Role of the Renin-Angiotensin System,Renal Sympathetic Nerve System,and Oxidative Stress in Chronic Foot Shock-Induced Hypertension in Rats

Objective: The renin-angiotensin system (RAS) and renal sympathetic nerve system (RSNS) are involved in the development of hypertension. The present study is designed to explore the possible roles of the RAS and the RSNS in foot shock-induced hypertension.Methods: Male Sprague-Dawley rats were divided into six groups: control, foot shock, RSNS denervation, denervation plus foot shock, Captopril (angiotensin I converting enzyme inhibitor, ACE inhibitor) plus foot shock, and Tempol (superoxide dismutase mimetic) plus foot shock. Rats received foot shock for 14 days. We measured the quantity of thiobarbituric acid reactive substances (TBARS), corticosterone, renin, and angiotensin II (Ang II) in plasma, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and renal noradrenaline content. RAS component mRNA and protein levels were quantified in the cerebral cortex and hypothalamus.Results: The two week foot shock treatment significantly increased systolic blood pressure, which was accompanied by an increase in angiotensinogen, renin, ACE1, and AT1a mRNA and protein expression in the cerebral cortex and hypothalamus, an increase of the plasma concentrations of renin, Ang II, corticosterone, and TBARS, as well as a decrease in plasma SOD and GSH-Px activities. Systolic blood pressure increase was suppressed by denervation of the RSNS or treatment with Captopril or Tempol. Interestingly, denervation or Tempol treatment both decreased main RAS components not only in the circulatory system, but also in the central nervous system. In addition, decreased antioxidant levels and increased TBARS and corticosterone levels were also partially restored by denervation or treatment with Tempol or Captopril.Conclusions: RAS, RSNS and oxidative stress reciprocally potentiate to play important roles in the development of foot shock-induced hypertension.     

VD缺乏相关疾病及其合理补充的临床意义

：众所周知,人体内维生素D水平与少年佝偻病和老年骨质疏松直接相关。最近大量流行病学证据还表明,维生素D（VD）缺乏是多种自身免疫性疾病,癌症,心血管疾病,抑郁症,老年痴呆症,感染性疾病,肌肉骨骼功能下降等的危险因素之一。另外,胰岛素抵抗,高血压和高胆固醇血症也与维生素D缺乏有关。因此,合理补充维生素D可以降低多种疾病风险,并对心血管疾病的风险有益。本文系根据已有的研究结论,阐述维生素D水平与多种临床疾病之间的关联,并对人体血清VD浓度合理监测及合理补充的临床意义做一综述。     

The Role of Oxidative Stress in Nervous System Aging

While oxidative stress is implicated in aging, the impact of oxidative stress on aging in the peripheral nervous system is not well understood. To determine a potential mechanism for age-related deficits in the peripheral nervous system, we examined both functional and morphological changes and utilized microarray technology to compare normal aging in wild-type mice to effects in copper/zinc superoxide dismutase-deficient (Sod1^−/−) mice, a mouse model of increased oxidative stress. Sod1^−/− mice exhibit a peripheral neuropathy phenotype with normal sensory nerve function and deficits in motor nerve function. Our data indicate that a decrease in the synthesis of cholesterol, which is vital to myelin formation, correlates with the structural deficits in axons, myelin, and the cell body of motor neurons in the Sod1^+/+ mice at 30 months and the Sod1^−/− mice at 20 months compared with mice at 2 months. Collectively, we have demonstrated that the functional and morphological changes within the peripheral nervous system in our model of increased oxidative stress are manifested earlier and resemble the deficits observed during normal aging.     

