Tissue Nitric Oxide Levels Research Articles

Odoratin balances ROS/NO through EZH2/PPARγ signalling to improve myocardial fibrosis.

Myocardial fibrosis is a critical concern in clinical medicine. This study explores the potential of odoratin as a treatment for myocardial fibrosis and investigates its underlying mechanisms. In vitro experiments involved stimulating primary mouse cardiomyocytes with TGF-β1, followed by odoratin treatment, to assess levels of reactive oxygen species (ROS) and nitric oxide (NO). In vivo, a mouse model of myocardial fibrosis was established using abdominal aortic constriction (AAC) and treated with odoratin. ROS and NO levels in myocardial tissue were then evaluated. Immunofluorescence and Western blotting analysis showed that odoratin reduced excess ROS, enhanced NO production and decreased fibrosis-related protein expression in vitro. In vivo, odoratin significantly improved cardiac function, reduced ROS, increased NO levels and mitigated fibrosis in AAC-induced mice. Both in vitro and in vivo, odoratin inhibited the expression of NADPH oxidase 4 and EZH2, while promoting the expression of phosphorylated endothelial nitric oxide synthase (p-eNOS) and PPARγ. The anti-fibrotic effects of odoratin were reversed by PPARγ antagonism, and EZH2 overexpression diminished PPARγ activation by odoratin. These findings suggest that odoratin may combat myocardial fibrosis by balancing ROS and NO through PPARγ activation, with EZH2 inhibition likely playing a key regulatory role.

Effect of tangeretin on cisplatin-induced oxido-inflammatory brain damage in rats.

Cisplatin (CIS) is a platinum-derived chemotherapeutic agent commonly utilized in the treatment of various malignant tumours. However, anticancer doses of the drug cause serious damage to the brain. This study aimed to determine the potential protective effects of tangeretin, which has antioxidant and anti-inflammatory properties, in cisplatin-induced neurotoxicity on BALB/c mice brains. Male BALB/c mice were randomized and separated into four groups. Tangeretin was given for 10 days by gavage. CIS was injected as a single dose of 10 mg/kg intraperitoneally (ip) on the 10th day. Brain tissues, malondialdehyde (MDA), total glutathione (tGSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and nitric oxide (NO) levels were measured to determine oxidative damage and myeloperoxidase, tumour necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), IL-6 and IL-10 were measured to determine inflammatory activity. In addition, 8-OHdG and caspase-3 were analysed by immunofluorescence methods. While CIS administration remarkably elevated reactive oxygen species, MDA, and NO levels in brain tissue compared to the control, tGSH, GPx, SOD and CAT levels were significantly decreased. Also, it has been detected that TNF-α, IL-1β and IL-6 obtained in CIS-treated groups increased as well as IL-10 decreased, thereby elevating the inflammatory response. In addition, 8-OHdG and caspase-3 immunoreactivity in neurons increased with CIS administration. Treatment with tangeretin ameliorated the deterioration in oxidant/antioxidant status, overpowered neuroinflammation and ameliorated neurotoxicity-induced apoptosis. This study shows that tangeretin has beneficial effects on CIS-induced neurodegeneration. Possible mechanisms underlying these beneficial effects include the antioxidant and anti-inflammatory properties of tangeretin.

Curcumin as a Potential Therapeutic Agent for Mitigating Carbon Monoxide Poisoning: Evidence from an Experimental Rat Study.

