Mechanism of Huangqintang in Alleviating Side Effect of Chemotherapy for Endometrial Cancer Based on Network Pharmacology and Molecular Docking / 中国实验方剂学杂志

ObjectiveTo evaluate the utility and mechanism of Huangqintang combined with carboplatin in chemotherapy of endometrial cancer by experiments as well as network pharmacology and molecular docking. MethodThe xenograft model of endometrial carcinoma was induced in BALB/c nude mice. When the tumor volume reached about 100 mm3，24 nude mice were randomly assigned into a model group， a Huangqintang group （3.5 g·kg-1），a carboplatin group （50 mg·kg-1），and a combination group （3.5 g·kg-1 Huangqintang + 50 mg·kg-1 carboplatin）， with six mice in each group. The mice in the model group received 200 μL of normal saline by gavage， twice a day. The volume of the tumor and the body weight of the mice were measured every two days. After drug intervention for 20 days， the blood of the mice was collected for renal function and blood routine tests. Then the nude mice were euthanized and the tumor was weighted. In combination with the experimental results，the underlying mechanism of Huangqintang combined carboplatin was predicted through network pharmacology and the binding sites of active components were predicted by molecular docking. ResultThe tumor inhibition rates of the Huangqintang group，the carboplatin group， and the combination group were 8.87%，50.33% （P<0.05），and 64.66% （P<0.01），respectively. Compared with the results in the model group，the body weight，leukocyte，erythrocyte， and hemoglobin in the carboplatin group decreased，and creatinine and uric acid increased （P<0.05）. Compared with the carboplatin group，the combination group showed increased body weight，leukocyte， and hemoglobin （P<0.05），and decreased creatinine and uric acid （P<0.05）. A total of 114 potential active components of Huangqintang involved 200 targets related to the side effects of carboplatin. The core genes involved were mainly heat shock protein 90AA1 （HSP90AA1），transcription factor c-Jun （JUN）， and mitogen-activated protein kinase （MAPK）. Molecular docking showed that baicalein and wogonin could form a stable protein complex with HSP90AA1， serving as potential active molecules. Kyoto Encyclopedia of Genes and Genomes （KEGG） analysis revealed that it might be related to the regulation of tumor necrosis factor（TNF） signaling pathway，interleukin（IL）-17 signaling pathway， MAPK signaling pathway， and toll-like receptor pathway. ConclusionHuangqintang has no obvious inhibitory effect on endometrial cancer，and the tumor suppression effect is not significantly enhanced after combination with carboplatin，but Huangqintang can alleviate carboplatin-induced side effects. The mechanism may be related to the complex network of Chinese medicine.

Effect of cinobufotalin on growth of xenograft of endometrial carcinoma cell line ishikawa in nude mouse and its impact on RRM2 expression / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To investigate the inhibitory effect of cinobufotalin (CBT) on the growth of xenograft endometrial carcinoma cell line ishikawa in nude mice, and its impact on the expression of ribonucleotide reductase subunit M2 (RRM2).</p><p><b>METHODS</b>Eleven nude mice with xenograft were randomly divided into two groups, the CBT group and the control group, which received intra-tumor injection of CBT and saline respectively for one week. The sizes of xenografts were measured before and after the treatment to calculate the inhibition ratio of tumor proliferation; the RRM2-mRNA and protein expressions in tumor tissue were measured by RT-PCR and Western blot respectively.</p><p><b>RESULTS</b>After treatment, the size of xenografts in the CBT group was (0.1314 +/- 0.0304) cm3, which was significantly lower than that in the control group (0.360 0 +/- 0.1145) cm3, (P < 0.05), the tumor proliferation inhibition ratio being 43.46%. The differences of RRM2 mRNA and protein expression levels between the two group were significant (P = 0.019 and P = 0.001).</p><p><b>CONCLUSION</b>CBT significantly inhibits the growth of the xenografts of endometrial carcinoma Ishikawa in nude mice, and the action mechanism is possibly associated with the inhibition on RRM2 expression.</p>

Effects of inhibition of ANG-2 expression in Ishikawa cell line / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the effect of RNA interference mediated angiopoietin-2 (ANG-2) gene silencing on human endometrial carcinoma cell line Ishikawa.</p><p><b>METHODS</b>Short hairpin RNA (shRNA) targeting ANG-2 gene was designed and transfected into Ishikawa cells with Lipofectamine 2000. The mRNA and protein expression level of ANG-2, proliferation, morphological changes, apoptosis, cell cycle and invasive ability of the cells after transfection were analyzed.</p><p><b>RESULTS</b>The shRNA targeting the human ANG-2 gene effectively decreased the expression of ANG-2 on both mRNA and protein level, the proliferation inhibition rate of the Ishikawa cells was 63.11%, cell apoptosis was induced, and the cell cycle was arrested in G1 phase. The apoptotic rate of the Ishikawa cells in the transfected group was significantly higher, and the invasive ability was decreased markedly, than that of control groups.</p><p><b>CONCLUSION</b>The shRNA targeting human ANG-2 gene could reduce ANG-2 expression, inhibit cellular growth and invasion in Ishikawa cells in vitro.</p>

