Investigation Driven by Network Pharmacology on Potential Components and Mechanism of DGS, a Natural Vasoprotective Combination, for the Phytotherapy of Coronary Artery Disease.

Phytotherapy offers obvious advantages in the intervention of Coronary Artery Disease (CAD), but it is difficult to clarify the working mechanisms of the medicinal materials it uses. DGS is a natural vasoprotective combination that was screened out in our previous research, yet its potential components and mechanisms are unknown. Therefore, in this study, HPLC-MS and network pharmacology were employed to identify the active components and key signaling pathways of DGS. Transgenic zebrafish and HUVECs cell assays were used to evaluate the effectiveness of DGS. A total of 37 potentially active compounds were identified that interacted with 112 potential targets of CAD. Furthermore, PI3K-Akt, MAPK, relaxin, VEGF, and other signal pathways were determined to be the most promising DGS-mediated pathways. NO kit, ELISA, and Western blot results showed that DGS significantly promoted NO and VEGFA secretion via the upregulation of VEGFR2 expression and the phosphorylation of Akt, Erk1/2, and eNOS to cause angiogenesis and vasodilation. The result of dynamics molecular docking indicated that Salvianolic acid C may be a key active component of DGS in the treatment of CAD. In conclusion, this study has shed light on the network molecular mechanism of DGS for the intervention of CAD using a network pharmacology-driven strategy for the first time to aid in the intervention of CAD.

Effect of grape seed proanthocyanidins on tumor vasculogenic mimicry in human triple-negative breast cancer cells.

Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive tumor cells to mimic the pattern of embryonic vasculogenesis, which was associated with invasion and metastasis. The grape seed proanthocyanidins (GSPs) had attracted much attention as a potential bioactive anti-carcinogenic agent. However, GSPs regulation of VM and its possible mechanisms in a triple-negative breast cancer cells (TNBCs) remain not clear. Therefore, we examined the effect of GSPs on VM information in HCC1937 cell model. In this study, we identified the VM structure via the three-dimensional (3D) matrix in vitro. Cell viability was measured using the CCK8 assay. The effects of GSPs on human triple-negative breast cancer cells (TNBCs) HCC1937 in terms of related proteins of VM information were determined using western blot analysis. In vitro, the tubular networks were found in highly invasive HCC1937 cells but not in the non-invasive MCF-7 cells when plated on matrigel. The number of vascular channels was significantly reduced when cells were exposed in GSPs (100 µg/ml) and GSPs (200 µg/ml) groups (all p<0.001). Furthermore, we found that treatment with GSPs promoted transition of the mesenchymal state to the epithelial state in HCC1937 cells as well as reducing the expression of Twist1 protein, a master EMT regulator.GSPs has the ability to inhibit VM information by the suppression of Twist1 protein that could be related to the reversal of epithelial-to-mesenchymal (EMT) process. It is firstly concluded that GSPs may be an potential anti-VM botanical agent for human TNBCs.

Low-dose radiation induces antitumor effects and erythrocyte system hormesis.

OBJECTIVE: Low dose radiation may stimulate the growth and development of animals, increase life span, enhance fertility, and downgrade the incidence of tumor occurrence.The aim of this study was to investigate the antitumor effect and hormesis in an erythrocyte system induced by low-dose radiation. METHODS: Kunming strain male mice were subcutaneously implanted with S180 sarcoma cells in the right inguen as an experimental in situ animal model. Six hours before implantation, the mice were given 75mGy whole body X-ray radiation. Tumor growth was observed 5 days later, and the tumor volume was calculated every other day. Fifteen days later, all mice were killed to measure the tumor weight, and to observe necrotic areas and tumor-infiltration-lymphoreticular cells (TILs). At the same time, erythrocyte immune function and the level of 2,3-diphosphoglyceric acid (2,3- DPG) were determined. Immunohistochemical staining was used to detect the expression of EPO and VEGFR of tumor tissues. RESULTS: The mice pre-exposed to low dose radiation had a lower tumor formation rate than those without low dose radiation (P < 0.05). The tumor growth slowed down significantly in mice pre-exposed to low dose radiation; the average tumor weight in mice pre-exposed to low dose radiation was lighter too (P < 0.05). The tumor necrosis areas were larger and TILs were more in the radiation group than those of the group without radiation. The erythrocyte immune function, the level of 2,3-DPG in the low dose radiation group were higher than those of the group without radiation (P < 0.05). After irradiation the expression of EPO of tumor tissues in LDR group decreased with time. LDR-24h, LDR-48h and LDR-72h groups were all statistically significantly different from sham-irradiation group. The expression of VEGFR also decreased, and LDR-24h group was the lowest (P < 0.05). CONCLUSION: Low dose radiation could markedly increase the anti-tumor ability of the organism and improve the erythrocyte immune function and the ability of carrying O2. Low-dose total body irradiation, within a certain period of time, can decrease the expression of hypoxia factor EPO and VEGFR, which may improve the situation of tumor hypoxia and radiosensitivity of tumor itself.

Activation of ERK1/2 and Akt is associated with cisplatin resistance in human lung cancer cells.

