Oxidative Stress In Hypothalamus Research Articles

Duodenal-jejunal bypass improves hypothalamic oxidative stress and inflammation in diabetic rats via glucagon-like peptide 1-mediated Nrf2/HO-1 signaling.

Type 2 diabetes mellitus (T2DM) is often accompanied by impaired glucose utilization in the brain, leading to oxidative stress, neuronal cell injury and infla-mmation. Previous studies have shown that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats, the role and the metabolism of DJB in improving brain oxidative stress and inflammation condition in T2DM rats remain unclear. To investigate the role and metabolism of DJB in improving hypothalamic oxidative stress and inflammation condition in T2DM rats. A T2DM rat model was induced via a high-glucose and high-fat diet, combined with a low-dose streptozotocin injection. T2DM rats were divided into DJB operation and Sham operation groups. DJB surgical intervention was carried out on T2DM rats. The differential expression of hypothalamic proteins was analyzed using quantitative proteomics analysis. Proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of T2DM rats were analyzed by flow cytometry, quantitative real-time PCR, Western blotting, and immunofluorescence. Quantitative proteomics analysis showed significant differences in proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of rats with T2DM-DJB after DJB surgery, compared to the T2DM-Sham groups of rats. Oxidative stress-related proteins (glucagon-like peptide 1 receptor, Nrf2, and HO-1) were significantly increased (P < 0.05) in the hypothalamus of rats with T2DM after DJB surgery. DJB surgery significantly reduced (P < 0.05) hypothalamic inflammation in T2DM rats by inhibiting the activation of NF-κB and decreasing the expression of interleukin (IL)-1β and IL-6. DJB surgery significantly reduced (P < 0.05) the expression of factors related to neuronal injury (glial fibrillary acidic protein and Caspase-3) in the hypothalamus of T2DM rats and upregulated (P < 0.05) the expression of neuroprotective factors (C-fos, Ki67, Bcl-2, and BDNF), thereby reducing hypothalamic injury in T2DM rats. DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the glucagon-like peptide 1 receptor-mediated Nrf2/HO-1 signaling pathway.

Role of gallic acid against hypothalamic oxidative stress and insulin resistance in diet-induced obesity

Role of gallic acid against hypothalamic oxidative stress and insulin resistance in diet-induced obesity

Decrease in reproductive dysfunction using aflatoxin B1 exposure: a treatment with 3-indolepropionic acid in albino Wistar rat.

We assessed the individual and combined consequence of 3-indolepropionic acid on aflatoxin B1-induced reproductive toxicity in rats. The experimental cohorts were dosed for four consecutive weeks with aflatoxin B1 (50μg/kg), 3-indolepropionic acid (50mg/kg), and both (aflatoxin B1: 50μg/kg+3-indolepropionic acid: 25 or 50mg/kg), and the untreated control. Following sacrifice, biomarkers of testicular, epididymal and hypothalamic oxidative status, lipid peroxidation, reactive oxygen and nitrogen species, nitric oxide levels and myeloperoxidase activity were determined. Besides, tumour necrosis factor-alpha, Bcl-2 and Bax proteins were also assessed. Aflatoxin B1-induced testicular, epididymal and hypothalamic oxidative stress was significantly alleviated with 3-indolepropionic acid co-treatment. Also, increases in biomarkers of oxidative stress and reduced levels of antioxidants were abated significantly in rats co-treated with 3-indolepropionic acid. Aflatoxin B1-mediated increase in tumour necrosis factor-alpha, Bax, nitric oxide and myeloperoxidase activity in the examined organs was decreased significantly in aflatoxin B1 and 3-indolepropionic acid co-treated rats. Also, 3-indolepropionic acid dose dependently reduced Bcl-2 levels in the treated rats. The degree of aflatoxin B1-induced histopathological injuries was minimised in rats co-treated with 3-indolepropionic acid. Our results demonstrated that 3-indolepropionic acid protected experimental rats from aflatoxin B1-induced oxido-inflammatory stress and apoptotic response in the examined organs.

Inflammation in Metabolic and Cardiovascular Disorders-Role of Oxidative Stress.

