Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies: JACC: CardioOncology State-of-the-Art Review.

Proteasome inhibitors (PIs) are the backbone of combination treatments for patients with multiple myeloma and AL amyloidosis, while also indicated in Waldenström's macroglobulinemia and other malignancies. PIs act on proteasome peptidases, causing proteome instability due to accumulating aggregated, unfolded, and/or damaged polypeptides; sustained proteome instability then induces cell cycle arrest and/or apoptosis. Carfilzomib, an intravenous irreversible PI, exhibits a more severe cardiovascular toxicity profile as compared with the orally administered ixazomib or intravenous reversible PI such as bortezomib. Cardiovascular toxicity includes heart failure, hypertension, arrhythmias, and acute coronary syndromes. Because PIs are critical components of the treatment of hematological malignancies and amyloidosis, managing their cardiovascular toxicity involves identifying patients at risk, diagnosing toxicity early at the preclinical level, and offering cardioprotection if needed. Future research is required to elucidate underlying mechanisms, improve risk stratification, define the optimal management strategy, and develop new PIs with safe cardiovascular profiles.

Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury.

Using the Cre-loxP system, we generated the first mouse model in which estrogen receptor-α non-nuclear signaling was inactivated in endothelial cells. Estrogen protection against mechanical vascular injury was impaired in this model. This result indicates the pivotal role of endothelial estrogen receptor-α non-nuclear signaling in the vasculoprotective effects of estrogen.

Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity.

Background: Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph+) leukemia. Objectives: We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). Methods: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. Results: Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Conclusions: Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.

Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function.

The glycocalyx attached to the apical surface of vascular endothelial cells is a rich network of proteoglycans, glycosaminoglycans, and glycoproteins with instrumental roles in vascular homeostasis. Given their molecular complexity and ability to interact with the intra- and extracellular environment, heparan sulfate proteoglycans uniquely contribute to the glycocalyx's role in regulating endothelial permeability, mechanosignaling, and ligand recognition by cognate cell surface receptors. Much attention has recently been devoted to the enzymatic shedding of heparan sulfate proteoglycans from the endothelial glycocalyx and its impact on vascular function. However, other molecular modifications to heparan sulfate proteoglycans are possible and may have equal or complementary clinical significance. In this narrative review, we focus on putative mechanisms driving non-proteolytic changes in heparan sulfate proteoglycan expression and alterations in the sulfation of heparan sulfate side chains within the endothelial glycocalyx. We then discuss how these specific changes to the endothelial glycocalyx impact endothelial cell function and highlight therapeutic strategies to target or potentially reverse these pathologic changes.

Abnormal brain oxygen homeostasis in an animal model of liver disease.

Background & Aims: Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor. Methods: In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration. Results: In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. Conclusions: These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE. Lay summary: Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.

Portal Vein Thrombosis in Cirrhosis.

Patients with cirrhosis of the liver are at high risk of developing portal vein thrombosis (PVT), which has a complex, multifactorial cause. The condition may present with a myriad of symptoms and can occasionally cause severe complications. Contrast-enhanced computed tomography (CT) is the gold standard for the diagnosis of PVT. There are uncertainties regarding the effect on PVT and its treatment outcome in patients with cirrhosis. The main challenge for managing PVT in cirrhosis is analyzing the risk of hemorrhage compared to the risk of thrombus extension leading to complications. All current knowledge regarding non-tumor PVT in cirrhosis, including epidemiology, risk factors, classification, clinical presentation, diagnosis, impact on natural history, and treatment, is discussed in the present article.

The endothelial glycocalyx in critical illness: A pediatric perspective.

