Smedegaardcooke1610

Theabrownin (TB), a natural compound present in the fresh leaves of green tea, is a potential antitumor agent. However, so far whether and how TB affects glioma is unclear. In this study, we investigated the effect of TB on astroglioma and oligodendroglioma cells. Surprisingly, TB significantly reduced the viabilities of HOG and U251 cells in a dose-dependent manner, which was accompanied by the upregulation of active-Casp-3, Bax, and PTEN; meanwhile, the antiapoptotic gene Bcl-2 was downregulated. In addition, TB treatment induced cell cycle arrest at the G1 and G2/M phases in HOG and U251 cells, respectively. TB treatment caused the downregulating of c-myc, cyclin D, CDK2, and CDK4 and upregulating of p21 and p27 in the HOG cell, while TB increased P53, p21, and p27 levels and decreased the levels of cell cycle regulator proteins such as CDK and cyclin A/B in the U251 cells. Therefore, the c-myc- and P53-related mechanisms were proposed for cell cycle arrest in these two glioma cell lines, respectively. Overall, our findings indicated that TB could be a novel candidate drug for the treatment of gliomas.The antifungal agent voriconazole (VRC) exhibits extreme inter-individual and intra-individual variation in terms of its clinical efficacy and toxicity. Inflammation, as reflected by C-reactive protein (CRP) concentrations, significantly affects the metabolic ratio and trough concentrations of voriconazole. Bacteroides fragilis (B. fragilis) is an important component of the human intestinal microbiota. Clinical data have shown that B. fragilis abundance is comparatively higher in patients not presenting with adverse drug reactions, and inflammatory cytokine (IL-1β) levels are negatively correlated with B. fragilis abundance. B. fragilis natural product capsular polysaccharide A (PSA) prevents various inflammatory disorders. We tested the hypothesis that PSA ameliorates abnormal voriconazole metabolism by inhibiting inflammation. Germ-free animals were administered PSA intragastrically for 5 days after lipopolysaccharide (LPS) stimulation. Their blood and liver tissues were collected to measure VRC concentrations. PSA administration dramatically improved the resolution phase of LPS-induced hepatic VRC metabolism and inflammatory factor secretion. It reversed inflammatory lesions and alleviated hepatic pro-inflammatory factor secretion. Both in vitro and in vivo data demonstrate that PSA reversed LPS-induced IL-1β secretion, downregulated the TLR4/NF-κB signaling pathway and upregulated CYP2C19 and P-gp. To the best of our knowledge, this study is the first to show that PSA from the probiotic B. fragilis ameliorates abnormal voriconazole metabolism by inhibiting TLR4-mediated NF-κB transcription and regulating drug metabolizing enzyme and transporter expression. Thus, PSA could serve as a clinical adjunct therapy.Biochanin A (BCA) is a natural organic compound of the class of phytochemicals known as flavonoids and isoflavone subclass predominantly found in red clover (Trifolium pratense). It has anti-inflammatory activity and some pro-resolving actions, such as neutrophil apoptosis. However, the effect of BCA in the resolution of inflammation is still poorly understood. In this study, we investigated the effects of BCA on the neutrophilic inflammatory response and its resolution in a model of antigen-induced arthritis. Male wild-type BALB/c mice were treated with BCA at the peak of the inflammatory process (12 h). BCA decreased the accumulation of migrated neutrophils, and this effect was associated with reduction of myeloperoxidase activity, IL-1β and CXCL1 levels, and the histological score in periarticular tissues. Joint dysfunction, as seen by mechanical hypernociception, was improved by treatment with BCA. Cynarin in vivo The resolution interval (Ri) was also quantified, defining profiles of acute inflammatory parameters that include the amplitude and duration of the inflammatory response monitored by the neutrophil infiltration. BCA treatment shortened Ri from ∼23 h observed in vehicle-treated mice to ∼5.5 h, associated with an increase in apoptotic events and efferocytosis, both key steps for the resolution of inflammation. These effects of BCA were prevented by H89, an inhibitor of protein kinase A (PKA) and G15, a selective G protein-coupled receptor 30 (GPR30) antagonist. In line with the in vivo data, BCA also increased the efferocytic ability of murine bone marrow-derived macrophages. Collectively, these data indicate for the first time that BCA resolves neutrophilic inflammation acting in key steps of the resolution of inflammation, requiring activation of GPR30 and via stimulation of cAMP-dependent signaling.The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.