Metabolic syndrome (MetS) is defined by the World Health Organisation (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidaemia. The components of MetS and the associated cardiovascular risks may disrupt the vascular endothelial function and the structure of the vascular wall, increasing the risk of atherosclerosis and vascular diseases. In this study we evaluated the relationship between the carotid intima–media thickness (CIMT), the redox balance parameters of plasma asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), and heme oxygenase 1 (HO-1), and the expression of oxidative stress-related nuclear factor kappa B (NF-kB), nuclear factor erythroid 2-related factor 2 (Nrf2), and HO-1 in peripheral blood mononuclear cells (PBMCs) in MetS. Significantly higher CIMT was established in MetS patients aged ≥ 55 years as compared with the control group (0.96 ± 0.29 vs. 0.74 ± 0.21, p < 0.05). Expression was higher in MetS patients aged < 55 years (83% for NF-kB, p < 0.05; 251% for Nrf2, p < 0.05, and 337% for HO-1, p < 0.05) in comparison to the control group. Similarly, expression was higher in CIMT < 0.90 mm than the control group by 80% for NF-kB, p < 0.01; 260% for Nrf2, p < 0.05, and 303% for HO-1, p < 0.05. In contrast, gene expression was under-regulated in the subgroups of MetS patients aged ≥ 55 years and MetS patients with CIMT ≥ 0.90 mm. Significantly higher plasma levels for MDA, ADMA, and HO-1 were established in the age < 55 and age ≥ 55 MetS subgroups and the CIMT < 0.90 mm and CIMT ≥ 0.90 mm subgroups. In conclusion, MetS individuals aged ≥ 55 are at higher risk of increased CIMT and impaired redox balance.

Potential of various herbs in regard to their ability to counteract obesity and related metabolic disturbances has been extensively studied. The aim of the current study was to assess the potential of Agrimonia eupatoria aqueous infusion (AE) to counteract fructose induced changes in serum total cholesterol (TC) and triglycerides (TG), the ratio of retroperitoneal adipose tissue weight/body weight and adipose tissue gene expression of the proteins Lipe, Fasn, Dgat, Hmgcr and adipokines AdipoQ and Plin. Twenty-four male Wistar rats were equally divided in to four groups -standard diet (ST); standard diet with AE (ST+AE); fructose overloaded (FR); fructose overloaded with AE (FR+AE). FR group showed significantly higher levels of TC, TG and adipose tissue weight relative to other groups. AE administration resulted in lower TC and TG levels, as compared to ST group (0.93 +/- 0.43 mmol/L vs. 1.29 +/- 0.57 mmol/L, p < 0.05 and 0.59 +/- 0.1 vs. 0.91 +/- 0.17 mmol/L, p < 0.001, respectively). Similarly, TC and TG were decreased also in ST+AE group (0.47 +/- 0.21 mmol/L vs. 0.87 +/- 0.57 mmol/L, p < 0.01 and 0.77 +/- 0.15 vs. 0.92 +/- 0.25 mmol/L, p < 0.05, respectively) in comparison to ST group. Gene expression analysis revealed a significant increase in Lipe (2.35 fold change, p < 0.05) and Hmgcr (2.86 fold change, p < 0.05) and a decrease (83%, p < 0.001) in Fasn mRNA levels in the FR group. AE consumption contributed to a significant decrease in the expression of Dgat2 (56%, p < 0.05) and Hmgcr (0.52%, p < 0.05) in Fr+AE group and of Fasn (71%, p < 0.001) in the ST+AE group. In conclusion, recent study demonstrated that Agrimonia eupatoria aqueous infusion intake improved total cholesterol and triglycerides imbalance in Wistar rats and modulated adipose tissue gene expression, which indicated that the herb might exert its favourable effects on adipose tissue possibly by preventing triglyceride synthesis and inducing mobilization of stored TG.

