Inhibitory effect of daidzein on the calcium-activated chloride channel TMEM16A and its anti-lung adenocarcinoma activity.

TMEM16A is highly expressed in a variety of tumor cells and is involved in the growth and metastasis of malignancies. It has been established that down-regulation of TMEM16A expression or functional activity can inhibit tumor cells growth. However, there is a lack of targeted inhibitors with high efficiency and low toxicity. Here, we identified a novel inhibitor daidzein from dozens of natural product molecules. Whole-cell patch clamp data indicated that daidzein inhibits TMEM16A channel in a dose-dependent manner, with IC50 of 1.39 ± 0.59 µM. Western blot result showed that daidzein can also reduce the expression of TMEM16A protein in LA795 cells. These results indicated that the inhibitory effects of daidzein exert on TMEM16A in two ways, both inhibiting TMEM16A current and decreasing its protein expression. In addition, the putative binding sites of daidzein on TMEM16A are G608, G628, and K839 through molecular docking. Moreover, daidzein concentration-dependently reduced cell viability and cell migration, causing G1/S cell cycle arrest in vitro. It was also confirmed that daidzein can effectively inhibit the growth of LA795 lung adenocarcinoma cells implanted nude mice in vivo. In conclusion, daidzein can be used as a lead compound for the development of therapeutic drugs for lung adenocarcinoma.

Deep vein thrombosis and validation of the Caprini risk assessment model in Chinese orthopaedic trauma patients: a multi-center retrospective cohort study enrolling 34,893 patients.

BACKGROUND: The risk of venous thromboembolism among orthopaedic trauma patients is high, but prevalence of deep vein thrombosis (DVT) remains unknown. In addition, the Caprini risk assessment model (RAM) score in orthopaedic trauma patients is undetermined in previous research. This study is aimed to determine the incidence of DVT and then validate the Caprini RAM in orthopaedic trauma patients. METHODS: This is a retrospective cohort study enrolling orthopaedic trauma inpatients from seven tertiary and secondary hospitals during a 3-year period (from April 1, 2018 through April 30, 2021). Caprini RAM scores were assessed by experienced nurses on admission. The patients with suspected DVT were verified through duplex ultrasonography by qualified radiologists, and then prospectively followed once a year after discharge. RESULTS: In total, 34,893 patients were enrolled in our study. The Caprini RAM identified 45.7% of patients at low risk (Caprini score 0-2), 25.9% at medium risk (3-4), and 28.3% at high risk (5-6), highest risk (7-8), and superhigh risk (> 8). Patients with Caprini score > 5 were likely to be older, female, and with longer length of hospital stay. Moreover, 8695 patients had received ultrasonography to detect DVT. The prevalence of DVT was determined to be 19.0% [95% confidence interval (CI) 18.2-19.9%], which significantly increased with Caprini score. The area under curve of the Caprini RAM for DVT was 0.77 (95% CI 0.76-0.78) with a threshold of 4.5. Furthermore, 6108 patients who had received ultrasonography completed the follow-up. DVT patients had a hazard ratio of 1.75 (95% CI 1.11-2.76; P = 0.005) in the mortality, compared to non-DVT ones. Caprini scores were significantly associated with increase in the mortality [odds ratio (OR) 1.14; 95% CI 1.07-1.21; P < 0.001]; DVT remained an independent effect (OR 1.5; 95% CI 1.02-2.26; P = 0.042). CONCLUSIONS: The Caprini RAM may be valid in Chinese orthopaedic trauma patients. Prevalence of DVT and higher Caprini score were significantly associated with increased all-cause mortality among orthopaedic trauma patients after discharge. Further study is warranted to explore the causes of higher mortality in patients with DVT.

Emerging Modulators of TMEM16A and Their Therapeutic Potential.

Calcium-activated chloride channels (CaCCs) are widespread chloride channels which rely on calcium activation to perform their functions. In 2008, TMEM16A (also known as anoctamin1, ANO1) was identified as the molecular basis of the CaCCs, which provided the possibility to study the physiological function of CaCCs. TMEM16A is widely expressed in various cells and controls basic physiological functions, including neuronal and cardiac excitability, nerve transduction, smooth muscle contraction, epithelial Cl- secretion and fertilization. However, the abnormal function of TMEM16A may cause a variety of diseases, including asthma, gastrointestinal motility disorder and various cancers. Therefore, TMEM16A is a putative drug target for many diseases, and it is important to determine specific and efficient modulators of TMEM16A channel. In recent years, we and others have screened several natural modulators of TMEM16A against cancers and gastrointestinal motility dysfunction. This article reviews the screening methods, efficacy of TMEM16A modulators and pharmacological effects of TMEM16A modulators on different diseases. GRAPHIC ABSTACT.