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Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Colitis while Dysregulating the Inflammatory Response.
Maseda D, Zackular JP, Trindade B, Kirk L, Roxas JL, Rogers LM, Washington MK, Du L, Koyama T, Viswanathan VK, Vedantam G, Schloss PD, Crofford LJ, Skaar EP, Aronoff DM
(2019) mBio 10:
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, CD4-Positive T-Lymphocytes, Clostridium Infections, Gastrointestinal Microbiome, Indomethacin, Intestinal Mucosa, Mice, Neutrophils, Prostaglandins, Survival Analysis
Show Abstract · Added April 7, 2019
infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in -infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4 cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses. infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.
Copyright © 2019 Maseda et al.
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2 Members
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11 MeSH Terms
Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders.
Hirten RP, Iacucci M, Shah S, Ghosh S, Colombel JF
(2018) Clin Gastroenterol Hepatol 16: 1374-1384
MeSH Terms: Anti-Inflammatory Agents, Arthritis, Rheumatoid, Biological Products, Drug Therapy, Combination, Drug-Related Side Effects and Adverse Reactions, Humans, Immunologic Factors, Inflammatory Bowel Diseases, Psoriasis, Scleritis, Treatment Outcome
Show Abstract · Added March 3, 2020
Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (Clinical Trials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn's disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
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1 Members
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MeSH Terms
Aspirin for Sepsis Prophylaxis: An Ounce of Prevention?
Casey JD, Semler MW, Bastarache JA
(2017) Crit Care Med 45: 1959-1960
MeSH Terms: Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Humans, Sepsis
Added May 31, 2018
0 Communities
1 Members
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4 MeSH Terms
Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage.
Velez Edwards DR, Edwards TL, Bray MJ, Torstenson E, Jones S, Shrubsole MJ, Muff HJ, Hartmann KE
(2017) Sci Rep 7: 9874
MeSH Terms: Abortion, Spontaneous, Adult, Alleles, Anti-Inflammatory Agents, Non-Steroidal, Cytochrome P-450 Enzyme System, Disease Susceptibility, Female, Genotype, Humans, Intramolecular Oxidoreductases, Odds Ratio, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors
Show Abstract · Added February 21, 2019
This study evaluates the relationship between single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID) metabolism and related pathways and spontaneous abortion (SAB, gestation < 20 weeks) risk. Women were enrolled in Right from the Start (2004-2010) prospective cohort. Periconceptional NSAIDs reported through the sixth week of pregnancy were obtained from study interviews. We evaluated 201 SNPs in 600 European American women. Interaction analyses between NSAID use and SNPs were conducted using logistic regression, adjusted for confounders. We also evaluated prostaglandin E2 urinary metabolite (PGE-M) in an independent population for association with SNPs using linear regression. NSAID use was reported by 63% of cases and 62% controls. The most significant interaction was at prostacyclin synthase (PGIS) rs5602 (OR = 0.34, 95% CI 0.19-0.60, p = 2.45 × 10) and was significant after a Bonferroni correction. NSAID users were protected from SAB (OR = 0.78, 95% CI 0.56-1.10), while non-NSAID users were at increased risk (OR = 2.11, 95% CI 1.35-3.29) in rs5602 stratified analyses. rs5602 also associated with increased PGE-M levels (Beta = 0.09, 95% CI -0.002-0.19, p = 0.033). We identified an association between a PGIS variant and SAB risk that is modified by NSAIDs use during pregnancy and directly associated with increased levels of PGE metabolites. This suggests the potential use of genetic information to guide pharmaceutical intervention to prevent adverse pregnancy outcomes.
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14 MeSH Terms
Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium.
