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A new series of 2-substituted-4-(benzo[d][1,3]dioxol-5-yl)-6-phenylpyridazin-3(2H)-one derivatives has been synthesized and studied. The in vivo anti-inflammatory and analgesic activities of the synthesized compounds were evaluated using carrageen rat paw edema model and acetic acid induced writhing model, respectively. Side effect profile of the newly synthesized pyridazinones was assessed by gastric ulcerogenic and anti-platelet activity. The compounds were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2) by in vitro colorimetric COX (ovine) inhibitor screening assay method. The p-flourophenylpiperazine substituted analogue 14 exhibited most potent anti-inflammatory and analgesic activities with lower ulcer index and extremely good selectivity towards COX-2 versus COX-1 enzyme with a selectivity index of 10. Molecular docking studies showed appreciable binding of new pyridazinone analogues with the amino acids present at the active site of hCOX-2 enzyme., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Anti-epileptic drugs (AEDs) have high risk of teratogenic side effects, including neural tube defects while mother is on AEDs for her own prevention of convulsions during pregnancy. The present study investigated the interaction of major marketed AEDs and human placental (hp)-cadherin protein, in-silico, to establish the role of hp-cadherin protein in teratogenicity and also to evaluate the importance of Ca(2+) ion in functioning of the protein. A set of 21 major marketed AEDs were selected for the study and 3D-structure of hp-cadherin was constructed using homology modelling and energy minimized using MD simulations. Molecular docking studies were carried out using selected AEDs as ligand with hp-cadherin (free and bound Ca(2+) ion) to study the behavioural changes in hp-cadherin due to presence of Ca(2+) ion. The study reflected that four AEDs (Gabapentin, Pregabalin, Remacimide and Vigabatrine) had very high affinity towards hp-cadherin and thus the later may have prominent role in the teratogenic effects of these AEDs. From docking simulation analysis it was observed that Ca(2+) ion is required to make hp-cadherin energetically favourable and sterically functional., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Adipose tissue is a major source of energy for the human body. It is also a source of major adipocytokines adiponectin and leptin. Insulin resistance is a condition in which insulin action is impaired in adipose tissue and is more strongly linked to intra-abdominal fat than to fat in other depots. The expression of adiponectin decreases with increase in the adiposity. Adiponectin mediates insulin-sensitizing effect through binding to its receptors AdipoR1 and AdipoR2, leading to activation of adenosine monophosphate dependent kinase (AMPK), PPAR-α, and presumably other yet-unknown signalling pathways. Weight loss significantly elevates plasma adiponectin levels. Reduction of adiponectin has been associated with insulin resistance, dyslipidemia, and atherosclerosis in humans. The other major adipokine is leptin. Leptin levels increase in obesity and subcutaneous fat has been a major determinant of circulating leptin levels. The leptin signal is transmitted by the Janus kinase, signal transducer and activator of transcription ((JAK-STAT) pathway. The net action of leptin is to inhibit appetite, stimulate thermogenesis, enhance fatty acid oxidation, decrease glucose, and reduce body weight and fat., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Recurrent pregnancy loss (RPL) is defined as the occurrence of three or more consecutive miscarriages prior to 20 weeks gestation. Exaggerated maternal immune response to fetal antigens has been proposed to be one of the mechanisms underlying recurrent pregnancy loss., Method: A comprehensive literature search was conducted from the websites of the National Library of Medicine (http://www.ncbl.nlm.nih.gov) and Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature (http://www.pubmedcentral.nih.gov/). The data was assessed from books and journals that published relevant articles in this field., Result: In normal pregnancy, tolerance of the genetically incompatible fetus by the maternal immune system depends on the interactions of an array of cytokines secreted by maternal and fetal cells at the site of implantation. Earlier research indicated that altered immunity in RPL is dominated by the Th1/Th2 hypothesis, which proposed that the fetus escapes maternal-derived T-cell responses through skewing the Th0 differentiation toward Th2 pathway which dampens pro-inflammatory Th1-type immunity. Recent studies indicate the role of proinflammatory Th17 cells and immunoregulatory Treg cells in RPL in addition to Th1/Th2 interactions., Conclusion: Cytokines form a complex regulatory network which maintains homeostasis between the fetal unit and the maternal immune system. If this delicate balance is adversely affected, immunoregulatory mechanisms may be insufficient to restore homeostasis and this may lead to pregnancy failure., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Monocyte Chemoattractant Protein (MCP)-1, a potent monocyte attractant, is a member of the CC chemokine subfamily. MCP-1 exerts its effects through binding to G-protein-coupled receptors on the surface of leukocytes targeted for activation and migration. Role of MCP-1 and its receptor CCR2 in monocyte recruitment during infection or under other inflammatory conditions is well known., Method: A comprehensive literature search was conducted from the websites of the National Library of Medicine (http://www.ncbl.nlm.nih.gov) and Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature (http://www.pubmedcentral.nih.gov/). The data was assessed from books and journals that published relevant articles in this field., Result: Recent and ongoing research indicates the role of MCP-1 in various allergic conditions, immunodeficiency diseases, bone remodelling, and permeability of blood - brain barrier, atherosclerosis, nephropathies and tumors., Conclusion: MCP-1 plays an important role in pathogenesis of various disease states and hence MCP-1 inhibition may have beneficial effects in such conditions., (2010 Elsevier B.V. All rights reserved.)