Correlation between dietary inflammation and mortality among hyperlipidemics.

BACKGROUND AND OBJECTIVE: Although the the Dietary Inflammatory Index (DII) serves to be one of the reliable indicator for hyperlipidaemia, there is still uncertainty about its relationship to prognosis in the hyperlipidaemic population. In current study, the DII levels were analyzed in relation to the mortality risk among among the hyperlipidaemic individuals with the aim of determining any prospective correlation. METHODS: 14,460 subjects with hyperlipidaemia from the 10-year (2001-2010) National Health and Nutrition Examination Survey (NHANES) were chosen for this study. The endpoint event for follow-up was all-cause mortality, and subjects were tracked for up to December 31, 2019, or death, whichever occurred first. The tertiles of the DII levels were utilized for categorizing the study population into three groups. Survival curves, Cox proportional hazards regression models, restricted cubic spline (RCS), subgroup and interaction analyses, and sensitivity analyses were employed sequentially for the purpose of evaluating the association of the DII with mortality. RESULTS: 3170 (21.92%) all-cause deaths were recorded during an average 148-month follow-up period. Kaplan-Meier survival curves indicated that the survival rate of participants divided into the low DII group was substantially improved compared to that of those in the higher DII group (log-rank P < 0.001). After controlling for confounders, higher levels of DII were observed to be meaningfully linked to an elevated risk of death, no matter whether DII was specified for the continuous (hazard ratio (HR): 1.06; 95% confidence interval (CI): 1.04-1.08) or the categorical variable (HR: 1.22; 95% CI: 1.11-1.33). The DII and mortality displayed a linear association, according to the RCS. Stratified and sensitivity analyses reinforced the proof that these findings were reliable. CONCLUSION: Among patients with hyperlipidaemia, the risk of death was positively and linearly linked with DII levels.

Shikonin Inhibits Candida albicans Biofilms via the Ras1-cAMP-Efg1 Signalling Pathway.

Objective: To investigate the influence of shikonin (SK) on the formation of Candida albicans biofilms and discuss the possible mechanism. Methods: The inhibition of the formation of C. albicans biofilms by SK was observed by scanning electron microscopy. A silicone film method and a water-hydrocarbon two-phase assay were performed to investigate the effects of SK on cell adhesion. Real-time reverse-transcription polymerase chain reaction was used to analyse the expression of genes related to cell adhesion and Ras1-cyclic adenosine monophosphate (cAMP) - enhanced filamentous growth protein 1 (Efg1) signalling pathway. Finally, the level of cAMP in C. albicans was detected and exogenous cAMP rescue experiment was conducted. Results: The results showed that SK could destroy the typical three-dimensional structure of the biofilms, inhibit cell surface hydrophobicity and cell adhesion, downregulate the expression of Ras1-cAMP-Efg1 signalling pathway-related genes (ECE1, HWP1, ALS3, RAS1, CYR1, EFG1 and TEC1) and effectively reduce the production of key messenger cAMP in the Ras1-cAMP-Efg1 pathway. Meanwhile, exogenous cAMP reversed the inhibitory effect of SK on biofilms formation. Conclusion: Our results suggest that SK exhibits potential anti-C. albicans biofilms effects related to the inhibition of Ras1-cAMP-Efg1 pathway.

Remdesivir powders manufactured by jet milling for potential pulmonary treatment of COVID-19.

Remdesivir is one of the effective drugs proposed for the treatment of coronavirus disease 2019 (COVID-19). However, the study on inhalable regimen is currently limited though COVID-19 is respiratory diseases and infects lung area. This work aims to prepare inhalable remdesivir formulations and verify their effectiveness through in vitro evaluations. Formulations containing different ratios of jet-milled inhalable remdesivir (5, 10, 20,40, and 70%) with excipients were produced and characterized in terms of the particle size distribution, particle morphology, flowability, water content, crystallinity, the water sorption and desorption capabilities, and the aerodynamic performance. Results indicating that drug loading are a vital factor in facilitating the dispersion of remdesivir dry powder, and the ternary excipient plays a negligible role in improving aerosol performance. Besides, the 70% remdesivir with lactose carrier (70% RD-Lac) was physically stable and retain high aerosol performance after conditioned at 40 °C and 75% RH for a month. Therefore, formulation 70% RD-Lac might be recommended as a candidate product for the potential treatment of COVID-19.

