sildenafil-citrate and Inflammation

Kidney diseases are major health problem and understanding the underlined mechanisms that lead to kidney diseases are critical research points with a marked potential impact on health. Cadmium (Cd) is a heavy metal that occurs naturally and can be found in contaminated food. Kidneys are the most susceptible organ to heavy metal intoxication as it is the main route of waste excretion. The harmful effects of Cd were previously well proved. Cd induces inflammatory responses, oxidative injury, mitochondrial dysfunction and disturbs Ca

Topics: Acetylcysteine; Cadmium; Cytochalasin D; Cytokines; Humans; Inflammation; Kidney Diseases; NF-kappa B; Polysaccharides; Sildenafil Citrate; Telmisartan

Obstructive sleep apnoea (OSA) may negatively affect a couple's sexual relationship. This systematic review evaluated what characteristics are determinants of sexual function and dysfunction in women and men with OSA, and what interventions are shown to be effective.. A systematic literature review was conducted using PubMed, CINAHL, Cochrane and TRIP, and articles published between January 2004 and December 2014 in English; original research; adults ≥ 18 years; and both experimental and non-experimental designs. The Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies was used to assess study quality. Of 21 studies, six studies (no randomised control trials, RCTs) included women and 15 (with six RCTs) studies included men. Extracted data were scrutinised and adjusted until consensus was reached; suitable quantitative data were pooled in statistical meta-analysis.. Sexual function was affected similarly in both genders, but effective interventions were reported only for men. In some studies, OSA severity and medications contributed to greater sexual dysfunction. In women, menopausal status, hormone levels and SaO2 < 90% were determinants of sexual dysfunction, while for men factors included BMI, hormonal status and inflammatory markers. Continuous positive airway pressure (CPAP) not only improved clinical measures such as excessive daytime sleepiness but also the erectile and orgasmic function. Nevertheless, sildenafil was superior CPAP with regard to erectile dysfunction.. The findings illustrate important contributors to sexual dysfunction; however, firm generalisations cannot be made. There were limited RCTs and none for women, indicating further RCTs are needed to determine how OSA affects sexual function.

Topics: Body Mass Index; Continuous Positive Airway Pressure; Female; Hormones; Humans; Inflammation; Male; Menopause; Phosphodiesterase 5 Inhibitors; Severity of Illness Index; Sexual Dysfunction, Physiological; Sildenafil Citrate; Sleep Apnea, Obstructive

Preeclampsia is a pregnancy-induced hypertensive disorder found most commonly in nulliparous women. Recent research performed in animal models of the disease has revealed some of the underlying mechanisms of preeclampsia. Specifically, placental insufficiency and the resulting hypoxia/ischemia have been shown to be crucial to disease progression. In response to placental hypoxia/ischemia, several pathways are activated, which contribute to the clinical manifestations of the disease: increased circulating levels of the anti-angiogenic protein sFlt-1, activation of the maternal inflammatory response, suppressed nitric oxide production, enhanced endothelin-1 production, and induction of reactive oxygen formation. Despite advances in the understanding of the disorder, therapeutic approaches to the treatment of preeclampsia are severely limited. New lines of research, however, indicate some possible new therapeutic approaches for the management of preeclampsia and offer hope for an effective pharmacologic intervention.

Topics: Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypoxia; Inflammation; Phosphodiesterase 5 Inhibitors; Piperazines; Placenta; Pre-Eclampsia; Pregnancy; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A

Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects.. We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy.. An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks.. Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased.. Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF.

Topics: Adult; Biomarkers; Cystic Fibrosis; Drug Monitoring; Female; Humans; Inflammation; Leukocyte Elastase; Lung; Male; Phosphodiesterase 5 Inhibitors; Severity of Illness Index; Sildenafil Citrate; Sputum; Treatment Outcome

Erectile dysfunction (ED) is associated with an incremental inflammatory activation. Evidence suggests that chronic phosphodiesterase 5 (PDE-5) inhibition may have a favorable effect on inflammatory activation and surrogate markers of ED. The aim of this study is to investigate the acute effect of sildenafil on circulating pro-inflammatory markers/mediators in ED patients.. The study comprised a randomized, double-blind, crossover trial carried out on two separate arms: one with sildenafil 100mg, and one with placebo. Twenty-seven subjects participated in the study (seven in the pilot and 20 in the main phase). In the main phase, blood samples were collected at baseline and at 2 and 4h after sildenafil or placebo administration to determine fibrinogen, high sensitivity C-reactive protein (hsCRP), high sensitivity interleukin-6 (hsIL-6) and tumor necrosis factor α (TNF-α).. Administration of sildenafil produced a significant sustained reduction of fibrinogen, hsCRP and hsIL-6 (maximal absolute response of -44mg/dl, 0.42mg/l and 0.68pg/ml at 4h). Likewise, TNF-α was acutely decreased after sildenafil (maximal response of -13pg/ml, 2h). The effect of sildenafil on fibrinogen, hsCRP and hsIL-6 and TNF-α was independent of the baseline values of these markers/mediators or the baseline testosterone level (all P<0.05). Soluble vascular cell adhesion molecule 1 (sVCAM-1) levels remained unchanged.. The present study shows for the first time the acute effect of sildenafil administration on pro-inflammatory markers/mediators in men with vasculogenic ED. This finding may have important implications in ED patients who are considered to be at increased cardiovascular risk.

Topics: Biomarkers; Cross-Over Studies; Cytokines; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Impotence, Vasculogenic; Inflammation; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Risk Factors; Sildenafil Citrate

Pulmonary hypertension (PH) is a progressive and life-threatening disease with poor prognosis despite many advances in medical therapy over the past 20 years. Novel therapies which target on the underlying pathology of PH are still urgent to be met. TPN171H is a recently found new compound that exhibits potent pharmacological effects in PH via inhibiting phosphodiesterase type 5 (PDE-5). However, as one icariin derivative, the anti-inflammatory effects of TPN171H for treating PH are not clear. The present study was designed to investigate the therapeutical effect of TPN171H against inflammation in PH and reveal the underlying mechanism. Hypoxia and monocrotaline (MCT)-induced PH rat models were established, which were treated by oral administration of TPN171H (5, 25 mg/kg/d) or sildenafil (25 mg/kg/d). The right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and vascular remodeling were measured. The results suggested that TPN171H significantly reduced RVSP and RVHI, and reversed pulmonary vascular remodeling in rats with both models. Furthermore, in in vivo and in vitro research, our data suggested that TPN171H remarkably suppressed cathepsin B-mediated NLRP3 inflammasome activation, which may contribute to its therapeutical function for PH.