BACKGROUND Carbon monoxide (CO) is a poisonous gas and causes tissue damage through oxidative stress. We aimed to investigate the protective value of curcumin in CO poisoning. MATERIAL AND METHODS Twenty-four female Spraque Dawley rats were divided into 4 subgroups: controls (n=6), curcumin group (n=6), CO group (n=6), and curcumin+CO group (n=6). The experimental group was exposed to 3 L/min of CO gas at 3000 ppm. Curcumin was administered intraperitoneally at a dosage of 50 mg/kg. Hippocampal tissues were removed and separated for biochemical and immunohistochemical analysis. Tissue malondialdehyde (MDA) levels, nitric oxide (NO) levels, and superoxide dismutase (SOD) and catalase (CAT) activities were assayed spectrophotometrically, and serum asymmetric dimethylarginine (ADMA) were measured using the ELISA technique. Tissue Bcl-2 levels were detected by the immunohistochemistry method. RESULTS Tissue CAT and SOD activities and NO levels were significantly lower, and MDA and serum ADMA levels were higher in the CO group than in the control group (P<0.001). The curcumin+CO group had higher CAT activities (P=0.007) and lower MDA than the CO group (P<0.001) and higher ADMA levels than the control group (P=0.023). However, there was no significant difference observed for tissue SOD activity or NO levels between these 2 groups. In the curcumin+CO group, the Bcl-2 level was higher than that in the CO group (P=0.017). CONCLUSIONS The positive effect of curcumin on CAT activities, together with suppression of MDA levels, has shown that curcumin may have a protective effect against CO poisoning.

Dietary Nitrate Metabolism in Porcine Ocular Tissues Determined Using 15N-Labeled Sodium Nitrate Supplementation.

Nitrate (NO3-) obtained from the diet is converted to nitrite (NO2-) and subsequently to nitric oxide (NO) within the body. Previously, we showed that porcine eye components contain substantial amounts of nitrate and nitrite that are similar to those in blood. Notably, cornea and sclera exhibited the capability to reduce nitrate to nitrite. To gain deeper insights into nitrate metabolism in porcine eyes, our current study involved feeding pigs either NaCl or Na15NO3 and assessing the levels of total and 15N-labeled NO3-/NO2- in various ocular tissues. Three hours after Na15NO3 ingestion, a marked increase in 15NO3- and 15NO2- was observed in all parts of the eye; in particular, the aqueous and vitreous humor showed a high 15NO3- enrichment (77.5 and 74.5%, respectively), similar to that of plasma (77.1%) and showed an even higher 15NO2- enrichment (39.9 and 35.3%, respectively) than that of plasma (19.8%). The total amounts of NO3- and NO2- exhibited patterns consistent with those observed in 15N analysis. Next, to investigate whether nitrate or nitrite accumulate proportionally after multiple nitrate treatments, we measured nitrate and nitrite contents after supplementing pigs with Na15NO3 for five consecutive days. In both 15N-labeled and total nitrate and nitrite analysis, we did not observe further accumulation of these ions after multiple treatments, compared to a single treatment. These findings suggest that dietary nitrate supplementation exerts a significant influence on nitrate and nitrite levels and potentially NO levels in the eye and opens up the possibility for the therapeutic use of dietary nitrate/nitrite to enhance or restore NO levels in ocular tissues.

Urinary excretion of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine is positively related to nitric oxide level in tissues of normotensive and hypertensive rats

Nitric oxide (NO) is one of the gaseous transmitters which play a very important role in the regulation of the circulatory system. Decreased NO availability is associated with hypertension, cardiovascular and kidney diseases. Endogenous NO is generated enzymatically by nitric oxide synthase (NOS) depending on the availability of the substrate, cofactors, or presence/absence of inhibitors, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). The objective of this study was to evaluate the potential relationship between NO level in rat tissues (heart and kidneys) and the concentrations of endogenous metabolites related to NO in plasma and urine. The experiment was carried out with 16- and 60-week-old male Wistar Kyoto (WKY) and age-matched male Spontaneously Hypertensive Rats (SHR). NO level in tissue homogenates was determined by the colorimetric method. RT-qPCR was used to verify the expression of the eNOS (endothelial NOS) gene. Plasma and urine concentrations of arginine, ornithine, citrulline, and dimethylarginines were examined by the UPLC-MS/MS method. 16-week-old WKY rats had the highest tissue NO and plasma citrulline levels. Furthermore, 16-week-old WKY rats showed higher urinary excretion of ADMA/SDMA compared to other experimental groups, however, plasma concentrations of arginine, ADMA, and SDMA were comparable between the groups. In conclusion, our research shows that hypertension and aging decrease tissue NO levels and are associated with reduced urinary excretion of NOS inhibitors, i.e., ADMA and SDMA.