Endothelial dysfunction is one of the major factors in the pathogenesis of metabolic syndrome (MetS), and its molecular mechanisms are not completely understood. The present study aimed to examine the connection between nuclear factor2-related factor2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), heme oxygenase 1 (HO-1), and plasma asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) in people with MetS. Participants in the study were as follows: with MetS (n = 30) and without MetS (Control) (n = 14). Expression of Nrf2, NF-kB, and HO-1 was measured in peripheral blood mononuclear cells (PBMCs). Plasma ADMA was determined using the ELISA technique and MDA via the thiobarbituric acid method. Our study showed that mRNA of NF-kB, Nrf2, and HO-1 levels in PBMCs in the MetS group were significantly higher than in the controls by 53%, 130%, and 185% (p < 0.05), respectively. Similarly, elevated levels of MDA (by 78%, p < 0.001) and ADMA (by 18.7%, p < 0.001) were established in the MetS group. Our findings show the importance of transcription factor Nrf2, playing an integral role in the protection of the endothelium, and of NF-κB, a transcription factor mediating the inflammatory response in MetS. Knowledge of complex cellular–molecular mechanisms would allow the use of biomarkers such as Nrf2, NF-kB, HO-1, and ADMA for the assessment of endothelial dysfunction in clinical practice.

The aim of the study was to examine the plasma levels ADMA, MDA and lipid markers in people with metabolic syndrome as well as in clinically asymptomatic people. We further studied whether such elevation of ADMA as marker of endothelial dysfunction was correlated with oxidative stress and conventional risk factors. According to modified ATP III criteria the participants (52 females, 8 males) of the study were divided in four group: G1, n=19 people with MetS; G2, n=12 peoples with genetic predisposition and risk for MetS; G3, n=15 people with unhealthy life style and risk of MetS and Control group n=14). The study revealed significant differences between people groups with and without anamnestic data of MetS in terms of ADMA, MDA and lipid markers. Plasma levels of ADMA and MDA in G1 were significantly higher (p<0.001) compared to these of G3. The levels of lipid markers (TG, TChol and LDL-C, HDL-C) in G1 were close to the control. The levels of ADMA significantly correlated with plasma MDA levels. These results suggest a link between plasma ADMA and MDA as indicator of oxidative stress and their role as predictive biomarkers for of endothelial dysfunction and cardiometabolic risk.

Severe burn trauma triggers oxidative gastric mucosal injury. The purpose of this study was to investigate the antioxidant defence mechanisms and protective effect of melatonin in the gastric mucosa after burn injury. In order to investigate the mechanisms involved in the gastric antioxidant defence in a rat burn model, quantitative real-time PCR and immunohistochemistry techniques were applied. An analysis of glutathione peroxidase 4 (GPx4), glutathione reductase (GR), and catalase (Cat) gene expression was performed along with the evaluation of the gastric Cu/Zn superoxide dismutase (Cu/Zn SOD) activity. Melatonin was applied immediately and 12 h after 30% of total body surface area burns. The burn injury significantly increased the Gpx4 mRNA (P < 0.000 1) and Gsr mRNA (P < 0.000 1) expression. It also had a slight positive effect on the Cat mRNA expression and Cu/Zn SOD activity. Melatonin, in turn, markedly augmented the burn-induced Cu/Zn SOD (P < 0.000 1) activity, reversed the Gpx4 mRNA (P < 0.000 1) and Gsr mRNA (P < 0.000 1) expression, and inhibited the Cat mRNA level. In conclusion, the present study suggests that a burn injury adaptively increases the Cu/Zn SOD activity and enhances the Gpx4 and Gsr gene expression in the gastric mucosa. Melatonin effectively modulates the expression of the cellular antioxidant enzymes, and improves the antioxidant defence by augmenting the Cu/Zn SOD activity.