Topics: Animals; Anti-Inflammatory Agents; Cathepsin B; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Inflammasomes; Inflammation; Monocrotaline; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Vascular Remodeling

BACKGROUND To explore the efficacy of beraprost sodium combined with sildenafil and its effects on the vascular endothelial function and inflammation in left heart failure patients complicated with pulmonary arterial hypertension. MATERIAL AND METHODS A total of 80 patients with left heart failure complicated with pulmonary arterial hypertension was enrolled as the subjects of this study and assigned into an observation group (n=40) and a control group (n=40) using a random number table. The changes in pulmonary arterial hypertension-associated indicators at 3 months after treatment and the alterations in the levels of cardiac function-associated biochemical indicator brain natriuretic peptide (BNP), inflammatory factor tumor necrosis factor alpha (TNF-alpha), and mean pulmonary arterial pressure during treatment were compared between the 2 groups. RESULTS At 3 months after treatment, the pulmonary arterial hypertension-associated indicators human urotensin II and calcitonin gene-related peptide in the observation group were lower and higher, respectively, than those in control group. Moreover, the observation group had significantly lower BNP and TNF-alpha levels and mean pulmonary arterial pressure than the control group. After intervention, the echocardiographic parameters left ventricular ejection fraction (LVEF), cardiac output (CO), and stroke volume (SV) in both groups were significantly higher than those before intervention, and the observation group had significantly higher LVEF, SV, and CO than the control group after intervention. CONCLUSIONS Beraprost sodium combined with sildenafil for left heart failure complicated with pulmonary arterial hypertension can effectively improve pulmonary arterial hypertension, alleviate left heart failure, and reduce inflammatory responses, thereby achieving better clinical efficacy in patients.

Topics: Aged; Aged, 80 and over; Echocardiography; Endothelial Cells; Epoprostenol; Exercise Tolerance; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Ventricular Function, Right

The kynurenine pathway (KP, IDO/Kyn pathway) is an important metabolic pathway related to many diseases. Although cranial radiotherapy is the mainstay in metastatic tumors management, its efficacy is limited owing to the associated neuropsychiatric disorders. Sildenafil (SD) and simvastatin (SV) were reported to have antioxidant/anti-inflammatory effects and to serve as NO donor/BH4 regulator, respectively. Fluoxetine (Fx) is an FDA-approved anti-depressant agent and one of the selective serotonin reuptake inhibitor drugs (SSRI), used in neurological disorder treatment. The study objective was to investigate the role of cranial irradiation (C-IR) on KP signaling impairment and the possible intervention by SD and/or SV (as nitric oxide (NO) donor/Tetrahydrobiopterin (BH4) regulatory) on KP following C-IR-induced disruption compared with Fx (as standard drug).Herein, rats were exposed to C-IR at a single dose level of 25 Gy, then treated with sildenafil (SD) and/or simvastatin (SV), and fluoxetine (Fx) at doses of 75, 20, 10 mg/kg/day, respectively. The body weight gain and forced swimming test (FST) were used for evaluation along with the biochemical quantifications of KP intermediates and histopathological examination of cortex and hippocampus. The results indicated a significant activation of KP following C-IR as manifested by decreased Trp content and increased activities of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) with a rise in kynurenine (KYN) and quinolinic acid (QA) hippocampal contents. In addition, a state of C-IR-induced oxidative stress, inflammation, NO-pathway dysregulation and neuronal apoptosis were observed as compared to the control group. However, significant modulations were recorded after the combined administration of SD and SV than those offered by each of them alone and by Fx. The biochemical assessment results were supported by the histopathological tissue examination. It could be concluded that the co-administration of SV and SD offers a neuroprotective effect against irradiation-induced brain injury due to its NO donor/BH4 regulatory activities, anti-inflammatory and antioxidant properties that modulate IDO/KYN pathway.

Topics: Animals; Antidepressive Agents, Second-Generation; Apoptosis; Biopterins; Brain; Brain Injuries; Cranial Irradiation; Depression; Fluoxetine; Gamma Rays; Inflammation; Male; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Rats; Signal Transduction; Sildenafil Citrate; Simvastatin

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease linked to insulin resistance, oxidative stress, and cytokine imbalance. Phosphodiesterase (PDE) inhibitors have shown remarkable antioxidant and anti-inflammatory potential in different disease sets including liver diseases. This study aimed to compare the ameliorative effect of different PDE inhibitors on a high-fat diet (HFD)-induced NAFLD. Male Wistar rats were fed a HFD for 16 weeks to induce NAFLD, and then, oral treatments of a vehicle or different PDE inhibitors (pentoxifylline (50 mg/kg), cilostazol (20 mg/kg), or sildenafil (5 mg/kg)) were started in the last four weeks and given on a daily basis. Rats' body composition and liver indices were recorded. Serum levels of liver enzymes, glucose, insulin, bilirubin, total cholesterol, triglycerides, and nitric oxide were measured. Liver tissues were used for histopathological examination and detecting oxidative stress and inflammatory markers. Results showed that different PDE inhibitors exhibited different efficacy against liver injury and metabolic disorders associated with HFD-induced NAFLD in rodents evident by different strength-ameliorated effects on the aforementioned parameters. Compared to cilostazol and sildenafil, insulin resistance, hepatic oxidative stress, and inflammatory markers were significantly reduced by pentoxifylline treatment. Furthermore, pentoxifylline nearly completely reversed hepatocyte steatosis and exhibited superior rectifying effect on the rats' liver status compared with other PDE inhibitors. This investigation highlighted the potential role of PDE inhibitors in NAFLD treatment. Pentoxifylline had the most remarkable ameliorative effects against NAFLD, while sildenafil was the least effective.

