DNA binding properties and cell viabilities of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazone.

OBJECTIVE: This study aims to investigate the CT-DNA (Calf thymus DNA) binding properties and HeLa cell viabilities of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone (H2L1) and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazone (HL2). MATERIALS AND METHODS: A series of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone (H2L1) and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazonewere (HL2) were synthesized, and their structures were characterized through FT-IR, ESI-MS, elemental analysis, molar conductivities and X-ray diffraction. DNA binding properties between CT-DNA and metal complexes were investigated by UV-Vis spectrophotometry and viscosity titration. The toxicological properties of compounds on HeLa cell were measured in vitro. RESULTS: Ligand H2L1 or HL2 exhibits a tridentate and anion ligand and uses oxygen anion, nitrogen atom and sulfur atom to coordinate with metal ions. When coordinated with metal ions, the unit O=C-NH- of each ligand has been enolized and deprotonated into -O-C=N-. The suggested chemical formulas of metal complexes are: [Co(HL1)2], [Ni(HL1)2], [Cu(HL1)2], [Co(L2)2], [Cu(L2)2], [Zn(L2)2], [ScL2(NO3)2(H2O)2], [Pr(L2)2(NO3)] and [Dy(L2)2(NO3)]. Both ligands and their metal complexes can bind strongly to CT-DNA through hydrogen bond and intercalation with Kb of 104~105 L mol-1 compared to ethidium bromide [classical DNA intercalator, Kb(EB-DNA) = 3.068 × 104 L mol-1]; however, the groove pattern cannot be excluded. The coexistence of multiple binding modes may be a common form of drug binding to DNA. HeLa cell shows lower viabilities in the presence of [Ni(HL1)2] and [Cu(HL1)2] (*p < 0.05) compared to the other compounds, with the LC50 of 2.6 µmol L-1 and 2.2 µmol L-1, respectively. CONCLUSIONS: These compounds, especially [Ni(HL1)2] and [Cu(HL1)2], will be promising for anti-tumor drugs, which should be further studied.

MicroRNA-449b-5p promotes the progression of osteoporosis by inhibiting osteogenic differentiation of BMSCs via targeting Satb2.

OBJECTIVE: We aimed to explore the role of microRNA-449b-5p in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and its mechanism of action. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) assay was used to detect the expression levels of microRNA-449b-5p and osteogenic markers including RUNX2, OCN during BMSCs differentiation. The microRNA-449b-5p mimic and microRNA-449b-5p inhibitors were transfected into BMSCs to achieve microRNA-449b-5p overexpression and knockdown, then the expressions of osteogenic markers were detected by qRT-PCR. The ALP activity staining and the alizarin red staining were used to detect the activity of ALP and the mineralization ability of cells after overexpression and knockdown of microRNA-449b-5p. Binding sites for microRNA-449b-5p and Satb2 were predicted by TargetScan, the PicTar and microRNAanda programs, and confirmed by dual-luciferase reporter gene assay. The relationship between microRNA-449b-5p and Satb2 was analyzed by QRT-PCR and Western blot. The microRNA-449b-5p inhibitor and shSATB2 lentivirus were simultaneously transfected in BMSCs, and the expression levels of RUNX2, OCN and ALP were detected by qRT-PCR and ALP activity assays. RESULTS: microRNA-449b-5p expression gradually decreased during osteogenic differentiation. Overexpression of microRNA-449b-5p inhibited BMSCs differentiation by down-regulating ALP activity, RUNX2, and OCN expression, while the opposite result was observed after knockdown of microRNA-449b-5p. MicroRNA-449b-5p can bind to the 3'UTR end of Satb2, which was involved in the osteogenic differentiation of microRNA-449b-5p-regulated BMSCs, and silencing of Satb2 can abolish the positive effect of the microRNA-449b-5p inhibitor on osteoblasts differentiation. CONCLUSIONS: microRNA-449b-5p could aggravate osteoporosis by inhibiting osteogenic differentiation of BMSCs through targeting Satb2.

Terlipressin resolves ascites of cirrhotic rats through downregulation of aquaporin 2.

OBJECTIVES: To investigate the presence of aquaporin (AQP) 1 and AQP2 in kidneys of cirrhotic rats with ascites, and to determine the effect of terlipressin on AQP1 and AQP2 levels and its therapeutic efficacy in ascites treatment. METHODS: Eighteen rats were randomly divided into normal noncirrhotic rats treated with saline, cirrhotic rats treated with saline and cirrhotic rats treated with terlipressin (n = 6 per group). In all rats, 24-h net fluid-excretion volume, presence or absence of ascites and portal vein pressure were measured; AQP1 and AQP2 mRNA and protein levels in renal tissue were evaluated. RESULTS: Terlipressin resolved ascites in all animals in the terlipressin-treated group, and significantly increased the 24-h net fluid-excretion volume and decreased portal vein pressure compared with saline treatment. AQP1 and AQP2 were significantly upregulated in cirrhotic rat kidneys compared with normal control rat kidneys. Terlipressin administration significantly down regulated AQP2 in rat kidneys but did not affect AQP1. CONCLUSIONS: AQP1 and AQP2 are important factors in ascites induction. Terlipressin appears to be an effective drug for the treatment of ascites due to liver cirrhosis in a rat model, possibly due to AQP2 reduction in kidneys.

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study

BACKGROUND: Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL. METHODS: Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival. RESULTS: The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (<9 %). No new safety signals were reported. Objective response rate in 195 evaluable Chinese patients was 68.8 %, including four complete responses (2.1 %). Time to disease progression (TTP) and overall survival were 8.8 and 18.5 months, respectively. CONCLUSIONS: The safety and efficacy of first-line bevacizumab-based treatment in Chinese population with advanced NS-NSCLC are consistent with those in previous studies as well as in Asian subgroup population from SAiL study. No new safety signals were reported (AU)

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