Investigation of CYP2E1 and Caspase-3 Gene Expressions in COVID-19 patients.

BACKGROUND: COVID-19 pandemic spread around the world like an infectious disease that presents waved effects on patients. Some patients needed ICU and respiratory support. Some patients only had flu-like symptoms. Cytokine storm and elevated ROS were serious problems for treatment. Apoptotic genes and CYP Family are part of these mechanisms. AIM: In this study, our aim was to examine the gene expression CYP2E1 and Caspase-3 in patients with COVID-19 infection. METHOD: 60 COVID-19(+) patients (ICU and non-ICU patients) and 30 healthy volunteers were enrolled to study. To measure the level of gene expression qPCR was used. The 2-ΔΔCt method was utilized to analyze gene expression. RESULTS: The expression of CYP2E1 and Caspase-3 genes showed a significant discrepancy between patients and healthy individuals. Caspase-3 expression increased (p=0,0041) but CYP2E1 expression decreased (p=0,0214) in COVID-19 patients compared to healthy individuals. Both levels of gene expression were lower in patients with affected lungs than patients with unaffected lungs (p<0,05). Laboratory findings including d-Dimer, LDH, platelet count, lymphocyte count were related to both gene expressions (p<0,05). We found no correlation between CYP2E1 and Caspase-3 expressions. CONCLUSION: The expression of Caspase-3 demonstrated apoptotic situations of patients but was not related to the CYP2E1 expression level. CYP2E1 gene expression is an important actor to metabolize endogens and xenobiotics however, COVID-19 patients demonstrated decreased CYP2E1 expression. CYP2E1 and Caspase-3 gene expression levels may be used as a diagnostic tool for COVID-19 patients.

Effects of umbelliferone isolated from the Ferulago pauciradiata Boiss. & Heldr. Plant on cecal ligation and puncture-induced sepsis model in rats.

Sepsis is a pathophysiological event involving systemic inflammatory response syndrome, multiple organ failure syndromes, and tissue damage. Overproduction of free radicals as a result of tissue damage during sepsis contributes to cellular toxicity, organ failure, and even mortality. Antioxidants, which scavenge free radicals, play a protective role against various diseases. Previous studies have shown that umbelliferone (UF) has antioxidant and anti-inflammatory effects. Since oxidative stress is naturally associated with sepsis-induced organ dysfunction, the application of antioxidant compounds could potentially illuminate the pathophysiology of sepsis, which does not yet have an effective treatment. The sepsis model induced by cecal ligation and puncture (CLP) was applied to rats. Different doses of UF (10░mg/kg, 20░mg/kg, and 40░mg/kg) on oxidant-antioxidant in septic rats, mRNA of inflammatory mediators such as tumor necrosis factor- α (TNF-α) and interleukin (IL)-1 its effects on expression levels were evaluated in lung, kidney, and liver tissues. When the lung, kidney, and liver tissues of septic rats were compared with those of the control group, it was found that UF administration increased dose-dependent superoxide dismutase activity and glutathione levels and significantly decreased malondialdehyde levels. The effects of UF administration on oxidative parameters were dose-dependent. The 40░mg/kg UF dose showed greater anti-oxidative properties than the 20░mg/kg and 10░mg/kg doses for all the evaluated parameters. Further, the TNF- α mRNA expression of the CLP +40░mg/kg group was reduced to a level comparable to that of the control group. UF has been found to be an effective molecule in reducing oxidative stress by supporting endogenous antioxidants and enhancing the scavenging effects of free radicals. The potent antioxidant property of UF may also be related to the suppression of the cytokine cascade during sepsis. The results suggest that UF administration may represent a new treatment for the prevention of lung, kidney and liver damage caused by septic conditions.

The role of 5-HT7 receptors on isoproterenol-induced myocardial infarction in rats with high-fat diet exacerbated coronary endothelial dysfunction.

