Currently, the combined effects of NPs and plasticizers remain unclear. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer that has raised much concern owing to its ubiquitous pollution and endocrine-disrupting potential. This study aimed to investigate the toxic effects on the male reproductive system upon coexposure to NPs and DEHP. The C57BL/6J mice were orally administrated with polystyrene nanoparticles (PSNPs), DEHP or both for 35 days to evaluate their effects on sperm quality, histology of testes and epididymides, testicular transcriptomic characteristics as well as expression of some important genes in the epididymides. The low-dose PSNPs used here did not induce significant changes in sperm quality, while DEHP alone or cotreatment with DEHP and PSNPs caused notable impairment, mainly manifesting as decreased sperm quality and aberrant structure of the testis and epididymis. Moreover, enhanced toxic effects were found in the cotreatment group when compared with the individual DEHP treatment group, as manifested by more obvious alterations in the sperm parameters as well as histological changes in the testis and epididymis. Testicular transcriptomic analysis revealed differential regulation of genes involved in immune response, cytoplasmic pattern recognition receptor signaling pathways, protein ubiquitination, oxidative stress, necrotic cell death, ATP synthesis and the cellular respiratory chain. RT-qPCR verified that the expression patterns of Cenpb, Crisp1 and Mars were changed in testes, and genes relevant to epididymal function including Aqp9 and Octn2 were downregulated in epididymides, particularly in the cotreatment group. Collectively, our results emphasize that DEHP at an environmentally relevant dose can induce male reproductive toxicity, and PSNPs may aggravate the toxic effects.

Active case finding with case management: the key to tackling the COVID-19 pandemic.

COVID-19 was declared a pandemic by WHO on March 11, 2020, the first non-influenza pandemic, affecting more than 200 countries and areas, with more than 5·9 million cases by May 31, 2020. Countries have developed strategies to deal with the COVID-19 pandemic that fit their epidemiological situations, capacities, and values. We describe China's strategies for prevention and control of COVID-19 (containment and suppression) and their application, from the perspective of the COVID-19 experience to date in China. Although China has contained severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and nearly stopped indigenous transmission, a strong suppression effort must continue to prevent re-establishment of community transmission from importation-related cases. We believe that case finding and management, with identification and quarantine of close contacts, are vitally important containment measures and are essential in China's pathway forward. We describe the next steps planned in China that follow the containment effort. We believe that sharing countries' experiences will help the global community manage the COVID-19 pandemic by identifying what works in the struggle against SARS-CoV-2.

Comparison of yield and relative costs of different screening algorithms for tuberculosis in active case-finding: a cross-section study.

BACKGROUND: Part of tuberculosis (TB) patients were missed if symptomatic screening was based on the main TB likely symptoms. This study conducted to compare the yield and relative costs of different TB screening algorithms in active case-finding in the whole population in China. METHODS: The study population was screened based on the TB likely symptoms through a face-to-face interview in selected 27 communities from 10 counties of 10 provinces in China. If the individuals had any of the enhanced TB likely symptoms, both chest X-ray and sputum tests were carried out for them furtherly. We used the McNemar test to analyze the difference in TB detection among four algorithms in active case-finding. Of four algorithms, two were from WHO recommendations including 1a/1c, one from China National Tuberculosis Program, and one from this study with the enhanced TB likely symptoms. Furthermore, a two-way ANOVA analysis was performed to analyze the cost difference in the performance of active case-finding adjusted by different demographic and health characteristics among different algorithms. RESULTS: Algorithm with the enhanced TB likely symptoms defined in this study could increase the yield of TB detection in active case-finding, compared with algorithms recommended by WHO (p < 0.01, Kappa 95% CI: 0. 93-0.99) and China NTP (p = 0.03, Kappa 95% CI: 0.96-1.00). There was a significant difference in the total costs among different three algorithms WHO 1c/2/3 (F = 59.13, p < 0.01). No significant difference in the average costs for one active TB case screened and diagnosed through the process among Algorithms 1c/2/3 was evident (F = 2.78, p = 0.07). The average costs for one bacteriological positive case through algorithm WHO 1a was about two times as much as the costs for one active TB case through algorithms WHO 1c/2/3. CONCLUSIONS: Active case-finding based on the enhanced symptom screening is meaningful for TB case-finding and it could identify more active TB cases in time. The findings indicated that this enhanced screening approach cost more compared to algorithms recommend by WHO and China NTP, but the increased yield resulted in comparative costs per patient. And it cost much more that only smear/bacteriological-positive TB cases are screened in active case-finding.

