Japanese herbal medicine, Saiko-keishi-to, prevents gutischemia／reperfusion-induced liver injurv in rats via nitric oxide

AIM: To determine whether Saiko-keishi-to (TJ-10), a Japanese herbal medicine, could protect liver injury induced by gut ischemia/reperfusion (I/R), and to investigate the role of NO. METHODS: Male Wistar rats were exposed to 30-min gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor leukocyte recruitment. Plasma tumor necrosis factor (TNF) levels and alanine aminotransferase (ALT) activities were measured. TJ-10 1 g/(kg.d) was intragastrically administered to rats for 7 d. A NO synthase inhibitor was administered. RESULTS: In control rats, gut I/R elicited increases in the number of stationary leukocytes, and plasma TNF levels and ALT activities were mitigated by pretreatment with TJ-10. Pretreatment with the NO synthase inhibitor diminished the protective effects of TJ-10 on leukostasis in the liver, and the increase of plasma TNF levels and ALT activities. Pretreatment with TJ-10 increased plasma nitrite/nitrate levels. CONCLUSION: TJ-10 attenuates the gut I/R-induced hepatic microvascular dysfunction and sequential hepatocellular injury via enhancement of NO production.     

Japanese herbal medicine, Saiko-keishi-to, prevents gut ischemia/reperfusion-induced liver injury in rats via nitric oxide

AIM:To determine whether Saiko-keishi-to(TJ-10),aJapanese herbal medicine,could protect liver injury inducedby gut ischemia/reperfusion(I/R),and to investigate therole of NO.METHODS:Male Wistar rats were exposed to 30-min gutisohemia followed by 60 min of reperfusion.Intravital microscopywas used to monitor leukocyte recruitment.Plasma tumornecrosis factor(TNF)levels and alanine aminotransferase(ALT)activities were measured.TJ-10 1 g/(kg.d)wasintragastrically administered to rats for 7 d.A NO synthaseinhibitor was administered.RESULTS:In control rats,gut I/R elicited increases in thenumber of stationary leukocytes,and plasma TNF levelsand ALT activities were mitigated by pretreatment withTJ-10.Pretreatment with the NO synthase inhibitordiminished the protective effects of TJ-10 on leukostasisin the liver,and the increase of plasma TNF levels andALT activities.Pretreatment with TJ-10 increased plasmanitrite/nitrate levels.CONCLUSION:TJ-10 attenuates the gut I/R-induced hepaticmicrovascular dysfunction and sequential hepatocellularinjury via enhancement of NO production.     

Relationship between inducible nitric oxide synthase expression and angiogenesis in primary gallbladder carcinoma tissue

AIM:To explore the relationship between angiogenesis andbiological behaviors of primary gallbladder carcinoma (PGBC),the relationship between the expression of inducible nitricoxide synthase (iNOS) and biological behaviors of PGBC andits relationship with the expression of iNOS and angiogenesisof PGBC.METHODS:The expression of iNOS and micro-vessel density(MVD) were assessed by immunohistochemical method andimage analysis system in 40 specimens of PGBC and in 8specimens of normal gallbladder.The immunostaining resultsand related clinicopathologic materials were analyzed bystatistical methods.RESULTS:MVD in PGBC was significantly higher than thatin normal gallbladder tissue (46±14 vs 14±6,P<0.05),andwas not related with age,gender,tumor size and histologicaltype.MVD of poorly and undifferentiated tumor tissues washigher than that of moderately-differentiated and well-differentiated tumor tissues (52±9 vs 43±9 vs 33±6,P<0.01).MVD of Nevin Ⅳ and Ⅴ stages was higher than that of NevinⅠ,Ⅱ and Ⅲ stages (52±8 vs 37±13,P<0.01).MVD of caseswith lymphatic or liver metastasis was significantly higherthan that without liver metastasis (55±6 vs 42±10,P<0.05)or lymphatic metastasis (53±8 vs 38±8,P<0.01).The positivelevel index (PLI) of iNOS in PGBC was 0.435±0.134,and wasnot related with age,gender,tumor size,histological type,differentiation and clinical stage of PGBC.The PLI of iNOSin cases with lymphatic metastasis was higher than thatwithout lymphatic metastasis (0.573±0.078 vs 0.367±0.064,P<0.01).The PLI of iNOS in cases with liver metastasis washigher than that without liver metastasis (0.533±0.067 vs0.424±0.084,P<0.05).There was a significant correlationbetween PLI of iNOS and MVD in PGBC (P<0.05).CONCLUSION:Angiogenesis of PGBC is significantly relatedto the biological behaviors of PGBC.The expression of iNOSis related to the biological behaviors of PGBC.The detectionof MVD and the expression of iNOS in PGBC can be used asparameters to determine the degree of malignancy and prognosis.     

