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Interest in the physiological role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens...
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Interest in the physiological role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens, which embody several groups of non-steroidal oestrogens including isoflavones & lignans that are widely distributed within the plant kingdom. Data from animal and in vitro studies provide plausible mechanisms to explain how phytoestrogens may influence hormone dependent states, but although the clinical application of diets rich in these oestrogen mimics is in its infancy, data from preliminary studies suggest potential beneficial effects of importance to health. Phytoestrogens are strikingly similar in chemical structure to the mammalian oestrogen, oestradiol, and bind to oestrogen receptors (ER) with a preference for the more recently described ER beta. This suggests that these compounds may exert tissue specific effects. Numerous other biological effects independent of the ER (e.g. antioxidant capacity, antiproliferative and antiangiogenic effects) have been ascribed to these compounds. Whether phytoestrogens have any biological activity in humans, either hormonal or non hormonal is a contentious issue and there is currently a paucity of data on human exposure. Much of the available data on the absorption and metabolism of dietary phytoestrogens is of a qualitative nature; it is known that dietary phytoestrogens are metabolised by intestinal bacteria, absorbed, conjugated in the liver, circulated in plasma and excreted in urine. Recent studies have addressed quantitatively what happens to isoflavones following ingestion--with pure compound and stable isotope data to compliment recent pharmacokinetic data for soy foods. The limited studies conducted so far in humans clearly confirm that soya isoflavones can exert hormonal effects. These effects may be of benefit in the prevention of many of the common diseases observed in Western populations (such as breast cancer, prostate cancer, menopausal symptoms, osteoporosis) where the diet is typically devoid of these biologically active naturally occurring compounds. However since biological effects are dependent on many factors including dose, duration of use, protein binding affinity, individual metabolism and intrinsic oestrogenic state, further clinical studies are necessary to determine the potential health effects of these compounds in specific population groups. However we currently know little about age related differences in exposure to these compounds and there are few guidelines on optimal dose for specific health outcomes.
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Steroid sulfatase (STS) plays a momentous role in the conversion of sulfated steroids, which are biologically inactive, into biologically active un-sulfated steroid hormones, which support the development and growth of a number of...
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Steroid sulfatase (STS) plays a momentous role in the conversion of sulfated steroids, which are biologically inactive, into biologically active un-sulfated steroid hormones, which support the development and growth of a number of hormone-dependent cancers, including breast cancer. Therefore, inhibitors of STS are supposed to be potential drugs for the treatment of breast and other steroid-dependent cancers. The present review concentrates on broad chemical classification of steroid sulfatase inhibitors. The inhibitors reviewed are classified into four main categories: Steroid sulfamate based inhibitors; Steroid non-sulfamate based inhibitors; Non-steroidal sulfamate based inhibitors; Non-steroidal non-sulfamate based inhibitors. A succinct overview of current treatment of cancer, estradiol precursors, STS enzyme and its role in breast cancer is herein described. (C) 2016 Elsevier Masson SAS. All rights reserved.
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Aromatase Inhibitors (AI) inhibit the metabolism of androgens into estrogens. Third generation AI are more potent and more specific than the previous ones. They can be divided in two classes, the steroidal and non-steroidal AI; th...
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Aromatase Inhibitors (AI) inhibit the metabolism of androgens into estrogens. Third generation AI are more potent and more specific than the previous ones. They can be divided in two classes, the steroidal and non-steroidal AI; they are active in postmenopausal breast cancer patients. Two non-steroidal AI (Anastrozole and Letrozole) have been compared to Tamoxifen as first line hormone therapy in metastatic breast cancer; they are at least as effective and probably more, and better tolerated than Tamoxifen; however no change in overall survival has been observed. A phase III trial is ongoing with the steroidal AI Exemestane.
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The structural features of copper(ii), nickel(ii), cobalt(ii) and zinc(ii) complexes with the antimicrobial drugs quinolones and non-steroidal anti-inflammatory drugs (NSAIDs) as ligands are discussed. The binding properties of th...
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The structural features of copper(ii), nickel(ii), cobalt(ii) and zinc(ii) complexes with the antimicrobial drugs quinolones and non-steroidal anti-inflammatory drugs (NSAIDs) as ligands are discussed. The binding properties of these complexes to biomolecules (calf-thymus DNA, bovine or human serum albumin) are presented and evaluated. The biological activity (antimicrobial, antioxidant and antiproliferative) of selected complexes is investigated. Further perspectives concerning the synthesis and the biological activity of novel complexes with quinolones or NSAIDs attractive to synthetic chemists, biochemists and/or biologists are presented.
