Bicyclol alleviates obesity-induced renal injury by inhibiting JNK and NF-κB-mediated inflammation.

Obesity is recognized as a major risk factor for chronic kidney disease (CKD), which is accompanied by increased renal lipid build-up, fibrosis, inflammation, apoptosis and pyroptosis. Bicyclol (BIC), a Chinese marketed hepatoprotective drug, has shown excellent anti-inflammatory, anti-fibrosis, anti-apoptotic, and lipid regulation effects in different animal models. In this study, we explored the role and mechanism of BIC in high-fat diet (HFD)-induced obesity-related nephropathy. Mice were fed with HFD for 24 weeks to develop obesity-related nephropathy, while mice in the BIC administration group were treated with BIC (50 mg/kg or 100 mg/kg, once every two days) at the last 12 weeks. We found that BIC treatment relieved the impairment of kidney structure and renal dysfunction caused by HFD. In addition, we found that BIC mitigated HFD-induced renal fibrosis, inflammation, apoptosis and pyroptosis by inhibiting JNK and NF-κB pathways. SV40-MES-13 cells treated with palmitate (PA) were used as the in vitro model. Our data show that BIC pre-administration relieved cellular damage caused by PA through suppressing JNK and NF-κB signaling pathways. In conclusion, we demonstrated that BIC attenuated obesity-induced renal injury by inhibiting chronic inflammation, fibrosis, apoptosis and pyroptosis via targeting JNK and NF-κB pathways. Our data suggested that BIC could be potentially used to prevent obesity-associated nephropathy, which warrants future investigation.

Toll-like receptor 2 deficiency ameliorates obesity-induced cardiomyopathy via inhibiting NF-κB signaling pathway.

Growing evidence demonstrates that chronic low-grade inflammation, which is induced by high-fat diet (HFD) or saturated fatty acid, plays an important role in the obesity-induced cardiomyopathy (OIC) process. Moreover, obesity is associated with the activation of different inflammatory pathways, including nuclear factor-κB (NF-κB), Toll-like-receptor-2 (TLR2) and Toll-like-receptor-4 (TLR4). In this study, we established an HFD-induced cardiac injury mouse model and palmitate (PA)-induced myocardial cell model to evaluate the role of TLR2 in OIC. Our data show that TLR2 blockade using TLR2 knockout (KO) mice or a TLR2-specific inhibitor, C29, markedly ameliorated HFD- or PA-induced inflammation, myocardial fibrosis, and hypertrophy both in vivo and in vitro. Moreover, the PA-induced myocardial cell injury was mediated via inducing the formation of TLR2-MyD88 complex in a TLR4-independent manner in cardiomyocytes. Our data prove the critical role of cardiac TLR2 in the pathogenesis of HFD- and saturated fatty acid-induced myocarditis, fibrosis, myocardial hypertrophy, and cardiac dysfunction. Inhibition of TLR2 pathway may be a therapeutic strategy of OIC.

Compound c17 alleviates inflammatory cardiomyopathy in streptozotocin-induced diabetic mice by targeting MyD88.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and is associated with increased morbidity and mortality due to cardiac dysfunction. Chronic inflammation plays a significant role in the development of DCM, making it a promising target for novel pharmacological strategies. Our previous study has synthesized a novel compound, c17, which exhibited strong anti-inflammatory activity by specifically targeting to myeloid differentiation primary response 88 (MyD88). In this study, we evaluated the therapeutic effect of c17 in DCM. METHODS: The small molecular selective MyD88 inhibitor, c17, was used to evaluate the effect of MyD88 on DCM in both high concentration of glucose- and palmitic acid-stimulated macrophages and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice. RESULTS: The treatment of c17 in T1DM mice resulted in improved heart function and reduced cardiac hypertrophy, inflammation and fibrogenesis. RNA sequencing analysis of the heart tissues revealed that c17 effectively suppressed the inflammatory response by regulating the MyD88-dependent pathway. Co-immunoprecipitation experiments further confirmed that c17 disrupted the interaction between MyD88 and Toll-like receptor 4 (TLR4), consequently inhibiting downstream NF-κB activation. In vitro studies demonstrated that c17 exhibited similar anti-inflammatory activity by targeting MyD88 in macrophages, which are the primary regulators of cardiac inflammation. Furthermore, conditioned medium derived from c17-treated macrophages showed reduced capacity to induce hypertrophy, pro-fibrotic reactions, and secondary inflammation in cardiomyocytes. CONCLUSIONS: In conclusion, the small-molecule MyD88 inhibitor, c17, effectively combated the inflammatory DCM, therefore could be a potential candidate for the treatment of this disease.

