Assessment of the inhibitory effects and molecular docking of some sulfonamides on human serum paraoxonase 1

Paraoxonase‐1 (PON1) is an organophosphate hydrolyzer and antiatherogenic enzyme. Due to the PON1's crucial functions, inhibitors and activators of PON1 must be known for pharmacological applications. In this study, we investigated the in vitro effects of some sulfonamides compounds on human serum PON1 (hPON1). For this aim, we purified the hPON1 from human serum with high specific activity by using simple chromatographic methods, and after the purification processes, we investigated in vitro interactions between the enzyme and some sulfonamides (2‐amino‐5‐methyl‐1,3‐benzenedisulfonamide, 2‐chloro‐4‐sülfamoilaniline, 4‐amino‐3‐methylbenzenesulfanilamide, sulfisoxazole, sulfisomidine, and 5‐amino‐2‐methylbenzenesulfonamide). IC₅₀, K_i values, and inhibition types were calculated for each sulfonamide. 2‐amino‐5‐methyl‐1,3‐benzenedisulfonamide and 2‐chloro‐4‐sülfamoilaniline exhibited noncompetitive inhibition effect, whereas 4‐amino‐3‐methylbenzenesulfanilamide, sulfisoxazole, and sulfisomidine exhibited mixed type inhibition. On the other hand, 5‐amino‐2‐methylbenzenesulfonamide showed competitive inhibition and so molecular docking studies were performed for this compound in order to assess the probable binding mechanism into the active site of hPON1.     

Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model

In a continuing study of our clinical candidate 5 VN/124-1 (TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure–activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ∼2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer.     

Effect of TNF-α and IL-1β genetic variants on the development of myocardial infarction in Turkish population

Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) genetic variants which resulting in TNF-α and IL-1 overproduction may increase susceptibility to autoimmune diseases such as atherosclerosis. We have studied the association of TNF-α G308A and IL-1β (+3953) C/T polymorphism with myocardial infarction in Turkish population. 143 patients with myocardial infarction and 213 age-matched healthy controls were included in the study. In univariant analysis, the frequencies of IL-1β, TNF-α genotype or allele, and haplotype of C:A and T:A were significantly elevated in patients when compared with those of controls. GA genotype of TNF-α, T allele of IL-1β and A of TNF-α allele seem to be risk factors for myocardial infarction. In contrast, CC genotype of IL-1β and GG genotype of TNF-α have protective effect against myocardial infarction. In multivariate logistic regression analysis, TNF-α A allele, gender and smoking were associated with myocardial infarction. In conclusion, we can state that TNF-α A allele might be associated with myocardial infarction.     

Gastroprotective,cytoprotective and antioxidant effects of Oleum cinnamomi on ethanol induced damage

Peptic ulcer disease is a gastrointestinal disorder defined by mucosal damage and free oxygen radicals associated with peptic ulcer and gastritis. Cinnamon is a traditional herb used for many diseases and it has also effects as an antioxidant, anti-inflammatory, antispasmodic and anti-ulcerative. Our research is based on oxidative stress and effects of Oleum cinnamomi on stomach, liver and kidney disorders induced by ethanol. In our experiment, 2–3 month old male Sprague–Dawley rats were used. One hour before the mucosal damage induced by 70 % ethanol, O. cinnamomi (2.5 ml/kg) was added into the groups. Gastric pH, analysis of gastric mucus and ulcer index were calculated from samples obtained from the stomach. Superoxide dismutase (SOD), malondialdehyde and catalase (CAT) levels were determined in stomach, liver and kidney homogenates and erythrocyte hemolysate. Histopathological examination of stomach, liver and kidney were determined with H&E staining. The non-treated ulcerative group showed higher scores than the control group which was treated with O. cinnamomi, when ulcer scores, gastric mucus and pH level of stomach are compared. Increased lipid peroxidation levels were observed in the liver, kidney and erythrocyte hemolysate. SOD activity was decreased in liver whereas increased in stomach of ethanol treated ulcerative groups. CAT levels were increased in stomach and liver of ethanol treated rats. Histopathological findings showed that ethanol treatment cause multiply organ damage such as stomach, liver and kidney injury. O. cinnamomi treatment protected these tissues from ethanol-induced damage. Consequently, the current investigation shows that O. cinnamomi has protective effects on ethanol-induced oxidative and mucosal damage.     

The p97 segregase cofactor Ubxn7 facilitates replisome disassembly during S-phase

Complex cellular processes are driven by the regulated assembly and disassembly of large multiprotein complexes. While we are beginning to understand the molecular mechanism for assembly of the eukaryotic DNA replication machinery (replisome), we still know relatively little about the regulation of its disassembly at replication termination. Recently, the first elements of this process have emerged, revealing that the replicative helicase, at the heart of the replisome, is polyubiquitylated prior to unloading and that this unloading requires p97 segregase activity. Two different E3 ubiquitin ligases have now been shown to ubiquitylate the helicase under different conditions: Cul2^Lrr1 and TRAIP. Here, using Xenopus laevis egg extract cell-free system and biochemical approaches, we have found two p97 cofactors, Ubxn7 and Faf1, which can interact with p97 during replisome disassembly during S-phase. We show only Ubxn7, however, facilitates efficient replisome disassembly. Ubxn7 delivers this role through its interaction via independent domains with both Cul2^Lrr1 and p97 to allow coupling between Mcm7 ubiquitylation and its removal from chromatin. Our data therefore characterize Ubxn7 as the first substrate-specific p97 cofactor regulating replisome disassembly in vertebrates and a rationale for the efficacy of the Cul2^Lrr1 replisome unloading pathway in unperturbed S-phase.     

Size‐based interactions and trophic transfer efficiency are modified by fish predation and cyanobacteria blooms in Lake Mývatn,Iceland

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Paraoxonase 55 and 192 polymorphism and its relationship to serum paraoxonase activity and serum lipids in Turkish patients with non-insulin dependent diabetes mellitus

We investigated the effect of PON 55 and PON 192 polymorphisms on serum PON1 activity and lipid profiles in 213 non-insulin dependent diabetes mellitus (NIDDM) individuals and 116 non-diabetic controls among Turkish subjects. The distribution of PON 55/192 gene polymorphism was determined by polymerase chain reaction-based restriction fragment length polymorphism. Serum lipid levels were measured enzymically. PON activity was measured by spectrophotometric assay of p-nitrophenol production following addition of paraoxon. We found that PON 55 and 192 genotype distribution was similar in patients and controls and paraoxonase activity was generally lower in diabetics than in control subjects. We showed that PON 55 and 192 genotypes have a major effect on serum PON activity. PON 192 BB homozygotes had significantly higher PON activity than AA and AB genotypes among the control and NIDDM populations (p<0.001). PON 55 MM homozygotes had significantly lower PON activity than did LL and LM genotypes in control and NIDDM populations (p<0.05). The PON1 55 and 192 polymorphisms did not consistently influence the serum lipid profiles in either population. In conclusion, our results suggest that the paraoxonase activities are affected by PON1 genetic variability in Turkish NIDDM patients and controls.