Efficacy of Agmatine Treatment in Experimental Acute Pancreatitis Rat Model.

BACKGROUND/AIMS: Acute pancreatitis which is characterized by pancreatic inflammation can sometimes be difficult to treat because of limited therapeutic options. The purpose of the study was to assess the effects of agmatine in the acute pancreatitis experimental rat model. MATERIALS AND METHODS: An acute pancreatitis model was created with the administration of cerulein in 40 female Sprague-Dawley rats. Agmatine was administered as a protective agent at 5 mg/kg (low dose) and 10 mg/kg (high dose). The rats were divided into 5 groups, each with 8 rats: group 1 (acute pancreatitis); group 2 (acute pancreatitis+low-dose agmatine 5 mg/kg); group 3 (acute pancreatitis+high-dose agmatine 10 mg/kg); group 4 (placebo, acute pancreatitis+saline); and group 5 (sham and saline infusion). All rats were sacrificed 24 hours after the last injection, and the levels of superoxide dismutase, interleukin-1 beta, and tumor necrosis factor-alpha were assessed in blood samples collected via cardiac puncture. Histopathological examination was performed by a pathologist, who was blind to the groups, according to the Schoenberg's pancreatitis scoring index. RESULTS: The amylase (16.67 and 37.89 U/L), glutathione peroxidase (13.62 and 18.44 ng/mL), tumor necrosis factor-α (39.68 and 64 ng/mL), interleukin-1 (484.73 and 561.83 pg/mL), and transforming growth factor-ß (110.52 and 126.34 ng/L) levels were significantly lower and superoxide dismutase (1.29 and 0.98 ng/L) and malondialdehyde (0.99 and 0.96 nmol/mL) levels were significantly higher in group 3 compared to group 1 (P < .05). Moreover glutathione peroxidase, tumor necrosis factor-α, and transforming growth factor-ß levels were lower, and malondialdehyde levels were higher in the group 3 compared to group 2 (P < .05). Although the Schoenberg's pancreatitis scoring index was not significantly different between the high- and low-dose treatment groups, rats who received high-dose treatment had significantly lower scores compared to those with acute pancreatitis group. CONCLUSION: This is the first study that evaluated the efficacy of agmatine in an experimental model of acute pancreatitis. Agmatine, an anti-inflammatory and antioxidant agent, had a protective effect in an experimental rat model of acute pancreatitis.

Advances in the role of GPX3 in ovarian cancer (Review).

Ovarian cancer (OC) is the 5th most common malignancy in women, and the leading cause of death from gynecologic malignancies. Owing to tumor heterogeneity, lack of reliable early diagnostic methods and high incidence of chemotherapy resistance, the 5­year survival rate of patients with advanced OC remains low despite considerable advances in detection and therapeutic approaches. Therefore, identifying novel therapeutic targets to improve the prognosis of patients with OC is crucial. The expression of glutathione peroxidase 3 (GPX3) plays a crucial role in the growth, proliferation and differentiation of various malignant tumors. In OC, GPX3 is the only antioxidant enzyme the high expression of which is negatively correlated with the overall survival of patients. GPX3 may affect lipid metabolism in tumor stem cells by influencing redox homeostasis in the tumor microenvironment. The maintenance of stemness in OC stem cells (OCSCs) is strongly associated with poor prognosis and recurrence in patients. The aim of the present study was to review the role of GPX3 in OC and investigate the potential factors and effects of GPX3 on OCSCs. The findings of the current study offer novel potential targets for drug therapy in OC, enhance the theoretical foundation of OC drug therapy and provide valuable references for clinical treatment.

