{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T03:33:56Z","timestamp":1769571236067,"version":"3.49.0"},"reference-count":89,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,9]],"date-time":"2025-03-09T00:00:00Z","timestamp":1741478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Sepsis has been shown to depress arterial baroreceptor function, and this effect is counterbalanced by the cholinergic anti-inflammatory pathway. Considering the importance of central adenosine receptors in baroreceptor function, this study tested whether central adenosine A3 receptors (A3ARs) modulate the cholinergic-baroreflex interaction in sepsis and whether this interaction is modulated by mitogen-activated protein kinases (MAPKs) and related proinflammatory cytokines. Methods: Sepsis was induced by cecal ligation and puncture (CLP) and rats were instrumented with femoral and intracisternal (i.c.) catheters. Baroreflex sensitivity (BRS) was measured 24 h later in conscious animals using the vasoactive method, which correlates changes in blood pressure caused by i.v. phenylephrine (PE) and sodium nitroprusside (SNP) to concomitant reciprocal changes in heart rate. Results: The reduction in reflex bradycardic (BRS-PE), but not tachycardic (BRS-SNP), responses elicited by CLP was reversed by i.v. nicotine in a dose-related manner. The BRS-PE effect of nicotine was blunted following intracisternal administration of IB-MECA (A3AR agonist, 4 \u00b5g\/rat). The depressant action of IB-MECA on the BRS facilitatory action of nicotine was abrogated following central inhibition of MAPK-JNK (SP 600125), PI3K (wortmannin), and TNF\u03b1 (infliximab), but not MAPK-ERK (PD 98059). Additionally, the nicotine suppression of sepsis-induced upregulation of NF\u03baB and NOX2 expression in the nucleus tractus solitarius (NTS) was negated by A3AR activation. The molecular effect of IB-MECA on NF\u03baB expression disappeared in the presence of SP 600125, wortmannin, or infliximab. Conclusions: The central PI3K\/MAPK-JNK\/TNF\u03b1 pathway contributes to the restraining action of A3ARs on cholinergic amelioration of sepsis-induced central neuroinflammatory responses and impairment of the baroreceptor-mediated negative chronotropism.<\/jats:p>","DOI":"10.3390\/ph18030388","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T08:46:41Z","timestamp":1741596401000},"page":"388","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Cholinergic Amelioration of Sepsis-Induced Baroreflex Dysfunction and Brainstem Inflammation Is Negated by Central Adenosine A3 Receptors"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4661-293X","authenticated-orcid":false,"given":"Amany E.","family":"El-Naggar","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21511, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mai M.","family":"Helmy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21511, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahar M.","family":"El-Gowilly","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21511, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8855-7070","authenticated-orcid":false,"given":"Mahmoud M.","family":"El-Mas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21511, Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, College of Medicine, Kuwait University, Jabriya 46301, Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1093\/bjaceaccp\/mkv003","article-title":"Pathophysiology of cardiovascular dysfunction in sepsis","volume":"15","author":"Greer","year":"2015","journal-title":"BJA Educ."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"de Castilho, F.M., Ribeiro, A.L.P., Nobre, V., Barros, G., and de Sousa, M.R. (2018). Heart rate variability as predictor of mortality in sepsis: A systematic review. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203487"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1053\/j.jvca.2010.11.026","article-title":"Myocardial dysfunction in severe sepsis and septic shock: More questions than answers?","volume":"25","author":"Hochstadt","year":"2011","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.biopha.2017.08.066","article-title":"Cardiovascular dysfunction in sepsis at the dawn of emerging mediators","volume":"95","author":"Sergi","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1097\/01.CCM.0000266683.64081.02","article-title":"Mechanisms of sepsis-induced cardiac dysfunction","volume":"35","author":"Rudiger","year":"2007","journal-title":"Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1097\/01.shk.0000126647.51109.5c","article-title":"Arterial baroreflex function determines the survival time in lipopolysaccharide-induced shock in rats","volume":"21","author":"Shen","year":"2004","journal-title":"Shock"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.autneu.2007.10.006","article-title":"Autonomic dysfunction in experimental sepsis induced by cecal ligation and puncture","volume":"138","author":"Pancoto","year":"2008","journal-title":"Auton. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1007\/s00210-022-02289-1","article-title":"Central \u03b17 and \u03b14\u03b22 nicotinic acetylcholine receptors offset arterial baroreceptor dysfunction in endotoxic rats","volume":"395","author":"Sallam","year":"2022","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1097\/FJC.0b013e31805c942d","article-title":"The survival time post-cecal ligation and puncture in sinoaortic denervated rats","volume":"50","author":"Shi","year":"2007","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Milanez, M.I.O., Liberatore, A.M.A., Nishi, E.E., Bergamaschi, C.T., Campos, R.R., and Koh, I.H.J. (2022). Patterns of renal and splanchnic sympathetic vasomotor activity in an animal model of survival to experimental sepsis. Braz. J. Med. Biol. Res., 55.","DOI":"10.1590\/1414-431x2021e11873"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R891","DOI":"10.1152\/ajpregu.90444.2008","article-title":"Endotoxemia causes central downregulation of sympathetic vasomotor tone in healthy humans","volume":"295","author":"Sayk","year":"2008","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhang, W., Lin, H., Zou, M., Yuan, Q., Huang, Z., Pan, X., and Zhang, W. (2022). Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.826889"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"El-Naggar, A.E., Helmy, M.M., El-Gowilly, S.M., and El-Mas, M.M. (2023). Adenosine A1 receptors of the medullary solitary tract arbitrate the nicotine counteraction of neuroinflammation and cardiovascular dysfunction in septic rats. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-44601-w"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"El-Naggar, A.E., Helmy, M.M., El-Gowilly, S.M., and El-Mas, M.M. (2024). Suppression by central adenosine A3 receptors of the cholinergic defense against cardiovascular aberrations of sepsis: Role of PI3K\/MAPKs\/NF\u03baB signaling. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1418981"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107683","DOI":"10.1016\/j.neuropharm.2019.107683","article-title":"Brainstem cholinergic pathways diminish cardiovascular and neuroinflammatory actions of endotoxemia in rats: Role of NF\u03baB\/\u03b17\/\u03b14\u03b22AChRs signaling","volume":"157","author":"Sallam","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1086\/430323","article-title":"The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis","volume":"191","author":"Giebelen","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1093\/infdis\/jit669","article-title":"Stimulation of the \u03b17 Nicotinic Acetylcholine Receptor Protects Against Sepsis by Inhibiting Toll-like Receptor via Phosphoinositide 3-Kinase Activation","volume":"209","author":"Kim","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.ejphar.2018.07.008","article-title":"Additive counteraction by \u03b17 and \u03b14\u03b22-nAChRs of the hypotension and cardiac sympathovagal imbalance evoked by endotoxemia in male rats","volume":"834","author":"Sallam","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chen, L., Lei, X., and Mahnke, K. (2024). Adenosine and Its Receptors in the Pathogenesis and Treatment of Inflammatory Skin Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115810"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"F369","DOI":"10.1152\/ajprenal.00470.2004","article-title":"A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis","volume":"289","author":"Gallos","year":"2005","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R959","DOI":"10.1152\/ajpregu.00034.2006","article-title":"A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis","volume":"291","author":"Lee","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.ejphar.2014.07.012","article-title":"Adenosine A1 receptor antagonist, L-97-1, improves survival and protects the kidney in a rat model of cecal ligation and puncture induced sepsis","volume":"740","author":"Wilson","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/SHK.0b013e318160dad4","article-title":"A3 and P2Y2 receptors control the recruitment of neutrophils to the lungs in a mouse model of sepsis","volume":"30","author":"Inoue","year":"2008","journal-title":"Shock"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1186\/s12974-020-02009-7","article-title":"Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury","volume":"17","author":"Farr","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1016\/j.pain.2014.09.016","article-title":"A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways","volume":"155","author":"Janes","year":"2014","journal-title":"Pain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"694","DOI":"10.18632\/aging.202178","article-title":"Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats","volume":"13","author":"Li","year":"2020","journal-title":"Aging"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1002\/glia.22686","article-title":"Systemic inflammation regulates microglial responses to tissue damage In Vivo","volume":"62","author":"Gyoneva","year":"2014","journal-title":"Glia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"H172","DOI":"10.1152\/ajpheart.01099.2007","article-title":"Stimulation of NTS A1 adenosine receptors differentially resets baroreflex control of regional sympathetic outputs","volume":"294","author":"Scislo","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1046\/j.1440-1681.2001.03404.x","article-title":"Differential patterns of sympathetic responses to selective stimulation of nucleus tractus solitarius purinergic receptor subtypes","volume":"28","author":"Scislo","year":"2001","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1179\/016164105X21959","article-title":"Purinergic