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Diabetes mellitus (DM) is a metabolic disorder characterized by frequent urination, hunger and high blood sugar level. α-glucosidase inhibitors are considered as a frontline treatment for the DM. This research article deals with the identification of benzothiazine derivatives as α-glucosidase inhibitors through in-silico techniques and then the confirmation through in-vitro analysis. Molecular docking studies were carried out to find out the binding interactions of targeted molecules with receptor molecule i.e., α-glucosidase enzyme. The synthetic compounds 1 (a-n), 2 (a-d) and 3 (ab) were evaluated for in-vitro alpha glucosidase inhibitory activities that resulted in the discovery of various potent molecules. Majority of the compounds (1c, 1f, 1g, 1k-n, 2a-d and 3a-b) exhibited good inhibitory activity against α-glucosidase. Compounds 1c, 1g, 1k and 1m appeared as the potent active compounds with the IC50 values 17.44, 27.64, 24.43, 42.59 and 16.90 µM respectively. Compounds 1c & 2c were found almost 3-folds more active than the standard acarbose. The study may lead to discover potent drug candidates with less complication for the treatment of the type II diabetes mellitus. [ABSTRACT FROM AUTHOR]

α-Glucosidase inhibitors occupy a prominent position among the various treatments of type-2 diabetes mellitus (DM2). In this study, a series of new norfloxacin-acetanilide hybrid molecules were synthesized and screened for α-glucosidase inhibition activity. The synthetic methodology involves the synthesis of a series of α-bromoacetanilides by condensing bromoacetyl bromide with various substituted anilines. These α-bromoacetanilides were coupled with norfloxacin in DMF to get the titled hybrids. The structure elucidation of synthesized compounds were characterized by ¹H NMR, 13C NMR and LC-MS. Finally, the compounds were screened for their α-glucosidase inhibition activity using acarbose as a reference drug (IC50 =58 µM). Among the tested compounds, 3i and 3j displayed potent α-glucosidase inhibition activity with IC50 values of 7.81±0.038 and 5.55±0.012 µM respectively. In-addition, 3m, 3f and 3k were demonstrated moderate alpha-glucosidase inhibition activities with IC50 values of 52.905±0.041, 23.79± 0.087 and 23.06±0.026 µM respectively. The structure-activity relationship was established with the help of molecular docking by using Molecular Operating Environment software (MOE 2014). [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) and the problems associated with it are the most prominent causes of death in the whole world. Statins are accustomed to lower lipid levels in CAD patients. The target of this study was to analyze whether or not common variations in HMGCoA Reductase (HMGCR) and Apolipoprotein E (ApoE) genes are responsible for metabolism of lipid and statin that modify the impact of statins on serum level of lipids and lipoprotein concentrations in Coronary heart disease patients. One hundred CAD patients were registered for the study. At the start of the study biochemical measurements were performed to work out the baseline levels. Patients were treated with twenty mg Lipitor for one month and biochemical measurements were tested again. According to the post-treatment, LDL-c levels, patients were divided into a pair of group as non-responders and responders, independently. The information concerning the risk factors like smoking, alcohol consumption etc. was conjointly obtained. DNA was extracted from peripheral blood. The presence of rs17244841 and rs17238540 mutations in HMGCR and e2, e3 and e4 variants of ApoE were settled by performing RT-PCR. Results were assessed statistically. HMGCR mutations were principally found in responders and e4 variant of ApoE was principally found in non-responders. It was found that the presence of HMGCR mutations causes a big reduction in total cholesterol and LDL-c levels. Conjointly, the presence of e2 variant of Apo E causes a statistically vital increase in triglyceride levels. Our findings should be investigated by different researchers to clarify the mechanism. [ABSTRACT FROM AUTHOR]