Role of inducible nitric oxide synthase expression in aberrant crypt foci－adenoma－carcinoma sequence

AIM: To investigate the expression of inducible nitric oxidesynthase (iNOS) in aberrant crypt foci (ACF) -adenomacarcinoma sequence and its relation with tumor cellapoptosis, proliferation and angiogenesis. METHODS: The expression of iNOS, proliferating cellnuclear antigen (PCNA) and microvessel density (MVD) indifferent stages of colorectal cancer were studied by immunohistochemical method from 30 normal tissues, 30nonhyperplastic ACF, 30 hyperplastic ACF, 30 dysplastic ACF,30 adenomas and 60 carcinomas. The apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method using an Apop Tag in situ detection kit. RESULTS: The immunoreactivity of iNOS significantly increased in the transition from hyperplastic ACF to dysplastic ACF. This transition was associated with a significant decrease in the apoptotic index (AI) (0.73+0.37 vs0.61±0.35, P＜0.05)and significant increases in the PCNA labeling index (LI)(27.3+2.80 vs 40.3+3.11, P＜0.01) and microvessel density (MVD) (55±11.5 vs 70±13.2, P＜0.01). The expression of iNOS was in low levels and positively correlated with PCNALI (r=0.812, P＜0.01) and MVD (r=0.863, P＜0.01) during transition from normal mucosa to nonhyperplastic ACF and hyperplastic ACF. The expression of iNOS was in high levels and positively correlated with AI (r=0.901, P＜0.01) after transition from hyperplastic ACF to dysplastic ACF, adenoma and carcinoma. CONCLUSION: The results suggest that the transition from hyperplastic ACF to dysplastic ACF may be a crucial step in the ACF-adenoma-carcinoma sequence, in which iNOS plays an important role by regulating tumor cell apoptosis,proliferation and angiogenesis.     

Effects of L-arginine on serum nitric oxide, nitric oxide synthase and mucosal Na^＋-K^＋-ATPase and nitric oxide synthase activity in segmental small-bowel autotransplantation model

AIM:To explore a simple method to create intestinal autotransplantation in rats and growing pigs and to investigate the effect of L-arginine supplementation on serum nitric oxide (NO), nitric oxide synthase (NOS) and intestinal mucosal NOS and Na+-K+-ATPase activity during cold ischemia-reperfusion (IR) in growing pigs. METHODS: In adult Wistar rat models of small bowel autotransplantation, a fine tube was inserted into mesenteric artery via the abdominal aorta. The superior mesenteric artery and vein were occluded. Isolated terminal ileum segment was irrigated with Ringer's solution at 4℃ and preserved in the same solution at 0-4℃ for 60 min. Then, the tube was removed and reperfusion was established. In growing pig models, a terminal ileum segment, 50 cm in length, was isolated and its mesenteric artery was irrigated via a needle with lactated Ringer's solution at 4℃. The method and period of cold preservation and reperfusion were described above. Ten white outbred pigs were randomly divided into control group and experimental group. L-arginine (150 mg/kg) was continuously infused for 15 min before reperfusion and for 30 min after reperfusion in the experimental group. One, 24, 48, and 72 h after reperfusion, peripheral vein blood was respectively collected for NO and NOS determination. At the same time point, intestinal mucosae were also obtained for NOS and Na+-K+-ATPase activity measurement. RESULTS: In adult rat models, 16 of 20 rats sustained the procedure, three died of hemorrhage shock and one of deep anesthesia. In growing pig models, the viability of small bowel graft remained for 72 h after cold IR in eight of 10 pigs. In experimental group, serum NO level at 1 and 24 h after reperfusion increased significantly when compared with control group at the same time point (152.2±61.4μmol/L /s60.8±31.6μmol/L, t=2.802, P=0.02<0.05; 82.2±24.0μmol/L vs 54.0±24.3μmol/L, t=2.490, P=0.04<0.05). Serum NO level increased significantly at 1 h post-reperfusion when compared with the same group before cold IR, 24 and 48 h post-reperfusion (152.2±61.4μmol/L vs 75.6±16.2μmol/L,t=2.820, P=0.02<0.05,82.2±24.0μmol/L,t=2.760, P= 0.03<0.05, 74.2±21.9μmol/L, t=2.822, P= 0.02<0.05). Serum NOS activity at each time point had no significant difference between two groups. In experimental group, intestinal mucosal NOS activity at 1 h post-reperfusion reduced significantly when compared with pre-cold IR (0.79±0.04 U/mg vs 0.46±0.12 U/mg, t = 3.460, P= 0.009<0.01). Mucosal NOS activity at 24, 48, and 72 h post-reperfusion also reduced significantly when compared with pre-cold IR (0.79±0.04 U/mg vs 0.57±0.14 U/mg, t= 2.380, P=0.04 <0.05, 0.61±0.11 U/mg, t= 2.309, P = 0.04<0.05, 0.63±0.12U/mg, t = 2.307, P= 0.04<0.05). In control group, mucosal NOS activity at 1 and 24 h post-reperfusion was significantly lower than that in pre-cold IR (0.72±0.12 U/mg vs 0.60±0.07 U/mg, t= 2.320, P= 0.04<0.05, 0.58±0.18 U/mg, t=2.310, P= 0.04<0.05). When compared to the normal value, Na+-K+-ATPase activity increased significantly at 48 and 72 h post-reperfusion in experimental group (2.48±0.59μmol/mg vs 3.89±1.43μmol/mg, t=3.202, P= 0.04<0.05, 3.96±0.86μmol/mg, t=3.401, P= 0.009 <0.01) and control group (2.48±0.59μmol/mg vs 3.58±0.76 μmol/mg, t=2.489, P= 0.04<0.05, 3.67±0.81μmol/mg, t= 2.542, P= 0.03<0.05). CONCLUSION: This novel technique for intestinal autotransplantation provides a potentially consistent and practical model for experimental studies of graft cold preservation. L-arginine supplementation during cold IR may act as a useful adjunct to preserve the grafted intestine.     

Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma： Correlation with microvessel density

AIM: Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide. Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas. METHODS: We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ductal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data. RESULTS: Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2. The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density. However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data. CONCLUSION: Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2 expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.     

Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma:Correlation with microvessel density

AIM:Cydooxygenases (COX) are key enzymes for conversionof arachidonic acid to prostaglandins.Nitric oxide synthase(NOS) is the enzyme responsible for formation of nitric oxide.Both have constitutive and inducible isoforms.The inducibleisoforms (iNOS and COX-2) are of great interest as regulatorsof tumor angiogenesis,tumorigenesis and inflammatoryprocesses.This study was to clarify their role in pancreaticadenocarcinomas.METHODS:We investigated the immunohistochemical iNOSand COX-2 expression in 40 pancreatic ductal adenocardnomasof different grade and stage.The results were comparedwith microvessel density and dinicopathological data.RESULTS:Twenty-one (52.5%) of the cases showed iNOSexpression,15 (37.5%) of the cases were positive for COX-2.The immunoreaction was heterogeneously distributed withinthe tumors.Staining intensity was different between thetumors.No correlation between iNOS and COX-2 expressionwas seen.There was no relationship with microvessel density.However,iNOS positive tumors developed more often distantmetastases and the more malignant tumors showed a higherCOX-2 expression.There was no correlation with otherclinicopathological data.CONCLUSION:Approximately half of the cases expressediNOS and COX-2.These two enzymes do not seem to bethe key step in angiogenesis or carcinogenesis of pancreaticadenocarcinomas.Due to a low prevalence of COX-2expression,chemoprevention of pancreatic carcinomas byCOX-2 inhibitors can only achieve a limited success.     

Does inchinkoto,a herbal medicine,have hepatoprotective effects in major hepatectomy? A prospective randomized study

Objectives

This randomized clinical trial was designed to investigate whether inchinkoto has a hepatoprotective effect on postoperative outcome after major hepatectomy.

Methods

Sixty-one patients scheduled for major hepatectomy were randomly assigned to one of two groups in which preoperative inchinkoto was (inchinkoto group, n = 30) or was not (non-inchinkoto group, n = 31) administered. Inchinkoto was administered for at least 7 days before surgery. The primary endpoint was the incidence of post-hepatectomy liver damage. The expression of nuclear factor E2-related factor 2 (Nrf2) and other oxygen stress-related markers in the liver were also determined.

