miRNA-449c-5p regulates the JAK-STAT pathway in inhibiting cell proliferation and invasion in human breast cancer cells by targeting ERBB2.

BACKGROUND: Breast cancer is a highly prevalent disease worldwide, and early diagnosis and treatment could reduce the mortality rate of breast cancer patients. microRNAs (miRNA) have been shown to regulate the occurrences and progression of many types of cancers. Thus, it is crucial to find novel biomarkers in breast cancer. miR-449c-5p acted as a biomarker in non-small cell lung cancer, gastric carcinoma, and so forth. ERBB2 is an ideal target for breast cancer therapy. However, the molecular mechanisms between miR-449c-5p and ERBB2 in breast cancer remain poorly understood. Our study focused on the regulatory role of miR-449c-5p in breast cancer and its targeting relationship with ERBB2. METHODS: The miR-449c-5p expression in breast cancer tissue and normal tissue was searched from the online database (Starbase). The clinical prognosis of miR-449c-5p and ERBB2 was predicted by using the Kaplan-Meier analysis method. The expression of miR-449c-5p mimics and inhibitors was measured by qRT-PCR. T47D cells were transfected with miR-449c-5p mimics and miR-449c-5p inhibitors. After that, CCK-8, colony formation assays and Transwell assays were used to evaluate the cell proliferation ability, migration and invasion. Whether ERBB2 was the target gene of the miR-449c-5p was predicted by Starbase and verified by dual-luciferase activity assay. In addition, protein levels and the relationship between signalling pathways were measured and validated using western blotting analysis. RESULTS: We confirmed that miR-449c-5p was highly expressed in breast cancer tissue, and its downregulation was linked with poor prognosis. Overexpression of miR-449c-5p inhibited the proliferation, migration and invasion of breast cancer cells. ERBB2 was a target of miR-449c-5p. The invasion, migration, and proliferation of breast cancer cells were inhibited by miR-449c-5p/ERBB2 through JAK-STAT. CONCLUSION: This study demonstrated that miR-449c-5p inhibits breast cancer cell proliferation, migration and invasion by targeting ERBB2 via JAK/STAT, which means miR-449c-5p, is a potential biomarker for breast cancer and provides a novel insight for diagnosis.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Alternative Lengthening of Telomeres and Mediated Telomere Synthesis.

Telomeres are DNA-protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin, and ALT also frequently occurs during experimental cellular immortalization of mesenchymal cells. ALT is a process that relies on homologous recombination (HR) to elongate telomeres. However, some processes in the ALT mechanism remain poorly understood. Here, we review the most recent understanding of ALT mechanisms and processes, which may help us to better understand how the ALT pathway is activated in cancer cells and determine the potential therapeutic targets in ALT pathway-stabilized tumors.

Knockdown of circular RNA septin 9 inhibits the malignant progression of breast cancer by reducing the expression of solute carrier family 1 member 5 in a microRNA-149-5p-dependent manner.

Breast cancer (BC) is the most frequently diagnosed cancer in women. Increasing evidence suggests that circular RNA (circRNA) exerts critical functions in BC progression. However, the roles of circRNA septin 9 (circSEPT9) in BC development and the underneath mechanism remain largely unclear so far. In this work, the RNA levels of circSEPT9, microRNA-149-5p (miR-149-5p) and solute carrier family 1 member 5 (SLC1A5) were detected by quantitative real-time polymerase chain reaction. Western blot was performed to check protein expression. Glutamine uptake, cell proliferation and cell apoptosis were investigated by glutamine uptake, cell counting kit-8, cell colony formation, 5-Ethynyl-29-deoxyuridine, flow cytometry analysis or DNA content quantitation assay. The interactions of miR-149-5p with circSEPT9 and SLC1A5 were identified by a dual-luciferase reporter assay. Mouse model assay was carried out to analyze the effect of circSEPT9 on tumor formation in vivo. Results showed that circSEPT9 and SLC1A5 expression were significantly upregulated, while miR-149-5p was downregulated in BC tissues and cells as compared with paracancerous normal breast tissues and human normal breast cells. Knockdown of circSEPT9 or SLC1A5 inhibited glutamine uptake and cell proliferation, but induced cell apoptosis in BC cells. SLC1A5 overexpression relieved circSEPT9 silencing-induced repression of BC cell malignancy. In mechanism, circSEPT9 regulated SLC1A5 expression by sponging miR-149-5p. In support, circSEPT9 knockdown led to delayed tumor tumorigenesis in vivo. In summary, these results indicates that circSEPT9 may act an oncogenic role in BC malignant progression by regulating miR-149-5p/SLC1A5 pathway, providing a novel mechanism responsible for BC development.