Toxic effect of carpet dust on the biochemical indices and histological structure of the lung in rats: the potential role of cytochrome P450 2E1 and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways

Background: Carpet dust exposure in the carpet industry causes various respiratory hazards that lead to permanent loss of lung function. This study investigated the potentially toxic effects of knotted and tufted carpet dust on rat lungs and the possible involvement of cytochrome P450 2E1 (CYP2E1) and extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathways in the induced toxicity, as well as histological changes in the lung induced by carpet dust. Methods: This study divided 48 adult rats into six groups: group I was the control group, group II (vehicle group) received phosphate buffer saline (50 µL/rat), groups III and IV received knotted dust (2.5 and 5 mg/kg, respectively), and groups V and VI received tufted dust (2.5 and 5 mg/kg, respectively). All treatments were intranasally administered once a day for 7 days. Results: Both dust types significantly decreased the lung content of GSH compared with the control. Significantly elevated malondialdehyde (MDA) and nitric oxide (NO) lung contents were observed with an increased CYP2E1, interleukin (IL)-6, nuclear factor kappa B (NF-κβ), and ERK/MAPK. The histological lung structure was moderately affected with a moderately increased number of CD68-positive macrophages in the lung parenchyma of knotted dust-exposed rats, whereas tufted dust exposure severely affected the lung tissue with significantly increased CD68-positive macrophages. Conclusions: Carpet dust exposure could induce oxidative stress and inflammatory response in the lung tissue via induction of CYP2E1 that stimulates ERK/MAPK signalling pathway proteins, resulting in elevated MDA, NO and IL-6 levels in the lung tissue with suppressed GSH content. Tufted dust could possess a more toxic response than knotted ones.

Luteolin ameliorates hypoxia-induced pulmonary hypertension via regulating HIF-2α-Arg-NO axis and PI3K-AKT-eNOS-NO signaling pathway

BackgroundPulmonary hypertension (PH) is a devastating disease with poor prognosis and high mortality. Hypoxia induced pulmonary hypertension (HPH) is a persistent threat to human health, especially to people who live on high altitude plateau. Pulmonary vascular endothelial cell is involved in numerous pathophysiological processes, including in vasoconstriction, oxidative stress, cell growth and differentiation. Endothelial cells (ECs) are the first layer to be exposed to changed oxygen levels and hypoxia could lead to ECs dysfunction. Endothelial-derived nitric oxide (NO) is the most important bioactive molecule, which could regulate endothelial homeostasis. PH pathophysiology has been linked to the disruption of NO pathways. PurposeLuteolin is a kind of plant active ingredient with multiple pharmacological activities. The purpose of this study is to detect the effect of luteolin on HPH with in vivo, ex vivo and in vitro analyses and to further elucidate luteolin's pharmaceutical mechanism with NO related signaling pathway regulation. MethodsHypobaric chamber was used to establish HPH animal model. Rats were intragastrically administrated luteolin for 28 days. Then hemodynamic indexes, histopathological changes, pulmonary artery endothelial function, NO content and arginase activity in lung tissue, NO related pathway proteins expression were measured to evaluate the effect of luteolin on HPH. PAECs were treated with 1% O2 and incubated with or without luteolin. PAECs vitality, NO content in cells supernatant, and NO related pathway proteins expression were tested to reveal the protective mechanism of luteolin. ResultsLuteolin decreased mean pulmonary hypertension of HPH rats, alleviated right ventricular and pulmonary vascular remodeling. Immunofluorescence staining (vWF), isolated perfused/ventilated rat lung experiment indicated that luteolin protected pulmonary vascular endothelial function of HPH rats. Luteolin increased NO content in PAECs supernatant while decreased NO level in lung tissues of HPH rats. Further, it was demonstrated that luteolin inhibited HIF-2α-Arg axis in PAECs and HPH rats. PI3K-AKT-eNOS signaling pathway was upregulated in PAECs, but which was downregulated in lung tissues of HPH rats. Pharmacological effect of luteolin was equivalent or better than sildenafil. ConclusionLuteolin ameliorated HPH in rats by protecting pulmonary vascular endothelial function via regulating HIF-2α-Arg-NO axis and PI3K-AKT-eNOS-NO signaling pathway. This study may provide a novel perspective and approach to alleviate the devastating disease of HPH.

