Neoamphimedine circumvents metnase-enhanced DNA topoisomerase IIα activity through ATP-competitive inhibition

Type IIα DNA topoisomerase (TopoIIα) is among the most important clinical drug targets for the treatment of cancer. Recently, the DNA repair protein Metnase was shown to enhance TopoIIα activity and increase resistance to TopoIIα poisons. Using in vitro DNA decatenation assays we show that neoamphimedine potently inhibits TopoIIα-dependent DNA decatenation in the presence of Metnase. Cell proliferation assays demonstrate that neoamphimedine can inhibit Metnase-enhanced cell growth with an IC(50) of 0.5 μM. Additionally, we find that the apparent K(m) of TopoIIα for ATP increases linearly with higher concentrations of neoamphimedine, indicating ATP-competitive inhibition, which is substantiated by molecular modeling. These findings support the continued development of neoamphimedine as an anticancer agent, particularly in solid tumors that over-express Metnase.     

Turning Meat,Poultry, Eggs,and Dairy Products Into Nutraceuticals Through Increasing Their Conjugated Linoleic Acid Levels,Part One: Reviewing the Literature of Benefits Claimed for Conjugated Linoleic Acids in Human Health

ABSTRACT

In the first of this two-part series of articles, the debate in the clinical literature over the reality or extent of particular positive health benefits of a putative nutraceutical, conjugated linoleic acids (CLAs), in human subjects will be reviewed. In the second article, the means by which animal scientists and farmers—responding as much to annual sales in the hundreds of millions of dollars in health food stores of seed oil capsules rich in CLAs, as opposed to any conclusive clinical science—are aggressively pursuing ways to feed livestock that would naturally increase the concentration of CLAs per conventional consumer dietary portions, essentially allowing meat, eggs, fluid milk and the processed foods derived from them to be marketed as functional foods. In both installments in this series, the core journals covering developments in CLA-related research are identified for agricultural and food science librarians.     

Combined targeting blockage of miR-29b/92b/106b inhibits gastric can-cer cell growth and migration

AIM: To investigate the metastasis-associated microRNAs (miRNAs, miR) in gastric cancer, and to determine their biological and therapeutic roles in this malignancy. METHODS: The tumor tissue samples from gastric cancer patients with or without lymph node metastasis were collected (n=3 each). miRNA microarray was used to determine the metastasis-associated miRNAs. Gastic cancer cell line BGC-823 was transfected with locked nucleic acidmodified antisense oligonucleotides of candidate miRNAs and subsequently used for functional assays including CCK-8 assay, flow cytometry, wound healing assay and Transwell migration assay. Furthermore, the in vivo xenograft mice were used to evaluate the tumor suppressive effect of collaborative inhibition of the candidate miRNAs. RESULTS: miR-29b, miR-92b and miR-106b were up-regulated in the tumor tissues from the gastric cancer patients with lymph node metastasis. The functional assays showed that blockage of miR-29b, miR-92b and miR-106b by antisense oligonucleotides in the BGC-823 cells significantly inhibited cell growth and migration, and induced apoptosis. Furthermore, the collaborative inhibition of these triple miRNAs remarkably suppressed tumor growth in vivo. CONCLUSION: miR-29b, miR-92b and miR-106b are metastasis-associated miRNAs. These miRNAs may provide promising therapeutic targets in gastric cancer.     

Relationship between phosphoglycerate kinase 1 and clinical features of prostate cancer and its role in prognosis

AIM: To study the expression and prognostic functions of phosphoglycerate kinase 1 (PGK1) in prostate cancer. METHODS: The prostatic samples were collected from the patients with prostate cancer and benign prostatic hyperplasia (BPH) in TCM-Integrated Hospital of Southern Medical University from Jan 2013 to Dec 2013. The protein expression of PGK1 in the prostate specimens was detected by immunohistochemical analysis and Western blot. Furthermore, the correlations of PGK1 expression with the clinicopathological features and prognosis of prostate cancer were also evaluate. RESULTS: The expression of PGK1 in the prostate specimens was significantly up-regulated compared with the BPH individuals. In addition, the expression of PGK1 was significantly correlated with the local infiltration, Gleason score, TNM grade, bone metastasis, and serum prostate-specific antigen (PSA) concentration. Finally, bone metastasis, serum PSA level and PGK1 expression were independent risk factors for prostate cancer illustrated by Cox analysis, and high expression of PGK1 was correlated with poor prognosis. CONCLUSION: PGK1 expression is an independent risk factor for prostate cancer, and it might act as a prognostic biomarker for prostate cancer.     

Association of tumor budding with tumor-infiltrating lymphocytes and prognosis in breast cancer patients

AIM: To investigate the relationship of tumor budding with clinicopathologic parameters, tumor-infiltrating lymphocytes (TILs) of tumor microenvironment and the prognosis in breast cancer patients.METHODS: A total of 178 HE section samples were collected from the breast cancer patients treated with surgery in the First Affilated Hospital of Jinan University during Jan. 2012 to Dec. 2016. The tumor budding and stromal tumor-infiltrating lymphocytes were observed under light microscope. The correlation of tumor budding with the clinicopathologic status and TILs were analyzed by χ² test. Kaplan-Meier survival analysis and Log-rank test were used to estimate the disease-free survival (DFS) and overall survival (OS).RESULTS: High tumor budding level was associated with more positive lymph nodes, higher grade, and more lymphovascular invasion. In addition, the patients with higher tumor budding level showed fewer TILs, while the patients with lower tumor budding level had more TILs. Furthermore, the patients with higher tumor budding level had a worse disease-free survival and overall survival than those with lower tumor budding level.CONCLUSION: Tumor budding is significantly associated with adverse clinicopathological characteristics of breast cancer and negatively correlated with TILs. Therefore, tumor budding may serve as a potential biomarker to predict the prognosis of breast cancer.     

