salicylates and Inflammation

Postinflammatory hyperpigmentation (PIH) has posed a substantial challenge for patients with higher Fitzpatrick skin types, specifically types III to VI. Treatment modalities pose a number of limitations due to the number of treatments required, potential side effects, and overall efficacy. Fortunately, multiple therapies have been delineated that can be moderately to highly efficacious in treating PIH in patients with skin of color. This article will review some of these modalities and procedures for this common patient concern.

Topics: Chemexfoliation; Dermatitis; Dermatologic Agents; Dicarboxylic Acids; Drug Combinations; Ethanol; Glycolates; Humans; Hydroquinones; Hyperpigmentation; Inflammation; Keratolytic Agents; Lactic Acid; Pyrones; Resorcinols; Salicylates; Salicylic Acid; Skin Pigmentation; Tretinoin

Chronic inflammation may participate in the pathogenesis of insulin resistance, type 2 diabetes, and cardiovascular disease and may be a common denominator that links obesity to these disease states.. Epidemiologic studies have linked inflammatory biomarkers to incident diabetes and cardiovascular disease risk. Cellular and animal studies have provided support to the idea that inflammation mediates these disease processes, providing impetus to pharmacologically target these pathways for disease treatment and prevention. We review clinical strategies to target inflammation, with a focus on the antiinflammatory and antihyperglycemic effects of salicylates.. The evolving concept of diet-induced obesity driving insulin resistance, type 2 diabetes, and cardiovascular disease through immunologic processes provides new opportunities for the use of antiinflammatory strategies to correct the metabolic consequences of excess adiposity.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Inflammation; Insulin Resistance; Obesity; Salicylates

Inflammation disorders such as rheumatoid arthritis, asthma and inflammatory bowel disease can be considered as 'gene expression' diseases in which the pro-inflammatory gene program of the organism is aberrantly activated. Over the past 20 years, great attention has been given to the transcription factor nuclear factor-kappaB (NF-kappaB) for its involvement in inflammatory and immune diseases. Recently, several studies have been devoted to the development of new molecules that can prevent the expression of inflammatory genes by targeting NF-kappaB pathways. Therefore, it is possible to hypothesize that these molecules might represent the future class of drugs for the treatment of inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Glucocorticoids; Humans; Inflammation; NF-kappa B; Peptides; Plant Bark; Plant Extracts; Plant Preparations; Salicylates; Salix; Signal Transduction

Potent selective cyclooxygenase-2 (COX-2) inhibitors are effective in controlling inflammatory disorders but are associated with cardiovascular complications. Their clinical use has been severely limited. We propose that transcription-based inhibition of COX-2 expression represents a therapeutic strategy that may circumvent the undesired complications of COX-2 inhibitors. Reported data from several laboratories including ours have identified C/EBPbeta as a key transactivator mediating COX-2 transcriptional activation induced by diverse pro-inflammatory mediators. Results from our recent work show that sodium salicylate at pharmacological concentrations inhibits C/EBPbeta binding to COX-2 promoter by direct inhibition of p90 ribosomal S6 kinase (RSK). RSK phosphorylates C/EBPbeta and stimulates its binding to enhancer elements. We propose that RSK1/2 is a potential target for screening drugs with novel anti-inflammatory and anti-neoplastic therapeutic potentials.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; CCAAT-Enhancer-Binding Protein-beta; Colonic Neoplasms; Cyclooxygenase 2; Gene Expression Regulation, Enzymologic; Genetic Therapy; Humans; Inflammation; Phosphorylation; Promoter Regions, Genetic; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases, 90-kDa; RNA Interference; RNA, Small Interfering; Salicylates; Transcription, Genetic; Transcriptional Activation

Antidiabetic effects associated with salicylates have been known for years, although the underlying mechanisms were not understood. We have been reinvestigating these effects in the light of recent discoveries in the areas of signal transduction and insulin resistance. Our findings showed that signaling pathways leading to I kappa B kinase beta (IKK beta) and NF-kappa B are activated in insulin-responsive tissues of obese and high-fat-fed animals. Since activation correlates with the development of insulin resistance, we asked whether signaling through this might be involved in the pathogenesis of insulin resistance. Heterozygous gene deletion (Ikk beta+/-) or salicylates, working as IKK beta inhibitors, improved insulin sensitivity in insulin-resistant rodent models. Furthermore, high doses of salicylates (aspirin or salicylate) improved insulin sensitivity in patients with type II diabetes. Our studies implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus and identify the IKK beta/NF-kappa B pathway as a molecular mediator of insulin resistance and pharmacological target for insulin sensitization.

Topics: Animals; Dietary Fats; Humans; I-kappa B Kinase; Inflammation; Insulin Resistance; Mice; NF-kappa B; Obesity; Protein Serine-Threonine Kinases; Rats; Salicylates

An overview of the literature on the effects of salicylic acid and its derivatives with particular consideration being given to their antiinflammatory properties is presented. While acetylsalicylic acid, in common with most non-steroidal anti-inflammatory drugs, has a marked inhibitory effect on cyclooxygenase in vitro, salicylic acid only weakly inhibits this enzyme. Animal inflammation models, however, have shown that the two substances are comparable in terms of efficacy. It is therefore assumed that the antiinflammatory properties of salicylic acid and its derivatives are also based on prostaglandin-independent mechanisms. Both salicylates and salicylic acid are used for topical applications. Their penetration into deeper tissue layers, as also their efficacy after local application have been demonstrated in both animal studies and clinical trials.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Aspirin; Humans; Inflammation; Salicylates; Salicylic Acid

Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Inflammation; Neutrophils; Prostaglandin Antagonists; Salicylates

The history of the use of aspirin and salicylate is briefly reviewed, as are the many putative mediators of inflammation. The theory that aspirin-like drugs bring about their anti-inflammatory effects through inhibition of prostaglandin biosynthesis is presented, in the light of other arachidonic acid products such as the leukotrienes. The selective inhibition of cyclo-oxygenase by the large group of aspirin-like non-steroidal anti-inflammatory drugs explains their therapeutic activity. The elucidation of other pathways of oxidative metabolism of arachidonic acid has revealed new targets for the development of drugs with potentially greater therapeutic activity in the treatment of inflammation, cardio-thrombotic diseases and asthma.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Cyclooxygenase Inhibitors; Humans; Inflammation; Prostaglandin-Endoperoxide Synthases; Salicylates

Inflammation is caused by release of chemicals from tissues and migrating cells. Most strongly implicated are the prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, and, more recently, platelet-activating factor (PAF) and interleukin-1. Evidence for their involvement comes from studies with competitive antagonists for their receptors and inhibitors of their synthesis. H1 histamine antagonists are effective for hay fever and some skin allergies such as urticaria, which indicates the importance of histamine in these conditions. Symptoms of rheumatoid arthritis are alleviated by the aspirinlike anti-inflammatory drugs, which inhibit the cyclo-oxygenase enzyme and reduce synthesis of prostanoids. Corticosteroids prevent the formation of both PGs and LTs by causing the release of lipocortin, which by inhibition of phospholipase A2 reduces arachidonic acid release. They suppress the inflammation of rheumatoid arthritis and asthma. Currently, high doses of nonsedating H1 antihistamines and PAF antagonists are being tested for the treatment of allergic asthma.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Bradykinin; Colchicine; Cyclooxygenase Inhibitors; Gold; Histamine; Humans; Inflammation; Interleukin-1; Lipoxygenase Inhibitors; Platelet Activating Factor; Salicylates

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Drug Interactions; Female; Humans; Ibuprofen; Indomethacin; Inflammation; Kinetics; Male; Prostaglandin Antagonists; Prostaglandins; Prostaglandins E; Prostaglandins F; Salicylates; Sex Factors

Topics: Anti-Inflammatory Agents; Arthritis; Aspirin; Child; Drug Tolerance; Female; Gastric Mucosa; Gastritis; Humans; Indomethacin; Infant, Newborn; Inflammation; Kidney; Kinetics; Liver; Maternal-Fetal Exchange; Pregnancy; Prostaglandins; Salicylates; Stomach Ulcer

Efforts have been made to develop noncorticosteroidal anti-inflammatory therapy. The goals of such therapy have been to eradicate the primary cause, prevent the initial tissue injury, moderate inflammatory response, and enhance tissue repair while minimizing and eliminating the undesirable aspects of the therapy.

Topics: Animals; Anti-Inflammatory Agents; Blood Platelets; Eye Diseases; Humans; Inflammation; Lymphokines; Oxyphenbutazone; Phenylbutazone; Prostaglandins; Salicylates

Topics: Acid-Base Equilibrium; Adenosine Triphosphatases; Anti-Inflammatory Agents; Ascorbic Acid; Autacoids; Chloroquine; Glycosaminoglycans; Gold; Histamine H1 Antagonists; Humans; Hydrogen-Ion Concentration; Indomethacin; Inflammation; Phenylbutazone; Salicylates; Salts

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Aspirin; Blood Chemical Analysis; Bradykinin; Bronchi; Cats; Chemical Phenomena; Chemistry; Constriction; Dogs; Enzyme Inhibitors; Epithelium; Exudates and Transudates; Gastric Mucosa; Guinea Pigs; Haplorhini; Hemostasis; Histamine; Inflammation; Kidney Tubules; Mice; Muscle, Smooth; Muscles; Neurons; Pain; Peptides; Rabbits; Rats; Salicylates

Topics: Adolescent; Adult; Anti-Inflammatory Agents; Child; Child, Preschool; Enzyme Therapy; Eye Diseases; Female; Flufenamic Acid; Humans; Indomethacin; Inflammation; Male; Mefenamic Acid; Middle Aged; Oxyphenbutazone; Phenylbutazone; Placebos; Pyrimidines; Salicylates

Topics: Analgesics; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antigen-Antibody Reactions; Antipyretics; Biochemical Phenomena; Biochemistry; Blood Chemical Analysis; Hypersensitivity; Inflammation; Necrosis; Pharmacology; Phenylbutazone; Proteins; Rheumatic Diseases; Salicylates

Topics: Adrenal Cortex Hormones; Arthritis; Electrocardiography; Humans; Inflammation; Morphine; Myocardial Infarction; Myositis; Pericarditis; Peritonitis; Pleurisy; Pneumonia; Salicylates

Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease.. To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque.. In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned between September 23, 2008, and July 5, 2012, to 30 months of salsalate or placebo in addition to standard, guideline-based therapies. Randomization was computerized and centrally allocated, with patients, health care professionals, and researchers masked to treatment assignment. Participants were overweight and obese statin-using patients with established, stable coronary heart disease.. Salsalate (3.5 g/d) or placebo orally over 30 months.. The primary outcome was progression of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography. Secondary outcomes were other measures of safety and efficacy.. Two hundred fifty-seven participants were randomized to salsalate (n = 129) or placebo (n = 128). Their mean (SD) age was 60.8 (7.0) years, and 94.0% (236 of 251) were male. One hundred ninety participants (89 in the salsalate group and 101 in the placebo group) completed the study. Compared with baseline, there was no increase in noncalcified plaque volume in the placebo-treated patients and no difference in change between the salsalate and placebo groups (mean difference, -1 mm3; 95% CI, -11 to 9 mm3; P = .87). Salsalate treatment decreased total white blood cell, lymphocyte, monocyte, and neutrophil counts and increased adiponectin levels without change in C-reactive protein levels. Fasting glucose, triglycerides, uric acid, and bilirubin levels were decreased in the salsalate group compared with the placebo group, while hemoglobin levels were increased. Urinary albumin levels increased, with tinnitus and atrial arrhythmias more common, in the salsalate group compared with the placebo group.. Salsalate when added to current therapies that include a statin does not reduce progression of noncalcified coronary plaque volume assessed by multidetector computed tomographic angiography in statin-using patients with established, stable coronary heart disease. The absence of progression of noncalcified plaque volume in the placebo group may limit interpretation of the trial results.. clinicaltrials.gov Identifier: NCT00624923.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Obesity; Overweight; Plaque, Atherosclerotic; Salicylates

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Bone Remodeling; Diabetes Mellitus, Type 2; Humans; Inflammation; Osteocalcin; Salicylates; Treatment Outcome

Salsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.. A randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.. In those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01).. Findings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation.

Topics: Adipose Tissue; Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; California; Double-Blind Method; Female; Glucose Tolerance Test; Glycemic Index; Hispanic or Latino; Humans; Inflammation; Insulin; Insulin Secretion; Male; Obesity; Salicylates; Treatment Outcome

To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D).. We conducted an ancillary study to the National Institutes of Health-sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g/day or placebo. The primary end point was change in FMD at 6 months.. A total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg/m(2)), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol/mol; P < 0.001), fasting glucose by 16.1 mg/dL (P < 0.001), and white blood cell count by 430 cells/µL (P < 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI -0.86 to 2.25%]; P = 0.38) or NMD (-0.59% [95% CI -2.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg/dL higher, respectively, and urinary albumin was 2.0 µg/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P < 0.009).. Salsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Brachial Artery; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Inflammation; Male; Middle Aged; Regional Blood Flow; Salicylates; Single-Blind Method; Time Factors; Treatment Outcome; Ultrasonography; Vasodilation

Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance.. We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment.. Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI -39%, 56%]; placebo 6% [95% CI -20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (-16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2).. In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement.. ClinicalTrials.gov NCT00330733.. Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214.