Dixon SC, Nagle CM, Wentzensen N, Trabert B, Beeghly-Fadiel A, Schildkraut JM, Moysich KB, deFazio A, Australian Ovarian Cancer Study Group, Risch HA, Rossing MA, Doherty JA, Wicklund KG, Goodman MT, Modugno F, Ness RB, Edwards RP, Jensen A, Kjær SK, Høgdall E, Berchuck A, Cramer DW, Terry KL, Poole EM, Bandera EV, Paddock LE, Anton-Culver H, Ziogas A, Menon U, Gayther SA, Ramus SJ, Gentry-Maharaj A, Pearce CL, Wu AH, Pike MC, Webb PM
(2017) Br J Cancer 116: 1223-1228
MeSH Terms: Acetaminophen, Adult, Aged, Analgesics, Anti-Inflammatory Agents, Non-Steroidal, Anticarcinogenic Agents, Aspirin, Disease-Free Survival, Female, Humans, Middle Aged, Ovarian Neoplasms, Proportional Hazards Models, Risk Factors
Show Abstract · Added April 18, 2017
BACKGROUND - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with improved survival in some cancers, but evidence for ovarian cancer is limited.
METHODS - Pooling individual-level data from 12 Ovarian Cancer Association Consortium studies, we evaluated the association between self-reported, pre-diagnosis use of common analgesics and overall/progression-free/disease-specific survival among 7694 women with invasive epithelial ovarian cancer (4273 deaths).
RESULTS - Regular analgesic use (at least once per week) was not associated with overall survival (pooled hazard ratios, pHRs (95% confidence intervals): aspirin 0.96 (0.88-1.04); non-aspirin NSAIDs 0.97 (0.89-1.05); acetaminophen 1.01 (0.93-1.10)), nor with progression-free/disease-specific survival. There was however a survival advantage for users of any NSAIDs in studies clearly defining non-use as less than once per week (pHR=0.89 (0.82-0.98)).
CONCLUSIONS - Although this study did not show a clear association between analgesic use and ovarian cancer survival, further investigation with clearer definitions of use and information about post-diagnosis use is warranted.
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14 MeSH Terms
Identification of a novel series of anti-inflammatory and anti-oxidative phospholipid oxidation products containing the cyclopentenone moiety and : Implication in atherosclerosis.
Lu J, Guo S, Xue X, Chen Q, Ge J, Zhuo Y, Zhong H, Chen B, Zhao M, Han W, Suzuki T, Zhu M, Xia L, Schneider C, Blackwell TS, Porter NA, Zheng L, Tsimikas S, Yin H
(2017) J Biol Chem 292: 5378-5391
MeSH Terms: Animals, Anti-Inflammatory Agents, Antioxidants, Atherosclerosis, Cyclopentanes, Foam Cells, Humans, Inflammation, Lipoproteins, LDL, Macrophages, Mice, Mice, Transgenic, Oxidative Stress, Phospholipids, Signal Transduction
Show Abstract · Added March 29, 2017
Oxidative stress and inflammation are two major contributing factors to atherosclerosis, a leading cause of cardiovascular disease. Oxidation of phospholipids on the surface of low density lipoprotein (LDL) particles generated under oxidative stress has been associated with the progression of atherosclerosis, but the underlying molecular mechanisms remain poorly defined. We identified a novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A/J-isoprostanes-phosphocholine, from 1-palmitoyl-2-arachidonoyl--glycero-3-phosphocholine using mass spectrometry and by comparison to a chemically synthesized standard. Transcriptomic analysis (RNA-seq) demonstrated that these compounds affected >200 genes in bone marrow-derived macrophages, and genes associated with inflammatory and anti-oxidative responses are among the top 5 differentially expressed. To further investigate the biological relevance of these novel oxidized phospholipids in atherosclerosis, we chemically synthesized a representative compound 1-palmitoyl-2-15-deoxy-δ-12,14-prostaglandin J--glycero-3-phosphocholine (15d-PGJ-PC) and found that it induced anti-inflammatory and anti-oxidant responses in macrophages through modulation of NF-κB, peroxisome proliferator-activated receptor γ (PPARγ), and Nrf2 pathways; this compound also showed potent anti-inflammatory properties in a mice model of LPS-induced systematic inflammatory response syndrome. Additionally, 15d-PGJ-PC inhibited macrophage foam cell formation, suggesting a beneficial role against atherosclerosis. These properties were consistent with decreased levels of these compounds in the plasma of patients with coronary heart disease compared with control subjects. Our findings uncovered a novel molecular mechanism for the negative regulation of inflammation and positive enhancement of anti-oxidative responses in macrophages by these oxidized phospholipids in LDL in the context of atherosclerosis.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
1 Members
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15 MeSH Terms
Validation of maternal recall of early pregnancy medication exposure using prospective diary data.