Cardiovascular diseases (CVD) constitute the main cause of death worldwide. Both inflammation and oxidative stress have been reported to be involved in the progress of CVD. It is well known that generation of oxidative stress during the course of CVD is involved in tissue damage and inflammation, causing deleterious effects such as hypertension, dysfunctional metabolism, endothelial dysfunction, stroke, and myocardial infarction. Remarkably, natural antioxidant strategies have been increasingly discovered and are subject to current scientific investigations. Here, we addressed the activation of immune cells in the context of ROS production, as well as how their interaction with other cellular players and further (immune) mediators contribute to metabolic and cardiovascular disorders. We also highlight how a dysregulated complement system contributes to immune imbalance and tissue damage in the context of increases oxidative stress. Additionally, modulation of hypothalamic oxidative stress is discussed, which may offer novel treatment strategies for type-2 diabetes and obesity. Together, we provide new perspectives on therapy strategies for CVD caused by oxidative stress, with a focus on oxidative stress.

Dietary switch to Western diet induces hypothalamic adaptation associated with gut microbiota dysbiosis in rats.

Early hyperphagia and hypothalamic inflammation encountered after Western diet (WD) are linked to rodent propensity to obesity. Inflammation in several brain structures has been associated with gut dysbiosis. Since gut microbiota is highly sensitive to dietary changes, we hypothesised that immediate gut microbiota adaptation to WD in rats is involved in inflammation-related hypothalamic modifications. We evaluated short-term impact of WD consumption (2 h, 1, 2 and 4 days) on hypothalamic metabolome and caecal microbiota composition and metabolome. Data integration analyses were performed to uncover potential relationships among these three datasets. Finally, changes in hypothalamic gene expression in absence of gut microbiota were evaluated in germ-free rats fed WD for 2 days. WD quickly and profoundly affected the levels of several hypothalamic metabolites, especially oxidative stress markers. In parallel, WD consumption reduced caecal microbiota diversity, modified its composition towards pro-inflammatory profile and changed caecal metabolome. Data integration identified strong correlations between gut microbiota sub-networks, unidentified caecal metabolites and hypothalamic oxidative stress metabolites. Germ-free rats displayed reduced energy intake and no changes in redox homoeostasis machinery expression or pro-inflammatory cytokines after 2 days of WD, in contrast to conventional rats, which exhibited increased SOD2, GLRX and IL-6 mRNA levels. A potentially pro-inflammatory gut microbiota and an early hypothalamic oxidative stress appear shortly after WD introduction. Tripartite data integration highlighted putative links between gut microbiota sub-networks and hypothalamic oxidative stress. Together with the absence of hypothalamic modifications in germ-free rats, this strongly suggests the involvement of the microbiota-hypothalamus axis in rat adaptation to WD introduction and in energy homoeostasis regulation.

Effects of copper on oxidative stress and autophagy in hypothalamus of broilers

The purpose of this research was to discuss the effects of copper (Cu)-induced toxicity on oxidative stress and autophagy in hypothalamus of broilers. In this study, 240 one-day-old broilers were randomly divided into 4 groups and the contents of dietary Cu in 4 groups were 11 mg/kg (control group), 110 mg/kg (group I), 220 mg/kg (group II), and 330 mg/kg (group III). The experiment lasted for 49 days and the hypothalamus tissues were collected for histological observation and detection of Cu content. Additionally, the indicators related to oxidative stress in hypothalamus were determined. Moreover, the mRNA expression levels of autophagy-related genes and the protein expression levels of Beclin1, LC3-II/LC3-I, and p62 in hypothalamus were measured. Results showed that the treated groups were observed vacuolar degeneration in hypothalamus compared to control group, and the Cu content in hypothalamus was increased with the increase of dietary Cu. Furthermore, the activities of SOD, CAT, T-AOC were increased in group I and group II and then decreased in group III, and the content of MDA and the mRNA levels of Nrf2, HO-1, SOD-1, CAT, GCLC, GCLM, and GST in treated groups were elevated compared to control group. Moreover, the mRNA expression levels of Beclin1, Atg5, LC3-I, LC3-II and the protein expression levels of Beclin1 and LC3-II/LC3-I up-regulated significantly with the increasing levels of Cu. However, the mRNA expression levels of p62 and mTOR and the protein expression level of p62 down-regulated remarkably. Taken together, our present study evidenced that excessive intake of Cu could induce oxidative stress and autophagy in hypothalamus of broilers.