Topics: Adiponectin; Adipose Tissue; Aged; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; C-Peptide; Cardiovascular Diseases; Female; Glucose Tolerance Test; Humans; Inflammation; Insulin; Insulin Resistance; Male; Middle Aged; NF-kappa B; Risk Factors; Salicylates; Triglycerides

Chronic subacute inflammation is implicated in the pathogenesis of insulin resistance and type 2 diabetes. Salicylates were shown years ago to lower glucose and more recently to inhibit NF-kappaB activity. Salsalate, a prodrug form of salicylate, has seen extensive clinical use and has a favorable safety profile. We studied the efficacy of salsalate in reducing glycemia and insulin resistance and potential mechanisms of action to validate NF-kappaB as a potential pharmacologic target in diabetes.. In open label studies, both high (4.5 g/d) and standard (3.0 g/d) doses of salsalate reduced fasting and postchallenge glucose levels after 2 weeks of treatment. Salsalate increased glucose utilization during euglycemic hyperinsulinemic clamps, by approximately 50% and 15% at the high and standard doses, respectively, and insulin clearance was decreased. Dose-limiting tinnitus occurred only at the higher dose. In a third, double-masked, placebo-controlled trial, 1 month of salsalate at maximum tolerable dose (no tinnitus) improved fasting and postchallenge glucose levels. Circulating free fatty acids were reduced and adiponectin increased in all treated subjects.. These data demonstrate that salsalate improves in vivo glucose and lipid homeostasis, and support targeting of inflammation and NF-kappaB as a therapeutic approach in type 2 diabetes.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Calorimetry; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin; Insulin Resistance; Male; NF-kappa B; Placebos; Salicylates

Sedentary lifestyle and a western diet promote subacute-chronic inflammation, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the efficacy of the anti-inflammatory drug salsalate to improve glycemia by reducing systemic inflammation in obese adults at risk for the development of type 2 diabetes.. In a double-masked, placebo controlled trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or placebo.. Compared with placebo, salsalate reduced fasting glucose 13% (P < 0.002), glycemic response after an oral glucose challenge 20% (P < 0.004), and glycated albumin 17% (P < 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P < 0.03), consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin clearance. Adiponectin increased 57% after salsalate compared with placebo (P < 0.003). Additionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein were reduced by 34% (P < 0.05).. This proof-of-principle study demonstrates that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. These data support the hypothesis that subacute-chronic inflammation contributes to the pathogenesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeutic route for diabetes prevention.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Dietary Carbohydrates; Double-Blind Method; Exercise; Female; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Inflammation; Male; Obesity; Placebos; Salicylates; Serum Albumin

The inflammatory process involving Helicobacter pylori-associated gastritis is thought to lead to epithelial damage and contribute to the development of gastric cancer. Evidence exists from animal and in vitro studies suggesting that tetracyclines have both anti-inflammatory and tissue-protectant effects unrelated to their antimicrobial activity. We attempted to modulate components of H. pylori's inflammatory process by: (i) eliminating the infection; (ii) using tetracycline to alter the host's reaction to the infection without reducing the bacterial load; and (iii) using calcium to counteract the effect of excessive dietary salt.. We conducted a 16-week placebo-controlled clinical trial with 374 H. pylori-associated gastritis patients randomly assigned to one of five groups: (1) triple therapy consisting of metronidazole, amoxicillin and bismuth subsalicylate for 2 weeks, followed by bismuth alone for 14 weeks; (2) calcium carbonate; (3) triple therapy and calcium carbonate; (4) tetracycline; or (5) placebo.. Subjects in the tetracycline and triple therapy groups, but not the calcium carbonate only group, showed a reduction in inflammation and epithelial damage vs. those in the placebo group, independent of a change in H. pylori density and other factors. Our results also indicate that epithelial damage may be affected by mechanisms independent of H. pylori density or inflammation.. The results are consistent with the hypothesis that tetracycline can decrease inflammation independent of a reduction in the bacterial load. More research is needed to investigate mechanisms leading to epithelial damage which are independent of H. pylori density and inflammation.

Topics: Adult; Aged; Amoxicillin; Antacids; Anti-Bacterial Agents; Bismuth; Calcium Carbonate; Drug Therapy, Combination; Epithelium; Female; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Male; Metronidazole; Middle Aged; Organometallic Compounds; Penicillins; Placebos; Risk Factors; Salicylates; Stomach Neoplasms; Tetracycline; Treatment Outcome

Sixty-four patients with proven ulcerative colitis who had been maintained on sulphasalazine as their sole form of treatment for a minimum period of one year were entered into a controlled trial of sulphasalazine versus dummy tablets for a period of six months. All the patients admitted were not only symptom-free but also showed no evidence of inflammation on sigmoidoscopy and rectal biopsy. A patient was judged to have relapsed when there was a recurrence of colitic symptoms accompanied by sigmoidoscopic and histological evidence of inflammation. The patients who received dummy tablets had more than four times the relapse rate of those receiving sulphasalazine. The results were similar in patients who had been on maintenance treatment with sulphasalazine for less than three years before entry into the trial and in those who had been on this treatment for more than three years. It is concluded that maintenance treatment of ulcerative colitis with sulphasalazine should be continued indefinitely unless contraindicated by side effects.

Topics: Biopsy; Blood Cell Count; Blood Sedimentation; Clinical Trials as Topic; Colitis, Ulcerative; Headache; Hemoglobins; Humans; Inflammation; Nausea; Placebos; Prednisolone; Psychology; Rectum; Remission, Spontaneous; Salicylates; Sigmoidoscopy; Sulfasalazine

Topics: Acetanilides; Acetates; Analgesics; Arthritis, Rheumatoid; Aspirin; Blood Sedimentation; Clinical Trials as Topic; Female; Humans; Inflammation; Male; Middle Aged; Pain; Salicylates

Medicinal properties of Gaultheria have been used in traditional medicine to treat pain and inflammation.. Hence, the purpose of this study was to evaluate the analgesic, antipyretic, and anti-inflammatory properties of Gaultheria trichophylla Royle extract and salicylate-rich fraction in vivo, in vitro, and in silico.. In vivo analgesic, antipyretic, and anti-inflammatory of extract and a salicylate-rich fraction (at doses of 100, 200, 300, and 150 mg/kg) were assessed using healthy albino mice employing acetic acid-induced writhing, tail immersion test, carrageenan-induced inflammation, and croton oil-induced edema. For in vitro testing of extracts COX and LOX enzyme inhibition assays were used. Molecular docking studies were conducted for in silico testing of the inhibitory activity of the dominant compound Gaultherin against COX and LOX.. G-EXT 200 and 300 and G-SAL 150 mg/kg reduced pyrexia significantly (P < 0.05 and P < 0.01). G-EXT-200, 300, and G-SAL 150 reduce the writing to a significant level (p > 0.05, p < 0.01). G-EXT 200 and 300 and G-SAL 150 mg/kg doses the analgesic effect was significant (p > 0.05, p > 0.01) and was comparable to tramadol. G-EXT 100 200, 300 mg/kg showed 43.8%, 47.94% and 56% respectively. G-SAL 150 mg, rich in salicylates, showed maximum inhibition of 65.75% next to standard drug diclofenac with 76.7% inhibition. G-EXT 100 and 200 mg/kg dose showed significant (p < 0.05) reduction in ear edema. With 300 mg/kg dose the effect was more (61.89%, p < 0.01). The salicylate-rich fraction G-SAL and Celecoxib showed an almost similar effect (p < 0.01). Significance inhibition was shown in the COX-2 test (G-EXT 39.70 and G-SAL 77.20 IC50 μg/ml) and in the 5-LOX test (G-EXT 28.3 and G-SAL 39.70 IC50 μg/ml). The preliminary in silico results suggest that the investigated compound showed excellent inhibitory activity against COX and LOX enzymes as evident from the free binding energy. Molecular docking revealed that Gaultherin binds well in the COX and LOX enzyme catalytic region.. The extract and salicylate-rich fraction obtained from G. trichophylla showed significant analgesic, anti-inflammatory, and antipyretic effects in vivo, in vitro, and in silico assays that support its use in traditional medicine.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antipyretics; Carrageenan; Edema; Ericaceae; Fever; Gaultheria; Inflammation; Mice; Molecular Docking Simulation; Plant Extracts; Salicylates

The roles of the kynurenine pathway (KP) of tryptophan (Trp) degradation in serotonin deficiency in major depressive disorder (MDD) and the associated inflammatory state are considered in the present study. Using molecular docking in silico, we demonstrate binding of antidepressants to the crystal structure of tryptophan 2,3-dioxygenase (TDO) but not to indoleamine 2,3-dioxygenase (IDO). TDO is inhibited by a wide range of antidepressant drugs. The rapidly acting antidepressant ketamine does not dock to either enzyme but may act by inhibiting kynurenine monooxygenase thereby antagonising glutamatergic activation to normalise serotonin function. Antidepressants with anti-inflammatory properties are unlikely to act by direct inhibition of IDO but may inhibit IDO induction by lowering levels of proinflammatory cytokines in immune-activated patients. Of six anti-inflammatory drugs tested, only salicylate docks strongly to TDO and apart from celecoxib, the other five dock to IDO. TDO inhibition remains the major common property of antidepressants and TDO induction the most likely mechanism of defective serotonin synthesis in MDD. TDO inhibition and increased free Trp availability by salicylate may underpin the antidepressant effect of aspirin and distinguish it from other nonsteroidal anti-inflammatory drugs. The controversial findings with IDO in MDD patients with an inflammatory state can be explained by IDO induction being overridden by changes in subsequent KP enzymes influencing glutamatergic function. The pathophysiology of MDD may be underpinned by the interaction of serotonergic and glutamatergic activities.

Topics: Anti-Inflammatory Agents; Antidepressive Agents; Depressive Disorder, Major; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Kynurenine; Molecular Docking Simulation; Salicylates; Serotonin; Tryptophan

As a worldwide health issue, obesity is associated with the infiltration of monocytes/macrophages into the adipose tissue causing unresolved inflammation. Monocyte chemoattractant protein-1 (MCP-1) exerts a crucial effect on obesity-related monocytes/macrophages infiltration. Clinically, aspirin and salsalate are beneficial for the treatment of metabolic diseases in which adipose tissue inflammation plays an essential role. Herein, we investigated the effect and precise mechanism of their active metabolite salicylate on TNF-α-elevated MCP-1 in adipocytes. The results indicated that salicylate sodium (SAS) could lower the level of MCP-1 in TNF-α-stimulated adipocytes, which resulted from a previously unrecognized target phosphodiesterase (PDE), 3B (PDE3B), rather than its known targets IKKβ and AMPK. The SAS directly bound to the PDE3B to inactivate it, thus elevating the intracellular cAMP level and activating PKA. Subsequently, the expression of MKP-1 was increased, which led to the decrease in p-EKR and p-p38. Both PDE3B silencing and the pharmacological inhibition of cAMP/PKA compromised the suppressive effect of SAS on MCP-1. In addition to PDE3B, the PDE3A and PDE4B activity was also inhibited by SAS. Our findings identify a previously unrecognized pathway through which SAS is capable of attenuating the inflammation of adipocytes.

Topics: Adipocytes; Chemokine CCL2; Cyclic Nucleotide Phosphodiesterases, Type 3; Humans; Inflammation; Obesity; Salicylates; Tumor Necrosis Factor-alpha

Topics: Acetylation; Animals; Asthma; Histone Acetyltransferases; Inflammation; Interleukin-33; Mice; Salicylates

Inflammatory bowel diseases are the most common chronic intestinal inflammatory conditions, and their incidence has shown a dramatic increase in recent decades. Limited efficacy and questionable safety profiles with existing therapies suggest the need for better targeting of therapeutic strategies. Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of cellular metabolism and has been implicated in intestinal inflammation. Macrophages execute an important role in the generation of intestinal inflammation. Impaired AMPK in macrophages has been shown to be associated with higher production of proinflammatory cytokines; however, the role of macrophage AMPK in intestinal inflammation and the mechanism by which it regulates inflammation remain to be determined. In this study, we investigated the role of AMPK with a specific focus on macrophages in the pathogenesis of intestinal inflammation.. A dextran sodium sulfate-induced colitis model was used to assess the disease activity index, histological scores, macroscopic scores, and myeloperoxidase level. Proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β were measured by enzyme-linked immunosorbent assay. Transient transfection of AMPKβ1 and LC3-II siRNA in RAW 264.7 cells was performed to elucidate the regulation of autophagy by AMPK. The expression of p-AMPK, AMPK, and autophagy markers (eg, LC3-II, p62, Beclin-1, and Atg-12) was analyzed by Western blot.. Genetic deletion of AMPKβ1 in macrophages upregulated the production of proinflammatory cytokines, aggravated the severity of dextran sodium sulfate-induced colitis in mice, which was associated with an increased nuclear translocation of nuclear factor-κB, and impaired autophagy both in vitro and in vivo. Notably, the commonly used anti-inflammatory 5-aminosalicylic acid (ie, mesalazine) and sodium salicylate ameliorated dextran sodium sulfate-induced colitis through the activation of macrophage AMPK targeting the β1 subunit.. Together, these data suggest that the development of therapeutic agents targeting AMPKβ1 may be effective in the treatment of intestinal inflammatory conditions including inflammatory bowel disease.

Topics: AMP-Activated Protein Kinases; Animals; Colitis; Cytokines; Dextran Sulfate; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; RAW 264.7 Cells; Salicylates

To test in mice with a double mutation of the ApoE gene (ApoE-/-) whether spinal cord injury (SCI) hastens the native trajectory of, and established component risks for, atherosclerotic disease (AD), and whether Salsalate anti-inflammatory pharmacotherapy attenuates the impact of SCI.. ApoE-/- mice were anesthetized and underwent a T9 laminectomy. Exposed spinal cords were given a contusion injury (70 k-dynes). Sham animals underwent all surgical procedures, excluding injury. Injured animals were randomized to 2 groups: SCI or SCI+Salsalate [120 mg/Kg/day i.p.]. Mice were serially sacrificed at 20-, 24-, and 28-weeks post-SCI, and body mass was recorded. At sacrifice, heart and aorta were harvested intact, fixed in 10% buffered formalin, cleaned and cut longitudinally for en face preparation. The aortic tree was stained with oil-red-O (ORO). AD lesion histomorphometry was calculated from the proportional area of ORO. Plasma total cholesterol, triglycerides and proatherogenic inflammatory cytokines (PAIC's) were analyzed.. AD lesion in the aortic arch progressively increased in ApoE-/-, significant at 24- and 28-weeks. AD in SCI is significantly greater at 24- and 28-weeks compared to time-controlled ApoE-/-. Salsalate treatment attenuates the SCI-induced increase at these time points. Body mass in all SCI groups are significantly reduced compared to time-controlled ApoE-/-. Cholesterol and triglycerides are significantly higher with SCI by 24- and 28-weeks, compared to ApoE-/-, and Salsalate reduces the SCI-induced effect on cholesterol. PAIC's interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-C motif) ligand 5 (CCL-5) are significantly greater with SCI compared to ApoE-/- at varying timepoints. Salsalate confers a marginal reducing effect on PAIC's by 28-weeks compared to SCI. Regression models determine that each PAIC is a significant and positive predictor of lesion. (p's <0.05).. SCI accelerates aortic AD and associated risk factors, and anti-inflammatory treatment may attenuate the impact of SCI on AD outcomes. PAIC's IL-1β, IL-6, TNFα, MCP-1, and CCL-5 may be effective predictors of AD.

Topics: Animals; Anti-Inflammatory Agents; Aorta, Thoracic; Atherosclerosis; Body Weight; Cardiometabolic Risk Factors; Cytokines; Inflammation; Lipids; Mice, Knockout, ApoE; Regression Analysis; Risk Factors; Salicylates; Spinal Cord Injuries

Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson's disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 μM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson's disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Administration, Oral; Animals; Benzoates; Cell Survival; Cyclooxygenase 2; Disease Models, Animal; Drug Design; In Vitro Techniques; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microglia; Models, Theoretical; Neuroglia; Neurons; Nitric Oxide; Parkinson Disease; Peptides; Phosphorylation; Salicylates; Signal Transduction

New type of carriers based on grafted poly(ionic liquid)s was designed for delivery of ionically attached salicylates (Sal). Choline derived ionic liquid monomeric units were successfully introduced with various content in the side chains by the controlled radical polymerization. Properly high amounts of ionic pharmaceutics in the polymer systems were achieved by the well-fitted length and grafting degree of the side chains. In aqueous solution the graft copolymers were self-assembled into the spherical superstructures with sizes up to 73 nm. Delivery studies showed "burst" release within 4 h, after that it was slower yielding ~70% of released drug within 80 h. Proposed nanocarriers supported low toxicity against human cells (NHDF and BEAS-2B), anti-inflammation activity evaluated with the use of pro-inflammatory interleukins (IL-6 and IL-8) and antibacterial activities towards E. coli. Adjustment of ionic drug content by structural parameters of graft copolymers, including grafting degree and graft length, are advantageous to tailor nanocarriers with self-assembly properties in aqueous media. Effective release process by ionic exchange and biological activity with low toxicity are promising for further development of this type of drug delivery (DDS).

