Molecular structure-activity relationship study of some non-steroidal antiinflammatory agents using electrostatic potential mapping

A series of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acids (DOAA) which are known to be anti-inflammatory agents were studied. The geometries of some of the molecules obtained from X-ray crystallography were used in the calculations as such while the geometries of their derivatives were obtained by local, partial geometry optimization around the Sites of substitution employing the AMI method, keeping the remaining parts of the geometries the same as those in the parent molecules. Molecular electrostatic potential (MEP) mapping was performed for the molecules using optimized hybridization displacement charges (HDC) combined with Lowdin charges, as this charge distribution has been shown earlier to yield near ab initio quality results. A good correlation has been found between the MEP values near the oxygen atoms of the hydroxyl groups of the carboxy groups of the molecules and their anti-inflammatory activities. The result is broadly in agreement with the model proposed earlier by other authors regarding the structure-activity relationship for other similar molecules.

Recurrent Acute Pancreatitis and Therapy for Ulcerative Colitis.

Drugs are a rare cause of pancreatitis. Whereas some drugs are well known to induce an attack of pancreatitis, some people may be more prone to develop pancreatitis because of personal susceptibility. We describe a recurrent case of acute pancreatitis after administration of several drugs in a patient with intestinal inflammatory bowel disease that needed to be treated with subsequent antiinflammatory agents. Genetic mutation in the CFTR gene was found in the patient that led us to postulate that CFTR was a trigger for drug-induced acute pancreatitis. In conclusion, genetic analysis should be advised in case of recurrent pancreatitis in patient with intestinal inflammatory bowel disease.

Inhibition of proinflammatory biomarkers in THP1 macrophages by polyphenols derived from chamomile, meadowsweet and willow bark.

Antiinflammatory compounds in the diet can alleviate excessive inflammation, a factor in the pathogenesis of common diseases such as rheumatoid arthritis, atherosclerosis and diabetes. This study examined three European herbs, chamomile (Matricaria chamomilla), meadowsweet (Filipendula ulmaria L.) and willow bark (Salix alba L.), which have been traditionally used to treat inflammation and their potential for use as antiinflammatory agents. Aqueous herbal extracts and isolated polyphenolic compounds (apigenin, quercetin and salicylic acid, 0–100 μM) were incubated with THP1 macrophages, and interleukin (IL)-1β, IL-6 and tumour necrosis factor-alpha (TNF-) were measured. At concentrations of 10 μM, both apigenin and quercetin reduced IL-6 significantly ( p < 0.05). Apigenin at 10 μM and quercetin at 25 μM reduced TNF- significantly ( p < 0.05). Amongst the herbal extracts, willow bark had the greatest antiinflammatory activity at reducing IL-6 and TNF- production. This was followed by meadowsweet and then chamomile. The lowest effective antiinflammatory concentrations were noncytotoxic (MTT mitochondrial activity assay). The Comet assay, which was used to study the protective effect of the isolated phenols against oxidative damage, showed positive results for all three polyphenols. These are the first findings that demonstrate the antiinflammatory capacity of these herbal extracts.

Glucocorticoids in Vivo Induce Both Insulin Hypersecretion and Enhanced Glucose Sensitivity of Stimulus-Secretion Coupling in Isolated Rat Islets