Effect of red beetroot juice on oxidative status and islet insulin release in adult male rats

IntroductionBeetroot is rich in inorganic nitrate and it has been shown that inorganic nitrate has beneficial effects on metabolic syndrome. This study aims to investigate the effect of red beetroot juice (RBJ) on carbohydrate metabolism in adult insulin-resistant rats.Materials and methodsSixteen male Wistar rats (32 weeks old) were divided into two equal groups: control and RBJ. Treatment with drinking water (control) and 100% RBJ (RBJ) was lasted for 5 weeks. At the end of the 4th week the intraperitoneal glucose tolerance test was performed and at the end of the study period animals were sacrificed and blood and tissue (aorta, heart, and liver) samples were collected. Furthermore, pancreatic islets were isolated and their insulin secretion activity was investigated in different glycemic conditions.ResultsCompared to the control group, RBJ-treated rats showed lower blood glucose and insulin levels in the glucose tolerance test. Serum and tissue levels of nitric oxide in the RBJ group were significantly higher than those in the control group. The liver peroxidation and serum aspartate transaminase levels were significantly increased in the RBJ-treated animals compared to the control group. The islets of RBJ group exhibited lower insulin secretion, especially in 16.7 mM glucose concentration (supraphysiologic condition) than control group.ConclusionsRBJ consumption improves glucose metabolism in rats via increasing nitric oxide metabolites in an insulin-independent manner. However, future studies are needed to minimize the potential hepatic adverse consequences.

Grapefruit peel extract mitigates paroxetine-induced erectile dysfunction in rats through stimulation of erectile response, antioxidant status, and inhibition of key enzymes related with impaired penile erection.

Despite the antidepressant potency of paroxetine, its side effect of erectile dysfunction is burdensome. Grapefruit peels (GFPs) are underutilized cultivar wastes with wide range of therapeutic potentials which have been attributed to their antioxidant behavior and phenolic contents' abilities to effectively inhibit enzymatic activities and manage endothelial dysfunction in cardiovascular disorders. This study aims to investigate the erectogenic potentials of GFP extract in a rat model of paroxetine-induced ED. Experimental rats were sectioned into five groups: [1: control; 2: paroxetine (10mg/kg); 3: paroxetine + sildenafil (5mg/kg); 4: paroxetine + GFP (50 mg/kg); 5: paroxetine + GFP (100 mg/kg)] and treated for 28 days. Sexual behavior of rats was assessed and effect of GFP on ecto-5' nucleotidases, phosphodiesterase-5, and adenosine deaminase (ADA) activities was determined in rats' penile tissues. The levels of malondialdehyde, nitric oxide (NO) as well as superoxide dismutase (SOD) and catalase activities were also determined. HPLC-DAD analysis showed the presence of naringin, rutin, caffeic acid, quercitrin, quercetin, and kaempferol glycoside. Oral administration of paroxetine reduced erectile response as revealed by their low intromission and mounting numbers as well as high intromission and mounting latencies. Paroxetine caused a significant elevation of ADA and phosphodiesterase-5 activities and malondialdehyde levels with drastic reduction in levels of NO, SOD, and catalase activities in rats' penile tissues. However, GFP extract reversed PDE-5, ADA, and antioxidant activities to normal levels, raised the concentration of NO. These results suggest the erectogenic effects and protective potentials of GFP extract against paroxetine-induced erectile dysfunction. PRACTICAL APPLICATION: Grapefruit peels are an environmental menace in many countries and this study showed that the peels can be used in the prevention / management of erectile dysfunction. The therapeutic potentials of the peels are due to the presence of bioactive compounds such as flavonoids and phenolic acids. Therefore, exploring the erectogenic potentials of the peels will translate to conversion of the wastes to therapeutic products.