The presence of 5-HT7r's in both human and rat cardiovascular and immune tissues and their contribution to inflammatory conditions prompted us to hypothesize that these receptors contribute in acute myocardial infarction (MI) with underlying chronic endothelial dysfunction. We investigated the role of 5-HT7 receptors on heart tissue that damaged by isoproterenol (ISO)-induced MI in rats with high-fat diet (HFD). In vitro and in vivo effects of 5-HT7r agonist (LP44) and antagonist (SB269970) have been investigated on the H9C2 cell line and rats, respectively. For in vivo analyses, rats were fed with HFD for 8 weeks and after this period ISO-induced MI model has been applied to rat. To investigate the role of 5-HT7r's, two different doses of LP44 and SB269970 were evaluated and compared with standard hypolipidemic agent, atorvastatin. In vitro studies showed that LP44 has protective and proliferative effects on rat cardiomyocytes. Also in in vivo studies stimulating 5-HT7r's by LP44 improved blood lipid profile (decreased total cholesterol, low-density lipoprotein-C, and triglyceride, increased high-density lipoprotein), decreased cardiac damage markers (creatine kinase and troponin-I), and corrected inflammatory status (tumor necrosis factor-α, interleukin-6). Our results showed significant improvement in LP44 administered rats in terms of histopathologic analyses. In damaged tissues, 5-HT7 mRNA expression increased and agonist administration decreased this elevation significantly. We determined for the first time that 5-HT7r's are overexpressed in ISO-induced MI of rats with underlying HFD-induced endothelial dysfunction. Restoration of this overexpression by LP44, a 5-HT7r agonist, ameliorated heart tissue in physiopathologic, enzymatic, and molecular level, showing the cardiac role of these receptors and suggesting them as future potential therapeutic targets.

Effects of oral zinc administration on long-term ipsilateral and contralateral testes damage after experimental testis ischaemia-reperfusion.

The purpose of this study was to examine potential long-term post-torsion changes that can occur in the histopathology, biochemistry and spermatogenesis of both torsioned and nontorsioned opposite testes. The study also determines the effect of zinc (Zn) administration on the testicular torsion/detorsion (T/D) damage on both testes. Forty-eight male rats, divided equally into eight groups: (SHAM), (SHAM+,Zn+), (T/D+, Zn- 1 month), (T/D+,Zn- 2 months), (T/D+,Zn- 3 months), (T/D+,Zn+ 1 months), (T/D+,Zn+ 2 months), (T/D+,Zn+ 3 months), have been used. Drug administration was carried out by adding 100 µg (0.016 ml/rat) Zn per rat to drinking water in related groups. Testicular damage decreased superoxide dismutase (SOD) and glutathione (GSH) and increased malondialdehyde (MDA) in the testis tissues of rats, while Zn administration increased SOD and GSH and decreased MDA in the testis tissues in comparison with the SHAM group. The beneficial effect of zinc sulphate was more evident on the nonrotated testis than the rotated testis. In the histopathological study, a significant decrease in torsion and detorsion injuries was observed in the treatment groups compared to the torsion and detorsion groups. We found a protective effect of zinc sulphate on oxidative stress as a result of T/D injuries in rats, especially for the nonrotated testis; results were supported histopathologically.

Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats.

To evaluate the protective role of bosentan (BOS), an endothelin-1 (ET-1) receptor antagonist, and to show the changes in rats with experimentally induced diabetic erectile dysfunction (ED), a total of 24 albino Wistar rats were allocated into four groups. Group 1 was the healthy group and Group 2 had diabetes mellitus (DM) induced by intraperitoneal injection of 60 mg kg-1 streptozotocin (STZ). Following the establishment of DM, Group 3 and Group 4 were treated with oral BOS doses of 50 mg kg-1 and 100 mg kg-1 , respectively, for 60 days. At the end of the treatment, we evaluated yawning and erection response to apomorphine treatment and then the animals were sacrificed. ET-1, eNOS, iNOS, tumour necrosis factor (TNF)-α, ET-RA and ET-RB mRNA expressions were analysed in cavernosal tissue. It was observed that yawning and erection response decreased in the diabetic group; however, both of these improved with BOS treatment. While ET-1, TNF-α and iNOS gene expressions increased, eNOS, ET-RA and ET-RB gene expressions decreased in the DM group compared to the healthy group. DM has a negative impact on cavernosal tissue blood flow through activating vasoconstrictor mediators in cavernosal tissue. BOS regulates significantly eNOS, iNOS and TNF-α expressions in a dose-dependent manner.

Anti-inflammatory and anti-oxidative effects of alpha-lipoic acid in experimentally induced acute otitis media.