Silicon dioxide nanoparticles induced neurobehavioral impairments by disrupting microbiota-gut-brain axis.

BACKGROUND: Silicon dioxide nanoparticles (SiO2NPs) are widely used as additive in the food industry with controversial health risk. Gut microbiota is a new and hot topic in the field of nanotoxicity. It also contributes a novel and insightful view to understand the potential health risk of food-grade SiO2NPs in children, who are susceptible to the toxic effects of nanoparticles. METHODS: In current study, the young mice were orally administrated with vehicle or SiO2NPs solution for 28 days. The effects of SiO2NPs on the gut microbiota were detected by 16S ribosomal RNA (rRNA) gene sequencing, and the neurobehavioral functions were evaluated by open field test and Morris water maze. The level of inflammation, tissue integrity of gut and the classical indicators involved in gut-brain, gut-liver and gut-lung axis were all assessed. RESULTS: Our results demonstrated that SiO2NPs significantly caused the spatial learning and memory impairments and locomotor inhibition. Although SiO2NPs did not trigger evident intestinal or neuronal inflammation, they remarkably damaged the tissue integrity. The microbial diversity within the gut was unexpectedly enhanced in SiO2NPs-treated mice, mainly manifested by the increased abundances of Firmicutes and Patescibacteria. Intriguingly, we demonstrated for the first time that the neurobehavioral impairments and brain damages induced by SiO2NPs might be distinctively associated with the disruption of gut-brain axis by specific chemical substances originated from gut, such as Vipr1 and Sstr2. Unapparent changes in liver or lung tissues further suggested the absence of gut-liver axis or gut-lung axis regulation upon oral SiO2NPs exposure. CONCLUSION: This study provides a novel idea that the SiO2NPs induced neurotoxic effects may occur through distinctive gut-brain axis, showing no significant impact on either gut-lung axis or gut-liver axis. These findings raise the exciting prospect that maintenance and coordination of gastrointestinal functions may be critical for protection against the neurotoxicity of infant foodborne SiO2NPs.

Birth weight charts for a Chinese population: an observational study of routine newborn weight data from Chongqing.

BACKGROUND: To construct birth weight charts for the Chongqing municipality, China and to identify whether differences in birth weight exist across urban/rural populations, thereby warranting separate charts. METHODS: Secondary analysis of routinely collected data from 338,454 live infants between 2014 and 2017 in Chongqing municipality. Sex-specific birth weight-for-gestational age centiles were constructed by the lambda-mu-sigma method via the GAMLSS R-based package. This method remodels the skewed birth weight distribution to estimate a normal distribution, allowing any birth weight centile to be generated. A separate set of centiles were created, accounting for urban/rural differences in birth weight. RESULTS: The centiles performed well across all gestational ages. For example, 2.37% (n = 4176) of males and 2.26% (n = 3656) of females were classified as below the 2nd centile (expected percentage = 2.28%), 49.75% of males (n = 87,756) and 50.73% of females (n = 82,203) were classified as below the 50th centile (expected proportion = 50%) and 97.52% of males (n = 172,021) and 97.48% of females (n = 157,967) were classified as below the 98th centile (expected proportion = 97.72%). The overall estimated centiles of birth weight for rural infants were higher than the centiles for urban infants at the earlier gestational ages (< 37 gestational weeks). However, this trend was reversed in infants born at term. CONCLUSION: We have constructed a readily utilizable set of birth weight references from a large representative sample of births in Chongqing. The method used to construct the references allows for the calculation of the exact centile for any infant delivered between 28 and 42 completed weeks, which was not possible with previous charts.

Gas chromatography-mass spectrometry based metabolomics profile of hippocampus and cerebellum in mice after chronic arsenic exposure.

Intake of arsenic (As) via drinking water has been a serious threat to global public health. Though there are numerous reports of As neurotoxicity, its pathogenesis mechanisms remain vague especially its chronic effects on metabolic network. Hippocampus is a renowned area in relation to learning and memory, whilst recently, cerebellum is argued to be involved with process of cognition. Therefore, the study aimed to explore metabolomics alternations in these two areas after chronic As exposure, with the purpose of further illustrating details of As neurotoxicity. Twelve 3-week-old male C57BL/6J mice were divided into two groups, receiving deionized drinking water (control group) or 50 mg/L of sodium arsenite (via drinking water) for 24 weeks. Learning and memory abilities were tested by Morris water maze (MWM) test. Pathological and morphological changes of hippocampus and cerebellum were captured via transmission electron microscopy (TEM). Metabolic alterations were analyzed by gas chromatography-mass spectrometry (GC-MS). MWM test confirmed impairments of learning and memory abilities of mice after chronic As exposure. Metabolomics identifications indicated that tyrosine increased and aspartic acid (Asp) decreased simultaneously in both hippocampus and cerebellum. Intermediates (succinic acid) and indirect involved components of tricarboxylic acid cycle (proline, cysteine, and alanine) were found declined in cerebellum, indicating disordered energy metabolism. Our findings suggest that these metabolite alterations are related to As-induced disorders of amino acids and energy metabolism, which might therefore, play an important part in mechanisms of As neurotoxicity.

