Enhanced anti-ulcer effect of pioglitazone on gastric ulcers in cirrhotic rats: The role of nitric oxide and IL-1β

BackgroundThe frequency of gastrointestinal ulcerations is higher in cirrhotic patients than in the normal population. It has been shown that pioglitazone exhibits gastroprotective actions. This study was designed to investigate the effect of pioglitazone, on the gastric mucosal lesions in cirrhotic rats.MethodsDifferent groups of bile duct-ligated and sham animals received solvent, or 5, 10 or 15 mg/kg pioglitazone, for 5 days in the last days of 28-day period of cirrhosis. On day 28, rats were killed 1 h after oral ethanol administration and the area of gastric lesions was measured. The serum of rats was also collected to evaluate serum concentrations of TNF-α and IL-1β. Histopathologic examination of liver specimens was also done with hematoxylin-eosin to show possible toxicity of pioglitazone in cirrhosis.ResultsPretreatment with pioglitazone dose dependently attenuated gastric lesions induced by ethanol in both sham and cirrhotic rats, but this effect was more prominent in cirrhotic ones. L-NAME, a non-selective inhibitor of nitric oxide synthase, decreased pioglitazone-induced gastric healing effect in cirrhotic rats, while aminoguanidine, a selective inducible nitric oxide synthase inhibitor, increased pioglitazone-induced gastric healing effect in the same group. The protective effect of pioglitazone was accompanied by a fall in serum IL-1β level.ConclusionsChronic treatment with pioglitazone exerts a more prominent gastroprotective effect on the stomach ulcers of cirrhotic rats compared to control group probably due to constitutive nitric oxide synthase induction or inducible nitric oxide synthase inhibition. Suppression of IL-1β could be another mechanism in pioglitazone-induced healing effect of gastric ulcers in cirrhotic rats.     

Protective effect of cordycepin-enriched Cordyceps militaris on alcoholic hepatotoxicity in Sprague–Dawley rats

This study was to investigate the protective effect of cordycepin-enriched Cordyceps militaris against alcohol-induced hepatotoxicity in Sprague–Dawley rats. Alcohol-feeding rats were fed diets with Paecilomyces japonica as CPJ group, C. militaris as CCM group, cordycepin-enriched C. militaris as CCMα group at the 3% (w/w) level and silymarin at the 0.1% (w/w) level for 4 weeks. Alcohol administration resulted in a significant increase in the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) and the levels of blood alcohol and acetaldehyde in serum. However, CCMα group markedly prevented from alcohol-induced elevation of these parameters in serum. CCMα group showed the increased both hepatic activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Unlike the action of alcohol treatment on alcoholic fatty liver, CCMα group was also attenuated lipid droplet accumulation in the hepatocytes. Present study was also confirmed the beneficial roles of silymarin (hepatoprotective agent) against alcohol-induced liver injury in rats. Therefore, cordycepin-enriched C. militaris can be a promising candidate to prevent from alcohol-induced hepatotoxicity.     

Valproic acid prevents the deregulation of lipid metabolism and renal renin–angiotensin system in l-NAME induced nitric oxide deficient hypertensive rats

The present study was aimed to investigate the antihyperlipidemic and renoprotective potential of valproic acid against N^ω-nitro-l arginine methyl ester hydrochloride (l-NAME) induced hypertension in male albino Wistar rats. In hypertensive rats, mean arterial pressure (MAP), kidney weight, levels of oxidative stress markers in tissues were increased. Dyslipidemia was also observed in hypertensive rats. Moreover, enzymatic and nonenzymatic antioxidant network also deregulated in tissues. Valproic acid (VPA) supplementation daily for four weeks brought back all the above parameters to near normal level and showed no toxicity which was established using serum hepatic marker enzyme activities and renal function markers. Moreover the up regulated expression of renin–angiotensin system (RAS) components were also attenuated by VPA treatment. All the above outcomes were confirmed by the histopathological examination. These results suggest that VPA has enough potential to attenuate hypertension, dyslipidemia and renal damage in nitric oxide deficiency induced hypertension.     

Influence of nitric oxide on the cardiovascular action of secretin in intact rats. Part A. Does nitric oxide influence the effect of secretin on arterial blood pressure?