OBJECTIVES: To investigate the anti-inflammatory, anti-oxidative and tissue protective effects, as well as the potential therapeutic role, of alpha-lipoic acid in experimentally induced acute otitis media. METHODS: Twenty-five guinea pigs were assigned to one of five groups: a control (non-otitis) group, and otitis-induced groups treated with saline, penicillin G, alpha-lipoic acid, or alpha-lipoic acid plus penicillin G. Tissue samples were histologically analysed, and oxidative parameters in tissue samples were measured and compared between groups. RESULTS: The epithelial integrity was better preserved, and histological signs of inflammation and secretory metaplasia were decreased, in all groups compared to the saline treated otitis group. In the alpha-lipoic acid plus penicillin G treated otitis group, epithelial integrity was well preserved and histological findings of inflammation were significantly decreased compared to the saline, penicillin G and alpha-lipoic acid treated otitis groups. The most favourable oxidative parameters were observed in the control group, followed by the alpha-lipoic acid plus penicillin G treated otitis group. CONCLUSION: Alpha-lipoic acid, with its antioxidant, anti-inflammatory and tissue protective properties, may decrease the clinical sequelae and morbidity associated with acute otitis media.

The role of endothelin-1 and endothelin receptor antagonists in allergic rhinitis inflammation: ovalbumin-induced rat model.

OBJECTIVE: Desloratadine is a biologically active metabolite of loratadine which is indicated for the treatment of allergic rhinitis. Bosentan is a dual endothelin receptor antagonist used to treatment of pulmonary artery hypertension (PAH). In this study, we aimed to determine the role of endothelins in allergic rhinitis (AR) and the effects of endothelin receptor antagonists in AR rat models through comparison with desloratadine. METHODS: In total, 20 adult Sprague-Dawley rats were used in this study. An ovalbumin-induced allergic rhinitis model was formed in three study groups except for the control group. Bosentan (100 mg/kg/day) was given to the bosentan-treated group for 7 days and desloratadine (10 mg/kg/day) was administered to the antihistaminic-treated group for 7 days. Nasal symptom scorings and histopathological examinations of the nasal tissues were carried out. Serum IgE levels and ET-1 and TNF-alpha mRNA expression levels were analysed. Between group comparisons for nasal symptoms, histopathological analysis, and molecular analyses were performed with a one-way ANOVA and Duncans multiple comparison tests. Significance was accepted at p smaller than 0.05. RESULTS: Bosentan inhibited nasal symptom more significantly than desloratadine. The IgE level, ET-1 and TNF-alpha mRNA expression levels statistically increased in the allergic rhinitis group when compared to other groups. Conversely, the bosentan-treatment group showed a significant recovery from the same parameters. The deterioration in histopathological parameters reached the highest levels in the allergic rhinitis group. The histopathological findings were close to those of the control group in the bosentan and antihistaminic-treated group. CONCLUSIONS: ET-1 is one of the mediators that impact AR development and ET-1 antagonists can be useful for symptom control and for decreasing allergic inflammation in AR patients.

The protective effects of carvacrol and thymol against paracetamol-induced toxicity on human hepatocellular carcinoma cell lines (HepG2).

Acetaminophen (APAP) overdose could induce liver damage and lead to acute liver failure. The treatment of APAP overdoses could be improved by new therapeutic strategies. Thymus spp., which has many beneficial effects and has been used in folk medicine, is one such potential strategy. In the present study, the hepatoprotective activity of the main constituents of Thymus spp., carvacrol and thymol, were evaluated in light of APAP-induced hepatotoxicity. We hoped to understand the hepatoprotective mechanism of these agents on the antioxidant system and pro-inflammatory cytokines in vitro. Dose-dependent effects of thymol and carvacrol (25, 50, and 100 µM) were tested on cultured HepG2 cells. N-Acetylcysteine (NAC) was tested as positive control. We showed that APAP inhibited HepG2 cell growth by inducing inflammation and oxidative stress. Incubating APAP-exposed HepG2 cells with carvacrol and thymol for 24 h ameliorated this inflammation and oxidative stress. We also evaluated alanine transaminase and lactate dehydrogenase levels of HepG2 cells. We found that thymol and carvacrol protected against APAP-induced toxicity in HepG2 cells by increasing antioxidant activity and reducing pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin 1ß. Taking together high-dose thymol and carvacrol treatment has an effect close to NAC treatment in APAP toxicity, but thymol has better treatment effect than carvacrol.

