{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:51:31Z","timestamp":1788457891397,"version":"build-2803163510"},"reference-count":91,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T00:00:00Z","timestamp":1658275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institutional Fund Projects","award":["264-130-1442"],"award-info":[{"award-number":["264-130-1442"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Severe infections such as viral, bacterial, or fungal sepsis can cause an inflammatory response in the host, leading to organ failure and septic shock\u2014phosphodiesterase-4 (PDE-4) inhibiting related agents from suppressing cyclic adenosine monophosphate (cAMP) degradation. Regulatory organisations have approved some substances in this category to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with chronic bronchitis and a history of COPD exacerbations. Roflumilast has been shown to alleviate inflammatory responses, thus regulating airway inflammation. Additionally, roflumilast therapy dramatically enhanced B-cell lymphoma 2 (Bcl-2) expression, an anti-apoptotic marker lowered in septic animals. Previous research has indicated that roflumilast may help reverse sepsis-induced liver and lung harm, but whether it is also effective in reversing sepsis-induced renal impairment remains unknown. Therefore, this review determines whether roflumilast protects against renal dysfunction, inflammatory response, and apoptosis in sepsis-induced kidney damage. Additionally, we discussed the molecular mechanism through which roflumilast exerts its protective effect to uncover a possible treatment agent for sepsis-induced renal impairment.<\/jats:p>","DOI":"10.3390\/ph15070899","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T03:34:40Z","timestamp":1658374480000},"page":"899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Phosphodiesterase-4 Inhibitor Roflumilast-Mediated Protective Effect in Sepsis-Induced Late-Phase Event of Acute Kidney Injury: A Narrative Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1881-5219","authenticated-orcid":false,"given":"Imran","family":"Kazmi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad A.","family":"Al-Abbasi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2570-3223","authenticated-orcid":false,"given":"Muhammad","family":"Afzal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah 72341, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4112-0925","authenticated-orcid":false,"given":"Muhammad Shahid","family":"Nadeem","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2635-9383","authenticated-orcid":false,"given":"Hisham N.","family":"Altayb","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Gupta","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura 302017, Jaipur, India"},{"name":"Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 602105, Tamil Nadu, India"},{"name":"Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun 248007, Uttarakhand, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1152\/ajpendo.00555.2011","article-title":"cAMP signaling in skeletal muscle adaptation: Hypertrophy, metabolism, and regeneration","volume":"303","author":"Berdeaux","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_2","first-page":"1288","article-title":"Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: Benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments","volume":"165","author":"Keravis","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1111\/brv.12020","article-title":"Biological roles of cAMP: Variations on a theme in the different kingdoms of life","volume":"88","author":"Gancedo","year":"2013","journal-title":"Biol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nrd4228","article-title":"Advances in targeting cyclic nucleotide phosphodiesterases","volume":"13","author":"Maurice","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0140-6736(09)61255-1","article-title":"Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials","volume":"374","author":"Calverley","year":"2009","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.jcrc.2016.02.014","article-title":"Is plasma neutrophil gelatinase-associated lipocalin a predictive biomarker for acute kidney injury in sepsis patients? A systematic review and meta-analysis","volume":"33","author":"Kim","year":"2016","journal-title":"J. Crit. Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1164\/rccm.201607-1349OC","article-title":"Effect of Roflumilast and Inhaled Corticosteroid\/Long-Acting \u03b22-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial","volume":"194","author":"Martinez","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1038\/npp.2009.66","article-title":"Antidepressant- and Anxiolytic-like Effects of the Phosphodiesterase-4 Inhibitor Rolipram on Behavior Depend on Cyclic AMP Response Element Binding Protein-Mediated Neurogenesis in the Hippocampus","volume":"34","author":"Li","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1111\/bph.12189","article-title":"Attenuation of TNF production and experimentally induced inflammation by PDE4 inhibitor rolipram is mediated by MAPK phosphatase-1","volume":"169","author":"Korhonen","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_10","first-page":"57","article-title":"Roflumilast, a Novel Phosphodiesterase 4 Inhibitor, for COPD Patients with a History of Exacerbations","volume":"5","author":"Field","year":"2011","journal-title":"Clin. Med. Insights: Circ. Respir. Pulm. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1007\/s00125-012-2632-z","article-title":"The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db\/db mice","volume":"55","author":"Vollert","year":"2012","journal-title":"Diabetologia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E1476","DOI":"10.1210\/jc.2014-1430","article-title":"Phosphodiesterase 4 Inhibition as a Potential New Therapeutic Target in Obese Women with Polycystic Ovary Syndrome","volume":"99","author":"Jensterle","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"256","DOI":"10.4161\/adip.21158","article-title":"Metabolic benefits of inhibiting cAMP-PDEs with resveratrol","volume":"1","author":"Chung","year":"2012","journal-title":"Adipocyte"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Park, S.-J., Ahmad, F., Bahde, R.J., Philp, A., Kim, J., Huang, T., Kim, M.K., Trenkle, W.C., and Chung, J.H. (2021). Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253269"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/j.bbrc.2014.07.039","article-title":"Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy","volume":"450","author":"Tikoo","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R47","DOI":"10.1186\/cc6863","article-title":"Early acute kidney injury and sepsis: A multicentre evaluation","volume":"12","author":"Bagshaw","year":"2008","journal-title":"Crit. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.2215\/CJN.03681106","article-title":"Septic acute kidney injury in critically ill patients: Clinical characteristics and outcomes","volume":"2","author":"Bagshaw","year":"2007","journal-title":"Clin. J. Am. Soc. Nephrol. CJASN"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1186\/1745-6215-15-270","article-title":"Impact on mortality of the timing of renal replacement therapy in patients with severe acute kidney injury in septic shock: The IDEAL-ICU study (initiation of dialysis early versus delayed in the intensive care unit): Study protocol for a randomized controlled trial","volume":"15","author":"Barbar","year":"2014","journal-title":"Trials"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cpem.2014.04.005","article-title":"Acute Kidney Injury in Pediatric Sepsis","volume":"15","author":"Mickells","year":"2014","journal-title":"Clin. Pediatr. Emerg. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.semnephrol.2015.01.002","article-title":"Sepsis-associated acute kidney injury","volume":"35","author":"Alobaidi","year":"2015","journal-title":"Semin. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.kint.2019.05.026","article-title":"Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment","volume":"96","author":"Peerapornratana","year":"2019","journal-title":"Kidney Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/ki.2011.379","article-title":"Chronic kidney disease after acute kidney injury: A systematic review and meta-analysis","volume":"81","author":"Coca","year":"2012","journal-title":"Kidney Int."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gallagher, M., Cass, A., Bellomo, R., Finfer, S., Gattas, D., Lee, J., Lo, S., McGuinness, S., Myburgh, J., and Parke, R. (2014). Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial. PLOS Med., 11.","DOI":"10.1371\/journal.pmed.1001601"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1097\/CCM.0000000000000042","article-title":"The association between renal replacement therapy modality and long-term outcomes among critically ill adults with acute kidney injury: A retrospective cohort study","volume":"42","author":"Wald","year":"2014","journal-title":"Crit. Care Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.semnephrol.2015.01.003","article-title":"Clinical Approach to the Patient with AKI and Sepsis","volume":"35","author":"Godin","year":"2015","journal-title":"Semin. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R204","DOI":"10.1186\/cc2872","article-title":"Acute renal failure\u2014Definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group","volume":"8","author":"Bellomo","year":"2004","journal-title":"Crit. Care"},{"key":"ref_28","first-page":"c179","article-title":"KDIGO Clinical Practice Guidelines for Acute Kidney Injury","volume":"120","author":"Khwaja","year":"2012","journal-title":"Nephron Exp. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1128\/IAI.01220-05","article-title":"Mechanisms of Mortality in Early and Late Sepsis","volume":"74","author":"Xiao","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.intimp.2015.04.034","article-title":"Genipin attenuates sepsis-induced immunosuppression through inhibition of T lymphocyte apoptosis","volume":"27","author":"Kim","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1016\/j.febslet.2007.03.074","article-title":"Stress molecules in sepsis and systemic inflammatory response syndrome","volume":"581","author":"Cavaillon","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_32","first-page":"1","article-title":"Role of Circulating Lymphocytes in Patients with Sepsis","volume":"2014","author":"Monserrat","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1097\/MCC.0000000000000153","article-title":"Sepsis-induced acute kidney injury revisited: Pathophysiology, prevention and future therapies","volume":"20","author":"Zarbock","year":"2014","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.3389\/fimmu.2017.01722","article-title":"Goats without Prion Protein Display Enhanced Proinflammatory Pulmonary Signaling and Extracellular Matrix Remodeling upon Systemic Lipopolysaccharide Challenge","volume":"8","author":"Salvesen","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"623","DOI":"10.4049\/jimmunol.179.1.623","article-title":"Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response","volume":"179","author":"Osuchowski","year":"2007","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1189\/jlb.4A0415-168RR","article-title":"Marked alterations of neutrophil functions during sepsis-induced immunosuppression","volume":"98","author":"Demaret","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11897-010-0004-x","article-title":"Galectin-3 in Cardiac Remodeling and Heart Failure","volume":"7","author":"Yu","year":"2010","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1681\/ASN.V8111647","article-title":"Epithelial galectin-3 during human nephrogenesis and childhood cystic diseases","volume":"8","author":"Winyard","year":"1997","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/S0002-9440(10)64595-6","article-title":"Up-Regulation of Galectin-3 in Acute Renal Failure of the Rat","volume":"157","author":"Nishiyama","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1681\/ASN.V123515","article-title":"Galectin-3 Modulates Ureteric Bud Branching in Organ Culture of the Developing Mouse Kidney","volume":"12","author":"Bullock","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"288","DOI":"10.2353\/ajpath.2008.070726","article-title":"Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis","volume":"172","author":"Henderson","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"F245","DOI":"10.1152\/ajprenal.00326.2010","article-title":"Galectin-3 preserves renal tubules and modulates extracellular matrix remodeling in progressive fibrosis","volume":"300","author":"Okamura","year":"2011","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-021-03538-0","article-title":"Galectin-3 in septic acute kidney injury: A translational study","volume":"25","author":"Sun","year":"2021","journal-title":"Crit. Care"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.semnephrol.2015.01.011","article-title":"Mitochondrial Function and Disturbances in the Septic Kidney","volume":"35","author":"Parikh","year":"2015","journal-title":"Semin. Nephrol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrneph.2015.214","article-title":"Mitochondrial dysfunction in inherited renal disease and acute kidney injury","volume":"12","author":"Emma","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(18)30696-2","article-title":"Sepsis and septic shock","volume":"392","author":"Cecconi","year":"2018","journal-title":"Lancet"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0140-6736(02)09459-X","article-title":"Association between mitochondrial dysfunction and severity and outcome of septic shock","volume":"360","author":"Brealey","year":"2002","journal-title":"Lancet"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1164\/rccm.201003-0326OC","article-title":"Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis","volume":"182","author":"Orban","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1172\/JCI58662","article-title":"PGC-1\u03b1 promotes recovery after acute kidney injury during systemic inflammation in mice","volume":"121","author":"Tran","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nature17184","article-title":"PGC1\u03b1 drives NAD biosynthesis linking oxidative metabolism to renal protection","volume":"531","author":"Tran","year":"2016","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"F853","DOI":"10.1152\/ajprenal.00035.2011","article-title":"Persistent disruption of mitochondrial homeostasis after acute kidney injury","volume":"302","author":"Funk","year":"2012","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1097\/CCM.0b013e3182676657","article-title":"Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness","volume":"41","author":"Gunst","year":"2013","journal-title":"Crit. Care Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s40139-013-0023-x","article-title":"Mitochondrial Homeostasis in Acute Organ Failure","volume":"1","author":"Stallons","year":"2013","journal-title":"Curr. Pathobiol. Rep."