ArticleRedox biology2015
Bilirubin inhibits the up-regulation of inducible nitric oxide synthase by scavenging reactive oxygen species generated by the toll-like receptor 4-dependent activation of NADPH oxidase.
Article in Redox biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 2 of them syntheses that pooled it.
What it found
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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
48 citing papers in PubMed, 2 syntheses or guidelines pooled it, 63 citations in OpenAlex.
- Pooled it
- Elevated bilirubin levels and risk of developing chronic kidney disease: a dose-response meta-analysis and systematic review of cohort studies.International urology and nephrology · 2018Pooled it
- Indirect bilirubin mitigates tubular vacuolization and injury in experimental contrast nephropathy.BMC nephrology · 2026Article
- Integrated analysis of UGT1A1 promoter polymorphism, gene expression, and IL-1β reveals genotype-driven susceptibility in Gilbert syndrome.Molecular biology reports · 2026Article
- Targeting Highly Reactive Oxygen Species (hROS) for Prodrug Activation through a Cascade Reaction with Kinetic Tunability (CReKT) to Effect Linker Cleavage.Journal of medicinal chemistry · 2026Article
- Transforming Toxicity into Therapy: Exploring Bilirubin's Benefits and Its Molecular Role in Cardiac Health and Disease.Biomolecules · 2026Review
- Formulation of Gamma-Oryzanol Encapsulated Nanoparticles and Their Modulation Effects on Inducible Nitric Oxide Synthase and Nitric Oxide in LPS-Stimulated RAW 264.7 Macrophages.Pharmaceutics · 2026Article
- Clinical and biochemical factors associated with moderate-to-severe ulcerative colitis: a retrospective case-control study.BMC gastroenterology · 2026Article
- The HO-1/bilirubin axis in cardiovascular protection: critical evidence for modulation by plant metabolites and traditional multi-component formulations used in Chinese medicine.Frontiers in pharmacology · 2026Review
- Neuroprotective role of bilirubin in Parkinson's disease.Frontiers in aging neuroscience · 2026Review
- Simultaneous targeting of multiple etiological using a nanosized strategy for psoriasis management.Materials today. Bio · 2025Article
- An Explicative Review on Nanotechnology-based Drug Delivery Systems for Alleviating Oxidative Stress-driven Pathologies.Current drug metabolism · 2025Review
- Article
- Serum metabolites and hypercholesterolemia: insights from a two-sample Mendelian randomization study.Frontiers in cardiovascular medicine · 2024Article
- Neonatal asphyxia as an inflammatory disease: Reactive oxygen species and cytokines.Frontiers in pediatrics · 2023Review
- ROS-scavenging materials for skin wound healing: advancements and applications.Frontiers in bioengineering and biotechnology · 2023Review
- Challenges and opportunities in the islet transplantation microenvironment: a comprehensive summary of inflammatory cytokine, immune cells, and vascular endothelial cells.Frontiers in immunology · 2023Review
- Atazanavir-induced unconjugated hyperbilirubinemia prevents vascular hyporeactivity during experimental human endotoxemia.Frontiers in immunology · 2023Article
- PGC-1α in osteoarthritic chondrocytes: From mechanism to target of action.Frontiers in pharmacology · 2023Review
- Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
It has been previously shown that bilirubin prevents the up-regulation of inducible nitric oxide synthase (iNOS) in response to LPS. The present study examines whether this effect is exerted through modulation of Toll-Like Receptor-4 (TLR4) signaling. LPS-stimulated iNOS and NADPH oxidase (Nox) activity in RAW 264.7 murine macrophages was assessed by measuring cellular nitrate and superoxide ( [Formula: see text] ) production, respectively. The generation of both nitrate and [Formula: see text] in response to LPS was suppressed by TLR4 inhibitors, indicating that activation of iNOS and Nox is TLR4-dependent. While treatment with superoxide dismutase (SOD) and bilirubin effectively abolished LPS-mediated [Formula: see text] production, hydrogen peroxide and nitrate release were inhibited by bilirubin and PEG-catalase, but not SOD, supporting that iNOS activation is primarily dependent upon intracellular H2O2. LPS treatment increased nuclear translocation of the redox-sensitive transcription factor Hypoxia Inducible Factor-1α (HIF-1α), an effect that was abolished by bilirubin. Cells transfected with murine iNOS reporter constructs in which the HIF-1α-specific hypoxia response element was disrupted exhibited a blunted response to LPS, supporting that HIF-1α mediates Nox-dependent iNOS expression. Bilirubin, but not SOD, blocked the cellular production of interferon-β, while interleukin-6 production remained unaffected. These data support that bilirubin inhibits the TLR4-mediated up-regulation of iNOS by preventing activation of HIF-1α through scavenging of Nox-derived reactive oxygen species. Bilirubin also suppresses interferon-β release via a ROS-independent mechanism. These findings characterize potential mechanisms for the anti-inflammatory effects of bilirubin.
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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.