The present study aimed to determine the influence of nitric oxide (NO) on the action of secretin in the cardiovascular system in intact rats. The studies involved the in vivo measurements of the systolic (SBP) and diastolic (DBP) blood pressure. The measurements were conducted when NO was absent, which was attained by the use of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), and when NO was in excess which was obtained by the administration of L-arginine (L-arg), the substrate for NO synthase or exogenous donor of NO, sodium nitroprusside (SNP). Secretin given at the following three doses: 0.75, 1.5 and 3.0 micromoles/kg iv increased SBP and DBP. L-NAME inhibited the slight hypertensive effect of secretin. L-arg abolished the hypertensive effect of the peptide given at the smallest dose, did not change the effect of secretin administered at the medium dose (which did not raise the pressure) and preserved the action of the highest secretin dose. SNP abolished the hypertensive effect of all doses of the peptide. In conclusion, the study has shown that both the lack and excess of NO change the in vivo effect of secretin in intact rats.     

Influence of nitric oxide on the cardiovascular action of secretin in intact rats. Part B. Does nitric oxide influence the effect of secretin on isolated heart function?

The present study was designed to examine the effect of absence or excess of NO on secretin-mediated responses in the isolated heart. This problem was investigated using the modified Langendorff's method. Secretin administered at two higher doses increased the cardiac contraction amplitude (p < 0.05), but did not change the heart rate and coronary outflow. NO was depleted from experimental system by perfusion of the isolated heart with NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester) at 10 microM. It caused a significant decrease in coronary outflow (p < 0.01) and the tendency to bradycardia (p > 0.05) with no change in cardiac contraction amplitude. L-NAME abolished the positive inotropic effect of the medium secretin dose and preserved the inotropic effect of the highest dose of the peptide. It reversed the tendency to decrease coronary outflow induced by secretin (and L-NAME) given separately. To study the effect of NO excess, we applied the substrate for NO synthesis, amino acid L-arginine (L-arg) (100 microM) or exogenous donor of NO--sodium nitroprusside (SNP) (100 microM). Both substances did not affect the isolated heart function. L-arg did not change the effect of secretin, however it abolished non significant decrease in coronary outflow evoked by the highest dose of secretin. SNP preserved the positive inotropic action of the peptide and expressively reversed the negative values of coronary outflow observed after its co-administration with the highest dose of secretin. These results indicate that both the absence and excess of NO change the cardiac effect of secretin in the same direction.     

Interleukin-1β-induced nitric oxide synthesis in aortic rings from normal and hyperinsulinaemic rats: effect of physical exercise

Insulin has been suggested to prevent the induction of nitric oxide synthase (NOS) in vitro in arterial smooth muscle, but whether such a mechanism is operative in vivo is not known. Therefore, we evaluated the sensitivity of smooth muscle NOS to induction by interleukin-1β (IL-1β) in aortic rings of lean and obese Zucker rats, a model of experimental hyperinsulinaemia. In order to modulate the insulin and glucose balance of the rats, a 22-week-long treadmill exercise was included in the study. The training attenuated weight gain and reduced blood glucose in the obese and lean rats, whereas the abnormally high plasma insulin of the obese rats remained unaffected. A 6-h incubation of aortic rings with IL-1β (10 ng/ml) increased cyclic GMP in smooth muscle by approximately threefold in all groups, and this effect was prevented by methylene blue. The contractile sensitivity of endothelium-denuded aortic rings to phenylephrine was reduced by incubation with IL-1β (1 ng/ml and 10 ng/ml) in the exercised obese and lean rats, whereas no significant change was observed in the sedentary groups. The aortic maximal contractile force induced by phenylephrine was reduced in sedentary and exercised obese rats by incubation with IL-1β, while no change was detected in the lean rats. The aortic relaxation to exogenous L-arginine was augmented by IL-1β in all groups, while the relaxation sensitivity to L-arginine after induction by IL-1β was enhanced by exercise in the obese but not in the lean rats. Finally, the relaxation to nitroprusside was not significantly affected by IL-1β in any of the study groups. In conclusion, since maximal contractile force generation to phenylephrine was reduced by IL-1β in the obese but not in the lean rats, the sensitivity of NOS to induction by IL-1β was higher in arterial smooth muscle of the obese than the lean Zucker rats. Thus, this model of hyperinsulinaemia was not associated with reduced sensitivity of smooth muscle NOS to induction by IL-1β. Regular exercise did not change plasma insulin concentrations, but it enhanced the action of insulin in both strains as reflected by reduced blood glucose, and increased the sensitivity of smooth muscle NOS to induction by IL-1β. Received: 12 October 1998 / Accepted: 14 April 1999 / Published online: 2 July 1999     