The vascular endothelium is the interface between circulating blood and end organs and thus has a critical role in preserving organ function. The endothelium is lined by a glycan-rich glycocalyx that uniquely contributes to endothelial function through its regulation of leukocyte and platelet interactions with the vessel wall, vascular permeability, coagulation, and vasoreactivity. Degradation of the endothelial glycocalyx can thus promote vascular dysfunction, inflammation propagation, and organ injury. The endothelial glycocalyx and its role in vascular pathophysiology has gained increasing attention over the last decade. While studies characterizing vascular glycocalyx injury and its downstream consequences in a host of adult human diseases and in animal models has burgeoned, studies evaluating glycocalyx damage in pediatric diseases are relatively few. As children have unique physiology that differs from adults, significant knowledge gaps remain in our understanding of the causes and effects of endothelial glycocalyx disintegrity in pediatric critical illness. In this narrative literature overview, we offer a unique perspective on the role of the endothelial glycocalyx in pediatric critical illness, drawing from adult and preclinical data in addition to pediatric clinical experience to elucidate how marked derangement of the endothelial surface layer may contribute to aberrant vascular biology in children. By calling attention to this nascent field, we hope to increase research efforts to address important knowledge gaps in pediatric vascular biology that may inform the development of novel therapeutic strategies.

Glycocalyx mechanotransduction mechanisms are involved in renal cancer metastasis.

Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the tumor glycocalyx leading to activation of cell motility and metastasis. Using a highly metastatic renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule Suberoylanilide Hydroxamic Acid (SAHA) inhibits the heparan sulfate synthesis enzyme N-deacetylase-N-sulfotransferase-1, reduces heparan sulfate in the glycocalyx and suppresses SN12L1 motility in response to interstitial flow. SN12L1 cells implanted in the kidney capsule of SCID mice formed large primary tumors and metastasized to distant organs, but when treated with SAHA metastases were not detected. In another set of experiments, the role of hyaluronic acid was investigated. Hyaluronan synthase 1, a critical enzyme in the synthetic pathway for hyaluronic acid, was knocked down in SN12L1 cells and in vitro experiments revealed inhibition of interstitial flow induced migration. Subsequently these cells were implanted in mouse kidneys and no distant metastases were detected. These findings suggest new therapeutic approaches to the treatment of kidney carcinoma metastasis.

Cardiac Gene Therapy With Relaxin Receptor 1 Overexpression Protects Against Acute Myocardial Infarction.

Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice. Up-regulation of Rxfp1 was confirmed via quantitative polymerase chain reaction, and overexpressing animals showed increased sensitivity to relaxin-induced ventricular inotropic response. Overexpressing animals also demonstrated reduced infarct size and preserved cardiac function 24 hours after ischemia-reperfusion. Up-regulation of RXFP1 via AAV9 vectors has potential therapeutic utility in preventing adverse remodeling after myocardial infarction.

Thermal dysregulation in patients with multiple sclerosis during SARS-CoV-2 infection. The potential therapeutic role of exercise.

Thermoregulation is a homeostatic mechanism that is disrupted in some neurological diseases. Patients with multiple sclerosis (MS) are susceptible to increases in body temperature, especially with more severe neurological signs. This condition can become intolerable when these patients suffer febrile infections such as coronavirus disease-2019 (COVID-19). We review the mechanisms of hyperthermia in patients with MS, and they may encounter when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finally, the thermoregulatory role and relevant adaptation to regular physical exercise are summarized.

Diacerein ameliorates kidney injury induced by cisplatin in rats by activation of Nrf2/Ho-1 pathway and Bax down-regulation.

Cisplatin is an antineoplastic medicine used for solid tumor treatment. The main side effect that limits its dose is nephrotoxicity. Diacerein has been used for the treatment of joint diseases like osteoarthritis. It also has exhibited analgesic effects and antipyretic activities in animal models so this study targets to indicate the diacerein effect on nephrotoxicity induced by cisplatin in rats. Rats were distributed into four groups: normal healthy control; diacerein, which received diacerein daily by gastric gavage (50 mg/kg/day); cisplatin, which received only one intraperitoneal injection of cisplatin (6 mg/kg) and cisplatin and diacerein, which received diacerein daily after the cisplatin injection till 7th and 12th days, respectively. Diacerein treatment decreased kidney function markers so the cisplatin effect was reversed. Also, diacerein increased the renal antioxidants and decreased oxidative stress. Diacerein up-regulated Ho-1 (heme oxygenase 1), Nrf2 (Nuclear factor erythroid 2-related factor 2) and endothelial nitric oxide synthase (eNOS) genes expression, while down-regulated Bcl-2-associated X protein (Bax) gene expression. Furthermore, the renal transforming growth factor beta-1 (TGF-ß1) decreased by the diacerein effect. Consequently, diacerein has a curative effect against cisplatin due to its anti-inflammatory, antioxidant, and antiapoptotic properties.

