Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and its prevalence has been increasing all over the world, which is also the leading cause of end-stage renal failure. Hydroxysafflor yellow A (HSYA) is the main active chemical component of Carthamus tinctorius L., and it is commonly used in patients with cardiovascular and cerebrovascular diseases in China. The aim of this study was to investigate the renal protective effects and molecular mechanisms of HSYA on high-fat diet (HFD) and streptozotocin- (STZ-) induced DN in rats. The DN rats were treated with HSYA for eight weeks. We assessed creatinine (CR), urea nitrogen (UN), glomerular volume, podocyte number, renal inflammation, oxidative stress, and cells apoptosis markers after HSYA treatment. The number of apoptotic cells was measured by the TUNEL assay, and apoptosis-related proteins BAX, caspase-3, and BCL-2 in the renal tissue were analyzed by western blot. The treatment with HSYA significantly decreased fasting blood glucose, CR, UN, and blood lipid profile, including triglyceride and total and low-density lipoprotein cholesterol, even though it did not change the rats’ body weights. The western blot results indicated that HSYA reversed the upregulation of BAX and caspase-3 and significantly increased BCL-2 in renal tissue. Moreover, the levels of TNF-α and the inflammatory products, including free fatty acids (FFA) and lactic dehydrogenase (LDH) in the HSYA group, were significantly decreased. For the oxidative stress marker, the superoxide dismutase (SOD) markedly increased in the HSYA treatment group, while the malondialdehyde (MDA) in the serum and kidney tissue evidently decreased. In conclusion, HSYA treatment preserved kidney function in diabetic nephropathy in the HFD- and STZ-induced rats. The potential mechanism of renal protective effect of HSYA might be through inhibiting oxidative stress, reducing inflammatory reaction, and attenuating renal cell apoptosis. Our studies present a promising use for Hydroxysafflor yellow A in the treatment of type 2 diabetes mellitus.

No abstract

No abstract

Two-Dimensional (2D) and Three-Dimensional (3D) Quantitative Structure -Activity Relationships (QSARs) of a series of analogues of ARC-111 with antitumor activity expressed as pIC 50 , which is defined as the negative value of the logarithm of necessary molar concentration of these compounds to cause 50% growth inhibition against tumor cell lines P388, have been studied by using a combined method of the DFT, MM2, and statistics for 2D, as well as the Comparative Molecular Field Analysis (CoMFA) for 3D. The established 2D-QSAR model shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient R 2 A of 0.869 and the square of the crossvalidation coefficient q 2 of 0.834 as well as the square of predictive correlation coefficient R 2 pred of 0.867 for the test set. The 3D-QSAR model also shows good correlative and predictive capabilities in terms of R 2 (0.993) and q 2 (0.674) when CoMFA fields are used for the whole studied compounds. The results from 2D-and 3D-QSAR analyses conformably show that the steric interaction plays a crucial role in determining the cytotoxicity of the compounds and that selecting a moderate-size substituent R as well as increasing the negative charge of C 28 at the same time are advantageous to improving the antitumor activity. Such results might offer some useful theoretical references for understanding the action mechanism and directing the molecular design of this kind of compound with antitumor activity.

The chemotherapeutic agents doxorubicin (dox) or 5-fluorouracil (5FU) are used to treat cancer cells as they cause irreparable DNA damage, inducing these aberrant cells to undergo cell death. The mediator of this process is presumed to be in part the tumor suppressor p53 which regulates genes involved in DNA repair and cell death. When MCF-7 breast cancer cells are treated with these drugs, we observed that the level of p53 and the p53 negative regulator, Mdm2, increased, as seen by others. But contrary to some reports, we observed minimal phosphorylation of p53 at serine 15 in MCF-7 cells after drug treatment. Interestingly, we determined that there was differential regulation of the kinases ATM and Chk2 with the drug treatments, likely the cause for the lack of phosphorylation of p53. We found a dramatic drop in p53 DNA binding affinity for p21 and other gene response elements (RE) after drug treatment. To determine if the p53 that accumulated in the drug treated cells was functionally active, we monitored changes in the protein products of two p53-regulated genes following drug treatment with and without the addition of a p53-specific siRNA. In response to 5FU, both p21 and Mdm2 proteins increased and that increase was alleviated if a p53-specific siRNA was added. This effect was not seen with the addition of dox. Thus, the phosphorylation at serine 15 is not necessary for the functional activation of this transcription factor. We propose a new model for the regulation of p53, Mdm2, and MdmX after drug treatment.

No abstract

No abstract

The hydrolysis process of Ru (III) complex (HL)[trans- RuCl 4L(dmso-S)] (L=4-amino-1,2,4-triazole) (1), a potential antitumor complex similar to the well-known antitumor agent (ImH)[trans- RuCl 4(dmso-S)(Im)](NAMI-A), was investigated using density functional theory (DFT) with the conductor-like polarizable continuum model (CPCM). The structural characteristics and the detailed energy profiles for the hydrolysis processes of this complex were obtained. For the first hydrolysis step, complex 1 with 4-amino-1,2,4-triazole ligand shows much faster aquation than NAMI-A with imidazole ligand and complex 2 with 4H-1,2,4-triazole ligand, and such a calculated result is in good agreement with the experimental one. For the second hydrolysis step, the formation of cis-diaqua products is found to be thermodynamically preferred over the trans isomers. In addition, on the basis of the analysis of electronic characteristics of species in the hydrolysis process, the trend in abilities (A) of hydrolysis products attacked nucleophilicly by pertinent biomolecules is revealed. These theoretical results will help in understanding the action mechanism of this potential Ru (III) drug with pertinent biomolecular targets.