Topics: Animals; Antioxidants; Biomarkers; Cilostazol; Diet, High-Fat; Fatty Liver; Inflammation; Insulin; Insulin Resistance; Liver; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Pentoxifylline; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Sildenafil Citrate; Triglycerides

Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies.. A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID-19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin, and/or nutraceuticals that have been published to support immune function including glutathione, vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and "cytokine storm syndrome" with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to "acute respiratory distress syndrome" (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NF-κB and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione with associated anti-viral effects should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID-19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis ind. A three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with ivermectin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NF-κB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.

Topics: Acetazolamide; Anti-Inflammatory Agents; Anticoagulants; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; COVID-19 Testing; Diet Therapy; Humans; Immune System; Inflammation; Ivermectin; Mass Screening; NF-E2-Related Factor 2; NF-kappa B; Pandemics; Pneumonia, Viral; Randomized Controlled Trials as Topic; Resource Allocation; Risk; Sildenafil Citrate; Treatment Outcome

In trying to understand the biochemical mechanism involved in the recent pandemic COVID-19, there is currently growing interest in angiotensin-converting enzyme II (ACE2). Nevertheless, the attempts to counteract COVID-19 interference with this enzymatic cascade are frustrating, and the results have thus far been inconclusive. Let's start again by considering the involved factors in an alternative way: we could postulate that COVID-19 could be more aggressive/fatal due to a high level of "basal" inflammation with low Nitric Oxide (NO) levels in hypertensive, diabetic and obese patients. Interestingly, the "protective" effects of several factors (such as estrogens) may play a role by increasing the formation of endogenous NO. From a therapeutic point of view, phosphodiesterase type 5 inhibitors such as oral Tadalafil, could be used in order to increase the basal NO levels. In this way, we don't fight the virus, but we may be able to mitigate its effects.

Topics: Angiotensin-Converting Enzyme 2; Animals; Betacoronavirus; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Estrogens; Humans; Hypertension; Inflammation; Interleukins; Models, Animal; Models, Biological; Nitric Oxide; Obesity; Off-Label Use; Pandemics; Peptidyl-Dipeptidase A; Phosphodiesterase 5 Inhibitors; Pneumonia, Viral; Receptors, Virus; SARS-CoV-2; Sildenafil Citrate; Tadalafil

High plasma cholesterol levels are able to trigger several pathophysiological events, including inflammation, cell damage and especially oxidative stress. Previously, studies have shown that sildenafil exhibited antioxidant effects in several experimental models. Here we evaluate the role of sildenafil in liver redox equilibrium of apolipoprotein E knockout (apoE-KO) mice.. ApoE-KO mice were divided in two groups: one group received the PDE5 inhibitor sildenafil (40 mg/kg/day) for 3 weeks (apoE-KO + Sil) and was compared to a second group of apoE-KO mice, which received only the vehicle (water) for 3 weeks (apoE-KO). Control group (C57 mice) received only a standard chow diet. At the age of 18 weeks, mice livers were collected for the measurement of intracellular ROS levels and apoptotic cells by flow cytometry analysis, and mitochondria isolation for proteomic analysis.. Compared to the control group, liver cells from apoE-KO presented some typical redox imbalance features: higher levels of intracellular ROS (global oxidative stress ˜60%, superoxide anion ˜82%, and peroxynitrite/hydroxyl radical ˜53%), higher amounts of apoptotic cells (up to ˜19%) and higher mitochondrial intensity of catalase (+339%) and transferrin spots (+914%). After treatment with sildenafil, apoE-KO presented ROS levels and the number of apoptotic cells similar to those observed in C57. In addition, when compared to apoE-KO, apoE-KO + Sil showed lower spots volumes of catalase (-23%) and transferrin (-71%) and up-regulation of urate oxidase (+94%).. The treatment with sildenafil is able to induce beneficial changes in liver mitochondrial protein dynamics, which restores the redox homeostasis contributing to a potential hepatoprotection.

Topics: Animals; Antioxidants; Apolipoproteins E; Atherosclerosis; Catalase; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Mitochondria; Mitochondrial Proteins; Oxidative Stress; Proteomics; Reactive Oxygen Species; Sildenafil Citrate; Superoxides; Triglycerides

Cyclic neucleotides are involved in many cellular functions including smooth muscle relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3',5' cyclic monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma.. Wistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 μg of aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in serum and bronchoalveolar lavage fluid (BALF). The oxidative stress markers malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide metabolites (NO. Pre-treatment with sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) significantly reduced the levels of pro-inflammatory cytokines IL-4 and TNF-α in rat serum and BALF. In addition, pre-treatment with both the drugs decreased the levels of MDA and NO. Sildenafil and tadalafil decreased pro-inflammatory cytokines in serum and BALF. Both drugs inhibit oxidative and nitrosative stress in animal model of bronchial asthma and could have a therapeutic potential in bronchial asthma.

Topics: Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Female; Glutathione; Inflammation; Lung; Male; Malondialdehyde; Nitric Oxide; Nitrosative Stress; Oxidative Stress; Rats; Rats, Wistar; Sildenafil Citrate; Tadalafil

Male infertility prevalence is higher in diabetic patients. Those patients exhibit testicular oxidative damage due to sustained hyperglycemia and inflammation. The study has investigated the efficacy of cilostazol, a phosphodiesterase 3 inhibitor, on testicular damage of diabetic rats.. Streptozotocin-induced diabetes in rats was used as a model. Six control male rats and 24 diabetic male rats were divided into the following: diabetic, cilostazol at low dose, cilostazol at high dose, and sildenafil treated rat groups. Treatment period was 4 weeks. Then, serum testosterone, testicular oxidative parameters, and testicular oxidant defenses were assayed. Real time PCR was done for quantification of Phosphoinositide 3-kinase (PI3K), Akt, and nuclear factor (NF)-κB mRNA. Expression of testicular inducible nitric oxide synthase (iNOS) was assessed.. Diabetes negatively affected the testicular tissue as evident by biochemical analysis and histopathology. Four weeks of cilostazol or sildenafil treatment improved anti-oxidative capacity, ameliorated lipid peroxidation and the pro-inflammatory iNOS expression in testicular tissue. Testosterone level and the spermatogenesis showed marked improvement. Quantitative mRNA expression showed an elevation in PI3K and Akt by cilostazol with decreasing in NF-κB level by both drugs.. Our findings suggest the beneficial role of cilostazol and sildenafil in diabetic testicular damage dependent on anti-inflammatory and anti-oxidant effects.

