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Purpose Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, and this widespread use is complicated by safety issues. Method A Literature review was conducted. Results NSAIDs are a leading cause of drug-related morbidity, especially in the elderly and patients with comorbidities. Most adverse effects are related to generalized inhibition of the major targets of NSAIDs: cyclooxygenases I and II. These enzymes are not only involved in pain and inflammation pathogenesis but are also required in the gastrointestinal (GI) tract for mucosal protection and gut motility, and in the kidneys for functional integrity. Thus, the mechanisms of NSAID toxicity are well understood, but the consequences are largely uncontrolled in clinical practice. GI ulcers, including bleeding ulcers, may occur in several percent of all chronic unprotected, high-dose NSAID users. Renal side effects may precipitate renal failure, resulting in acute dialysis and chronic retention. This includes sodium retention, resulting in arterial hypertension, heart failure, and atherosclerotic events. Cardiovascular risk may be tripled by chronic high-dose NSAID use in long-term clinical trials though “real-life studies” indicate lower risk ratios. Off-target side effects include allergic reactions, drug-induced liver injury, and central nervous system effects. Conclusions Management of pain and inflammation must consider those risks and find alternative drugs or approaches to limit the negative impact of NSAIDs on mortality and morbidity. Alternative drugs, low-dose/short-term use, but especially non-pharmacologic approaches, such as physiotherapy, exercise, neurophysiologic measures, and local therapies, need to be further utilized. The appalling equation “less pain–more deaths/morbidity” ultimately necessitates treatment optimization in the individual patient.

Rationale Lithium remains the most effective treatment for bipolar disorder and also has important effects to lower suicidal behaviour, a property that may be linked to its ability to diminish impulsive, aggressive behaviour. The antioxidant drug, ebselen, has been proposed as a possible lithium-mimetic based on its ability in animals to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. Objectives The aim of the study was to determine whether treatment with ebselen altered emotional processing and diminished measures of risk-taking behaviour. Methods We studied 20 healthy participants who were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, randomized, cross-over design. Three hours after the final dose of ebselen/placebo, participants completed the Cambridge Gambling Task (CGT) and a task that required the detection of emotional facial expressions (facial emotion recognition task (FERT)). Results On the CGT, relative to placebo, ebselen reduced delay aversion while on the FERT, it increased the recognition of positive vs negative facial expressions. Conclusions The study suggests that at the dosage used, ebselen can decrease impulsivity and produce a positive bias in emotional processing. These findings have implications for the possible use of ebselen in the disorders characterized by impulsive behaviour and dysphoric mood.

The antiplatelet effects of aspirin are caused by the irreversible inhibition of the activity of the enzyme cyclooxygenase. In contrast, nonsteroidal antiinflammatory drugs (NSAIDs) are reversible inhibitors of this activity and have only transient effects on platelet function. This study found that pretreatment with ibuprofen before the administration of aspirin blocked the antiplatelet effects of aspirin. Neither the cyclooxygenase-2 inhibitor rofecoxib nor acetaminophen had this blocking effect. Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed, 1 and the use of aspirin has increased since it was shown to reduce the risk of myocardial infarction and stroke. 2 , 3 Aspirin acts by irreversibly acetylating a serine residue at position 529 in platelet prostaglandin G/H synthase, 4 an enzyme colloquially known as cyclooxygenase. The predominant product of cyclooxygenase in platelets is thromboxane A 2 . 5 The anucleate platelet affords a unique target for aspirin, since once cyclooxygenase has been acetylated by aspirin, the substrate's access to its active site is impeded for the lifetime of the platelet. Thus, the formation of thromboxane A . . .

Curcumin is a natural ingredient with antioxidant effects, widely studied as a treatment for various types of cancer. However, its effects on ultraviolet radiation have not been fully explored. The effects of single or daily application of 0.1–100 μM curcumin on cell apoptosis in ultraviolet B (UVB)-induced mice were tested using an experimental double-blind posttest design with a control group and two research models: a single application of curcumin before a single UVB exposure and daily application of curcumin for 7 days before a single UVB exposure on the seventh day. Apoptotic cells were counted using a tunnel system kit. The number of apoptotic cells under a single or daily application of curcumin for 7 days was significantly lower than that of the UVB controls (p ≤ 0.05). The number of apoptotic cells decreased with the increasing concentration of curcumin, and the maximum effect was observed at 100 μM. Daily application of topical curcumin was superior in preventing apoptosis (mean apoptotic cell count of 14.86 ± 1.68) compared with a single application (17.46 ± 0.60; p = 0.011). Topical curcumin can act as a potential photoprotective agent in preventing cutaneous malignancies due to UVB radiation. Further studies are warranted, especially in humans.