The comparison of microbial communities in thyroid tissues from thyroid carcinoma patients.

Thyroid carcinoma is a common endocrine organ cancer associated with abnormal hormone secretion, leading to the disorder of metabolism. The intestinal microbiota is vital to maintain digestive and immunologic homeostasis. The relevant information of the microbial community in the gut and thyroid, including composition, structure, and relationship, is unclear in thyroid carcinoma patients. A total of 93 samples from 25 patients were included in this study. The results showed that microbial communities existed in thyroid tissue; gut and thyroid had high abundance of facultative anaerobes from the Proteobacteria phyla. The microbial metabolism from the thyroid and gut may be affected by the thyroid carcinoma cells. The cooccurrence network showed that the margins of different thyroid tissues were unique areas with more competition; the stabilization of microcommunities from tissue and stool may be maintained by several clusters of species that may execute different vital metabolism processes dominantly that are attributed to the microenvironment of cancer.

Diagnostic Value of Serum lncRNA HOTAIR Combined with Galectin-3 in Benign and Papillary Thyroid Carcinoma.

PURPOSE: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. LncRNA HOTAIR (HOx Transcript AntIsense RNA) and Galectin-3 are involved in PTC. This study explored the clinical effect of lncRNA HOTAIR/Galectin-3 on PTC patients. METHODS: Subjects were assigned into PTC (160 cases) and benign thyroid tumor groups (150 cases). Fasting peripheral venous blood was collected. LncRNA HOTAIR/Galectin-3 expressions in serum were detected. Subjects were assigned into HOTAIR/Glactin-3 high/low expression groups and their correlation with age, gender, BMI, tumor size, pathological stage, TSH, TPO-Ab, and TG-Ab in PTC was analyzed. Receiver operating characteristic (ROC) curve was conducted on diagnostic efficacy of HOTAIR or/and Galectin-3. The difference of area under the curve (AUC) was compared and analyzed. RESULTS: HOTAIR and Glactin-3 were higher in PTC group and correlated with tumor pathological stage. Higher HOTAIR/Glactin-3 expression indicated a more advanced TNM stage. LncRNA HOTAIR was positively correlated with TPO-Ab and TG-Ab. AUC of HOTAIR for PTC diagnosis was 0.895, with 96.00% specificity and 80.63% sensitivity. AUC of Glactin-3 for PTC diagnosis was 0.817, with 66.67% specificity and 78.75% sensitivity. AUC of HOTAIR combining with Glactin-3 for PTC diagnosis was 0.969 with 96.00% specificity and 87.50% sensitivity. AUC of lncRNA HOTAIR was higher than that of Glactin-3, while AUC of the combination was higher than that of lncRNA HOTAIR or Glactin-3. CONCLUSION: LncRNA HOTAIR and Glactin-3 were highly expressed in PTC. The combination detection of lncRNA HOTAIR/Glactin-3 had higher diagnostic efficiency on the differential diagnosis of benign thyroid tumor and PTC.

Peripheral Blood Leukocytes and Platelets Serve as Prognostic Factors in Breast Cancer.