},{"key":"ref_54","first-page":"1","article-title":"Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI","volume":"25","author":"Star","year":"2021","journal-title":"Crit. Care"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1007\/s11010-021-04131-3","article-title":"Activation of AMPK inhibits Galectin-3-induced pulmonary artery smooth muscle cells proliferation by upregulating hippo signaling effector YAP","volume":"476","author":"Zhang","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7036","DOI":"10.1096\/fj.201901900R","article-title":"Activation of AMP-activated protein kinase during sepsis\/inflammation improves survival by preserving cellular metabolic fitness","volume":"34","author":"Jin","year":"2020","journal-title":"FASEB J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3892\/ijmm.2021.4852","article-title":"Inhibition of aerobic glycolysis alleviates sepsis-induced acute kidney injury by promoting lactate\/Sirtuin 3\/AMPK-regulated autophagy","volume":"47","author":"Tan","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1089\/ars.2012.5149","article-title":"Reactive Oxygen Species in Inflammation and Tissue Injury","volume":"20","author":"Mittal","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"30188","DOI":"10.1074\/jbc.M102061200","article-title":"Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis factor-alpha secretion through IKK regulation of NF-kappa B","volume":"276","author":"Sanlioglu","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1124\/jpet.105.092056","article-title":"Roflumilast inhibits lipopolysaccharide-induced inflammatory mediators via suppression of nuclear factor-kappaB, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase activation","volume":"315","author":"Kwak","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"F576","DOI":"10.1152\/ajprenal.00477.2019","article-title":"Inhibition of PDE4\/PDE4B improves renal function and ameliorates inflammation in cisplatin-induced acute kidney injury","volume":"318","author":"Xu","year":"2020","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"136","DOI":"10.23736\/S0031-0808.18.03446-8","article-title":"Why is there an emerging need to look for a suitable drug delivery platform in targeting and regulating microbiota?","volume":"60","author":"Dua","year":"2018","journal-title":"Panminerva Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1124\/mol.56.1.170","article-title":"Phosphodiesterase 4B2 Is the Predominant Phosphodiesterase Species and Undergoes Differential Regulation of Gene Expression in Human Monocytes and Neutrophils","volume":"56","author":"Wang","year":"1999","journal-title":"Mol. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7628","DOI":"10.1073\/pnas.122041599","article-title":"Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-\u03b1 responses","volume":"99","author":"Jin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","first-page":"1728","article-title":"Anti-inflammatory effect of ciclamilast in an allergic model involving the expression of PDE4B","volume":"19","author":"Zheng","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fimmu.2016.00123","article-title":"The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases","volume":"7","author":"Raker","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1164\/rccm.201003-0416OC","article-title":"Essential Role of CCR2 in Neutrophil Tissue Infiltration and Multiple Organ Dysfunction in Sepsis","volume":"183","author":"Souto","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1111\/aas.13451","article-title":"Neutrophil activation in septic acute kidney injury: A post hoc analysis of the FINNAKI study","volume":"63","author":"Nisula","year":"2019","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"181643","DOI":"10.1155\/2015\/181643","article-title":"Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and \u03b2-Cell Dysfunction","volume":"2015","author":"Keane","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41419-017-0135-z","article-title":"Cellular death, reactive oxygen species (ROS) and diabetic complications","volume":"9","author":"Volpe","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1097\/CCM.0000000000000742","article-title":"Lactate measurements in sepsis-induced tissue hypoperfusion: Results from the Surviving Sepsis Campaign database","volume":"43","author":"Casserly","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.bpa.2016.11.001","article-title":"Lactate levels and hemodynamic coherence in acute circulatory failure","volume":"30","author":"Bakker","year":"2016","journal-title":"Best Pract. Res. Clin. Anaesthesiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e8712","DOI":"10.15252\/emmm.201708712","article-title":"Reprogramming of basic metabolic pathways in microbial sepsis: Therapeutic targets at last?","volume":"10","author":"Vandewalle","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1042\/CS20160235","article-title":"Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1\/AMPK\/PGC-1\u03b1 pathway","volume":"130","author":"Yuan","year":"2016","journal-title":"Clin. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"E751","DOI":"10.1152\/ajpendo.00745.2009","article-title":"AMPK and SIRT1: A long-standing partnership?","volume":"298","author":"Ruderman","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.jnutbio.2011.06.003","article-title":"Resveratrol induces Sirt1-dependent apoptosis in 3T3-L1 preadipocytes by activating AMPK and suppressing AKT activity and survivin expression","volume":"23","author":"Chen","year":"2011","journal-title":"J. Nutr. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"217","DOI":"10.2337\/db11-0416","article-title":"Sirtuin 1\u2013Mediated Cellular Metabolic Memory of High Glucose Via the LKB1\/AMPK\/ROS Pathway and Therapeutic Effects of Metformin","volume":"61","author":"Zheng","year":"2012","journal-title":"Diabetes"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3892\/mmr.2015.4617","article-title":"Epigallocatechin-3-gallate suppresses alveolar epithelial cell apoptosis in seawater aspiration-induced acute lung injury via inhibiting STAT1-caspase-3\/p21 associated pathway","volume":"13","author":"Liu","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_79","first-page":"1771","article-title":"Fish oils protects against cecal ligation and puncture-induced septic acute kidney injury via the regulation of inflammation, oxidative stress and apoptosis","volume":"44","author":"Lin","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ejphar.2016.04.006","article-title":"Glycyrrhizic acid pretreatment prevents sepsis-induced acute kidney injury via suppressing inflammation, apoptosis and oxidative stress","volume":"781","author":"Zhao","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_81","first-page":"1335","article-title":"Influence of roflumilast on sepsis mice through the JAK\/STAT signaling pathway","volume":"23","author":"Chang","year":"2019","journal-title":"Eur. Rev. Med Pharmacol. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1016\/j.molimm.2009.03.018","article-title":"The adenylyl cyclase-cAMP system suppresses TARC\/CCL17 and MDC\/CCL22 production through p38 MAPK and NF-\u03baB in HaCaT keratinocytes","volume":"46","author":"Qi","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/labinvest.2017.59","article-title":"Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice","volume":"97","author":"Feng","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1080\/0886022X.2016.1193816","article-title":"Kidney injury molecule-1 in kidney disease","volume":"38","author":"Yin","year":"2016","journal-title":"Ren. Fail."},{"key":"ref_85","first-page":"111","article-title":"Neutrophil gelatinase-associated lipocalin (NAGL): A novel biomarker for acute kidney injury","volume":"150","author":"Abassi","year":"2011","journal-title":"Harefuah"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-015-0941-6","article-title":"Diagnostic value of neutrophil gelatinase-associated lipocalin, cystatin C, and soluble triggering receptor expressed on myeloid cells-1 in critically ill patients with sepsis-associated acute kidney injury","volume":"19","author":"Dai","year":"2015","journal-title":"Crit. Care"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1111\/cea.12670","article-title":"Effect of roflumilast on airway remodelling in a murine model of chronic asthma. Clinical and experimental allergy","volume":"46","author":"Kim","year":"2016","journal-title":"J. Br. Soc. Allergy Clin. Immunol."},{"key":"ref_88","first-page":"e921319","article-title":"Roflumilast, a Phosphodiesterases-4 (PDE4) Inhibitor, Alleviates Sepsis-induced Acute Kidney Injury","volume":"26","author":"Xu","year":"2020","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.pupt.2010.03.011","article-title":"The preclinical pharmacology of roflumilast\u2014A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease","volume":"23","author":"Hatzelmann","year":"2010","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/ana.24815","article-title":"Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3)","volume":"80","author":"Aldrich","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1016\/j.jid.2016.06.619","article-title":"PDE4 Inhibition as Potential Treatment of Epidermolysis Bullosa Acquisita","volume":"136","author":"Koga","year":"2016","journal-title":"J. Investig. Dermatol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/7\/899\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:54:46Z","timestamp":1760140486000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/7\/899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,20]]},"references-count":91,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ph15070899"],"URL":"https:\/\/doi.org\/10.3390\/ph15070899","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,20]]}}}