BackgroundVascular dysfunction is a distinctive phenotype in diabetes mellitus. Current treatments mostly focus on the tight glycemic control and few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. As a classical natural medicine, berberine has been explored as a possible therapy for DM. In addition, it is reported that berberine has an extra-protective effect in diabetic vascular dysfunction. However, little is known whether the berberine treatment could ameliorate the smooth muscle contractility independent of a functional endothelium under hyperglycemia. Furthermore, it remains unknown whether berberine affects the arterial contractility by regulating the intracellular Ca2+ handling in vascular smooth cells (VSMCs) under hyperglycemia.MethodsSprague–Dawley rats were used to establish the diabetic model with a high-fat diet plus injections of streptozotocin (STZ). Berberine (50, 100, and 200 mg/kg/day) were intragastrically administered to control and diabetic rats for 8 weeks since the injection of STZ. The intracellular Ca2+ handling of isolated cerebral VSMCs was investigated by recording the whole-cell L-type Ca2+ channel (CaL) currents, assessing the protein expressions of CaL channel, and measuring the intracellular Ca2+ in response to caffeine. Our results showed that chronic administration of 100 mg/kg/day berberine not only reduced glucose levels, but also inhibited the augmented contractile function of cerebral artery to KCl and 5-hydroxytryptamine (5-HT) in diabetic rats. Furthermore, chronic administration of 100 mg/kg/day berberine significantly inhibited the CaL channel current densities, reduced the α1C-subunit expressions of CaL channel, decreased the resting intracellular Ca2+ ([Ca2+]i) level, and suppressed the Ca2+ releases from RyRs in cerebral VSMCs isolated from diabetic rats. Correspondingly, acute application of 10 μM berberine could directly inhibit the hyperglycemia-induced CaL currents and suppress the hyperglycemia-induced Ca2+ releases from RyRs in cerebral VSMCs isolated from normal control rats.ConclusionsOur study indicated that berberine alleviated the cerebral arterial contractility in the rat model of streptozotocin-induced diabetes via regulating the intracellular Ca2+ handling of smooth muscle cells.

Hyperglycemia and hypertension are considered to be the two leading risk factors for vascular disease in diabetic patients. However, few pharmacologic agents could provide a combinational therapy for controlling hyperglycemia and hypertension at the same time in diabetes. The objectives of this study are to investigate whether berberine treatment could directly reduce blood pressure and identify the molecular mechanism underlying the vascular protection of berberine in diabetic rats. Berberine was intragastrically administered with different dosages of 50, 100 and 200 mg/kg/day to diabetic rats for 8 weeks since the injection of streptozotocin. The endothelium-dependent/-independent relaxation in middle cerebral arteries was investigated. The activity of large-conductance Ca-activated K channel (BK) was investigated by recording whole-cell currents, analyzing single-channel activities and assessing the expressions of α- and β1-subunit at protein or mRNA levels. Results of the study suggest that chronic administration of 100 mg/kg/day berberine not only lowered blood glucose but also reduced blood pressure and improved vasodilation in diabetic rats. Furthermore, berberine markedly increased the function and expression of BK β1-subunit in cerebral vascular smooth muscle cells (VSMCs) isolated from diabetic rats or when exposed to hyperglycemia condition. The present study provided initial evidences that berberine reduced blood pressure and improved vasodilation in diabetic rats by activation of BK channel in VSMCs, which suggested that berberine might provide a combinational therapy for controlling hyperglycemia and blood pressure in diabetes. Furthermore, our work indicated that activation of BK channel might be the underlying mechanism responsible for the vascular protection of berberine in diabetes.