Background: Tumor-infiltrating lymphocytes have been reported to be associated with response to neoadjuvant chemotherapy and survival in breast cancer (BC) patients. However, little is known about the value of peripheral blood parameter in predicting the prognosis in BC. Methods: In this study, parameters of complete blood count from 417 BC patients with a median 7.6-year follow-up after surgery were collected and correlated with patient survival. Results: It was found that leukocyte counts were positively correlated with disease-free survival (DFS, p = 0.016) and overall survival (OS, p = 0.014), whereas platelet counts were negatively correlated with DFS (p = 0.003) and OS (p = 0.082) in BC. Leukocyte and platelet counts were independent prognostic factors for the BC patient survival. Besides, the prognostic value of leukocyte and platelet counts was further evaluated in the BC patients with different molecular subtypes. Together, BC patients with high leukocyte counts and low platelet counts had better DFS (p = 0.001) and OS (p = 0.017) than the other patients. Conclusion: Parameters of complete blood count could be acquired easily and serve as cost-effective prognostic biomarkers in BC.

LncRNA EGOT decreases breast cancer cell viability and migration via inactivation of the Hedgehog pathway.

The long noncoding RNA (lncRNA) Eosinophil Granule Ontogeny Transcript (EGOT) has been reported to inhibit the proliferation and migration of glioma cells, and promote the development and progression of gastric cancer through the Hedgehog (Hh) signaling pathway. This study was conducted to assess the role of EGOT in the progression of breast cancer. We observed that EGOT is significantly down-regulated in breast cancer tissues and cell lines, and EGOT expression is negatively correlated with the Ki67 expression. Overexpression of EGOT in BT549 cells decreased cell viability and migration. In addition, overexpression of EGOT resulted in decreases in expression of key genes in the Hh pathway, including Gli1, smoothened protein, protein patched homolog 1 and Hedgehog-interacting protein (HHIP). Breast cancer tissues exhibited an increase in Gli1 expressions. Altered expression of Gli1, smoothened protein, protein patched homolog 1 and HHIP caused by EGOT overexpression were fully restored in cells transfected with plasmid complementory DNA (pcDNA) EGOT and treated with purmorphamine, an agonist of the Hh pathway. Cell viability and migration were also restored by purmorphamine. We conclude that lncRNA EGOT may inhibit breast cancer cell viability and migration via inactivation of the Hh pathway.

Application of circulating tumor DNA in breast cancer.

Precision medicine has been well recognized since it was proposed, and the invention of liquid biopsy meets the needs of this era. Circulating tumor DNA (ctDNA), one of the most promising components of liquid biopsies, has quickly become the focus of research in recent years because of its unique advantages in clinical application. This article reviews the clinical application of ctDNA in breast cancer detection in recent years and its potential clinical value.

FoxP3 promotes lymph node metastasis in patients with papillary thyroid carcinoma complicated with Hashimoto's thyroiditis.

BACKGROUND: To investigate the effect of Treg cells on patients with PTC complicated with HT. METHODS: We collected thyroid fresh tissue of human after surgery, paraffin tissue and serum samples (cancer tissue which was diagnosed by pathology). Analysed the expression of nuclear specific marker gene FoxP3 in Treg cells by Envision immunohistochemical staining. Transwell cell chamber was used to simulate the co-action environment of umbilical cord blood initial T lymphocytes and thyroid papillary carcinoma cells (TPC-1and K1). Compared with human normal thyroid follicular epithelial cell line Nthy-ori 3-1. Flow cytometry was used to detect the proportion of Treg cells (CD4+CD25+CD127-/CD4+CD25+%) at 0, 24, 36, 48, 60 h after co-administration of thyroid papillary carcinoma cell lines (TPC-1 and K1) and umbilical cord blood initial T lymphocytes. The expression of FoxP3 protein in co-acting T lymphocytes was detected by Western blot. RESULTS: The results showed that the positive expression of FoxP3 in the tumor microenvironment of PTC patients with or without HT promoted lymph node metastasis of tumors and played a role in inhibiting tumor immunity. PTC cancer cells could induce initial T lymphocyte differentiating into Treg cells. At 36 h, the ratio of Th17 cells and Treg cells which were differentiated was the highest. The balance of Th17/Treg was significantly biased toward Th17. The proportion of FoxP3 induced by K1 cell line with lymph node metastasis was higher than that of TPC-1 cell line without lymph node metastasis. CONCLUSIONS: FoxP3 could promote lymph node metastasis to inhibit tumor immunity by dysregulation of Th17/Treg balance in PTC patients complicated with HT.

Distribution and prognostic value of tumor­infiltrating T cells in breast cancer.