Protection Against Oxidative Stress Caused by Intermittent Cold Exposure by Combined Supplementation with Vitamin E and C in the Aging Rat Hypothalamus

This study investigated the effects of combined supplementation with vitamin E and C against oxidative stress (OS) caused by intermittent cold exposure (ICE) in the hypothalamus (HY) of aging male Wistar rats [adult (3-months), middle-aged (18-months) and old (24-months)]. Each age was divided into sub-groups: control (CON), cold-exposed at 10 °C (C10), cold-exposed at 5 °C (C5), supplemented control (CON+S) and supplemented cold-exposed at either 5 °C (C5+S) or 10 °C (C10+S). The supplement was a daily dose of 400 mg vitamin C and 50 IU of vitamin E/kg body weight. Cold exposure lasted 2 h/day for 4 weeks. All age groups exposed to cold showed increase in body mass and feeding efficiency. Feeding efficiency in the supplemented old group showed a statistically significant increase in the cold (p < 0.001). Age-related increases in levels of hydrogen peroxide (H₂O₂), protein carbonyl (PrC), advanced oxidation protein products and thiobarbituric acid reactive substances (TBARS) were further increased by cold in the HY. Cold reduced thiol(P-SH) levels and increased superoxide dismutase (SOD) and, catalase (CAT) activities as well as Hsp72 levels. However, supplementation lowered H₂O₂, PrC and TBARS with decreases in Hsp72 levels and in SOD and CAT activities. These changes were concomitant with elevations in P-SH, vitamin E and C levels. The results show that the OS caused by ICE in the HY and its subsequent protection following supplementation is related to the intensity of ICE as well as age of the animal. Immunohistochemical studies are underway to examine the findings on ICE-induced oxidative injury in the HY, and the prospects for vitamin E and C supplementation in the senescent.     

Role of Trace Elements,Oxidative Stress and Immune System: a Triad in Premature Ovarian Failure

Cadmium is an environmental pollutant closely linked with cardiovascular diseases that seems to involve endothelium dysfunction and reduced nitric oxide (NO) bioavailability. Knowing that NO causes dilatation through the activation of potassium channels and Na⁺/K⁺-ATPase, we aimed to determine whether acute cadmium administration (10 μM) alters the participation of K⁺ channels, voltage-activated calcium channel, and Na⁺/K⁺-ATPase activity in vascular function of isolated aortic rings of rats. Cadmium did not modify the acetylcholine-induced relaxation. After L-NAME addition, the relaxation induced by acetylcholine was abolished in presence or absence of cadmium, suggesting that acutely, this metal did not change NO release. However, tetraethylammonium (a nonselective K⁺ channels blocker) reduced acetylcholine-induced relaxation but this effect was lower in the preparations with cadmium, suggesting a decrease of K⁺ channels function in acetylcholine response after cadmium incubation. Apamin (a selective blocker of small Ca²⁺-activated K⁺ channels—SK_Ca), iberiotoxin (a selective blocker of large-conductance Ca²⁺-activated K⁺ channels—BK_Ca), and verapamil (a blocker of calcium channel) reduced the endothelium-dependent relaxation only in the absence of cadmium. Finally, cadmium decreases Na⁺/K⁺-ATPase activity. Our results provide evidence that the cadmium acute incubation unaffected the calcium-activated potassium channels (SK_Ca and BK_Ca) and voltage-calcium channels on the acetylcholine vasodilatation. In addition, acute cadmium incubation seems to reduce the Na⁺/K⁺-ATPase activity.     

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

The pathogenesis of nonalcoholic steatohepatitis (NASH) is a two-stage process in which steatosis is the “first hit” and an unknown “second hit.” We hypothesized that “a binge” could be a “second hit” to develop NASH from obesity-induced simple steatosis. Thirty-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were administered 10 mL of 10% ethanol orally for 5, 3, 2, and 1 d/wk for 3 consecutive weeks. As control, male Otsuka Long-Evans Tokushima (OLET) rats were administered the same amount of alcohol. Various biochemical parameters of obesity, steatosis and NASH were monitored in serum and liver specimens in untreated and ethanol-treated rats. The liver sections were evaluated for histopathological alterations of NASH and stained for cytochrome P-4502E1 (CYP2E1) and 4-hydroxy-nonenal (4-HNE). Simple steatosis, hyperinsulinemia, hyperglycemia, insulin resistance, hypertriglycemia and marked increases in hepatic CYP2E1 and 4-HNE were present in 30-wk-old untreated OLETF rats. Massive steatohepatitis with hepatocyte ballooning was observed in the livers of all OLETF rats treated with ethanol. Serum and hepatic triglyceride levels as well as tumor necrosis factor (TNF)-α mRNA were markedly increased in all ethanol-treated OLETF rats. Staining for CYP2E1 and 4-NHE demonstrated marked increases in the hepatic tissue of all the groups of OLETF rats treated with ethanol compared with OLET rats. Our data demonstrated that “a binge” serves as a “second hit” for development of NASH from obesity-induced simple steatosis through aggravation of oxidative stress. The enhanced levels of CYP2E1 and increased oxidative stress in obesity play a significant role in this process.     