Topics: Animals; Cilostazol; Diabetes Complications; Diabetes Mellitus, Experimental; Glutathione; Heme Oxygenase (Decyclizing); Hyperglycemia; Infertility, Male; Inflammation; Male; Malondialdehyde; Oxygen; Phosphatidylinositol 3-Kinases; Phosphodiesterase 3 Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Sildenafil Citrate; Streptozocin; Superoxide Dismutase; Testis; Tetrazoles

Objectives Diabetic neuropathy (DN) induces lifetime disability and there is currently no effective therapy to treat or to minimize patients suffering, so it is thereby imperative to develop therapeutic strategies for this disease. Since oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial mechanisms in development and progression of DN, it is important to explore tools by which one can reduce factors related to these pathways. Herein, the understandings of the sildenafil neuroprotective effect through increase of cGMP level and the mediation of oxidative stress, apoptosis, and inflammation pathways on neurotoxicity induced by high glucose (HG) in PC12 cells as an in vitro cellular model for DN were investigated. Methods We reported that the PC12 cells pre-treatment with sildenafil (0.008 μM) for 60 min and then exposing the cells to HG (25 mM for 72 h) or normal glucose (NG) (5 mM for 72 h) condition, show: Results (1) significant attenuation in reactive oxygen species, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, mitochondrial membrane potential, and ATP levels. Conclusion All these data together led us to propose neuroprotective effect of sildenafil is probably through its antioxidant, antiapoptotic, and anti-inflammatory activities. Of course, further studies are required to explain the underlying mechanism of the sildenafil effects.

Topics: Animals; Apoptosis; Cell Survival; Diabetic Neuropathies; Glucose; Inflammation; Lipid Peroxidation; Membrane Potential, Mitochondrial; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Rats; Sildenafil Citrate; Tumor Necrosis Factor-alpha

Topics: Animals; Colonic Neoplasms; Colorectal Neoplasms; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Inflammation; Mice; Mutation; Sildenafil Citrate

The current study aimed to determine the effects of sildenafil-associated aerobic exercise training (ET) on the physical performance, hemodynamic, autonomic and inflammatory parameters of rats. Male Wistar rats were randomly assigned to: sedentary rats placebo-treated (SP); sedentary rats sildenafil-treated (SS); trained rats placebo-treated (TP); and trained rats sildenafil-treated (TS). Sildenafil treatment consisted of 8 weeks of daily oral gavage (1.5 mg/kg), one hour before the session of ET (60-75% of maximal running speed, 5 days/week, for 8 weeks). After ET period, physical capacity, hemodynamic, autonomic and skeletal muscle inflammatory profile were assessed. Chronic sildenafil treatment causes an additional increase of physical capacity in aerobically trained rats. However, these beneficial effects were accompanied by unwanted alterations, as increased of arterial pressure and peripheral sympathetic modulation, as well as exacerbated inflammatory status on skeletal muscle of rats. Taken together, these data suggest the positive and negative effects of sildenafil chronic administration, associated to aerobic ET, at doses used in clinical practice. This report stresses the importance of paying greater attention to the indiscriminate use of this substance in high-performance sports.

Topics: Animals; Autonomic Nervous System; Baroreflex; Body Weight; Hemodynamics; Inflammation; Male; Muscle, Skeletal; Performance-Enhancing Substances; Phosphodiesterase 5 Inhibitors; Physical Conditioning, Animal; Rats, Wistar; Sildenafil Citrate

The erectile dysfunction drug sildenafil has cardiopulmonary protective actions, and a nephroprotective action in cisplatin and ischemia-reperfusion-induced acute kidney injury. Here, we assessed its possible ameliorative action in a model of chronic kidney disease (CKD) using adenine feeding. Eight groups of rats were treated with saline (controls), adenine (0.25% w/w in feed daily for 5 weeks), and oral sildenafil (0.1, 0.5 or 2.5 mg/kg), either alone, or concomitantly with adenine. Urine was collected 24 h after the end of the treatments from all rats and blood pressure measured, followed by collection of blood and kidneys for the measurement of several functional, biochemical and histopathological parameters. Adenine treatment reduced body weight, creatinine renal clearance, and increased water intake and urine output, as well as the plasma concentrations of urea and creatinine, neutrophil gelatinase-associated lipocalin, and N-acetyl-β-D-glucosaminidase activity, and albumin in urine. Adenine also increased the concentrations of the uremic toxins indoxyl sulfate, uric acid and phosphate, and a number of proteins and inflammatory cytokines, and decreased that of several anti - oxidant indices. Renal histopathological markers of damage (inflammation and fibrosis) were significantly increased by adenine. Sildenafil, given simultaneously with adenine, induced a dose - dependent improvements in most of the above parameters, suggesting its possible use as adjunct treatment for CKD in humans.