Hypothalamic oxidative stress and inflammation, and peripheral glucose homeostasis in Sprague-Dawley rat offspring exposed to maternal and postnatal chocolate and soft drink

BackgroundPredisposition to obesity and type 2 diabetes can arise during foetal development and in early postnatal life caused by imbalances in maternal nutritional overload. We aimed to investigate the effects of maternal and postnatal intake of chocolate and soft drink on hypothalamic anti-oxidative stress markers, inflammation and peripheral glucose homeostasis.MethodsPregnant Sprague-Dawley rats were fed ad libitum chow diet only (C) or with chocolate and high sucrose soft drink supplements (S). At birth, litter size was adjusted into 10 male offspring per dam. After weaning at 3 weeks of age, offspring from both dietary groups were assigned to either S or C diet, giving four groups until the end of the experiment at 26 weeks of age.ResultsOffspring exposed to maternal S had up-regulated hypothalamic anti-oxidative markers such as SOD2 and catalase at 3 weeks of age as an indication of oxidative stress. However, at 12 weeks of age these anti-oxidative markers tended to decrease while pro-inflammatory markers such as TNF and IL-1β became up-regulated of all offspring exposed to S diet during some point of their life. Thus, despite an increase in anti-oxidative stress response, offspring exposed to maternal S had a reduced ability to counteract hypothalamic inflammation. At the same time point, postnatal S resulted in increased adiposity, reduced glucose tolerance and insulin sensitivity with no effect on body weight. However, at 25 weeks of age, the impaired glucose tolerance was reversible to the response of the control regardless of increased adiposity and body weight pointing towards a compensatory response of the insulin sensitivity or insulin secretion.ConclusionIndications of hypothalamic oxidative stress was observed prior to the inflammatory response in offspring exposed to maternal S. Both maternal and postnatal S induced hypothalamic inflammation prior to increased weight gain and thus contributing to obese phenotype.

Long Feeding High-Fat Diet Induces Hypothalamic Oxidative Stress and Inflammation, and Prolonged Hypothalamic AMPK Activation in Rat Animal Model.

Scope: The hypothalamus is a key brain region involved in the control of feeding and energy expenditure. Hypothalamic inflammation and oxidative stress are landmarks of both obesity and aging processes, although the molecular mechanisms are still unknown. Therefore, with the aim to understand the neurobiological mechanisms of energy homeostasis during aging, we evaluate the effects of long feeding high-fat diet (HFD) in rats, at different age, on modulation of hypothalamic molecular pathway, oxidative stress, and inflammation.Procedures: Male Wistar rats were divided into two groups: control group, receiving standard diet (CD), and treated group, receiving HFD. Both groups were treated with the appropriate diet for 1, 3, 6, 12, or 18 weeks. We investigated energy balance and body composition, as well as lipid profile, homeostatic model assessment index, and inflammatory state in serum. Furthermore, we also analyzed, at hypothalamic level, inflammation and oxidative stress, and adenosine monophosphate-dependent kinase (AMPK) and pAMPK expression levels.Results: Our data showed that aging and HFD induce increased energy intake and energy efficiency and decreased energy expenditure associated, at hypothalamic level, with inflammation and oxidative stress and activation of AMPK.Conclusion: Our results indicate that the age at which HFD feeding starts and the diet duration are critical in obesity development. The prolonged activation of hypothalamic AMPK may be related to the alterations in energy homeostasis.