mechanisms of the nucleus of the solitary tract and neural cardiovascular control","volume":"27","author":"Scislo","year":"2005","journal-title":"Neurol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.tim.2011.01.001","article-title":"Cecal ligation and puncture: The gold standard model for polymicrobial sepsis?","volume":"19","author":"Dejager","year":"2011","journal-title":"Trends Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/SHK.0b013e318181a343","article-title":"Experimental models of sepsis and their clinical relevance","volume":"30","author":"Garrido","year":"2008","journal-title":"Shock"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1161\/HYPERTENSIONAHA.123.19460","article-title":"Autonomic Nervous System: A Therapeutic Target for Cardiac End-Organ Damage in Hypertension","volume":"81","author":"Gottlieb","year":"2024","journal-title":"Hypertension"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1097\/00005344-200111000-00012","article-title":"Testosterone facilitates the baroreceptor control of reflex bradycardia: Role of cardiac sympathetic and parasympathetic components","volume":"38","author":"Afify","year":"2001","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1097\/SHK.0b013e3182767daf","article-title":"Infusion of Escherichia coli lipopolysaccharide toxin in rats produces an early and severe impairment of baroreflex function in absence of blood pressure changes","volume":"39","author":"Radaelli","year":"2013","journal-title":"Shock"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.taap.2011.04.014","article-title":"Role of adenosine A2A receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control","volume":"254","author":"Fouda","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1523\/JNEUROSCI.05-02-00544.1985","article-title":"Autoradiographic localization of adenosine uptake sites in rat brain using [3H]nitrobenzylthioinosine","volume":"5","author":"Bisserbe","year":"1985","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0301-0082(95)00034-8","article-title":"Neurochemical modulation of cardiovascular control in the nucleus tractus solitarius","volume":"48","author":"Lawrence","year":"1996","journal-title":"Prog. Neurobiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0031-6997(24)01373-5","article-title":"Receptors for purines and pyrimidines","volume":"50","author":"Ralevic","year":"1998","journal-title":"Pharmacol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.4049\/jimmunol.1001567","article-title":"A2B adenosine receptor blockade enhances macrophage-mediated bacterial phagocytosis and improves polymicrobial sepsis survival in mice","volume":"186","author":"Belikoff","year":"2011","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Moore, C.C., Martin, E.N., Lee, G.H., Obrig, T., Linden, J., and Scheld, W.M. (2008). An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models. BMC Infect. Dis., 8.","DOI":"10.1186\/1471-2334-8-141"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.imbio.2011.03.008","article-title":"Suppression of inflammation response by a novel A3 adenosine receptor agonist thio-Cl-IB-MECA through inhibition of Akt and NF-\u03baB signaling","volume":"216","author":"Lee","year":"2011","journal-title":"Immunobiology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6340","DOI":"10.1038\/s41467-024-50466-y","article-title":"Adenosine triggers early astrocyte reactivity that provokes microglial responses and drives the pathogenesis of sepsis-associated encephalopathy in mice","volume":"15","author":"Guo","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s12974-019-1512-6","article-title":"Neuroinflammation in the NTS is associated with changes in cardiovascular reflexes during systemic inflammation","volume":"16","author":"Amorim","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"R183","DOI":"10.1152\/ajpregu.00176.2009","article-title":"IL-6 microinjected in the nucleus tractus solitarii attenuates cardiac baroreceptor reflex function in rats","volume":"298","author":"Takagishi","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Basak, B., and Akashi-Takamura, S. (2024). IRF3 function and immunological gaps in sepsis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1336813"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"111271","DOI":"10.1016\/j.intimp.2023.111271","article-title":"PVB exerts anti-inflammatory effects by inhibiting the activation of MAPK and NF-\u03baB signaling pathways and ROS generation in neutrophils","volume":"126","author":"Ouyang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/j.1440-1681.2005.04210.x","article-title":"Role of the central nucleus of the amygdala in the control of blood pressure: Descending pathways to medullary cardiovascular nuclei","volume":"32","author":"Saha","year":"2005","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/ar.23829","article-title":"The Carotid Sinus Nerve\u2014Structure, Function, and Clinical Implications","volume":"302","author":"Porzionato","year":"2019","journal-title":"Anat. Rec."