Pyrazoline and benzimidazoles derivatives have been widely studied due to their potential applications in the medicinal field. In this research project, we have hybridized these two heterocyclic systems in the same molecule. A new series of compounds, 2-((3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-1H-benzo[d]imidazole (5a-i) were synthesized through a multistep reaction. In the first step, chalcones 3a-i were prepared by coupling of various acetophenones and benzaldehydes under alkaline conditions. These chalcones were cyclized with hydrazine hydrate to form a series of pyrazolines which were finally coupled with 2-chloromethyl-1H-benzimidazole to get a new series of titled hybrid molecules. The structures of these compounds were elucidated by spectral (1H NMR and 13C NMR) analysis. The antidiabetic potential of these compounds was studied by screening them for their a-glucosidase inhibition activity. The SAR was established through molecular docking analysis. Compound 5d appeared as effective inhibitor with IC50 = 50.06µM as compared to reference drug (acarbose) having IC50 = 58.8µM. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic disease in which the infected cells do not have the ability to produce sufficient amount of insulin that results in the abnormality of carbohydrates metabolism and an increase in blood glucose level. Long time exposure to diabetes mellitus results in failure or dysfunction of different organs like kidneys, nerves, heart, eyes, etc. A common practice to cure diabetes is the use of a-glucosidase inhibitors which help in lowering the blood glucose level. We presented 1,2-benzothiazine 1,1-dioxide derivatives as novel and more potent a-glucosidase inhibitors via their in vitro and in silico screenings. Excellent enzyme inhibitions were observed for compounds 2, 8, 10 and 12 having IC50 values of 6.91, 14.0, 4.2, 5.9 and 29.2µM respectively which were found better than the reference acarbose (IC50 =38.31µM). Molecular docking studies suggested high binding energies and good binding interactions of these compounds with the active site residues of the receptor protein. A good agreement was found between the results of both modes of evaluation. Moreover, the envisioned candidates have a good potential to treat diabetes. [ABSTRACT FROM AUTHOR]

The transcription factor NF- E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch- like ECH-associated protein 1 (KEAP1), significantly contribute to regulation of redox, metabolic and protein homeostasis, as well as inflammation. Therefore, activation of NRF2 imparts cytoprotective effect in numerous pathophysiological conditions including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders and cancer initiation. The objective of this study was to screen library of phytochemicals to identify phytochemicals for direct inhibition of the Keap1-Nrf2 interaction using molecular docking approach. As a result, natural compounds such as 3-(Dimethylamino)-3-imino-N-(4-methylphenyl) propanamide, Phlorizin, Diffutin, Liquiritin and Dihydrogenistin were identified as direct inhibitors of the Keap1-Nrf2 interaction, as evident from its high binding affinity and occupancy of specific binding sites of Klech domain. Thus these phytochemical could be proposed to improve cell resistance to oxidative stress, suggesting their potential as antioxidants. Moreover, the selected compounds fulfilled the Lipinksi rule and appropriate ADMET properties potentiating its efficacy. However, these need to be validated through experimental approaches to ensure its safety profile and efficacy. [ABSTRACT FROM AUTHOR]

Survivin (IAP proteins) is considered as a significant target for anticancer drug research owing to its upregulation in tumor cells to mediate resistance to apoptotic stimulus. The current study aimed to investigate phytochemicals as inhibitors of survivin with caspases to reactivate the functioning of caspases through molecular docking. The compounds namely 2(R), 4(R)-dihydroxypyrrolidine, 4-hydroxy-2-(4-methoxyphenyl)-1,1-dioxo-3,4-dihydrothieno[3,2-e]thiazine-6-sulfonamide, 2,3-Diketo-L-gulonic acid, (3-hydroxy-2-octadeca-9,12-dienoyloxypropyl) octadecanoate, 2-[[4-[[4-[(4-formamido-1-methylimidazole-2-carbonyl)amino]-1-methylimidazole-2-carbonyl]amino]-1-methylimidazole-2-carbonyl]amino]ethyl-dimethylazanium, Picolinic acid and (2-Hydroxy-5-nitrophenyl) dihydrogen phosphate successfully bind inside the pocket of survivin. ADMETsar was used to evaluate the anticancer potential of selected compounds. These compounds can be proposed as effective inhibitors, disrupting the survivin-caspases interaction and reactivating the caspases function of apoptosis. The study might facilitate the development of cost-effective and natural drugs against cancer. However, further validation is essential for confirmation of its drug efficacy and bio-compatibility. [ABSTRACT FROM AUTHOR]