Tumor-infiltrating lymphocytes are associated with the response to neoadjuvent chemotherapy and prognosis in breast cancer. However, the distribution, interaction and prognostic value of tumor­infiltrating T cells, the main component of the tumor microenvironment, have seldom been reported. In the present study, surgical specimens of 72 breast cancer patients were analyzed. Tumor­infiltrating T cell subsets [cluster of differentiation (CD)4+T, CD8+T and regulatory T cells] and expression of their cytokines [interferon­Î³, interleukin (IL)­4, and IL­17] were evaluated by flow cytometry. These parameters together with The Cancer Genome Atlas database were used to demonstrate the distribution, interaction and prognostic value of tumor­infiltrating T cells in breast cancer. Tumor­infiltrating lymphocytes were closely associated with histological grade (P=0.03), estrogen receptor status (P=0.006), human epidermal growth factor receptor 2 status (P=0.047) and molecular subtype in breast cancer (P=0.012). The gene expression of CD4, CD8A and forkhead box protein P3 in the tumor was increased compared with healthy breast tissue, and was positively associated with the prognosis of breast cancer patients. HER2+ and triple­negative breast cancer exhibited a significantly increased percentage of CD4+T cells (P=0.01) and regulatory T cells (P=0.035), and a decreased percentage of CD8+T cells (P=0.006) compared with the luminal subtype. Furthermore, the regulatory T cell number was positively correlated with CD8+T cell number in tumors (R=0.7, P=1.5x10­162) and significantly inhibited the cytokine secretion of T cells. These results reveal the distribution and interaction of tumor­infiltrating T cell subsets, and indicate that CD8+T cells and regulatory T cells may be used as reliable predictors of prognosis in breast cancer.

Effect of resveratrol on doxorubicin resistance in breast neoplasm cells by modulating PI3K/Akt signaling pathway.

In the study, we probed into the effect of Resveratrol (RES) on Doxorubicin (DOX)-resistant breast neoplasm cell line MCF-7/DOX as well as the mechanism of RES underlying the DOX-resistant breast cancer. CCK-8 assay was utilized to assess the survival rates and sensitivity of breast neoplasm cell lines MCF-7 or MDA-MB-231 to DOX and RES. DOX-resistant MCF-7 cell line was successfully cultivated with DOX dose increasing and was named MCF-7/DOX. Afterwards, wound healing and Transwell assays were performed to measure the migration and invasion capabilities of MCF-7/DOX cells, while cell propagation and apoptosis were determined by colony formation assay and flow cytometry analysis. Both western blotting and immunohistochemistry were conducted to examine the expression of proteins involved in PI3K/Akt signaling pathway. Nude mice xenograft model was constructed to further verify the effects of DOX and RES on breast neoplasm in vivo. RES restored DOX sensitivity in MCF-7/DOX cells, inhibiting biological functions of MCF-7/DOX cells and promoting cell apoptosis in vitro and impeding tumor growth in vivo. It was revealed by the mechanistic studies that MCF-7/DOX cells could regain the drug sensibility with RES treatment through inactivating the PI3K/Akt signal transduction pathway. RES could reverse DOX resistance in breast neoplasm cells and inhibited DOX-resistant breast cancer cell propagation and metastasis and facilitated cell apoptosis by modulating PI3K/Akt signaling pathway. © 2018 IUBMB Life, 70(6):491-500, 2018.

The relationship between RASSF1A promoter methylation and thyroid carcinoma: A meta-analysis of 14 articles and a bioinformatics of 2 databases (PRISMA).