Anxiety-like behavioural effects of extremely low-frequency electromagnetic field in rats

In recent years, extremely low-frequency electromagnetic field (ELF-EMF) has received considerable attention for its potential biological effects. Numerous studies have shown the role of ELF-EMF in behaviour modulation. The aim of this study was to investigate the effect of short-term ELF-EMF (50Hz) in the development of anxiety-like behaviour in rats through change hypothalamic oxidative stress and NO. Ten adult male rats (Wistar albino) were divided in two groups: control group-without exposure to ELF-EMF and experimental group-exposed to ELF-EMF during 7days. After the exposure, time open field test and elevated plus maze were used to evaluate the anxiety-like behaviour of rats. Upon completion of the behavioural tests, concentrations of superoxide anion (O2·-), nitrite (NO2-, as an indicator of NO) and peroxynitrite (ONOO-) were determined in the hypothalamus of the animals. Obtained results show that ELF-EMF both induces anxiety-like behaviour and increases concentrations of O2·- and NO, whereas it did not effect on ONOO- concentration in hypothalamus of rats. In conclusion, the development of anxiety-like behaviour is mediated by oxidative stress and increased NO concentration in hypothalamus of rats exposed to ELF-EMF during 7days.

Maternal High Fat‐High Sucrose Diet is Associated with Elevated Offspring Hypothalamic Oxidative Stress and Blood Pressure Responses to Psychological Stress.

There is mounting evidence that diets high in fat and sucrose (HFS) during pregnancy adversely affect offspring cardiovascular health. The aims of the present study were to assess the level of oxidative stress (OS) in brainstem cardiovascular control sites and compare blood pressure (BP) responses to psychological stress in HFS and control offspring.Dams were fed a HFS diet (21% fat, 34% sucrose; control, 4.8% fat, 0% sucrose) from 4 weeks prior to mating until weaning. Three‐month old male offspring (n=7) were assessed for levels of the antioxidant glutathione and the OS marker protein carbonyl (PCs) in brainstem cardiovascular nuclei. At 9–12 months, cardiovascular variables were acquired from both males (control n=5; HFS=6) and females (control n=4; HFS=3) at rest and in response to mild (air jet, AJ) and moderate (restraint, RS) psychological stress using telemetry. Male rats were perfused and brains were processed immunohistochemically for Fos protein expression. Data are expressed as mean ± SE, statistical significance was taken as p&lt;0.05.HFS offspring exhibited increased retroperitoneal adiposity as a percentage of wet weight (2% vs 3.7%). Markers of OS were elevated in the hypothalamus, comprising a two‐fold increase in PCs and 40% reduction in glutathione. No significant differences were observed in the medulla or midbrain of programmed offspring.Resting mean blood pressure (BP) was higher in both male and female HFS offspring than controls (male; 102.0±3.0 vs 94.2±2.6 mmHg, female; 104.4±3.7 vs 93.1±2.9 mmHg). BP responses to psychological stress were also enhanced. In HFS males, both stressors elicited greater initial increases in systolic BP (AJ; +30±3.3 vs +17±2.1 mmHg, RS; +39±1.9 vs +26±2.8 mmHg), while recovery was slower in AJ only (45 min post‐AJ, +13±1.6 vs +3±2.4 mmHg from baseline). A larger increase in blood pressure variability (low frequency component) was also observed in HFS males during both stressors, while no difference in heart rate or heart rate variability was observed between groups.In HFS females, the initial systolic BP response to RS was greater (+41.3±1.9 vs 33.3±0.9 mmHg), however, there was no difference in AJ (HFS, 25.0±2.3 vs 24.3±4.3 mmHg). In contrast to males, recovery was similar to controls in HFS females.HFS offspring also showed reduced Fos expression in the midbrain periaqueductal grey (PAG) in response to stress. Following AJ, the number of Fos‐positive neurons was reduced by ~40% in the lateral and ventrolateral PAG, while post‐RS a decrease in Fos expression was observed in the dorsomedial (70% reduction), dorsolateral (43%) and lateral (47%) PAG. No difference in Fos expression was observed in the hypothalamus.The results suggest that maternal HFS elicits increased OS in the hypothalamus of offspring and programs a pro‐hypertensive phenotype characterised by exaggerated cardiovascular responses to psychological stress.

Activation of ATP-sensitive potassium channel by iptakalim normalizes stress-induced HPA axis disorder and depressive behaviour by alleviating inflammation and oxidative stress in mouse hypothalamus.