Metabolomic biomarkers and novel dietary factors associated with gestational diabetes in China.

INTRODUCTION: Gestational diabetes mellitus (GDM) is impaired glucose tolerance first recognised during pregnancy; its development is associated with many adverse outcomes. Mechanisms of GDM development are not fully elucidated and few studies have used Chinese participants. OBJECTIVES: The aim of this study was to investigate the maternal metabolome associated with GDM in a Chinese population, and explore the relationship with maternal diet. METHODS: Ninety-three participants were recruited at 26-28 weeks' gestation from Chongqing, China. Maternal urine, serum, and hair metabolomes were analysed using gas and liquid chromatography-mass spectrometry. Dietary intake was assessed using a 96-item food frequency questionnaire. RESULTS: Of the 1064 metabolites identified, 73 were significantly different between cases and controls (P < 0.05), but only 2-aminobutyric acid had both a p- and q-value < 0.05. A "snack-based-dietary-pattern" was associated with an increased likelihood of GDM (odds ratio 2·1; 95% confidence interval 1.1-3.9). The association remained significant after adjustment for calorie intake but not food volume. CONCLUSION: This study provides a comprehensive characterization of the maternal metabolome. The snack-based dietary pattern associated with GDM suggests that timing and frequency of consumption are important factors in the relationship between maternal diet and GDM.

Adverse Events Associated with Treatment of Multidrug-Resistant Tuberculosis in China: An Ambispective Cohort Study.

BACKGROUND Adverse events are under-appreciated negative consequences that are significant clinical problems for patients undergoing anti-MDR-TB treatment due to longer duration of treatment and more need for concurrent use of multiple second-line drugs. The aim of this study was to determine the incidence of adverse events and their impact on MDR-TB therapy and treatment outcome, and to identify possible drug-event pairs in China. MATERIAL AND METHODS An ambispective cohort study was conducted based on hospital medical records, which included a retrospective study that enrolled 751 MDR-TB patients receiving standardized regimen between May 2009 and July 2013, and a follow-up investigation of treatment outcome conducted in December 2016 in China. Adverse events were determined according to laboratory results or clinical criteria. Cox's proportional hazards regression models were used for evaluating associations. RESULTS There were 681(90.7%) patients experienced at least 1 type of adverse event and 55.2% of them required a changed MDR-TB treatment; 51(6.8%) patients required permanent discontinuation of the offending drug due to adverse events. The occurrence of adverse events was associated with poor treatment outcome (adjusted hazard ratio, 1.54; 95% CI 1.21, 1.87). A total of 10 different drug-event pairs were identified. CONCLUSIONS Adverse events occurred commonly during MDR-TB treatment in China, and often resulted in MDR-TB treatment change. The occurrence of adverse events affected MDR-TB poor outcome after treatment.

Inhibition of α-Synuclein contributes to the ameliorative effects of dietary flavonoids luteolin on arsenite-induced apoptotic cell death in the dopaminergic PC12 cells.

Arsenite is a toxic metalloid that may increase the risk of Parkinson's disease by inducing dopaminergic neuronal apoptosis. Luteolin, a common dietary flavonoid, possesses variety of biological functions, but potential effects of luteolin on arsenite toxicity remain elusive. In this study, we demonstrated that luteolin prevented arsenite-induced apoptosis in the dopaminergic PC12 cells. Administration of luteolin to cells attenuated arsenite-induced ROS production, enhanced caspase-3 activity and γ-H2AX expression. Our results further showed the expression of α-Synuclein (α-Syn) was significantly increased in arsenite-treated cells, but co-treatment with luteolin reversed the expression of α-Syn back toward normal level. Inhibition of α-Syn by siRNA remarkably enhanced the beneficial effect of luteolin against arsenite-induced apoptotic cell death. Taken together, these results demonstrate that the ameliorative effects of luteolin against arsenite in the dopaminergic cell may be modulated by α-Syn, and indicating that luteolin may be developed as a chemopreventive supplementary agent to ameliorate dopaminergic cell apoptosis resulting from arsenite exposure.