Topics: Adenine; Animals; Biomarkers; Blood Pressure; Body Weight; Creatinine; Cytokines; Fibrosis; Inflammation; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sildenafil Citrate; Urea

Topics: Animals; Chemoprevention; Colonic Neoplasms; Colorectal Neoplasms; Inflammation; Mice; Sildenafil Citrate

The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM-derived progenitor cells, we induced pulmonary remodelling in rats by two-week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM-derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH-induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH-induced increase in c-kit

Topics: Animals; Blood Gas Analysis; Bone Marrow Cells; Cell Hypoxia; Cyclic GMP; Inflammation; Lung; Male; Muscles; Proto-Oncogene Proteins c-kit; Rats, Sprague-Dawley; Receptors, CXCR4; Sildenafil Citrate; Stem Cells; Vascular Endothelial Growth Factor Receptor-2

Pre-eclampsia (PE), a hypertensive disorder of pregnancy, is detrimental to both mother and foetus. There is currently no effective treatment, but we have shown that Sildenafil Citrate (SC) improve various foetal outcomes in N

Topics: Animals; Biomarkers; Blood Pressure; Disease Models, Animal; Female; Gene Expression Regulation; Inflammation; Interferon-gamma; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sildenafil Citrate; Time Factors; Transforming Growth Factor beta; Uterus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has endothelium protective and angiogenic effects.. To test if sildenafil improves tissue perfusion and neovascularization and downregulates proinflammatory molecules following limb ischemia.. 30 ApoE-/- male mice, bred with cholesterol rich diet for 4 weeks, were anesthetized and underwent unilateral hind-limb ischemia with ligation of the left femoral artery. Mice were randomized in 2 groups: sildenafil (1 mg/Kg for 7 days intraperitoneally, i.p.) or normal saline (0.4 ml for 7 days, i.p.). Bilateral hind-limb perfusion was estimated by laser Doppler imaging after surgery on days 0, 7 and 28.. Sildenafil significantly reduced at day 28 compared with day 0 levels of soluble intracellular adhesion molecule-1(sICAM-1) [2.24(1.81-2.41) vs. 1.29(0.87-1.45) ng/ml, p=0,01], soluble E-selectin (sE-Selectin) [5.52 (3.67-6.14) vs 1.71 (1.42-2.86) ng/ml, p=0.02] and tissue plasminogen activator inhibitor- 1 (tPAI-1) [0.13(0.07-0.21) vs 0.08 (0.04-0.10) ng/ml, p=0.01] while normal saline had no effect on the levels of sICAM-1, sE-Selectin and tPAI-1. Treatment with sildenafil was associated with increased perfusion in the ischemic limb compared with controls.. Sildenafil exerts significant beneficial effects on tissue perfusion and inflammatory status after limb ischemia, a finding implying neovascularization and potential vascular protective properties of sildenafil.

Topics: Angiogenesis Inducing Agents; Animals; Anti-Inflammatory Agents; Atherosclerosis; Blood Flow Velocity; Disease Models, Animal; E-Selectin; Hindlimb; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Ischemia; Male; Mice, Knockout, ApoE; Muscle, Skeletal; Neovascularization, Physiologic; Plasminogen Activator Inhibitor 1; Regional Blood Flow; Sildenafil Citrate; Time Factors

T helper 1 (Th1) type cytokines and chemokines are bioactive mediators in inflammation underling several diseases and co-morbid conditions, such as cardiovascular and metabolic disorders. Th1 chemokine CXCL10 participates in heart damage initiation/progression; cardioprotection has been recently associated with sildenafil, a type 5 phosphodiesterase inhibitor. We aimed to evaluate the effect of sildenafil on CXCL10 in inflammatory conditions associated with diabetic cardiomyopathy. We analyzed: CXCL10 gene and protein in human cardiac, endothelial, and immune cells challenged by pro-inflammatory stimuli with and without sildenafil; serum CXCL10 in diabetic subjects at cardiomyopathy onset, before and after 3 months of treatment with sildenafil vs. placebo. Sildenafil significantly decreased CXCL10 protein secretion (IC50 = 2.6 × 10(-7)) and gene expression in human cardiomyocytes and significantly decreased circulating CXCL10 in subjects with chemokine basal level ≥ 930 pg/ml, the cut-off value as assessed by ROC analysis. In conclusion, sildenafil could be a pharmacologic tool to control CXCL10-associated inflammation in diabetic cardiomyopathy.

Topics: Cells, Cultured; Chemokine CXCL10; Diabetic Cardiomyopathies; Gene Expression; Humans; Inflammation; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Inhaled nitric oxide therapy reaches not only pulmonary vessels, but also other vasculatures, presenting anti-inflammatory effects. Therefore, this study investigated the effects of inhaled nitric oxide on a mice model of carrageenan-induced paw edema. Paw edema was induced in male Swiss mice (20-30 g) by subplantar injection of carrageenan (0.05 ml of a 1% suspension in 0.9% saline). The evaluation of time-course edema (mililiter) was measured by plethysmometry until 12 h following carrageenan administration. Thirty minutes after carrageenan injection, some groups received inhaled nitric oxide (300 ppm at variable doses and times) or Indometacin (INDO 5 mg/Kg, v.o), while others received sildenafil (1 mg/Kg, i.p) or rolipram (3 mg/Kg, i.p.) with or without inhaled nitric oxide. Paws were assessed for edema levels by plethysmometry, mieloperoxidase activity and histological analysis. Inhaled nitric oxide significantly reduced carrageenan-induced paw edema, mieloperoxidase activity and inflammatory infiltrate, although similar results were also observed in sildenafil and rolipram treated groups. In addition, significant effects between inhaled nitric oxide with pharmacological therapy was observed. Inhaled nitric oxide presents anti-inflammatory effects on carrageenan-induce paw edema, as observed through reduced edema, mieloperoxidase activity and neutrophil infiltration, indicating that inhaled nitric oxide therapy goes beyond lung vascular effects.

Topics: Animals; Carrageenan; Edema; Inflammation; Male; Mice; Nitric Oxide; Piperazines; Purines; Rolipram; Sildenafil Citrate; Sulfonamides

Topics: Cytokines; Humans; Impotence, Vasculogenic; Inflammation; Male; Sildenafil Citrate

There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms.. Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GABA and glutamate receptors was analyzed using BS3 cross-linker. Spatial learning was analyzed using the radial and Morris water mazes. To assess if sildenafil reverses the alterations, rats were treated with sildenafil in the drinking water.. PCS rats show increased IL-1β and TNF-α levels and phosphorylation (activity) of p38 in hippocampus. Membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1β and TNF-α levels, p38 phosphorylation, and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning.. Increased IL-1β alters GABAergic and glutamatergic neurotransmission in hippocampus and impairs spatial learning in rats with MHE. Sildenafil reduces neuroinflammation and restores learning. Phosphodiesterase-5 inhibitors may be useful to improve cognitive function in patients with MHE.