Naringin prevents cyclophosphamide-induced erythrocytotoxicity in rats by abrogating oxidative stress.

Earlier reports have shown that Cyclophosphamide (CYCP), an anti-malignant drug, elicited cytotoxicity; and that naringin has several beneficial potentials against oxidative stress and dyslipidaemias. We investigated the influence of naringin on free radical scavenging, cellular integrity, cellular ATP, antioxidants, oxidative stress, and lipid profiles in the CYCP-induced erythrocytotoxicity rat model. Rats were pretreated orally by gavage for fourteen consecutive days with three doses (50, 100, and 200 mg/kg) naringin before single CYCP (200 mg/kg, i.p.) administration. Afterwards, the rats were sacrificed. Naringin concentrations required for 50 % scavenging hydrogen peroxide and nitric oxide radical were 0.27 mg/mL and 0.28 mg/mL, respectively. Naringin pretreatment significantly (p < 0.05) protected erythrocytes plasma membrane architecture and integrity by abolishing CYCP-induced decrease in the activity of erythrocyte LDH (a marker of ATP). Pretreatment with naringin remarkably (p < 0.05) reversed CYCP-induced decreases in the erythrocytes glutathione levels, activities of glutathione-S-transferase, catalase, glutathione peroxidase, and glutathione reductase; attenuated CYCP-mediated increases in erythrocytes levels of malondialdehyde, nitric oxide, and major lipids (cholesterol, triacylglycerol, phospholipids, and non-esterified fatty acids). Taken together, different acute pretreatment doses of naringin might avert CYCP-mediated erythrocytes dysfunctions via its antioxidant, free-radical scavenging, and anti-dyslipidaemia properties.

Sirtuin 1 in Endothelial Dysfunction and Cardiovascular Aging.

Sirtuin 1 (SIRT1) is a histone deacetylase belonging to the family of Sirtuins, a class of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes with multiple metabolic functions. SIRT1 localizes in the nucleus and cytoplasm, and is implicated in the regulation of cell survival in response to several stimuli, including metabolic ones. The expression of SIRT1 is associated with lifespan and is reduced with aging both in animal models and in humans, where the lack of SIRT1 is regarded as a potential mediator of age-related cardiovascular diseases. In this review, we will summarize the extensive evidence linking SIRT1 functional and quantitative defects to cellular senescence and aging, with particular regard to their role in determining endothelial dysfunction and consequent cardiovascular diseases. Ultimately, we outline the translational perspectives for this topic, in order to highlight the missing evidence and the future research steps.

Angiotensin II type 1 receptor is involved in hypertension and vascular alterations caused by environmental toxicant hexachlorobenzene.

Environmental hexachlorobenzene (HCB) increases blood pressure (BP) in female rats, causing alterations in arterial structure and function. Here we study the role of Angiotensin II receptor type 1 (AT1) in HCB-induced hypertension through the use of AT1 antagonist losartan. HCB-treated male rats showed a 22.7% increase in BP which was prevented by losartan. Losartan blocked HCB-induced changes in arterial morphology (decreased aorta cell number and increased wall thickness). Losartan also prevented HCB-induced alterations in artery relaxation by acetylcholine and nitroprusside but not the reduction in the maximum contraction by phenylephrine. Losartan rescued arterial molecular alterations caused by HCB (i.e. an increase in TGF-ß1 and AT1 expression and a decrease in eNOS expression and nitrite levels) and reduced hydrogen sulfide plasma concentration. In conclusion: in this work we demonstrate that AT1 activity is involved in HCB effects on the vascular system leading to hypertension.

Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy.

Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.

Implications of Iron Deficiency in STEMI Patients and in a Murine Model of Myocardial Infarction.

