ArticleHepatology (Baltimore, Md.)2019
Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench.
Article in Hepatology (Baltimore, Md.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 59 citations in OpenAlex.
- Past, Present, and Future Therapies for Alcohol-associated Hepatitis.Clinical therapeutics · 2023Pooled it
- Modulation of ER Stress via cAMP Signaling: Protective Role of Rolipram in Paracetamol-Induced Liver Injury.Chemical research in toxicology · 2026Article
- Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease.Cellular & molecular immunology · 2025Review
- Article
- ATP8B1 Deficiency Causes Phosphodiesterase 4-Mediated Glucagon Resistance and Impaired Gluconeogenesis in Mouse and Human Liver.Liver international : official journal of the International Association for the Study of the Liver · 2025Article
- Pharmacokinetics and Biodistribution of Polymeric Nanoparticles Loaded with a Small Molecule Drug in Mice with Alcoholic Liver Disease.Molecular pharmaceutics · 2025Article
- Potential Ameliorating Effects of Fluvoxamine in a Rat Model of Endotoxin-Induced Neuroinflammation: Molecular Aspects Through SIRT-1/GPX-4 and HMGB-1 Signaling.Molecular neurobiology · 2025Article
- Targeting Phosphodiesterase 4 in Gastrointestinal and Liver Diseases: From Isoform-Specific Mechanisms to Precision Therapeutics.Biomedicines · 2025Review
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Back to phosphodiesterase inhibitors for liver disease: Are we ready for clinical trials?Hepatology (Baltimore, Md.) · 2025Article
- Dysregulated hepatic alcohol metabolism: a key factor involved in the pathogenesis of alcohol-associated liver disease.American journal of physiology. Gastrointestinal and liver physiology · 2025Article
- Baseline Pathological Liver Function Tests in Patients With Psoriasis Support the Indication for Systemic Therapy Rather Than Being a Reason Against It: A Real-World Analysis.Psoriasis (Auckland, N.Z.) · 2025Article
- Targeting cAMP signaling and phosphodiesterase 4 for liver disease treatment.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2024Article
- Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury.Expert opinion on therapeutic targets · 2024Review
- High Fischer Ratio Oligopeptides of Gluten Alleviate Alcohol-Induced Liver Damage by Regulating Lipid Metabolism and Oxidative Stress in Rats.Foods (Basel, Switzerland) · 2024Article
- Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury.Frontiers in immunology · 2024Article
- Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.The Journal of pathology · 2023Article
- Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies.Biology · 2023Article
- Exacerbating effects of single-dose acute ethanol exposure on neuroinflammation and amelioration by GPR110 (ADGRF1) activation.Journal of neuroinflammation · 2023Article
- Effect of Europinidin against Alcohol-Induced Liver Damage in Rats by Inhibiting the TNF-α/TGF-β/IFN-γ/NF-kB/Caspase-3 Signaling Pathway.ACS omega · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
Alcoholic liver disease (ALD) is a major cause of liver-related mortality. There is still no US Food and Drug Administration-approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up-regulation of cAMP-degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol-induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up-regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti-inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin-inducible proinflammatory cytokine production ex vivo in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol-mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in in vivo and in vitro models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol-induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both in vivo and in vitro. Conclusion: Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.
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.