Sundermann AC, Hartmann KE, Jones SH, Torstenson ES, Velez Edwards DR
(2017) Ann Epidemiol 27: 135-139.e2
MeSH Terms: Adolescent, Adult, Anti-Inflammatory Agents, Non-Steroidal, Data Collection, Female, Humans, Interviews as Topic, Maternal Exposure, Mental Recall, Middle Aged, Nonprescription Drugs, North Carolina, Pregnancy, Pregnancy Complications, Pregnancy Trimester, First, Prescription Drugs, Prospective Studies, Sensitivity and Specificity, Tennessee, Texas, Young Adult
Show Abstract · Added February 21, 2019
PURPOSE - Data about maternal recall accuracy for classifying early pregnancy medication exposure are meager. Nonetheless, studies often rely on recall to evaluate potential impact of pharmaceuticals on the developing fetus.
METHODS - Right from the Start is a community-based pregnancy cohort that enrolled women from North Carolina, Tennessee, and Texas. A subset of 318 women participated in daily medication diaries initiated before conception (2006-2012). We examined nonsteroidal anti-inflammatory drugs (NSAIDs) as an example of a drug type that is difficult to study due to its intermittent and primarily over-the-counter use as well as its incomplete documentation in medical and pharmaceutical records. Selective serotonin reuptake inhibitors (SSRI) were assessed as a prescription medication comparator. Maternal recall of NSAID and SSRI use in early pregnancy was examined by comparing diary data (gold standard) to first-trimester interview.
RESULTS - Sensitivity and specificity for recall of NSAID exposure were 78.6% and 62.3%, respectively (kappa statistic: 0.41), with 72.3% agreement for exposure classification. Sensitivity and specificity for recall of SSRI exposure were 77.8% and 99.0%, respectively (kappa statistic: 0.79), with 97.8% agreement.
CONCLUSIONS - Our findings suggest the validity of maternal recall varies with medication type and prospective data collection should be prioritized when studying early pregnancy drug exposures.
Copyright © 2016 Elsevier Inc. All rights reserved.
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The human intestinal microbiota of constipated-predominant irritable bowel syndrome patients exhibits anti-inflammatory properties.
Gobert AP, Sagrestani G, Delmas E, Wilson KT, Verriere TG, Dapoigny M, Del'homme C, Bernalier-Donadille A
(2016) Sci Rep 6: 39399
MeSH Terms: Animals, Anti-Inflammatory Agents, Colitis, Cytokines, Dextran Sulfate, Dysbiosis, Gastrointestinal Microbiome, Humans, Inflammation, Intestines, Irritable Bowel Syndrome, Mice, Mice, Inbred C57BL, Microbiota, Rats
Show Abstract · Added December 17, 2016
The intestinal microbiota of patients with constipated-predominant irritable bowel syndrome (C-IBS) displays chronic dysbiosis. Our aim was to determine whether this microbial imbalance instigates perturbation of the host intestinal mucosal immune response, using a model of human microbiota-associated rats (HMAR) and dextran sulfate sodium (DSS)-induced experimental colitis. The analysis of the microbiota composition revealed a decrease of the relative abundance of Bacteroides, Roseburia-Eubacterium rectale and Bifidobacterium and an increase of Enterobacteriaceae, Desulfovibrio sp., and mainly Akkermansia muciniphila in C-IBS patients compared to healthy individuals. The bacterial diversity of the gut microbiota of healthy individuals or C-IBS patients was maintained in corresponding HMAR. Animals harboring a C-IBS microbiota had reduced DSS colitis with a decreased expression of pro-inflammatory cytokines from innate, Th1, and Th17 responses. The pre-treatment of conventional C57BL/6 mice or HMAR with A. muciniphila, but not with Escherichia coli, prior exposure to DSS also resulted in a reduction of colitis severity, highlighting that the anti-inflammatory effect of the gut microbiota of C-IBS patients is mediated, in part, by A. muciniphila. This work highlights a novel aspect of the crosstalk between the gut microbiota of C-IBS patients and host intestinal homeostasis.