Stress-induced disturbance of the hypothalamic-pituitary-adrenal (HPA) axis is strongly implicated in incidence of mood disorders. A heightened neuroinflammatory response and oxidative stress play a fundamental role in the dysfunction of the HPA axis. We have previously demonstrated that iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could prevent oxidative injury and neuroinflammation against multiple stimuli-induced brain injury. The present study was to demonstrate the impacts of Ipt in stress-induced HPA axis disorder and depressive behavior. We employed 2 stress paradigms: 8 weeks of continuous restraint stress (chronic restraint stress, CRS) and 2h of restraint stress (acute restraint stress, ARS), to mimic both chronic stress and severe acute stress. Prolonged (4 weeks) and short-term (a single injection) Ipt treatment was administered 30min before each stress paradigm. We found that HPA axis was altered after stress, with different responses to CRS (lower ACTH and CORT, higher AVP, but normal CRH) and ARS (higher CRH, ACTH and CORT, but normal AVP). Both prolonged and short-term Ipt treatment normalized stress-induced HPA axis disorders and abnormal behaviors in mice. CRS and ARS up-regulated mRNA levels of inflammation-related molecules (TNFα, IL-1β, IL-6 and TLR4) and oxidative stress molecules (gp91phox, iNOS and Nrf2) in the mouse hypothalamus. Double immunofluorescence showed CRS and ARS increased microglia activation (CD11b and TNFα) and oxidative stress in neurons (NeuN and gp91phox), which were alleviated by Ipt. Therefore, the present study reveals that Ipt could prevent against stress-induced HPA axis disorders and depressive behavior by alleviating inflammation and oxidative stress in the hypothalamus.

Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress

The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout (KO) of selenocysteine-tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). These Trsp-KO (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β cells, leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals are suppressed, and numbers of proopiomelanocortin-positive neurons in the hypothalamus are decreased. In contrast, Trsp-KO mice (TrspIns1KO) expressing Cre specifically in pancreatic β cells, but not in the hypothalamus, do not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related factor 2) regulates antioxidant gene expression. Increased Nrf2 signaling suppresses hypothalamic oxidative stress and improves insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.

Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway.

Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.

Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis.

In our previous work, we demonstrated that the intracerebroventricular (i.c.v.) injection of an interleukin-1 receptor antagonist (IL-1ra) prevented the impairment in vasopressin secretion and increased survival rate in septic rats. Additionally, we saw a reduction in nitric oxide (NO) levels in cerebroventricular spinal fluid (CSF), suggesting that the IL-1ra prevents apoptosis that seems to occur in vasopressinergic neurons. Here, we investigated the effect of IL-1ra pre-treatment on the sepsis-induced increase in oxidative stress markers in the hypothalamus of rats. The animals were pre-treated by an i.c.v. injection of IL-1ra (9nmol) or vehicle (0.01M PBS) before being subjected to cecal ligation and puncture (CLP) or left as control (sham-operation or naive). After 4, 6, and 24h, the animals were decapitated (n = 9/group) and the brain removed for hypothalamic tissue collection. Transcript and protein levels of IL-1, inducible nitric oxide synthase (iNOS), caspase-3, and hypoxia-inducible factor 1-alpha (HIF-1α) were measured by quantitative polymerase chain reaction (qPCR) and western blot, respectively. Hypothalamic mRNA levels of all these genes were significantly (P < 0.005) increased at 4, 6, and 24h CLP, as compared to sham-operated animals. IL-1ra pre-treatment in these CLP animals significantly decreased IL-1 gene expression at all time points and also of iNOS, caspase-3, and HIF-1α at 24h when compared to vehicle-treated CLP animals. The effect of the pre-treatment on protein expression was most clearly seen for IL-1β and iNOS at 24h. Our results showed that blocking the IL-1-IL-1r signaling pathway by central administration of an IL-1ra decreases hypothalamic oxidative stress markers during sepsis.

Use of a Caspase Multiplexing Assay to Determine Apoptosis in a Hypothalamic Cell Model

The ability to multiplex assays in studies of complex cellular mechanisms eliminates the need for repetitive experiments, provides internal controls, and decreases waste in costs and reagents. Here we describe optimization of a multiplex assay to assess apoptosis following a palmitic acid (PA) challenge in an in vitro hypothalamic model, using both fluorescent and luminescent based assays to measure viable cell counts and caspase-3/7 activity in a 96-well microtiter plate format. Following PA challenge, viable cells were determined by a resazurin-based fluorescent assay. Caspase-3/7 activity was then determined using a luminogenic substrate, DEVD, and normalized to cell number. This multiplexing assay is a useful technique for determining change in caspase activity following an apoptotic stimulus, such as saturated fatty acid challenge. The saturated fatty acid PA can increase hypothalamic oxidative stress and apoptosis, indicating the potential importance of assays such as that described here in studying the relationship between saturated fatty acids and neuronal function.

