ReviewToxicological sciences : an official journal of the Society of Toxicology2013
Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies.
Review in Toxicological sciences : an official journal of the Society of Toxicology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
71 citing papers in PubMed, 138 citations in OpenAlex.
- Ultra-deformable transethosomal vesicle for enhancing transdermal delivery of NSAIDs: a comprehensive review.Inflammopharmacology · 2026Review
- The multiple sclerosis drug fingolimod induces pore-like membrane defects, contributing to its antimicrobial activity.The Journal of biological chemistry · 2026Article
- Evaluation of Hemoadsorption Capacity of the CytoSorb Adsorber for Toxic Doses of Diclofenac and Meloxicam in Porcine Plasma.Journal of clinical apheresis · 2026Article
- Development of a gut microbiota model for the analysis of bacterial modifications of xenobiotics.Applied microbiology and biotechnology · 2026Article
- Sex-dependent responses in mice to indomethacin-induced organ injury and gut microbiome-targeted alleviation.Scientific reports · 2025Article
- Emerging gut microbial glycoside hydrolase inhibitors.RSC chemical biology · 2025Review
- Commercially Purchased and In-House Bred C57BL/6 Mice with Different Gut Microbiota Exhibit Distinct Indomethacin-Induced Toxicities.Gut microbes reports · 2025Article
- In Vitro Protective Effects of a Standardized Extract ofAntioxidants (Basel, Switzerland) · 2024Article
- Mitochondrial Dysfunction and Risk Factors for Noncommunicable Diseases: From Basic Concepts to Future Prospective.Diseases (Basel, Switzerland) · 2024Review
- A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy.Acta pharmacologica Sinica · 2024Article
- Drug-microbiota interactions: an emerging priority for precision medicine.Signal transduction and targeted therapy · 2023Review
- Human Gut Microbiota and Drug Metabolism.Microbial ecology · 2023Review
- Review
- The Protective Effect of Walnut Oligopeptides against Indomethacin-Induced Gastric Ulcer in Rats.Nutrients · 2023Article
- Development of 3D-Bioprinted Colitis-Mimicking Model to Assess Epithelial Barrier Function Using Albumin Nano-Encapsulated Anti-Inflammatory Drugs.Biomimetics (Basel, Switzerland) · 2023Article
- Possible relationship between the gut leaky syndrome and musculoskeletal injuries: the important role of gut microbiota as indirect modulator.AIMS public health · 2023Review
- Characterizing the metabolic effects of the selective inhibition of gut microbial β-glucuronidases in mice.Scientific reports · 2022Article
- The role of gut microbial β-glucuronidase in drug disposition and development.Drug discovery today · 2022Review
- Development of anFrontiers in microbiology · 2022Article
- NSAID-Associated Small Intestinal Injury: An Overview From Animal Model Development to Pathogenesis, Treatment, and Prevention.Frontiers in pharmacology · 2022Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients. The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury. Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy. The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial β-glucuronidase produces critical aglycones. The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates. The "first hit" is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death. The "second hit" is created by the significant subsequent inflammatory response that would follow such a first-hit injury. Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites. Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific β-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID-induced enteropathy. Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.