Topics: Cell Line; Choline; Drug Carriers; Drug Delivery Systems; Escherichia coli; Free Radicals; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Interleukin-8; Ionic Liquids; Polymerization; Polymers; Salicylates; Water

Inflammation plays a causative role in atherosclerosis development. Salsalate is an anti-inflammatory drug used to treat atherosclerosis, but the mechanisms by which it affects atherosclerotic progression remain unclear.. Human umbilical vascular endothelial cells (HUVECs) and THP-1 human monocytes were treated with salsalate. Heme oxygenase 1 (HO-1) and sirtuin 1 (SIRT1) small interfering RNAs (siRNAs) were used to suppress each gene expression. Protein analyses were performed for measuring the expression of HO-1, SIRT1, nuclear factor kappa B (NFκB), cell adhesion molecules, and endoplasmic reticulum (ER) stress markers. Furthermore, cell adhesion assay, caspase 3 activity assay, and ELISA were also performed.. In this study, we show that salsalate increases the expression of HO-1 and SIRT1 in HUVEC and suppresses lipopolysaccharide (LPS)-induced atherosclerotic responses via HO-1- and SIRT1-mediated pathways. Salsalate treatment of HUVEC and THP-1 cells reduced LPS-induced phosphorylation of NFκB and secretion of the proinflammatory cytokines TNFα and MCP-1. Salsalate treatment of HUVEC reduced the expression of the adhesion molecules ICAM, VCAM, and E-selectin and the LPS-induced adhesion of THP-1 cells to HUVEC. Salsalate treatment also attenuated LPS-induced ER stress and cell apoptosis. These anti-atherosclerotic effects were reversed by treating cells with siRNA for HO-1 and SIRT1.. Salsalate ameliorates LPS-induced atherosclerotic reactions via HO-1 and SIRT1-dependent reduction of inflammation and ER stress. Activation of these pathways by salsalate may provide therapeutic strategies for treating atherosclerosis.

Topics: Atherosclerosis; Chemokine CCL2; Endoplasmic Reticulum Stress; Heme Oxygenase-1; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lipopolysaccharides; NF-kappa B; RNA, Small Interfering; Salicylates; Sirtuin 1; THP-1 Cells; Tumor Necrosis Factor-alpha

This pilot study examined the effect of adjunctive salsalate on psychopathology and cognition in patients with schizophrenia. This was a 12-week, open-label trial of salsalate (1.5 g, twice per day) in patients with schizophrenia. Psychopathology, cognition, and daily function were assessed at baseline and week 12 using various rating scales. Blood levels of inflammatory markers including white blood cell count, high-sensitivity C-reactive protein, and interleukin-6 levels were also measured. Eight patients completed the study. There was no significant change in any of the rating scales at week 12. However, there was a trend decrease in the Positive and Negative Syndrome Scale total score, and a trend improvement in the Brief University of California San Diego Performance-based Skills Assessment total score (58.3±11.4 vs. 53.5±11.9, P=0.072; 69.7±18.2 vs. 79.1±15.9, P=0.084, respectively). There was a trend improvement in quality of life as measured by the Quality of Life Scale total score (74.0±20.8 vs. 76.9±22.7, P=0.080). There was a significant decrease in white blood cell count (6.8±1.3 vs. 6.0±1.2 k/mm, P=0.022). There was no change in the levels of high-sensitivity C-reactive protein or interleukin-6 over 12 weeks (P's>0.1). Salsalate may have positive therapeutic effect in patients with schizophrenia. Future studies to examine potential benefits of salsalate as an adjunctive treatment to improve clinical symptoms and daily function in patients with schizophrenia are warranted.

Topics: Activities of Daily Living; Adult; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; C-Reactive Protein; Cognition; Drug Monitoring; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Outpatients; Pilot Projects; Psychiatric Status Rating Scales; Psychopathology; Quality of Life; Salicylates; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

This present investigation examined the mitigating impact of Ginkgolic acid in the organization on oxidized low-density lipoproteinox-LDL (ox- LDL) animated in HUVECs, and to clear up its fundamental molecular components. The levels of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines were measured by Griess examine and catalyst connected immunosorbent test. The declarations of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), mitogen-initiated protein kinases (MAPKs), and Akt were measured utilizing Western smearing. ox-LDL-instigated was utilized as the HUVECs cell model of inflammation. Ginkgolic acid significantly inhibited the production of NO, PGE2, and pro-inflammatory cytokines in a dose-dependent manner and suppressed the expression of iNOS and COX-2 in ox-LDL-stimulated HUVECs cells. Ginkgolic acid strongly suppressed NF-κB by preventing degradation of inhibitor of κB-α as well as by inhibiting phosphorylation of Akt and MAPKs. Ginkgolic acid reduced LDL-stimulated inflammation in endothelial cells. These outcomes suggest that the anti-inflammatory properties of Ginkgolic acid are related to a down-control of iNOS, COX-2, and master provocative cytokines through the restraint of NF-κB pathway in ox- LDL-animated endothelial cells.

Topics: Anti-Inflammatory Agents; Cyclooxygenase 2; Cytokines; Dinoprostone; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lipoproteins, LDL; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Salicylates

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications in inflammatory illnesses. However, the gastrointestinal bleeding and toxicity associated with NSAIDs long term use prompted the quest towards investigations for new anti-inflammatory agents. Natural and natural-derived molecules proved its anti-inflammatory efficacy in vitro as well as in vivo. Given this background, the scope of this research involves structural changes of the natural polyphenol (tyrosol) generating two new salicylate derivatives and testing their biological properties, focusing on anti-inflammatory effects assessed in vitro and in vivo assays. The first molecular modification was the introduction of a carboxylic acid group adjacent to the phenol group present in this compound, which creates a new salicylate-like tyrosol. In addition, the acetylation of phenol group in this molecule produced an acetylsalicylate derivative, which may be regarded as aspirin-like natural polyphenol. Interestingly, tyrosol and its novel derivatives attenuated the edema in acute inflammatory response on carrageenan- induced local inflammation in mice. In addition, our results demonstrated that tyrosol and its novel derivatives were able to reduce the chemotaxis of neutrophil assessed in vitro model by chemo attractant (fMLP). Furthermore, only derivative 2 was able to reduce this effect in the acute inflammatory model. In (DPPH)- scavenging activity, tyrosol derivatives demonstrated a minor antioxidant activity, which may suggest that radical scavenging is not a major pathway involved in the anti-inflammatory effects of these derivatives. Salicylate-like tyrosol derivatives are of particular interest for future studies.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Edema; Inflammation; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Phenylethyl Alcohol; Salicylates; Structure-Activity Relationship

Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

Topics: Adipose Tissue, Brown; Animals; Animals, Genetically Modified; C-Reactive Protein; Fatty Acids, Nonesterified; Humans; Hypertension; Inflammation; Insulin Resistance; Lipid Metabolism; Liver; Metabolic Syndrome; NLR Proteins; Oxidative Stress; PPAR alpha; Rats; Salicylates; Tumor Necrosis Factor-alpha

Neuroinflammation plays a critical role in the pathogenesis of traumatic brain injury (TBI). TBI induces rapid activation of astrocytes and microglia, infiltration of peripheral leukocytes, and secretion of inflammatory cytokines. In the context of modest or severe TBI, such inflammation contributes to tissue destruction and permanent brain damage. However, it is clear that the inflammatory response is also necessary to promote post-injury healing. To date, anti-inflammatory therapies, including the broad class of non-steroidal anti-inflammatory drugs (NSAIDs), have met with little success in treatment of TBI, perhaps because these drugs have inhibited both the tissue-damaging and repair-promoting aspects of the inflammatory response, or because inhibition of inflammation alone is insufficient to yield therapeutic benefit. Salsalate is an unacetylated salicylate with long history of use in limiting inflammation. This drug is known to block activation of NF-κB, and recent data suggest that salsalate has a number of additional biological activities, which may also contribute to its efficacy in treatment of human disease. Here, we show that salsalate potently blocks pro-inflammatory gene expression and nitrite secretion by microglia in vitro. Using the controlled cortical impact (CCI) model in mice, we find that salsalate has a broad anti-inflammatory effect on in vivo TBI-induced gene expression, when administered post-injury. Interestingly, salsalate also elevates expression of genes associated with neuroprotection and neurogenesis, including the neuropeptides, oxytocin and thyrotropin releasing hormone. Histological analysis reveals salsalate-dependent decreases in numbers and activation-associated morphological changes in microglia/macrophages, proximal to the injury site. Flow cytometry data show that salsalate changes the kinetics of CCI-induced accumulation of various populations of CD11b-positive myeloid cells in the injured brain. Behavioral assays demonstrate that salsalate treatment promotes significant recovery of function following CCI. These pre-clinical data suggest that salsalate may show promise as a TBI therapy with a multifactorial mechanism of action to enhance functional recovery.

Topics: Animals; Brain; Brain Injuries, Traumatic; Cell Line; Gene Flow; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Oxytocin; Recovery of Function; Salicylates; Thyrotropin-Releasing Hormone

The aim of this study was to evaluate the influence of diabetes mellituson tissue response and mineralization ability of Sealapex®and MTA Fillapex® sealers. Twenty-four Wistar rats were divided into two groups: diabetic and non-diabetic. The materials were placed in polyethylene tubes and implanted into dorsal connective tissue of rats for 7 and 30 days. Six animals from each group received injection of calcein, alizarin, and oxytetracycline on days 7, 14, and 21, respectively. The animals were killed after 7 and 30 days and specimens were prepared for histologic analysis by staining with hematoxylin and eosin or Von Kossa or left unstained for polarized light or fluorescence microscopy. On day 7, inflammatory reactions were characterized. Moderate inflammatory responses were observed for all groups and on day 30, a mild inflammatory response against MTA Fillapex® and a moderate inflammatory response against Sealapex® were observed. Von Kossa-positive structures were observed in response to both materials and birefringent structures were observed upon polarized light analysis; these had no relation to the diabetic condition (p > 0.05). The fluorescence intensity was unaffected in diabetic rats (p > 0.05). In conclusion, diabetes mellitus did not influence the tissue response or mineralization stimulated by Sealapex® or MTA Fillapex®.

Topics: Aluminum Compounds; Animals; Biocompatible Materials; Calcium Compounds; Calcium Hydroxide; Diabetes Mellitus, Experimental; Drug Combinations; Inflammation; Male; Materials Testing; Microscopy, Fluorescence; Oxides; Rats, Wistar; Salicylates; Silicates; Subcutaneous Tissue; Time Factors

Obturation of the root canal system aims to fill empty spaces, promoting hermetic sealing and preventing bacterial activity in periapical tissues. This should provide optimal conditions for repair, stimulating the process of biomineralization. An endodontic sealer should be biocompatible once it is in direct contact with periapical tissues. The aim of this study was to evaluate the rat subcutaneous tissue response to implanted polyethylene tubes filled with Smartpaste Bio, Acroseal, and Sealapex and investigate mineralization ability of these endodontic sealers. Forty Wistar rats were assigned to the three sealers groups and control group, (n = 10 animals/group) and received subcutaneous implants containing the test sealers, and the control group were implanted with empty tubes. After days 7, 15, 30, and 60, animals were euthanized and polyethylene tubes were removed with the surrounding tissues. Inflammatory infiltrate and thickness of the fibrous capsule were histologically evaluated. Mineralization was analyzed by Von Kossa staining and polarized light. Data were tabulated and analyzed via Kruskal-Wallis and Dunn's test. All tested materials induced a moderate inflammatory reaction in the initial periods. Smartpaste Bio induced the mildest inflammatory reactions after day 15. No difference was observed among groups after days 30 or 60. Von Kossa-positive staining and birefringent structures observed under polarized light revealed a larger mineralization area in Sealapex-treated animals followed by Smartpaste Bio-treated animals. At the end of the experiment, all tested sealers were found to be biocompatible. All sealers induced biomineralization, except Acroseal, which induced a mild tissue reaction.

Topics: Animals; Biocompatible Materials; Calcium Hydroxide; Ceramics; Epoxy Resins; Inflammation; Male; Materials Testing; Rats, Wistar; Reproducibility of Results; Root Canal Filling Materials; Salicylates; Subcutaneous Tissue; Time Factors

Topics: Anti-Inflammatory Agents, Non-Steroidal; Attention; Blood Glucose; Cardiovascular Diseases; Humans; Inflammation; Salicylates

Topics: Animals; Autoantibodies; Cytokines; Disease Progression; Female; Glycosides; Inflammation; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Salicylates; Signal Transduction; Terpenes

Neuropeptide Y (NPY)/Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus induce feeding and decrease energy expenditure. With consumption of a diet high in fat, there is an increase in circulating saturated free fatty acids, including palmitate, leading to the development of neuroinflammation and secretion of cytokines, such as TNFα, and in turn activation of the canonical IKKβ/NFκB cascade. We describe a model of palmitate- and TNFα-induced neuroinflammation in a functionally characterized, immortalized NPY/AgRP-expressing cell model, mHypoE-46, to study whether the anti-diabetic metformin alone or in combination with the anti-inflammatory agent salicylate can ameliorate these detrimental effects. Treatment with palmitate increased mRNA expression of feeding peptides Npy and Agrp, and inflammatory cytokines Tnfa and Il-6, whereas treatment with TNFα increased mRNA expression of Npy, Nfkb, Ikba, Tnfa, and Il-6. The effects of metformin and/or sodium salicylate on these genes were assessed. Metformin increased phosphorylation of AMPK and S6K, while sodium salicylate increased phospho-AMPK and decreased phospho-S6K, but neither had any effect on phospho-ERK, -JNK or -p38 in the mHypoE-46 NPY/AgRP neurons. Furthermore, we utilized a pre-treatment and/or co-treatment paradigm to model potential clinical regimens. We determined co-treatment with metformin or sodium salicylate alone was successful in alleviating changes observed in feeding peptide mRNA regulation, whereas a preventative pre-treatment with metformin and sodium salicylate together was able to alleviate palmitate- and TNFα-induced induction of NPY and/or AgRP mRNA levels. These results highlight important differences in reactive versus preventative treatments on palmitate- and TNFα-induced neuroinflammation in NPY/AgRP neurons.