Effects of amlodipine on ischaemia/reperfusion injury in the rat testis.

The aim of this study was to examine the effects of amlodipine (AML) in rat testicular torsion/detorsion damage. In this study, rats were divided into eight groups: (i) sham; (ii) testicular ischaemia, 2 h of ischaemia; (iii) testicular ischaemia/reperfusion (I/R), 2 h of ischaemia followed by 2 h of reperfusion; (iv) ischaemia + AML (5 mg kg(-1)) administered 30 min before ischaemia; (v) ischaemia + AML (10 mg kg(-1)) administered 30 min before ischaemia; (vi) and (vii) I/R + AML (5 mg kg(-1)) and I/R + AML (10 mg kg(-1)) administered 1.5 h after the induction of ischaemia, respectively, and at the end of a 2-h ischaemia period and a 2-h reperfusion period applied; and (viii) sham + AML (10 mg kg(-1)). Significant decreases in levels of superoxide dismutase and glutathione were observed in ischaemia and reperfusion groups when compared with healthy controls. These antioxidant levels increased in AML groups while malondialdehyde levels significantly decreased. While increases in tumour necrosis factor-alpha and transforming growth factor-beta levels were found in the torsion and detorsion groups, significant decreases in the levels of these inflammatory cytokines were observed in the treatment groups. These results demonstrate that AML significantly produced protective effects on testis tissue damage that occurs in the torsion/detorsion model via biochemical, histopathological and molecular pathways.

Comparative study on effects of nebulized and oral salbutamol on a cecal ligation and puncture-induced sepsis model in rats.

AIM: The present study aimed to compare the effects of different routes of salbutamol administration (oral and nebulized) at different doses in a cecal ligation and puncture-induced (CLP-induced) sepsis model of rats. METHODS: Rats were separated into 8 groups: 1) sham, 2) sham+4 mg/kg oral salbutamol, 3) sham+6 min 2 mg/ml nebulized salbutamol, 4) CLP, 5) CLP+2 mg/kg oral salbutamol, 6) CLP+4 mg/kg oral salbutamol, 7) CLP+3 min 2 mg/ml nebulized salbutamol, 8) CLP+6 min 2 mg/ml nebulized salbutamol. Subsequently, sepsis was induced by CLP through 16 h. RESULTS: CLP-induced sepsis increased serum cytokine levels (TNF-α, IL-1ß, and IL-6), increased tissue oxidative stress (8-Isoprosraglandin F2α), decreased antioxidant parameters (SOD, GSH), and increased lung injury by inflammatory cell accumulation. CONCLUSION: This study showed for the first time that oral administration of salbutamol exerted protective effects on CLP-induced sepsis and related lung injury in rats. We conclude that despite the greater side effects of oral salbutamol, it should be considered for administration in oral form due to its systemic effectiveness during septic conditions in emergency settings.

Blockade of endothelin receptors with bosentan limits ischaemia/reperfusion-induced injury in rat ovaries.

OBJECTIVE: To investigate the role of endothelin receptors in ovarian ischaemia/reperfusion (I/R) injury in rats using the endothelin receptor antagonist bosentan. STUDY DESIGN: Group 1: sham operation; Group 2: sham operation and bosentan 60 mg/kg; Group 3: bilateral ovarian ischaemia; Group 4: 3-h period of ischaemia followed by 3h of reperfusion; Groups 5 and 6: bosentan 30 and 60 mg/kg, respectively, with bilateral ovarian ischaemia applied 30 min later; the bilateral ovaries were removed after 3h of ischaemia; Groups 7 and 8: 3h of bilateral ovarian ischaemia was applied, with bosentan 30 and 60 mg/kg, respectively, administered 2.5h after the induction of ischaemia; following the 3-h period of ischaemia, 3h of reperfusion was applied, after which the ovaries were removed. RESULTS: Ischaemia and I/R decreased superoxide dismutase (SOD) activity and the level of glutathione (GSH) in ovarian tissue, but increased the level of malondialdehyde (MDA) significantly compared with the sham operation group. Bosentan 30 and 60 mg/kg before ischaemia and I/R decreased the MDA level and increased SOD activity and the GSH level in the experimental groups. The serum levels of the inflammatory cytokines interleukin (IL)-1ß, IL-6 and tumour necrosis factor-α were also measured in the I/R injury model in rat ovaries. The levels of these cytokines were significantly higher in the ischaemia and I/R groups compared with the sham operation and sham operation plus bosentan groups. The histopathological findings also demonstrated the protective role of bosentan against I/R-induced injury in rat ovaries. CONCLUSION: Administration of bosentan protects the ovaries against oxidative damage and I/R-induced injury.

