Antitumor mechanism of kangliu pill on gliomas in mice through PI3K-Akt signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Gliomas are common malignant intracranial tumors that have worse prognosis and pose a serious threat to human health. The Kangliu pill (KLP) is an innovative herbal compound from Xuanwu Hospital of Capital Medical University that has been clinically used for the treatment of gliomas for more than 40 years, and is one of the few drugs for primary treatment of this disorder. But the fundamental molecular mechanisms and pathways of KLP are not clear. AIM OF THE STUDY: To investigate the therapeutic mechanism of KLP in the treatment of gliomas. MATERIALS AND METHODS: An in situ xenograft model of red fluorescent protein-labeled human glioma cell line (U87-RFP) in BALB/c-nu mouse was established, and the therapeutic effect of KLP on gliomas was assessed by tumor weights and fluorescence areas. A quantitative proteomics approach using tandem mass tags combined with liquid chromatography-tandem mass spectrometry was performed to explore differentially expressed proteins (DEPs) in glioma tissues, and bioinformatics analyses including Gene Ontology analysis, pathway analysis, and network analysis were performed to analyze the proteins involved in the network therapeutic mechanisms responsible for key metabolic pathways. Cytological experiments corroborated the above analysis results. RESULTS: Network pharmacology approach screened 246 bioactive compounds contained in KLP, targeting 724 proteins and 173 potential targets of KLP for glioma treatment. The important targets obtained after visualizing the PPI network were AKT1, INS, GAPDH, SRC, TP53, etc. The KEGG enrichment results showed that 9 proteins were related to cancer, including Pathways in cancer, PI3K/AKT signaling pathway, etc. KLP had antitumor activity in gliomas, which reduced tumor weights and fluorescence areas. A number of DEPs possibly associated with gliomas were identified through quantitative proteomic techniques. Among these DEPs, 50 (25 upregulated and 25 downregulated) were identified that might be associated with KLP action. Bioinformatics showed that these 50 DEPs were mainly focused on focal adhesion, extracellular matrix (ECM)-receptor interactions, and the PI3K-Akt signaling pathway. Cytological experiments revealed that KLP significantly inhibited the proliferation and promoted apoptosis of U87-MG human glioma cells, and its mechanism was through the inhibition of PI3K/AKT signaling pathway. CONCLUSION: Therapeutic effect of KLP was regulation of multiple pathways in the treatment of gliomas. In specific, it interacts through the PI3K-Akt signaling pathway. This work may contribute proteomic insights for further research on the medical treatment of glioma using KLP.

The Quaternary evolutionary history, potential distribution dynamics, and conservation implications for a Qinghai-Tibet Plateau endemic herbaceous perennial, Anisodus tanguticus (Solanaceae).

Various hypotheses have been proposed about the Quaternary evolutionary history of plant species on the Qinghai-Tibet Plateau (QTP), yet only a handful of studies have considered both population genetics and ecological niche context. In this study, we proposed and compared climate refugia hypotheses based on the phylogeographic pattern of Anisodus tanguticus (three plastid DNA fragments and nuclear internal transcribed spacer regions from 32 populations) and present and past species distribution models (SDMs). We detected six plastid haplotypes in two well-differentiated lineages. Although all haplotypes could be found in its western (sampling) area, only haplotypes from one lineage occurred in its eastern area. Meanwhile, most genetic variations existed between populations (F ST = 0.822). The SDMs during the last glacial maximum and last interglacial periods showed range fragmentation in the western area and significant range contraction in the eastern area, respectively, in comparison with current potential distribution. This species may have undergone intraspecific divergence during the early Quaternary, which may have been caused by survival in different refugia during the earliest known glacial in the QTP, rather than geological isolation due to orogenesis events. Subsequently, climate oscillations during the Quaternary resulted in a dynamic distribution range for this species as well as the distribution pattern of its plastid haplotypes and nuclear genotypes. The interglacial periods may have had a greater effect on A. tanguticus than the glacial periods. Most importantly, neither genetic data nor SDM alone can fully reveal the climate refugia history of this species. We also discuss the conservation implications for this important Tibetan folk medicine plant in light of these findings and SDMs under future climate models. Together, our results underline the necessity to combine phylogeographic and SDM approaches in future investigations of the Quaternary evolutionary history of species in topographically complex areas, such as the QTP.