Protective effect of L-carnitine and coenzyme Q10 on CCl₄-induced liver injury in rats

This study provides an information about the mechanisms of liver injury induced by CCl(4), and determines the influence of administration of L-carnitine or/and CoQ10 as prophylactic agents against CCl(4) deteriorative effect. The study was carried out on 80 adult male albino rats divided into eight groups, 10 animals each, as follows: four normal groups (control, treated with L-carnitine, treated with CoQ10, and treated with a combination of Lcarnitine and CoQ10) and four liver injury groups treated with CCl(4) (control, treated with L-carnitine, treated with CoQ10, and treated with a combination of L-carnitine and CoQ10). Liver injury was induced by s.c. injection of a single dose of CCl(4) (1 ml/kg). L-carnitine (50 mg/kg/day) was given i.p. for four successive days 24 hours before CCl(4) injection, and CoQ10 (200 mg/kg) was given as a single i.p. dose 24 hours before CCl(4) injection. Animals were sacrificed 24 hours after CCl(4) injection, blood samples were withdrawn and liver tissue samples were homogenized. The levels of the following parameters were determined: hepatic reduced glutathione, serum ALT and AST, hepatic lipid peroxides, hepatic vitamin C, hepatic and serum total protein, serum albumin, serum sialic acid, serum nitrite, and serum and hepatic total LDH activities and LDH isoenzymes. The obtained data revealed that CCl(4) injection produced a significant decrease in reduced glutathione content, vitamin C, total protein and albumin levels. However, there was a significant increase in serum ALT and AST activities, lipid peroxides, sialic acid, nitric oxide, serum and hepatic total LDH activities. On the other hand, groups treated with L-carnitine or/and CoQ10 prior to CCl(4) injection showed an improvement in most parameters when compared with cirrhotic control group. It has been concluded that L-carnitine and coenzyme Q10 have a pronounced prophylactic effect against liver damage induced by halogenated alkanes such as carbon tetrachloride.     

Dimethylarginine dimethylaminohydrolase/nitric oxide synthase pathway in liver and kidney: protective effect of cyanidin 3-O-β-D-glucoside on ochratoxin-A toxicity

The aim of the present study was to evaluate the effect of long-term cyanidin 3-O-β-D-glucoside (C3G) and/or Ochratoxin A (OTA)-exposure on dimethylarginine dimethylamino hydrolase/nitric oxide synthase (DDAH/NOS) pathway in rats. The experiments were performed in rats supplemented with C3G (1 g/kg feed), OTA (200 ppb), and OTA + C3G. After 4 weeks of daily treatment, liver and kidneys were processed for eNOS, iNOS and DDAH-1 Western blotting, nitrite levels evaluation and DDAH activity determination. Results show that OTA is able to induce iNOS both in kidney and liver, whereas OTA is able to induce eNOS and DDAH-1 overexpression and DDAH activation only in kidney, resulting in increased nitrite levels. In kidney of OTA + C3G fed rats, iNOS, eNOS and DDAH-1 expression were less pronounced compared with those observed in the OTA-treated group. Coherent with the decreased iNOS, eNOS and DDAH-1 expression a decrease in nitrite levels and DDAH activity was observed in the OTA + C3G group. Results demonstrate that C3G is able to counteract the deleterious effects of chronic consumption of OTA and also suggest a possible involvement of iNOS-eNOS-DDAH impairment in OTA nephrocarcinogenity.     

Antihypertensive effect of <Emphasis Type="Italic">Melothria maderaspatana</Emphasis> leaf fractions on DOCA-salt-induced hypertensive rats and identification of compounds by GC–MS analysis

The present study was designed to investigate the antihypertensive effect of Melothria maderaspatana leaf fractions on deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats and to identify compounds from the active fraction by GC–MS analysis. Administration of DOCA salt significantly increased the systolic and diastolic blood pressure compared to sham-operated control rats. When treated with chloroform (CFM), ethyl acetate (EAFM) or methanol fractions of M. maderaspatana (MFM), EAFM alone significantly lowered the systolic and diastolic blood pressure. The levels of magnesium and copper significantly increased in plasma and decreased in tissues while the zinc level significantly increased in plasma and tissues, and administration of EAFM brought these parameters back to sham-operated control levels. By GC–MS analysis, phytochemicals such as coumarin, vallinic acid, p-coumaric acid, gallic acid, caffeic acid, and ferulic acid were identified in EAFM. In conclusion, the EAFM controls blood pressure in DOCA-salt hypertensive rats and reverts the metabolic alterations in magnesium, copper and zinc.     