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In the present investigation, several phenolics based structurally related compounds of steroidal and nonsteroidal skeletons were synthesized and tested for their modulatory effect on ornithine decarboxylase (ODC) activity, an enz...
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In the present investigation, several phenolics based structurally related compounds of steroidal and nonsteroidal skeletons were synthesized and tested for their modulatory effect on ornithine decarboxylase (ODC) activity, an enzyme overexpressed in cancer. Additionally, these compounds were also examined for radical scavenging action to establish a correlation with the cancer chemopreventive property. Our result suggests that the tested compounds possessed radical scavenging activity, for being the inherent property of the phenolics. 3-(3',4'5'-trimethoxyphenyl)-4,5,6-trimethoxyindan-1-one oxime (15) exhibited highest inhibition of enzyme activity (91%) followed by 1-(2,4-dibromophenyl)-3-[3-methoxyestra 1,3,5(10)-trien-17-acetate,2-yl]-2-propen-1-one (26) (85%), 2-Hydroxy, 3-(3',4',5'-trimethoxy phenyl)-4,5,6-trimethoxy ind-2-en-1-one (17) (80%), 1-(3,4-methylenedioxyphenyl)-3-(3,4,5-trimethoxyphenyl)-2-propen-1-one (13) (74%) and 1-(3-methoxy, 4-hydroxyphenyl)-3-[3-methoxyestra 1,3,5(10)-trien-17-acetate, 2-yl]-2-propen-1-one (28)(67%). Furthermore, it was observed that 1-(3-Methoxy, 4-hydroxyphenyl)-3-[3-methoxyestra 1,3,5 (10)-trien-17-acetate, 2-yl]-2-propen-1-one (28) showed the highest scavenging effect (67%) in nitric oxide (NO) assay, whereas 1-(3-methylphenyl)-3-[3-methoxy, 17-hydroxyestra 1,3,5(10)-trien, 2-yl]-2-propen-1-one (25) showed maximum inhibition of radical formation in 2,2-diphenyl-1-picrylhydrazyl (DPPH) analysis. Most of these compounds possessed a 3,4,5-trimethoxyphenyl unit which might be inducing enzyme inhibition and scavenging radical formation which could be further investigated to establish the structure-activity relationship.
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While some synthetic chemicals have been demonstrated to disrupt normal endocrine function by binding to the androgen receptor (AR), the mechanism by which ligands bind to the ligand binding domain (LBD) remained unclear. In this ...
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While some synthetic chemicals have been demonstrated to disrupt normal endocrine function by binding to the androgen receptor (AR), the mechanism by which ligands bind to the ligand binding domain (LBD) remained unclear. In this study, docking and comparative molecular similarity index analysis (CoMSIA) were performed to study the AR ligand binding mechanism of steroids and non-steroidal chemicals. The obtained docking conformations and predictive CoMSIA models (r_(pred)~2 values as 0.842 and 0.554) indicated the primary interaction site and key residues in the binding process. The major factors influence the binding affinity of steroids and non-steroidal chemicals were electrostatic and hydrophobic interactions, respectively. The results indicated that besides amino-acid residues Gln711, Arg752 and Thr877 which have previously been reported to be important in binding ligands, Leu701 and Leu704 are also important. Residues Val746, Met749 and Phe764 are crucial only for steroids, while Met742 and Met787 are important only for non-steroidal chemicals. This knowledge of key interactions and important amino-acid residues governing ligands to the AR allow better prediction of potency of AR agonists so that their potential to disrupt AR-mediated pathways and to design less potent alternatives.
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Background: The last step in the production of androgen testosterone from 4-androstene-3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3).Blocking this microsomal enzyme with an inhibi...
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Background: The last step in the production of androgen testosterone from 4-androstene-3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3).Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently,could be an approach for the treatment of androgen-dependent diseases. RM-532-105 wasdeveloped as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known.Objective: To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH,as well as inhibitor RM-532-105.Methods: Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand,a homology model was prepared followed by molecular docking, and enzymatic assay experimentswere performed.Results: Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity forthe transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate,a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with thesecells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive actionwith the substrate 4-dione.Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site,from the two possibilities predicted by the docking experiments, and appear to be in agreement withprevious structure-activity relationships.
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Management of the gastro-toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) remains a crucial problem, because the commercially available anti-ulcer drugs have side effects and are often expensive. Hence, the potential of ...
