Enhanced expression of beta cell Ca(v)3.1 channels impairs insulin release and glucose homeostasis

Voltage-gated calcium 3.1 (Ca(v)3.1) channels are absent in healthy mouse beta cells and mediate minor T-type Ca2+ currents in healthy rat and human beta cells but become evident under diabetic conditions. Whether more active Ca(v)3.1 channels affect insulin secretion and glucose homeostasis remains enigmatic. We addressed this question by enhancing de novo expression of beta cell Ca(v)3.1 channels and exploring the consequent impacts on dynamic insulin secretion and glucose homeostasis as well as underlying molecular mechanisms with a series of in vitro and in vivo approaches. We now demonstrate that a recombinant adenovirus encoding enhanced green fluorescent protein-Ca(v)3.1 subunit (Ad-EGFP-Ca(v)3.1) efficiently transduced rat and human islets as well as dispersed islet cells. The resulting Ca(v)3.1 channels conducted typical T-type Ca2+ currents, leading to an enhanced basal cytosolic-free Ca2+ concentration ([Ca2+](i)). Ad-EGFP-Ca(v)3.1-transduced islets released significantly less insulin under both the basal and first phases following glucose stimulation and could no longer normalize hyperglycemia in recipient rats rendered diabetic by streptozotocin treatment. Furthermore, Ad-EGFP-Ca(v)3.1 transduction reduced phosphorylated FoxO1 in the cytoplasm of INS-1E cells, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III. These effects were prevented by inhibiting Ca(v)3.1 channels or the Ca2+ -dependent phosphatase calcineurin. Enhanced expression of beta cell Ca(v)3.1 channels therefore impairs insulin release and glucose homeostasis by means of initial excessive Ca2+ influx, subsequent activation of calcineurin, consequent dephosphorylation and nuclear retention of FoxO1, and eventual FoxO1-mediated down-regulation of beta cell exocytotic proteins. The present work thus suggests an elevated expression of Ca(v)3.1 channels plays a significant role in diabetes pathogenesis

Inositol hexakisphosphate primes syndapin I/PACSIN 1 activation in endocytosis

Endocytosis is controlled by a well-orchestrated molecular machinery, where the individual players as well as their precise interactions are not fully understood. We now show that syndapin I/PACSIN 1 is expressed in pancreatic β cells and that its knockdown abrogates β cell endocytosis leading to disturbed plasma membrane protein homeostasis, as exemplified by an elevated density of L-type Ca(2+) channels. Intriguingly, inositol hexakisphosphate (InsP(6)) activates casein kinase 2 (CK2) that phosphorylates syndapin I/PACSIN 1, thereby promoting interactions between syndapin I/PACSIN 1 and neural Wiskott–Aldrich syndrome protein (N-WASP) and driving β cell endocytosis. Dominant-negative interference with endogenous syndapin I/PACSIN 1 protein complexes, by overexpression of the syndapin I/PACSIN 1 SH3 domain, decreases InsP(6)-stimulated endocytosis. InsP(6) thus promotes syndapin I/PACSIN 1 priming by CK2-dependent phosphorylation, which endows the syndapin I/PACSIN 1 SH3 domain with the capability to interact with the endocytic machinery and thereby initiate endocytosis, as exemplified in β cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04305-2

Development of novel 9-O-substituted-13-octylberberine derivatives as potential anti-hepatocellular carcinoma agents

A series of novel 9-O-substituted-13-octylberberine derivatives were designed, synthesised and evaluated for their anti-hepatocellular carcinoma (HCC) activities. Compound 6k showed the strongest activity against three human hepatoma cells including HepG2, Sk-Hep-1 and Huh-7 cells with IC50 values from 0.62 to 1.69 μM, which were much superior to berberine (IC50 >50 μM). More importantly, 6k exhibited lower cytotoxicity against normal hepatocytes L-02 with good lipid-water partition properties. The mechanism studies revealed that 6k caused G2/M phase arrest of the cell cycle, stabilised G-quadruplex DNA, and induced apoptosis via a mitochondrial apoptotic pathway. Finally, the invivo anti-HCC activity of 6k was validated in the H22 liver cancer xenograft mouse model. Collectively, the current study would provide a new insight into the discovery of novel, safe and effective anti-HCC agents