Aminoguanidine – effects on endoneurial vasoactive nitric oxide and on motor nerve conduction velocity in control and streptozotocin-diabetic rats

1. The effects of aminoguanidine (AG) treatment on reductions in motor nerve conduction velocity (MNCV) and sciatic nerve blood flow, indexed by laser Doppler flux (LDF), were investigated in rats with experimental diabetes (streptozotocin-induced; 8–10 weeks duration). The contribution of endoneurial vasoactive nitric oxide to the LDF of these animals was also investigated by the direct micro-injection of N^G-nitro-L-arginine methyl ester (L-NAME; 1 nmol in 1 μl), followed by L-arginine (100 nmol in 1 μl), into the sciatic nerve endoneurium.
2. The MNCV (m s⁻¹, mean±1 s.d.) of diabetic rats (38.2±1.5) was lower (P<0.01) than that of age-matched controls (47.2±4.2). AG treatment (50 mg kg⁻¹ day⁻¹, i.p.) attenuated the diabetes-induced deficits in MNCV (43.4±5.9; P<0.01), but had no effect in controls (48.8±3.8) or, if administered via drinking water (1 g l⁻¹), diabetics (37.4±4.1).
3. L-NAME markedly reduced the resting LDF (arbitrary units; mean±s.e.mean) of controls (209±13 to 120±18; P<0.005), an effect reversed by subsequent L-arginine (to 206±27). In diabetic rats the LDF reduction following L-NAME was much smaller (111±11 to 84±6; P<0.05), but the change with L-arginine was significantly increased (to 145±12; P<0.001).
4. AG treatment increased the resting LDF of control (265±34) and diabetic rats (133±14 for daily injection and 119±13 for drinking water). The responses to L-NAME and L-arginine were not changed markedly by AG treatment. However, L-arginine appeared to be less effective.
5. In conclusion, these data suggest that AG treatment may affect nitric oxide production in the vasa nervorum of peripheral nerves. However, the effects of AG-treatment are not consistent with the prevention of a diabetes-associated reduction in endoneurial nitric oxide production. The mechanisms by which AG attenuates nerve conduction slowing in streptozotocin-diabetic rats therefore remain unclear.

     

Protective effect of fermented sea tangle against ethanol and carbon tetrachloride-induced hepatic damage in Sprague–Dawley rats

Sea tangle has long been used as Korean folk remedy to promote material health, and is one of the popular dietary supplement. This study was designed to evaluate the protective effect of fermented sea tangle (FST) against ethanol and carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Sprague–Dawley rats were orally treated with FST (25, 250, 2500 mg/kg/day) with administration of ethanol (5 mL/kg) for 13 weeks and the single intraperitoneal (i.p.) dose of 50% CCl₄ (5 mL/kg/day, CCl₄ in olive oil) at 12 week, and repeated i.p. dose of 20% CCl₄ (2 mL/kg/day) for 1 week. Hepatotoxicity was evaluated by measuring the serum levels of glutamic pyruvate transaminase (GPT), gamma glutamyl transpeptidase (γ-GT) and malondialdehyde (MDA) as well as the tissue levels of antioxidant enzyme such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Ethanol and CCl₄-induced the rat liver damage, and significantly increased (p < 0.05) the GPT, γ-GT and MDA levels, and decreased the SOD, CAT and GPx levels. However, treatment with FST could decrease serum GPT, γ-GT, and MDA levels significantly in plasma, and increase the activities of SOD, CAT, and GPx in liver tissues compared with ethanol and CCl₄-treated group.     