BACKGROUND: DNA promoter methylation can suppresses gene expression and shows an important role in the biological functions of Ras association domain family 1A (RASSF1A). Many studies have performed to elucidate the role of RASSF1A promoter methylation in thyroid carcinoma, while the results were conflicting and heterogeneous. Here, we analyzed the data of databases to determine the relationship between RASSF1A promoter methylation and thyroid carcinoma. METHODS: We used the data from 14 cancer-normal studies and Gene Expression Omnibus (GEO) database to analyze RASSF1A promoter methylation in thyroid carcinoma susceptibility. The data from the Cancer Genome Atlas project (TCGA) database was used to analyze the relationship between RASSF1A promoter methylation and thyroid carcinoma susceptibility, clinical characteristics, prognosis. Odds ratios were estimated for thyroid carcinoma susceptibility and hazard ratios were estimated for thyroid carcinoma prognosis. The heterogeneity between studies of meta-analysis was explored using H, I values, and meta-regression. We adopted quality criteria to classify the studies of meta-analysis. Subgroup analyses were done for thyroid carcinoma susceptibility according to ethnicity, methods, and primers. RESULTS: Result of meta-analysis indicated that RASSF1A promoter methylation is associated with higher susceptibility to thyroid carcinoma with small heterogeneity. Similarly, the result from GEO database also showed that a significant association between RASSF1A gene promoter methylation and thyroid carcinoma susceptibility. For the results of TCGA database, we found that RASSF1A promoter methylation is associated with susceptibility and poor disease-free survival (DFS) of thyroid carcinoma. In addition, we also found a close association between RASSF1A promoter methylation and patient tumor stage and age, but not in patients of different genders. CONCLUSIONS: The methylation status of RASSF1A promoter is strongly associated with thyroid carcinoma susceptibility and DFS. The RASSF1A promoter methylation test can be applied in the clinical diagnosis of thyroid carcinoma.

Papillary thyroid carcinoma risk factors in the Yunnan plateau of southwestern China.

OBJECTIVE: This study investigated clinical and pathological characteristics and risk factors in papillary thyroid carcinoma (PTC) patients' native to Yunnan plateau in southwestern China. METHODS: Clinical data from 1,198 patients diagnosed with PTC (n=578) and control subjects (n=620) with benign thyroid disease (ie, thyroid nodule disease, benign thyroid diseases [BTD]) in Yunnan province were analyzed retrospectively. RESULTS: The mean patient age was lower for PTC than for BTD. Positive ratios of thyroid peroxidase antibody, thyroglobulin antibody (TGAb), and thyrotrophin receptor antibody (TRAb) were higher in PTC than in BTD patients. The ratio of PTC coexisting with Hashimoto's thyroiditis (HT) or with lymphocytic thyroiditis was higher than that of BTD. The number of patients whose age at menarche was ≤13 years, who had given birth to less than or equal to two children, or who were in premenopause were higher in the PTC than in the BTD group. Multivariate conditional logistic regression analyses revealed that age >45 years, nodal size >1 cm, and elevated TG levels were protective factors against PTC. Abnormally elevated TGAb and TRAb levels were independent risk factors for PTC in females. CONCLUSION: HT was not an independent risk factor for but was associated with PTC. TRAb is a risk factor for PTC in individuals living in the Yunnan plateau, but not for those in the plains region.

A Systematic Analysis of the Relationship of CDH13 Promoter Methylation and Breast Cancer Risk and Prognosis.

BACKGROUND: CDH13 (cadherin 13) is a special cadherin cell adhesion molecule, and the methylation of its promoter causes inactivation in a considerable number of human cancers. To explore the association between CDH13 promoter methylation and breast cancer risk and prognosis, we systematically integrated published articles to investigate the diagnostic performance of the CDH13 methylation test for breast cancer. An independent DNA methylation microarray dataset from The Cancer Genome Atlas project (TCGA) project was used to validate the results of the meta-analysis. METHODS: The relevant literature was searched using the PubMed, Cochrane Library, Web of Science and Google Scholar databases for articles published in English up to May 2015. Data were analyzed using random effect or fixed effect models. The effect sizes were estimated by measuring an odds ratio (OR) or hazard ratio (HR) with a 95% confidence interval (CI). A chi-squared based Q test and sensitivity analysis were performed to examine the between-study heterogeneity and the contribution of single studies to the final results, respectively. Funnel plots were constructed to evaluate publication bias. RESULTS: Seven hundred and twenty-six breast tumor samples and 422 controls were collected from 13 published studies. The data from the TCGA set include both tumor and normal samples. A significant association was observed between CDH13 promoter methylation and breast cancer, with an aggregated OR equal to 13.73 (95%CI: 8.09~23.31, z = 9.70, p<0.0001) as measured using the fixed effect model and 14.23 (95%CI: 5.06~40.05, z = 5.03, p<0.0001) as measured using a random effect model. The HR values were calculated as 0.77 (95%CI: 0.27~2.21, z = -0.49, p = 0.622) and 0.38 (95%CI: 0.09~1.69, z = -1.27, p = 0.20) for overall survival (OS) and disease-free survival (DFS), respectively, using the random effect model. This result indicated that breast cancer patients with CDH13 promoter methylation correlated non-significantly with prognosis and is therefore similar to the findings of the TCGA project. CONCLUSIONS: The methylation status of CDH13 promoter was strongly associated with breast cancer risk. However, CDH13 promoter methylation was not significantly related to the OS and DFS of breast cancer and may have limited prognostic value for breast cancer patients.