Topics: Agouti-Related Protein; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Cells, Cultured; Embryo, Mammalian; Female; Gene Expression Regulation; Hypoglycemic Agents; Hypothalamus; Inflammation; Male; Metformin; Mice; Mice, Inbred BALB C; Neurons; Neuropeptide Y; Palmitates; Phosphorylation; Salicylates; Tumor Necrosis Factor-alpha

Inflammation has a critical role in the tumor progression, free radical damage can worse the status of patients in cancer condition. The anti-cancer agents capable of inhibiting inflammation and scavenging free radicals attract a lot of our interest. Aimed at the discovery of such anti-tumor agent, a novel intercalator, benzyl 1-[4-hydroxy-3-(methoxycarbonyl)-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (BPIC) was presented. The docking investigation of BPIC and doxorubicin towards the DNA (PDB ID: 1NAB) gave equal score and similar feature. The anti-proliferation assay of 8 cancer cells identified S180 cells had equal sensitivity to BPIC and doxorubicin. The anti-tumor assay defined the efficacy of BPIC been 2 folds higher than that of doxorubicin. At 1μmol/kg of dose BPIC effectively inhibited xylene-induced ear edema and decreased the plasma TNF-α and IL-8 of the mice. BPIC scavenged ∙OH, ∙O2(-) and NO free radicals in a concentration dependent manner and NO free radicals had the highest sensitivity. BPIC could be a novel anti-tumor lead capable of simultaneously inhibiting inflammation and scavenging free radicals.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Carbolines; Cell Line, Tumor; Free Radical Scavengers; Free Radicals; Humans; Inflammation; Intercalating Agents; Mice; Molecular Docking Simulation; Neoplasms; Salicylates

This study aims to investigate whether and how pharmacological activation of AMP-activated protein kinase (AMPK) improves endothelial function by suppressing mitochondrial ROS-associated endoplasmic reticulum stress (ER stress) in the endothelium. Experimental approach Palmitate stimulation induced mitochondrial fission and ER stress-associated endothelial dysfunction. The effects of AMPK activators salicylate and AICA riboside (AICAR) on mitochondrial ROS production, Drp1 phosphorylation, mitochondrial fission, ER stress, thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation, inflammation, cell apoptosis and endothelium-dependent vasodilation were observed. Key results "Silencing" of TXNIP by RNA interference inhibited NLRP3 inflammasome activation in response to ER stress, indicating that TXNIP was a key link between ER stress and NLRP3 inflammasome activation. AMPK activators salicylate and AICAR prevented ROS-induced mitochondrial fission by enhancing dynamin-related protein 1 (Drp1) phosphorylation (Ser 637) and thereby attenuated IRE-1α and PERK phosphorylation, but their actions were blocked by knockdown of AMPK. Salicylate and AICAR reduced TXNIP induction and inhibited NLRP3 inflammasome activation by reducing NLRP3 and caspase-1 expression, leading to a reduction in IL-1β secretion. As a result, salicylate and AICAR inhibited inflammation and reduced cell apoptosis. Meanwhile, salicylate and AICAR enhanced eNOS phosphorylation and restored the loss of endothelium-dependent vasodilation in the rat aorta. Immunohistochemistry staining showed that AMPK activation inhibited ER stress and NLRP3 inflammasome activation in the vascular endothelium.. Pharmacological activation of AMPK regulated mitochondrial morphology and ameliorated endothelial dysfunction by suppression of mitochondrial ROS-associated ER stress and subsequent TXNIP/NLRP3 inflammasome activation. These findings suggested that regulation of Drp1 phosphorylation by AMPK activation contributed to suppression of ER stress and thus presented a potential therapeutic strategy for AMPK activation in the regulation of endothelium homeostasis.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Carrier Proteins; Caspase 1; Cell Cycle Proteins; Dynamins; Endoplasmic Reticulum Stress; Endothelium, Vascular; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Mitochondrial Dynamics; Rats; Ribonucleotides; Salicylates; Vasodilation

In this study, we evaluated the edema and hyperalgesic response induced by BpirMP, a P-I class metalloproteinase isolated from Bothrops pirajai snake venom. The animals were injected with the metalloproteinase or sterile PBS (control group) and evaluated for 1, 2, 3, 4, 5, 6 and 24h. The intraplantar injection of BpirMP (5-50μg/paw) induced a dose- and time-dependent response. BpirMP (50μg) induced paw edema in rats rapidly, with peak response two hours after injection of the toxin. Also, BpirMP injection caused a significant reduction in the nociceptive threshold of the animals tested, with peak response three hours after injection of the toxin. The inflammatory mediators involved in these responses were assayed by pretreatment of animals with synthesis inhibitors or receptor antagonists. Peak responses were significantly reduced by pretreatment of animals with pyrilamine, a histamine receptor antagonist, sodium cromoglycate, a mast cell degranulation inhibitor and valeryl salicylate and meloxicam, cyclooxygenase inhibitors. The analysis of the peritoneal cavity exudate revealed an acute inflammatory response with recruitment of leukocytes, increased levels of total proteins, nitric oxide and the cytokines IL-6, TNF-α and IL-10. In conclusion, our results demonstrated that BpirMP induces inflammation mediated by mast cell degranulation, histamine, prostaglandins and cytokine production.

Topics: Animals; Bothrops; Cell Degranulation; Cromolyn Sodium; Crotalid Venoms; Cyclooxygenase Inhibitors; Edema; Female; Histamine H1 Antagonists; Hyperalgesia; Inflammation; Interleukin-10; Interleukin-6; Leukocytes; Male; Mast Cells; Meloxicam; Metalloproteases; Mice; Mice, Inbred BALB C; Nitric Oxide; Nociception; Pyrilamine; Rats; Rats, Wistar; Salicylates; Thiazines; Thiazoles; Tumor Necrosis Factor-alpha; Viper Venoms

Methyl salicylate 2-O-β-d-lactoside (MSL), whose chemical structure is similar to that of salicylic acid, is a natural product derivative isolated from a traditional Chinese herb. The aim of this study was to investigate the therapeutic effect of MSL in mice with collagen-induced arthritis (CIA) and explore its underlying mechanism.. The anti-arthritic effects of MSL were evaluated on human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and CIA in mice in vivo by obtaining clinical scores, measuring hind paw thickness and inflammatory cytokine levels, radiographic evaluations and histopathological assessments.. Treatment with MSL after the onset of arthritis significantly prevented the progression and development of rheumatoid arthritis (RA) in CIA mice without megascopic gastric mucosa damage. In addition, MSL inhibited the production of pro-inflammatory mediators, the phosphorylation and translocation of NF-κB, and cell proliferation induced by TNF-α in FLS. MSL non-selectively inhibited the activity of COX in vitro, but was a more potent inhibitor of COX-2 than COX-1. MSL also inhibited the phosphorylation of inhibitor of NF-κB kinase, IκBα and p65, thus blocking the nuclear translocation of NF-κB in TNF-α-stimulated FLS.. MSL exerts therapeutic effects on CIA mice, suppressing the inflammatory response and joint destruction by non-selectively inhibiting the activity of COX and suppressing activation of the NF-κB signalling pathway, but without damaging the gastric mucosa. Therefore, MSL has great potential to be developed into a novel therapeutic agent for the treatment of RA.

Topics: Animals; Ankle Joint; Antirheumatic Agents; Arthritis, Experimental; Cell Proliferation; Collagen; Humans; Inflammation; Inflammation Mediators; Lactose; Male; Mice; Mice, Inbred DBA; Rats; Rats, Wistar; Salicylates; Synovial Membrane; Tumor Necrosis Factor-alpha

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Inflammation; Male; Salicylates; Vasodilation

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Inflammation; Male; Salicylates; Vasodilation

Activated microglia cells are well recognized as mediators of neuroinflammation, as they release nitric oxide and pro-inflammatory cytokines in various neuroinflammatory diseases. Thus, suppressing microglial activation may alleviate neuroinflammatory and neurodegenerative processes. In the present study, we synthesized and investigated the anti-neuroinflammatory effect of a novel HTB (2-hydroxy-4-trifuoromethylbenzoic acid) derivative in lipopolysaccharide (LPS)-stimulated microglial cells. Among the synthesized derivatives, the BECT [But-2-enedioic acid bis-(2-carboxy-5-trifluoromethyl-phenyl) ester] significantly decreased production of nitric oxide and other pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in microglial cells. BECT also mitigated the expression of inducible nitric oxide synthase and cyclooxygenase-2 at both the mRNA and protein levels. Further mechanistic studies demonstrated that the HTB derivative inhibited phosphorylation of JNK and p38 mitogen-activated protein kinase and nuclear translocation of nuclear factor kappa-B in LPS-stimulated BV-2 microglial cells. Thus BECT, our novel synthesized compound have anti-inflammatory activity in microglial cells, and may have therapeutic potential for treating neuroinflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cyclooxygenase 2; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Microglia; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Salicylates; Signal Transduction; Tumor Necrosis Factor-alpha

This study evaluated the response of apical and periapical tissues of dogs' teeth with pulp vitality after root canal filling with the endodontic sealers Sealapex Xpress and Real Seal XT.. Thirty-eight root canals with vital pulp from dogs' premolars were used. After instrumentation, the canals were filled with Sealapex Xpress and gutta-percha (group SX/GP, n = 16) or Real Seal XT and Resilon cones (group RS/R, n = 22). The animals were killed after 90 days, and the teeth with surrounding tissues were subjected to histotechnical processing. Hematoxylin-eosin-stained sections were examined by conventional light microscopy for a quantitative histopathologic analysis (sealing of apical opening by newly formed mineralized tissue [biological sealing], inflammatory cell infiltrate, root and bone tissue resorption), according to a scoring system. The subsequent sections were evaluated by immunohistochemistry for identification of mineralization markers (osteopontin, alkaline phosphatase, and RUNX2). Data were analyzed by nonparametric Mann-Whitney U test (α = 0.05).. Complete biological sealing was observed in 50% and 22.7% of the specimens of groups SX/GP and RS/R, respectively. Partial biological sealing was observed in 25% and 54.6% and absence of sealing in 25% and 22.7% of the specimens of groups SX/GP and RS/R, respectively. There were no significant differences (P > .05) between the groups for the scores attributed to the histopathologic parameters. Positive staining for osteopontin, alkaline phosphatase, and RUNX2 was observed in both groups, especially in the periodontal ligament.. Sealapex Xpress and RealSeal XT feature tissue compatibility in vivo and allow for sealing of apical opening by deposition of mineralized tissue.

Topics: Alkaline Phosphatase; Alveolar Bone Loss; Animals; Apexification; Biocompatible Materials; Calcium Hydroxide; Composite Resins; Core Binding Factor Alpha 1 Subunit; Dental Bonding; Dogs; Gutta-Percha; Inflammation; Osteopontin; Periapical Tissue; Periodontal Ligament; Root Canal Filling Materials; Root Canal Obturation; Root Canal Preparation; Root Resorption; Salicylates

It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD)-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi)), whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.

Topics: Adipose Tissue; Animals; Cell Count; Diet, High-Fat; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Insulin Resistance; Macrophage Activation; Macrophages; Mice; Multigene Family; Obesity; Oligonucleotide Array Sequence Analysis; Pioglitazone; Salicylates; Thiazolidinediones

Activation of Ras and its downstream signaling pathways, likely contribute to the development of hepatocarcinoma. We have previously shown that intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) blocks Ras activation and prevents heptocarcinoma development in rats receiving weekly injections of the carcinogene diethylnitrosamine (DEN) for 16 wk. Using this in vivo model, we evaluated the relationship between the tumor preventive effect of Ras inhibition and activation of downstream signaling pathways, cell proliferation, cell cycle events, and angiogenesis. Western blotting, quantitative PCR, immunohistochemistry, and transcription factor activity assays were used. DEN-induced activation of NFkB and Stat3 was abrogated by FTS treatment. FTS treatment showed no effect on DEN-induced elevation of TNFα, interleukin 6 and TLR4, known activators of these transcription factors. FTS significantly reduced phosphorylation of the MAPkinase p38 and of the p70S6 kinase, a surrogate marker for mTor activation, without affecting ERK and AKT phosphorylation. These events were associated with reduced c-myc and cyclin D expression as well as reduced cell proliferation in transformed, GSTp-positive hepatocytes. Moreover, FTS treatment shifted cell proliferation from transformed hepatocytes to apparently normal, GSTp negative hepatocytes. FTS treatment did not down-regulate expression of angiogenesis markers HIFα, VEGF, VEGF receptor1, and placenta growth factor. FTS treatment inhibits important signaling pathways involved in cellular proliferation leading to strongly reduced proliferation of transformed hepatocytes without affecting normal hepatocytes. This re-adjustment of the proliferation balance likely contributes to the tumor preventive of FTS in the context of Ras inhibition in hepatocarcinogenesis.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Cell Cycle; Cell Proliferation; Cyclin D; Diethylnitrosamine; Disease Models, Animal; Down-Regulation; Farnesol; Inflammation; Liver Neoplasms, Experimental; Male; Neovascularization, Pathologic; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-myc; ras Proteins; Rats; Rats, Wistar; Salicylates; STAT3 Transcription Factor

Channel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded ΔF508-CFTR and are poorly responsive to potentiators, because ΔF508-CFTR is intrinsically unstable at the plasma membrane (PM) even if rescued by pharmacological correctors. We have demonstrated that human and mouse CF airways are autophagy deficient due to functional sequestration of BECN1 and that the tissue transglutaminase-2 inhibitor, cystamine, or antioxidants restore BECN1-dependent autophagy and reduce SQSTM1/p62 levels, thus favoring ΔF508-CFTR trafficking to the epithelial surface. Here, we investigated whether these treatments could facilitate the beneficial action of potentiators on ΔF508-CFTR homozygous airways. Cystamine or the superoxide dismutase (SOD)/catalase-mimetic EUK-134 stabilized ΔF508-CFTR at the plasma membrane of airway epithelial cells and sustained the expression of CFTR at the epithelial surface well beyond drug withdrawal, overexpressing BECN1 and depleting SQSTM1. This facilitates the beneficial action of potentiators in controlling inflammation in ex vivo ΔF508-CFTR homozygous human nasal biopsies and in vivo in mouse ΔF508-CFTR lungs. Direct depletion of Sqstm1 by shRNAs in vivo in ΔF508-CFTR mice synergized with potentiators in sustaining surface CFTR expression and suppressing inflammation. Cystamine pre-treatment restored ΔF508-CFTR response to the CFTR potentiators genistein, Vrx-532 or Vrx-770 in freshly isolated brushed nasal epithelial cells from ΔF508-CFTR homozygous patients. These findings delineate a novel therapeutic strategy for the treatment of CF patients with the ΔF508-CFTR mutation in which patients are first treated with cystamine and subsequently pulsed with CFTR potentiators.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Animals; Antioxidants; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cell Membrane; Child; Cystamine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Epithelium; Female; Genistein; Heat-Shock Proteins; Humans; Inflammation; Lipopolysaccharides; Lung; Male; Membrane Proteins; Mice; Molecular Targeted Therapy; Nasal Mucosa; Nasal Polyps; Organometallic Compounds; Protein Glutamine gamma Glutamyltransferase 2; Salicylates; Sequestosome-1 Protein