Results

There was no significant difference in clinical characteristics between the inchinkoto and non-inchinkoto groups. Serum levels in liver function tests and incidences of post-hepatectomy liver failure did not differ significantly between the two groups. However, there was a significantly higher induction of antioxidant factors in the liver, such as Nrf2 protein and heme oxygenase-1 mRNA, after hepatectomy in the inchinkoto group than in the non-inchinkoto group.

Conclusions

The preoperative administration of inchinkoto did not have a significant impact on the overall outcome of major hepatectomy. However, inchinkoto induced the expression of Nrf2 during hepatectomy and may have exerted an antioxidative effect on the liver.     

Evaluation of nitric oxide synthase activity, nitric oxide, and homocysteine levels in patients with active Behcet’s disease

Behcet’s disease (BD) is a chronic, progressive disorder that affects many systems of the body including the eye. The aim of this study was to examine the effects of nitric oxide synthase activity (NOS), nitric oxide , and homocysteine (Hcy) levels in patients with active BD. Included in this study were 18 male BD patients and 16 male healthy volunteers as controls. Erythrocyte NOS activity, , erythrocyte sedimentation rate, serum C-reactive protein, and plasma Hcy values in the patients with BD were significantly higher than those of the control group. Our results show that these parameters play a major role in the inflammatory reactions observed in BD.     

Selective inhibition of inducible nitric oxide synthase: A promising strategy in the therapy of septic shock?

Summary Nitric oxide (NO) is a short-lived effector molecule which is produced from L-arginine by several NO synthase (NOS) isoforms. Physiologically, small amounts of NO are produced by an endothelial constitutive NOS (ecNOS), which is involved in the regulation of vascular tone and blood flow distribution. On stimulation by bacterial products and various cytokines, an inducible NOS (iNOS) becomes diffusely expressed, producing large amounts of NO for extended periods of time, which are implicated in the pathogenesis of septic shock. The pharmacological inhibition of NO synthesis has been, therefore, proposed as a new therapy in this setting. Unfortunately, such inhibition has been frequently reported to be detrimental, and recent evidence reveals that this deleterious potential is a consequence of ecNOS blockade by nonselective NOS inhibitors. Thus, interest is now focusing in the identification of compounds able to selectively inhibit iNOS activity. Although the effects of such selective agents have been only poorly investigated so far, they appear extremely promising. Indeed, in various animal models of septic shock, selective iNOS inhibitors have produced a marked improvement in hemodynamics, tissue oxygenation, and organ function, leading to a reduced mortality. These favorable results, which markedly contrast with the deleterious influence of nonselective NOS inhibitors in similar conditions, suggest that selective iNOS inhibitors might become useful adjuncts to septic shock therapy in the future. Accepted: 26 January 1999     

Hypoxia inducible factor-1�� accumulation in steatotic liver preservation: Role of nitric oxide

AIM:To examine the relevance of hypoxia inducible factor(HIF-1)and nitric oxide(NO)on the preservation of fatty liver against cold ischemia-reperfusion injury(IRI). METHODS:We used an isolated perfused rat liver model and we evaluated HIF-1αin steatotic and non-steatotic livers preserved for 24 h at 4℃in University of Wisconsin and IGL-1 solutions,and then subjected to 2 h of normothermic reperfusion.After normoxic reperfusion,liver enzymes,bile production,bromosulfophthalein clearance,as well as HIF-1αand ...     

Increased oxidative DNA damage, inducible nitric oxide synthase, nuclear factor кB expression and enhanced antiapoptosis-related proteins in Helicobacter pylori-infected non-cardiac gastric adenocarcinoma