Cisplatin is widely used for the treatment of solid tumours including small cell lung cancers, but its success is often compromised by relapse and resistance to further treatment. Extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt are two major cell survival pathways that are upregulated and activated in lung cancer tissues. Phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt) can be further stimulated by chemotherapeutics in cancer cells. Although individually targeting the ERK1/2 or Akt pathway has been reported to sensitize cancer cells to therapy, the effect of concurrently blocking these two pathways on the sensitivity of lung cancer cells to cisplatin has not been investigated. In the present study, we aimed to determine whether the ERK1/2 and Akt pathways contribute to cisplatin resistance in human small cell lung cancer A549 cells. The results showed that cisplatin activates p-ERK1/2 and p-Akt in A549 cells. Blockade of either of these pathways with chemical inhibitors moderately sensitized A549 cells to cisplatin-induced apoptosis and reduced cell viability. Strikingly, concurrent inhibition of p-ERK1/2 and p-Akt significantly potentiated cisplatin cytotoxicity in vitro and in vivo. The sensitization of A549 cells to cisplatin cytotoxicity induced by p-Akt inhibition was mediated by the upregulation of PUMA, whereas that induced by p-ERK1/2 inhibition occurred by Bcl-2 downregulation. These data indicate that the cooperative effects of p-ERK1/2 and p-Akt on attenuating cisplatin cytotoxicity are mediated by PUMA and Bcl-2 regulation, and concurrently blocking these pathways may be an effective strategy for improving the efficacy of cisplatin as anticancer treatment.

Factors associated with delayed tuberculosis diagnosis in China.

BACKGROUND: Delays in the diagnosis of tuberculosis reflect a lack of access to care, and contribute to ongoing tuberculosis transmission in the community. The objective of this study was to evaluate the delay in tuberculosis testing and the associated risk factors in Shanghai, Shandong and Sichuan provinces in China. METHODS: A prospective cohort study of 765 culture-positive pulmonary tuberculosis patients registered between December 2006 and December 2008. The delay between the onset of symptoms and tuberculosis diagnosis testing and patient information were recorded in a questionnaire and analysed. RESULTS: The median delay was 36 days and was significantly shorter in patients from Shanghai compared with other places (30 vs. 42 days, P < 0.001). Multivariate analysis revealed that cough in Shanghai patients, lowest income level, being married and presenting expectoration in Shandong and Sichuan patients, were associated with a delay in the diagnosis testing of tuberculosis of >30 days. The only factor associated with a delay of >90 days was, in Shandong and Sichuan provinces only, female gender. The presence of other pulmonary symptoms like haemoptysis and loss of weight, fever and chills could shorten these delays. CONCLUSION: Efforts to shorten delays in the diagnosis of tuberculosis must target vulnerable populations. The non-specific symptom of cough is a risk factor associated with longer delays. Training for healthcare workers in areas with a high incidence of tuberculosis, where a delayed diagnosis in coughers may enhance tuberculosis transmission in the community, is of paramount importance.

The combination of ERCC1 and XRCC1 gene polymorphisms better predicts clinical outcome to oxaliplatin-based chemotherapy in metastatic colorectal cancer.

PURPOSE: To evaluate the effect of excision repair cross-complementing group 1 (ERCC1) and X-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcome in patients receiving oxaliplatin-based regimens for metastatic colorectal cancer. METHODS: Hundred and thirteen patients with a diagnosis of metastatic colorectal cancer were treated with oxaliplatin-based chemotherapy. ERCC1 codon 118C/T and XRCC1 codon 399A/G polymorphisms were tested by real-time polymerase chain reaction (RT-PCR) method in peripheral blood lymphocytes of these patients. Disease control rates and survivals were compared by types of genotypes. RESULTS: Analyses of the patterns of the polymorphism located at ERCC1 codon 118 showed that 55 (48.67%) patients were homozygous for C/C genotype, 15 (13.27%) were homozygous for the T/T genotype, and 43 (38.06%) were heterozygous for C/T genotype. Analyses of the polymorphism located at XRCC1 codon 399 showed that 61 (53.98%) patients were homozygous for A/A genotype, 13 (11.50%) were homozygous for the G/G genotype, and 39 (34.52%) were heterozygous for A/G genotype. After two cycles of chemotherapy, there was complete response (CR) in 1 patient, partial response (PR) in 24 patients, and stable disease (SD) in 56 patients. Altogether in 81 (71.68%) patients the disease was controlled after chemotherapy. Thirty-two (28.32%) patients showed disease progression. After adjusting for some clinical factors, both the ERCC1 polymorphism and the XRCC1 polymorphism lost their roles in predicting DCR (P = 0.662, P = 0.631) and MST (P = 0.692, P = 0.572). But the combination of ERCC1 and XRCC1 polymorphisms was significantly associated with DCR (P = 0.01) and MST (P = 0.000) independently. CONCLUSIONS: This is the first study which showed that polymorphisms of ERCC1 and XRCC1, in combination not individually, were independent predictors for DCR and OS. This may contribute to the selection of patients who would benefit from oxaliplatin-based chemotherapy for metastatic colorectal cancer.