Agomelatine: an antidepressant with new potent hepatoprotective effects on paracetamol-induced liver damage in rats.

Paracetamol was shown to induce hepatotoxicity or more severe fatal acute hepatic damage. Agomelatine, commonly known as melatonin receptor agonist, is a new antidepressant, which resynchronizes circadian rhythms with subjective and objective improvements in sleep quality and architecture, as melatonin does. In the present study, it was aimed to evaluate the hepatoprotective activity of agomelatine on paracetamol-induced hepatotoxicity and to understand the relationship between the hepatoprotective mechanism of agomelatine and antioxidant system and proinflammatory cytokines. A total of 42 rats were divided into 7 groups as each composed of 6 rats: (1) intact, (2) 40 mg/kg agomelatine, (3) 140 mg/kg N-acetylcysteine (NAC), (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 20 mg/kg agomelatine, and (7) 2 g/kg paracetamol + 40 mg/kg agomelatine groups. Paracetamol-induced hepatotoxicity was applied and liver and blood samples were analyzed histopathologically and biochemically. There were statistically significant increases in the activities of aspartate aminotransferase, alanine aminotransferase, levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and 8-iso-prostane, and decreases in the activity of superoxide dismutase and level of glutathione in the group treated with paracetamol. Administration of agomelatine and NAC separately reversed these changes significantly. In conclusion, agomelatine administration protects liver cells from paracetamol-induced hepatotoxicity via antioxidant activity and reduced proinflammatory cytokines, such as TNF-α and IL-6.

Prevention of bone loss by Panax ginseng in a rat model of inflammation-induced bone loss.

This study evaluated the protective effect of Panax Ginseng (PG) on bone metabolism in an experimental ovariectomy (OVX) model of osteoporosis in which inflammation was induced by subcutaneous magnesium silicate. The groups were: sham control (Group1, SH), sham+inflammation (Group2, SHinf), OVX (Group3), OVX+inflammation (Group4, OVXinf), OVX+inflammation+PG 100 mg/kg (Group5, OVXinf+PG1), OVX+inflammation+PG 200 mg/kg (Group6, OVXinf+PG2), OVX+PG 100 mg/kg (Group7, OVX+PG1), OVX+PG 200 mg/kg (Group8, OVX+PG1). After the OVX surgery, all the groups were allowed to recover for two months. On the 59th day after the OVX, inflammation was induced in Groups 2, 4, 5, and 6 by subcutaneous injections of magnesium silicate in the back of the animals. Groups 5 and 7 were administered oral PG 100 mg/kg, and Groups 6 and 8 were administered oral PG 200 mg/kg from the 60th to the 80th day. PG 200 mg/kg was able to restore BMD, up to values measured in both the OVX and the SH animals. The levels of OC and OP decreased in OVXinf+PG1 and OVXinf+PG2 groups. The serum levels of TNF­α, IL­1ß, and IL­6 were increased significantly in the OVXinf rats compared with the SH group. The present data showed that PG protected against in the OVX model and in inflammation-induced bone loss rat model.

Effects of diabetes and ovariectomy on rat hippocampus (a biochemical and stereological study).