Nitric oxide-releasing nanomaterials: from basic research to potential biotechnological applications in agriculture.

Nitric oxide (NO) is a multifunctional gaseous signal that modulates the growth, development and stress tolerance of higher plants. NO donors have been used to boost plant endogenous NO levels and to activate NO-related responses, but this strategy is often hindered by the relative instability of donors. Alternatively, nanoscience offers a new, promising way to enhance NO delivery to plants, as NO-releasing nanomaterials (e.g. S-nitrosothiol-containing chitosan nanoparticles) have many beneficial physicochemical and biochemical properties compared to non-encapsulated NO donors. Nano NO donors are effective in increasing tissue NO levels and enhancing NO effects both in animal and human systems. The authors believe, and would like to emphasize, that new trends and technologies are essential for advancing plant NO research and nanotechnology may represent a breakthrough in traditional agriculture and environmental science. Herein, we aim to draw the attention of the scientific community to the potential of NO-releasing nanomaterials in both basic and applied plant research as alternatives to conventional NO donors, providing a brief overview of the current knowledge and identifying future research directions. We also express our opinion about the challenges for the application of nano NO donors, such as the environmental footprint and stakeholder's acceptance of these materials.

Effects of curcumin on arginase enzyme activity, ornithine and nitric oxide levels in experimental breast cancer model

Breast cancer accounts for almost 30% of all cancer types, making it the most common type of tumor among women in the world. Arginase, an essential enzyme of the urea cycle, leads to the formation of urea and ornithine from L-arginine using the same substrate as nitric oxide synthase (NOS). Arginase has been reported to be higher in cancer patients and can be used as a useful biomarker. In this study, we aimed to investigate the effects of curcumin, an anticarcinogenic agent, on arginase enzyme activity, ornithine, and nitric oxide (NO) levels in experimental breast cancer model in mice. 43 male Balb/c mice were used, and Erhlich acid tumor model was created in the study. Mice were divided into five groups as healthy control group, curcumin treatment before tumor formation, curcumin treatment after tumor formation and cancer control groups. 100 mg/kg curcumin were given orally. Serum and tissue arginase enzyme activities, NO levels and tissue ornithine levels were determined spectrophotometrically. Increased serum arginase activity decreased with curcumin treatment, but this difference was not statistically significant. On the other hand, decreased NO levels were increased with curcumin treatment. In tumor tissue, arginase activity and ornithine levels decreased significantly with curcumin treatment and tissue NO levels increased significantly with curcumin treatment. In our study, we show that curcumin may have a protective effect on the development of breast cancer by inhibiting arginase enzyme activity and ornithine levels, which are the precursors of polyamines, as well as inducing NO production via NOS. As a promising anticancer agent, the net effects of curcumin in this mechanism should be supported by more advanced studies and new parameters.

Aloe vera gel attenuates acetic acid-induced ulcerative colitis in adult male Wistar rats.

Ulcerative colitis is a disease of undetermined etiology and treatment. It affects the colon and rectum and typically involves the mucosa, manifesting as continuous areas of inflammation and ulceration. Aloe gel contains more than a hundred potentially active constituents of different classes. This study investigated the effect of aloe gel on experimentally-induced ulcerative colitis. Male Wistar rats were randomly allocated into groups A to F of six rats each. Ulcerative colitis was induced to rats in groups B to F by single intra-colonic administration of 2 mL of 4% acetic acid with a size 6F pediatrics catheter. In contrast, group A received an equivalent volume of normal saline by the same route. Twenty-four hours after induction, rats in groups B and C received normal saline and 1 mg/kg b. wt. daily dose of dexamethasone, respectively. In contrast, those in groups D, E, and F received 20, 40, and 60 mg/kg b. wt. doses of aloe gel, respectively, for 14 days. They were sacrificed 24 h after the last administration. We assessed disease progression by determining the clinical activity index, gross inflammation, histological alterations, the intensity of DNA in colon cells, and tissue level of nitric oxide. All the parameters but one increased significantly in group B rats. The quantitative distribution of DNA in colon cells reduced significantly in this group. Aloe gel doses significantly reversed these changes in a dose-dependent manner. Dexamethasone showed lesser efficacy relative to 60 mg dose of the Aloe gel extract. We conclude that Aloe vera gel has therapeutic potential in the treatment and management of ulcerative colitis. The most significant effects were observed in the groups treated with the highest dose of Aloe gel (60 mg/kg b. wt.). It is also worth noting that the remediated potential of aloe gel in acetic acid-induced UC surpasses that of dexamethasone.