We tested the hypothesis that vascular endothelial function, assessed by endothelium-dependent dilation, is related to serum vitamin D status among middle-aged and older adults without clinical disease, and that this is linked to inflammation. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was lower (P<0.01) in vitamin D-insufficient (3.7 ± 0.2%; serum 25-hydroxyvitamin D [25(OH)D]: 20 to 29 ng/mL; 62 ± 1 years of age; n = 31; mean± SE) and vitamin D-deficient (3.2 ± 0.3%; 25(OH)D: <20 ng/mL; 63 ± 2 years of age; n = 22) versus vitamin D-sufficient (4.6 ± 0.4%; 25(OH)D: >29 ng/mL; 61 ± 1 years of age; n = 22) subjects, whereas endothelium-independent dilation (brachial dilation to sublingual nitroglycerine) did not differ (P = 0.45). Among all subjects, brachial flow-mediated dilation was positively related to serum 25(OH)D (%Δ: r = 0.35; P<0.01) but not 1,25-dihydroxyvitamin D (r = -0.06; P = 0.61), the active form of vitamin D. Vascular endothelial cell expression of the proinflammatory transcription factor nuclear factor κB was greater in deficient versus sufficient subjects (0.59 ± 0.07 versus 0.44 ± 0.05; P<0.05), and inhibition of nuclear factor κB (4 days oral salsalate) improved flow-mediated dilation to a greater extent in subjects with lower versus higher 25(OH)D (+3.7 ± 0.6 versus +2.0 ± 0.2%; P<0.05). Endothelial cell expression of the downstream proinflammatory cytokine interleukin-6 also was higher in deficient versus sufficient subjects (0.67 ± 0.08 versus 0.47 ± 0.05; P<0.01) and inversely related to serum 25(OH)D level (r = -0.62; P<0.01), whereas vitamin D receptor and 1-α hydroxylase, the 25(OH)D to 1,25-dihydroxyvitamin D converting enzyme, were lower (P<0.05). Inadequate serum 25(OH)D is associated with vascular endothelial dysfunction among healthy middle-aged/older adults, and this is mediated in part by nuclear factor κB-related inflammation. Reduced vitamin D receptor and 1-α hydroxylase may be molecular mechanisms linking vitamin D insufficiency to endothelial dysfunction.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Aged; Brachial Artery; Endothelium, Vascular; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; NF-kappa B; Nitroglycerin; Receptors, Calcitriol; Salicylates; Vascular Diseases; Vasodilation; Vitamin D; Vitamin D Deficiency

To evaluate the kinetics of the inflammatory tissue response to three root canal sealers using a physicochemical method for quantification of the enhanced vascular permeability and histopathological analysis.. Twenty-eight male Wistar rats randomly assigned to four groups according to the evaluation periods (1, 3, 7 and 14 days) were used to assess the vascular permeability and histopathological reaction to RoekoSeal, AH Plus and Sealapex (new formulation) sealers, using saline and Chloropercha as negative and positive controls, respectively. Seven rats were sacrificed per period. The biocompatibility of the sealers was evaluated spectrophotometrically and histopathologically.. At day 14, Sealapex produced significantly more inflammatory exudate than AH Plus and RoekoSeal (P < 0.05); however, there was no significant difference between AH Plus and RoekoSeal (P > 0.05). Sealapex (new formulation) was the most irritating sealer, producing severe inflammation with the presence of multinucleated giant cells. RoekoSeal was the most biocompatible sealer, producing the least amount of inflammatory exudate.. RoekoSeal root canal sealer was biocompatible when implanted in connective tissue.

Topics: Animals; Balsams; Calcium Hydroxide; Capillary Permeability; Dental Cements; Drug Combinations; Edema; Epoxy Resins; Foreign-Body Reaction; Gutta-Percha; Implants, Experimental; Inflammation; Injections, Subcutaneous; Male; Pilot Projects; Rats; Rats, Wistar; Root Canal Filling Materials; Salicylates; Statistics, Nonparametric; Time Factors; Zinc Oxide

Siegesbeckia orientalis has been traditionally used as a topical anti-inflammatory and analgesic agent.. Current study was designed to explore the topical anti-inflammatory and analgesic effects of a constituent isolated from Siegesbeckia orientalis (Compositae), in order to validate its folk use.. Kirenol was isolated from ethanolic extract of Siegesbeckia orientalis. Several topical formulations containing kirenol were investigated for anti-inflammatory and analgesic activities in rat. The effects were studied using carrageenan-induced rat acute inflammation model, complete Freund's adjuvant (CFA)-induced chronic inflammation and formalin test in rats. Piroxicam gel and methyl salicylate ointment were studied as positive control for anti-inflammatory and analgesic activity, respectively.. The anti-inflammatory effect of kirenol 0.4-0.5% (w/w) was similar to the effect of piroxicam gel 4h after carrageenan injection. The analgesic activity of topical preparation with more than 0.4% (w/w) was observed in the late phase. These effects may be due, at least in part, to the pro-inflammatory cytokine production of IL-1β and TNF-α. The administration of kirenol cream at the dose of 0.3, 0.4 and 0.5% (w/w) significantly inhibited the development of joint swelling induced by CFA, which was auxiliary supported by histopathological studies.. Kirenol has demonstrated its significant potential to be further investigated for its discovery as a new lead compound for management of topical pain and inflammation, although further pharmacological research is necessary to fully understand its mechanism of action. It also supports the potential beneficial effect of topically administered Siegesbeckia orientalis in inflammatory diseases.

Topics: Administration, Topical; Analgesics; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Asteraceae; Carrageenan; Diterpenes; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Ethanol; Formaldehyde; Freund's Adjuvant; Inflammation; Inflammation Mediators; Interleukin-1beta; Pain; Piroxicam; Plant Components, Aerial; Plants, Medicinal; Rats; Salicylates; Solvents; Time Factors; Tumor Necrosis Factor-alpha

Accumulation of unwanted/misfolded proteins in aggregates has been observed in airways of patients with cystic fibrosis (CF), a life-threatening genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show how the defective CFTR results in defective autophagy and decreases the clearance of aggresomes. Defective CFTR-induced upregulation of reactive oxygen species (ROS) and tissue transglutaminase (TG2) drive the crosslinking of beclin 1, leading to sequestration of phosphatidylinositol-3-kinase (PI(3)K) complex III and accumulation of p62, which regulates aggresome formation. Both CFTR knockdown and the overexpression of green fluorescent protein (GFP)-tagged-CFTR(F508del) induce beclin 1 downregulation and defective autophagy in non-CF airway epithelia through the ROS-TG2 pathway. Restoration of beclin 1 and autophagy by either beclin 1 overexpression, cystamine or antioxidants rescues the localization of the beclin 1 interactome to the endoplasmic reticulum and reverts the CF airway phenotype in vitro, in vivo in Scnn1b-transgenic and Cftr(F508del) homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTR(F508del) to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation.

Topics: Acetylcysteine; Adaptor Proteins, Signal Transducing; Adolescent; Adult; Animals; Antioxidants; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Cell Line; Cystamine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Sodium Channels; GTP-Binding Proteins; Heat-Shock Proteins; Humans; Inflammation; Membrane Proteins; Mice; Mice, Inbred CFTR; Mice, Inbred Strains; Mice, Transgenic; Microtubule-Associated Proteins; Models, Biological; Nasal Polyps; Organometallic Compounds; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Binding; Protein Glutamine gamma Glutamyltransferase 2; Protein Transport; Reactive Oxygen Species; Respiratory Mucosa; Salicylates; Sequestosome-1 Protein; Small Ubiquitin-Related Modifier Proteins; Transglutaminases; Young Adult

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 2; Endocrinology; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Hypoglycemic Agents; Inflammation; Salicylates

Inflammation plays an important role in all stages of atherosclerosis, but little is known about the therapeutic effects of quenching inflammation in already existing atherosclerotic lesions. Putative beneficial effects of salicylate, an inhibitor of NF-κB activation, were studied in mice with established lesions.. ApoE*3-Leiden mice received a high-cholesterol diet (HC) to establish atherosclerotic lesions. Reference mice (REF) were sacrificed to determine the lesion area at the start of two interventions. In one intervention group HC diet feeding was continued, but the diet contained salicylate (HC+SAL). As salicylate not only quenches inflammation but also reduces plasma cholesterol, a second intervention group was fed a low-cholesterol diet (LC) resulting in cholesterol levels comparable to HC+SAL. The effects of these interventions on lesion area and composition were assessed after 8 and 16 weeks.. HC+SAL markedly reduced hepatic NF-κB activity compared to REF, and was significantly more effective than LC diet feeding. HC+SAL and LC also quenched aortic NF-κB activity. While continuing HC diet typically further increases total lesion area, 16 weeks of intervention with HC+SAL and LC halted further disease progression and resulted in lesion sizes comparable to that of REF. At the same time, lesion composition was significantly improved, particularly with salicylate. Strikingly, HC+SAL resulted in a lower lesional macrophage content and a greater plaque stability index (ratio of collagen to macrophage area) than LC.. Anti-inflammatory salicylate reduces atherosclerotic macrophage content and increases lesion stability of pre-existing plaques through quenching of NF-κB activity and reducing plasma cholesterol.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Atherosclerosis; Cholesterol; Disease Models, Animal; Female; Inflammation; Macrophages; Mice; Mice, Transgenic; NF-kappa B; Salicylates; STAT3 Transcription Factor; Treatment Outcome

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP(23) transgenic mice receiving strokes. Six month-old APP(23) mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP(23) mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antigens, CD; Brain Ischemia; Disease Models, Animal; Endothelin-1; Humans; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Platelet Aggregation Inhibitors; Salicylates; Stroke; tau Proteins; Tumor Necrosis Factor-alpha

The aim of this study was to evaluate the rat subcutaneous tissue response to implanted polyethylene tubes filled with Endo-CPM-Sealer (Portland Cement Modified Sealer) (EGEO S.R.L., Buenos Aires, Argentina) compared with Sealapex (SybronEndo, Glendora, CA) and Angelus MTA (Angelus, Londrina, Brazil). These materials were placed in polyethylene and dentin tubes and implanted into dorsal connective tissue of Wistar rats for 7, 15, 30, 60, and 90 days. The specimens were prepared to be stained with hematoxylin and eosin or Von Kossa or not stained for polarized light. Qualitative and quantitative evaluations of the reaction were performed. Both materials caused mild to moderate reactions at 7 days that decreased with time. The response was similar to the control on the 30th day with Endo-CPM-Sealer and Angelus MTA and on the 60th day with Sealapex. Mineralization and granulations birefringent to the polarized light were observed with all materials. It was possible to conclude that Endo-CPM-Sealer was biocompatible and stimulated mineralization.

Topics: Aluminum Compounds; Animals; Calcium Carbonate; Calcium Compounds; Calcium Hydroxide; Dentin, Secondary; Drug Combinations; Inflammation; Male; Materials Testing; Oxides; Rats; Rats, Wistar; Root Canal Filling Materials; Salicylates; Silicates; Subcutaneous Tissue; Time Factors

Antidiabetic effects of salicylates have been known for years, however the cellular and molecular mechanisms of the hypoglycemic activity are not well elucidated. We examined the effects of salicylate on inflammation-related changes in gene or/and protein expressions of several adipokines in 3T3-L1 adipocytes and of LPS-induced inflammatory factors in RAW 264.7 cell. Especially, we focused our attention on the cross-talk between the macrophages and adipocytes. Exposure to RAW-CM medium resulted in an increase in the gene expression or/and protein secretion of TNF-alpha, IL-6 and resistin, and at the same time, a decrease in the gene expression of PPARgamma and adiponectin in 3T3-L1 adipocytes. Salicylate effectively reversed these changes, and up-regulated glucose consumption in adipocytes. We also found salicylate inhibited phosphorylation of NF-kappaB in RAW-CM-stimulated adipocytes. We conclude salicylate blocks inflammatory process in the pathogenesis of inflammation-related insulin resistance.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Dose-Response Relationship, Drug; Inflammation; Macrophages; Mice; Salicylates; Time Factors

Topics: Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Inflammation; Salicylates; Signal Transduction; Translational Research, Biomedical

Salicylideneamino-2-thiophenol (Sal) regulated the redox status and the expression of chemokines induced by tert-butyl hydroperoxide (t-BHP). Sal (100 microM) increased reduced/oxidized glutathione (GSH/GSSG) ratios and thiol (SH) levels by 210 and 157%, respectively, and decreased reactive oxygen species (ROS) levels by 60% in t-BHP-treated macrophages. The inductions of regulated upon activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8) and hypoxia inducible factor-1alpha (HIF-1alpha) by t-BHP (10 microM) were decreased to 250, 80, 80 and 500% by Sal (100 microM), respectively. In the Sal signaling pathway, c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (ERK) and p38 signaling protein modulation were decreased by 67, 69 and 119%, respectively, by Sal at 100 microM. Sal (100 microM) also altered cytosol and nuclear NF-kappaB protein expression by 169 and 5%, respectively. Sal also attenuated NF-kappaB nuclear binding activity. Sal thus has a protective effect against t-BHP-induced inflammation and that this, in part, is due to the inhibition of the production of RANTES, MCP-1, IL-8 and HIF-1alpha via the modulation of the NF-kappaB and mitogen-activated protein kinase (MAPK) pathways.

Topics: Animals; Chemokine CCL2; Chemokine CCL5; Gene Expression Regulation; Glutathione; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-8; Macrophages, Peritoneal; Mitogen-Activated Protein Kinases; NF-kappa B; Phenols; Rats; RNA, Messenger; Salicylates; Salicylic Acid; Sulfhydryl Compounds; tert-Butylhydroperoxide

It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cell Death; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Inflammation; Male; NF-kappa B; NF-kappa B p50 Subunit; Protein Transport; Random Allocation; Rats; Rats, Inbred Lew; Retina; Retinal Ganglion Cells; Salicylates; Sodium Salicylate; Sulfasalazine; Transcription Factor RelA

Cyclooxygenase-2 (COX-2) is a useful biomarker of the inflammatory potential of biomaterials in vitro. In this study we investigate the effects of soluble extracts from 3 selected root canal sealers (AH26, Sealapex, and N2 Universal) on COX-2 mRNA expression in cultured murine macrophage cells. Root canal sealers and the addition of lipopolysaccharide (LPS) both produced significant increases in COX-2 mRNA expression in RAW 264.7 macrophages. In addition, both Sealapex and N2 Universal produced a synergistic 6- to 8-fold increase in COX-2 mRNA expression, whereas AH26 did not demonstrate synergy with LPS. These results suggest that LPS and certain root canal sealers have a synergistic effect on the inflammatory responses of macrophages. Under the conditions of this in vitro study, the results suggest that one potential mechanism of periapical inflammatory reactions might be the synergistic effects of certain root canal sealers on LPS-induced COX-2 expression by macrophage cells.

Topics: Animals; Bismuth; Calcium Hydroxide; Cell Line; Cell Survival; Cyclooxygenase 2; Drug Combinations; Drug Synergism; Epoxy Resins; Inflammation; Lipopolysaccharides; Macrophages; Mice; RNA, Messenger; Root Canal Filling Materials; Salicylates; Silver; Titanium

One of the major factors limiting the use of non-steroidal anti-inflammatory drugs is gastrointestinal toxicity. Gaultherin, 2-[(6-O-beta-D-Xylopyranosyl-beta-D-glucopyranosyl)oxy] benzoic acid methyl ester, a natural salicylate derivative extracted from Gaultheria yunnanensis, has been shown to have analgesic and anti-inflammatory effects and lack gastric ulcerogenic effect compared to aspirin in our primary study. The aim of this study was to investigate the mechanism of action of gaultherin, which may rely on its active metabolite, and the mechanism responsible for the non-ulcerogenic property. The results showed that gaultherin (200 mg/kg) significantly inhibited the abdominal contractions in the acetic acid-induced writhing test in mice. The anti-inflammatory effect of gaultherin was demonstrated in the croton oil-induced ear edema model in mice. The results showed that gaultherin and equimolar dose of aspirin produced comparable inhibitory effects. The study of the metabolism characters of gaultherin in mice and rats indicated that gaultherin could be metabolically converted to salicylate, which produced the pharmacological effects, and provided effective concentrations for an extended period. In vitro metabolism experiment showed that gaultherin was metabolized by beta-glycosidase produced by human intestinal bacteria and esterases in intestine, blood and liver successively to release salicylate finally. The study suggested gaultherin did not cause gastric ulcer for the reason that it released salicylate in intestine slowly, not in stomach and it left the cyclooxygenase-1 unaffected, which was the source of cytoprotective prostaglandins in gastric epithelium.