Combination of dihydromyricetin and cisplatin significantly induces overexpression of Noxa and Bim in PC3 cells

AIM:To investigate the adjuvant effect of dihydromyricetin on cisplatin-based chemotherapy in prostate cancer and its mechanisms. METHODS:The viability of LNCaP and PC3 cells treated with different concentrations of dihydromyricetin and cisplatin was measured by MTT assay. The expression of FOXO1, Noxa and Bim, release of cytochrome C from mitochondria, and activation of caspase-9 and caspase-3 in PC3 cells treated with dihydromyricetin and cisplatin were determined by Western blot. Co-immunoprecipitation was performed to detect the interaction of apoptotic protease-activating factor-1 (Apaf-1) and caspase-9 in the PC3 cells. The apoptotic rate of PC3 cells was analyzed by flow cytometry. RESULTS:Adjuvant therapy of dihydromyricetin significantly enhanced the anti-tumor effect of cisplatin against prostate cancer in vitro. Dihydromyricetin significantly promoted the expression of FOXO1 in the PC3 cells. However, transfection with FOXO1 small interfering RNA (siRNA) obviously suppressed the adjuvant effect of dihydromyricetin. Combination of cisplatin and dihydromyricetin significantly induced the overexpression of Noxa and Bim, the release of cytochrome C, the interaction of Apaf-1 and caspase-9, the activation of caspase-9 and caspase-3, and the apoptosis in the PC3 cells. On the other hand, transfection with FOXO1 siRNA obviously suppressed the apoptotic pathway of PC3 cells treated with dihydromyricetin and cisplatin. CONCLUSION:Dihydromyricetin enhances the cytotoxicity of cisplatin against prostate cancer through the FOXO1-Bim/Noxa pathway in vitro.     

Juglone inhibits epithelial-mesenchymal transition of prostate cancer cells by regulating Wnt/β-catenin/Snail signaling pathway

AIM: To investigate the mechanism of juglone on epithelial-mesenchymal transition in prostate cancer cells. METHODS: Human prostate cancer LNCaP cells were divided into control group (without juglone), 12.5 μmol/L juglone group and 25 μmol/L juglone group. LNCaP cells in the latter 2 groups were treated with juglone for 24 h. The invasion ability of the LNCaP cells was detected by Transwell assay. The protein expression of E-cadherin, vimentin, Snail and β-catenin was determined by Western blot. The LNCaP cells were treated with LiCl and juglone in combination for 24 h, and the protein expression of Snail and E-cadherin was detected by Western blot.RESULTS: The results of Trans-well invasion assay showed that the invasion ability in juglone groups was significantly decreased (P<0.01). The protein expression of E-cadherin in the LNCaP cells treated with juglone was increased, and the expression levels of vimentin and β-catenin were reduced (P<0.01). Treatment with LiCl significantly attenuated the inhibitory effect of juglone on Snail expression and subsequent down-regulation of E-cadherin expression. CONCLUSION: Juglone inhibits the epithelial-mesenchymal transition by inhibiting the Wnt/β-catenin/Snail signaling pathway in the LNCaP cells.     

Progress on role of CCN1 in pulmonary diseases

Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) is an extracellular matrix-associated signaling protein consisting of 381 amino-acid residues, which has the regulatory function for a multitude of cellular responses. The pleiotropic effects of CCN1 on the initiation and resolution of inflammation as well as oncogenesis and development of tumor were reported. According to the numerous data from experimental and clinical studies, this article provides an overview on CCN1 and summarizes the latest understanding of the role of CCN1 in pulmonary diseases.     

Study on expression of long non-coding RNA in colon cancer tissues and adjacent tissues

AIM: To screen the differentially expressed long non-coding RNA (lncRNA) in colon cancer, and to explore its expression in colon cancer tissues and adjacent tissues. METHODS: The "Colon adenocarcinoma:Person neoplasm cancer status" which consisted of 36 cases of colon cancer tissues and 29 cases of normal colonic tissues was downloaded from the lncRNAtor database. The candidate genes were selected from these differentially expressed lncRNAs based on artificial criterion (P<0.01; fold change ≥ 2 or<0.5) and then validated by real-time PCR in 60 pairs of colon cancer tissues and adjacent tissues. RESULTS: A total of 50 lncRNAs were differentially expressed in colon cancer tissues, including 28 up-regulated and 22 down-regulated (P<0.01). The verifying results displayed that HNF1A-AS1 and ZDHHC8P1 were up-regulated (P<0.01), and SUZ12P expression was down-regulated (P<0.05), but the expression of AC069513.3 was not statistically significant between colon cancer tissues and adjacent tissues. The abilities of HNF1A-AS1, ZDHHC8P1, SUZ12P and AC069513.3 to discriminate the colon cancer from normal adjacent tissue by the ROC curve with an AUC of 0.729 (sensitivity 78%, specificity 67%), 0.617 (sensitivity 68%, specificity 55%), 0.689 (sensitivity 66%, specificity 55%) and 0.518 (sensitivity 52%, specificity 48%) were observed. CONCLUSION: Long non-coding RNA HNF1A-AS1 and ZDHHC8P1 are up-regulated and SUZ12P is down-regulated in colon cancer tissues, suggesting that they may be involved in the pathogenesis of colon cancer.