Introduction: Оbesity has been labelled as a “non-infectious pandemic of our time”. It increases the risk of several debilitating diseases , including cardiovascular disorders, diabetes mellitus, tumors, and other pathologies. Up to date both therapeutic and preventive approaches have been largely unsuccessful. At the present time body mass index (BMI) is considered the most common anthropometric method to diagnose obesity. According to a variety of in vivo and in vitro studies, exogenous melatonin has a pronounced effect on carbohydrate and lipid metabolism. Furthermore, supplementation with melatonin improves oxidative stress and insulin resistance preventing hypertrophy of the adipose tissue and body weight gain. Aim: We evaluated the effect of melatonin supplementation on BMI and retroperitoneal fat mass in diet-induced obesity rat model. Materials and Methods: Male Wistar rats (n = 32), provided with standard rat chow and tap water freely available, were randomly divided into four groups as follows: control group – rats received standard rodent diet and tap water; melatonin group – rats received standard rodent diet and tap water, and melatonin administered per os (4 mg/kg/24h); fructose group – rats received standard rodent diet and tap water supplemented with 20% fructose; and fructose plus melatonin group – rats received standard rodent diet and tap water supplemented with 20% fructose, and melatonin administered per os (4 mg/kg/24 h). At the end of the experimental period, the animals were sacrificed, zoo metric measurements were taken and BMI was calculated . Results: St atistically significant differences were observed between the anthropometric parameters of the experimental groups. When compared with the control group, fructose-supplemented rats showed a remarkable increase in retroperitoneal fat mass and BMI. In contrast, groups supplemented with melatonin showed s ignificant reductions in these parameters. Conclusion: Melatonin supplementation reduces fructose-induced obesity. In particular, body weight, retroperitoneal fat mass and BMI were remarkably decreased in melatonin-treated groups.

4-Hydroxynonenal (HNE), a major end-product of free-radical activated peroxidation of polyunsaturated fatty acids, has attracted great scientific interest. HNE is more stable than free radicals and can diffuse within the cell or leave it and react with targets far from the initial site. These reactive aldehyde species are considerably reactive, producing multiple intra- and inter-molecular covalent adducts with biomolecules such as proteins, DNA and phospholipids. HNE is the most intensively studied aldehyde in relation to its physiological and protective function as a signalling molecule that stimulates gene expression and cell survival, as well as for its pathophysiological role as a toxic messenger that can propagate and amplify oxidative injury and promote mitochondrial dysfunction and cell death. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world associated with oxidative stress, mitochondrial dysfunction and hepatocellular apoptosis. In this review we focus our attention on the molecular mechanism of the signalling and regulatory action of HNE. The role of HNE as a potent mediator for progression of liver injury in NAFLD is also discussed.

Objective: Burn- induced acute hepatic injury due to increased production of lipid peroxides and increased cellular apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is essential for cytoprotection against oxidative stress. We hypothesized that melatonin by activation of Nrf2 may shift Bax/Bcl-2 ratio to protect rat hepatocytes against apoptosis and progressive liver injury. The aim of this experimental study was to investigate the protective effects of melatonin against burn-induced apoptotic injury and the relationship between lipid peroxides expression of transcription factor Nrf2 and apoptotic protein in burn rat model. Methods: Melatonin was applied immediately after the burn. The expression of hepatic 4-hydroxynonenal (4-HNE), as a marker of liver peroxidative injury, Nrf2, as a marker of antioxidant defense and apoptosis-related genes Bcl-2 and Bax were evaluated using light immunоhistochemistry. Results: Burns caused an increased expression of 4-HNE, Bax and Bax/Bcl-2 ratio and induced apoptosis of sinusoidal endothelial cells (SECs) in liver tissue. Melatonin treatment augmented the increase in Nrf2 expression, decreased both burn-induced peroxidative damage and hepatic apoptosis as evidenced by reduced expression of Bax, enhanced expression of Bcl-2. In conclusion, our data suggest that activation of transcription factor Nrf2 by melatonin is protective against oxidative stress, apoptosis and hepatic injury in burns. The available information by melatonin`s effect on the redox sensing transcription factor Nrf2, as a regulator of antioxidant enzymes, antioxidants and antioxidant protection of the liver is limited. Melatonin activates the Nrf2/signaling pathway and acts as a natural inducer of anti-apoptotic and antioxidant protection under condition of burn-induced oxidative stress. This is a new cellular mechanism for protection against progressive burn-induced liver damage not only in animals but also in humans.