A case-control study on risk factors of breast cancer in China

Introduction: To screen the risk factors associated with breast cancer among Chinese women in order to evaluate the individual risk of developing breast cancer among women in China. Material and methods: A case-control study on 416 breast cancer patients and 1156 matched controls was conducted in 14 hospitals in 8 provinces of China in 2008. Controls were age- and region-matched to the cases. Clinicians conducted in-person interviews with the subjects to collect information on demographics and suspected risk factors for breast cancer that are known worldwide. Conditional logistic regression was used to derive odds ratios (OR) and 95% confidence intervals (CI) for the associations between risk factors and breast cancer. Results: Compared with matched controls, women with breast cancer were significantly more likely to have higher body mass index (BMI, OR = 4.07, 95% CI; 2.98-5.55), history of benign breast disease (BBD) biopsy (OR = 1.68, 95% CI; 1.19-2.38), older age of menarche (AOM) (OR = 1.41, 95% CI: 107-187), stress anticipation (SA), for grade 1-4, OR = 2.15, 95% CI; 1.26-3.66; for grade 5-9, OR = 3.48, 95% CI; 2.03-5.95) and menopause (OR = 2.22, 95% CI: 1.50-3.282) at the level of p < 0.05. Family history of breast cancer (FHBC) in first-degree relatives (OR = 1.66, 95% CI; 0.77-3.59) and use of oral contraceptives (OC) (OR = 1.59, 95% CI; 0.83-3.05) were associated with an increased risk of breast cancer at the level of p < 0.20. Conclusions: Our results showed that BMI, history of BBD biopsy, older AOM, SA and menopause were associated with increased risk of breast cancer among Chinese women. The findings derived from the study provided some suggestions for population-based prevention and control of breast cancer in China.Medicine, General & InternalSCI(E)15ARTICLE2303-309

Synthesis and Bio-Activity Evaluation of Scutellarein as a Potent Agent for the Therapy of Ischemic Cerebrovascular Disease

Scutellarein, the main metabolite of scutellarin in vivo, has relatively better solubility, bioavailability and bio-activity than scutellarin. However, it is very difficult to obtain scutellarein in nature compared with scutellarin. Therefore, the present study focused on establishing an efficient route for the synthesis of scutellarein by hydrolyzing scutellarin. The in vitro antioxidant activities of scutellarein were evaluated by measuring its scavenging capacities toward DPPH, ABTS+•, •OH free radicals and its protective effect on H2O2-induced cytotoxicity in PC12 cells using MTT assay method. The results showed that essential point to the synthesis was the implementation of H2SO4 in 90% ethanol in N2 atmosphere; scutellarein had stronger antioxidant activity than scutellarin. The results have laid the foundation for further research and the development of scutellarein as a promising candidate for ischemic cerebrovascular disease

Worshipers and Warriors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68415/2/10.1177_009770047600200102.pd

Anticancer Therapy-Induced Atrial Fibrillation: Electrophysiology and Related Mechanisms

Some well-established immunotherapy, radiotherapy, postoperation, anticancer drugs such as anthracyclines, antimetabolites, human epidermal growth factor receptor 2 blockers, tyrosine kinase inhibitors, alkylating agents, checkpoint inhibitors, and angiogenesis inhibitors, are significantly linked to cardiotoxicity. Cardiotoxicity is a common complication of several cancer treatments. Some studies observed complications of cardiac arrhythmia associated with the treatment of cancer, including atrial fibrillation (AF), supraventricular arrhythmias, and cardiac repolarization abnormalities. AF increases the risk of cardiovascular morbidity and mortality; it is associated with an almost doubled risk of mortality and a nearly 5-fold increase in the risk of stroke. The occurrence of AF is also usually researched in patients with advanced cancer and those undergoing active cancer treatments. During cancer treatments, the incidence rate of AF affects the prognosis of tumor treatment and challenges the treatment strategy. The present article is mainly focused on the cardiotoxicity of cancer treatments. In our review, we discuss these anticancer therapies and how they induce AF and consequently provide information on the precaution of AF during cancer treatment