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Management of the gastro-toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) remains a crucial problem, because the commercially available anti-ulcer drugs have side effects and are often expensive. Hence, the potential of a new water-soluble GPx mimic, DL-trans-3,4-dihydroxy-1-selenolane (DHSred) in healing the indomethacin-induced stomach ulceration in mice was examined. Administration of indomethacin (18 mg/kg, p. o.) induced ulceration in the glandular portion of the gastric mucosa, accompanied by increased lipid peroxidation (1.3-fold, p <0.001) and protein oxidation (1.5-fold, p < 0.001), depletion of thiol-defense (42.5%, p < 0.01), plasma total antioxidant status (53.4%, p < 0.001) and mucin (47.5%, p < 0.01), as well as reduced expressions of cyclooxygenases and prostaglandin synthesis (54.7%, p < 0.001) in the gastric tissues of mice. Daily oral administration of DHSred (2.5 mg/kg) or omeprazole (Omez) (3 mg/kg) for 3 days respectively produced ?74% and 69% (p < 0.001) healing of the acute gastric ulceration. The test samples also significantly reversed all the adverse effects of indomethacin on the biochemical parameters. Apparently, the gastric ulcer healing action of DHSred and Omez was due to their antioxidant action and their ability to protect mucin and augment PG synthesis by upregulation of the COX isozymes. The results suggested that the non-toxic and inexpensive compound, DHSred, may be a good candidate for further evaluation as a potent anti-ulcer drug.
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BACKGROUND:Osteoarthritis (OA) often affects the hands, knees, and hip joints, causing considerable pain and disability, and often affecting the patient's quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are common ...
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BACKGROUND:Osteoarthritis (OA) often affects the hands, knees, and hip joints, causing considerable pain and disability, and often affecting the patient's quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are common pain relievers often applied as first line therapies for OA. However, prolonged NSAIDs application can have unwanted side effects. Given this, this study was designed to systematically evaluate the efficacy and safety of topical and oral NSAIDs for the treatment of OA.METHODS:We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for relevant papers from their inception dates to May 2021. Our study only included randomized controlled trials comparing topical and oral NSAIDs and all data were analyzed using Review Manager version 5.3 (RevMan version 5.3).RESULTS:We identified 8 RCTs (2096 patients with OA), for evaluation and revealed that, in general, topical and oral NSAIDs presented with similar efficacies for the treatment of OA. The Western Ontario and McMaster Osteoarthritis Index for assessing pain relief in OA patients was (standardized mean difference [SMD] 0.07; 95%CI -0.02, 0.17) and visual analog scale was (SMD -0.01; 95%CI -0.02, 0.18), and improved stiffness in OA patients (SMD 0.09; 95%Cl 0.03, 0.20).CONCLUSIONS:Topical NSAIDs are as effective as oral NSAIDs for the treatment of OA and both topical and oral NSAIDs are equally effective in reducing pain and improving physical function in OA patients. In terms of safety, a larger number of samples are still needed to determine if there are any differences in the safety profile of topical or oral NSAIDs.REGISTRATION NUMBER:INPLASY 2021110009.Copyright ? 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
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Diclofenac potassium is one of the most common non-steroidal anti-inflammatory drugs that used during pregnancy period for pain, inflammation, fever, dysmenorrheal, and menorrhagia. Their mechanism of action is through the inhibit...
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Diclofenac potassium is one of the most common non-steroidal anti-inflammatory drugs that used during pregnancy period for pain, inflammation, fever, dysmenorrheal, and menorrhagia. Their mechanism of action is through the inhibition of the biosynthesis of prostaglandins. The previous studies showed that diclofenac potassium has teratogenic effect. However, the mechanism of its teratogenic effect is not yet understood. Here, we investigated for the first time, the effects of diclofenac potassium on the fetal organs and placenta as attempt to find the mechanism of its teratogenicity through inhibition of placental development. The pregnant rats have been divided into 3 groups; (G1) control, (G2) administrated orally with 15.4 mg/kg diclofenac potassium from 5th to 13th gestation day, and (G3) treated with the same dose from 13th to 19th GD. The pregnant rats were sacrificed at the 20th GD. The uteri were isolated and the fetuses have been exposed to morphological examination and skeletal staining. Moreover, biochemical studies on placenta, maternal liver, and fetal liver have been done. We recorded high embryonic resorption rate, subcutaneous hematoma in different parts of fetuses of the treated animals and skeletal abnormalities that mostly observed in the ossification of skull, ribs, and vertebrae. Moreover, wavy ribs were detected. Biochemical studies indicated a significant alteration in SOD, GSH, Catalase, and MDA levels. Diclofenac potassium should be avoided during pregnancy and given in just if its benefits outweigh the maternal and fetal risks, at the possible lowest effective dose and for the shortest duration.
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