Oxidative stress is one of the main reasons of both menopause and diabetes. So, it plays crucial role in the pathogeneses of that condition and disease. Therefore, the objective of the present study was to investigate the effects of menopause and diabetes upon the hippocampus using a rat model. Adult female Sprague Dawley rats (n = 24) were allocated randomly as follows; control (C group) ovariectomized (O group), diabetic (D group) and ovariectomy plus diabetic groups (DO group) (n = 6; in each group), respectively. For evaluating the results, tissue biochemistry and stereological analysis were made. Biochemistry results (lipid peroxidase (LPO); catalase (CAT); superoxide dismutase (SOD); total glutatyon (GSH); and myeloperoxidase (MPO) values) in Group C-DO were determined as 12.27, 21.88, 23.08 and 29.90 nmol/gr tissue; 59.3, 70.06, 69.7 and 78.1 mmol/min/mg tissue; 174.2, 156.4, 159.7 and 154.6 mmol/min/mg tissue; 3.63, 3.61, 4.21 and 3.97 nmol/mg tissue; and 5.05, 5.68, 5.58 and 6.19 µmol/min/mg tissue, respectively. Moreover, both menopause and diabetes led to change of lipid profiles. There were significant differences between the control and other groups (Group C and D-DO) (p < 0.01) and among experimental groups (p < 0.01) in terms of neuron number. When the volumes of the hippocampus were compared, there were no significant differences between the all groups (P > 0.05). At this point, we suggested that diabetes could aggravate deleterious effects of ovariectomy.

The role of oxidative stress in diabetic cardiomyopathy: an experimental study.

BACKGROUND: Diabetes mellitus (DM) has a negative effect on cardiovascular functions. Little, however, is known of the overall effect of DM on the cardiac histology or the pathophysiological basis of this. AIM: We aimed to investigate the role of oxidative stress on the pathogenesis of diabetic cardiomyopathy in an experimental model. MATERIALS AND METHODS: 12 week-old female Sprague Dawley rats were randomly allocated into a healthy control group (n=6) and an DM group (n=6). After 12 weeks of alloxan induced DM, the groups' cardiac tissues were histopathologically analyzed and examined for determination of oxidant and antioxidant enzymes [activities of catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) and amount of reduced glutathione (GSH) and lipid peroxidation (LPO)]. RESULTS: When compared to the control group, the DM group showed cardiomyopathic changes. In the DM group, activities of CAT (144 +/- 0.9 vs. 112 +/- 1.4, p < 0.05) and LPO amount (27.0 +/- 0.74 vs. 14.4 +/- 0, 20, p < 0.05) were significantly increased whereas activities of SOD (142 +/- 0.2 vs. 146 +/- 0.7, p < 0.05) and amount of GSH (3.48 +/- 0.01 vs. 3.73 +/- 0.01, p < 0.05) were significantly decreased when compared to the control group. Besides, activities of MPO (7.3 +/- 0.02 vs. 8.6 +/- 0.11, p < 0.05) were comparable between groups. CONCLUSIONS: Using the experimental animal model, we were able to demonstrate that DM causes cardiomyopathic changes, and we propose that these changes could be mediated by an oxidative stress.

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study.

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.

Relation of adrenergic receptors, which have roles in gastroprotective and anti-inflammatory effect of adrenal gland hormones, with cyclooxygenase enzyme levels in rats.

BACKGROUND AND AIMS: COX-2 enzyme inhibition is responsible for the anti-inflammatory effects of NSAIDs, COX-1 for their effects upon the gastrointestinal system (GIS), along with other side effects. We investigated the relationship between COX levels and those adrenergic receptors known to play a role in gastroprotection and anti-inflammatory activity. METHOD: The effects of adrenaline and prednisolone on gastric COX-1 and COX-2 levels in both intact and adrenalectomized rats treated with doxazosin, yohimbine, propranolol, and metoprolol were determined. RESULTS: We found that adrenaline increases COX-1 levels in the gastric tissue of both intact and adrenalectomized rats by stimulating alpha-2 receptors. Adrenaline decreases COX-2 levels by stimulating beta-2 adrenergic receptors. Prednisolone inhibits both COX-1 and COX-2 in the gastric tissue of intact rats. In adrenalectomized rats, prednisolone increases gastric COX-1 by stimulating alpha-2 receptors, and decreases COX-2 levels by stimulating beta-2 receptors. CONCLUSION: Prednisolone cannot bind to a adrenergic receptors in the presence of adrenaline (intact rats) but, in its absence (adrenalectomy), binds to alpha-2 receptors, and stimulates them more effectively than adrenaline, suggesting a direct relationship between alpha-2 adrenergic receptors and COX-1 levels, whereas beta-2 receptors are directly related to COX-2 levels.

Nimesulide is a selective COX-2 inhibitory, atypical non-steroidal anti-inflammatory drug.