Melatonin, a basic secretory pineal gland product, is a nontoxic, multifunctional molecule. It has antioxidant and anti-apoptotic activities and protects tissues from injury. The objective of the present study was to determine the molecular mechanism of melatonin anti-apoptotic effect on gastric injury in a rat burn model. We hypothesized that melatonin gastric protection may be related to the activation of transcription erythroid 2-related factor 2 (Nrf2). Using a 30% total body surface area (TBSA) rat burn model, melatonin (10 mg/kg, i.p.) was injected immediately and 12 h after thermal skin injury. Via light immunohistochemistry, we determined the tissue level of 4-hydroxy-2-nonenal (4-HNE) as a marker of lipid peroxidation, Bcl-2 and Bax as apoptosis-related proteins, and Nrf2. Results are presented as medians (interquartile range (IQR)). Thermal trauma in burned animals, compared with the controls, increased the expression of pro-apoptotic Bax protein (1.37 (0.94–1.47)), decreased anti-apoptotic Bcl-2 protein (1.16 (1.06–1.23), p < 0.001) in epithelial cells, and elevated Bax/Bcl-2 ratios (p < 0.05). Tissue 4-HNE and Nrf2 levels were increased following severe burns (1.55 (0.98–1.61) and 1.16 (1.01–1.25), p < 0.05, respectively). Melatonin significantly decreased 4-HNE (0.87 (0.74–0.96), p < 0.01) and upregulated Nrf2 (1.55 (1.52–1.65), p < 0.001) levels. It also augmented Bax (1.68 (1.5–1.8), p < 0.001) and Bcl-2 expressions (1.96 (1.89–2.01), p < 0.0001), but reduced Bax/Bcl-2 ratios (p < 0.05). Our results suggest that experimental thermal trauma induces oxidative gastric mucosal injury. Melatonin manifests a gastroprotective effect through Nrf2 activation, lipid peroxidation attenuation, and Bax/Bcl-2 ratio modification as well.

Introduction. Thermal injury activates an inflammatory response. Melatonin possesses antioxidant and anti-inflammatory properties. The objective of the present work was to study melatonin effects on the inflammatory response under conditions of oxidative stress during the early stage of thermal injury. Materials and methods. We used 24 white male rats of Wistar breed, randomly divided into three experimental groups. Group one was the control, group two was inflicted with burn trauma, and group three was inflicted with burn trauma, with melatonin application following the thermal injury. Melatonin was applied twice in doses of 10 g/kg b.m. immediately after the burn trauma and again at 12 hours. Plasma levels of tumor necrosis-factor-a (TNF-alpha), a pro-inflammatory mediator, and of interleukin-10 (Il-10), an anti-inflammatory mediator, were examined and their ratio was calculated. The levels of malondialdehyde (MDA), an oxidative stress marker, were also estimated. Results. Thermal trauma significantly increased plasma TNF-alpha levels (partial derivative<0.01) and TNF-alpha/IL-10 ratio but did not change IL-10 ones. Plasma MDA concentrations were significantly elevated as well (partial derivative<0.0001). Melatonin application significantly reduced TNF-alpha (partial derivative<0.05), increased IL-10 (partial derivative<0.05), down-regulated TNF-alpha/IL-10 ratio and changed MDA concentrations (partial derivative<0.01). In conclusion, our results show that local alteration induces oxidative stress and inflammatory response with TNF-alpha/IL-10 disbalance. Melatonin modulates this response and attenuates oxidative stress in experimental burn injury.

