جستجوی مقالات مرتبط با کلیدواژه "مهارکننده" در نشریات گروه "پزشکی"

Polychlorinated biphenyls (PCB) industrial pollutants are one of the most important environmental pollutants whose removal is very important. PCBs are degraded biologically by several enzymes and in a multi-step process. One of these enzymes is called DHBD (2,3-dihydroxy biphenyl 1,2-dioxygenase) and is encoded by the BphC gene. Enhancing the function of the enzyme and reducing the binding affinity of the enzyme to the inhibitor (tert-butanol) will improve the function of the enzyme and increase its efficiency. This research has been carried out in bioinformatics to strengthen the enzyme and weaken the inhibitory effect through mutation in the amino acids of the active site.

The amino acid sequence of the enzyme was obtained from the UniPprot database and to check similar sequences with PSI-BLAST method, similar sequences were searched from close to distant protein species. By performing multiple alignments of PSI-BLAST sequences, 250 sequences were matched. The results of sequencing the amino acids of the active site showed that some sites have variable amino acids and were used as candidates for mutagenesis. The position of the T-Butanol inhibitor was simulated using DISCOVERY software.

By molecular docking with PYRX software between the wild enzyme and the substrate, the binding energy -6.2 Kcalmol-1and for the candidates of mutations resulting from the alignment, Phenylalanine 201 to Threonine (6. 9 Kcalmol-1) and Threonine 280 to serine (6. 8 Kcalmol-1) Calculated.

The more negative binding energy indicates the greater stability of this interaction in the mutant enzyme. As a result, these mutations will be able to improve the strength of the enzyme function. The simulation of the position of the inhibitor and the starting material in the enzyme showed that the distance of the inhibitor from the active site and the starting material is likely to be favorable if the interaction of the inhibitor on the amino acids of the active site is reduced and as a result, the binding stability of the biphenyl starting material with the enzyme is increased. Decreasing the inhibitory power will increase the catalytic power of the enzyme in the destruction of PCBs.

  Diabetes mellitus is a group of metabolic disorders that are associated with elevated blood glucose levels due to impaired insulin secretion, insulin function, or both. alpha-glucosidase is a key enzyme in hydrolyzing carbohydrates and raising blood sugar levels. This study aimed to investigate the bioinformatics of inhibition of the alpha-glucosidase enzyme by the main constituents of Salvia officinalis.

This research was done by descriptive-analytical method. To study how the compounds interact and the amount of binding energy in the active site of the enzyme, the three-dimensional structure of the compounds and proteins were obtained from PubChem and PDB database, respectively. After energy optimization by Hyperchem software, docking studies were performed by AutoDock 4.2 software and the Swiss ADME server was used to obtain Lipinski parameters and physical and chemical properties of the compounds.

The studied compounds were similar to the two positive control compounds, Voglibose and miglitol, in terms of binding energy and how they interact. The best docking results are related to the camphor . In fact, this compound with the most negative binding energy level (-3.95 Kcal / mol) has a greater tendency to bind to key amino acids in the active site of the alpha glucosidase enzyme.

Due to the appropriate interactions of Salvia officinalis.compounds with enzymes, after confirming the results in vitro and in vivo, this plant can be used as a suitable drug candidate in the treatment of diabetes.

Aromatase is an enzyme that plays an important role in the development of estrogen-positive breast cancer. Estrogens are essential in human and mainly in women because of their role in sexual development and reproduction. Adverse effects of some aromatase inhibitors increase the need to discover new inhibitors with higher selectivity, lower toxicity and improved potency. In this study, the binding state of all three generations of aromatase inhibitors to the molecular structure of this protein using molecular docking method has been studied.

In general, the inhibitors based on steroid scaffolds (formestane and exemestane) have higher binding energy than azole scaffolds (fadrozole, anastrozole, letrozole), which may be due to their high structural strength.

Among all the considered structures studied, exemestane had the highest (negative) binding energy as well as the lowest inhibitory constant. The free energy of binding and the inhibitory constants was -8.77 kcal mol-1 and 373.32 nM respectively, which means that aromatase activity will be inhibited at the low concentrations of this anti-cancer drug.

The knowledge gained from this study will have important implications regarding for pharmaceutical design.

High Blood glucose levels is one of the main problems in diabetes. α-glucosidase with decomposition of polysaccharides increases the absorption of carbohydrates from the intestine, resulting in blood glucose upsurge. Inhibition of this enzyme is one of the most important strategies for treatment of diabetes.

The aim of this study was to investigate in silico inhibitory effect of flavones, found in fruit and plants, on the α-glucosidase activity.