Identification and attribute analysis of key stakeholders who influence multidrug-resistant tuberculosis prevention and control in China.

BACKGROUND: There could be various stakeholders who influencing multidrug-resistant tuberculosis (MDR-TB) policy development and implementation, yet their attributes and roles remain unclear in practice. This study aimed to identify key stakeholders in the process of policy-making for MDR-TB control and prevention and to analyse the attributes and relationships of the stakeholders, providing evidence for further policy research on MDR-TB control. METHODS: This study was conducted from October 2018 to March 2019 and applied the stakeholder analysis guidelines and domestic stakeholder analysis. An initial candidate stakeholder list was developed by policy scanning. Ten experts were invited to identify these candidate stakeholders. The major attribute of these stakeholders were analysed using the Michell scoring method. Based on these results, the intertwined relationships among groups of stakeholders were analysed and mapped through a systematic scan of the policy and literature on MDR-TB control, as well as information obtained from the interviews. RESULTS: A list of 21 types of candidate stakeholders was developed after a literature review and policy scanning, of which 11 received 100% approval. After expert evaluation and identification (the total expert authority was 0.80), 19 categories of stakeholders were approved and included in the stakeholder analysis. We categorized all of the stakeholders into three groups: (i) definitive stakeholders who are mainly involved in administrative departments and the Provincial Center for Disease Control and Prevention (CDC); (ii) expectant stakeholders who are mainly involved with MDR-TB patients, clinical departments of TB hospitals at different levels, community health care facilities, prefectural CDC and charity organizations; and (iii) latent stakeholders who mainly involved family members and neighbours of MDR-TB patients and TB related products manufacturers. Government departments and higher-level CDCs have strong decision-making power in developing MDR-TB control policies whereas the recommendations from service providers and the concerns of patients should be considered. CONCLUSIONS: The MDR-TB prevention system was a multistakeholder cooperation system that was mainly led by government stakeholders. Enhancing communications with front-line service providers and patients on their unmet needs and evidence-based suggestions would highly benefit policy-making of MDR-TB prevention and control.

The influence of home-based exercise on gestational diabetes: a meta-analysis of randomized controlled trials.

Introduction: The impact of home-based exercise for gestational diabetes remains controversial. We conduct a systematic review and meta-analysis to explore the influence of home-based exercise on glycemic control for gestational diabetes.Methods: We search PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases through April 2018 for randomized controlled trials (RCTs) assessing the effect of home-based exercise on glycemic control for gestational diabetes.Results: Five RCTs involving 266 patients are included in the meta-analysis. Overall, compared with control group for gestational diabetes, home-based exercise shows no important impact on fasting glucose (std. MD =0.18; 95% CI = -0.11-0.46; p = .22), HbA1c (std. MD = -0.05; 95% CI = -0.32-0.22; p = .70), insulin requirement (risk ratios (RR) = 1.63; 95% CI =0.51-5.17; p = .41), insulin sensitivity index (std. MD = -0.18; 95% CI = -1.02-0.66; p = .67), gestational age at delivery (std. MD =0.01; 95% CI = -0.26-0.28; p = .95), preterm birth (RR =1.01; 95% CI =0.34-2.99; p = .99), birth weight (std. MD =0.06; 95% CI = -0.45-0.58; p = .81) and head circumference (std. MD =0.11; 95% CI = -0.16-0.38; p = .44).Conclusions: Home-based exercise demonstrates no substantial benefits to fasting glucose, HbA1c, insulin requirement, insulin sensitivity index, gestational age at delivery, preterm birth, birth weight and head circumference for gestational diabetes women.

Tuberculosis outbreaks among students in mainland China: a systematic review and meta-analysis.