Introduction: Severe thermal burns disturb tissue homeostasis of many organs, but the exact mechanisms of gastric mucosa changes are not yet clear. Various cellular mechanisms, such as cell activation, mitochondrial dysfunction, free oxygen radicals and cytokine overproduction may be involved in this process. Aim: The aim of this study was to assess the levels of malondialdehyde (MDA), apoptotic proteins Bax and Bcl-2 in normal gastric mucosa and to test the hypothesis that oxidative stress activation induces apoptotic processes in the stomach after experimental thermal trauma. Materials and M ethods: Under anesthesia, the shaved rats` dorsum was exposed to 90° C bath for 10 s to induce third-degree burn injury, involving 30% of the total body surface area. We determined the tissue level of MDA, a lipid peroxidation marker, by spectrophotometric method and the apoptosis of epithelial cells in gastric mucosa, which was immunohistochemically determined at the level of Bcl-2 and Bax in burn trauma. Results: The gastric MDA level was higher (p<0.01) in the burned group compared to the control group 24 hours after thermal injury. The gastric mucosa in the treated group showed congestion, degenerative changes in the surface epithelium, focal destruction of glandular epithelium with formation of acute erosions. Bax expressed moderately in epithelial cells, predominantly in the basal parts of the gastric glands, while in the control group protein content was localized in the same region, but it was weak. Bcl-2 protein in the control group revealed nuclear expression in surface epithelium, while in the basal layer of gastric mucosa the expression was moderate and mainly cytoplasmic. In the burned group, Bcl-2 expression was more diffuse, nuclear and cytoplasmic, but cytoplasmic expression was weak. C onclusion : Thermal skin trauma induces gastric mucosal injury through the activation of lipid peroxidation, increase of pro-apoptotic Bax protein expression and decrease of anti-apoptotic Bcl-2 protein expression in epithelial cells. We suggest that apoptosis is a possible mechanism for structural changes in the gastric mucosa.

Introduction: Melatonin, the principal secretory product of the pineal gland, has antioxidant functions as a potent antioxidant and free radical scavenger. Objectives of the present study were to investigate the effect of melatonin against inflammatory response, burn-induced oxidative damage and apoptotic changes of rat liver. Methods: Melatonin (10 mg /kg, i.p.) was applied immediately after 30% of total body surface area (TBSA) burns on male Wistar rats. The level of malondialdehyde (MDA) as a marker of an oxidative stress was quantified by thiobarbituric method. Hepatic TNFα and IL-10 as inflammatory markers were assayed by ELISA. Using light immunоchistochemistry the expression Ki67 proliferative marker was investigated. Results: Hepatic MDA and TNF-α levels increased significantly following burns without any change in IL-10 level. Intracellular vacuolization, hepatic cell degeneration and apoptosis occurred in rats after burns. The number of apoptotic cells was increased whereas no significant increase in Ki67 proliferative marker. Melatonin decreased the MDA and TNF-α content and increased the IL-10 level. It also limited the degenerative changes and formation of apoptotic cells in rat liver but did not increase expression of the marker of proliferation. In conclusion, our data show that melatonin relieves burn-induced hepatic damage associated with modulation of the proinflammatory/anti-inflammatory balance, mitigation of lipid peroxidation and hepatic apoptosis.

Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver disease, obesity and diabetes-features of metabolic syndrome. We evaluated the relationship between lipid peroxidation and other oxidative stress biomarkers with changes in expression of heme oxygenase-1 (HO-1) in rat fatty liver, induced by high fructose diet (HFD) and the effect of S-adenosylmethionine (SAMe). Twenty-one male rats were randomly assigned to three groups of seven animals each: HFD (35% fructose in drinking water for 16 weeks) group, HFD + SAMe (20 mg/kg b.w. in drinking water for 16 weeks) group and control group. HO-1 expression, malonyl dialdehyde (MDA) (a marker of lipid peroxidation), triglycerides (TG), SH group levels and histological studies were performed on hepatic tissue. HFD group showed microvesicular steatosis without inflammation and fibrosis. In HFD+SAM group microvesicular steatosis was not established. The HO-1 expression was significantly increased in HFD rats. SEMe augmented the increase in expression of HO-1. The levels of MDA and TG were elevated in HFD group. In HFD rats with lower levels of SH exhibited higher expression of HO-1. SAMe inhibited the increase in lipid peroxidation and TG levels and prevented the decrease in SH levels. In conclusion, SAMe has an important hepatoprotective effect and its protection is most probably exerted by increasing the expression of the antioxidant enzyme HO-1, in order to prevent the development of fatty liver.