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15 MeSH Terms
High prevalence of non-steroidal anti-inflammatory drug use among acute kidney injury survivors in the southern community cohort study.
Lipworth L, Abdel-Kader K, Morse J, Stewart TG, Kabagambe EK, Parr SK, Birdwell KA, Matheny ME, Hung AM, Blot WJ, Ikizler TA, Siew ED
(2016) BMC Nephrol 17: 189
MeSH Terms: Acetaminophen, Acute Kidney Injury, Analgesics, Non-Narcotic, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Comorbidity, Diabetes Mellitus, Female, Heart Failure, Humans, Hypertension, Male, Middle Aged, Prevalence, Prospective Studies, Renal Insufficiency, Chronic, Southeastern United States, Survivors
Show Abstract · Added January 2, 2017
BACKGROUND - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been linked to acute kidney injury (AKI), chronic kidney disease (CKD) and cardiovascular disease (CVD). Patients who survive an AKI episode are at risk for future adverse kidney and cardiovascular outcomes. The objective of our study was to examine the prevalence and predictors of NSAID use among AKI survivors.
METHODS - The Southern Community Cohort Study is a prospective study of low-income adults aged 40-79 in the southeastern US. Through linkage with Centers for Medicare and Medicaid Services, 826 participants with an AKI diagnosis (ICD-9 584.5-584.9) at any age prior to cohort enrollment were identified. At baseline, data were collected on regular use of prescription and over-the-counter NSAIDs, as well as demographic, medical and other characteristics. Additional comorbidities were ascertained via linkage with CMS or the US Renal Data System.
RESULTS - One hundred fifty-four AKI survivors (19%) reported regular NSAID use at cohort enrollment (52 prescription, 81 OTC, 21 both) and the percentage of NSAID users did not vary by time since AKI event. Over 58% of users were taking NSAIDS regularly both before and after their AKI event. Hypertension (83%), arthritis (71%), heart failure (44%), CKD (36%) and diabetes (35%) were prevalent among NSAID users. In a multivariable model, history of arthritis (OR: 3.00; 95% CI: 1.92, 4.68) and acetaminophen use (OR: 2.43; 95% CI: 1.50, 3.93) were significantly associated with NSAID use, while prevalent CKD (OR: 0.63; 95% CI: 0.41, 0.98) and diabetes (OR: 0.44; 95% CI: 0.29, 0.69) were significantly inversely associated.
CONCLUSIONS - NSAID use among AKI survivors is common and highlights the need to understand physician and patient decision-making around NSAIDs and to develop effective strategies to reduce NSAID use in this vulnerable population.
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2 Members
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18 MeSH Terms
Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer's Disease.
McClure R, Ong H, Janve V, Barton S, Zhu M, Li B, Dawes M, Jerome WG, Anderson A, Massion P, Gore JC, Pham W
(2017) J Alzheimers Dis 55: 797-811
MeSH Terms: Administration, Inhalation, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Anti-Inflammatory Agents, Non-Steroidal, Cognition Disorders, Curcumin, Dendritic Spines, Disease Models, Animal, Hippocampus, Humans, Maze Learning, Memory, Short-Term, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Transmission, Mutation, Neurons, Presenilin-1
Show Abstract · Added April 10, 2017
We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.
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3 Members
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22 MeSH Terms