Understanding human 15-hydroxyprostaglandin dehydrogenase binding with NAD+ and PGE2 by homology modeling, docking and molecular dynamics simulation

Homology modeling, molecular docking, and molecular dynamics simulation have been performed to determine human 15-hydroxyprostaglandin dehydrogenase (15-PGDH) binding with its NAD+ cofactor and prostaglandin E2 (PGE2) substrate. The computational studies have led to a three-dimensional (3D) model of the entire 15-PGDH-NAD+-PGE2 complex, demonstrating the detailed binding of PGE2 with 15-PGDH for the first time. This 3D model shows specific interactions of the protein with the cofactor and substrate in qualitative agreement with available experimental data. Our model demonstrates the PGE2-binding cavity of the protein for the first time. The model further leads to an interesting prediction that the catalytic activity of 15-PGDH should also significantly be affected by Gln148, in addition to the previously known three catalytic residues (Ser138, Tyr151, and Lys155). The reported 3D model of 15-PGDH-NAD+-PGE2 complex might be valuable for future rational design of novel inhibitors of 15-PGDH.     

Expression of prostaglandin D synthase and the prostaglandin D2 receptors DP and CRTH2 in human nasal mucosa

BACKGROUND: Prostaglandin D2 (PGD2) is released from mast cells during the allergic response. OBJECTIVE: Since PGD2 has been shown to induce nasal congestion in humans, we investigated the distribution of hematopoietic prostaglandin D synthase (PGDS) and the two PGD2 receptors, DP and CRTH2 in human nasal mucosa from healthy subjects and subjects suffering from polyposis, a severe form of chronic rhinosinusitis. METHODS: DP mRNA expression was detected by in situ hybridization while PGDS, CRTH2 and various leukocyte markers expression were revealed by immunohistochemistry. RESULTS: In the normal mucosa, PGDS was only detected in few resident mast cells while CRTH2 was undetectable. In contrast, DP receptor mRNA was detected in epithelial goblet cells, serous glands and in the vasculature. In the nasal mucosa of subjects suffering from polyposis: (1) PGDS was detected in mast cells and other large infiltrating inflammatory cells, (2) both DP mRNA and CRTH2 were detected in eosinophils and (3) CRTH2 was detected on a subset of infiltrating T cells. Although DP mRNA could not be detected in the T cells invading the nasal mucosa, it was found to be expressed in the T cells present in the lymph node and the thymus from normal individuals. CONCLUSION: This study indicates that cells capable of producing PGD2 are present in the nasal mucosa and that both PGD2 receptors, DP and CRTH2, might play a role in inflammatory disease of the upper airways.     

Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet‐fed streptozotocin‐treated diabetic rats

Dapagliflozin (DAPA) is used for treating type 2 diabetes, whereas lansoprazole (LPZ) is used as a traditional antiulcer drug. The present study investigated the possible antidiabetic effects of LPZ on fortified diet‐fed streptozotocin (FDF/STZ)‐induced insulin‐resistant diabetic rats. On the basis of the current results, it can be concluded that LPZ could be used as an add‐on drug along with the conventional treatment for T2D as it showed beneficial effects in the current experimental model of insulin resistance.     

Human,Oceanographic and Habitat Drivers of Central and Western Pacific Coral Reef Fish Assemblages

Coral reefs around US- and US-affiliated Pacific islands and atolls span wide oceanographic gradients and levels of human impact. Here we examine the relative influence of these factors on coral reef fish biomass, using data from a consistent large-scale ecosystem monitoring program conducted by scientific divers over the course of >2,000 hours of underwater observation at 1,934 sites, across ~40 islands and atolls. Consistent with previous smaller-scale studies, our results show sharp declines in reef fish biomass at relatively low human population density, followed by more gradual declines as human population density increased further. Adjusting for other factors, the highest levels of oceanic productivity among our study locations were associated with more than double the biomass of reef fishes (including ~4 times the biomass of planktivores and piscivores) compared to islands with lowest oceanic productivity. Our results emphasize that coral reef areas do not all have equal ability to sustain large reef fish stocks, and that what is natural varies significantly amongst locations. Comparisons of biomass estimates derived from visual surveys with predicted biomass in the absence of humans indicated that total reef fish biomass was depleted by 61% to 69% at populated islands in the Mariana Archipelago; by 20% to 78% in the Main Hawaiian islands; and by 21% to 56% in American Samoa.     

The effect of radiotherapy and chemotherapy on osmotic fragility of red blood cells and plasma levels of malondialdehyde in patients with breast cancer

BackgroundGamma radiation effects on the erythrocyte membrane from three different functional parts, lipid bilayer, cytoskeleton and protein components. When the red cell membrane is exposed to radiation, it loses its integrity and hemoglobin leaks out. In addition, irradiation leads to lipid peroxidation and the products of this process, leading to hemolysis. The aim of the present study was to measure osmotic fragility (OF) of red blood cells and malondialdehyde (MDA) levels as a marker of oxidative injury in breast cancer patients treated with radiation and chemotherapy.Materials and MethodsThe OF test was performed using different concentrations of a salt solution. The measurement of MDA was done with chemical methods.¹¹ The sampling was taken during three stages of treatment: first sample was taken before starting chemotherapy, the second sample was taken before radiation therapy and the third sample was taken after radiotherapy.ResultsNo statistically significant differences between levels of MDA in these three stages of treatment were observed. However, the comparison of mean levels of MDA showed an increase after radiotherapy. The OF rate did not show significant difference (P > 0.05) during the stages of treatment.ConclusionIn a standard treatment program of radiotherapy and chemotherapy lipid peroxidation level and OF do not significantly increase.     