Topics: Animals; Hepatic Encephalopathy; Hippocampus; Inflammation; Interleukin-1beta; Macrophage Activation; Male; Maze Learning; Microglia; p38 Mitogen-Activated Protein Kinases; Portacaval Shunt, Surgical; Rats; Rats, Wistar; Receptors, GABA; Receptors, Glutamate; Sildenafil Citrate; Tumor Necrosis Factor-alpha; Vasodilator Agents

The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain.. HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals.. Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination.. Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.

Topics: Animals; Animals, Newborn; Blood Gas Analysis; Blood Pressure; Cell Death; Cerebrovascular Circulation; Cyclic GMP; Functional Laterality; Hypoxia-Ischemia, Brain; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Macrophage Activation; Microcirculation; Motor Activity; Neuroglia; Neuroprotective Agents; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Psychomotor Performance; Purines; Rats; Sildenafil Citrate; Sulfones

Wound healing is a complex process that necessitates organization of different cell types and several signalling molecules. The aim of this study is to evaluate the effect of different concentrations of sildenafil citrate, which decreases cGMP degradation, on wound healing by secondary intention.This study was performed using 25 Sprague Dawley rats weighing 200-250 grams. 4 dorsal defects were created. Four different treatment modalities which were 1% and 5% sildenafil citrate gel prepared with carbopol, pure carbopol gel without any drug in it and 0,9% NaCl solution; were applied to each lesion of the same rat. Randomly selected five rats (25 rats in total) were sacrificed on 3rd, 5th, 7th, 10th, and 14th days; and the effect of each modality was evaluated by means of defect area measurement, histopathological examination and measurement of tissue hydroxyproline levels.Sildenafil citrate gel application decreased the defect areas in a dose independent manner starting from 3rd day and dose dependent manner after 7th day. By means of vascularization, sildenafil citrate increased vascularity starting from 3rd day. The strength of acute inflammation was superior in sildenafil groups starting from 5th day; and the amount and maturation of granulation in the wound bed, as well as the strength of chronic inflammation were superior in defects treated with sildenafil citrate as early as 7th day.

Topics: Acrylic Resins; Administration, Topical; Animals; Collagen; Dose-Response Relationship, Drug; Female; Hydroxyproline; Inflammation; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Time Factors; Treatment Outcome; Wound Healing

Severe burn induces systemic inflammation and reactive oxygen species leading to lipid peroxidation which may play role in remote organs injury. Sildenafil is a selective and potent inhibitor of cyclic guanosine monophosphate specific phosphodiesterase-5. Sildenafil reduces oxidative stress and inflammation in distant organs. The aim of the present study was to evaluate the effects of different dosages of sildenafil in remote organs injury.. A total of thirty-two rats were randomly divided into four equal groups. The groups were designated as follows: Sham, Control, 10, and T20 mg/kg sildenafil treatment groups. Levels of malondialdehyde (MDA), vascular endothelial growth factor (VEGF), VEGF receptor (Flt-1), activities of glutathione peroxidase (Gpx), levels of total antioxidative capacity (TAC), and total oxidant status (TOS) were measured in both tissues and serum, and a semi-quantitative scoring system was used for the evaluation of histopathological findings.. Sildenafil increased levels of Gpx, and Flt-1, and decreased MDA and VEGF levels in tissues. Sildenafil also increased serum levels of TAC and Flt-1 and decreased TOS, OSI, and VEGF.. Sildenafil decreased inflammation scores in remote organs in histopathological evaluation. It has protective effects in severe burn-related remote organ injuries by decreasing oxidative stress and inflammation.

Topics: Animals; Burns; Female; Inflammation; Kidney; Lipid Peroxidation; Liver; Malondialdehyde; Models, Animal; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Soft Tissue Injuries; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vasodilator Agents

We recently demonstrated that sildenafil reduces the expression of cytokines, COX-2, and GFAP in a demyelinating model induced in wild-type (WT) mice. Herein, the understandings of the neuroprotective effect of sildenafil and the mediation of iNOS/NO system on inflammatory demyelination induced by cuprizone were investigated. The cerebella of iNOS(-/-) mice were examined after four weeks of treatment with cuprizone alone or combined with sildenafil. Cuprizone increased GFAP, Iba-1, TNF- α , COX-2, IL-1 β , and IFN- γ expression, decreased expression of glutathione S-transferase pi (GSTpi), and damaged myelin in iNOS(-/-) mice. Sildenafil reduced Iba-1, IFN- γ , and IL-1 β levels but had no effect on the expression of GFAP, TNF- α , and COX-2 compared to the cuprizone group. Sildenafil elevated GSTpi levels and improved the myelin structure/ultrastructure. iNOS(-/-) mice suffered from severe inflammation following treatment with cuprizone, while WT mice had milder inflammation, as found in the previous study. It is possible that inflammatory regulation through iNOS-feedback is absent in iNOS(-/-) mice, making them more susceptible to inflammation. Sildenafil has at least a partial anti-inflammatory effect through iNOS inhibition, as its effect on iNOS(-/-) mice was limited. Further studies are required to explain the underlying mechanism of the sildenafil effects.