Role of oxidative stress and nitric oxide in the protective effects of α-lipoic acid and aminoguanidine against isoniazid–rifampicin-induced hepatotoxicity in rats

Despite the great efficacy of isoniazid (INH) and rifampicin (RIF) combination, in the treatment of tuberculosis, hepatotoxicity is the most common serious complication. The potential protective effect of α-lipoic acid and aminoguanidine; against combination-induced hepatotoxicity was investigated in the present study. Administration of INH–RIF combination (50 mg/kg each for 14 days) resulted in an elevation of serum hepatic marker enzymes and a significant increase in lipid profile parameters. Combinations treatment increased lipid peroxidation products, decreased glutathione content, superoxide dismutase, catalase and myeloperoxidase activities. Furthermore, liver total nitrite level was significantly increased in INH–RIF treated rats. Co-administration of either α-lipoic acid or aminoguanidine significantly ameliorate combination-induced alterations in hepatic marker enzymes. These effects were directly linked to a greater decrease in the combination-induced elevation in lipid peroxidation products and total nitrite levels. Furthermore, co-administration of α-lipoic acid and aminoguanidine restore superoxide dismutase, catalase and myeloperoxidase activities and maintained the imbalance in the glutathione level. Additionally, such beneficial effect of α-lipoic acid was linked to a marked lipid-lowering effect. Histopathological examination revealed preservation of liver integrity of the protected groups compared to combination-treated rats alone.     

Protective effect of isoliquiritigenin on experimental diabetic nephropathy in rats: Impact on Sirt-1/NFκB balance and NLRP3 expression

The prevalence of diabetes mellitus (DM) drastically increases worldwide. Persistent hyperglycemia affects body microvasculature causing injuries to kidney producing diabetic nephropathy (DNE). Manifestation of these microvascular complications is associated with disturbed redox homeostasis. The current study evaluated the effect of isoliquiritigenin (ISLQ), a bioactive chalcone found in licorice which is known for its antioxidant effect, on diabetes-induced renal injury. DM was prompted in male rats by streptozotocin (STZ, 50 mg/kg, intraperitoneally). ISLQ was administrated by oral gavage for 8 weeks at a dose (20 mg/kg/day). Features of renal injury were observed in kidneys of diabetic rats including, albuminuria and deteriorated renal function. Renal dysfunction was associated with reduced sirtuin-1 (Sirt-1) expression, increased renal oxidative stress, nucleotide-binding domain and leucine-rich repeat containing protein-3 (NLRP3), nuclear factor-κB (NFκB) and inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, there was significant downregulation of anti-inflammatory cytokine interleukin-10 (IL-10), glomerular and tubular injury and collagen accumulation. ISLQ administration preserved renal function and architecture, restored Sirt1 and renal oxidant-antioxidant balance, dampened inflammation and attenuated collagen accumulation. It can be inferred that ISLQ possess a protective effect and could have a potential as a food supplement to halt development and progression of DNE.     

Effects of rosiglitazone on native low-density-lipoprotein-induced respiratory burst in circulating monocytes and on the leukocyte–endothelial interaction in cholesterol-fed rats

Low-density lipoprotein (LDL) has been implicated in the initiation and progression of atherosclerotic vascular disease. But whether LDL can elicit similar effects in the microcirculation remain unexplored. To approach this issue, the hypothesis that LDL promotes oxidative stress in monocytes and results in microvascular inflammation was tested. Native LDL was capable of stimulating respiratory burst in rat monocytes, and this was blocked by BAPTA, cytochalasin B, apocynin, and diphenyliodonium. In monocytes from rats on a high-cholesterol (4%) diet, increased intracellular calcium, actin polymerization, respiratory burst, and surface CD18 expression were found. Concurrently, leukocyte–endothelial interaction was enhanced in the cremaster microcirculation. Rosiglitazone, an insulin-sensitizing agent with antiinflammatory properties, was found to suppress native-LDL-induced actin polymerization and respiratory burst in monocytes. It also improved leukocytes activation and leukocyte–endothelial interaction due to the high cholesterol intake. Hence, native LDL stimulation of monocytes contributed to hypercholesterolemia-associated microvascular inflammation, which could be treated by rosiglitazone.     

Protective effect of kobophenol A on nitric oxide-induced cell apoptosis in human osteoblast-like MG-63 cells: involvement of JNK, NF-κB and AP-1 pathways

