Eicosanoid Metabolomic Profile of Remdesivir Treatment in Rat Plasma by High-Performance Liquid Chromatography Mass Spectrometry.

Remdesivir, a nucleotide analog prodrug, has displayed pharmacological activity against SARS-CoV-2. Recently, eicosanoids are widely involved in regulating immunity and inflammation for COVID-19 patients. Rats were intravenously administered remdesivir at a dose of 5 mg/kg, and series of blood samples were collected before and after treatment. Targeted metabolomics regarding the eicosanoid profile were investigated and quantitated simultaneously using the previously reported reliable HPLC-MS/MS method. Additionally, interplay relationship between metabolomics and pharmacokinetic parameters was performed using the Pearson correlation analysis and PLS model. For the longitudinal metabolomics of remdesivir, metabolic profiles of the same rat were comparatively substantial at discrete sampling points. The metabolic fingerprints generated by individual discrepancy of rats were larger than metabolic disturbance caused by remdesivir. As for the transversal metabolomics, the prominent metabolic profile variation was observed between the baseline and treatment status. Except for TXB2, the inflammatory- and immunology-related eicosanoids of resolvin D2, 5-HEPE, 5-HETE, and DHA were significantly disturbed and reduced after single administration of remdesivir (p < 0.05, p < 0.001). Moreover, the metabolite of PGE2 correlated with GS-441524 (active metabolite of remdesivir) concentration and pharmacokinetic parameters of Cmax, AUC0-t, AUC0-infinity, and CL significantly. Eicosanoid metabolic profiles of remdesivir at both longitudinal and transversal levels were first revealed using the robust HPLC-MS/MS method. This initial observational eicosanoid metabolomics may lighten the therapy for fighting COVID-19 and further provide mechanistic insights of SARS-CoV-2 virus infection.

HSD3B1 variant and androgen-deprivation therapy outcome in prostate cancer.

OBJECTIVE: Rate-limiting enzyme 3b-hydroxysteroid dehydrogenase type 1 (3ßHSD1) encoded by HSD3B1 catalyzes the transition of dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT). The HSD3B1 (1245C) variant renders 3bHSD1 of resistant to ubiquitination and degradation, leading to a large amount of protein accumulation in the cell. Multiple clinical studies have shown that this mutation was correlated with resistance to androgen-deprivation therapy in prostate cancer. However, the results were not consistent depending on different treatment strategy and in some researches, the number of observed cases was relatively small. METHODS: To determine the effects of HSD3B1 (1245C) variant on resistance to androgen-deprivation therapy in prostate cancer, we performed a meta-analysis of the available literature. Electronic database searches identified appropriately designed studies that detected HSD3B1 in prostate cancer. We conducted a systematic search of studies in the following databases: PubMed, and EMBASE published until August 10, 2020 using the following search terms: (HSD3B1 AND ((((prostate cancer) OR prostatic neoplasm) OR prostatic carcinoma) OR prostatic cancer). RESULTS: Eight researches were included in this research. The result validated that the HSD3B1 (1245C) variant allele was associated with a shorter PFS (HR, 1.97; 95% CI, 1.39-2.79; P = 0.0001) (homozygous wild-type group) in men with prostate cancer when treated with ADT, however, a higher PFS (HR, 0.68; 95% CI, 0.48-0.96; P = 0.03) when treated with ADT and CYP17A1 inhibitor. CONCLUSION: The HSD3B1 (1245C) variant is a predictor of ADT plus CYP17A1 inhibitor response in prostate cancer.

Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study.

BACKGROUND: This study was planned to investigate the association betweenhuman cytomegalovirus (HCMV) infection and gastrointestinal cancer (GIC) risk, by undertaking a meta-analysis and case-control cross-sectional study. SUMMARY: A cross-sectional study analysis of 160 GIC patients and 100 control subjects indicated significantly higher HCMV prevalence in GIC patients based on the HCMV IgM test. However, a similar analysis based on an IgG test revealed no significant relationship. Further meta-analysis of 11 studies, including 1,044 patients and 991 healthy subjects, displayed HCMV infection as an important risk factor for not only colorectal cancer occurrence and development based on a HCMV DNA test, but also for GIC based on a HCMV IgM test. However, the IgG test again displayed no significant relationship between HCMV infection and GIC occurrence. Key Message: Overall, our study revealed that HCMV infection is associated with an increased GIC risk. However, additional studies are warranted to elucidate the molecular mechanism underlying this association.

Curcumin inhibits the formation of atherosclerosis in ApoE-/- mice by suppressing cytomegalovirus activity in endothelial cells.

BACKGROUND: Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells. AIMS: This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro. MATERIALS AND METHODS: Cur (0.5, 1, and 2 µM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE-/- mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo. KEY FINDINGS: As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments. SIGNIFICANCE: This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.

(5-Bromo-2-hy-droxy-phen-yl)(4-propyl-cyclo-hex-yl)methanone.

In the title compound, C(16)H(21)BrO(2), the cyclo-hexane ring adopts a chair conformation. The hy-droxy and carbonyl groups are involved in an intra-molecular O-H⋯O hydrogen bond. In the crystal, weak C-H⋯O inter-actions link the mol-ecules into zigzag chains along [010].