Use of a Caspase Multiplexing Assay to Determine Apoptosis in a Hypothalamic Cell Model

The ability to multiplex assays in studies of complex cellular mechanisms eliminates the need for repetitive experiments, provides internal controls, and decreases waste in costs and reagents. Here we describe optimization of a multiplex assay to assess apoptosis following a palmitic acid (PA) challenge in an in vitro hypothalamic model, using both fluorescent and luminescent based assays to measure viable cell counts and caspase-3/7 activity in a 96-well microtiter plate format. Following PA challenge, viable cells were determined by a resazurin-based fluorescent assay. Caspase-3/7 activity was then determined using a luminogenic substrate, DEVD, and normalized to cell number. This multiplexing assay is a useful technique for determining change in caspase activity following an apoptotic stimulus, such as saturated fatty acid challenge. The saturated fatty acid PA can increase hypothalamic oxidative stress and apoptosis, indicating the potential importance of assays such as that described here in studying the relationship between saturated fatty acids and neuronal function.

88 BRAIN MINERALOCORTICOID RECEPTOR ACTIVATION MEDIATES ARTERIAL PRESSURE ELEVATION THROUGH BRAIN OXIDATIVE STRESS-INDUCED SYMPATHOEXCITATION IN SALT-SENSITIVE AND OBESITY-INDUCED HYPERTENSION

Objectives and Background: We have shown previously that sympathoexcitation by brain oxidative stress mediates arterial pressure (AP) elevation in salt-sensitive and obesity-induced hypertension. Sympathoexcitatory roles of brain mineralocorticoid receptor (MR) have been documented, but the detailed mechanisms have not been fully elucidated. We have also shown that MR activation could mediate oxidative stress-induced cardiac and renal dysfunction. Then, we hypothesized that brain MR activation could mediate AP elevation through brain oxidative stress-induced sympathoexcitation. Design and methods: We used high-salt (8%)-loaded Dahl-salt-sensitive rats (Dahl-S) as the salt-sensitive hypertension model, and high-fat (45% kcal as fat)-fed Sprague-Dawley rats as the obesity-induced hypertension model. Sgk-1 and PAI-1 mRNA expression in the isolated hypothalamus was evaluated by real-time quantitative RT-PCR. We examined effects of chronic intracerebroventricular eplerenone on sympathetic nerve activity (response to hexamethonium and urinary norepinephrine) and AP. In Dahl-S, we evaluated the responses of renal sympathetic nerve activity (RSNA) and AP to acute intracerebroventricular administration of tempol, and the hypothalamic oxidative stress level. Results: Salt loading in Dahl-S and fat loading in Sprague-Dawley rats significantly enhanced mRNA expression of Sgk-1 and PAI-1 in the hypothalamus. Intracerebroventricular eplerenone significantly reduced sympathetic nerve activity and AP both in salt-loaded Dahl-S and high-fat-fed rats. Reductions in RSNA and AP values elicited by acute intracerebroventricular tempol, and hypothalamic oxidative stress level were significantly suppressed in intracerebroventricular eplerenone-treated salt-loaded Dahl-S compared with vehicle-treated group. Conclusions: Brain MR activation can be a possible common pathogenic background of AP elevation through brain oxidative stress-induced sympathoexcitation in salt-sensitive and obesity-induced hypertension.