Topics: Abdominal Pain; Acetic Acid; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chromatography, High Pressure Liquid; Croton Oil; Disaccharides; Disease Models, Animal; Ear Diseases; Esterases; Gastric Mucosa; Gaultheria; Glycoside Hydrolases; Humans; Immersion; Inflammation; Intestines; Male; Mice; Plant Leaves; Plant Stems; Rats; Rats, Wistar; Restraint, Physical; Salicylates; Stomach Ulcer; Stress, Psychological; Water

Salicylate is a small amphiphilic molecule which has diverse effects on membranes and membrane-mediated processes. We have utilized micropipette aspiration of giant unilamellar vesicles to determine salicylate's effects on lecithin membrane elasticity, bending rigidity, and strength. Salicylate effectively reduces the apparent area compressibility modulus and bending modulus of membranes in a dose-dependent manner at concentrations above 1 mM, but does not greatly alter the actual elastic compressibility modulus at the maximal tested concentration of 10 mM. The effect of salicylate on membrane strength was investigated using dynamic tension spectroscopy, which revealed that salicylate increases the frequency of spontaneous defect formation and lowers the energy barrier for unstable hole formation. The mechanical and dynamic tension experiments are consistent and support a picture in which salicylate disrupts membrane stability by decreasing membrane stiffness and membrane thickness. The tension-dependent partitioning of salicylate was utilized to calculate the molecular volume of salicylate in the membrane. The free energy of transfer for salicylate insertion into the membrane and the corresponding partition coefficient were also estimated, and indicated favorable salicylate-membrane interactions. The mechanical changes induced by salicylate may affect several biological processes, especially those associated with membrane curvature and permeability.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biophysics; Cattle; Cell Membrane; Dose-Response Relationship, Drug; Elasticity; Electrochemistry; Inflammation; Kinetics; Lipid Bilayers; Lipids; Liposomes; Membranes; Models, Chemical; Models, Statistical; Phosphatidylcholines; Salicylates; Salicylic Acid; Serum Albumin; Spectrophotometry; Thermodynamics; Time Factors

Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Our rat model demonstrates that this interaction may be mediated through inflammatory cells and pathways. Thus, anti-inflammatory agents such as Triflusal, a nonsteroidal anti-inflammatory agent (NSAID), may provide neuroprotection for susceptible neurons in AD and cerebral ischemia.. AD was modeled by cerebroventricular injections of beta-amyloid (Abeta25-35) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined by immunohistochemical analysis. Behavioral tasks were assessed with the Montoya staircase test.. Triflusal reduced pathologic and inflammatory markers and functional deficits in rats receiving Abeta or endothelin alone but was less effective in the more severe pathology of the combined Abeta/endothelin model.. Higher doses or more prolonged treatment with NSAIDs may be required for more effective neuroprotection in combined AD and stroke conditions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Astrocytes; Behavior, Animal; Brain; Brain Ischemia; Corpus Striatum; Cytokines; Disease Models, Animal; Endothelins; Glial Fibrillary Acidic Protein; Hippocampus; Immunohistochemistry; Inflammation; Microglia; Neurons; Peptides; Rats; Rats, Wistar; Salicylates; Temperature

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cartilage, Articular; Chondrocytes; Humans; Inflammation; Osteoarthritis; Proteoglycans; Salicylates

Previous studies found that repeated application of smoke condensate from tobacco-burning reference cigarettes to chemically initiated SENCAR mouse skin promoted the development of tumors in a statistically significant and dose-dependent manner, while condensate from prototype cigarettes that primarily heat tobacco promoted statistically fewer tumors. Based on the recognized correlation between sustained, potentiated epidermal hyperplasia and tumor promotion, we conducted tests to examine the utility of selected short-term analyses for discriminating between condensates exhibiting significantly different promotion activities. In vitro analyses assessing the potential for inducing cytotoxicity (ATP bioluminescence) or free radical production (cytochrome c reduction, salicylate trapping) demonstrated significant reductions when comparing condensate collected from prototype cigarettes to reference condensate. Short-term in vivo analyses conducted within the context of a mouse skin, tumor-promotion protocol (i.e., comparative measures of epidermal thickness, proliferative index, myeloperoxidase activity, leukocyte invasion, mutation of Ha-ras, and formation of modified DNA bases) provided similar results. Reference condensate induced statistically significant and dose-dependent increases (relative to vehicle control) for nearly all indices examined, while prototype condensate possessed a significantly reduced potential for inducing changes that we regarded as consistent with sustained epidermal hyperplasia and/or inflammation. Collectively, these data support the contention that selected short-term analyses associated with sustained hyperplasia and/or inflammation are capable of discriminating between smoke condensates with dissimilar tumor-promotion potentials. Moreover, our results suggest that comparative measures of proliferative index and myeloperoxidase activity, both possessing favorable correlation coefficients relative to tumor formation (i.e., > or = 0.95 after 8 or 12 weeks of promotion), may constitute reasonable end points for further investigation.

Topics: Adenosine Triphosphate; Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Cell Proliferation; Cytochromes c; DNA Adducts; Genes, ras; Hydroxyl Radical; Hyperplasia; Inflammation; Leukocytes; Luminescent Measurements; Mice; Mice, Inbred SENCAR; Oxidation-Reduction; Oxidative Stress; Peroxidase; Salicylates; Skin; Skin Neoplasms; Smoke; Superoxides

The effect of valeryl salicylate (VS), an inhibitor of cyclooxygenase-1 (COX-1), was evaluated in arachidonic acid or croton oil-induced ear oedema and carrageenan-induced paw oedema in mice. Ear oedema was induced by topical administration of arachidonic acid (2mg per ear; 20 microliters) or croton oil (1mg per ear; 20 microliters) to the inner surface of the left ear and the change in the ear's thickness was measured with a precision micrometer (Fisher, USA). VS significantly inhibited the arachidonic acid ear oedema after lh at doses of 1.5-45 micrograms per ear; however, only at the dose of 45 micrograms per ear was it able to significantly reduce the croton oil-induced oedema at 6h. Paw oedema was induced by the injection of 25 microliters of 1% carrageenan into the plantar aponeurosis of the right hind paw. The oedema was evaluated at 0.5, 1, 2, 4, 24, 48 and 72h. Previously in our experiments, we observed two peaks in paw oedema formation: one at 2h, in the early phase (0-4h), and the other, occurring at 48h after carrageenan injection, in the late phase (24-72h). The pre-treatment with VS significantly reduced the paw oedema at 2h, the same effect observed with celecoxib and indomethacin treatments. At 24h, VS did not inhibit oedema but significantly increased it mainly at 48h after carrageenan injection. These results showed that VS was pharmacologically active in these models and suggest that COX-1 may participate in the early and late phases of inflammation in the models studied.

Topics: Acute Disease; Animals; Arachidonic Acid; Carrageenan; Celecoxib; Croton Oil; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Ear, External; Edema; Foot; Indomethacin; Inflammation; Irritants; Isoenzymes; Male; Membrane Proteins; Mice; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Salicylates; Sulfonamides

This study was conducted to observe the healing process of intentional lateral root perforation repaired with mineral trioxide aggregate (MTA). Forty-eight root canals of dogs' teeth were instrumented and filled. After partial removal of the filling, an intentional perforation was made with a bur in the lateral area of the root. The perforations were repaired with MTA or Sealapex (control group). Histological analysis occurred 30 and 180 days after treatment. Results showed no inflammation and deposition of cementum over MTA in the majority of the specimens. In the 180-day period, Sealapex exhibited chronic inflammation in all the specimens and slight deposition of cementum over the material in only three cases. In conclusion, MTA exhibited better results than the control group.

Topics: Aluminum Compounds; Animals; Calcium Compounds; Calcium Hydroxide; Connective Tissue; Dental Cementum; Dental Pulp Cavity; Dogs; Drug Combinations; Follow-Up Studies; Giant Cells; Inflammation; Macrophages; Oxides; Periodontal Ligament; Root Canal Filling Materials; Root Canal Preparation; Salicylates; Silicates; Tooth Root; Wound Healing

The poor cyclooxygenase (COX) inhibitor and major aspirin metabolite salicylic acid is known to exert analgesic and anti-inflammatory effects by still unidentified mechanisms. In RAW 264.7 macrophages, lipopolysaccharide (LPS)-induced COX-2-dependent synthesis of prostaglandin E(2) (PGE(2)) was suppressed by aspirin (IC(50) of 5. 35 microM), whereas no significant inhibition was observed in the presence of sodium salicylate and the salicylate metabolite salicyluric acid at concentrations up to 100 microM. However, the salicylate metabolite gentisic acid (2,5-dihydroxybenzoic acid; 10-100 microM) and salicyl-coenzyme A (100 microM), the intermediate product in the formation of salicyluric acid from salicylic acid, significantly suppressed LPS-induced PGE(2) production. In contrast, gamma-resorcylic acid (2,6-dihydroxybenzoic acid) as well as unconjugated coenzyme A failed to affect prostanoid synthesis, implying that the para-substitution of hydroxy groups and the activated coenzyme A thioester are important for COX-2 inhibition. Using real-time RT-PCR, none of the salicylate derivatives tested were found to interfere with COX-2 expression. Overall, our results suggest that certain metabolites of salicylic acid may contribute to the pharmacological action of its parent compound by inhibiting COX-2-dependent PGE(2) formation at sites of inflammation.

Topics: Acyl Coenzyme A; Animals; Aspirin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Gentisates; Hydroxybenzoates; Inflammation; Isoenzymes; Lipopolysaccharides; Macrophages; Mice; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salicylates; Sodium Salicylate

The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Inflammation; Isoenzymes; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Membrane Proteins; NF-kappa B; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Lew; Salicylates

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 NFkappaB 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 NFkappaB, 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 NFkappaB. 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 NFkappaB.

Topics: Adenosine Deaminase; Animals; Aspirin; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Female; Glucocorticoids; Inflammation; Isoenzymes; Leukocytes; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; NF-kappa B; NF-kappa B p50 Subunit; Prostaglandin-Endoperoxide Synthases; Protein Precursors; Purinergic P1 Receptor Antagonists; Salicylates; Sodium Salicylate; Sulfasalazine; Theobromine

This study evaluated the inflammatory response to Sealapex, CRCS, Apexit, and Sealer 26 in the subcutaneous tissue and in peritoneal cavity of Balb/c mice. The inflammatory response of subcutaneous tissue was analyzed after 2, 4, 8, and 16 days. Intense neutrophilia was seen in response to all sealers during the initial periods. Differences among them related to the presence of necrosis and the number of inflammatory cells. In the intermediate phase marked differentiation of cells of the mononucleate phagocytic system into macrophages, epithelioid cells and multinucleate giant cells were observed with Sealapex. This response was less intense with CRCS and Apexit. Tissue necrosis was observed only at tissue sealer interfaces and only during the initial period with Sealapex but was seen throughout the experiment with all other sealers. The animals were injected in the peritoneal cavity with solutions containing the sealers and five mice from each group were killed 6 and 24 h, and 5 and 15 days later. During the initial periods (6 and 24 h) there was an intense migration of polymorphonuclear leukocytes to the peritoneal cavity in response to all sealers compared to the control. This migration was more intense for Sealer 26 and Apexit. An increase in mononucleate cell number was observed after 6 and 24 h and 5 days for all sealers and no differences were observed in relation to the control after 15 days.

Topics: Animals; Bismuth; Calcium Hydroxide; Chemotaxis, Leukocyte; Connective Tissue; Female; Inflammation; Injections, Intraperitoneal; Leukocytes, Mononuclear; Mice; Mice, Inbred BALB C; Neutrophils; Root Canal Filling Materials; Salicylates; Statistics, Nonparametric; Zinc Oxide

Topics: Alprostadil; Arachidonic Acid; Bucladesine; Calcium-Calmodulin-Dependent Protein Kinases; Carbachol; Cell Adhesion; Cell Aggregation; Cyclic GMP; Dibutyryl Cyclic GMP; Enzyme Activation; Humans; In Vitro Techniques; Inflammation; Kinetics; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Salicylates; Salicylic Acid; Virulence Factors, Bordetella

Peroxynitrite anion is a powerful oxidant which can initiate nitration and hydroxylation of aromatic rings. Peroxynitrite can be formed in several ways, e.g. from the reaction of nitric oxide with superoxide or from hydrogen peroxide and nitrite at acidic pH. We investigated pH dependent nitration and hydroxylation resulting from the reaction of hydrogen peroxide and nitrite to determine if this reaction proceeds at pH values which are known to occur in vivo. Nitration and hydroxylation products of tyrosine and salicyclic acid were separated with an HPLC column and measured using ultraviolet and electrochemical detectors. These studies revealed that this reaction favored hydroxylation between pH 2 and pH 4, while nitration was predominant between pH 5 and pH 6. Peroxynitrite is presumed to be an intermediate in this reaction as the hydroxylation and nitration profiles of authentic peroxynitrite showed similar pH dependence. These findings indicate that hydrogen peroxide and nitrite interact at hydrogen ion concentrations present under some physiologic conditions. This interaction can initiate nitration and hydroxylation of aromatic molecules such as tyrosine residues and may thereby contribute to the biochemical and toxic effects of the molecules.

Topics: Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxylation; Inflammation; Iron; Nitrates; Oxidative Stress; Salicylates; Salicylic Acid; Sodium Nitrite; Tyrosine

The tissue toxicity of zinc oxide-eugenol, Tubli seal, Sealapex, and Endoflas F.S. was investigated by injecting them into the subcutaneous connective tissue of the dorsal surface of rats and studying the tissue response histologically. Animals were killed after time intervals of 48 h, 7 days, 14 days, 1 month, and 3 months; tissue sections were taken from the injection sites. Histological examination of the tissue sections revealed that all of the sealers caused some inflammation that decreased with time, except in the case of zinc oxide-eugenol where it increased from the 48th hour to the 7th day and after that showed a decreasing trend. Overall, Sealapex showed the least inflammatory reaction compared with other sealers used, because it showed moderate inflammation at 48 h that became mild in later periods. Zinc oxide-eugenol, Tubli seal, and Endoflas F.S. were severely toxic at 48 h and 7 days. This toxicity decreased gradually in later time periods. No inflammatory reaction was seen at 3 months with any of the sealers used.

