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To investigate the preventive effect of Volvariella volvacea fruit body polypeptides (VVFP) on acute alcoholic liver injury in mice and its influence on the intestinal microbiota, VVFP (1–3 kDa molecular mass) which had been previously obtained by our laboratory was given by gavage to mice. The mice were randomly divided into six groups: blank control, model, positive control, low-dose VVFP, moderate-dose VVFP and high-dose VVFP. Serum indexes, liver indexes and histopathological sections were compared among these groups, and 16S rDNA gene high-throughput sequencing was used to analyze the diversity of the intestinal microflora and the relative abundance at the phyla and genus levels in each sample. Results showed that VVFP significantly reduced the levels of triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in the serum and malondialdehyde (MDA) in the liver, and decreased the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and significantly increased the activities of alcohol dehydrogenase (ADH), total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) in the liver. The 16S rRNA sequencing showed that VVFP significantly reduced the α-diversity indices Chao1 and observed species, increased the Shannon index, and regulated the abundance of Bacteroides, Firmicutes, Streptomyces, Lactobacillus and Vibrio, thereby reducing liver damage. In conclusion, VVFP can reduce alcoholic liver injury, which will provide a theoretical basis for the application of VVFP in the field of functional foods.

Potassium (K+) is the main intracellular cation in the body. Elevated K+ levels (hyperkalemia) increase the risk of life‐threatening arrhythmias and sudden cardiac death. However, the details of K+ homeostasis and the effects of orally administered K+ binders, such as sodium zirconium cyclosilicate (SZC), on K+ redistribution and excretion in patients remain incompletely understood. We built a fit‐for‐purpose systems pharmacology model to describe K+ homeostasis in hyperkalemic subjects and capture serum K+ (sK+) dynamics in response to acute and chronic administration of SZC. The resulting model describes K+ distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K+, and K+–SZC binding and excretion in the GI tract. The model, which was fit to time‐course sK+ data for individual patients from two clinical trials, accounts for bolus delivery of K+ in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose–response and inform clinical trial design in two new applications: emergency lowering of sK+ in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end‐stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit‐for‐purpose, model‐informed drug development after initial approval of a drug. [ABSTRACT FROM AUTHOR]

Background: Adenosine receptor type 2 (A2AR) inhibitor, AZD4635, has been shown to reduce immunosuppressive adenosine effects within the tumor microenvironment (TME) and to enhance the efficacy of checkpoint inhibitors across various syngeneic models. This study aims at investigating anti-tumor activity of AZD4635 alone and in combination with an anti-PD-L1-specific antibody (anti-PD-L1 mAb) across various TME conditions and at identifying, via mathematical quantitative modeling, a therapeutic combination strategy to further improve treatment efficacy. Methods: The model is represented by a set of ordinary differential equations capturing: 1) antigen-dependent T cell migration into the tumor, with subsequent proliferation and differentiation into effector T cells (Teff), leading to tumor cell lysis; 2) downregulation of processes mediated by A2AR or PD-L1, as well as other immunosuppressive mechanisms; 3) A2AR and PD-L1 inhibition by, respectively, AZD4635 and anti-PD-L1 mAb. Tumor size dynamics data from CT26, MC38, and MCA205 syngeneic mice treated with vehicle, anti-PD-L1 mAb, AZD4635, or their combination were used to inform model parameters. Between-animal and between-study variabilities (BAV, BSV) in treatment efficacy were quantified using a non-linear mixed-effects methodology. Results: The model reproduced individual and cohort trends in tumor size dynamics for all considered treatment regimens and experiments. BSV and BAV were explained by variability in T cell-to-immunosuppressive cell (ISC) ratio; BSV was additionally driven by differences in intratumoral adenosine content across the syngeneic models. Model sensitivity analysis and model-based preclinical study simulations revealed therapeutic options enabling a potential increase in AZD4635-driven efficacy; e.g. , adoptive cell transfer or treatments affecting adenosine-independent immunosuppressive pathways. Conclusions: The proposed integrative modeling framework quantitatively characterized the mechanistic activity of AZD4635 and its potential added efficacy in therapy combinations, across various immune conditions prevailing in the TME. Such a model may enable further investigations, via simulations, of mechanisms of tumor resistance to treatment and of AZD4635 combination optimization strategies. [ABSTRACT FROM AUTHOR]