Predictive role of the overexpression for CXCR4, C-Met, and VEGF-C among breast cancer patients: A meta-analysis.

BACKGROUND: The overexpression of CXCR4, C-Met and VEGF-C present widely in breast tumors, they may be markers of resistance to treatment. However, the studies are still controversial. Thus, this meta-analysis aims to research the relationship between the overexpression of CXCR4, C-Met, VEGF-C and clinical prognosis among breast cancer patients. METHODS: PubMed and EMBASE databases were searched for eligible literature. The outcomes of interest were progression-free survival (PFS), relapse-free survival (RFS) and overall survival (OS). All tests of statistical significance were two sided. RESULTS: A total of 7830 patients from 28 eligible studies were assessed. The overexpression of the CXCR4 and C-Met both implied significantly worse PFS compared with normal expression [HR = 2.56, 95% CI = 1.34-4.91, P = 0.005; and HR = 1.63 95% CI = 1.20-2.22, P = 0.002]. Meanwhile, if patients had high expression of CXCR4, they would have worse OS [HR = 2.56 95% CI = 1.52-4.31, P = 0.000]. However, the overexpression of C-Met did not relate to OS for breast cancer patients [HR = 1.16, 95% CI = 0.69-1.95, P = 0.570]. Meanwhile, no statistically significant different was observed with respect to PFS and OS between VEGF-C overexpression and normal expression [HR = 0.99, 95% CI = 0.64-1.52, P = 0.968; and HR = 0.76, 95% CI = 0.43-1.33, P = 0.333]. CONCLUSIONS: Our meta-analysis showed that CXCR4 and C-Met were efficient prognostic factors for breast cancer. Nevertheless, highly expressing VEGF-C was not related to progression-free survival and overall survival. Due to the small samples and insufficient date, further studies should be conducted to clarify the association between the overexpression of CXCR4 or C-Met or VEGF-C and the prognosis about breast cancer patients.

New Cytotoxic Tigliane Diterpenoids from Croton caudatus.

Three new tigliane-type diterpenoids were isolated from the methanolic extract of the twigs and leaves of Croton caudatus, trivially named crotusins A-C (1-3). The structures of compounds 1-3 were elucidated on the basis of extensive spectral methods. These new compounds were highly oxygenated and heavily substituted. Cytotoxic activity against five human tumor cell lines was assessed for compounds 1-3 of which compound 3 showed significant inhibitory activity with IC50 values ranging from 0.49 to 4.19 µM against these cells, while crotusins A and B exhibited moderate activity.

Potent anti-inflammatory and analgesic steroidal alkaloids from Veratrum taliense.