Sinoacutine inhibits inflammatory responses to attenuates acute lung injury by regulating NF-\u03baB and JNK signaling pathways

BackgroundStephania yunnanensis H. S. Lo is widely used as an antipyretic, analgesic and anti-inflammatory herbal medicine in SouthWest China. In this study, we investigated the anti-inflammatory activity and mechanism of sinoacutine (sino), one of the primary components extracted from this plant.MethodsA RAW264.7 cell model was established using lipopolysaccharide (LPS) induced for estimation of cytokines in vitro, qPCR was used to estimate gene expression, western blot analysis was used to estimate protein level and investigate the regulation of NF- κB, JNK and MAPK signal pathway. In addition, an acute lung injury model was established to determine lung index and levels of influencing factors.ResultsUsing the RAW264.7 model, we found that sino reduced levels of nitric oxide (NO), tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and prostaglandin E2 (PGE2) but increased levels of IL-6. qPCR analysis revealed that sino (50, 25 μg/ml) inhibited gene expression of nitric oxide synthase (iNOS). western blot analysis showed that sino significantly inhibited protein levels of both iNOS and COX-2. Further signalling pathway analysis validated that sino also inhibited phosphorylation of p65 in the NF-κB and c-Jun NH2 terminal kinase (JNK) signalling pathways but promoted the phosphorylation of extracellular signal regulated kinase (ERK) and p38 in the MAPK signalling pathway. In addition, in a mouse model induced by LPS, we determined that sino reduced the lung index and the levels of myeloperoxidase (MPO), NO, IL-6 and TNF-α in lung tissues and bronchoalveolar lavage fluid (BALF) in acute lung injury (ALI).ConclusionTaken together, our results demonstrate that sino is a promising drug to alleviate LPS-induced inflammatory reactions.

The Combination of Stromal Vascular Fraction Cells and Platelet-Rich Plasma Reduces Malondialdehyde and Nitric Oxide Levels in Deep Dermal Burn Injury.

IntroductionThermal burns release reactive oxygen species, which cause profound systemic and local changes. Stromal vascular fraction cells (SVFs) combined with platelet-rich plasma accelerate burn wound healing. This study investigated the effect of a combination of locally injected SVFs and PRP on malondialdehyde (MDA) and nitric oxide (NO) serum and tissue levels in a deep dermal burn model in Wistar rats.MethodsThirty-six adult Wistar rats weighing between 150 and 250 grams were used in this study to establish a deep dermal degree burn wound model. They were randomly divided into 4 groups: locally injected the combination SVFs and PRP, the Vaseline group, the placebo group, and healthy Wistar rats (the normal control group). MDA and NO levels in blood serum and burn wound tissue were measured at 8, 24, and 48 hours. Data were analyzed with one-way ANOVA followed by multiple comparisons tests and regression tests.ResultsLocal injection of SVFs and PRP in combination affected blood MDA, tissue MDA, blood NO and tissue NO levels, with reductions of 0.257µmol/L, 0.427 µmol/L, 21.78nmol/mg, and 23.777nmol/mg, respectively. Injection of SVFs and PRP in combination reduced tissue MDA levels by 1.282 times, NO blood levels by 2.305, and NO tissue levels by 2.377 times compared to Vaseline application.ConclusionThe combination of SVFs and PRP undeniably reduced the MDA and NO levels in blood and tissue compared to those in the Vaseline and placebo groups. The injection of these two preparations in combination inhibited the local and systemic stress oxidative response, as illustrated by the decreased MDA and NO levels in blood serum and tissue.

