Study on the objectivity and biological mechanism of Psoralea corylifolia Linn.'s 'Great dryness damages the liver' / 药学学报

According to the theory of 'Xingben Dazao' of Psoralea corylifolia Linn. (BL), the susceptible syndromes and biomarkers of liver injury caused by BL were searched. Rat models of kidney-yin deficiency syndrome (M_yin) and kidney-yang deficiency syndrome (M_yang) were established, and all animal experimental operations and welfare following the provisions of the First Affiliated Experimental Animal Ethics and Animal Welfare Committee of Henan University of Traditional Chinese Medicine (No. YFYDW2020017). The results showed that BL significantly decreased the body weight, water intake, and urine weight of M_yin rats and increase the organ indexes of the liver, testis, adrenal gland, and spleen and the expression of alanine aminotransferase (ALT). Meantime, BL significantly increased the urine weight of M_yang rats and decreased the expression of ALT and aspartate aminotransferase (AST). Hematoxylin and eosin (HE) staining showed that BL could aggravate inflammatory infiltration of hepatocytes in rats with M_yin and alleviate liver injury in rats with M_yang. Metabolomics identified 17 BL co-regulated significant differential metabolic markers in M_yin and M_yang rats. Among them, 8 metabolites such as glutamine, quinolinate, biliverdin, and lactosylceramide showed opposite trends, mainly involving cysteine and methionine metabolism, tyrosine metabolism, tryptophan metabolism, purine metabolism, sphingolipid metabolism, glycerol phospholipid metabolism, glutamine metabolism, and other pathways. M_yin/M_yang may be the susceptible constitution of BL for liver damage or protection, which may be related to the regulation of amino acid metabolism and sphingolipid metabolism. The study can provide some experimental data support for the safe and accurate use of BL in the clinical practice of traditional Chinese medicine.

The Antileukemia Activity of ZSTK474 on U937 Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the antileukemia activity of phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 on human leukemia cell line U937.@*METHODS@#MTT, soft agar assay, flow cytometric analysis and western blot were used to detect the effect of ZSTK474 on U937 cell proliferation, tumorigenicity, cell cycle, cell apoptosis and phosphorylation levels of the key factor of PI3K/AKT pathway. Chou-Talalay method was used to evaluate the combination of ZSTK474 with Cytarabine or Homoharringtonine.@*RESULTS@#PI3K inhibitor ZSTK474 could inhibit the proliferation and tumorigenicity of U937 cell, induce G@*CONCLUSION@#ZSTK474 can inhibit the pathway of PI3K/AKT, ZSTK474 alone or in combination with Homoharringtonine shows potential antileukemia activity on U937 cells.

The anti-tumour mechanism of Shuanghuang Qizhen Keliu Prescription based on network pharmacology / 中国药理学通报

Aim To explore the anti-tumour mechanism of Shuanghuang Qizhen Keliu Prescription based on network pharmacology. Methods The active components and targets of Shuanghuang Qizhen Keliu Prescription were searched and selected through the TCM-SP database. Related targets of tumor were screened and retrieved by OMIM. The key anti-tumor targets of Shuanghuang Qizhen Keliu Prescription were obtained by using Venn diagram analysis. The key target PPI network was constructed and the key targets were obtained by Cytoscape. Metascape platform was used for GO and KEGG enrichment analysis of key targets. Results There were many active components such as quercetin, kaempferol, and beta-sitosterol in Shuanghuang Qizhen Keliu Prescription, and their targets might be TP53, AKT1, JUN, MAPK1, TNF, RELA, IL-6 and so on. The anti-tumour mechanism might be proliferation inhibition, migration inhibition and apoptosis promotion. Conclusions This study preliminarily discusses the potential anti-tumour mechanism of Shuanghuang Qizhen Keliu Prescription, providing ideas and basis for subsequent experimental research.