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A₂ formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.

Soft corals have been endorsed as a plentiful source of bioactive compounds with promising anti-inflammatory activities; therefore, exploring their potential as source of anti-inflammatory metabolites has stimulated a growing research interest. To investigate the anti-inflammatory potential of the soft coral, sp., in its bulk and silver nanostructure. Metabolomics analysis of sp., followed by molecular docking studies, was also conducted in order to explore and predict the secondary metabolites that might provide its inhibitory actions on inflammation. The petroleum ether and ethyl acetate fractions were used to synthesize silver nanoparticles. The prepared silver nanoparticles were characterized through UV-vis spectrophotometric, transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) analyses. Testing for the anti-inflammatory activity was performed against COX-1 and COX-2. Furthermore, liquid chromatography-mass spectrometry (LC-MS) based metabolomics analysis and molecular docking were also applied. A variety of secondary metabolites were identified, among them, sesquiterpenes were found to prevail. The petroleum ether and acetone fractions of sp. showed the highest COX-2 inhibitory activities, possibly attributable to their substantial contents of terpenoids. Additionally, the green synthesized silver nanoparticles of both the petroleum ether and ethyl acetate fractions of sp. demonstrated higher anti-COX-2 properties. The obtained results showed the effectiveness of non-targeted metabolomics technique in metabolic profiling of sp., helping the search for new bioactive metabolites in future chemical studies on this soft coral. The interesting anti-inflammatory potential of the tested extracts and their nanoparticles could also be relevant to the development of new, effective anti-inflammatory agents.

Cyclooxygenase 2 (COX-2) and the production of cytokines/chemokines are important targets for the modulation of the inflammatory response. Although a large variety of inhibitors of these pathways have been commercialized, some of those inhibitors present severe side effects, governing the search for new molecules, as alternative anti-inflammatory agents. This study was undertaken to study an hitherto not evaluated group of flavonoids, concerning its capacity to inhibit COX-1 and COX-2 enzymes, as well as to inhibit the production of the cytokines and a chemokine, in a complex matrix involved in the systemic inflammatory process, the blood, aiming the establishment of a structure–activity relationship. The results obtained reveal promising flavonoids for the modulation of the inflammatory process, namely the ones presenting a catechol group in B ring, as some flavonoids were able to simultaneously inhibit the production of inflammatory prostaglandin E 2 and pro-inflammatory cytokines.

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors. Modulating the host immune response during tuberculosis is an emerging and critical advance in the therapeutic approach. Here the authors present data from a first-in-human phase I/II randomised trial on the safety and immunogenicity of adjuvant therapy of the H56:IC31 vaccine and cyclooxygenase-2 inhibitors in patients with tuberculosis.

Initiation and resolution of inflammation are considered to be tightly connected processes. Lipoxins (LX) are proresolution lipid mediators that inhibit phlogistic neutrophil recruitment and promote wound-healing macrophage recruitment in humans via potent and specific signaling through the LXA ₄ receptor (ALX). One model of lipoxin biosynthesis involves sequential metabolism of arachidonic acid by two cell types expressing a combined transcellular metabolon. It is currently unclear how lipoxins are efficiently formed from precursors or if they are directly generated after receptor-mediated inflammatory commitment. Here, we provide evidence for a pathway by which lipoxins are generated in macrophages as a consequence of sequential activation of toll-like receptor 4 (TLR4), a receptor for endotoxin, and P2X ₇, a purinergic receptor for extracellular ATP. Initial activation of TLR4 results in accumulation of the cyclooxygenase-2–derived lipoxin precursor 15-hydroxyeicosatetraenoic acid (15-HETE) in esterified form within membrane phospholipids, which can be enhanced by aspirin (ASA) treatment. Subsequent activation of P2X ₇ results in efficient hydrolysis of 15-HETE from membrane phospholipids by group IVA cytosolic phospholipase A ₂, and its conversion to bioactive lipoxins by 5-lipoxygenase. Our results demonstrate how a single immune cell can store a proresolving lipid precursor and then release it for bioactive maturation and secretion, conceptually similar to the production and inflammasome-dependent maturation of the proinflammatory IL-1 family cytokines. These findings provide evidence for receptor-specific and combinatorial control of pro- and anti-inflammatory eicosanoid biosynthesis, and potential avenues to modulate inflammatory indices without inhibiting downstream eicosanoid pathways.

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.