The Effect of Acute Exercise on the Interaction between Doxorubicin Administration and Nitric Oxide Metabolism in Heart and Liver Cells

A portion of the reactive species produced as a result of doxorubicin (DOX)-induced oxidative stress is associated with the overproduction of nitric oxide (NO). The subsequent accumulation of DOX in cardiac and liver tissue make these areas particularly susceptible to DOX-induced damage. The purpose of this study was to examine the interaction between DOX administration and exercise on NO metabolism in heart and liver cells. Thirty male Sprague-Dawley rats received an intraperitoneal injection of DOX (4.5 mg/kg) and were randomly separated into 5 experimental groups (n=6). Groups A and E did not perform any exercise and were euthanized at 24 and 48 hours, respectively. Groups B and C underwent a single bout of swimming exercise for 60 min and were sacrificed at 25 and 48 hrs, respectively. Group D exercised at 24 and 48 hrs and were sacrificed at 49 hrs. No changes (P>0.05) in NO concentrations were observed in liver tissue following exercise as compared the non-exercised groups. In contrast, a consistent pattern was observed in cardiac tissues that showed a decrease in NO concentrations in the exercised (B, C, and D) vs. the non-exercised groups (groups A and E). For example, the NO concentrations in the left atrium of group A (non-exercised) was 20±1.1 μmol/mg and decreased (P<0.05) to 15.6±0.6 μmol/mg in group D (exercised). These results suggest that exercise may play a role in lowering DOX induced elevations in NO levels in cardiac tissue, indicating that exercise may assist in mitigating the cardiotoxic effects of chemotherapy.

Effect of Hesperidin against Induced Colon Cancer in Rats: Impact of Smad4 and Activin A Signaling Pathway

Scope To evaluate the chemopreventive efficacy of hesperidin (Hsd) in 1,2-dimethylhydrazine (DMH)-induced colorectal cancer (CRC) and demonstrate its role in mothers against decapentaplegic homolog 4(Smad4) and activin A signaling pathways. Methods and results A CRC rat model was established by DMH exposure, and the animals were randomly divided into five groups: Control group, Hsd, DMH, DMH + Hsd, and DMH followed by Hsd. The resected colon was subjected to macroscopic, microscopic, molecular, histopathological, and immunohistochemical examination. Activin A, Smad4, malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) levels in tissues were also measured. The DMH group exhibited a significant increase in the gene and protein expression of activin A as well as MDA and NO levels in tissues. There was a significant reduction in the gene and protein expression of Smad4 as well as GSH and SOD levels in tissues. Administration of Hsd significantly upregulated Smad4 and activin A gene expressions in both the DMH + Hsd and DMH followed by Hsd groups. Moreover, Hsd improved the antioxidant status of the former two groups. Conclusion This study demonstrated the chemopreventive effect of Hsd against CRC by modulating Smad4 and activin A signaling in vivo. Further studies are needed to demonstrate its clinical value and explore its possible role in advanced malignancy.

Comparison of ischemic preconditioning and BotulinumA Toxin injection for the prevention of ischemia-reperfusion injury in musculocutaneous flaps

Background/aimThe aim of the study was to evaluate the protective effect of Botulinum A toxin injection against ischemia-reperfusion injury.Materials and methodsThirty-two Sprague-Dawley rats were divided into: control, ischemia-reperfusion, ischemic preconditioning, and botulinum groups. In all groups the musculocutaneous pedicle flap was occluded for 4 h, and then reperfused to induce ischemia-reperfusion injury. Serum and tissue myeloperoxidase (MPO) and nitric oxide (NO) levels were measured at 24 h and at 10 days.ResultsTissue MPO levels did not differ significantly between the ischemic preconditioning and botulinum groups at 24 h but was significantly lower in the botulinum group at 10 days. Tissue NO levels were significantly higher in the ischemic preconditioning group compared to the botulinum group at 24 h and at 10 days. Serum MPO showed no significant difference between these two groups at 24 h but was significantly lower in the ischemic preconditioning group compared to the botulinum group at 10 days. Serum NO levels were not significantly different at 24 h but significantly higher in the botulinum group at 10 days.ConclusionFindings show that botulinum has a protective effect against the ischemia-reperfusion injury via increased NO and decreased MPO levels in tissue. Based on tissue NO levels, ischemic preconditioning was significantly higher than botulinum.