Topics: Animals; Cuprizone; Cyclic GMP; Demyelinating Diseases; Glutathione S-Transferase pi; Inflammation; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Myelin Sheath; Neurons; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Malignant melanoma is known by its rapid progression and poor response to currently applied treatments. Despite the well-documented melanoma immunogenicity, the results of immunotherapeutic clinical trials are not satisfactory. This poor antitumor reactivity is due to the development of chronic inflammation in the tumor microenvironment characterized by infiltrating leukocytes and soluble mediators, which lead to an immunosuppression associated with cancer progression. Using the ret transgenic mouse melanoma model that closely resembles human melanoma, we demonstrated increased levels of chronic inflammatory factors in skin tumors and metastatic lymph nodes, which correlated with tumor progression. Furthermore, Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSC), known to block tumor-reactive T cells, were enriched in melanoma lesions and showed an enhanced immunosuppressive capacity. This MDSC accumulation was associated with a strong TCR ζ-chain downregulation in T cells suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon administration of phosphodiesterase-5 inhibitor sildenafil or paclitaxel in non-cytotoxic doses, we observed reduced levels of chronic inflammatory mediators in association with decreased MDSC amounts and immunosuppressive function. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of beneficial outcome of both drugs, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.

Topics: Animals; CD8-Positive T-Lymphocytes; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Immunosuppression Therapy; Inflammation; Melanoma; Mice; Mice, Knockout; Paclitaxel; Piperazines; Proto-Oncogene Proteins c-ret; Purines; Receptors, Antigen, T-Cell; Sildenafil Citrate; Sulfones; Tumor Microenvironment; ZAP-70 Protein-Tyrosine Kinase

Obesity is characterized by chronic inflammation of adipose tissue, which contributes to insulin resistance and diabetes. Although nitric oxide (NO) signaling has antiinflammatory effects in the vasculature, whether reduced NO contributes to adipose tissue inflammation is unknown. We sought to determine whether (1) obesity induced by high-fat (HF) diet reduces endothelial nitric oxide signaling in adipose tissue, (2) reduced endothelial nitric oxide synthase (eNOS) signaling is sufficient to induce adipose tissue inflammation independent of diet, and (3) increased cGMP signaling can block adipose tissue inflammation induced by HF feeding.. Relative to mice fed a low-fat diet, an HF diet markedly reduced phospho-eNOS and phospho-vasodilator-stimulated phosphoprotein (phospho-VASP), markers of vascular NO signaling. Expression of proinflammatory cytokines was increased in adipose tissue of eNOS-/- mice. Conversely, enhancement of signaling downstream of NO by phosphodiesterase-5 inhibition using sildenafil attenuated HF-induced proinflammatory cytokine expression and the recruitment of macrophages into adipose tissue. Finally, we implicate a role for VASP, a downstream mediator of NO-cGMP signaling in mediating eNOS-induced antiinflammatory effects because VASP-/- mice recapitulated the proinflammatory phenotype displayed by eNOS-/- mice.. These results imply a physiological role for endothelial NO to limit obesity-associated inflammation in adipose tissue and hence identify the NO-cGMP-VASP pathway as a potential therapeutic target in the treatment of diabetes.

Topics: Adipose Tissue; Animals; Cell Adhesion Molecules; Cyclic GMP; Dietary Fats; Disease Models, Animal; Endothelium, Vascular; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Phosphodiesterase 5 Inhibitors; Phosphoproteins; Phosphorylation; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones

Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.

Topics: Animals; Cell Proliferation; Humans; Immune Tolerance; Inflammation; Lymphatic Metastasis; Lymphatic System; Lymphocytes, Tumor-Infiltrating; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Phosphodiesterase 5 Inhibitors; Piperazines; Proto-Oncogene Proteins c-ret; Purines; Receptors, Antigen, T-Cell; Sildenafil Citrate; Skin Neoplasms; Sulfones; T-Lymphocytes; Tumor Microenvironment

Sepsis is a systemic inflammatory response to infection and a major cause of morbidity and mortality. Sildenafil (SLD) is a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase PDE5. We aimed to investigate the protective effects of sildenafil on caecal ligation and puncture (CLP)-induced sepsis in rats. Four groups of rats were used, each composed of 10 rats: (i) 10 mg/kg SLD-treated CLP group; (ii) 20 mg/kg SLD-treated CLP group; (iii) CLP group; and (iv) sham-operated control group. A CLP polymicrobial sepsis model was applied to the rats. All groups were killed 16 h later, and lung, kidney and blood samples were analysed histopathologically and biochemically. Sildenafil increased glutathione (GSH) and decreased the activation of myeloperoxidase (MPO) and of lipid peroxidase (LPO) and levels of superoxide dismutase (SOD) in the septic rats. We observed a significant decrease in LPO and MPO and a decrease in SOD activity in the sildenafil-treated CLP rats compared with the sham group. In addition, 20 mg/kg sildenafil treatment in the sham-operated rats improved the biochemical status of lungs and kidneys. Histopathological analysis revealed significant differences in inflammation scores between the sepsis group and the other groups, except the CLP + sildenafil 10 mg/kg group. The CLP + sildenafil 20 mg/kg group had the lowest inflammation score. Sildenafil treatment decreased the serum tumour necrosis factor (TNF)-α level when compared to the CLP group. Our results indicate that sildenafil is a highly protective agent in preventing lung and kidney damage caused by CLP-induced sepsis via maintenance of the oxidant-anti-oxidant status and decrease in the level of TNF-α.