Progress in research on the anti-tumor effect of artesunate / 中国结合医学杂志

It has been found in recent years that Artesunate (Art), a water soluble derivative of arteannuin, mainly previously used for its anti-malarial activity, has some other effects, e.g. it could act as an anti-tumor agent by way of inducing cell apoptosis, antagonizing angiogenesis, reversing immunosuppression of tumor cells, etc. More and more attention is being paid to the anti-tumor effects of Art. Such progress is reviewed in this paper.

Changes in gene expression profiles of hydatidiform mole and choriocarcinoma as compared with trophoblast hyperplasia / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the relationship of changes in gene expression profiles of hydatidiform mole and choriocarcinoma with hyperplasia of trophoblasts.</p><p><b>METHODS</b>The differentially expressed genes were analyzed in two pairs of tissues of hydatidiform mole versus normal villi, and in two pairs of normal primary culture trophoblasts versus JAR cell line of chariocarcinoma, using cDNA microarray containing 4096 genes. To confirm the results of cDNA microarray analysis, expressions of some up-regulated genes related to DNA synthesis in normal villi, hydatidiform mole, and 2 choriocarcinoma cell lines (JAR and JEG-3) were examined by immunohistochemistry, immunoblotting and RT-PCR.</p><p><b>RESULTS</b>A total of 89 genes were differentially expressed in all hydatidiform moles, accounting for 2.2% of the genes arrayed. Of the 89 genes, 24 were up-regulated and 65 were down-regulated. Compared with normal primary trophoblasts, there were 433 genes up-regulated and 380 genes down-regulated in JAR cell line. Forty six genes were up-regulated in both hydatidiform mole and choriocarcinoma, while 13 genes were down-regulated. Some genes associated with cell proliferative inhibition were significantly down-regulated, whereas those associated with cell proliferation, malignant transformation, metastasis and drug resistance were highly up-regulated. The expressions of thymidine kinase 1, the small subunit of ribonucleotide reductase (RRM2) were significantly increased in hydatidiform mole, JAR and JEG-3 cells.</p><p><b>CONCLUSION</b>Abnormal expression of genes exists in hydatidiform mole and choriocarcinoma. Hyperplasia of trophoblasts may be related to over-expression of genes coding for synthetic enzymes.</p>

Expression of R2 protein in gestational trophoblastic diseases / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To study the expression of the small subunit ribonucleotide reductase (R2) in gestational trophoblastic diseases (GTD) and to assess its prognostic value.</p><p><b>METHODS</b>The expression of R2 was detected with immunohistochemical method in 15 cases of normal villi, 38 cases of hydatidiform mole (HM), 42 cases of invasive moles (IM) and 18 cases of choriocarcinoma (CC).</p><p><b>RESULTS</b>R2 expression in HM, IM and CC was significantly increased compared with that of normal villi (P=0.000). There were no significant differences in R2 protein expression among HM, IM and CC. Among 38 cases of HM, R2 expression in 8 cases with malignant transformation was significantly higher than in 30 cases of non-malignant transformation mole (P=0.02). Preoperative chemotherapy of gestational trophoblastic tumor including IM and CC did not influence the R2 expression. Compared with patients of stage I (WHO), the R2 protein in gestational trophoblastic tumor (GTT) patients of stage III or stage II was significantly increased (P=0.023 and P=0.038, respectively). The value of R2 in GTT patients with middle or high risk in WHO prognostic scoring system was higher than in the patients with low risk (P=0.018 and P=0.006, respectively).</p><p><b>CONCLUSION</b>R2 expression in GTD is increased, which may be associated with the hyperplasia of trophoblasts, malignant transformation of hydatidiform mole and drug resistance of trophoblastic tumor.</p>

Preliminary study on gene expression profile of endometrial adenocarcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To determine candidate genes of endometrial adenocarcinoma.</p><p><b>METHODS</b>To compare the gene expression profile in 2 endometrial adenocarcinoma tissues and 2 normal endometria by HGEC-40s GeneChip probe including 4096 genes array. Expression differences between normal and malignant tissue groups were measured by GenePixPro3.0 software.</p><p><b>RESULTS</b>350 genes with a ratio below 0.5 and above 2.0 showed discrimination between normal and malignant groups. Thirty three genes with ratio above 3 were up-regulated, forty-four genes with ratio below 0.3 were down-regulated.</p><p><b>CONCLUSION</b>The overexpression of oncogenes with their disturbed or constitutively activated signal transduction cascades alone or in combination with the mutation-induced silencing of tumor suppressor genes is associated with malignant transformation.</p>