Activation of PI3K/Akt pathway by G protein-coupled receptor 37 promotes resistance to cisplatin-induced apoptosis in non-small cell lung cancer.

OBJECTIVES: Lung cancer is a major public health concern and represents the most common cause of cancer-related death worldwide. Among eukaryotes, the G protein-coupled receptor (GPCR) family stands as the largest group of membrane proteins. Alterations in GPCR gene expression and dysregulation of signal transduction have been recognized as the markers of malignancy. As a member of the GPCR family, G protein-coupled receptor 37 (GPR37) exhibits unknown functions in tumors, particularly in non-small-cell lung cancer (NSCLC) METHODS: We explored the expression and prognosis of GPR37 in NSCLC through TCGA, GTEx, GEO, and GEPIA2. We detected the expression of GPR37 in NSCLC tissues and cell lines. The study explored the influence of GPR37 on tumor cell proliferation. Furthermore, we examined the effects of GPR37 on tumor cell apoptosis and invasion. Most importantly, we investigated whether GPR37 affects cisplatin-induced drug resistance in NSCLC. Furthermore, by conducting animal experiments, we assessed the impact of GPR37 on NSCLC and delved into underlying mechanisms. RESULTS: (1) In NSCLC, the expression of GPR37 is markedly higher than that in corresponding normal tissues. We found that elevated GPR37 expression predicts an unfavorable prognosis. (2) It was demonstrated that GPR37 positively regulates NSCLC cell invasion, migration, and proliferation, suppresses cell apoptosis, heightens resistance to cisplatin, and promotes tumor formation and growth. Conversely, we observed that GPR37 knockdown suppresses NSCLC cell invasion, migration, and proliferation, promotes cell apoptosis, increases sensitivity to cisplatin, and affects tumor formation and growth. (3) GPR37 activates PI3K/Akt/mTOR signal transduction pathways to mediate epithelial-mesenchymal transition (EMT), thereby promoting the progression of NSCLC. CONCLUSIONS: It was suggested that GPR37 acts a crucial role in promoting the occurrence and development of NSCLC. Knockdown of GPR37 significantly inhibits the occurrence and development of NSCLC. Therefore, our findings demonstrated that GPR37 may represent a viable therapeutic target for NSCLC.

Safety, pharmacokinetics, and pharmacodynamics of TG103, a novel long-acting GLP-1/Fc fusion protein after a single ascending dose in Chinese healthy subjects.

BACKGROUND AND OBJECTIVE: TG103 is a novel GLP-1/Fc fusion protein, developed for the treatment of type 2 diabetes and obesity. This trial was designed to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profiles after single ascending dose of TG103 in healthy Chinese subjects. METHOD: In this double-blind, randomized, placebo-controlled phase I study, Chinese healthy subjects were admitted consecutively to TG103 3 mg, 7.5 mg, 15 mg, and 22.5 mg group with 8 subjects per group and randomized in a 3:1 ratio to receive TG103 treatment or placebo. Following a single subcutaneous(s.c.) injections of TG103, safety and tolerability were evaluated and blood samples were collected for PK and PD analysis at the specified time-points. RESULT: Overall, 32 healthy subjects were enrolled and completed the study. During the study, a total of 84 adverse effects (AEs) were reported in 25 subjects, all were mild or moderate and resolved spontaneously without intervention. The most common treatment related AEs in TG103 group were decreased appetite (41.7%), nausea, flatulence, elevated urinary ß2-microglobulin, increased serum total bile acid (20.8% each), decreased high-density lipoprotein (16.7%), abdominal distension (12.5%). After a single s.c. administration of TG103 3-22.5 mg, the median Tmax was 36∼48 h, and mean t1/2 was about 147.16∼184.72 h. The mean Cmax for each group was 94.35±52.19, 337.67±56.71, 757.67±206.99, 1236.33±666.25 ng/mL, with AUC0-t of 14.93±7.67, 59.15±7.39, 91.79±20.41, 163.61±55.99 µg·h/mL, respectively. It showed a linear pharmacokinetic profile in the single dose of TG103 3 mg to 22.5 mg. Compared with placebo, fasting blood glucose decreased in all dose groups, most notably in the 15 mg group, which was consistent with the changes in blood glucose during OGTT, while 2-hour postprandial glucose decreased in all dose groups except 3 mg group. CONCLUSION: TG103 offers a potential option for hypoglycemic therapy with good tolerability and safety. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03990090; registered 18 June 2019.

Anwuligan inhibits the progression of non-small cell lung cancer via let-7c-3p/PI3K/AKT/mTOR axis.

BACKGROUND: Anwuligan (ANW) isolated from nutmeg, also known as myristyl lignan, has attracted attention due to its therapeutic potential in diseases. However, its effect on lung cancer is still unclear. METHODS: In this study, the cytotoxicity of ANW on non-small cell lung cancer (NSCLC) cells was detected using a Cell Counting Kit-8 (CCK-8) assay. In vitro, clone formation, wound healing, and Transwell assays were used to investigate the migratory and invasive abilities of NSCLC cells after ANW treatment. The expression levels of the associated proteins were detected using Western blotting. A luciferase assay was used to validate the binding of let-7c-3p to the 3'-untranslated region (UTR) of PIK3CA. In vivo, an A549 cell xenograft mouse model was used to verify the effect of ANW on tumor growth. RESULTS: The results showed that ANW treatment (20 or 50 µM) had obvious cytotoxicity against A549 and H460 cells, suppressing cell proliferation and migration in vitro. In vivo, the growth of the implanted tumor was inhibited by ANW in a nude mouse model. The growth of NSCLC cells was also inhibited by let-7c-3p overexpression in vitro and in vivo. The inhibitory effect of ANW on the proliferation and metastasis of NSCLC cells was weakened by the downregulation of let-7c-3p, whereas it was enhanced by the overexpression of let-7c-3p; PIK3CA was the main target of let-7c-3p. CONCLUSIONS: In summary, ANW inhibits the growth and metastasis of NSCLC cells in vivo and in vitro by upregulating the expression of let-7c-3p, which can regulate the PI3K/AKT/mTOR signaling pathway. PIK3CA is the main target of let-7c-3p.

Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes: A 24-week, multi-centre, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial.

AIM: To evaluate the efficacy and safety of DBPR108 (prusogliptin), a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, as an add-on therapy in patients with type 2 diabetes (T2D) that is inadequately controlled with metformin. MATERIALS AND METHODS: In this 24-week, multi-centre, randomized, double-blind, placebo-controlled, superiority, phase III study, adult T2D patients with HbA1c levels ranging from 7.0% to 9.5% on stable metformin were enrolled and randomized (2:1) into the DBPR108 + metformin and placebo + metformin groups. The primary endpoint was the change from baseline in HbA1c at week 24 of DBPR108 versus placebo as an add-on therapy to metformin. RESULTS: At week 24, the least-square mean (standard error) change from baseline in HbA1c was significantly greater in the DBPR108 group (-0.70% [0.09%]) than in the placebo group (-0.07% [0.11%]) (P < .001), with a treatment difference of -0.63% (95% confidence interval: -0.87%, -0.39%) on the full analysis set. A higher proportion of patients achieved an HbA1c of 6.5% or less (19.7% vs. 8.5%) and an HbA1c of 7.0% or less (50.0% vs. 21.1%) at week 24 in the DBPR108 + metformin group. Furthermore, add-on DBPR108 produced greater reductions from baseline in fasting plasma glucose and 2-hour postprandial plasma glucose without causing weight gain. The overall frequency of adverse events was similar between the two groups. CONCLUSIONS: DBPR108 as add-on therapy to metformin offered a significant improvement in glycaemic control, was superior to metformin monotherapy (placebo) and was safe and well-tolerated in patients with T2D that is inadequately controlled with metformin.

The Effect of Residential Environment on Respiratory Diseases and Pulmonary Function in Children from a Community in Jilin Province of China.

PURPOSE: Respiratory disease is a major and increasingly global epidemic that has a great impact on humans, especially children. The purpose of this study was to identify environmental risk factors for respiratory diseases and pulmonary function in children. PATIENTS AND METHODS: A population-based, cross-sectional survey of respiratory diseases and environmental risk factors was conducted in Jilin Province, China. Complete questionnaire information was available for 2419 children, while adequate pulmonary function data were available for a subgroup of 627 children. RESULTS: Our study found that environmental risk factors for respiratory health in children were mainly concentrated indoors. After adjusting for demographic factors, insecticide exposure and passive smoking were risk factors for respiratory disease and industrial pollutant sources, insecticide exposure and the use of a fume exhauster may be independent risk factors for recurrent respiratory infections. The main fuel for cooking in the winter and passive smoking were the main influencing factors of pulmonary function indicators. CONCLUSION: The primary risk factors differ in different respiratory diseases. Passive smoking remains a critical adverse factor for respiratory illness and pulmonary function in children, and it is important to reduce children's exposure to passive smoking to increase pulmonary health. Insecticide exposure may be a neglected environmental risk factor, and further investigations are still needed to explore the relationship and mechanisms between insecticide exposure and children's respiratory health.

Analysis of Dose-response Relationship between BMI and Hypertension in Northeastern China Using Restricted Cubic Spline Functions.

High body mass index (BMI) was significantly associated with hypertension. The purpose of this study is to investigate the association between BMI and hypertension in people in northeast China. Our study was a cross-sectional study conducted from June to August 2012. According to multistage, stratified cluster sampling, a total of 21435 inhabitants aged between 18 and 79 years in Jilin Province were selected randomly. The prevalence of hypertension was 35.66% overall. After adjusting for potential confounders, the multivariable-adjusted odds ratios for the BMI- hypertension association for overweight and obesity were 2.503 (95% confidence interval = 1.912-2.204) and 4.259 (95% confidence interval = 3.883-4.671). The results of multivariable restricted cubic spline regression analysis showed that there was a non-linear relationship between the continuous change of BMI and hypertension (P < 0.001) after adjusting the confounding factors of different genders and age groups, which indicated that there was an adjusted dose-response association between continuous BMI and hypertension.

Urban-rural differences in related factors of second-hand smoke exposure: a cross-sectional study of adult non-smokers in Northeast China.

BACKGROUND: this study aims to examine the different factors associated with exposure to second-hand smoke (SHS) between urban and rural areas and to facilitate a reduction in SHS exposure in Northeast China. METHODS: a multistage stratified random cluster sampling design was used in this 2012 cross-sectional survey in Jilin Province, Northeast China. A total of 13 056 non-smokers were included in this study. The Rao-Scott χ2 test, multiple regression analysis and discriminant function analysis were used. RESULTS: the SHS prevalence among adult non-smokers was 60.2% in urban areas and 61.8% in rural areas. In urban areas, males were more likely to be exposed to SHS, while in rural areas, females were more likely to be exposed to SHS (P < 0.05). Increasing age was a protective factor against SHS exposure both in urban and rural areas (P < 0.05). Tobacco-relevant knowledge was positively associated with SHS exposure. Among urban non-smokers, high education level and engagement in manual work were risk factors for SHS exposure, and retired subjects were less likely to be exposed to SHS (P < 0.01). CONCLUSIONS: non-smokers from urban and rural areas differ in the factors associated with SHS exposure, and urban-rural differentials, especially with regard to gender, should be considered in tobacco control.

Awareness, treatment and control of hypertension among hypertensive patients aged 18 to 59 years old in the northeast of China.

Hypertension not only has a high prevalence, but also brings disease burden to the affected patients. To assess the level of awareness, treatment and control of hypertension in the northeast of China, we investigated the rates of awareness, treatment and control of hypertension and identified its related factors among hypertensive patients aged 18 to 59 years old in Jilin, China. The data (n = 4632) for the present study were extracted from a cross-sectional study in Jilin. Among individuals with hypertension, the standardized rates of awareness, treatment and control of hypertension were 44.9%, 36.5%, 24.3%, respectively. The rates of awareness and treatment of hypertension among middle aged patients were higher than those among young patients. Compared to patients with normal Body Mass index (BMI), obese hypertensive patients had a higher rate of treatment (43.7% vs. 25.9%) and a lower rate of control (18.9% vs. 29.6%). Compared to patients with normal BMI, patients who were obese were more likely to take measures to treat hypertension (OR = 2.50, 95%CI: 2.05-3.05); but were less likely to have well-controlled blood pressure (OR = 0.55, 95%CI: 0.40-0.78). BMI is one of the influencing factors of hypertension awareness, treatment and control among patients 18 to 59 years old with hypertension.

Smoking and Risk for Alzheimer Disease: A Meta-Analysis Based on Both Case-Control and Cohort Study.

This study was performed to identify the association between smoking and Alzheimer's disease (AD). To perform this meta-analysis based on case-control and cohort studies, PubMed, Google Scholar, and the CNKI electronic databases were searched through April 30, 2017. Our meta-analysis included 27 studies, including 16 that reported odds ratios (ORs) and 11 that reported hazard ratios (HRs) or ratio risks. No significant association was found between smoking and AD among the studies that reported ORs (1.020, 95% confidence interval [CI] = 0.812-1.281, I = 67.9%, random model, p < 0.001). A subgroup analysis revealed no significant difference between different smoking statuses. The pooled HRs revealed a significant association between smoking and AD (HR = 1.520, 95% CI = 1.194-1.934, I = 83.6%, random model, p < 0.001). Cumulative meta-analysis of the HRs revealed that the effect of smoking on AD tended to be stable over time. Smoking may confer an increased risk of AD, and this effect has tended to be stable over time.

Short-term effects of fine particulate matter on non-accidental and circulatory diseases mortality: A time series study among the elder in Changchun.

BACKGROUND AND OBJECTIVES: Fine particulate matter (PM2.5, particulate matter with an aerodynamic diameter less than or equal to 2.5 µm) has multiple adverse effects on human health, especially on the respiratory and circulatory system. The purpose of this study was to evaluate the short-term effect of PM2.5 on the mortality risk of non-accidental and circulatory diseases, and to explore the potential effect modification by sex, education and death location. METHODS: We collected daily mortality counts of Changchun (China) residents, daily meteorology and air pollution data, from January 1, 2014, to January 1, 2017. We focused on the elderly (≥65 years old) population who died from non-accidental causes and circulatory diseases, and stratified them by sex, education, and death location. A generalized additive Poisson regression model (GAM) was used to analyse the impact of air pollutants on mortality. We fit single pollutant models to examine PM2.5 effects with different lag structures of single-day (distributed lag:lag0-lag3) and multi-day (moving average lag: lag01-lag03). To test the sensitivity of the model, a multi-pollutant model was established when the PM2.5 effect was strongest. RESULTS: In the single pollutant models, an increment of PM2.5 by 10 µg/m3 at lag0-3 was associated with a 0.385% (95% CI: 0.069% to 0.702%) increase in daily non-accidental mortality and a 0.442% (95% CI: 0.038% to 0.848%) increase in daily circulatory disease mortality. NO2 (lag1) and O3 (lag0, lag1, lag2, lag01,lag02, lag03) were associated with daily non-accidental death and NO2 (lag1, lag3, lag03) and O3 (lag0, lag1, lag01,lag02, lag03) were associated with daily circulatory disease mortality. In the co-pollutant models, the risk estimates for PM2.5 changed slightly. The excess mortality risk of non-accidental and circulatory diseases was higher for women, people with low education, and died outside hospital. CONCLUSIONS: We found that short-term exposure to PM2.5 increased the mortality risk of non-accidental and circulatory diseases among the elderly in Changchun. Women, people with low education and died outside hospital are more susceptible to PM2.5. NO2 and O3 were also associated with an increase in mortality from non-accidental and circulatory diseases and the O3 is a high effect.

The Study on the Correlation Between Six Kinds of Mineral Elements and Diabetes.

The study aimed to explore the relationship of six kinds of mineral elements and diabetes among adults in northeast China. A cross-sectional survey was conducted in Jilin Province, northeast China. A total of 366 males and 204 females aged 18 ~ 77 years from Jingyu town, Dongliao town, and Changling town were included using a multistage stratified random cluster sampling design. Data was obtained from face to face interview, physical examination, and laboratory measurement. We defined the normal people (3.9 ~ 6.0 mmol/L), impaired fasting glucose (IFG) individuals (6.1 ~ 6.9 mmol/L), and diabetes mellitus (DM) (> 7.0 mmol/L) according to the WHO diagnostic criteria. Kruskal-Wallis test, Spearman rank correlation, as well as binary logistic regression were used to analyze influencing factors. lg(Cu/Zn)was correlated with DM (OR 8.390; 95% CI of OR 1.272-55.347). The specific mineral elements such as Zn, Ca, as well as Cu/Zn ratio may be the potential risk factors for diabetes. So, the supplement or reduction of these elements is supposed to be told to IFG to prevent or delay the occurrence of diabetes or DM to avoid its complication.