Topics: Animals; Cecal Diseases; Glutathione; Inflammation; Kidney; Lipid Peroxidation; Lung; Lung Injury; Oxidative Stress; Peroxidase; Piperazines; Purines; Rats; Rats, Wistar; Sepsis; Sildenafil Citrate; Sulfones; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Diet-induced obesity (DIO) in mice causes vascular inflammation and insulin resistance that are accompanied by decreased endothelial-derived NO production. We sought to determine whether reduced NO-cGMP signaling contributes to the deleterious effects of DIO on the vasculature and, if so, whether these effects can be blocked by increased vascular NO-cGMP signaling.. By using an established endothelial cell culture model of insulin resistance, exposure to palmitate, 100 micromol/L, for 3 hours induced both cellular inflammation (activation of IKK beta-nuclear factor-kappaB) and impaired insulin signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase pathway. Sensitivity to palmitate-induced endothelial inflammation and insulin resistance was increased when NO signaling was reduced using an endothelial NO synthase inhibitor, whereas endothelial responses to palmitate were blocked by pretreatment with either an NO donor or a cGMP analogue. To investigate whether endogenous NO-cGMP signaling protects against vascular responses to nutrient excess in vivo, adult male mice lacking endothelial NO synthase were studied. As predicted, both vascular inflammation (phosphorylated I kappaB alpha and intercellular adhesion molecule levels) and insulin resistance (phosphorylated Akt [pAkt] and phosphorylated eNOS [peNOS] levels) were increased in endothelial NO synthase(-/-) (eNOS(-/-)) mice, reminiscent of the effect of DIO in wild-type controls. Next, we asked whether the vascular response to DIO in wild-type mice can be reversed by a pharmacological increase of cGMP signaling. C57BL6 mice were either fed a high-fat diet or remained on a low-fat diet for 8 weeks. During the final 2 weeks of the study, mice on each diet received either placebo or the phosphodiesterase-5 inhibitor sildenafil, 10 mg/kg per day orally. In high-fat diet-fed mice, vascular inflammation and insulin resistance were completely prevented by sildenafil administration at a dose that had no effect in mice fed the low-fat diet.. Reduced signaling via the NO-cGMP pathway is a mediator of vascular inflammation and insulin resistance during overnutrition induced by high-fat feeding. Therefore, phosphodiesterase-5, soluble guanylyl cyclase, and other molecules in the NO-cGMP pathway (eg, protein kinase G) constitute potential targets for the treatment of vascular dysfunction in the setting of obesity.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Cell Adhesion Molecules; Cells, Cultured; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dietary Fats; Disease Models, Animal; Down-Regulation; Endothelial Cells; Enzyme Inhibitors; Humans; I-kappa B Kinase; Inflammation; Inflammation Mediators; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Palmitic Acid; Phosphatidylinositol 3-Kinases; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-akt; Purines; Signal Transduction; Sildenafil Citrate; Sulfones

Airway inflammation with mucus overproduction is a distinguishing pathophysiological feature of many chronic respiratory diseases. Phosphodiesterase (PDE) inhibitors have shown anti-inflammatory properties. In the present study, the effect of sildenafil, a potent inhibitor of PDE5 that selectively degrades cyclic guanosine 3',5'-monophosphate (cGMP), on acrolein-induced inflammation and mucus production in rat airways was examined. Rats were exposed to acrolein for 14 and 28 days. Sildenafil or distilled saline was administered intragastrically prior to acrolein exposure. Bronchoalveolar lavage fluid (BALF) was acquired for cell count and the detection of pro-inflammatory cytokine levels. Lung tissue was examined for cGMP content, nitric oxide (NO)-metabolite levels, histopathological lesion scores, goblet cell metaplasia and mucin production. The results suggested that sildenafil pretreatment reversed the significant decline of cGMP content in rat lungs induced by acrolein exposure, and suppressed the increase of lung NO metabolites, the BALF leukocyte influx and pro-inflammatory cytokine release. Moreover, sildenafil pretreatment reduced acrolein-induced Muc5ac mucin synthesis at both mRNA and protein levels, and attenuated airway inflammation, as well as epithelial hyperplasia and metaplasia. In conclusion, sildenafil could attenuate airway inflammation and mucus production in the rat model, possibly through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, and, thus, might have a therapeutic potential for chronic airway diseases.

Topics: Acrolein; Analysis of Variance; Animals; Blotting, Western; Bronchoalveolar Lavage; Cyclic GMP; Cytokines; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Inflammation; Leukocytes; Lung Diseases; Male; Mucins; Nitric Oxide; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones

Morphine can inhibit inflammatory edema in experimental animals. The mechanisms and sites by which opioids exert this effect are still under debate. Since the spinal level is a site for modulation of the neurogenic component of inflammation, we investigated the effect of intrathecal (i.t.) administration of morphine, and the involvement of spinal nitric oxide (NO)/cyclic-guanosine monophosphate-GMP pathway in carrageenan (CG)-induced paw edema.. Male Wistar rats received i.t. injections of drugs (20 microL) 30 min before paw stimulation with CG (150 microg). Edema was measured as paw volume increase (mL), and neutrophil migration was evaluated indirectly by myeloperoxidase (MPO) assay.. Morphine (37, 75, and 150 nmol) inhibited inflammatory edema, but had no effect on MPO activity. Coinjection with naloxone (64 nmol) reversed the effect of morphine. The corticosteroid synthesis inhibitor, aminoglutethimide (50 mg/kg, v.o.), administered 90 min before morphine injection did not modify its antiedematogenic effect. Low doses of the NO synthase inhibitor, N(omega)-nitro-L-arginine (L-NNA; 10 and 30 pmol) increased, while higher doses (3 and 30 nmol) inhibited edema. The guanylate cyclase inhibitor 1H-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 21 and 42 nmol) increased, while the phosphodiesterase type 5 inhibitor sildenafil (0.15 and 1.5 nmol) inhibited paw edema. Coadministration of a subeffective dose of L-NNA (3 pmol) or ODQ (10 nmol) with morphine prevented its antiedematogenic effect, but sildenafil (0.15 nmol) rendered a subeffective dose of morphine effective (18 nmol). ODQ also prevented the antiedematogenic effect of the NO donor S-nitroso-N-acetyl-penicilamine.. These results support the idea that morphine can act on opioid receptors at the spinal level to produce antiedematogenic, and that the NO/cGMP pathway seems to be an important mediator in this effect.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Guanylate Cyclase; Inflammation; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Neutrophil Infiltration; Neutrophils; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroarginine; Oxadiazoles; Peroxidase; Phosphodiesterase Inhibitors; Piperazines; Purines; Quinoxalines; Rats; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; Signal Transduction; Sildenafil Citrate; Spinal Cord; Sulfones; Time Factors

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Formaldehyde; Inflammation; Injections, Spinal; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rats; Rats, Wistar; Rolipram; Sildenafil Citrate; Spinal Cord; Sulfones