Background: Chemotherapy is the major choice for advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor exon 20 insertion (EGFR ex20ins). The efficacy of pemetrexed-based with other chemotherapy regimens and EGFR ex20ins subtypes in this population has not been well studied. Methods: We screened patients with EGFR ex20ins by next-generation sequencing (NGS) from a large cohort. The clinicopathologic and medical information were collected in advanced NSCLC patients with EGFR ex20ins. We also compared the clinical outcomes among patients with different subtypes of EGFR ex20ins. Results: We retrospectively collected 119 stage IIIB/IV NSCLC patients with EGFR ex20ins from 9142 NSCLC patients across China from June 2013 to December 2018. The subtypes of EGFR ex20ins included

The incidence of epidermal growth factor receptor uncommon mutation (EGFRum) is relatively low and patients harboring EGFRum are resistant to the first-generation tyrosine kinase inhibitors (TKI). However, the mechanism of primary resistance remains unclear. Medical records of 98 patients who had never been treated by TKI and who accepted icotinib treatment were collected and followed. The circulating tumor DNA (ctDNA) were detected and analyzed using the next-generation sequencing (NGS) platform after progression on icotinib. The potential primary resistance mechanism of icotinib was explored. A total of 21 (21.4%) and 48 (49%) patients developed primary and acquired resistance to icotinib, respectively. The median progression-free survival (PFS) of primary resistance patients was 1.8 months (0.5-2.3, 95% CI = 1.50-2.10). Before treatment, 52.4% (11/21) of patients carried S768I, 23.8% (5/21) L861Q, 14.3% (3/21) G719X and 14.3% (3/21) exon 20-ins mutations. Approximately 23.8%(5/21) of patients harbored the combined pattern mutations and 76.2% (16/21) of patients harbored the single pattern mutations. The combined pattern with EGFR classical mutation (EGFRcm) had worse PFS than the combined with EGFRum and single pattern (P < .05). There were 6 (28.57%) patients with acquired EGFR extracellular domain mutation, 5 (23.81%) with BCL2L11 loss (BIM deletion polymorphism), 3 (14.29%) with MET amplification, 1 (4.76%) with ERBB2 amplification, 1 (4.76%) with MYC amplification, 1 (4.76%) with PTEN mutation, 1 (4.76%) with PIK3CA mutation and 3 (14.29%) with unknown status. EGFR extracellular domain mutation, BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN and PIK3CA mutations), MET amplification, ERBB2 amplification or MYC amplification might contribute to molecular mechanisms of primary resistance to icotinib in patients with advanced

The response to icotinib in advanced non‐small cell lung cancers (NSCLC) with EGFR uncommon mutation (EGFRum) is unclear. Here we reported the efficacy and potential resistance mechanism of icotinib in Chinese EGFRum NSCLC patients. Between July 2013 and November 2016, 3117 NSCLC patients were screened for EGFRum in a multi‐center study in China. Circulating tumor DNA (ctDNA) was detected and analyzed using next‐generation sequencing (NGS) after progression from icotinib. The efficacy, safety and the potential resistance mechanism of icotinib were explored. After a median follow‐up of 6.2 months, 69 patients (70.41%) developed disease progression, the objective rate (ORR) and disease control rate (DCR) were 13.27% and 29.59% respectively, and the median progression‐free survival (PFS) was 5.5 months (95% CI: 1.2‐13.0 months). Both complex‐pattern with EGFR classical mutations (EGFRcm) and single‐pattern have better PFS than complex‐pattern without EGFRcm (median PFS was 7.2 (95% CI: 4.65‐9.75), 5.2 (95% CI: 3.24‐7.16) and 3.2 (95% CI: 2.97‐3.44) months, respectively, P < .05); patients harboring S768I mutation had the worst PFS than others (2.0 months, P < .05). Diarrhea was the most frequent side effect (42.9%). Forty‐eight (69.6%) patients developed drug resistance after 3.0 months and 81.2% of them acquired T790M mutation. Better response was observed in complex‐pattern with the EGFRcm group. S768I mutation carriers may not benefit from icotinib. Acquired T790M mutation was common in icotinib‐resistant EGFRum NSCLC patients.