BACKGROUND: In recent years, tuberculosis outbreaks in schools have occurred more frequently in China than in other parts of the world, and have posed a public health threat to students and their families. This systematic review aimed to understand the epidemiological characteristics of tuberculosis (TB) outbreaks and analyze the factors associated with TB outbreaks in schools in China. METHODS: We conducted this systematic review following the standard procedures of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. The meta-analysis was performed with STATA using a random effects model. RESULTS: We included 107 studies involving 1795 student patients with TB in mainland China. The results of the systematic analysis indicated that TB outbreaks were more frequently reported in senior middle schools and in Eastern China. The outbreaks mainly occurred during the winter and spring, and the median outbreak duration was 4 months. The meta-analysis showed that the total attack rate and the class attack rate of tuberculosis outbreaks among students were 4.60% (95% CI 3.80 to 5.70%) and 22.70% (95% CI 19.20 to 27.00%), respectively. Subgroup analysis showed that outbreaks that occurred at universities or colleges had a relatively higher attack rate than those occurred in senior middle schools. The prevalence of latent tuberculosis infection (LTBI) among close contacts was 23.70% (95% CI 19.50 to 28.90%). The median case-finding interval was 2 months, and 47.40% of the index cases had a case-finding delay. CONCLUSION: The results of our review indicated that school TB outbreaks were reported most frequently in senior middle schools in China. The attack rates of outbreaks at universities or colleges were higher than those in senior middle schools. The TB outbreaks in schools usually occurred over prolonged periods. The case-finding delay in the index cases must be reduced to prevent transmission in classes and schools. Effective surveillance and screening of presumptive TB cases in schools should be strengthened to reduce outbreaks in schools.

Assessment of active tuberculosis findings in the eastern area of China: A 3-year sequential screening study.

BACKGROUND: Tuberculosis (TB) is a critical global public threat, and limited epidemiology studies have been performed to explore the efficacy of active TB screening. METHODS: Three sites located in eastern China were chosen in 2013, and three rounds of systematic screenings were performed in permanent residents aged older than 15 years. RESULTS: The TB incidence showed a downtrend after several rounds of active screening at the three sites, and a significant change was observed at site A in the overall population. In the target population at sites A and B, both the elderly and people with a history of TB had a remarkable decline through the first or second round of screening. The implementation of active case-finding identified 2.36 [1.47,3.81] (2013 vs. 2012) and 1.49 [1.1,2.03] (2013-2015 vs. 2010-2012) more potential cases than the passive case-finding by the surveillance system at site A. CONCLUSIONS: Active case-finding of tuberculosis might be effective in high prevalence area with a low economic level, particularly among the elderly and people with a history of TB. Additionally, new rapid diagnosis technology should be considered to decrease the prevalence among people with a history of TB. Ultimately, active screening identified more active TB cases than passive case-finding, particularly in high prevalence area with underdeveloped economics.

Suitable hepatitis B vaccine for adult immunization in China: a systematic review and meta-analysis.

Hepatitis B virus (HBV) infection remains an important public health problem in China, and adults need to be vaccinated. This systematic review and meta-analysis assessed the appropriate immunization of adults in China. Only randomized controlled trials (RCTs) were eligible, and seroprotection was defined as anti-HBs≥ 10 mIU/ml; 18,308 participants in 27 studies were included. Relative risk (RR) and random effects models were used. Twenty micrograms of HBV vaccine resulted in a better response than 10 µg (RR: 1.05, 95% confidence interval (CI): 1.02 to 1.08), and the 0-, 1-, and 6-month schedule was more effective than the 0-, 1-, and 2 - or 3-month schedule (RR: 0.98, 95% CI: 0.96 to 1.00). No significant differences were observed between 10 µg and 5 µg (RR: 1.05, 95% CI: 0.88 to 1.01); (yeast-derived hepatitis B vaccines) YDV and recombinant Chinese hamster ovary cell (CHO) hepatitis B vaccine (RR: 1.01, 95% CI: 0.98 to 1.04); domestic and imported (RR: 1.02, 95% CI: 0.99 to 1.05); or 0-, 1-, and 6-month and 0-, 1-, and 12-month schedules (RR: 1.02, 95% CI: 0.89 to 1.08). In conclusion, 20 µg of vaccine is recommended for adults in China, and the 0-, 1-, and 12-month immunization program schedule is also worth choosing when it is not possible to complete the 0-, 1-, and 6-month schedule.

