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Ischaemia–reperfusion (I/R) injury is one of the leading causes of acute kidney injury (AKI). Its pathologic mechanism is quite complex, involving oxidative stress, inflammatory response, autophagy, and apoptosis. Fibroblast growth factor 10 (FGF10) and 5‐hydroxydecanoate (5‐HD) play essential roles in kidney injury. Rats were divided into four groups: (i) sham group, sham‐operated animals with an unconstructed renal artery; (ii) I/R group, kidneys were subjected to 50 min of ischaemia followed by reperfusion for 2 days; (iii) I/R + FGF10 group, animals treated with 0.5 mg/kg FGF10 (i.p.) 1 h before ischaemia; and (iv) 5‐HD group, animals treated with 5 mg/kg 5‐HD (i.m.) 30 min before FGF10 treatment. Renal injury, apoptosis damage, mitochondrial oxidative damage, mitochondrial membrane potential (MMP), and expression of the ATP‐sensitive K+ (KATP) channel subunit Kir6.2 were evaluated. FGF10 treatment significantly alleviated I/R‐induced elevation in the serum creatinine level and the number of terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling–positive tubular cells in the kidney. In addition, FGF10 dramatically ameliorated renal mitochondrial‐related damage, including reducing mitochondrial‐dependent apoptosis, alleviating oxidative stress, maintaining the mitochondrial membrane potential, and opening the mitochondrial KATP channels. The protective effect of FGF10 was significantly compromised by the ATP‐dependent potassium channel blocker 5‐HD. Our data suggest that FGF10 offers effective protection against I/R and improves animal survival by attenuating mitochondrial damage. [ABSTRACT FROM AUTHOR]

Screening brain-penetrable antioxidants from natural products is a promising way for neuroprotective drug discovery. However, there is no screening methodology enables simultaneous investigation of antioxidant activity and blood-brain barrier (BBB) permeability of compounds from complex samples. Here we propose a novel strategy by combining BBB specific parallel artificial membrane permeability assay with 1,1-diphenyl-2-picrylhydrazyl recognition (BBB-PAMPA–DPPH) to achieve rapid multicomponent screening. First, BBB specific artificial membrane was constructed to separate the compounds with high BBB permeability in herbal extracts. The antioxidant activity of the isolated compounds could be optically recognized through the bleaching of the purple-colored DPPH. By off-line combined HPLC–UV/Q-TOF-MS analysis, the exact BBB-penetrable compounds responsible for the antioxidant activity could be rapidly screened. With this approach, compound 2,6,4′-trihydroxy-4-methoxybenzophenon in Rhizoma Anemarrhena was found to be an antioxidant with very high BBB permeability, which could also be detected in rat plasma and brain tissue after oral administration. Our findings suggested the BBB-PAMPA–DPPH method could be a powerful tool for neuroprotective drug discovery from natural products. [ABSTRACT FROM AUTHOR]

Background: Doxorubicin-Induced Cardiotoxicity (DIC) has greatly limited the clinical benefits of this frontline drug in oncotherapy. Drug combination with Natural Compounds (NCs) that possess potency against DIC is considered as a promising intervention strategy. However, the Mechanisms of Action (MoAs) underlying such drug interactions remain poorly understood. The aim of this study was to systematically pursuit of the molecular mechanisms of NCs against DIC., Methods: First, the gene expression signatures of DIC were characterized from transcriptomics datasets with doxorubicin-treated and untreated cardiomyocytes using differentially expressed gene identification, functional enrichment analysis, and protein-protein interaction network analysis. Secondly, reverse pharmacophore mapping-based network pharmacology was employed to illustrate the MoAs of 82 publicly reported NCs with anti-DIC potency. Cluster analysis based on their enriched pathways was performed to gain systematic insights into the anti-DIC mechanisms of the NCs. Finally, the typical compounds were validated using Gene Set Enrichment Analysis (GSEA) of the relevant gene expression profiles from a public gene expression database., Results: Based on their anti-DIC MoAs, the 82 NCs could be divided into four groups, which corresponded to ten MoA clusters. GSEA and literature evidence on these compounds were provided to validate the MoAs identified through this bioinformatics analysis. The results suggested that NCs exerted potency against DIC through both common and different MoAs., Conclusion: This strategy integrating different types of bioinformatics approaches is expected to create new insights for elucidating the MoAs of NCs against DIC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)