Edible Seaweed, Eisenia bicyclis, Protects Retinal Ganglion Cells Death Caused by Oxidative Stress

The purpose of the present study was to determine whether edible seaweed, Eisenia bicyclis, is effective in blunting the negative influence of N-methyl-D-aspartate (NMDA) on rat retinas and of oxidative stress-induced transformed retinal ganglion cell (RGC-5 cell line) death. The ethanol extract of E. bicyclis (EEEB) significantly attenuated the negative insult of L: -buthionine-(S,R)-sulfoximine plus glutamate on RGC-5 cells. Treatment of the RGC-5 cells with EEEB reduced the reactive oxygen species and recovered the reduced glutathione level caused by various radical species such as H(2)O(2), OH·, or O(2)·(-). Moreover, EEEB inhibited lipid peroxidation on rat brain homogenates caused by sodium nitroprusside. Applying NMDA to the retina affected the thickness of the inner plexiform layer (IPL) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) produced a positive effect on ganglion cells. Importantly, EEEB protected the thinning of IPL and increased TUNEL positive cells in the ganglion cell layer (GCL). Five phlorotannin derivatives were isolated using chromatographic methods and liquid chromatography-mass spectroscopy analysis which has been known as an antioxidant. In conclusion, EEEB has a neuroprotective effect in vitro and in vivo. Furthermore, the major constituents of this extract, phlorotannins, could possibly be active compounds due to their antioxidative potency.     

SRC-3 Deficiency Exacerbates Neurological Deficits in a Mouse Model of Intracerebral Hemorrhage: Role of Oxidative Stress

Intracerebral hemorrhage (ICH) causes long term neurological abnormality or death. Oxidative stress is closely involved in ICH mediated brain damage. Steroid receptor cofactor 3 (SRC-3), a p160 family member, is widely expressed in the brain and regulates transactivation of Nrf2, a key component of antioxidant response. Our study aims to test if SRC-3 is implicated in ICH mediated brain injury. We first examined levels of SRC-3 and oxidative stress in the brain of mice following ICH and analyzed their correlation. Then ICH was induced in wild type (WT) and SRC-3 knock out mice and how SRC-3 deletion affected ICH induced brain damage, oxidative stress and behavioral outcome was assessed. We found that SRC-3 mRNA and protein expression levels were reduced gradually after ICH induction in WT mice along with an increase in oxidative stress levels. Correlation analysis revealed that SRC-3 mRNA levels negatively correlated with oxidative stress. Deletion of SRC-3 further increased ICH induced brain edema, neurological deficit score and oxidative stress and exacerbated ICH induced behavioral abnormality including motor dysfunction and cognitive impairment. Our findings suggest that SRC-3 is involved in ICH induced brain injury, probably through modulation of oxidative stress.

     

Effects of Oxidative Stress on Immunosuppression Induced by Selenium Deficiency in Chickens