Topics: Animals; Calcium Hydroxide; Connective Tissue; Giant Cells; Inflammation; Lymphocytes; Macrophages; Neutrophils; Plasma Cells; Rats; Root Canal Filling Materials; Salicylates; Zinc Oxide-Eugenol Cement

Serum salicylate concentrations were measured in 60 patients with acute phase Kawasaki disease (KD), who were treated with intravenous aspirin (IVASP), to evaluate its anti-inflammatory effect in the treatment of KD. Patients with serum salicylate concentrations > or = 150 micrograms/ml showed shorter durations of fever (7.1 +/- 2.0 vs 10.4 +/- 6.6 days; P < 0.05), shorter durations of positive serum C-reactive protein (14.6 +/- 4.5 vs 22.3 +/- 10.6 days; P < 0.01) and lower incidences of coronary arterial involvements (0/10 vs 6/24; P < 0.05) than did patients with serum salicylate concentrations < 150 micrograms/ml. Significant linear correlations were recognized between daily IVASP dosage and serum salicylate concentrations (r = 0.73; P < 0.01), and between serum salicylate concentrations and serum free salicylate concentrations (r = 0.82; P < 0.01). These correlations did not differ between the presence and absence of coronary arterial involvements. Based on these findings we concluded that a beneficial anti-inflammatory effect in the treatment of KD is achieved when the serum salicylate concentration is > or = 150 micrograms/ml, and that such concentrations could be achieved by increasing the daily IVASP dosage to 100 mg/kg per day or more.

Topics: Acute Disease; Aspirin; Child; Child, Preschool; Coronary Disease; Female; Humans; Infant; Inflammation; Infusions, Intravenous; Male; Mucocutaneous Lymph Node Syndrome; Retrospective Studies; Salicylates; Treatment Outcome

WY-47,288 (2-[(1-naphthalenyloxy)methyl]quinoline) demonstrated topical antiinflammatory activity in several animal models of skin inflammation. Application of WY-47,288 to mouse ear surfaces inhibited arachidonic acid (ED50 = 0.3 mg/ear) and tetradecanoylphorbol acetate (TPA)-induced inflammation (40% at 1 mg/ear). Administration of WY-47,288 (1 mg/ear) at 30 min and 5 h after TPA reduced ear edema and epidermal proliferation by 50%. WY-47,288 also inhibited oxazolone-induced contact hypersensitivity in mouse ears (ED50 = 0.4 mg/ear) and UVB-induced guinea pig skin erythema (ED50 approximately 0.25 mg/spot). These antiinflammatory effects may be due to inhibition of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) since the synthesis of 5-LO and CO products by rat neutrophils and mouse macrophages was dose-dependently reduced by WY-47,288. By contrast, WY-47,288 demonstrated no appreciable inhibition of 12-LO (rabbit platelet), 15-LO (soybean) or phospholipase A2 (human platelet). Furthermore, no systemic adverse effects were observed after topical, parenteral or oral administration of WY-47,288, suggesting that WY-47,288 is a safe topical 5-LO/CO inhibitor for treating skin inflammation.

Topics: Animals; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Cyclooxygenase Inhibitors; Disease Models, Animal; Ear; Erythema; Female; Guinea Pigs; Inflammation; Lipoxygenase Inhibitors; Mice; Naphthalenes; Quinolines; Radiation Injuries; Salicylates; Skin; Skin Diseases; Tetradecanoylphorbol Acetate; Ultraviolet Rays

Cu(II) complexes with salicylates or aminopyrine were administered to rats with local inflammation (acute paw oedema elicited with carrageenan) to determine their anti-inflammatory activity and ulcerogenic effects following oral administration. The complexes were more effective than the parent ligands or appropriate mixtures of these ligands with Cu(II) as anti-inflammatory agents. All complexes indicated low ulcerogenity. The differences in pharmacologic activity between the complexes and mixtures in question are discussed.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Copper; Edema; Inflammation; Male; Organometallic Compounds; Rats; Rats, Inbred Strains; Salicylates; Stomach Ulcer

Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity. One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30- to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.

Topics: Animals; Aspirin; Cyclooxygenase Inhibitors; Inflammation; Kinetics; Male; Prostaglandins E; Rats; Rats, Inbred Strains; Salicylates; Thromboxane B2

The pro-inflammatory effects of prostaglandins have been clearly demonstrated with the use of various animal models of inflammation. Furthermore, the anti-inflammatory effects and some of the side effects of aspirin and other non-steroidal anti-inflammatory agents have been shown to depend on their ability to inhibit cyclo-oxygenase. These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane. They do not affect leukotriene production and there is no firm evidence to suggest that they alleviate inflammation through any other mechanism. In contrast, the corticosteroids facilitate the release of lipocortin which, through inhibition of phospholipase A2 reduces arachidonic acid release. These drugs possess potent anti-inflammatory properties and attempts have been made to develop non-steroidal drugs, such as BW755C, that display similar anti-inflammatory activity through inhibition of the 2 main pathways of the arachidonic acid cascade. Administration of low dose aspirin 40 mg/day selectively inhibits production of thromboxane A2 without affecting prostacyclin. This may be because, firstly, about 60% of an administered dose of aspirin is deacylated to salicylate during first-pass metabolism and, secondly, platelets cannot regenerate cyclo-oxygenase. Thus, absorbed aspirin irreversibly affects platelet thromboxane production in the pre-systemic circulation, but the systemic plasma aspirin concentration is likely to be too low to affect prostacyclin synthesis. Studies in experimental inflammation have shown that after the administration of aspirin, the concentration of salicylate in inflammatory exudate is considerably higher than that of aspirin. In addition, a comparison of prostaglandin synthesis inhibitory potencies shows that the concentration of salicylate, but not of aspirin, at the inflammatory site is high enough to substantially inhibit prostaglandin synthesis.

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Aspirin; Humans; Inflammation; Salicylates; Salicylic Acid

The analgesic activities of aspirin and salicylic acid were investigated by means of the lame-walking test in adjuvant-induced hind-paw-oedematous rats. Aspirin showed ca. 4 times more potent analgesic activity than did salicylic acid in the lame-walking test. The analgesic activity of aspirin was decreased to the level of that of salicylic acid by injection of prostaglandin E2 into the inflamed tissue. The analgesic activity of salicylic acid was not decreased by the same treatment. Salicylic acid inhibited the lame-walking reaction when given intracerebroventricularly. On the other hand, salicylic acid did not inhibit the lame-walking reaction by topical administration on the inflamed hind paw. However, with topical administration, salicylic acid inhibited the carrageenin-induced hind-paw oedema. These results suggest that aspirin has two analgesic effects on the inflammatory pain; one may be the inhibition of prostaglandin biosynthesis by acetylation of cyclo-oxygenase, and the other may be an action due to salicylic acid. Salicylic acid may produce its analgesic action mainly via a central mechanism.

Topics: Analgesia; Animals; Aspirin; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Inflammation; Male; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid

Topics: Anti-Inflammatory Agents; Antigen-Antibody Complex; Arthritis, Rheumatoid; Cartilage; Collagen; Humans; Immune Complex Diseases; Immunity; Inflammation; Osteoarthritis; Proteoglycans; Salicylates; Steroids; Water

Oxidants, such as those generated by metabolically activated phagocytes in inflammation, have been implicated in the metabolic activation of carcinogens, and in this study we demonstrate that the interaction of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP 7,8-dihydrodiol) with phorbol ester-stimulated polymorphonuclear leukocytes (PMNs) results in the generation of both a chemiluminescent intermediate and one that covalently binds to DNA. Cu(II)(3,5-diisopropylsalicylic acid)2 (CuDIPS), a biomimetic superoxide dismutase, and azide, a myeloperoxidase inhibitor, inhibited both of these reactions, indicating a dependency on oxygen-derived oxidants in these hydrocarbon-activation processes. Concordant with the formation of a carcinogen-DNA adduct, the admixture of BP 7,8-dihydrodiol and phorbol ester-stimulated PMNs elicited mutagenesis in Salmonella typhimurium strain TA100. 7,8-Dihydro-BP and BP cis-7,8-dihydrodiol were also mutagenic, whereas derivatives lacking a double bond at the 9,10 position were not. These results demonstrate that oxidants generated by metabolically stimulated PMNs can activate penultimate polycyclic aromatic hydrocarbons to a genotoxic metabolite and further defines a role for inflammation in carcinogenesis.

Topics: Azides; Benzopyrenes; Biotransformation; Dihydroxydihydrobenzopyrenes; DNA; Humans; Inflammation; Luminescent Measurements; Mutation; Neutrophils; Oxidation-Reduction; Peroxidase; Salicylates; Superoxides; Tetradecanoylphorbol Acetate

Administration of the antioxidants 2(3)-tert-butyl-4-hydroxyanisole (BHA) or 5-(P-methoxyphenyl)-3H-1,2-dithiol-3-thione (ADT) to female CD-1 mice starting 4 weeks after infection with 70 cercariae of Schistosoma mansoni resulted in a decrease in the size of the inner fibrotic region of the hepatic granuloma. The cellular composition of the granuloma was not altered by treatment with these two compounds. The administration of the specific superoxide scavenger copper diisopropylsalicylate (CuDIPS) resulted in a similar decrease in granuloma size, suggesting a role of superoxide radicals in the granulomatous response.

Topics: Anethole Trithione; Animals; Anisoles; Antioxidants; Butylated Hydroxytoluene; Chemotaxis, Leukocyte; Female; Free Radicals; Granuloma; Inflammation; Liver Diseases, Parasitic; Mice; Ovum; Oxygen; Salicylates; Schistosoma mansoni; Schistosomiasis mansoni; Superoxides; Triglycerides

Topics: Anti-Inflammatory Agents; Humans; Imidazoles; Inflammation; Prostaglandins; Salicylates

64Cu was administered in two anti-inflammatory formulations to normal rats and to rats with 2 forms of local inflammation, namely (a) an acute paw oedema (elicited with carrageenan) or (b) a chronic granulomatous response to an implanted irritant (Mycobacterium tuberculosis in a polyurethane sponge). The copper formulations used were (i) a slow release one consisting of Cu(II) salicylate applied dermally with ethanol/DMSO and (ii) short acting hydrophilic complex (Cu(I)Cu(II)-penicillamine)5- given subcutaneously. Three types of changes in copper biodistribution with these forms of inflammation were discerned based on determination of 64Cu and copper content in the following organs: inflammatory locus (foot or sponge implant), kidney, liver, spleen, adrenals, brain, blood, thymus, heart, and skin (site of application). The most evident changes were in the kidneys, liver, spleen, adrenals, thymus and serum from animals with chronic granulomatous inflammation. In contrast, a short term acute inflammatory stress (carrageenan paw oedema) had little effect. While copper D-penicillamine (applied subcutaneously) appeared to move as a bolus through the animals, the results with the percutaneous copper salicylate formulation are consistent with it providing a slow release source of copper(II). Exogenous 64Cu from both formulations was sequestered at inflammatory sites (relative to serum). This may partly explain how applied copper complexes can be anti-inflammatory.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Carrageenan; Copper; Edema; Granuloma; Inflammation; Injections, Subcutaneous; Male; Organometallic Compounds; Penicillamine; Radioisotopes; Rats; Rats, Inbred Lew; Salicylates; Tissue Distribution

Inflammation of the rat footpad followed injection of cryoglobulin in crystalline form (Type I) and injection of cryoglobulin in solution (Type II). Rats deficient in essential fatty acids responded with diminished swelling which corrected to normal levels by addition of prostaglandin E1 suggesting that this reaction is prostaglandin mediated. Addition of bradykinin produced no effect. Aggregated cryoglobulin proved more inflammogenic than non-aggregated cryoglobulin. Pre-treatment with choline salicylate and colchicine reduced swelling while pre-treatment with dipyridamole increased edema following cryoglobulin inoculation. Cryoglobulin is considered to be an acute phase reactant in inflammation.

Topics: Alprostadil; Animals; Choline; Colchicine; Cryoglobulins; Crystallization; Dipyridamole; Drug Combinations; Fatty Acids, Essential; Inflammation; Male; Rats; Rats, Inbred Strains; Salicylates

The penetration of the two components of imidazole 2-hydroxybenzoate (ITF 182), imidazole and salicylate, into inflamed sites induced by intrapleural injection of carrageenin in the rat and by a urate-cotton pellet implantation in the knee joint of the rabbit is studied. The results obtained show that the two components of the salt penetrate rapidly the inflamed sites and display different kinetic profiles: imidazole diffuses throughout inflamed and non-inflamed fluids without any specific localization, salicylate shows preferential localization in inflamed fluids and remains longer than imidazole.

Topics: Animals; Anti-Inflammatory Agents; Arthritis; Carrageenan; Exudates and Transudates; Imidazoles; Inflammation; Knee Joint; Male; Pleura; Pleurisy; Rabbits; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Synovial Membrane

In addition to proctocolectomy, new surgical techniques for treating ulcerative colitis include the Kock internal ileal reservoir and endorectal pullthrough of the ileum. In children three forms of Crohn's disease requiring operation have been identified. Ileocecal disease may be treated with resection and anastomosis; colorectal disease is best managed by primary proctocolectomy cutaneous ileostomy; and Crohn's disease of the small bowel should be managed by medical therapy in most cases.

Topics: Cecal Diseases; Child; Colectomy; Colitis, Ulcerative; Colostomy; Crohn Disease; Female; Humans; Ileostomy; Inflammation; Male; Methods; Prednisone; Proctitis; Salicylates; Sulfapyridine

Topics: Animals; Body Temperature; Cats; Dogs; Horses; Inflammation; Pain; Salicylates; Swine

While some salicylates (salicyclic acid and salicylaldehyde, especially) are as potent as aspirin as acute, orally-active anti-flammatory drugs in the rat, they are either inactive or far less potent as PG synthesis inhibitors when added directly to isolated platelets or when given orally. Although PGE1 and PGE2 produce anti-ulcerogenic effects when given to rats in the presence of selected non-steroidal anti-flammatory drugs, they fail to inhibit the acute anti-flammatory and anti-nociceptive effects of these drugs. They are anti-flammatory and anti-nociceptive under certain experimental conditions. PGE1 and PGE2 can also behave as hypothermic agents when given subcutaneously. Related studies, using PG synthesis stimulators in vivo and in vitro (substituted phenylureas), also cause anti-nociception and hypothermia. All of these indirect studies, when taken together, infer that PG synthesis inhibition per se fails to explain, entirely, the pharmacologic effects of non-steroidal anti-inflammatory drugs. They also suggest that the precise role of certain PGs in toxicopharmacology is far from simple and straightforward.

Topics: Analgesics; Animals; Blood Platelets; Body Temperature; Carrageenan; Edema; In Vitro Techniques; Inflammation; Male; Prostaglandins; Prostaglandins E; Rats; Salicylates; Stomach Ulcer

Topics: Acetanilides; Animals; Anti-Inflammatory Agents; Aspirin; Female; Inflammation; Male; Mice; Pain; Rats; Salicylates

Topics: Animals; Anti-Inflammatory Agents; Inflammation; Prostaglandins; Rats; Salicylates

Topics: Animals; Aspirin; Enterobacter; Escherichia coli; Female; Inflammation; Male; Mice; Platelet Aggregation; Rats; Salicylates; Stomach Ulcer; Swine

Caffeine has been found to potentiate the acute anti-inflammatory activity of aspirin, indomethacin, and phenylbutazone, but not the activity of sodium salicylate or hydrocortisone, in the carrageenan pleurisy or hindlimb models of inflammation in the rat. The mobilization of inflammatory cells was not affected by aspirin in the presence or absence of caffeine. The mild analgesia produced by aspirin was confined to a hyperalgesic test in which this drug was able to reduce inflammation and concomitant hyperalgesia and thereby produce an "apparent" analgesic effect. This "apparent" analgesia produced by aspirin was potentiated by caffeine. The mechanism responsible for the potentiated anti-inflammatory and mild analgesic activity of aspirin remains unknown since caffeine did not alter the plasma salicylate levels or prostaglandin synthetase inhibition produced by aspirin.