C/EBPß enhances efficacy of sorafenib in hepatoblastoma.

Hepatoblastoma (HB) is the predominant hepatic neoplasm in infants and young children. Sorafenib has been used to treat adult and pediatric hepatocellular carcinoma. However, efficacy of monotherapy of sorafenib in HB is not sustained. In this study, we tested a possible combinatory therapy of sorafenib with the CCAAT/enhancer-binding proteins (C/EBP) overexpression in HB cell line. Firstly, we evaluated the expression level of C/EBPß in the patients with HB by analyzing The Cancer Genome Atlas data. Lower level of C/EBPß was observed in tumor tissues in comparison with matched normal tissues. Next, we observed that combination of sorafenib and C/EBPß overexpression led to dramatic growth and migration inhibition of live tumor cells which implied promising probability for clinical trial. Mechanistically, C/EBPß which can be downregulated by Ras v12, augmented messenger RNA and protein levels of p53. These data suggested that a combination of sorafenib and C/EBPß overexpression inhibited tumor growth synergistically and provided a promising approach to treat HB.

NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast.

Invasive fungal diseases are a leading cause of mortality among immunocompromised populations. Treatment is notoriously difficult due to the limited number of antifungal drugs as well as the emergence of drug resistance. Tamoxifen (TAM), a selective estrogen receptor modulator frequently used for the treatment of breast cancer, has been found to have antifungal activities and may be a useful addition to the agents used to treat fungal infectious diseases. However, the molecular mechanisms underlying its antifungal actions remain obscure. Here, we screened for mutations that confer sensitivity to azole antifungal drugs by using the fission yeast Schizosaccharomyces pombe as a model and isolated a mutant with a mutation in cls1 (ccr1), an allele of the gene encoding the NADPH-cytochrome P450 reductase Ccr1. We found that strains with a deletion of the ccr1+ gene exhibited hypersensitivities to various drugs, including antifungal drugs (azoles, terbinafine, micafungin), the immunosuppressor FK506, and the anticancer drugs TAM and 5-fluorouracil (5-FU). Unexpectedly, the overexpression of Ccr1 caused yeast cell resistance to TAM but not the other drugs tested here. Additionally, strains with a deletion of Ccr1 displayed pleiotropic phenotypes, including defects in cell wall integrity and vacuole fusion, enhanced calcineurin activity, as well as increased intracellular Ca2+ levels. Overexpression of the constitutively active calcineurin suppressed the drug-sensitive phenotypes of the Δccr1 cells. Notably, TAM treatment of wild-type cells resulted in pleiotropic phenotypes, similar to those of cells lacking Ccr1. Furthermore, TAM inhibited Ccr1 NADPH-cytochrome P450 reductase activities in a dose-dependent manner. Moreover, TAM treatment also inhibited the NADPH-cytochrome P450 reductase activities of Candida albicans and resulted in defective cell wall integrity. Collectively, our findings suggest that Ccr1 is a novel target of TAM and is involved in the antifungal activity of TAM by regulating cell wall integrity in fission yeast.

Inhibitory effect of Shikonin on Candida albicans growth.

Our study showed that Shikonin (SK) could provide an action against almost all Candida albicans isolates tested. More importantly, to some Fluconazole (FCZ)-resistant Candida albicans, the action of SK (MIC(80) value 4 µg/mL) was shown to be >16 times higher than that of FCZ (MIC(80) >64 µg/mL). To clarify the mechanism underlying this action, we performed a comparative study in untreated control C. albicans and C. albicans treated with SK. In this study, we found that SK treatment increased generation of endogenous reactive oxygen species (ROS) and decreased mitochondrial membrane potential. Furthermore, anti-oxidants N-acetylcysteine (NAC) and glutathione (GSH) could reduce the antifungal activity of SK significantly in C. albicans. Our analyses also identified 9 differentially expressed genes, which were related to glycolysis-related genes (CDC19 and HXK2), fermentation-related genes (ALD5 and ADH1), antioxidant defense-related genes (SOD2 and SOD5), thioredoxin reductase-related gene (TRR1), mitochondrial respiratory electron transport chain-related gene (MRF1) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidoreductase-related gene (EBP1). These results suggest that mitochondrial aerobic respiration shift and endogenous ROS augmentation contribute to the action of SK against C. albicans.