Cholesterol has been proposed to play a critical role in regulating neurotransmitter release and synaptic plasticity. The neuronal porosome/fusion pore, the secretory machinery at the nerve terminal, is a 12−17 nm cup-shaped lipoprotein structure composed of cholesterol and a number of proteins, among them calcium channels, and the t-SNARE proteins syntaxin-1 and SNAP-25. During neurotransmission, synaptic vesicles dock and fuse at the porosome via interaction of their v-SNARE protein with t-SNAREs at the porosome base. Membrane-associated neuronal t-SNAREs interact in a circular array with liposome-associated neuronal v-SNARE, to form the t-/v-SNARE ring complex. The SNARE complex along with calcium is required for the establishment of continuity between opposing bilayers. Here we show that although cholesterol is an integral component of the neuronal porosome and is required for maintaining its physical integrity and function, it has no influence on the conformation of the SNARE ring complex.
Taselisib is a potent and selective tumor growth inhibitor through PI3K
pathway suppression. Thirty-four patients with locally advanced or metastatic
solid tumors were treated (phase I study, modified 3+3 dose escalation;
5 cohorts; 3-16 mg taselisib once daily capsule). Taselisib pharmacokinetics
were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent,
treatment-related adverse events included diarrhea, hyperglycemia, decreased
appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels,
dose limiting toxicities (DLT) were observed, with an accumulation of
higher-grade adverse events after the cycle 1 DLT assessment window.
Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient
tumor samples, consistent with preclinical PIK3CA-mutant tumor
xenograft models. Confirmed response rate was 36% for
PIK3CA-mutant tumor patients with measurable disease (5/14:
4 breast cancer, [3 patients at 12 mg]; 1 NSCLC) where responses
started at 3 mg, and 0% in patients with tumors without known
PIK3CA hotspot mutations (0/15).
The aim of this study was to explore whether rhein could enhance the effects of pemetrexed (PTX) on the therapy of non-small-cell lung cancer (NSCLC) and to clarify the associated molecular mechanism. Our study shows that rhein in combination with PTX could obviously increase the systemic exposure of PTX in rats, which would be mediated by the inhibition of organic anion transporters (OATs). Furthermore, the toxicity of PTX was significantly raised by rhein in A549 cells in a concentration-dependent manner.Concomitant administration of rhein and PTX-induced cell apoptosis compared with PTX alone in flow cytometry assays, which was further validated by the protein expressions of the apoptotic markers B-cell lymphoma-2/Bcl-2-associated x (Bcl-2/Bax) and Cleaved-Caspase3 (Cl-Caspase3). Meanwhile, the results of monodansylcadaverine (MDC) dyeing experiments showed that PTX-induced autophagy could be enhanced by combination therapy with rhein in A549 cells. Western blot analysis indicated that the synergistic effect of rhein on PTX-mediated autophagy may be interrelated to PI3K-AKT-mTOR pathway inhibition and to the enhancement of p-AMPK and light chain 3-Ⅱ (LC3-Ⅱ) protein levels.From these findings, it could be surmised that rhein enhanced the antitumor activity of PTX through influencing autophagy and apoptosis by modulating the PI3K-AKT-mTOR pathway and Bcl-2 family of proteins in A549 cells. Our findings demonstrated that the potential application of rhein as a candidate drug in combination with PTX is promising for treatment of the human lung cancer.
P2Y receptors have been implicated in the calcium mobilization by the response to neuroexcitatory substances in neurons and astrocytes, but little is known about P2Y receptors in microglia cells. In the present study, the effects of ADP on the intracellular calcium concentration ([Ca(2+)]i) in cultured dorsal spinal cord microglia were detected with confocal laser scanning microscopy using fluo-4/AM as a calcium fluorescence indicator that could monitor real-time alterations of [Ca(2+)]i. Here we show that ADP (0.01-100 μM) causes a rapid increase in [Ca(2+)]i with a dose-dependent manner in cultured microglia. The action of ADP on [Ca(2+)]i was significantly blocked by MRS2211 (a selective P2Y13 receptor antagonist), but was unaffected by MRS2179 (a selective P2Y1 receptor antagonist) or MRS2395 (a selective P2Y12 receptor antagonist), which suggest that P2Y13 receptor may be responsible for ADP-evoked Ca(2+) mobilization in cultured microglia. P2Y13-evoked Ca(2+) response can be obviously inhibited by BAPTA-AM and U-73122, respectively. Moreover, removal of extracellular Ca(2+) (by EGTA) also can obvious suppress the Ca(2+) mobilization. These results means both intracellular calcium and extracellular calcium are potentially important mechanisms in P2Y13 receptor-evoked Ca(2+) mobilization. However, P2Y13 receptor-evoked Ca(2+) response was not impaired after CdCl2 and verapamil administration, which suggest that voltage-operated Ca(2+) channels may be not related with P2Y13-evoked Ca(2+) response. In addition, Ca(2+) mobilization induced by ADP was abolished by different store-operated Ca(2+) channels (SOCs) blocker, 2-APB (50 μM) and SKF-96365 (1 mM), respectively. These observations suggest that the activation of P2Y13 receptor might be involved in the effect of ADP on [Ca(2+)]i in cultured dorsal spinal cord microglia. Furthermore, our results raise a possibility that P2Y13 receptor activation causes Ca(2+) release from Ca(2+) store, which leads to the opening of SOCs.
TPS1119 Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and > 300 patients have been enrolled. Clinical trial information: NCT02340221.
The incidence of abnormal glucose metabolism in patients with rheumatoid arthritis was considerably higher than the general population. The persistent systemic inflammatory state in rheumatoid arthritis might be associated with the glucose metabolism dysfunction. In this context, insulin resistance, islet β cell apoptosis, inflammatory cytokines, and other aspects which were linked with abnormal glucose metabolism in rheumatoid arthritis were reviewed. This review will be helpful in understanding the abnormal glucose metabolism mechanism in patients with rheumatoid arthritis and might be conducive to finding an effective treatment.
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