Although glucocorticoids are widely used as antiinflammatory agents in clinical therapies, they may cause serious side effects that include insulin resistance and hyperinsulinemia. To study the potential functional adaptations of the islet of Langerhans to in vivo glucocorticoid treatment, adult Wistar rats received dexamethasone (DEX) for 5 consecutive days, whereas controls (CTL) received only saline. The analysis of insulin release in freshly isolated islets showed an enhanced secretion in response to glucose in DEX-treated rats. The study of Ca(2+) signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca(2+) signals were found between both groups with tolbutamide or KCl, indicating that the alterations were probably related to metabolism. Thus, mitochondrial function was explored by monitoring oxidation of nicotinamide dinucleotide phosphate autofluorescence and mitochondrial membrane potential. Both parameters revealed a higher response to glucose in islets from DEX-treated rats. The mRNA and protein content of glucose transporter-2, glucokinase, and pyruvate kinase was similar in both groups, indicating that changes in these proteins were probably not involved in the increased mitochondrial function. Additionally, we explored the status of Ca(2+)-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase C alpha as well as an increased response of the phospholipase C/inositol 1,4,5-triphosphate pathway in DEX-treated rats. Finally, an increased number of docked secretory granules were observed in the beta-cells of DEX animals using transmission electron microscopy. Thus, these results demonstrate that islets from glucocorticoid-treated rats develop several adaptations that lead to an enhanced stimulus-secretion coupling and secretory capacity. (Endocrinology 151: 85-95, 2010)

Aspergillus species, cyclic dimeric dipeptide derivative substance P antagonist biosynthetic products thereof, and process for preparation thereof

A novel Aspergillus species, cyclic dimeric dipeptide derivatives which are biosynthetic products thereof and are useful as Substance P antagonists and therefore as analgesic and/or antiinflammatory agents, and a process for preparation of the biosynthetic products are disclosed.

In vitro response to functionalized self-assembled peptide scaffolds for three-dimensional cell culture

Nanomaterials are rich in potential, particularly for the formation of scaffolds that mimic the landscape of the host environment of the cell. This niche arises from the spatial organization of a series of biochemical and biomechanical signals. Self-assembling peptides have emerged as an important tool in the development of functional (bio-)nanomaterials; these simple, easily synthesized subunits form structures which present the properties of these larger, more complex systems. Scaffolds based upon these nanofibrous matrices are promising materials for regenerative medicine as part of a new methodology in scaffold design where a "bottom-up" approach is used in order to simulate the native cellular milieu. Importantly, SAPs hold the potential to be bioactive through the presentation of biochemical and biomechanical signals in a context similar to the natural extracellular matrix, making them ideal targets for providing structural and chemical support in a cellular context. Here, we discuss a new methodology for the presentation of biologically relevant epitopes through their effective presentation on the surface of the nanofibers. Here, we demonstrate that these signals have a direct effect on the viability of cells within a three-dimensional matrix as compared with an unfunctionalized, yet mechanically and morphologically similar system. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 197-205, 2014.

Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus-secretion coupling in isolated rat islets

Although glucocorticoids are widely used as antiinflammatory agents in clinical therapies, they may cause serious side effects that include insulin resistance and hyperinsulinemia. To study the potential functional adaptations of the islet of Langerhans to in vivo glucocorticoid treatment, adult Wistar rats received dexamethasone (DEX) for 5 consecutive days, whereas controls (CTL) received only saline. The analysis of insulin release in freshly isolated islets showed an enhanced secretion in response to glucose in DEX-treated rats. The study of Ca2 2+ signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca2 2+signals were found between both groups with tolbutamide or KCl, indicating that the alterations were probably related to metabolism. Thus, mitochondrial function was explored by monitoring oxidation of nicotinamide dinucleotide phosphate autofluorescence and mitochondrial membrane potential. Both parameters revealed a higher response to glucose in islets from DEX-treated rats. The mRNA and protein content of glucose transporter-2, glucokinase, and pyruvate kinase was similar in both groups, indicating that changes in these proteins were probably not involved in the increased mitochondrial function. Additionally,weexplored the status of Ca2 2+-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase Cα as well as an increased response of the phospholipase C/inositol 1,4,5-triphosphate pathway in DEX-treated rats. Finally, an increased number of docked secretory granules were observed in the β-cells of DEX animals using transmission electron microscopy. Thus, these results demonstrate that islets from glucocorticoid-treated rats develop several adaptations that lead to an enhanced stimulus-secretion coupling and secretory capacity. Copyright © 2010 by The Endocrine Society.

Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFκB

The antiinflammatory action of aspirin generally has been attributed to direct inhibition of cyclooxygenases (COX-1 and COX-2), but additional mechanisms are likely at work. These include aspirin’s inhibition of NFκB translocation to the nucleus as well as the capacity of salicylates to uncouple oxidative phosphorylation (i.e., deplete ATP). At clinically relevant doses, salicylates cause cells to release micromolar concentrations of adenosine, which serves as an endogenous ligand for at least four different types of well-characterized receptors. Previously, we have shown that adenosine mediates the antiinflammatory effects of other potent and widely used antiinflammatory agents, methotrexate and sulfasalazine, both in vitro and in vivo. To determine in vivo whether clinically relevant levels of salicylate act via adenosine, via NFκB, or via the “inflammatory” cyclooxygenase COX-2, we studied acute inflammation in the generic murine air-pouch model by using wild-type mice and mice rendered deficient in either COX-2 or p105, the precursor of p50, one of the components of the multimeric transcription factor NFκB. Here, we show that the antiinflammatory effects of aspirin and sodium salicylate, but not glucocorticoids, are largely mediated by the antiinflammatory autacoid adenosine independently of inhibition of prostaglandin synthesis by COX-1 or COX-2 or of the presence of p105. Indeed, both inflammation and the antiinflammatory effects of aspirin and sodium salicylate were independent of the levels of prostaglandins at the inflammatory site. These experiments also provide in vivo confirmation that the antiinflammatory effects of glucocorticoids depend, in part, on the p105 component of NFκB.

A Young Woman with Fever and Cervical Lymphadenopathy

Kikuchi-Fujimoto's disease is a self-limiting and rare disorder of unknown aetiology. The typical presentation includes fever, cervical lymphadenopathy and night sweats. Consequently, it is part of the differential diagnosis of infectious, lymphoproliferative and connective tissue diseases. Histology demonstrates necrotizing histiocytic lymphadenitis. Treatment is symptomatic with non-steroidal antiinflammatory agents, although there are reports of corticosteroid use in complicated cases. We present the case of a 23-year-old woman admitted to hospital for fever and cervical lymphadenopathies, and diagnosed with Kikuchi-Fujimoto's disease.

Agents that inhibit histamine release: A review

It is well known that histamine is found in high concentration in mast cell granules(1). The histamine content of these granules may be released to the extracellular space if an appropriate stimulus is provided(2). Besides histamine, other preformed active substances like enzymes, chemotatic factors and proteoglycans, as well as newly generated mediators like eicosanoids, platelet activating factor and adenosine are released during the secretion process of mast cells(3). The activation of mast cell degranulation has been associated with a number of pathologic disorders, most frequently, diseases derived from the atopic state(4). It is now evident that mast cells are the primary effector cells in the early reaction in both allergic and non-allergic asthma(5,6), although some authors doubt that the late reaction of asthma is a mast cell dependent event(6). Other studies point towards basophils as cellular elements involved in the secondary phase of inflammation in allergic diseases(7). Secretion would depend on a histamine releasing factor, and on the presence of IgE on the basophil's surface(8). There is also evidence suggesting involvement of mast cells in some non-allergic inflammatory processes like arthritis(9). The pharmacological management of these diseases basically consists in the use of methylxantines, beta 2-adrenergic agonists, glucocorticoids, sodium cromoglycate-like drugs, anticholinergic and antihistaminic H 1 antagonists(10). Their therapeutic effects include bronchodilatation, receptor and physiological antagonism, prevention of inflammatory responses induced by secondary cells, and finally, inhibition of mast cell activation(11). This review is concerned with compounds having inhibitory action on mast cell activation, and their possible importance on the pathophysiology of mast cell-related diseases.

Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis

OBJECTIVE: Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of bipolar depression. METHODS: Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone. RESULTS: Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was -0.40 (95% confidence interval -0.14 to -0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I² = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported. CONCLUSIONS: Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.