[Effect of air pollution on respiratory health in school-aged children in the main urban area of Chongqing, China].

OBJECTIVE: To investigate the effect of air pollution on respiratory health in school-aged children in the main urban area of Chongqing, China. METHODS: The main urban area of Chongqing was divided into polluted area and clean area according to the air pollution data shown on the Environmental Protection Agency Website of Chongqing between 2010 and 2015. A cluster sampling method was used to select 695 third- or fourth-grade children from 2 primary schools in the clean or polluted area as study subjects, with 313 children from the clean area and 382 children from the polluted area. Pulmonary function was examined for all children and a standard American epidemiological questionnaire (ATS-DLD-78-C) was used to investigate the prevalence of respiratory diseases and symptoms. RESULTS: Compared with the clean area, the polluted area had significantly higher concentrations of inhalable particles (PM10), fine particulate matter (PM2.5), and nitric oxide (NOX) (P<0.05). The multivariate logistic regression analysis was performed after adjustment for confounding factors, and the results showed that compared with those in the clean area, the children in the polluted area had significantly higher risks of cough (OR=1.644), cough during cold (OR=1.596), expectoration during cold (OR=2.196), persistent expectoration (OR=1.802), and wheezing (OR=2.415). The boys and girls in the clean area had significantly higher forced vital capacity and forced expiratory volume in one second than those in the polluted area (P<0.05). CONCLUSIONS: Air pollution in the main urban area of Chongqing is associated with the increased prevalence of respiratory symptoms in school-aged children and has certain effect on children's pulmonary function.

Annual risk of tuberculosis infection in rural China: a population-based prospective study.

Prospective population data on the incidence of tuberculosis (TB) infection has been sparsely reported in the global literature.A population-based prospective study was conducted in rural China to investigate the annual risk of TB infection, and its persistence using serial tuberculin skin tests (TSTs) and an interferon-γ release assay. In total, 13 580 eligible participants from four rural sites, identified as TST negative (<10 mm) or QuantiFERON-TB Gold In-Tube (QFT) (an interferon-γ release assay) negative from a baseline survey, were included in the first year's follow-up examination.The annual conversion rate of QFT among the study sites ranged between 2.1% and 4.9% (average 3.1%), and the incidence of TST conversion ranged between 6.0% and 31.1% (average 14.5%). During the second year's follow-up, infection persistence was investigated using 390 subjects with QFT conversions. Among them, 49.7% (164 out of 330) were found to be consistently QFT positive. Both the conversion and the persistence of QFT positivity were found to be significantly increased with increasing age.In conclusion, the annual TB infection rate was suggested to be ∼1.5% based on persistent positive results after QFT conversion in rural China. Therefore, infection control among those high-risk populations, including the elderly, should be prioritised for TB control in China.

Racial/ethnic disparities in human DNA methylation.

The racial/ethnic disparities in DNA methylation patterns indicate that molecular markers may play a role in determining the individual susceptibility to diseases in different ethnic groups. Racial disparities in DNA methylation patterns have been identified in prostate cancer, breast cancer and colorectal cancer and are related to racial differences in cancer prognosis and survival.

Tuberculosis prevalence in China, 1990-2010; a longitudinal analysis of national survey data.