Selenium (Se) is an important nutritional trace element possessing immune-stimulatory properties. The aim of this 75-day study was to investigate effect of oxidative stress on immunosuppression induced by selenium deficiency by determining antioxidative function, morphological changes, DNA damage, and immune function in immune organ of chickens. One hundred sixty 1-day-old chickens (egg-type birds) were randomly assigned to two groups of 80 each and were fed on a low-Se diet (0.032?mg/kg Se) or a control diet (0.282?mg/kg Se, sodium selenite), respectively. Se contents in blood and immune organ (thymus, spleen, bursa of Fabricius) were determined on days 30, 45, 60, and 75, respectively. Antioxidative function was examined by total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and xanthine oxidase (XOD), and oxidative damage was examined by malondialdehyde (MDA) detection. DNA damage was measured by comet assay, and immune function was examined by determining serum interleukin-1?? (IL-1??), interleukin-2 (IL-2), and tumor necrosis factor (TNF) contents. The results showed that Se concentrations in the low-Se group were significantly lower (P?<?0.05) than in the control group. Low-Se diet caused a decrease in the activities of T-AOC, SOD, GSH-Px, and an increase in XOD activity and MDA content. Pathological lesions and DNA damage of immune tissues were observed in low-Se group, while the serum IL-1?? and IL-2 contents decreased, and TNF content increased. The present study demonstrated that chickens fed deficient in Se diets exhibited lesions in immune organs, decreased serum IL-1??, IL-2 content, and serum TNF content, indicating that oxidative stress inhibited the development of immune organs and finally impaired the immune function of chickens.     

Initiation of Neuronal Damage by Complex I Deficiency and Oxidative Stress in Parkinson's Disease

Oxidative stress and partial deficiencies of mitochondrial complex I appear to be key factors in the pathogenesis of Parkinson's disease. They are interconnected; complex I inhibition results in an enhanced production of reactive oxygen species (ROS), which in turn will inhibit complex I. Partial inhibition of complex I in nerve terminals is sufficient for in situ mitochondria to generate more ROS. H2O2 plays a major role in inhibiting complex I as well as a key metabolic enzyme, alpha-ketoglutarate dehydrogenase. The vicious cycle resulting from partial inhibition of complex I and/or an inherently higher ROS production in dopaminergic neurons leads over time to excessive oxidative stress and ATP deficit that eventually will result in cell death in the nigro-striatal pathway.     

Impact of Selenium Deficiency on Inflammation,Oxidative Stress,and Phagocytosis in Mouse Macrophages

Biological Trace Element Research - Although it has been reported that selenium (Se) deficiency can trigger inflammation, however, there are few reports on the effect of Se on the function of mouse...     

Oxidative Stress in the Liver of Mice Caused by Intraperitoneal Injection with Lanthanoides

In order to study the mechanisms underlying the effects of lanthanoid (Ln) on the liver, ICR mice were injected with LaCl₃, CeCl₃, and NdCl₃ at a dose of 20 mg/kg BW into the abdominal cavity daily for 14 days. We then examined oxidative stress-mediated responses in the liver. The increase of lipid peroxide in the liver produced by Ln suggested an oxidative attack that was activated by a reduction of antioxidative defense mechanisms as measured by analyzing the activities of superoxide dismutase, catalase, and ascorbate peroxidase, as well as antioxidant levels such as glutathione and ascorbic acid, which were greatest in Ce³⁺ treatment, medium in Nd³⁺, and least in La³⁺. Our results also implied that the oxidative stress in the liver caused by Ln likely is Ce³⁺ > Nd³⁺ >La³⁺, but the mechanisms need to be further studied in future.     

Vitamin E Protects Against Oxidative Damage Caused by Formaldehyde in the Liver and Plasma of Rats