Alfa-Lipoic acid protects testosterone secretion pathway and sperm quality against 4-tert-octylphenol induced reproductive toxicity

The protective effect of α-lipoic acid (LA) (50mg/kg bw) against 4-tert-octylphenol (OP) (50mg/kg bw) induced reproductive toxicity in male rats was studied. LA was injected 1h prior to OP administration three times a week. OP caused significant increase in oxidative stress in hypothalamus and epididymal sperm, disturbed hormonal levels in serum, decreased sperm quality, increased DNA fragmentation and loss of 35 and 95kDa proteins in sperm, as well as elevated proliferating index in testis. LA protected against oxidative stress through promoting the levels of glutathione and glutathione-S-transferase in hypothalamus and sperm. In addition, LA prevented the decrease in testosterone, dehydroepiandrosterone sulfate, 3β-hydroxysteroid dehydrogenase, and inhibited the elevations in sex-hormone-binding globulin levels and showed normal sperm quality. LA modulated proliferation of germ cell, protected against DNA fragmentation and maintained membrane protein organization in the sperm. In conclusion, LA normalized oxidative stress and protected testosterone synthesis pathway across hypothalamus-testicular axis and sperm quality indicating its defensive influence against OP-induced oxidative reproductive dysfunction in male rats.

Dietary L‐Trp supplementation affects growth and stress responses of nursery pigs

Tryptophan (Trp) as a precursor of serotonin can affect serotonin activity in mediating stress. This study was to determine the optimal supplementation level of L-Trp maximizing the biological benefits on growth and stress responses. Pigs (n = 72) at 6 wk of age were housed individually and allotted to 6 treatments (n = 12) representing supplementation of 0, 0.2, 0.4, 0.6, 0.8, or 1.0% L-Trp to corn-soybean meal based diets fed for 15 d. Collection of BW, saliva, and blood were done on d 5, 10, and 15. On d 15, all pigs were euthanized to obtain hypothalamus. During the first 5 d, growth of pigs was improved (P < 0.05) when fed with 0.6 and 0.8% L-Trp compared with pigs without L-Trp. During the entire 15 d, pigs with 0.8% L-Trp tended to grow faster (P = 0.099) than pigs without L-Trp (537 vs 446 g/d, respectively). Pigs with L-Trp had reduced (P < 0.05) salivary cortisol (1.7 ng/mL) and malonedialdehyde in plasma and hypothalamus (15.0 μM and 60.5 μmol/g protein) compared with pigs without L-Trp (2.6 ng/mL, 20.9 μM, and 87.2 μmol/g protein, respectively). Pigs with 0.6 and 0.8% L-Trp had reduced (P < 0.05) plasma urea nitrogen (6.2 and 5.7 mg/dL) compared with pigs without L-Trp (8.0 mg/dL). Overall, dietary L-Trp supplementation improved growth, whereas reduced stress hormone secretion, and systemic and hypothalamic oxidative stress in pigs. These beneficial effects were maximized at 0.8% L-Trp supplementation. Grant Funding Source: CJ Bio, Inc

Hypertensive effects of central angiotensin II infusion and restraint stress are reduced with age

We investigated the effect of age on cardiovascular responses mediated by central angiotensin II (AngII) after intracerebroventricular infusion of AngII, and during restraint stress. Blood pressure (BP) and heart rate (HR) of young (5-month-old) and old (27-month-old) male Fischer-344 x Brown-Norway rats were measured using radiotelemetry. AngII was infused intracerebroventricularly using osmotic minipumps (10 ng/0.5 microl/h for 11 days). BP and HR responses to stress were evaluated by placing animals in restrainers for 20 min before and after intracerebroventricular infusion of the AngII-type-1 receptor inhibitor losartan (15 microg/microl per h for 3 days). Resting BP was significantly elevated and HR was significantly lower in old rats compared with young. AngII-induced BP increase was markedly reduced in old rats, but HR responses were similar. Diurnal variation of both BP and HR was lower in old animals, and AngII reduced the amplitude of BP variation in young rats, but not in old. Restraint stress-induced BP and HR elevations were reduced with age. BP responses were diminished by central losartan infusion in both young and old, but this effect was more significant in young rats. In addition, expression of CuZn-superoxide dismutase and catalase declined significantly with age in the hypothalamus, whereas baseline oxidative stress increased. In contrast, AngII-induced increase in hypothalamic oxidative stress decreased with age. This study demonstrates that the role of central AngII diminishes with age in the regulation of BP both during baseline conditions and during stress, whereas the involvement of AngII in the regulation of HR remains unaffected.