This is a descriptive-analytic approach. The structure of the flavone compounds and α-glucosidase downloaded from PubChem and PDB database respectively. Then physicochemical properties of flavone compounds were predicted by the Zink data base and Swiss ADME server. Finally, Molegro Virtual Docker 6.0 and Molecular Viewer Molegro 2.5 environments were used, to do molecular interaction among flavone compounds and the enzyme.

Physicochemical characteristics of investigated flavone compounds were desirable. As well all of the studied flavone compounds were able to inhibit the α-glucosidase. But among the studied compounds, luteolin and nobiletin had the lowest negative energy with 78.98 and 87.96 KJ/mole respectively, and therefore the most docking points than the miglitol (positive control).

Examined flavone compounds in this study, mainly nobiletin, are particularly suitable because of their fine placement in the active site of the enzyme. So they have more inhibitory effect than other similar compounds. As a result, after some in vitro and in vivo, complementary studies on this compound, it is possible to distinguish it as a potent pharmaceutical inhibitor of α- glucosidase, to be used in diabetes treatment.

Since the alpha-glucosidase enzyme degrades complex carbohydrates and opens the way for their subsequent absorption and increases blood glucose levels, inhibitors of this enzyme are used as drugs for the treatment of some forms of diabetes.One of the medical treatments that have been given so much attention throughout the world is herbal medicine. Therefore, plants are a very good source of bioactive compounds.

The aim of this study was to find strong and new inhibitors of alpha-glucosidase enzymes using plant sources.

Methanolic extracts of 32 plant species collected from central regions of Kurdistan province were investigated for their inhibitory activity on alpha-glucosidase enzymes at concentrations of 1, 0.1, 0.01 and 0.001 mg / ml. Acarbose was used as a positive control. All measurements were performed in three replications.

According to the results of this study, the extracts of Campanula involucrata Auch .ex DC, Hypericum scabrum L., Salvia suffruticosa Montbr. & Auch and Silene ampulata Bioss. showed inhibitory activities greater than 60% on the alpha-glucosidase enzyme. The inhibitory activity of the extract of Campanula involucrata and Silene ampulata was significantly higher, and their IC50 was 0.02 mg / ml.

Therefore, it can be concluded that the just-mentioned plants extract, due to the high inhibition rate and low IC50, can be an interesting topic for more accurate studies.

Diabetes is a metabolic abnormality in the body caused by the high activity of the α-glucosidase enzyme in the hydrolysis of carbohydrates to glucose. Alpha-glucosidase inhibitors involved in the digestion of carbohydrates, play a key role in controlling diabetes. Thymus vulgaris is a species of flowering plant in the mint family Lamiaceae with a chromosome number of 2n = 30. The essential oil of this plant has phenolic compounds such as thymol, carvacrol, cymene, linalool, and pinene. The aim of this study was to investigate the inhibitory effect of the main compounds found in the thyme extract on the activity of alpha-glucosidase by in vitro methods.

Extract was used to dissolve thyme powder in distilled water solution. The inhibitory effect of the extracts on the activity of alpha-glucosidase enzyme was investigated. In this experiment, the concentration of each extract that was required to inhibit 50% of the enzyme activity (IC 50) was obtained and compared with the needed acarbose as a positive control.

the results showed that aqueous extract of thyme Thymus vulgaris in all three concentrations (40, 20, 10, and 5 mg/ml) can inhibit the enzyme. And as expected, the concentration of 40 mg / ml was exercised the highest inhibitory effect on the enzyme. IC50 of aqueous extract of thyme Thymus vulgaris was equal to 29%.

Considering the effectiveness of plant extract compounds in in silico and in vitro studies, for supplemental studies, the effect of these plant compounds can be analyzed in vivo conditions.

Inhibitors of α-glucosidase by interfering with digestion of carbohydrates play a role in controlling diabetes. Thymus vulgaris is an herb belonging to the mint family (lamiaceae). The essence of this plant contain the phenols such as thymol and carvacrol, cymene, linalool, pinene. The aim of this study was to investigate the inhibitory effect of the constituents of the thymus vulgaris extract on the activity of α-glucosidase enzyme by molecular docking. In this study, to investigate how the compounds are attached to the active site of the enzyme, mapping of chemical structure of the compounds, energy optimization, docking studies and final analysis were carried out by ChemDraw, HyperChem, AutoDock 4.2, DS Visualizer and Lig Pluto software, respectively. All of the studied compounds were able to occupy the active site of the enzyme, among all of them, the best results of docking was related to the combination of Caryophlla-4- (12), 8 (13) -dien-5-β-ol. In fact, this compound has the most negative energy level of connection, the highest affinity for binding to the active site of the enzyme and the interaction site is similar to that of the co-crystal molecule. considering the high efficacy of plant extract compounds in the bioinformatics study, and for complementary studies, the effect of the extract of this plant can be analyzed in order to control the increase of glucose in vitro and in vivo conditions.