AIM:Several epidemiological studies have demonstrateda close association between Helicobacter pylori(H Pylori)infection and non-cardiac carcinoma of the stomach.Hpyloriinfection induces active inflammation with neutrophilicinfiltrations as well as production of oxygen free radicalsthat can cause DNA damage.The DNA damage induced byoxygen free radicals could have very harmful consequences,leading to gene modifications that are potentially mutagenicand/or carcinogenic.The aims of the present study wereto assess the effect of Hpyloriinfection on the expressionof inducible nitric oxidative synthase(iNOS)and theproduction of 8-hydroxy-deoxyguanosine(8-OHdG),asensitive marker of oxidative DNA injury in human gastricmucosa with and without tumor lesions,and to assess thepossible factors affecting cell death signaling due tooxidative DNA damage.METHODS:In this study,40 gastric carcinoma specimensand adjacent specimens were obtained from surgicalresection.We determined the level of 8-OHdG formationby HPLC-ECD,and the expression of iNOS and mechanismof cell death signaling [including nuclear factor-κB(NFκB),MEKK-1,Caspase 3,B Cell lyrnphomal leukemia-2(Bcl-2),inhibitor of apoptosis protein(IAP)and myeloid cellleukemia-1(Mcl-1)] by Western-blot assay.RESULTS:The concentrations of 8-OHdG,iNOS,NFκB,Mcl-1and IAP were significantly higher in cancer tissues than inadjacent non-cancer tissues.In addition,significantly higherconcentrations of 8-OHdG,iNOS,NFκB,Mcl-1 and IAP weredetected in patients infected with H pylori compared withpatients who were not infected with H pylori Furthermore,8-OHdG,iNOS,NFκB,Mcl-1 and IAP concentrations weresignificantly higher in stage 3 and 4 patients than in stage1 and 2 patients. CONCLUSION:Chronic H pylori infection induces iNOSexpression and subsequent DNA damage as well as enhancesanti-apoptosis signal transduction.This sequence of eventssupports the hypothesis that oxygen-free radical-mediateddamage due to H pylori plays a pivotal role in the developmentof gastric carcinoma in patients with chronic gastritis.     

Increased oxidative DNA damage, inducible nitric oxide synthase,nuclear factor κB expression and enhanced antiapoptosis-related proteins in Helicobacter pylori-infected non-cardiac gastric adenocarcinoma

AIM: Several epidemiological studies have demonstrated a dose association between Helicobacter pylori (H Pylon) infection and non-cardiac carcinoma of the stomach. H pylori infection induces active inflammation with neutrophilic infiltrations as well as production of oxygen free radicals that can cause DNA damage. The DNA damage induced by oxygen free radicals could have very harmful consequences,leading to gene modifications that are potentially mutagenic and/or carcinogenic. The aims of the present study were to assess the effect of H pyloriinfection on the expression of inducible nitric oxidative synthase (iNOS) and the production of 8-hydroxy-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA injury in human gastric mucosa with and without tumor lesions, and to assess the possible factors affecting cell death signaling due tooxidative DNA damage.METHODS: In this study, 40 gastric carcinoma specimens and adjacent specimens were obtained from surgical resection. We determined the level of 8-OHdG formation by HPLC-ECD, and the expression of iNOS and mechanism of cell death signaling [including nuclear factor-κB(NFκB),MEKK-1, Caspase 3, B Cell lymphomal leukemia-2 (Bcl-2),inhibitor of apoptosis protein (IAP) and myeloid cellleukemia-1 (Mcl-1)] by Western-blot assay.RFSULTS: The concentrations of 8-OHdG, iNOS, NFx3, Mcl-1 and IAP were significantly higher in cancer tissues than in adjacent non-cancer tissues. In addition, significantly higher concentrations of 8-OHdG, iNOS, NFxB, Mcl-1 and lAP were detected in patients infected with H pyloricompared with patients who were not infected with HpylorL Furthermore,8-OHdG, iNOS, NFκB, Mcl-1 and IAP concentrations were significantly higher in stage 3 and 4 patients than in stage1 and 2 patients.CONCLUSION: Chronic Hpylori infection induces iNOS expression and subsequent DNA damage as well as enhances anti-apoptosis signal transduction. This sequence of events supports the rihypothesis that oxygen-free radical-mediated damage due to Hpyloriplays a pivotal role in the development of gastric carcinoma in patients with chronic gastritis.     

Comparison of mRNA contents of interleukin-1Β and nitric oxide synthase in pancreatic islets isolated from female and male nonobese diabetic mice

