Although the biological processes of organism under hypoxic stress had been elucidated, the whole physiological changes of Saccharomyces cerevisiae are still unclear. In this work, we investigated the changes of biological process of S. cerevisiae under hypoxia by the methods of transcriptomics, proteomics, metabolomics, and bioinformatics. The results showed that the expression of a total of 1017 mRNA in transcriptome, 213 proteins in proteome, and 51 metabolites in metabolome had been significantly changed between the hypoxia and normoxia conditions. Moreover, based on the integration of system-omics data, we found that the carbohydrate, amino acids, fatty acid biosynthesis, lipid metabolic pathway, and oxidative phosphorylation were significantly changed in hypoxic stress. Among these pathways, the glycerophospholipid metabolic pathway was remarkably up-regulated from the mRNA, protein, and metabolites levels under hypoxic stress, and the expression of relevant mRNA was also confirmed by the qPCR. The metabolites of glycerophospholipid pathway such as phosphatidylcholine, phosphatidylethanolamine, phosphoinositide, and phosphatidic acids probably maintained the stability of cell membranes against hypoxic stress to relieve the cell injury, and kept S. cerevisiae survive with energy production. These findings in the hypoxic omics and integrated networks provide very useful information for further exploring the molecular mechanism of hypoxic stress.

A microfluidic multi-organ chip emulates the tissue culture microenvironment, enables interconnection of organ equivalents and overcomes interspecies differences, making this technology a promising and powerful tool for preclinical drug screening. In this study, we established a microfluidic chip-based model that enabled non-contact cocultivation of liver spheroids and renal proximal tubule barriers in a connecting media circuit over 16 days. Meanwhile, a 14-day repeated-dose systemic administration of cyclosporine A (CsA) alone or in combination with rifampicin was performed. Toxicity profiles of the two different doses of CsA on different target organs could be discriminated and that concomitant treatment with rifampicin from day6 onwards decreased the CsA concentration and attenuated the toxicity compared with that after treatment with CsA for 14 consecutive days. The latter is manifested with the changes in cytotoxicity, cell viability and apoptosis, gene expression of metabolic enzymes and transporters, and noninvasive toxicity biomarkers. The on chip coculture of the liver and the proximal tubulus equivalents showed its potential as an effective and translational tool for repeated dose multi-drug toxicity screening in the preclinical stage of drug development.

There is evidence suggesting that herbal extracts demonstrate greater bioactivities than their isolated constituents at an equivalent dose. This phenomenon could be attributed to the absence of interacting substances present in the extracts. By measuring the pharmacokinetic parameters of paeoniflorin (PF) and albiflorin (AF) after being orally administered to rats in isolated form, in combination with each other and within total peony glucosides (TPG), respectively, the current study aimed to identify positive pharmacokinetic interactions between components of peony radix extracts. Moreover, the pharmacokinetic profiles of PF and AF under normoxia and hypoxia were also investigated and compared. In order to achieve these goals, a highly sensitive and reproducible ultra-peformance liquid chromatography–mass spectrometry (UPLC-MS) method was developed and validated for simultaneously quantitation of PF and AF in rat plasma. This study found that compared with that of single component (PF/AF), the exposure of PF in rat plasma after combination administration or TPG administration was significantly increased, meanwhile the elimination of PF/AF was remarkably reduced. It was also noticed that AUC and C_max of PF in hypoxia rats were significantly decreased compared with that of normaxia rats, suggesting that there was a decreased exposure of PF in rats under hypoxia. The current study, for the first time, revealed the pharmacokinetic interactions between PF/AF and other constitutes in TGP and the pharmacokinetic profiles of PF and AF under hypoxia. In view of the current findings, it could be supposed that the clinical performance of total peony glucosides would be better than that of single constitute (PF/AF). The outcomes of this animal study are expected to serve as a basis for development of clinical guidelines on total peony glucosides usage.

Objectives: The aim was to investigate the pharmacokinetic interaction between puerarin and edaravone, and the effect of borneol on the brain distribution kinetics of puerarin in rats.Methods: A reversed-phase high performance liquid chromatography method was developed and validated for the simultaneous determination of puerarin and edaravone in rat plasma. The detection method was successfully applied to compare the pharmacokinetic interaction and brain distribution kinetics of puerarin and edaravone using in-situ microdialysis sampling in rats after intravenous administration and co-administration with a single dose.Key findings: The method gave good linearity and no endogenous material interfered with the two target compounds and internal standard peaks. The limit of detection of puerarin and edaravone was 0.03 and 0.05 μg/ml, respectively. The average recovery of the two compounds from rat plasma was >94%. The precision of the test was determined to be within 10%. The combination of puerarin and edaravone reduced drug elimination rates, gave a wider distribution, and the disposition of both drugs in rats was optimized. The distribution of puerarin in brain tissues was significantly increased and its elimination was noticeably slower with borneol pretreatment.Conclusions: The results provide important information for the improved combined use of puerarin and edaravone with borneol pretreatment in clinical practice.

Purpose: We designed a novel isoliquiritigenin (ISL) loaded micelle prepared with DSPE-PEG₂₀₀₀ as the drug carrier modified with the brain-targeting polypeptide angiopep-2 to improve the poor water solubility and low bioavailability of ISL for the treatment of acute ischemic stroke. Methods: Thin film evaporation was used to synthesize the ISL micelles (ISL-M) modified with angiopep-2 as the brain targeted ligands. The morphology of the micelles was observed by the TEM. The particle size and zeta potential were measured via the nanometer particle size analyzer. The drug loading, encapsulation and in vitro release rates of micelles were detected by the HPLC. The UPLC-ESI-MS/MS methods were used to measure the ISL concentrations of ISL in plasma and main tissues after intravenous administration, and compared the pharmacokinetics and tissue distributions between ISL and ISL-M. In the MCAO mice model, the protective effects of ISL and ISL-M were confirmed via the behavioral and molecular biology experiments. Results: The results showed that the drug loading of ISL-M was 7.63 ± 2.62%, the encapsulation efficiency was 68.17 ± 6.23%, the particle size was 40.87 ± 4.82 nm, and the zeta potential was − 34.23 ± 3.35 mV. The in vitro release experiments showed that ISL-M had good sustained-release effect and pH sensitivity. Compared with ISL monomers, the ISL-M could significantly prolong the in vivo circulation time of ISL and enhance the accumulation in the brain tissues. The ISL-M could ameliorate the brain injury induced by the MCAO mice via inhibition of cellular autophagy and neuronal apoptosis. There were no the cellular structural damages and other adverse effects for ISL-M on the main tissues and organs. Conclusion: The ISL-M could serve as a promising and ideal drug candidate for the clinical application of ISL in the treatment of acute ischemic stroke.