Topics: Animals; Arthritis, Rheumatoid; Aspirin; Caffeine; Cyclooxygenase Inhibitors; Drug Therapy, Combination; Indomethacin; Inflammation; Male; Phenylbutazone; Rats; Salicylates

In exudates of implanted sponges in rats, made thrombocytopenic by the administration of anti-platelet serum, there are significant reductions in the platelet and leucocyte counts and of the content of prostaglandin-like activity. It is concluded that platelets migrate into the developing sponge exudates, are the source of the prostaglandins and interact with complement to cause leucocyte migration. In normal animals the administration of indomethacin and sodium salicylate cause similar effects to thrombocytopenia whereas the injection of human plasma fraction affects only the leucocyte migration. One of the sites of the anti-inflammatory action of conventional non-steroidal drugs may be concerned with the migration of platelets into inflammatory lesions.

Topics: Animals; Blood Cell Count; Blood Platelets; Exudates and Transudates; Female; Immune Sera; Indomethacin; Inflammation; Leukocyte Count; Prostaglandins; Rats; Salicylates; Thrombocytopenia; Time Factors

1. The effect of (4-acetamido-phenyl)-2-acetoxy-benzoate (benorilate, Benortan) on the inflammatory process was studied thermographically and histologically in cotton-pellet tests on rats. 2. Following implantation of the cotton-pellet, thermography shows a clear inhibition of the local inflammation due to treatment with benorilate. 3. Histological examination shows a corresponding influence of benorilate upon the proliferative phase of the inflammation. 4. The success of antiphlogistic therapy is in correlation with the time of medication.

Topics: Animals; Carrageenan; Gossypium; Granuloma; Inflammation; Male; Rats; Salicylates; Thermography

Acetylsalicylic acid (aspirin) and sodium salicylate are equally effective in reducing the swelling in the carrageenan-induced paw test and the accumulation of leucocytes into the inflammatory exudate produced by the subcutaneous implantation of polyvinyl sponges in the rat. Aspirin but not sodium salicylate caused a significant reduction in the potentiation of paw oedema found after the concurrent administration of carrageenan and arachidonic acid. Some implications of these findings are discussed.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acids; Aspirin; Carrageenan; Cell Migration Inhibition; Female; In Vitro Techniques; Inflammation; Leukocytes; Prostaglandins; Rats; Salicylates; Time Factors

Topics: Administration, Topical; Anti-Infective Agents, Local; Anti-Inflammatory Agents; Chronic Disease; Deodorants; Drug Combinations; Hexachlorophene; Humans; Inflammation; Mouth Mucosa; Postoperative Complications; Propylene Glycols; Salicylates; Samarium

Topics: Amino Acids; Animals; Carbon Radioisotopes; Carboxy-Lyases; Carrageenan; Culture Media; Histidine; Hydrogen-Ion Concentration; Inflammation; Kinetics; Mice; Mitosporic Fungi; Pyridoxal Phosphate; Salicylates; Semicarbazides; Temperature

Topics: Administration, Topical; Gels; Humans; Humic Substances; Inflammation; Pain; Salicylates

Topics: Abnormalities, Drug-Induced; Acid Phosphatase; Animals; Cell Membrane; Drug Interactions; Drug Synergism; Edema; Embryo Implantation; Esters; Female; Fetal Death; Glucuronidase; Hindlimb; Inflammation; Lysosomes; Male; Methanol; Mice; Nicotinic Acids; Pregnancy; Rats; Salicylates; Stimulation, Chemical

Topics: Cell Adhesion; Humans; Inflammation; Leukemia, Myeloid; Lung; Neutrophils; Prednisone; Salicylates

Topics: Acetates; Adrenal Glands; Alpha-Globulins; Animals; Croton Oil; Female; Fibrinogen; Hydrocortisone; Inflammation; Kallikreins; Kininogens; Kinins; Lysine Carboxypeptidase; Phenylbutazone; Protein Precursors; Rats; Salicylates; Wounds and Injuries

Topics: Anti-Inflammatory Agents; Benzoates; Brachial Plexus Neuritis; Drug Combinations; Ethanolamines; Humans; Inflammation; Joint Diseases; Muscular Diseases; Nicotinic Acids; Ointments; Periarthritis; Rheumatic Diseases; Salicylates

A case of juvenile rheumatoid arthritis with vasculitis is presented. Sixteen months after the onset of the disease the patient developed digital artery thrombosis with incipient gangrene. Both the latter and the skin lesions resolved during treatment with azathioprine.

Topics: Arteries; Arteritis; Arthritis, Juvenile; Azathioprine; Blood Vessels; Child, Preschool; Female; Gangrene; Humans; Inflammation; Prednisone; Salicylates; Thrombosis; Thumb

Topics: Antibodies, Antinuclear; Arthritis, Rheumatoid; Biopsy; Connective Tissue; Dermatomyositis; Diphosphates; Gout; Humans; Hyperparathyroidism; Inflammation; Joint Diseases; Lupus Erythematosus, Systemic; Neutrophils; Polyarteritis Nodosa; Psoriasis; Rheumatoid Factor; Salicylates; Sarcoidosis; Spondylitis, Ankylosing; Synovial Fluid; Synovial Membrane; Uric Acid

Topics: Angioedema; Blood Platelets; Fibrinolysin; Humans; Indoles; Inflammation; Kinins; Pyrazoles; Salicylates

Topics: Acetaminophen; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Cells, Cultured; Histamine; Humans; In Vitro Techniques; Inflammation; Lysosomes; Membranes; Permeability; Salicylates; Skin Diseases; Synovial Membrane

Topics: Adrenocorticotropic Hormone; Aminobenzoates; Anti-Inflammatory Agents; Dental Pulp Capping; Edema; Enzyme Therapy; Female; Glucocorticoids; Humans; Indomethacin; Inflammation; Male; Mouth Diseases; Muramidase; Nicotinic Acids; Oxyphenbutazone; Postoperative Complications; Pyrazoles; Salicylates; Stomatitis

Topics: Adjuvants, Immunologic; Aminopyrine; Animals; Anti-Inflammatory Agents; Arthritis; Bradykinin; Chloroquine; Dermatitis, Contact; Drug Antagonism; Guinea Pigs; Histamine; Hypersensitivity, Delayed; Immune System Diseases; Indomethacin; Inflammation; Mice; Phenylbutazone; Rabbits; Rats; Salicylates; Serotonin; Skin Transplantation; Transplantation Immunology; Transplantation, Homologous; Xylenes

Topics: Animals; Anti-Inflammatory Agents; Cortisone; Disease Models, Animal; Edema; Erythema; Inflammation; Phenylbutazone; Rabbits; Rats; Salicylates

Topics: Aniline Compounds; Animals; Anti-Inflammatory Agents; Asbestos; Dextrans; Disease Models, Animal; Drug Combinations; Edema; Evaluation Studies as Topic; Female; Formaldehyde; Granuloma; Indomethacin; Inflammation; Kaolin; Phenylbutazone; Prednisolone; Rats; Rats, Inbred Strains; Salicylates; Serotonin; Sodium Salicylate

Topics: Acid-Base Equilibrium; Adrenal Cortex Hormones; Aminopyrine; Antineoplastic Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Gold; Health Education; Home Care Services; Humans; Indenes; Indomethacin; Inflammation; Phenylbutazone; Pyrazoles; Quinolines; Rest; Salicylates

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Benzoates; Heparin; Humans; Inflammation; Joint Diseases; Ointments; Pain; Salicylates; Spinal Diseases

Topics: Analgesics; Aniline Compounds; Anti-Inflammatory Agents; Aspirin; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Gastrointestinal Diseases; Humans; Indomethacin; Inflammation; Lysosomes; ortho-Aminobenzoates; Peptic Ulcer; Pyrazoles; Salicylates

Topics: Angioedema; Animals; Blood Coagulation Factors; Bradykinin; Carboxypeptidases; Carcinoid Tumor; Catecholamines; Chemical Phenomena; Chemistry; Colchicine; Complement System Proteins; Female; Glucocorticoids; Guinea Pigs; Haplorhini; Humans; Inflammation; Kallidin; Kallikreins; Kidney; Kinins; Muscle Contraction; Phenothiazines; Rats; Salicylates; Sheep; Shock, Septic; Stimulation, Chemical; Uterus; Vascular Diseases; Vascular Resistance; Vasodilator Agents

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arthritis; Aspirin; Codeine; Dextropropoxyphene; Erythema; Female; Guinea Pigs; Inflammation; Male; Oxyphenbutazone; Phenylbutazone; Placebos; Propionates; Rats; Salicylates; Sodium

Topics: Adrenal Glands; Amides; Dermatologic Agents; Flavoring Agents; Heparin; Humans; Inflammation; Iontophoresis; Salicylates; Skin Temperature; Tissue Extracts; Wounds and Injuries

Topics: Anti-Inflammatory Agents; Chemical Phenomena; Chemistry; Humans; Indomethacin; Inflammation; Pyrazoles; Quinolines; Salicylates

Topics: Animals; Chlorides; Chymotrypsin; Drug Synergism; Dry Ice; Guinea Pigs; Histamine; Inflammation; Injections, Intramuscular; Injections, Intraperitoneal; Lithium; Muramidase; Prednisolone; Rats; Salicylates

Topics: Adolescent; Adult; Burns; Female; Humans; Inflammation; Male; Methods; Middle Aged; Ointments; Salicylates; Samarium

Topics: Animals; Blood Vessels; Burns; Capillary Permeability; Chlorpromazine; Digoxin; Diphenhydramine; Indomethacin; Inflammation; Male; Permeability; Promethazine; Quinine; Rats; Salicylates; Strophanthins; Tissue Extracts; Turpentine

Topics: Acetylcysteine; Animals; Dexamethasone; Drug Synergism; Hydrocortisone; Inflammation; Male; Methionine; Penicillamine; Rabbits; Salicylates

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Heparinoids; Humans; Inflammation; Joint Diseases; Ointments; Salicylates; Wounds and Injuries

Topics: Acetates; Aminopyrine; Animals; Calcium Chloride; Coloring Agents; Dermatitis; Dextrans; Drug Synergism; Formaldehyde; Glucuronates; Histamine; Hydrocortisone; Inflammation; Male; Methods; Mice; Passive Cutaneous Anaphylaxis; Salicylates; Serum Albumin, Bovine; Spectrophotometry; Tripelennamine

Topics: Animals; Indomethacin; Inflammation; Phenylbutazone; Prednisone; Rats; Salicylates

Topics: Animals; Anti-Inflammatory Agents; Cortisone; Esterases; Flufenamic Acid; Indomethacin; Inflammation; Male; Mefenamic Acid; ortho-Aminobenzoates; Oxyphenbutazone; Phenylbutazone; Rats; Salicylates; Tyrosine

Topics: Animals; Anti-Allergic Agents; Blood Pressure; Blood Vessels; Capillary Permeability; Dogs; Emigration and Immigration; Fluorides; Histamine H1 Antagonists; Inflammation; Leukocytes; Lysergic Acid Diethylamide; Maleates; Permeability; Pharmacology; Rats; Research; Salicylates; Skin Tests; Tissue Extracts

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Dentistry; Drug Therapy; Gingivitis; Humans; Inflammation; Mouth Diseases; Pain; Salicylates; Stomatitis

Topics: Arthritis; Arthritis, Rheumatoid; Circadian Rhythm; Drug Therapy; Humans; Inflammation; Joint Diseases; Pain; Rheumatic Diseases; Salicylates; Toxicology

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Edema; Formaldehyde; Granuloma; Indoles; Inflammation; Pharmacology; Phenylbutazone; Rats; Research; Salicylates; Serotonin

Some substituted dihydroxybenzenes have been examined for suppression of the yeast-induced inflammatory reaction in the rat paw. This anti-inflammatory activity is greatest in those compounds derived from resorcinol and in particular the halogenated 5-methylresorcinols. The significance of the internuclear distance between the hydroxyl groups in the meta-position to each other in resorcinol and the importance of the enhanced activity due to the halogen atom(s) is discussed. In this series the toxicity and activity could not be divorced.

Topics: Anti-Inflammatory Agents; Benzene; Bromine; Inflammation; Mycoses; Pharmacology; Phenols; Rats; Research; Resorcinols; Salicylates

Topics: Amodiaquine; Anti-Allergic Agents; Anti-Inflammatory Agents; Aspirin; Chemistry, Pharmaceutical; Colchicine; Desoxycorticosterone; Dexamethasone; Heparin; Histamine H1 Antagonists; Hydrocortisone; Inflammation; Phenylbutazone; Prednisolone; Promethazine; Quinine; Rats; Research; Salicylates

Topics: Animals; Anti-Inflammatory Agents; Formaldehyde; Gossypium; Granuloma; Indomethacin; Inflammation; Male; Phenylbutazone; Rats; Salicylates

Topics: Adrenal Cortex Hormones; Animals; Edema; Inflammation; Kallidin; Phenylbutazone; Rats; Salicylates

Topics: Aminopyrine; Aspirin; Inflammation; Phenylbutazone; Quinolines; Salicylates

Topics: Adrenal Cortex Hormones; Connective Tissue; Granuloma; Humans; Inflammation; Prednisone; Salicylates; Sodium Salicylate; Turpentine

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antimalarials; Connective Tissue; Humans; Inflammation; Phenylbutazone; Rheumatic Diseases; Salicylates

Topics: Anti-Inflammatory Agents; Humans; Inflammation; Salicylates

Topics: Anti-Inflammatory Agents; Glycosaminoglycans; Inflammation; Salicylates; Steroids; Sulfates

Topics: Inflammation; Salicylates; Sodium Salicylate

Topics: Edema; Inflammation; Salicylates; Salicylic Acid

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Choline; Drug Combinations; Inflammation; Salicylates

Topics: Anti-Inflammatory Agents; Humans; Inflammation; Salicylates

Topics: Analgesics; Inflammation; Ion Exchange Resins; Resins, Synthetic; Rheumatic Diseases; Salicylates; Salicylic Acid

Topics: Cortisone; Inflammation; Salicylates

Topics: Edema; Energy Metabolism; Inflammation; Permeability; Salicylates

Topics: Adrenocorticotropic Hormone; Animals; Chloroform; Cortisone; Histamine H1 Antagonists; Inflammation; Rats; Salicylates

Topics: Eye Diseases; Humans; Inflammation; Salicylates

Topics: Adrenocorticotropic Hormone; Cortisone; Humans; Inflammation; Physical Examination; Rheumatic Fever; Salicylates

Topics: Humans; Inflammation; Salicylates

Topics: Anti-Inflammatory Agents, Non-Steroidal; Bursa, Synovial; Bursitis; Humans; Inflammation; Injections; Lithium; Quinine; Salicylates; Urethane

Topics: Inflammation; Rheumatic Fever; Salicylates