Summary Interleukin-1 (IL-1) has been suggested to mediate beta-cell destruction in insulin-dependent diabetes mellitus (IDDM) by inducing nitric oxide production. In this study, we assessed the levels of IL-1 and the inducible form of nitric oxide synthase (iNOS), using a semi-quantitative polymerase chain reaction assay, and performed determinations of nitrite accumulation and IL-1 bioactivity, on pancreatic islets isolated from 5- and 16-week-old female and male nonobese diabetic (NOD) mice and from nondiabetes prone NMRI mice. NOD mouse islets contained notable amounts of IL-1 mRNA. At 5 weeks of age, but not at 16 weeks, the values were higher in islets isolated from NOD females compared to males. The IL-1 bioactivity showed differences roughly reflecting the mRNA levels in the NOD mouse islets. In the NMRI mouse islets the IL-1 bioactivity was very low. The expression of iNOS mRNA increased in both male and female islets between 5 and 16 weeks of age. Immunocytochemistry of pancreatic sections indicated the presence of macrophages especially in the peri-insular area of the NOD mice which suggests that IL-1 was produced by macrophages. The levels of IL-1 activity and mRNA in freshly isolated islets from NOD 5-week-old females did not correlate to the iNOS mRNA content or to the nitrite production. However, after incubation with IL-1 in vitro, both NOD and NMRI islets responded with a marked increase in nitric oxide production. It is concluded that the presence of IL-1 in isolated NOD mouse islets, via an induction of iNOS expression and nitric oxide production, cannot explain the gender difference in diabetes incidence in NOD mice.Abbreviations BB BioBreeding - GAPDH glyceraldehyde-3-phosphate dehydrogenase - IDDM insulin-dependent diabetes mellitus - iNOS inducible form of nitric oxide synthase - IL-1 interleukin-1 - IL-1ra interleukin-1 receptor antagonist protein - IL-6 interleukin-6 - NMRI Naval Marine Research Institute - NO nitric oxide - NOD nonobese diabetic - PAP peroxidase-antiperoxidase - PCR polymerase chain reaction - SDS sodium dodecyl sulphate - TNF tumour necrosis factor - OD optical density     

A novel genetic polymorphism of inducible nitric oxide synthase is associated with an increased risk of gastric cancer

AIM:Inducible nitric oxide synthase(iNOS)plays a central role in the pathway of reactive oxygen and nitrogen species metabolism when Helicobacter pylori(H pylori)infection occurs in humans,iNOS Ser~(608)Leu allele,a novel genetic polymorphism(C/T)occurring within exon 16 of the iNOS reductase domain,may have a dramatic effect on the enzymatic activity.The aim of this study was to determine whether iNOS C/T polymorphism was associated with increased susceptibility to gastric cancer. METHODS:We conducted a population based case-control study in a high gastric cancer incidence area,Yangzhong, China.Questionnaires from 93 patients with intestinal type gastric cancer(IGC),50 with gastric cardia cancer(GCC) and 246 healthy controls were obtained between 1997 and 1998,and iNOS genotyping was carried out.Odds ratios (ORs),interaction index(γ),and 95% confidence intervals for the combined effects of iNOS genotype and H pylori infection,cigarette smoking or alcohol drinking were estimated. RESULTS:The frequency of(CT -TT)genotypes was higher in cases than in control group(24.48% vs23.17%),but the difference was not statistically significant.After adjusting for age and gender,past cigarette smokers with(CT TT) genotypes had a significantly increased risk of IGC(OR=3.62, 95% CI:1.23-10.64),while past alcohol drinkers with (CT TT)genotypes had a significantly increased risk of GCC(OR=3.33,95% CI:1.14-9.67).H pylori CagA negative subjects with(CT TT)genotypes had a significantly increased risk of both IGC and GCC(OR=2.19 and 3.52,respectively). CONCLUSION:iNOS Ser~(608)Leu allele may be a potential determinant of susceptibility to cigarette -alcohol induced gastric cancer,but larger studies are needed to confirm the observations.     

Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRβ/IRS-1 and Akt

Aim/hypothesis  

High-dose aspirin treatment improves fasting and postprandial hyperglycaemia in patients with type 2 diabetes, as well as in animal models of insulin resistance associated with obesity and sepsis. In this study, we investigated the effects of aspirin treatment on inducible nitric oxide synthase (iNOS)-mediated insulin resistance and on S-nitrosylation of insulin receptor (IR)-β, IRS-1 and protein kinase B (Akt) in the muscle of diet-induced obese rats and also in iNos (also known as Nos2)^−/− mice on high fat diet.     

Endogenous nitric oxide synthase inhibitors in the biology of disease: markers, mediators, and regulators?

The asymmetric methylarginines inhibit nitric oxide synthesis in vivo by competing with L-arginine at the active site of nitric oxide synthase. High circulating levels of asymmetric dimethylarginine predict adverse outcomes, specifically vascular events but there is now increasing experimental and epidemiological evidence that these molecules, and the enzymes that regulate this pathway, play a mechanistic role in cardiovascular diseases. Recent data have provided insight into the impact of altered levels of these amino acids in both humans and rodents, however these reports also suggest a simplistic approach based on measuring, and modulating circulating asymmetric dimethylarginine alone is inadequate. This review outlines the basic biochemistry and physiology of endogenous methylarginines, examines both the experimental and observational evidence for a role in disease pathogenesis, and examines the potential for therapeutic regulation of these molecules.