In patients with a first anterior ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention, iron deficiency (ID) was associated with larger infarcts, more extensive microvascular obstruction, and higher frequency of adverse left ventricular remodeling as assessed by cardiac magnetic resonance imaging. In mice, an ID diet reduced the activity of the endothelial nitric oxide synthase/soluble guanylate cyclase/protein kinase G pathway in association with oxidative/nitrosative stress and increased infarct size after transient coronary occlusion. Iron supplementation or administration of an sGC activator before ischemia prevented the effects of the ID diet in mice. Not only iron excess, but also ID, may have deleterious effects in the setting of ischemia and reperfusion.

Endothelial nitric oxide synthase alterations are independent of turbulence in the aorta of patients with a unicuspid aortic valve.

Objectives: Certain aortic valve malformations predispose to ascending aortic aneurysm, although the mechanisms are incompletely understood. The aim of this study was to determine whether turbulence across the unicuspid aortic valve (UAV) contributes to regional differences in endothelial nitric oxide (eNOS) signaling in the ascending aortic wall. Methods: Samples were collected intraoperatively from the convex and concave ascending aortic wall from 64 patients with tricuspid aortic valves (TAVs; 25 nondilated, 17 dilated), or UAVs (9 nondilated, 13 dilated). Results: In normal-sized aortas, eNOS protein was decreased in UAV compared with TAV (P = .02) whereas mRNA was similar (P = .62). eNOS protein was increased in UAV-dilated aortas compared with UAV-nondilated aortas (P = .04), whereas dilatation had no impact on eNOS protein levels in TAV aortas (P = .73). Comparing only aneurysmal aortas, we found no difference in eNOS mRNA or protein between dilated TAV and UAV aortas (P = .26, P = .76). For eNOS mRNA and protein levels in normal and dilated UAV-associated aortas, no differences were found between concavity and convexity (all P > .05). This differed from dilated TAV aortas, which showed decreased eNOS mRNA in the convexity (P = .004) whereas eNOS protein levels were similar (P = .75). Conclusions: eNOS downregulation is observed in the UAV-associated ascending aorta and is apparently independent of dilatation. No regional differences were found, however, which would be expected if eNOS changes occur due to wall shear stress. This implies a congenital defect in eNOS signaling that may be stronger than turbulence-induced expression patterns. Further research should define the role of eNOS in aortopathy associated with aortic valve disease.

Protective effect of piperine in ischemia-reperfusion induced acute kidney injury through inhibition of inflammation and oxidative stress.

BACKGROUND AND AIM: Renal ischemia-reperfusion is associated with inflammation and oxidative stress. As a major compound in black pepper, piperine has anti-inflammatory and anti-oxidative properties. In present study, the protective effects of oral administration of piperine in renal ischemia-reperfusion (IR) induced acute kidney injuries (AKI) were investigated. EXPERIMENTAL PROCEDURE: Male Wistar rats received piperine (10 or 20 mg/kg.bw) or vehicle for 10 days. The artery and vein of both kidneys were then clamped for 30 min, followed by a 24-h reperfusion period. Concentrations of creatinine and urea-nitrogen in descending aorta blood were measured, and malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels were measured in kidney tissue to evaluate the oxidative stress. Inflammation was evaluated by measuring the TNF-α and ICAM-1 mRNA expression levels in renal cortical tissue using Real Time PCR method and counting leukocytes infiltration to interstitium. Further measured were tissue damages in H & E stained sections. RESULTS: Renal IR reduced FRAP, while increasing the plasma concentrations of creatinine and urea-nitrogen, tissue MDA level, TNF-α and ICAM-1 mRNA expressions, leukocyte infiltration and histopathologic injuries. Piperine administration significantly reduced the plasma concentrations of creatinine and urea-nitrogen, expression of pro-inflammatory factors, oxidative stress and renal histopathologic injuries. It is to be noted that 20 mg/kg dose was more effective. CONCLUSION: Our results suggest piperine protects the kidney against ischemia-reperfusion induced acute kidney injuries by its anti-inflammatory and anti-oxidative properties.

Nuclear deformation mediates liver cell mechanosensing in cirrhosis.

