Ischemic stroke (IS) caused by cerebral arterial occlusion is the leading cause of global morbidity and mortality. Cellular oxidative stress and inflammation play a vital role in the pathological process...

Systematic investigations of complex pathological cascades during ischemic brain injury help to elucidate novel therapeutic targets against cerebral ischemia. Although some transcription factors (TFs) involved in cerebral ischemia, systematic surveys of their changes during ischemic brain injury have not been reported. Moreover, some multi-target agents effectively protected against ischemic stroke, but their mechanisms, especially the targets of TFs, are still unclear. Therefore, a comprehensive approach by integrating network pharmacology strategy and a new concatenated tandem array of consensus transcription factor response elements method to systematically investigate the target TFs critical in the protection against cerebral ischemia by a medication was first reported, and then applied to a multi-target drug, Danhong injection (DHI). High-throughput nature and depth of coverage, as well as high quantitative accuracy of the developed approach, make it more suitable for analyzing such multi-target agents. Results indicated that pre-B-cell leukemia transcription factor 1 and cyclic AMP-dependent transcription factor 1, along with six other TFs, are putative target TFs for DHI-mediated protection against cerebral ischemia. This study provides, for the first time, a systematic investigation of the target TFs critical to DHI-mediated protection against cerebral ischemia, as well as reveals more potential therapeutic targets for ischemic stroke.

Increasing attention has been paid to the application of precision medicine in heart failure (HF), and biomarker-based personalized medical care has shown great progress in HF management. Additionally, multicomponent drugs represented by traditional Chinese medicine (TCM) are demonstrating safety and efficacy in the management of HF. However, the potential mechanism is unclear, and the ambiguous clinical locations of TCM remain a hindrance to its extensive application. To meet this requirement, a precise investigation on the efficacy of multicomponent drugs against HF using the signature biomarkers-oriented approach was developed and applied to a conventional drug for cardiac disease, YiXinShu (YXS). On the basis of in vitro and in vivo efficacy evaluation of YXS against HF, and with the aid of proteomics and network pharmacology approaches, specific signatures regulated by YXS against HF were identified. YXS may show distinctive treatment features for those HF patients showing the elevation of fatty acid-binding protein 3 and cytoskeleton-associated protein 5, as well as other classic HF biomarkers. This study provides the first precise investigation of the efficacy of multicomponent drugs against HF and offers a practicable and low-cost approach for personalized management of HF.-Wei, J., Guo, F., Zhang, M., Xian, M., Wang, T., Gao, J., Wu, H., Song, L., Zhang, Y., Li, D., Yang, H., Huang, L. Signature-oriented investigation of the efficacy of multicomponent drugs against heart failure.

Ischemic stroke (IS), as a leading cause of disability worldwide, affects intestinal bacterial communities and their metabolites, while recent discoveries have highlighted the importance of the intestinal microflora in the development of IS. Systematic investigations of complex intestinal bacterial communities and their metabolites during ischemic brain injury contribute to elucidate the promising therapeutic targets for IS. However, the associations between intestinal microbiota and related circulating metabolic processes in IS remained unclear. Hence, to identify the changed microflora and their metabolites in IS of NaoMaiTong (NMT), an effective clinical medication, we established the middle cerebral artery occlusion/reperfusion (MCAO/R) model using conventionalized and pseudo-germ-free (PGF) rats. Subsequently, we systematically screen the microflora and related metabolites changing in IS via an integrated approach of cecal 16S rRNA sequencing combined with plasma metabolomics. We found that NMT relied on intestinal flora to improve stroke outcome in conventionalized rats while the protection of NMT was reduced in PGF rats. Total 35 differential bacterial genera and 26 differential microbial metabolites were regulated by NMT. Furthermore, L-asparagine and indoleacetaldehyde were significantly negatively correlated with Lachnospiraceae_UCG.001 and significantly positively correlated with Lachnoclostridium. Indoleacetaldehyde also presented a negative correlation with Lactobacillus and Bifidobacterium. 2-Hydroxybutyric acid was strongly negatively correlated with Ruminococcus, Lachnospiraceae_UCG.001 and Lachnospiraceae_UCG.006. Creatinine was strongly negatively correlated with Akkermansia. In summary, the research provided insights into the intricate interaction between intestinal microbiota and metabolism of NMT in IS. We identified above differential bacteria and differential endogenous metabolites which could be as prebiotic and probiotic substances that can influence prognosis in stroke and have potential to be used as novel therapeutic targets or exogenous drug supplements.