Optimization of clofibrate with O-desmethyl anetholtrithione lead to a novel hypolipidemia compound with hepatoprotective effect.

Oxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less liver damage, the structure of clofibrate was optimized by O-desmethyl anetholtrithione and got the target compound clofibrate-O-desmethyl anetholtrithione (CF-ATT). CF-ATT significantly reduced the levels of plasma triglycerides (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR-1339. In addition, CF-ATT has a significantly protective effect on the liver compared with CF. The liver weight and liver coefficient were reduced. The hepatic function indexes were also decreased, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Histopathological examination of the liver revealed that inflammatory cell infiltration, nuclear degeneration, cytoplasmic loosening and hepatocyte necrosis were ameliorated by administration with CF-ATT. The hepatoprotective mechanism showed that CF-ATT significantly up-regulated Nrf2 and HO-1 protein expression and down-regulated p-NF-κB P65 expression in the liver. CF-ATT has obviously antioxidant and anti-inflammatory activity. These findings suggested that CF-ATT has significant hypolipidemia activity and exact hepatoprotective effect possibly through the Nrf2/NF-κB-mediated signal pathway.

Which Is More Suitable for First-Line Treatment of Extensive-Stage Small Cell Lung Cancer, PD-L1 Inhibitors Versus PD-1 Inhibitors? A Systematic Review and Network Meta-Analysis.

BACKGROUND: In this network meta-analysis (NMA), the efficiency and safety of PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy were compared in the first-line therapy of patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: We searched research databases, conference abstracts, and trial registries and subsequently chose relevant studies and extracted dates. The NMA was conducted to estimate the efficiency and safety of the PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy on overall survival (OS), progression-free survival (PFS), overall remission rate (ORR), and adverse events (AEs). Studies were assessed for quality. Subgroup analyses were used to evaluate study heterogeneity. RESULTS: We included six randomized trials with a total of 3163 patients. Direct comparisons showed that patients who received either PD-1 inhibitors + chemotherapy (HR: 0.71, 95% CI: 0.57-0.87) or PD-L1 inhibitors + chemotherapy (HR: 0.74, 0.61-0.89) demonstrated significantly longer OS than those who received placebo + chemotherapy. The results of the NMA showed that no significant differences in OS (HR 0.96 95% CI: 0.72-1.3), PFS (HR 0.83, 95% CI: 0.51-1.4), and ORR (OR 1.3 95% CI: 0.66-2.5) were observed for PD-1 inhibitors + chemotherapy compared with PD-L1 inhibitors + chemotherapy, but the Bayesian ranking revealed that patients receiving PD-1 inhibitors + chemotherapy tended to have longer OS, PFS benefit, and better treatment response than patients receiving PD-L1 inhibitors + chemotherapy. In terms of safety, no significant difference was observed in their safety profiles. CONCLUSION: In comparison to placebo + chemotherapy, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy significantly improved survival for ES-SCLC. According to the available data, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy had equivalent efficacy and safety; however, the level of evidence of this type of comparison is limited.

Radioactivity research in mosses from typical Karst Regions in Leye Tiankeng, Southern China.

Radionuclides in environmental ecosystems have ecotoxicity and health impact on human and environment, so radioactive contamination has always been one of the global concerns. This study mainly focused on the radioactivity of mosses collected from the Leye Tiankeng Group in Guangxi. The activities of 239+240Pu measured by SF-ICP-MS and 137Cs measured by HPGe in moss and soil samples are as follows: 0-2.29 Bq/kg in mosses and 1.5-11.9 Bq/kg in soils for 137Cs, and 0.025-0.25Bq/kg in mosses and 0.07-0.51Bq/kg in soils for 239+240Pu. The range of 240Pu/239Pu atom ratios (0.201 in mosses and 0.184 in soils) and 239+240Pu/137Cs activity ratios (0.128 in mosses and 0.044 in soils) indicated that the 137Cs and 239+240Pu in study area were mainly contributed by global fallout. 137Cs and 239+240Pu showed similar distribution in soils. However, their behaviors in mosses were quite different due to the differences in the growth environment of mosses. The transfer factors of 137Cs and 239+240Pu from soil to moss varied in different growth stages and specific environments. A weak positive correlation among 137Cs, 239+240Pu in mosses and soil-derived radionuclides suggested that resettlement was predominant here. The negative correlation between 7Be, 210Pb and soil-derived radionuclides indicated that 7Be and 210Pb came from atmospheric components, while the weak correlation between them suggested that their specific sources were different. The Cu and Ni were moderately enriched in mosses here due to the use of agricultural fertilizers, At the same time, Zn was at a high level in the Lilang area, where transportation was more developed.

Monomeric C-reactive protein evokes TCR Signaling-dependent bystander activation of CD4+ T cells.

Bystander activation of T cells is defined as induction of effector responses by innate cytokines in the absence of cognate antigens and independent of T cell receptor (TCR) signaling. Here we show that C-reactive protein (CRP), a soluble pattern-recognition receptor assembled noncovalently by five identical subunits, can instead trigger bystander activation of CD4 + T cells by evoking allosteric activation and spontaneous signaling of TCR in the absence of cognate antigens. The actions of CRP depend on pattern ligand-binding induced conformational changes that result in the generation of monomeric CRP (mCRP). mCRP binds cholesterol in plasma membranes of CD4 + T cells, thereby shifting the conformational equilibrium of TCR to the cholesterol-unbound, primed state. The spontaneous signaling of primed TCR leads to productive effector responses manifested by upregulation of surface activation markers and release of IFN-γ. Our results thus identify a novel mode of bystander T cell activation triggered by allosteric TCR signaling, and reveal an interesting paradigm wherein innate immune recognition of CRP transforms it to a direct activator that evokes immediate adaptive immune responses.

S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway.

Cell senescence deters the activation of various oncogenes. Induction of senescence is, therefore, a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study, we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells. S1PR1 deletion promoted ovarian cancer cell senescence and sensitized ovarian cancer cells to cisplatin chemotherapy. Exposure of ovarian cancer cells to sphingosine-1-phosphate (S1P) increased the expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased the expression of large tumor suppressor 1/2 (LATS1/2), and induced phosphorylation of Yes-associated protein (p-YAP). Opposite results were obtained in S1PR1 knockout cells following pharmacological inhibition. After silencing LATS1/2 in S1PR1-deficient ovarian cancer cells, senescence was suppressed and S1PR1 expression was increased concomitantly with YAP expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.