Experimental investigations and clinical observations in cases of thermic shock reveal that microcirulation disorders rather often determined by disturbances of rheological properties of erythrocytes and partially of their flexibility present a characteristic peculiarity of this shock (3, 4). However, both pathogenetic mechanism and therapeutic influence concerning this important rheological index are not completely clarified yet and thus an object of experimental studies. A lot of authors relate the reduced deformability after thermic trauma with changed structural-functional activity of the erythrocyte membrane influenced by several factors such as catecholamines, kinins, prostaglandins, free fatty acids, etc. (2, 10). Recently, the concept is established that free-radical peroxide oxidation is one of the universal factors modifying membranes and reducing their functional activity (4). We could not find any data about the role of lipid peroxide oxidation (LPO) in the pathogenesis of disturbed erythrocyte flexibility in burns and after alpha-tocoferol (alpha-TF) treatment in the literature available. In the present work we have the purpose to study the effect of activated LPO on erythrocyte flexibility during the acute period after thermic trauma and after alpha-TF treatment considering alpha-TF a possible protector.

Melatonin, a major hormone of pineal gland, was recently show to attenuate acute gastric lesions induced by strong irritants because of the scavenging of free radicals.The effect of melatonin on burninduced gastric mucosal injury due to the skin burn is unclear.PURPOSE: This study investigated heme oxygenase-1 and markers linked with oxidative stress in gastric mucosa and the effect of melatonin in burn rat model.METHODS: Melatonin was applied immediately and 12 hours after 30% of total body surface area burns.Using light immunohistochemistry the expression of gastric mucosal inducible nitric oxide synthase (iNOS) and heme oxygenase (HO-1) was found out.Malondialdehyde (MDA) as a marker of oxidative injury was determined in gastric mucosa by the thiobarbituric acid method.RESULTS: Gastric MDA and iNOS levels were increased significantly after severe burn (p<0.05,p<0.0001, respectively).The increased HO-1 expression in the burned group was found out (p<0.05).Melatonin restricted the increased MDA (p<0.05) and iNOS (p<0.05)levels, and augmented the increase in HO-1 expression in gastric mucosa (p<0.05).In conclusion, melatonin ameliorates gastric mucosal injury via induction of antioxidant enzyme HO-1 and inhibition of oxidative stress beyond local burn skin injury.

Melatonin exerts beneficial effects on early liver injury by modulating hepatic oxidative stress. In order to understand the protective effect of melatonin against burn-induced hepatic injury we investigated the expression of 4-hydroxynonenal (4-HNE), a main product of lipid peroxidation and mediator of oxidative injury, the inducible heme-oxygenase-1 (HO-1), an antioxidant enzyme, and the anti-oxidative stress regulator erythroid 2-related factor 2 (Nrf2) in a burn rat model. Expression and localisation of HO-1, 4-HNE and Nrf2 in liver were investigated using light immunochemistry. Thermal skin injury caused a significant elevation in hepatic 4-HNE and degenerative liver changes. Concurrently, there was increased expression of HO-1, a rate-limiting enzyme for haem degradation and an oxidative stress marker in sinusoidal endothelial cells (SECs) and hepatocytes without changes in Nrf2 expression in the liver. Melatonin (20 mg/kg b.w.) augmented the increase in HO-1 expression, upregulated Nrf2 expression and also led to decreased 4-HNE levels and reduced levels of histopathological changes in rat liver. In conclusion, our results suggest that melatonin ameliorates burn-induced liver injury through the inhibition of oxidative stress, upregulation of the antioxidant enzyme HO-1 and activation of the antioxidant Nrf2 pathway. Stimulation of cellular protective mechanisms by activating the antioxidant stress response through Nrf2 is a new mechanism for protection against liver damage in burns.

