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Abnormal tumour cell adhesion is a key step in tumour metastasis， in which weakened homologous and enhanced heterologous adhesion of tumour cells is an important cause of tumour metastasis. Chronic stress can activate the sympathetic nervous system to link and regulate the homologous and heterologous adhesion of tumour cells and exacerbate tumour metastasis. Combining the understanding of traditional Chinese medicine （TCM） and Western medicine on tumour metastasis， it is believed that the mechanism of "qi constraint and stagnation， tumor toxin transmission and retention" in TCM theory is highly related to the abnormal adhesion of tumour cells triggered by chronic stress. Qi constraint and stagnation is closely related to chronic stress and its activation of the sympathetic nervous system， and transmission and retention of tumor toxin explained the mechanism of tumour metastasis due to abnormal adhesion of tumour cells from the perspective of TCM. By regulating the key link of sympathetic nervous system-tumour cell adhesion， application of the formulas of regulating qi and resolving toxin can improve chronic stress and inhibit tumour metastasis.
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ObjectiveTo explore the potential molecular mechanism of Qizhu Kang'ai Formula （芪术抗癌方， QZKAF） for the treatment of colorectal cancer （CRC）. MethodsNetwork pharmacology was used to analyze the active ingredients and targets of QZKAF for CRC， and analyze the key targets of QZKAF for the treatment of CRC by gene function annotation （GO） and Kyoto Encyclopedia of Genomes （KEGG） pathway enrichment analysis. Molecular docking was applied to predict the binding activity of the core active ingredients to the key targets. A orthotopic transplantation tumor mice model of CRC was established to validate the key targets of QZKAF for CRC obtained from network pharmacology analysis. Forty-eight mice were randomly divided into the sham operation group， the model group， the 5-fluorouracil （5-Fu） group， and the QZKAF low-， medium-， and high-dose groups， with 8 mice in each group. Except for the sham operation group， the remaining groups underwent colon cancer orthotopic transplantation tumor modeling. The 5-Fu group was given 30 mg/kg of 5-Fu by intraperitoneal injection once every 3 days on the alternate day after modeling， while the QZKAF low-， medium-， and high-dose groups were given 2.925， 5.85， and 11.7 g/（kg·d） of QZKAF by gastric gavage， respectively， and the sham-operation group and the model group were gavaged with 0.1 ml/10 g of normal saline every day， all for 21 days. The in situ tumors mass and the number of liver metastases were compared between the groups. The pathological changes of colon tumor tissues were observed by HE staining， and the protein expression of protein tyrosine phosphatase nonreceptor type 1 （PTPN1）， vinculin， integrin subunit αν， integrin subunit β3， and E-cadherin were detected in colon tumor tissues by Western blot. ResultsNetwork pharmacology screening yielded that the top six core active ingredients of QZKAF intervening in CRC were quercetin， kaempferol， apigenin， luteolin， baicalein and ursolic acid. There were 212 targets of action， and the ranked top three were prostaglandin endoperoxide synthase 1 （PTGS1）， prostaglandin endoperoxide synthase 2 （PTGS2）， and PTPN1， which may be the key targets of QZKAF in the treatment of CRC. These key targets were significantly enriched mainly in phosphatidylinositol 3-kinase/protein kinase B （PI3K-Akt） signaling pathway， focal adhesion and adhesion junction. Molecular docking results： except for PTGS1 with better binding activity to quercetin， kaempferol， and apigenin （binding energy ≥-7.0 kcal/mol）， PTGS1 showed strong binding activity to lignans， baicalein， ursolic acid， as well as PTGS2 and PTPN1 to the six core active ingredients （binding energy ＜-7.0 kcal/mol）. Experimental validation results： the protein expression of PTPN1， vinculin， integrin subunit αν， integrin subunit β3 in the colon tumor tissues of mice in the model group significantly increased， and the expression of E-cadherin significantly decreased compared to those in the sham operation group （P＜0.05）. Compared to those in the model group， the mass of the in situ tumors was reduced， and the number of hepatic metastasis nodules decreased in the high- and medium-dose QZKAF groups （P＜0.05）； the expression levels of PTNP1， vinculin， integrin subunit αν， integrin subunit β3 and E-cadherin in all QZKAF groups and 5-Fu group showed different degrees of retracement， and the changes of the indicators in all QZKAF groups showed a certain degree of dose-dependence （P＜0.05）. HE staining showed that the nuclei of tumor cells in the model group were mostly schizophrenic， and there were different degrees of nuclear fragmentation of tumor cells in all QZKAF groups with more in the medium- and high-dose groups. ConclusionQZKAF could inhibit the growth of in situ tumors and liver metastasis of CRC. Its mechanism might be related to the regulation of tumor cell-cell and tumor cell-extracellular matrix adhesion by PTPN1.