BACKGROUND: China scaled up a tuberculosis control programme (based on the directly observed treatment, short-course [DOTS] strategy) to cover half the population during the 1990s, and to the entire population after 2000. We assessed the effect of the programme. METHODS: In this longitudinal analysis, we compared data from three national tuberculosis prevalence surveys done in 1990, 2000, and 2010. The 2010 survey screened 252,940 eligible individuals aged 15 years and older at 176 investigation points, chosen by stratified random sampling from all 31 mainland provinces. All individuals had chest radiographs taken. Those with abnormal radiographs, persistent cough, or both, were classified as having suspected tuberculosis. Tuberculosis was diagnosed by chest radiograph, sputum-smear microscopy, and culture. Trained staff interviewed each patient with tuberculosis. The 1990 and 2000 surveys were reanalysed and compared with the 2010 survey. FINDINGS: From 1990 to 2010, the prevalence of smear-positive tuberculosis decreased from 170 cases (95% CI 166-174) to 59 cases (49-72) per 100,000 population. During the 1990s, smear-positive prevalence fell only in the provinces with the DOTS programme; after 2000, prevalence decreased in all provinces. The percentage reduction in smear-positive prevalence was greater for the decade after 2000 than the decade before (57% vs 19%; p<0.0001). 70% of the total reduction in smear-positive prevalence (78 of 111 cases per 100,000 population) occurred after 2000. Of these cases, 68 (87%) were in known cases-ie, cases diagnosed with tuberculosis before the survey. Of the known cases, the proportion treated by the public health system (using the DOTS strategy) increased from 59 (15%) of 370 cases in 2000 to 79 (66%) of 123 cases in 2010, contributing to reduced proportions of treatment default (from 163 [43%] of 370 cases to 35 [22%] of 123 cases) and retreatment cases (from 312 [84%] of 374 cases to 48 [31%] of 137 cases; both p<0.0001). INTERPRETATION: In 20 years, China more than halved its tuberculosis prevalence. Marked improvement in tuberculosis treatment, driven by a major shift in treatment from hospitals to the public health centres (that implemented the DOTS strategy) was largely responsible for this epidemiological effect. FUNDING: Chinese Ministry of Health.

Preventive use of hepatoprotectors yields limited efficacy on the liver toxicity of anti-tuberculosis agents in a large cohort of Chinese patients.

BACKGROUND AND AIMS: We aimed to explore the effectiveness of preventive usage of hepatoprotectors in patients with tuberculosis (TB) receiving anti-TB treatment. METHODS: With stratified cluster sampling strategy, a prospective cohort with 4488 sputum smears positive pulmonary TB patients was established from 52 counties of four regions in China. During anti-TB treatment, prescriptions of hepatoprotectors were documented in detail, and liver enzymes were routinely monitored. Anti-TB drug-induced liver injury (ATLI) was assessed based on liver enzymes following the criteria of American Thoracic Society. The incidence of ATLI between the preventive usage group and reference group was compared by propensity score adjusted Cox proportional hazard analysis. Preexisting diseases, history of liver disease, hepatitis B surface antigen status, primary/re-treatment of TB, income per year, and liver enzymes before anti-TB treatment were included in the propensity score model. RESULTS: After 6-9 months of follow-up and monitoring, 4304 patients sustained in our cohort. Two thousand seven hundred fifty-two (63.9%) patients preventively took hepatoprotectors with a median course of 183 days. Most frequently used drugs were Hu Gan Pian, silymarin, glucurone, and inosine. Two thousand one hundred forty-four (77.9%) patients took those drugs more than 6 months. Sixty-nine (2.4%) patients of preventive usage group and 37 (2.5%) of reference group experienced ATLI, respectively. Statistical significances were not found by propensity score analysis for the association between using hepatoprotectors (hazard ratio[HR] = 0.99, 95% confidence interval [CI]: 0.65-1.52), using hepatoprotectors in the whole course (HR = 0.94, 95% CI: 0.60-1.48), using Hu Gan Pians, silymarin, glucurone, and inosine with ATLI occurrence. CONCLUSIONS: No preventive effect of hepatoprotectors was observed in patients receiving anti-TB treatment.

DNMT3B Alleviates Liver Steatosis Induced by Chronic Low-grade LPS via Inhibiting CIDEA Expression.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease is the most prevalent chronic liver disease and threats to human health. Gut dysbiosis caused by lipopolysaccharide (LPS) leakage has been strongly related to nonalcoholic fatty liver disease progression, although the underlying mechanisms remain unclear. METHODS: Previous studies have shown that low-grade LPS administration to mice on a standard, low-fat chow diet is sufficient to induce symptoms of fatty liver. This study confirmed these findings and supported LPS as a lipid metabolism regulator in the liver. RESULTS: Mechanically, LPS induced dysregulated lipid metabolism by inhibiting the expression of DNA methyltransferases 3B (DNMT3B). Genetic overexpression of DNMT3B alleviated LPS-induced lipid accumulation, whereas its knockdown increased steatosis in mice and human hepatocytes. LPS-induced lower expression of DNMT3B led to hypomethylation in promoter region of CIDEA, resulting in increased binding of SREBP-1c to its promoter and activated CIDEA expression. Hepatic interference of CIDEA reversed the effect of LPS on lipogenesis. These effects were independent of a high-fat diet or high fatty acid action. CONCLUSIONS: Overall, these findings sustain the conclusion that LPS is a lipogenic factor and could be involved in hepatic steatosis progression.