Abstract Background: During myocardial ischemia, accumulation of end products from anaerobic glycolysis (hydrogen ions (H⁺), lactate) can cause cellular injury, consequently affecting organ function. The cells' ability to buffer H⁺ (buffering capacity (BC)) plays an important role in ischemic tolerance. Age related differences in myocardial lactate and H⁺ accumulation (one hour of ischemia) as well as differences in BC, myoglobin (Mb) and histidine (His) contents in the left (LV) and right (RV) ventricles were assessed in neonatal compared to adult pigs. The BC of the septum was also compared. Methods and Results: Neonatal RV and LV had lactate accumulations of 43% and 63% and significantly greater H⁺ (p < 0.004) compared to the adult. In the neonate LV, BC was 17% significantly poorer (p = 0.0001), had 33% lower Mb (p = 0.0002) and 15% lower His content (p = 0.0004) when compared to the adult. In the RV, despite similar BC between the neonate and adult, myoglobin content was 36% (p = 0.0004) lower in the neonate. The neonate septum had a BC that was 11% lower than that of the adult. With maturation, the adult LV had a BC that was 10% greater (p < 0.01) than the RV while the septum mirrored that of the LV. Conclusions: During maturation to adulthood, the BC of the septum begins to closely resemble the LV. Neonatal hearts have a potentially greater vulnerability to acid-base disturbances during ischemia in both ventricles when compared to hearts of adults. This is due to lower levels of myoglobin and histidine in the young, which could render them more susceptible to injury during ischemia.Condensed Abstract During myocardial ischemia, H⁺ and lactate accumulation may pose deleterious effects on the heart. The ability to buffer H⁺ (buffering capacity, BC) affects ischemic tolerance. Although lactate accumulation during 1 h of global ischemia was similar between ventricles of neonatal and adult swine, H⁺ accumulation was greater and BC, Mb and His content were lower. With maturation, LV BC was higher than the RV while septum developmentally resembled the LV. Thus, hearts of neonates may be at a greater risk of ischemic injury compared to hearts of adults. (Mol Cell Biochem xxx: 1–7, 2005)     

Human Adipose Tissue Derived Mesenchymal Stem Cells Aggravate Chronic Cyclosporin Nephrotoxicity by the Induction of Oxidative Stress

The aim of this study was to investigate whether hATMSCs protect against cyclosporine (CsA)-induced renal injury. CsA (7.5 mg/kg) and hATMSCs (3×10⁶/5 mL) were administered alone and together to rats for 4 weeks. The effect of hATMSCs on CsA-induced renal injury was evaluated by assessing renal function, interstitial fibrosis, infiltration of inflammatory cells, and apoptotic cell death. Four weeks of CsA-treatment produced typical chronic CsA-nephropathy. Combined treatment with CsA and hATMSCs did not prevent these effects and showed a trend toward further renal deterioration. To evaluate why hATMSCs aggravated CsA-induced renal injury, we measured oxidative stress, a major mechanism of CsA-induced renal injury. Both urine and serum 8-hydroxydeoxyguanosine(8-OHdG) levels were higher in the CsA+hATMSCs group than in the CsA group (P<0.05). An in vitro study showed similar results. Although the rate of apoptosis did not differ significantly between HK-2 cells cultured in hATMSCs-conditioned medium and those cultured in DMEM, addition of CsA resulted in greater apoptosis in HK-2 cells cultured in hATMSCs-conditioned medium. Addition of CsA increased oxidative stress in the hATMSCs-conditioned medium. The results of our study suggest that treatment with hATMSCs may aggravate CsA-induced renal injury because hATMSCs cause oxidative stress in the presence of CsA.     

Neurological Damage in MSUD: The Role of Oxidative Stress

Maple syrup urine disease (MSUD) is a metabolic disease caused by a deficiency in the branched-chain α-keto acid dehydrogenase complex, leading to the accumulation of branched-chain keto acids and their corresponding branched-chain amino acids (BCAA) in patients. Treatment involves protein-restricted diet and the supplementation with a specific formula containing essential amino acids (except BCAA) and micronutrients, in order to avoid the appearance of neurological symptoms. Although the accumulation of toxic metabolites is associated to appearance of symptoms, the mechanisms underlying the brain damage in MSUD remain unclear, and new evidence has emerged indicating that oxidative stress contributes to this damage. In this context, this review addresses some of the recent findings obtained from cells lines, animal studies, and from patients indicating that oxidative stress is an important determinant of the pathophysiology of MSUD. Recent works have shown that the metabolites accumulated in the disease induce morphological alterations in C6 glioma cells through nitrogen reactive species generation. In addition, several works demonstrated that the levels of important antioxidants decrease in animal models and also in MSUD patients (what have been attributed to protein-restricted diets). Also, markers of lipid, protein, and DNA oxidative damage have been reported in MSUD, probably secondary to the high production of free radicals. Considering these findings, it is well-established that oxidative stress contributes to brain damage in MSUD, and this review offers new perspectives for the prevention of the neurological damage in MSUD, which may include the use of appropriate antioxidants as a novel adjuvant therapy for patients.