Development of factor VIII (FVIII) inhibitor is the main problem of replacement therapy in patients with hemophilia A. Recently, the correlation of polymorphisms of some genes involved in immune system has been determined with inhibitor development. The reports showed that cytotoxic T lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation and thus, CTLA-4 gene polymorphism is related to genetic susceptibility to various autoimmune diseases. This study aimed at investigating the correlation between polymorphism of CTLA-4 gene and inhibitor development in Iranian hemophilia A patients for the first time.
In this case-control study, the genomic DNA was extracted from blood samples of 55 inhibitor positive and 45 inhibitor negative hemophilia A patients. Then, the genotyping of the CTLA-4 gene was performed using the Tetra Primer ARMS PCR. Moreover, the validation of single nucleotide polymorphisms (SNPs) in the CTLA-4 gene was determined by DNA sequencing. On the other hand, the role of HCV infection was determined in inhibitor-positive and inhibitor-negative HA patients.
Results showed that no statistically significant difference was observed between the genotypic and allelic frequencies with the presence of inhibitors (P>0.05). Moreover, a significant correlation was observed between HCV infections and development of inhibitors (P The CTLA-4 gene polymorphism does not play a role for inhibiting coagulation factor in Iranian patients with hemophilia type A.

Background and ObjectivesPI3K/Akt pathway plays a key role in cell growth and proliferation. Constitutive activation of this pathway is detectable in 50-70% of patients with acute promyelocytic leukemia (APL). Previous studies showed that PI3K activity in APL cells is mainly due to overexpression of p110δ isoform. In an effort to investigate the effect of PI3K inhibition in acute promyelocytic leukemia, APL-derived NB4 cells were subjected to different concentrations of Idelalisib, as a potent p110δ-specific inhibitor.
Materials and MethodsIn this experimental study, we examined the effect of Idelalisib on the viability and metabolic activity of NB4 cells. Moreover, flowcytometery and quantitative RQ-PCR were applied to investigate both induction of apoptosis and transcriptional activity of apoptosis-related genes, respectively.
Results The results revealed that Idelalisib not only decreased cell viability and metabolic activity in a dose- and time-dependent manner, but also induced cell death through the apoptotic pathway in NB4 cells. Our data also delineated that Idelalisib-induced apoptosis was mediated through induction of Bax and PUMA coupled with decreased expression of Mcl-1.
ConclusionsBased on P110δ activity in APL patients and the potent efficacy of Idelalisib in NB4 cells, it is tempting to suggest this inhibitor, as either single agent or in combination with common medications, for the treatment of patients with APL.

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine produced by a variety of cells, including hematopoietic and non-hematopoietic cells, malignant cells, macrophages, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, astrocytes, endothelial cells, and smooth muscle cells. TNF-α is a homo-trimeric molecular whose individual subunits are composed of antiparallel beta-sheets, forming a regular triangular prism shape. TNF-α binds to three receptor molecules through its receptor-binding sites, which are at the base of its pyramid structure. Biological responses to TNF-α are mediated through two different receptors: TNFR1 and TNFR2. These receptors are transmembrane glycoproteins with extracellular domains containing multiple cysteine-rich repeats that are structurally and functionally homologous, and the intracellular domains that are discrete and transduce their signals through both overlapping and distinct pathways. However, though TNF-α was initially discovered as an anti-tumor agent, it has been revealed that TNF-α and other ligands of this family are involved in some diseases like cancer, neurological, pulmonary, cardiovascular and autoimmune diseases and metabolic disorders. In general, TNF-α activates the control systems involved in cell proliferation, differentiation, inflammation and cell death, and the regulation of immune system. Although a normal level of TNF-α is very important for the regulation of immune responses, the persistence of the immune response as a result of inappropriate and excessive production of TNF-α can cause some inflammatory or autoimmune diseases. Accordingly, either neutralization TNF-α or blockade of its receptors using TNF-α inhibitors can be an effective therapeutic strategy to prevent or treat such inflammatory diseases. Several methods have been used to inhibit TNF-α, including the production of chimeric or fully human antibodies, soluble TNF-α receptors, or anti-TNF-α small molecules. The two previous agents are mostly capable of inhibiting the binding of TNF-α to its associated receptors, while anti-TNF-α small molecules, in addition to the above, inhibit the biosynthesis of TNF-α by blocking TNF-α mRNA biosynthesis, through the inhibition of its post-translational processing, or by blocking TNF-α receptors. Therefore, in this review article, we discuss the structure and characteristics of TNF-α and its related receptors: TNF-α signaling, TNF-α-mediated inflammatory diseases as well as TNF-α inhibition strategies.

Retard absorption of glucose by the inhibition of carbohydrate hydrolyzing enzymes is one of the therapeutic approaches to decrease the postprandial hyperglycemia. Commercial α-glucosidase inhibitors exhibited some serious side effects. So a great deal of attention has been paid to natural products like plants, as a reliable source for bioactive compounds.
The aim of this study was to find new potent inhibitors for Alpha-glucosidase among plant extracts.
Hexane extracts of 60 plants species were screened for their Alpha-glucosidase inhibitory activity at 0.001, 0.01, 0.1 and 1 mg/mL concentration. Alpha-glucosidase activity was determined spectrophotometrically at 405 nm on a Sunrise microplate reader (Tecan- Switzerland) by measuring the quantity of p-nitrophenol released from pNPG. Acarbose, dissolved in buffer, was used as a positive control. The assay was performed in triplicate. The concentration of the extract required to inhibit 50% of Alpha-glucosidase activity under the assay conditions was defined as the IC50value. The results are reported as %I ± SD.
Descurania sophia (L.) Webb & Berth, Fumaria vailantii Loisel, Ferula Haussknechti Wolf & Rech, Haplophyllum acutifolium (DC.) G.Don, Isatis cappadociaca Desv., Eremostachys laevigata Bunge, Silene aucheriana Boiss., exhibited more than 60% alpha-glucosidase inhibitory activity. Among them, Descurania sophia, Fumaria vailantii and Ferula haussknechti exhibited significant alpha glucosidase inhibitory activity with IC50 values of 0.9 µg/ml, 24.55 µg/ml and 2.71 µg/ml, respectively.
Because of its high inhibitory activity and low IC50, hexane extract of Descurania sophia would be interesting for further detailed studies to find and characterize any new inhibitor for Alpha-glucosidase.

The study emphasizes the reasons use of beta-lactamase inhibitors in combination with beta-lactam antibiotics. ß-lactam-ß-lactamase inhibitors are currently the most successful strategy for infections caused by extended-spectrum β-lactamase and carbapenemases bacteria.

Virus htlv-1 is in the retrovirus family; the virus causing human diseases such as adult T-Cell Leukemia (ATL), HAM / TSP and etc… One of the major proteins in the virus is protease that is essential for virus maturation. Inhibitors that ever made for the protease didn’t show any properly activity. We have created a new series of inhibitors and with using of computational tools to calculate the way of interactions to the protease protein. The compounds based on the similarity of the original peptide and based on peptidomemiticswere created. Compounds were created by software Hyperchem and optimization act on designed ligand and ligand with the protein crystal structure were performed after separating them. ADME and toxicity characteristics of the compounds were obtained by using Web applications in http://lazar-services.in-silico.ch and http://www.molinspiration.com and docking were performed on them. The results of studies on ADME designed compounds already showed a good result. Toxicity studies also indicate relatively good results; also the docking results were showed good specificity. Our studies showed that designed inhibitors can be effective drug-like compounds to inhibiting the protein and therefore use to contrast with this virus.

Lipoxygenases are non-hem iron-containing proteins responsible for the peroxidation of the unsaturated lipids in animals and plants. The critical role of the enzymes in creating inflammations, sensitivities and some of the cancers has been demonstrated in mammalians. The study of mechanism details of these category of enzymes and the metabolism of their peroxide products as well as the synthesis of appropriates inhibitors is of great importance for the mentioned enzymes. In this article, the inhibitory mechanisms of eugenyl adamantate which is a new synthetic potent inhibitor of lipoxygenase is studied. The lipoxygenase activity of soybean 15-lipoxygenase in the presence of eugenyl adamantate was assayed by using two spectrophotometric the formation of conjugated dien in 235 nm and DMAB-MBTH peroxide in 592 nm. The experiments show that the mentioned compound decreases the lipoxygenase activity in two concentration ranges of 80-120 nM and 5-13 µM. The kinetic studies show the mixed inhibitory mechanism including the competitive and non-competitive for this compound. The kinetic studies show the mixed inhibitory mechanism for the compound.