Research progress in targeting homologous recombination repair for tumor therapy / 药学学报

Applying poly(ADP-ribose) polymerase inhibitors (PARPi) to the treatment of cancers with homologous recombination deficiency (HRDness) has been a great advance in the field of molecular therapeutics. However, in the clinic patients lacking the specific mutations or developing reverse mutations in the process of PARPi treatment may not benefit from PARPi monotherapy. Therefore, targeting homologous recombination (HR) repair with molecularly targeted agents is becoming an attractive research focus and is raising the concept of "chemical HRDness". HR repair is an evolutionarily conserved and extensively regulated process that employs sister chromatids as the template to repair DNA double-strand breaks with high fidelity. In addition to directly targeting HR components, modulation of regulatory pathways controlling HR repair is effective in achieving the "HRDness" phenotype; this includes modulation of the cell cycle checkpoint regulatory pathway, the phosphatidylinositol 3-kinase (PI3K) signaling pathway, the chromatin remodeling pathway, etc. Targeting HR repair can not only result in "synthetic lethality" when combined with PARPi, but also sensitizes cancers to traditional radio/chemotherapy and novel immunotherapy. In this review we describe the HR repair pathway and its regulatory pathways, summarize the preclinical and clinical outcomes of targeting HR repair, discuss the remaining problems in this field and provide a prospective on its application in tumor therapy.

Anti-atherosclerotic effect of extract of traditional Chinese medicine formula Dan-yi-Iian in ApoE(-/-)mice / 中国药理学与毒理学杂志

OBJECTIVE To explore the anti-atherosclerotic effect of the extract of traditional Chinese medicine formula Dan-yi-lian(DYL)and the related mechanism.METHODS Atherosclerosis(AS)mod-el was established in ApoE(-/-)mice with a western diet. The mice were orally administered with differ-ent doses of DYL or vehicle daily for 28 d.The anti-atherosclerotic effect was evaluated by measuring the aortic atherosclerotic lesion area and media thickness with ultrasound imaging and histological sec-tions staining method. The effect on blood lipid was investigated by determining TC, TG, LDL, HDL, Apo-A1, Apo-B, etc. The anti-oxidative activity as assessed by determining the level of SOD, CAT, GSH,GSH-Px and MDA.Western blot analysis was used to determine the effect on ICAM-1,VCAM-1, MMP-2 and TNF-α. RESULTS In Dan-yi-lian administered ApoE(-/-)mice,the plaque area and media thickness were significantly reduced. Meanwhile, serum TC, TG, LDL and Apo-B were decreased, in contrast to the increased level of HDL and Apo-A1.On the other hand,SOD,CAT,GSH and GSH-Px were increased, while MDA was reduced in liver homogenate. In addition, the expression of ICAM-1, VCAM-1,MMP-2 and TNF-α was obviously inhibited by Dan-yi-lian.CONCLUSION Dan-yi-lian exhibit-ed potent anti-athero-sclerotic efficacy,in which the lipid-regulating,anti-oxidative and anti-inflammato-ry mechanism might be involved.

Effects of the PI3K inhibitor,ZSTK474,on the proliferation and cell cycle of human melanoma A375 cells / 国际药学研究杂志

Objective To investigate the effect and molecular mechanisms of phosphatidylinositol-3 kinase(PI3K)inhibitor ZSTK474 on human melanoma A375 cells in vitro. Methods The effect of ZSTK474 on the proliferation of A375 cells was deter?mined by MTT assay.Flow cytometric analysis was carried out to examine effect of ZSTK474 on the cell cycle of A375 cells.Western-blot was conducted to evaluate the effect of ZSTK474 on the expression of the cell cycle related proteins,cyclin B1 and cdc2.Chou-Talalay method was used to evaluate the combination of ZSTK474 with PD0332991.Results In the MTT assay,ZSTK474 inhibited the proliferation of A375 cells in a dose-dependent manner with the IC50value of 1.535 μmol/L.Furthermore,ZSTK474 arrested the cell cycle progression of the A375 cells at the G2/M phase via downregulating the expression of cyclin B1 and cdc2 at 1 and 5 μmol/L. In the synergistic assay,the combination of ZSTK474 with PD0332991 in the ratio 8×IC50 ZSTK474:1×IC50 PD0332991showed a synergistic ef?fect,with the combination index(CI)values of 0.463 ± 0.113,0.658 ± 0.009 and 0.941 ± 0.034 for ED50、ED75and ED90,respectively. Conclusion ZSTK474 could inhibit the proliferation of A375 cells and arrest the cell cycle at the G2/M phase.The combination of ZSTK474 with PD0332991 could exert a synergistic effect.The precent result has revealed that the PI3K inhibitor ZSTK474 is likely to be applied alone or in combination with the CDK4/6 inhibitor PD0332991 for the human melanoma therapy.