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.resp.2011.05.016","article-title":"Inflammation and cardiorespiratory control: The role of the vagus nerve","volume":"178","author":"Thayer","year":"2011","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1159\/000530908","article-title":"Autonomic Regulation of Inflammation in Conscious Animals","volume":"30","author":"Salgado","year":"2023","journal-title":"Neuroimmunomodulation"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Eid, A.H., Kobeissy, F., and El-Yazbi, A.F. (2024). Role of Oxidative Stress and Interrelated Cellular Offences in Sex Modulation of Cardiorenal Sequels of Sepsis. Oxidative Stress in Cardiovascular-Metabolic Diseases. Oxidative Stress in Applied Basic Research and Clinical Practice, Springer.","DOI":"10.1007\/978-3-031-62131-4"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.npep.2016.05.002","article-title":"Centrally administered TNF increases arterial blood pressure independently of nitric oxide synthase","volume":"58","author":"Kwiatkowski","year":"2016","journal-title":"Neuropeptides"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/s12974-019-1623-0","article-title":"Anti-neuroinflammation ameliorates systemic inflammation-induced mitochondrial DNA impairment in the nucleus of the solitary tract and cardiovascular reflex dysfunction","volume":"16","author":"Fu","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1161\/CIRCRESAHA.109.208926","article-title":"Shift to an involvement of phosphatidylinositol 3-kinase in angiotensin II actions on nucleus tractus solitarii neurons of the spontaneously hypertensive rat","volume":"105","author":"Sun","year":"2009","journal-title":"Circ. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.taap.2015.10.014","article-title":"The estrogen-dependent baroreflex dysfunction caused by nicotine in female rats is mediated via NOS\/HO inhibition: Role of sGC\/PI3K\/MAPKERK","volume":"289","author":"Fouda","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/FJC.0b013e31822555ca","article-title":"The functional role of PI3K in maintenance of blood pressure and baroreflex suppression in (mRen2)27 and mRen2.Lewis rat","volume":"58","author":"Logan","year":"2011","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.pharep.2017.09.008","article-title":"Hemin blunts the depressant effect of chronic nicotine on reflex tachycardia via activation of central NOS\/PI3K pathway in female rats","volume":"70","author":"Fouda","year":"2018","journal-title":"Pharmacol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1161\/HYPERTENSIONAHA.109.138636","article-title":"Angiotensin II type 1 receptor-activated caspase-3 through ras\/mitogen-activated protein kinase\/extracellular signal-regulated kinase in the rostral ventrolateral medulla is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats","volume":"55","author":"Kishi","year":"2010","journal-title":"Hypertension"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Jiang, J., Huang, K., Xu, S., Garcia, J.G.N., Wang, C., and Cai, H. (2020). Targeting NOX4 alleviates sepsis-induced acute lung injury via attenuation of redox-sensitive activation of CaMKII\/ERK1\/2\/MLCK and endothelial cell barrier dysfunction. Redox Biol., 36.","DOI":"10.1016\/j.redox.2020.101638"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.7150\/thno.81240","article-title":"NOX4 is a potential therapeutic target in septic acute kidney injury by inhibiting mitochondrial dysfunction and inflammation","volume":"13","author":"Li","year":"2023","journal-title":"Theranostics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1016\/j.freeradbiomed.2012.08.590","article-title":"NOX1\/NADPH oxidase is involved in endotoxin-induced cardiomyocyte apoptosis","volume":"53","author":"Matsuno","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ejphar.2017.01.023","article-title":"Cyclosporine counteracts endotoxemia-evoked reductions in blood pressure and cardiac autonomic dysfunction via central sGC\/MAPKs signaling in rats","volume":"797","author":"Sallam","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1097\/FJC.0000000000000400","article-title":"Modulation by Central MAPKs\/PI3K\/sGc of the TNF-\u03b1\/iNOS-dependent Hypotension and Compromised Cardiac Autonomic Control in Endotoxic Rats","volume":"68","author":"Sallam","year":"2016","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.joca.2022.09.004","article-title":"Direct comparison of non-osteoarthritic and osteoarthritic synovial fluid-induced intracellular chondrocyte signaling and phenotype changes","volume":"31","author":"Housmans","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"444","DOI":"10.2174\/092986652105140218112521","article-title":"Hypoxia upregulates MAPK(p38)\/MAPK(ERK) phosphorylation In Vitro: Neuroimmunological differential time-dependent expression of MAPKs","volume":"21","author":"Haddad","year":"2014","journal-title":"Protein Pept. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1007\/s11481-015-9601-5","article-title":"Activation of the Macrophage \u03b17 Nicotinic Acetylcholine Receptor and Control of Inflammation","volume":"10","year":"2015","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2401027","DOI":"10.1155\/2017\/2401027","article-title":"Stimulation of Alpha7 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Upregulation of MMP, MCP-1, and RANTES through Modulating ERK1\/2\/AP-1 Signaling Pathway in RAW264.7 and MOVAS Cells","volume":"2017","author":"Liu","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1007\/s12035-022-02797-4","article-title":"Nicotine Activating \u03b14\u03b22 Nicotinic Acetylcholine Receptors to Suppress Neuroinflammation via JAK2-STAT3 Signaling Pathway in Ischemic Rats and Inflammatory Cells","volume":"59","author":"Wang","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Duan, F., Zeng, C., Liu, S., Gong, J., Hu, J., Li, H., and Tan, H. (2021). \u03b11-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.724699"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14507","DOI":"10.1002\/jcp.27728","article-title":"Nicotine promotes atherosclerosis development in apolipoprotein E-deficient mice through \u03b11-nAChR","volume":"234","author":"Ren","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1097\/JTO.0b013e31828b51d4","article-title":"Nicotine induces resistance to epidermal growth factor receptor tyrosine kinase inhibitor by \u03b11 nicotinic acetylcholine receptor-mediated activation in PC9 cells","volume":"8","author":"Wang","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ejphar.2014.01.060","article-title":"Direct action and modulating effect of (+)- and (-)-nicotine on ion channels expressed in trigeminal sensory neurons","volume":"728","author":"Schreiner","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_74","first-page":"41","article-title":"Nicotine inhibits firing activity of dorsal raphe 5-HT neurones in vivo","volume":"362","author":"Engberg","year":"2000","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S0006-2952(00)00587-6","article-title":"Investigation of nicotine binding to THP-1 cells: Evidence for a non-cholinergic binding site","volume":"61","author":"Morgan","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0014-2999(00)00685-3","article-title":"Involvement of 5-hydroxytryptamine(1A) receptors in nicotine-induced tail tremor in rats","volume":"408","author":"Suemaru","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/nn.2379","article-title":"Nicotine activates the chemosensory cation channel TRPA1","volume":"12","author":"Talavera","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s00395-015-0473-x","article-title":"The infarct-sparing effect of IB-MECA against myocardial ischemia\/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A 2A receptors","volume":"110","author":"Tian","year":"2015","journal-title":"Basic Res. Cardiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/S0006-2952(00)00414-7","article-title":"Apparent involvement of the A(2A) subtype adenosine receptor in the anti-inflammatory interactions of CGS 21680, cyclopentyladenosine, and IB-MECA with human neutrophils","volume":"60","author":"Visser","year":"2000","journal-title":"Biochem. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.cmet.2012.10.003","article-title":"Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding","volume":"16","author":"Blouet","year":"2012","journal-title":"Cell Metab."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Bate, S.T., and Clark, R.A. (2014). The Design and Statistical Analysis of Animal Experiments, Cambridge University Press.","DOI":"10.1017\/CBO9781139344319"},{"key":"ref_82","first-page":"2860","article-title":"Cecal ligation puncture procedure","volume":"51","author":"Toscano","year":"2011","journal-title":"J Vis. Exp."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S0022-3565(24)37976-5","article-title":"Ethanol counteraction of I1-imidazoline but not alpha-2 adrenergic receptor-mediated reduction in vascular resistance in conscious spontaneously hypertensive rats","volume":"288","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1161\/01.RES.24.1.109","article-title":"Reflex regulation of arterial pressure during sleep in man. A quantitative method of assessing baroreflex sensitivity","volume":"24","author":"Smyth","year":"1969","journal-title":"Circ. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1152\/japplphysiol.01407.2005","article-title":"Effects of chronic cold exposure on the endothelin system","volume":"100","author":"Chen","year":"2006","journal-title":"J. Appl. Physiol."},{"key":"ref_86","unstructured":"Paxinos, G., and Watson, C. (1996). The Rat Brain in Stereotaxic Coordinates, Academic Press. [3rd ed.]."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1002\/jnr.21071","article-title":"Activation of adenosine A3 receptors reduces ischemic brain injury in rodents","volume":"84","author":"Chen","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Mohamed, H.E., Askar, M.E., Shaheen, M.A., Salama, A.E., Idris, R.A., and Younis, N.N. (2023). Infliximab substantially re-silenced Wnt\/\u03b2-catenin signaling and ameliorated doxorubicin-induced cardiomyopathy in rats. J. Biochem. Mol. Toxicol., 37.","DOI":"10.1002\/jbt.23312"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s12974-016-0710-8","article-title":"Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy","volume":"13","author":"Dadsetan","year":"2016","journal-title":"J. Neuroinflamm."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/3\/388\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:49:43Z","timestamp":1760028583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/3\/388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,9]]},"references-count":89,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ph18030388"],"URL":"https:\/\/doi.org\/10.3390\/ph18030388","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,9]]}}}