Global hypomethylation and promoter methylation in small intestinal neuroendocrine tumors: An in vivo and in vitro study

Aberrant DNA methylation is a feature of human cancer affecting gene expression and tumor phenotype. Here, we quantified promoter methylation of candidate genes and global methylation in 44 small intestinal-neuroendocrine tumors (SI-NETs) from 33 patients by pyrosequencing. Findings were compared with gene expression, patient outcome and known tumor copy number alterations. Promoter methylation was observed for WIF1, RASSF1A, CTNNB1, CXCL14, NKX2–3, P16, LAMA1, and CDH1. By contrast APC, CDH3, HIC1, P14, SMAD2, and SMAD4 only had low levels of methylation. WIF1 methylation was significantly increased (P = 0.001) and WIF1 expression was reduced in SI-NETs vs. normal references (P = 0.003). WIF1, NKX2–3, and CXCL14 expression was reduced in metastases vs. primary tumors (P < 0.02). Low expression of RASSF1A and P16 were associated with poor overall survival (P = 0.045 and P = 0.011, respectively). Global methylation determined by pyrosequencing of LINE1 repeats was reduced in tumors vs. normal references, and was associated with loss in chromosome 18. The tumors fell into three clusters with enrichment of WIF1 methylation and LINE1 hypomethylation in Cluster I and RASSF1A and CTNNB1 methylation and loss in 16q in Cluster II. In Cluster III, these alterations were low-abundant and NKX2-3 methylation was low. Similar analyses in the SI-NET cell lines HC45 and CNDT2 showed methylation for CDH1 and WIF1 and/or P16, CXCL14, NKX2-3, LAMA1, and CTNNB1. Treatment with the demethylating agent 5-azacytidine reduced DNA methylation and increased expression of these genes in vitro. In conclusion, promoter methylation of tumor suppressor genes is associated with suppressed gene expression and DNA copy number alterations in SI-NETs, and may be restored in vitro.     

Synthesis of N-Glycosylated Pyridiines as New Antimetabolite Agents

Abstract

Condensation of cyanoacetamide and cyanothioacetamide with the sodium salts of a-(hydroxymethylene)alkanones afforded the pyridine-2(1H)-ones and their corresponding thiones 3. Compounds 3 served as a key intermediates for the synthesis of N-glycosylated pyridines.     

The Influence of Lentinan on the Capacity of Repair of DNA Damage and Apoptosis Induced by Paclitaxel in Mouse Bone Marrow Cells

The ability of the flavonoid lentinan (LAN) to enhance the repair of paclitaxel (PAC)‐induced DNA damage and apoptosis in mouse bone marrow cells was investigated. Moreover, the possible mechanism underlying this modulation was determined. LAN was neither genotoxic nor apoptogenic at doses equivalent to 1 or 2 mg/kg/day. Pretreatment of mice with LAN significantly enhances the repair of PAC‐induced DNA damage and bone marrow suppression in a dose dependent manner. Moreover, LAN affords significant protection against PAC‐induced apoptosis. A significant increase of reactive oxygen species and a decrease in reduced glutathione levels were observed after PAC treatment and prior administration of LAN before PAC challenge ameliorated these oxidative stress markers. Conclusively, our study provides, for the first time, that LAN enhances the repair of PAC‐induced DNA damage and apoptosis that resides, at least in part, on its ability to modulate the cellular antioxidant levels and consequently protect bone marrow cells from PAC genotoxicity. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:370‐377, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21499     

Synthesis,anti-inflammatory,cytotoxic, and COX-1/2 inhibitory activities of cyclic imides bearing 3-benzenesulfonamide,oxime, and β-phenylalanine scaffolds: a molecular docking study

Abstract

Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2–4, and 9), oximes (11–13), and β-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2–82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED₅₀ of 35.4–45.3?mg kg^?1 relative to that of celecoxib (34.1?mg kg^?1). For the cytotoxic evaluation, the selected derivatives 2–6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59–5/59) at 10?μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2–5, and 9), acetophenone oxime (11–14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6–333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives 21–24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46–0.68.     

Exploring structure-activity relationship of S-substituted 2-mercaptoquinazolin-4(3H)-one including 4-ethylbenzenesulfonamides as human carbonic anhydrase inhibitors

Abstract

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2–13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2–13 with inhibition constants (K_Is) ranging from 57.8–740.2?nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with K_Is between 6.4 and 14.2?nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2–13 with K_I values ranging from 7.1 to 93.6?nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (K_Is ranging from 3.1 to 20.2?nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.