The potential beneficial effects of sildenafil and diosmin in experimentally-induced gastric ulcer in rats

Objectivesresearch in the treatment of gastric ulcer has involved the investigation of protective drugs. These drugs may be used as adjacent therapy with the traditional pharmacologic treatment of peptic ulcer. The present study is designed to investigate the gastro protective effects of diosmin (DIO), sildenafil (SILD) and their combinations with ranitidine (RANT) against indomethacin (INDO)-induced gastric ulcer in rats. Additionally, the potential mechanisms of their effect are addressed. MethodsDIO (100 mg/kg) and SILD (10 mg/kg) were administered by oral route for seven days prior to ulcer induction. Moreover, other rats were treated with RANT (50 mg/kg) not only to compare efficiency of the medications but also, to help clarify potential mechanisms of their effect. Following, after 24 h of fasting, INDO (100 mg/kg) was administered for induction of gastric ulcer. Furthermore, rats in each group were sacrificed 4 h later. Biochemical analysis of DIO, SILD, RANT and their combinations pre-treated host tissues demonstrated reduction in tumor necrosis factor (TNF)-α and malondialdehyde (MDA) contents and concomitant increase in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. ResultIt is observed, that SILD and DIO pre-treatment showed non-significant effect on gastric juice PH. However, their combinations with RANT is superior to using RANT alone. In addition, the results revealed, that combinations of (RANT and SILD) and (RANT and DIO) showed the highest increase in gastric tissue NO levels. But, these two combinations achieved the lowest MDA levels relative to the control (INDO) group. Despite, all groups displayed non-significant effect on reduced GSH content, (RANT and SILD) group increased GSH concentration by 39.75% relative to INDO group. In addition, DIO, RANT and (RANT and DIO) pre-treatment have anti-apoptotic activity on gastric mucosa. On the other hand, SILD did not affect caspase-3 immunostaining. These results are confirmed by histopathological findings. ConclusionThe work outcomes provide a new gastro protective agents in clinical gastropathy. So, this study not only provides an efficient way for peptic ulcer protection, but also it may be considered for future studies in ulcer healing and gastric cancer.

Enhancement of heat shock protein 70 attenuates inducible nitric oxide synthase in preeclampsia complicated with fetal growth restriction

Objectives Preeclampsia (PE) and fetal growth restriction (FGR) have abnormal placental implantation and endothelial dysfunction in common. However, their etiologies are not well understood. Both heat shock protein 70 (Hsp70) and nitric oxide (NO) are suggested to play a major role in the regulation of maternal and fetoplacental hemodynamics. In this study, the association of PE with FGR and Hsp70 or NO was analyzed. Methods A total of 30 cases of PE, 25 cases of PE complicated with FGR and 50 cases of normal pregnant women were chose, and PE and normal animal models were constructed. Subsequently, the levels of Hsp70 and NO in serum and placental tissues of humans and animals were measured and compared. Further, rats were injected with pLV-NC-shRNA, pLV-Hsp70-shRNA, pLV-EFIa-NC, and pLV-EFIa-Hsp70, respectively, the weight of each conceptus, number of pups, fetal crown to tail length, total weight of the placenta/fetus unit, and the content of NO were analyzed. Results The expression of Hsp70 in serum and placental tissues of PE complicated with or without FGR group was increased, whereas the content of NO was decreased compared to the normal group. The fetal weight (FW) of the Hsp70 targeted suppression group was higher than the other two groups, whereas the placental weight (PW) was reversed. Also, NO synthase (NOS) expression was decreased in the Hsp70 over-expression group. Conclusions We speculated that the enhancement of Hsp70 might be related to the development of PE combined with FGR through inhibiting the synthesis of NOS.

Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways.

Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (i.e., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e., nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.