Chronic pain has been defined as the persistence that remained for more than three months. The extent of previous time duration with the normal time of natural healing phase becomes poor and results in reduced life quality and morbidity. Opioids are well recognized therapy for pain management and the clinical prescriptions based on opioids have been defined with increasing implicating behavior among patients suffering with chronic pain. The association between the pain and immunity has long been established since the involvement of interleukin-1ß (IL-1ß) in sickness that is considered with the induced hyperalgesia. In the context of pharmacodynamics Toll like receptors (TLRs) are involved in the negative effects of opioids as analgesics. The soluble factors released by immune cells as well as from the disruptive cells bind to TLRs. This binding leads the pre and post-synaptic ends on endothelial and microglial cells that exhibit the activation of complex inhibitory and excitatory process at the synapses site. In TLRs, TLR4 is mostly reported that is strongly associated in specifically in areas of T cells and macrophages. The current study is designed to investigate the structural insights of the opioids and TLR4 interactions by using computational approach in the aspect of recognizing the chemical combinatorial factors that are involved in the pain management. This study targets that how opioids interact with TLR4 and the process of chemical interaction that leads to negative effects of opioids at neuroimmune interface as well as to investigate the extent of particular naltrexone that mediates with the negative effects of opioids. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are innate immune receptors that mediate the inflammatory response during HCV infections. The goal of this study was to evaluate the association of TLR9 gene polymorphism (rs5743836) in Pakistani patients infected with genotype 3a of HCV. Total 500 subjects were recruited, 400 HCV patients and 100 healthy individuals. Genotyping of TLR9 (-1237T/C, rs5743836) was carried out in 400 HCV patients (323 interferon responders and 77 interferon non responder) and control group by applying High resolution melting (HRM) curve assay. No remarkable differences in distribution of genotype between HCV (p<0.0001; OR= 3.21, 95% CI= (2.514.12) and control groups (p<0.0001; OR=0.092, 95%CI= (0.0580.14) were observed. In conclusion TLR9-1237T/C gene polymorphism may not be considered as a molecular risk for patients with HCV in Pakistan. [ABSTRACT FROM AUTHOR]

The study was planned to check the beneficial effects of various sources of omega-3 fatty acids (synthetic, flaxseed oil, fish oil) on 45 Wistar female rats. The rats were divided into five groups and assigned to different diets i.e. NC (Negative control), PC (Positive control), SO (Synthetic omega-3 250mg/kg/orally/daily), FO (flaxseed oil 250mg/kg/orally/daily) and F (fish oil 250mg/kg/orally/diet). Animals fed on different diets were induced PCOS by an intramuscular (IM) injection of estradiol-valerate (4mg/rat/IM) except NC group. Results of the lipid profile indicated that F showed highest increase in HDL level (35.67±1.45), while cholesterol, LDL, triglycerides, blood glucose and body weight were reduced in all three treatment groups. In case of a hormonal profile, testosterone, luteinizing hormone (LH) and insulin levels showed a significant reduction after treatments. It can be concluded form the study that different sources of omega-3 fatty acids can be a new approach to treat the symptoms of PCOS.

Dengue infection is prevailing among the people not only from the developing countries but also from the developed countries due to its high morbidity rate around the globe. Hence, due to the unavailability of any suitable vaccine for rigorous dengue virus (DENV), the only mode of its treatment is prevention. The circumstances require an urgent development of efficient and practical treatment to deal with these serotypes. The severe effects and cost of synthetic vaccines simulated researchers to find anti-viral agents from medicinal plants. Flavonoids present in medicinal plants, holds anti-viral activity and can be used as vaccine against viruses. Therefore, present study was planned to find anti-viral potential of 2500 flavonoids inhibitors against the DENVNS2B/NS3 protease through computational screening which can hinder the viral replication within the host cell. By using molecular docking, it was revealed that flavonoids showed strong and stable bonding in the binding pocket of DENV NS2B/NS3 protease and had strong interactions with catalytic triad. Drug capability and anti-dengue potential of the flavonoids was also evaluated by using different bioinformatics tools. Some flavonoids effectively blocked the catalytic triad of DENV NS2B/NS3 protease and also passed through drug ability evaluation. It can be concluded from this study that these flavonoids could act as potential inhibitors to stop the replication of DENV and there is a need to study the action of these molecules in-vitro to confirm their action and other properties.