ETHNOPHARMACOLOGICAL RELEVANCE: "Pimacao" (the roots and rhizomes of Veratrum taliense Loes.) has been used as traditional folk medicine in Yunnan province (PR China) for the treatment of pain, swelling, and inflammation. It is the main component of the renowned traditional Chinese medicine, "Yunnan Baiyao". Previous investigations and clinical research have shown significant analgesic activity of Pimacao. AIM OF THE STUDY: The aim of the present study was to find out the compounds responsible for anti-inflammatory and analgesic activity present in V. taliense. MATERIALS AND METHODS: The total alkaloids were the subject of phytochemical investigation and the compounds were isolated by multiple step chromatography. Their structures were elucidated on the basis of comprehensive spectroscopic data. Anti-inflammatory activity was evaluated using carrageenan induced paw oedema and analgesic activity was assessed using acetic acid-induced writhing in mice. RESULTS: Three new steroidal alkaloids, veratralines A-C (1-3), together with five known analogs, were isolated from the roots and rhizomes of V. taliense. All the compounds had the analgesic activity and significantly decreased the number of writhes caused by acetic acid much better than Dolantin. All the alkaloids except 8, possessed anti-inflammatory activity, in which 3, 5, and 7 significantly inhibited the paw oedema caused by carrageenan compared with Indomethacin. CONCLUSION: This is the first report of jervine-type alkaloids responsible for the anti-inflammatory and analgesic properties of Pimacao. We provide scientific evidence to support that the roots and rhizomes of V. taliense are useful in traditional Chinese medicine for the treatment of pain and inflammation.

Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for preeclampsia: a meta-analysis.

OBJECTIVES: MTHFR C677T and A1298C have been associated with the risk of preeclampsia (PE), but with conflicting results. We performed this meta-analysis to derive a more precise estimation of the association between MTHFR polymorphisms and PE. STUDY DESIGN: An electronic search of PubMed and Chinese Biomedicine database was conducted to select studies for meta-analysis. 54 case controlled studies containing MTHFR C677T and A1298C gene polymorphisms were chosen, and odds ratio (OR) with confidence interval (CI) was used to assess the strength of this association. RESULT: These studies evaluated 7398 cases and 11230 controls for MTHFR C677T. The overall results suggested that MTHFR C677T was associated with the risk of PE. (T vs. C: OR = 1.157, 95% CI: 1.057-1.266, p = 0.002; TT + CT vs. CC: OR = 1.165, 95% CI : 1.049-1.293, P = 0.004; TT vs. CT + CC: OR = 1.371, 95% CI: 1.153-1.63, p < 0.001). We also evaluated 1103 cases and 988 controls for MTHFR A1298C but could not demonstrate an increased risk of PE for this polymorphism (p = 0.667). A symmetric funnel plot, the Egger's test (p = 0.819) suggested a lack of publication bias. CONCLUSION: This meta-analysis supports the idea that MTHFR C677T genotype is associated with increased risk for PE, especially in the case of Asians and Caucasians.

The prognosis of MGMT promoter methylation in glioblastoma patients of different race: a meta-analysis.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair gene. Epigenetic silencing of the MGMT promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma (GBM) who receive alkylating agents. But the prognostic of MGMT promoter methylation in GBM patients of different race is still ambiguous. Based on an univariate or multivariate analysis between different race (Caucasian and Asian), a meta-analysis of the effects of MGMT promoter methylation on both progression-free survival (PFS) and overall survival (OS) among GBM patients was conducted. A total of 6,309 patients from 50 studies were involved in the analysis. Random effect models were applied to estimate the pooled hazard ratio (HR) with 95 % confidence intervals (CIs) for GBM patients of different race prognosis, the Chi square-based Q test was used to test heterogeneity. Begg's (funnel plot method) and Egger's linear regression tests were adopted to check publication bias (a bias with regard to what is likely to be published, among what is available to be published). The HR value estimated for OS was 0.524 (95 % CI 0.428-0.640) by univariate analysis and 0.427 (95 % CI 0.355-0.513) by multivariate analysis in Caucasian. The HR value estimated for OS was 0.892 (95 % CI 0.469-1.698) by univariate analysis and 0.562 (95 % CI 0.394-0.804) by multivariate analysis in Asian. The HR value estimated for PFS was 0.526 (95 % CI 0.372-0.743) by univariate analysis and 0.437 (95 % CI 0.356-0.537) by multivariate analysis in Caucasian. The HR value estimated for PFS was 0.132 (95 % CI 0.006-3.027) by multivariate analysis in Asian. This data revealed that GBM patients with MGMT promoter methylation had longer OS and PFS by univariate or multivariate analysis in Caucasian regardless of therapeutic intervention. However, GBM patients with MGMT promoter methylation only had longer OS by multivariate analysis in Asian.