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Angiogenesis is an important link of tumor growth, invasion and metastasis. The tumor angiogenesis targeting strategy for the treatment of cancer has become a hot spot in oncology research currently. Signal transduction of tumor angiogenesis is a complex, multi-factor, multi-way and cross network system. Treatment for a single target is often not sufficient to halt or reverse its highly heterogeneous structure and abnormal shape. Therefore, it will be an important research direction that the combination of different pathways and mechanisms of medications effect on signaling pathway in tumor angiogenesis by multi-target. A number of experimental studies found that qi-reinforcing and blood-activating medication can play a regulating role of multiple targets, multiple pathways in tumor angiogenesis. It had different effect on tumor angiogenesis against tumor invasion and metastasis.Qi-reinforcing and blood-activating medication will have broad prospects in the treatment of tumor and angiogenesis.
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This study was aimed to observe the influence on migration ability of human umbilical vein endothelial cell (HUVEC) in vitro by couplet medicines of reinforcing qi and activating blood, and initially screen medicines with relative obvious promoting or inhibiting effect on migration ability of HUVEC. The model of HUVEC cultured in vitro was established. The Paeonia, Ligusticum chuanxiong, Cortex moutan, Salvia, curcuma zedoaria, Sparganium, Astragalus, and ginseng were combined in pairs with the proportion of 1:2, 1:1, 2:1. There were 13 couplet medicines of reinforcing qi and activating blood. Serum pharmacological method was used to prepare medicated serum of the couplet medicines of reinforcing qi and activating blood. Scratch method was used to detect the effect of medicated serum of these couplet medicines of reinforcing qi and activating blood and activate blood herbs on the migration a-bility of HUVEC (with the density of 5í105/mL) after 24 hours. The results showed that compared with the blood serum of the blank group, the Cortex moutan group, Ligusticum chuanxiong group, Paeonia group, Salvia and Astra-galus (1:2) group, Salvia and Astragalus (1:1) group, Ligusticum chuanxiong and Astragalus (1:2) group had obvious promoting effect on the migration ability of VEC (P < 0.05 or P < 0.01). The Sparganium group, curcuma zedoaria group, Cortex moutan group, curcuma zedoaria and Astragalus (2:1) group, Sparganium and ginseng (2:1) group, Spar-ganium and Astragalus (1:1) group had obvious inhibiting effect on the migration ability of VEC (P< 0.05 or P<0.01). It was concluded that different compatibility of medicines of reinforcing qi and activating blood and activate blood herbs had different promoting or inhibiting effect on migration ability of HUVEC. It may be related to the mechanism of action of these drugs on promoting or inhibiting angiogenesis at the cellular level.
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This study was aimed to observe the influence of qi-reinforcing and blood-activating(QRBA) herbs onan-giogenesis of the myocardial microvascular, SDF-1 and CXCR4 protein expression as well as mRNA expression in the infarcted myocardium edge area of acute myocardial infarction (AMI) ratmodel. The AMI rat model was estab-lished. The immunohistochemical staining method was used in the detection of vWF protein expression in the myocar-dial tissues. The MVC account was recorded. The SDF-1 factor and its specific receptor factor CXCR4 were detected by the western blot and realtime-PCR technique in the infarcted myocardium edge area of rats from each group. The results showed that in the new generated microvessels which were staining marked by the vWF factor can be seen in infarcted myocardium edge area of rats from the sham-operated group, model group, each medication group. The new generated microvessels in the myocardium of rats in the sham-operated group were not obvious. Small amount of new generated microvessels can be seen in rats from the model group. More new generated microvessels can be seen in rats from each medication group. The comparison between the model group and the sham-operated group showed sta-tistical difference (P<0.05). The comparison between each medication group and the model group showed statistical difference(P<0.05 or P<0.01). Compared with the sham-operated group, SDF-1, CXCR4 and mRNA expression were obviously increased in the myocardium of rats in the model group (P<0.05 or P<0.01). Compared with the model group, SDF-1, CXCR4 protein and mRNA expression were obviously increased in the myocardium of rats from each medication group (P<0.05 or P<0.01). It was concluded that herbs such as Salvia, couplet herbs of Salvia and Astra-galushad stimulation effectonangiogenesis. Mechanism of these drugs in angiogenesismay be through the promotion of SDF-1 and CXCR4 protein as well as mRNA express.
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Because of many reasons, big changes occur in the varieties of ancient and modern Chinese herbs. Besides a significant increase in the number, there are many other features, such as significant differences among mainstream varieties, partly resolving the chaotic situation of uncoincidence of different herb names, increasing proportion of plant herbs, and herbal multi-polarization, etc.