In this review it is shown that nimesulide, a selective cyclooxigenase-2 (COX-2) inhibitor, is different from other selective COX-2 inhibitors and classical non-steroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory effect mechanism of nimesulide (inhibition of inflammatory mediators) is similar to other classic NSAIDs, but the protective effect of nimesulide on classic NSAID-induced ulcers elucidates the difference between nimesulide and these other drugs. It is known that the selective COX-2 inhibitor nimesulide prevents NSAID-induced ulcers, while celecoxib and rofecoxib, which are more selective to COX-2, failed to prevent these ulcers. Nimesulide produces gastro-protective effects via a completely different mechanism. In addition, while selective COX-2 inhibitors increase the risk for cardiovascular diseases, nimesulide does not exert significant cardiotoxicity. This data suggests that gastrointestinal side effects of classic NSAIDs cannot be related to the COX-1 inhibition alone and also suggest that nimesulide is an atypical NSAID, which is different from both non-selective and selective COX-2 inhibitors.

Indirect role of beta2-adrenergic receptors in the mechanism of anti-inflammatory action of NSAIDS.

In this study we investigated both intact and adrenalectomized rats to determine whether or not the anti-inflammatory effects of indomethacin, diclofenac sodium, ibuprofen, nimesulide, tenoxicam and aspirin (IDINTA) are related to adrenal gland hormones in carrageenan-induced inflammation model of rats. Also, we investigated the anti-inflammatory action mechanism of hormones (adrenalin, cortisol) which perform a role in the anti-inflammatory effect of IDINTAon the adrenergic receptors. he results show that IDINTA produces significant anti-inflammatory effects in intact rats (ID(50): 9.82, 10.81, 95.21, 75.23, 8.21 and 61.84 mg/kg), but insignificant effects in adrenalectomized rats (ID(50): 152.97, 188.17, 1275.0, 433.67, 188.16 and 1028.17 mg/kg). In addition, adrenalin and prednisolone caused anti-inflammatory effect rates of 78.3% and 95.7% respectively in adrenalectomized rats. The anti-inflammatory effects of adrenalin and prednisolone did not change when prazosin (alpha(1)-receptor blocker), yohimbine (alpha(2)a2-receptor blocker) and phenoxybenzamine (alpha(2)- and alpha(2)-receptor blocker) were given to rat groups; however, in adrenalectomized rats administered with propranolol (a non-selective blocker of beta(1) and beta(2)-receptors) the anti-inflammatory effect of adrenalin was lost, and that of prednisolone decreased to 36.2%. It was also found that metoprolol (a selective blocker of beta(1)-receptors) did not alter the anti-inflammatory effects of the drugs. As a result, it was shown that anti-inflammatory effects of IDINTA are related to adrenalin and cortisol (corticosterone in rats). It was also determined for the first time that adrenalin (totally) and prednisolone (partially) triggered anti-inflammatory effects via the beta(2)-receptors but not via the alpha(1), alpha(2) and beta(1)-receptors.

Gastroprotective and antioxidant effects of amiodarone on indomethacin-induced gastric ulcers in rats.

Reactive oxygen species (ROS) have been implicated in the etiology of indomethacin-induced gastric mucosal damage. This study investigated amiodarone's protective effects against oxidative gastric mucosal damage induced by indomethacin. Amiodarone is a widely used antiarrhythmic agent. We have investigated alterations in the glutathione level, and the activities of antioxidative enzymes [superoxide dismutase, catalase, glutathione s-transferase glutathione reductase and myeloperoxidase], as markers for ulceration process following oral administration of amiodarone and ranitidine in rats with indomethacin-induced ulcers. In the present study we found that 1) amiodarone, lansoprazole and ranitidine reduced the development of indomethacin-induced gastric damages, at a greater magnitude for amiodarone and lansoprazole than for ranitidine; 2) amiodarone and ranitidine alleviated increases in the activities of catalase and glutathione s-transferase enzymes resulting from ulcers; 3) amiodarone and ranitidine ameliorated depressions in the glutathione level and the activities of superoxide dismutase and glutathione reductase enzymes caused by indomethacin administration; and 4) all doses of amiodarone amplified the myeloperoxidase activity resulting from indomethacin-induced gastric ulcers. The results indicate that the gastroprotective activity of amiodarone, which may be linked to its intrinsic antioxidant properties, cannot be attributed to its effect on myeloperoxidase activity.