Nitric oxide (NO) is a multifunctional signaling molecule and the cytotoxic species responsible for a variety of pathologic disorders including bone destruction. High NO levels induce the apoptosis of osteoblasts and decrease the bone mineral density. We investigated the influence of kobophenol A (kob A) on apoptosis in cultured human osteoblast-like MG-63 cells. Direct NO donor sodium nitroprusside (SNP) that has been recognized as an inducer of apoptosis in various cell lines significantly induced cell death and NO production in MG-63 cells. Coincubation of kob A in SNP-treated MG-63 cells resulted in a significant protection against NO-induced cell death. This is associated with increase in intracellular reactive oxygen species (ROS) scavenging activity and the inhibition of decrease in mitochondrial membrane potential (MMP) by kob A. We also found that kob A inhibited the down-regulation of Bcl-2 and Bcl-X(L), whereas the level of Bax expression was decreased by kob A treatment in SNP-treated MG-63 cells. Furthermore, kob A inhibited SNP-induced phosphorylation of JNK and c-Jun, and SNP-induced reduction in NF-κΒ and AP-1 activities, implicating that protective effect of kob A may occur through the regulation of JNK, NF-κΒ and AP-1 signaling pathways. Together, these findings suggest that kob A has a protective effect against NO-mediated osteoblast apoptosis and might be a plausible candidate for treatment of inflammatory bone diseases relevant to osteoblast cell death.     

The protective effect of hesperidin on cardiac and renal tissue damage in DOCA/Salt hypertensive rats北大核心CSCD

Aim To investigate the protective effect of hesperidin (HES) on cardiorenal damage induced by DOCA/Salt hypertension and the underlying mechanisms. Methods Eighteen male SD rats were randomly divided into normal group (Ctrl), model group (DOCA/Salt), and DOCA/Salt with hesperidin group (DOCA/Salt + HES). HES was administered for four weeks. Blood pressure, serum creatinine and blood urea nitrogen were measured. The pathological changes in heart and kidney were examined by HE, Masson and Sirius red staining. The expression of α-SMA, collagen I and TGF-β were detected by Western blot. The mRNA levels of Nlrp3, TNF-α, IL-1β, IL-6 and NOXs were measured using qRT-PCR. Results Compared with the model group, HES administration significantly attenuated the occurrence of DOCA/Salt hypertension, improved renal function indicators of hypertensive rats, reduced renal and cardiac fibrosis, deduced the expression of α-SMA, collagen I and TGF-β, inhibited the expression of Nlrp3, TNF-α, IL-1β and IL-6, and decreased the expression of NOXs in renal and cardiac tissues. Conclusions HES can delay the occurrence of hypertension and protect against hypertension-induced renal and cardiac tissue damage, which may be related to the reduction of inflammatory reaction and oxidative stress by HES. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

Thrombin induces inducible nitric oxide synthase expression via the MAPK, MSK1, and NF-κB signaling pathways in alveolar macrophages

In this study, we investigated the roles of mitogen activated protein kinase (MAPK), mitogen stress-activated protein kinase 1 (MSK1), and nuclear factor-κB (NF-κB) signaling pathways in thrombin-induced inducible nitric oxide synthase (iNOS) expression in alveolar macrophages (NR8383). Treatment of NR8383 cells with thrombin caused an increase in iNOS expression in a concentration- and time-dependent manner. Treatment of NR8383 cells with SB203580 (4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-5-(4-pyridyl)-1H-imidazole, a p38 MAPK inhibitor), PD98059 (2'-amino-3'-methoxyflavone, a MAPK kinase (MEK) inhibitor), and SP600125 (anthra[1-9-cd]pyrazol-6(2H)-one, a JNK inhibitor) all inhibited thrombin-induced iNOS expression. Stimulation of cells with thrombin caused an increase in p38 MAPK, ERK, and JNK phosphorylation. Treatment of cells with Ro 31-8220 (an MSK1 inhibitor) and MSK1 small interfering RNA (MSK1 siRNA) both inhibited thrombin-induced iNOS expression. Thrombin caused time-dependent activation of MSK1 Ser531 phosphorylation, which was inhibited by SB203580 and PD98059, but not by SP600125. Treatment of cells with pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) inhibited thrombin-induced iNOS expression in a concentration-dependent manner. Treatment of NR8383 cells with thrombin induced κB-luciferase activity and p65 Ser276 phosphorylation. Thrombin-induced increases in p65 Ser276 phosphorylation and κB-luciferase activity were inhibited by SB203580, PD98059, Ro 31-8220, and MSK1 siRNA. Taken together, these results suggest that the signaling pathways of MAPK, MSK1, and NF-κB play important roles in thrombin-induced iNOS expression in alveolar macrophages.     

Protective Effects of 1-Methylnicotinamide on Aβ1–42-Induced Cognitive Deficits,Neuroinflammation and Apoptosis in Mice

Journal of Neuroimmune Pharmacology - The neurotoxicity of Aβ peptides has been well documented, but effective neuroprotective approaches against Aβ neurotoxicity are unavailable. In the...     

Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats.