LncRNA Gm15834 Aggravates Cardiac Hypertrophy by Interacting with Sam68 and Activating NF-κB Mediated Inflammation.

BACKGROUND: Cardiac hypertrophy is the common pathological process of multiple cardiovascular diseases. However, the molecular mechanisms of cardiac hypertrophy are unclear. Long non-coding RNA (lncRNA), a newly discovered type of transcript that has been demonstrated to function as crucial regulators in the development of cardiovascular diseases. This study revealed a novel regulatory pathway of lncRNA in cardiac hypertrophy. METHODS: The cardiac hypertrophy models were established by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) in HL-1 cardiomyocytes. Adeno-associated virus 9 (AAV9) in vivo and lncRNA Gm15834 and shRNA plasmids in vitro were used to overexpress and knock down lncRNA Gm15834. The myocardial tissue structure, cardiomyocyte area, cardiac function, protein expressions, and binding of lncRNA Gm15834 and Src-associated substrate during mitosis of 68 KDa (Sam68) were detected by hematoxylin and eosin (HE) staining, immunofluorescence staining, echocardiography, western blot and RNA immunoprecipitation (RIP), respectively. RESULTS: In cardiac hypertrophy models, inhibiting lncRNA Gm15834 could decrease Sam68 expression and nuclear factor kappa-B (NF-κB) mediated inflammatory activities in vivo and in vitro, but overexpressing lncRNA Gm15834 showed the opposite results. RIP experiments validated the binding activities between lncRNA Gm15834 and Sam68. Overexpression of Sam68 could counteract the anti-hypertrophy effects of lncRNA Gm15834 knockdown. Meanwhile, in vivo inhibition of lncRNA Gm15834 could inhibit Sam68 expression, reduce NF-κB mediated inflammatory activity and attenuate cardiac hypertrophy. CONCLUSION: Our study revealed a novel regulatory axis of cardiac hypertrophy, which comprised lncRNA Gm15834/Sam68/NF-κB/inflammation, shedding a new light for identifying therapy target of cardiac hypertrophy in clinic.

Association of circulating tumor cell-white blood cell clusters with survival outcomes in patients with colorectal cancer after curative intent surgery.

BACKGROUND: The analysis of circulating tumor cell-associated white blood cell (CTC-WBC) clusters represented the progress in the liquid biopsy of malignant tumors, however, related research in patients with colorectal cancer is still absent. METHODS: To explore associations between CTC-WBC clusters and the prognosis of these patients, we conducted an independent cohort of 329 colorectal cancer patients after curative intent surgery and pre-operative CTC detection in Nanfang Hospital, Southern Medical University, Guangzhou, China between January 1, 2017, and September 31, 2019. The primary cohort referred to patients with CTC-WBC clusters positive. The control cohort was defined as those with exclusively CTCs positive. CTCs were enriched and distinguished by The CanPatrol™ system (SurExam, China). The Kaplan-Meier curve was used to compare the progressive-free survival (PFS) and overall survival (OS) between two groups. The COX regression model was used to assess the predictive value of CTC-WBC clusters. RESULTS: Sixty three patients presented CTC-WBC clusters positive (CTC-WBC group) and 266 patients showed solely CTCs (CTC group). The number of CTCs was significantly different between two groups (P < 0.001) and the rest of clinical characteristics were not markedly associated with the presence of CTC-WBC clusters. Kaplan-Meier curves of PFS and OS exhibited that the CTC-WBC group had significantly shorter PFS (P = 0.011), while not for OS. The multivariate model further suggested that the CTC-WBC clusters (Hazard Ratio = 1.89, 95% Confidence Interval 1.02-3.51, P = 0.042) was an independent predictor for the PFS of in post-operation CRC patients. CONCLUSION: The CTC-WBC cluster is significantly associated with recurrence after operation in CRC patients. This finding facilitates the evaluation of this indicator in tumor progression.

Parental smoking exposure before and during pregnancy and offspring attention-deficit/hyperactivity disorder risk: A Chinese child and adolescent cohort study.

Background: Previous studies revealed that maternal smoking exposure during pregnancy was an essential risk factor for offspring developing attention-deficit/hyperactivity disorder (ADHD). The impact of paternal smoking exposure 1 year before pregnancy on offspring ADHD risk is still unclear. Methods: The present study included 2,477 school-age children and their parents from the Shanghai Child and Adolescent Health Cohort who had complete data for offspring ADHD diagnosis and parents' smoking exposure before and during pregnancy information. A multivariate logistic regression model and Firth's logistic regression model were used to determine the associations of paternal smoking and parental smoke exposure patterns before and during pregnancy with offspring ADHD risk. Results: Children whose fathers smoked before pregnancy had a higher risk of developing ADHD [odds ratio (OR) = 2.59, 95% confidence interval (CI): 1.35-4.98] compared to those whose fathers had never been exposed to smoking. Similarly, parents who were exposed to smoking or second-hand smoke before pregnancy had 1.96 times (OR = 1.96, 95% CI: 1.19-3.22) more likely to have offspring with ADHD. Moreover, children whose parents were exposed to smoking both before and during pregnancy were 2.01 times (OR = 2.01, 95% CI: 1.29-3.12) more likely to develop ADHD. Conclusion: Paternal smoking before pregnancy and parental smoking exposure 1 year ahead of and throughout pregnancy were all risk factors for offspring developing ADHD.

Environmental Exposure to 6:2 Polyfluoroalkyl Phosphate Diester and Impaired Testicular Function in Men.