Tuberculosis among Full-Time Teachers in Southeast China, 2005⁻2016.

Objective: To explore the incidence rate and characteristics of tuberculosis (TB) among full-time teachers from 2005 to 2016 in southeast China and to provide a basis for TB prevention and control measures in schools. Methods: Information about full-time teachers with TB was obtained from the National Tuberculosis Information Management System (NTIMS). Population data were collected from the Zhejiang Statistical Yearbook and the Zhejiang Education Yearbook. The TB incidence rates and epidemiological characteristics of full-time teachers were analyzed and the Chi-square test was used to analyze influencing factors of epidemiological characteristics and clinical characteristics, case-finding delay, and treatment outcomes. Results: A total of 1795 teachers with TB were reported from 2005 to 2016, and the annual incidence rate was 28.87 per 100,000. The average annual PTB (pulmonary TB) incidence rate among full-time teachers was 25.43/100,000 from 2005 to 2016 and the average annual PTB incidence rate among students was 15.40/100,000 from 2005 to 2016. The highest average incidence rates were observed in the QZ (Quzhou) and HZ (Hangzhou) districts. The male-to-female ratio of the patients was 0.95:1. Approximately half of the patients were 15⁻40 years old. The mean case-finding interval was 45.3 days. Multivariable logistic regression analysis of TB case-finding delay among full-time teachers revealed that the older (OR = 1.44, 95% CI = 1.18⁻1.76, p < 0.01), not local (OR = 1.81, 95% CI = 1.20⁻2.73, p < 0.01), retreatment (OR = 2.06, 95% CI = 1.39⁻3.08, p < 0.01) and extra-pulmonary tuberculosis (OR = 1.71, 95% CI = 1.13⁻2.61, p = 0.01) cases were at high risk of case-finding delay. Compared to physical examination, patients detected by referrals and tracking (OR = 2.26, 95% CI = 1.16⁻4.38, p = 0.02) and patients who directly visited the designated TB hospital (OR = 2.00, 95% CI = 1.03⁻3.88, p = 0.04) were more prone to case-finding delay. The cure rate of full-time teachers with TB was 77.10%. The cure rates differed significantly between groups classified based on age, case-finding patterns, diagnostic results, treatment classifications, and strategies of patient management. Conclusion: The TB incidence rate among full-time teachers decreased from 2005 to 2016, but teachers suffered a higher risk of TB than students. Western Zhejiang was a hotspot for TB incidence among full-time teachers. Female teacher and young and middle-aged teacher cases account for the majority of the reported patients. There was a case-finding delay among full-time teachers with TB. We should conduct regular physical examinations and strengthen full-course supervision to reduce the risk of TB patients with case-finding delay and increase the TB cure rate.

The effects of booster vaccination of hepatitis B vaccine on children 5-15 years after primary immunization: A 5-year follow-up study.

The aim of this study was to evaluate changes in hepatitis B surface antibody titers (anti-HBs) after booster vaccinations in children aged 5-15 y and to provide suitable immunization strategies. A total of 2208 children were initially enrolled in screening, and 559 children were finally included. The participants were divided into 2 groups according to their pre-booster anti-HBs levels: Group I, <10 mIU/ml and Group II, ≥10 mIU/ml. Group I was administered 3 doses of booster hepatitis B vaccine (0-1-6 months, 10 µg), and Group II was administered 1 dose of booster hepatitis B vaccine (10 µg). The antibody titer changes were examined at 4 time points: 1 month after dose 1 and dose 3, and 1 year and 5 years after dose 3. The protective seroconversion rates at those points were 95.65%, 99.67%, 97.59% and 91.05% (p < 0.001), respectively, in Group I, and 100.00%, 99.87%, 99.66% and 98.21% (χ2 = 6.04, p = 0.11), respectively, in Group II. The GMT in subjects aged 5-9 y were higher than that in subjects aged 10-15 y in both Group I and Group II at 1 month after dose 1, but no difference was observed at the other three time points. This study demonstrates that booster vaccination has a good medium-term effect. A booster dose for subjects with protective antibodies is not necessary but effective, and 3 doses of hepatitis B vaccination are recommended for those who have lost immunological memory. Receiving booster immunization at the age of 10-15 years may be more appropriate for individuals living in HBV high epidemic areas.