BACKGROUND & AIMS: Liver stiffness is increased in advanced chronic liver disease (ACLD) and accurately predicts prognosis in this population. Recent data suggest that extracellular matrix stiffness per se may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms. METHODS: Hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells were isolated from healthy rats or rats with cirrhosis (carbon tetrachloride or thioacetamide), and cultured on polyacrylamide gels with different physiologically relevant stiffness for 72 h. RESULTS: All cell types of rats with cirrhosis cultured at low stiffness showed a significant phenotype amelioration vs. rigid matrix (assessed by quantitative morphology, mRNA expression, protein synthesis, and electron microscopy imaging). Additionally, stiffness modified the antifibrotic effects of liraglutide in stellate cells of rats with cirrhosis. Finally, evaluation of nuclear morphology revealed that high stiffness induced nuclei deformation in all cell types, an observation confirmed in cells from human livers. Disconnecting the nucleus from the cytoskeleton by cytoskeleton disruption or a defective form of nesprin 1 significantly recovered spherical nuclear shape and quiescent phenotype of cells. CONCLUSIONS: The environment's stiffness per se modulates the phenotype of healthy rats and liver cells of rats with cirrhosis by altering the nuclear morphology through cytoskeleton-derived mechanical forces. The reversibility of this mechanism suggests that targeting the stiffness-mediated intracellular mechanical tensions may represent a novel therapeutic strategy for ACLD. LAY SUMMARY: During cirrhosis, the liver becomes scarred, stiff, and unable to perform its normal functions efficiently. In this study, we demonstrated that cells from diseased (stiff) livers recovered their functionality when placed in a soft environment (as that of a healthy liver). Furthermore, treatments aimed at tricking liver cells into believing they are in a healthy, soft liver improved their function and could potentially contribute to treat cirrhosis.

Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and RANKL; in complete Freund's adjuvant arthritis model: Downregulation of IL-6/JAK2/STAT3 signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is accompanied by progressive joint damage and disability. The intolerability of conventional antirheumatic drugs by some patients necessitates the search for effective antirheumatic agents having better tolerability. In the current work, we aimed to investigate the efficacy of cinnamaldehyde, tadalafil, and aliskiren as potential antirheumatic candidates and to explore their modulatory effects on joint destruction, inflammatory response, and intracellular signaling. Arthritis was induced in female Wistar rats by complete Freund's adjuvant (CFA) 0.4 ml s.c. on days 1, 4, and 7. Treated groups received their respective drugs, starting from day 13, daily for 3 weeks. Methotrexate and prednisolone were the standard antirheumatic drugs, while cinnamaldehyde, tadalafil, and aliskiren were the test agents. Treatment with cinnamaldehyde, tadalafil, or aliskiren reduced serum levels of rheumatoid factor, and pro-inflammatory cytokines; tumor necrosis factor-alpha and interleukin-6 (IL-6), along with elevated level of IL-10 which is an anti-inflammatory cytokine. Besides, cartilage and bone destruction biomarkers; matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear factor-kappa B ligand (RANKL); were significantly reduced after treatment with the test agents, which was further confirmed by histopathological investigation. The elevated protein expressions of phosphorylated-Janus kinase 2 (p-JAK2), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), and inducible nitric oxide synthase (iNOS) in articular tissue were markedly attenuated after treatment with cinnamaldehyde, tadalafil, or aliskiren, while that of endothelial nitric oxide synthase (eNOS) was greatly enhanced. In addition, oxidative stress and inflammatory markers such as malondialdehyde, nitric oxide, and myeloperoxidase were reduced in joint tissue after treatment with the test agents, while glutathione content was elevated. Furthermore, the renin inhibitor aliskiren produced effects close to those of the normal and methotrexate, the gold standard antirheumatic drug, in most of the measured parameters. Collectively, these findings led to the assumption that the downregulation of IL-6/JAK2/STAT3 signaling by cinnamaldehyde, tadalafil, and aliskiren could alleviate joint destruction by MMP-3 and RANKL, reduce iNOS, and enhance eNOS expressions. Moreover, aliskiren could be a promising therapeutic agent for RA, because of its ability to normalize most of the measured parameters after CFA-induced arthritis.