6:2 polyfluoroalkyl phosphate diester (6:2 diPAP) has been demonstrated to disrupt reproductive endocrine functions using experimental studies. However, evidence from humans is not available yet. This cross-sectional study aims to assess the relationship between 6:2 diPAP exposure and the testicular function among adult men. A total of 902 men seeking preconception care were included. Plasma 6:2 diPAP concentrations were determined, while the testicular function was assessed via semen quality and reproductive hormones in serum. The association was assessed by multiple linear regression. Stratified analyses by age and body mass index (BMI) were conducted to assess the potential effect modification by these two variables. Regression analyses revealed that 6:2 diPAP exposure was significantly inversely associated with androgens [i.e., total testosterone (TT) and free androgen index (FAI)], markers of testosterone production potential [i.e., TT/luteinizing hormone (LH) and FAI/LH], estradiol, and insulin-like factor 3, a biomarker of Leydig cell function. These associations were robust in sensitivity analyses. However, age and BMI did not modify these associations, and no association was observed between 6:2 diPAP and semen quality. Our study suggests that exposure to 6:2 diPAP may inhibit androgen synthesis and impair Leydig cell function in adult men.

A simple, rapid and sensitive method for the simultaneous determination of eighteen environmental phenols in human urine.

Environmental phenols are a typical group of endocrine disrupting compounds (EDCs) and have caused growing concerns upon the potential adverse effects on humans. Urinary concentrations of phenols can be used as valid biomarkers for the assessment of human exposure. A method was developed for the simultaneous determination of eighteen environmental phenols (six parabens, seven bisphenols, four benzophenones and triclosan) in human urine using liquid-liquid extraction (LLE) coupled to high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The optimized LLE was time saving and required low volumes of organic solvents. A volume of only 0.2 mL urine sample was extracted and analyzed. The method yielded good linearity (0.9925-0.9994) and satisfactory limit of detection (LOD) (≤0.08 ng mL-1). The relative recoveries ranged between 76.7% and 116% at three spiked levels, with intra- and inter-day precision less than 8.04% and 13.5%, respectively. Our method has been proved to be simple, rapid and sensitive by a comprehensive comparison between methods. This proposed method provides a large-scale biomonitoring tool for exposure assessment of human population to environmental phenols.

The transient receptor potential vanilloid-3 regulates hypoxia-mediated pulmonary artery smooth muscle cells proliferation via PI3K/AKT signaling pathway.

OBJECTVES: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca2+ -permeant cation channels. In this study, we aim to investigate the role of TRPV3 in pulmonary vascular remodeling and PASMCs proliferation under hypoxia. MATERIALS AND METHODS: The expression of TRPV3 was evaluated in patients with pulmonary arterial hypertension (PAH) and hypoxic rats, using hematoxylin and eosin (H&E) and immunohistochemistry. In vitro, MTT assay, flow cytometry, Western blotting and immunofluorescence were performed to investigate the effects of TRPV3 on proliferation of PASMCs. RESULTS: We found that, in vivo, the expression of TRPV3 was increased in patients with PAH and hypoxic rats. Right ventricular hypertrophy measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery were increased in chronic hypoxic rats. Moreover, the expression of proliferating cell nuclear antigen (PCNA), Cyclin D, Cyclin E and Cyclin A, phospho-CaMKII (p-CaMKII) were induced by hypoxia. In vitro, we revealed that hypoxia promoted PASMCs viability, increased the expression of PCNA, Cyclin D, Cyclin E, Cyclin A p-CaMKII, made more cells from G0 /G1 phase to G2 /M + S phase, enhanced the microtubule formation, and increased [Ca2+ ]i , which could be suppressed by Ruthenium Red, an inhibitor of TRPV3, and TRPV3 silencing has similar effects. Furthermore, the up-regulated expression of PCNA, Cyclin D, Cyclin E and Cyclin A, the increased number of cells in G2 /M and S phase, and the enhanced activation and expression of PI3K and AKT proteins induced by hypoxia and in presence of carvacrol (an agonist of TRPV3), was significantly attenuated by incubation of LY 294002, a specific inhibitor for PI3K/AKT. CONCLUSIONS: These findings suggest that TRPV3 is involved in hypoxia-induced pulmonary vascular remodeling and promotes proliferation of PASMCs and the effect is, at least in part, mediated via the PI3K/AKT pathway.

Carvacrol induces the apoptosis of pulmonary artery smooth muscle cells under hypoxia.

The abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). Carvacrol, an essential oil compound from oregano and thyme, has displayed antimicrobial, antitumor, and antioxidant properties. Although carvacrol has pro-apoptosis properties in tumor cells, the underlying mechanisms of carvacrol in PASMC apoptosis remain unclear. Thus, in this study, we aim to investigate the role of carvacrol in pulmonary vascular remodeling and PASMC apoptosis in hypoxia. Right Ventricular Hypertrophy Measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery increased in chronic hypoxia and were reversed by carvacrol treatment under hypoxia. Additionally, carvacrol inhibited PASMC viability, attenuated oxidative stress, induced mitochondria membrane depolarization, increased the percentage of apoptotic cells, suppressed Bcl-2 expression, decreased procaspase-3 expression, promoted caspase-3 activation, and inhibited the ERK1/2 and PI3K/Akt pathway. Taken together, these findings suggest that carvacrol attenuates the pulmonary vascular remodeling and promotes PASMC apoptosis by acting on, at least in part, the intrinsic apoptotic pathway. This process might provide us new insight into the development of hypoxic pulmonary hypertension.