SUMMARY Melatonin is indoleamine hormone derived from Ltryptophan. Due to its lipophilic nature, it is accessible to every cell. Melatonin has immunomodulatory and antioxidant activities thus protecting tissue injury. Heat shock proteins such as HSP32 known as heme oxygenase-1 (HO-1) possesses antioxidant, anti-inflammatory, and vasodilatory properties and plays an important role in the protecting of tissues from several stresses. The aim of study is to investigate the expression of HO-1 in gastric mucosa and its connection with oxidative stress and melatonin mediated protection after thermal injury. On rats back, under anesthesia, third degree burn was applied involving 30% of total body surface area (TBSA). Melatonin (10 mg per kg body mass) was injected i.p. immediately and 12 hours after thermal skin injury. We used tissue malondialdehyde (MDA), lipid peroxidation product, as a marker of oxidative stress. Gastric mucosa histopathology were observed on light microscopy and light immunohistochemistry investigating the HO-1 too. Results: The levels of MDA in gastric mucosa were elevated (p< 0.05). The HO-1 expression was significantly increased in rats with trauma. Melatonin inhibited elevation in lipid peroxidation product and augmented the increase in expression of HO-1 in the gastric mucosa. In conclusion, our data suggest that HO-1 induction following burn injury is an adaptive response protecting gastric mucosal against further oxidative damage. Melatonin increased the antioxidant capacity and restricted burn-induced oxidative damage in gastric mucosa and thus could be used therapeutically in organ protection.

Melatonin (N-acetyl-5-methoxytryptamine) is secreted in the pineal gland and extra pineal tissues. Melatonin possesses a wide variety of biological effects such as chronobiological, sedative and anxiolytic. Melatonin may act as an antioxidant and a potent scavenger of both oxygen and nitrogen reactive molecules. The free radical scavenging activity of melatonin is receptor independent process whereas the indirect effect likely involves specific receptors [6]. Melatonin stimulates the activity of enzymes involved in antioxidant defense and reduces the production of proinflammatory mediators [7,8]. Melatonin is a small, highly lipophilic and hydrophilic molecule. It passes freely through membranes and distributes in all subcellular compartments [5]. These evidences suggest that these pleiotropic functions of melatonin may be used clinically under conditions where its circulating levels are reduced [9,10]. Because of its antioxidant, anti-inflammatory and anti-apoptotic effects, exogenous melatonin attenuates ischemia/reperfusion and hepatotoxins induced liver injury [11-13].

Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the different tissues, leading to oxidative stress and several clinical syndromes. Hypoxia is known to modulate a number of cellular metabolic functions, including what has been called the stress response. One of the stress response proteins is heme oxygenase-1 (НО-1), a ratelimiting enzyme in heme catabolism. It is responsible for converting a potential oxidant, heme, into a potential antioxidant, biliverdin, gaseous carbon monoxide, and free Fe2+. Heme oxygenase cleaves the heme ring at the alpha-methene bridge to form either biliverdin or, if the heme is still attached to a globin, verdoglobin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. The physiological role of HO-1 induction in hypoxia is still under investigation. It has been proposed that carbon monoxide resulting from HO-1 activity in hypoxic vascular smooth muscle cells plays a role in the regulation of the vessel tone via activation of soluble guanylyl cyclase. Using immunocytochemistry, this study demonstrates the developmental changes of HO-1 protein expression in brain and lungs endothelia from rabbits exposed to severe hypobaric hypoxia in a hypobaric chamber. The results of the study suggest that acute high-altitude hypoxia may serve as a model for oxidative stress and will aid in better understanding and management of hypoxia-induced pathologies.