Application of an Integrative Drug Safety Model for Detection of Adverse Drug Events Associated With Inhibition of Glutathione Peroxidase 1 in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic Obstructive Pulmonary Disease is characterised by declining lung function and a greater oxidative stress burden due to reduced activity of antioxidant enzymes such as Glutathione Peroxidase 1. OBJECTIVES: The extent to which drugs may contribute to this compromised activity is largely unknown. An integrative drug safety model explores inhibition of Glutathione Peroxidase 1 by drugs and their association with chronic obstructive pulmonary disease adverse drug events. METHODS: In silico molecular modelling approaches were utilised to predict the interactions that drugs have within the active site of Glutathione Peroxidase 1 in both human and bovine models. Similarities of chemical features between approved drugs and the known inhibitor tiopronin were also investigated. Subsequently the Food and Drug Administration Adverse Event System was searched to uncover adverse drug event signals associated with chronic obstructive pulmonary disease. RESULTS: Statistical and molecular modelling analyses confirmed that the use of several registered drugs, including acetylsalicylic acid and atenolol may be associated with inhibition of Glutathione Peroxidase 1 and chronic obstructive pulmonary disease. CONCLUSION: The integration of molecular modelling and pharmacoepidemological data has the potential to advance drug safety science. Ongoing review of medication use and further pharmacoepidemiological and biological analyses are warranted to ensure appropriate use is recommended.

Pirfenidone alleviates vascular intima injury caused by hyperhomocysteinemia.

OBJECTIVES: Hyperhomocysteinemia (HHcy) can induce vascular inflammatory and oxidative damage and accelerate intimal hyperplasia. This study investigated the protective effect of pirfenidone (PFD) on the recovery process of injured endothelial arteries during HHcy. MATERIALS AND METHODS: Thirty rabbits were randomly separated into three groups: A control group (n=10, standard rabbit chow), a model group (n=10, control diet plus 30 g methionine/kg food), and a PFD group (n=10, model diet plus oral administration of 90 mg/day of PFD). After 14 weeks of arterial injury, histopathological changes were determined. Plasma homocysteine (Hcy) concentrations, lipid profiles and oxidant and antioxidant status were evaluated. Macrophage infiltration was assessed using immunohistochemical staining. RESULTS: PFD supplementation decreased macrophage infiltration of iliac artery significantly without changes in blood lipids and Hcy concentrations. Compared with the model group, PFD restored superoxide dismutase and glutathione peroxidase activities and reduced malondialdehyde and reactive oxygen species levels. A high-methionine diet significantly increased neointimal area and the ratio between neointimal and media area. Systemic administration of PFD inhibited neointimal formation. CONCLUSIONS: PFD can partly alleviate intimal hyperplasia by inhibiting inflammatory and oxidative stress response induced by HHcy during endothelial injury. It may be a potential therapeutic agent for the prevention and treatment of endothelial injury-associated diseases such as atherosclerosis.

Effects of Modified Duhuo Jisheng Decoction Combined with Arthroscopic Surgery on Bone Metabolism, Oxidative Stress, and Serum TLR4 and TGF-ß1 in Patients with Knee Osteoarthritis.

Objective: To analyze the effects of modified Duhuo Jisheng Decoction combined with arthroscopic surgery on bone metabolism, oxidative stress, and serum TLR4 and TGF-ß1 in patients with knee osteoarthritis (KOA). Methods: Prospectively select 82 patients with KOA from January 2020 to January 2022 in our hospital and divide them into the control group and observation group according to the random number table method, with 41 patients in each group. The control group was treated with arthroscopic surgery alone and routine anti-infection after operation. The observation group was treated with Duhuo Jisheng Decoction on the basis of the treatment of the control group. The patients in the two groups were treated continuously for 4 weeks. The improvement of patients' symptoms was evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Before treatment and 4 weeks after treatment, the scores of traditional Chinese medicine (TCM) symptoms, bone metabolism indicators (cartilage oligomeric matrix protein (COMP), collagen type II carboxy terminal peptide (ctx-II), and matrix metalloproteinase-3 (MMP-3)), oxidative stress indicators (superoxide dismutase (SOD), glutathione peroxidase (GSHPx), malondialdehyde (MDA), nitric oxide (NO)), serum Toll-like receptor 4 (TLR4), and transforming growth factor ß (TGF-ß) level were compared between the two groups. Results: After treatment, the WOMAC score of the two groups decreased (42.45 ± 10.83) in the observation group and (67.81 ± 14.63) in the control group. The WOMAC score of the observation group was lower than that of the control group (P < 0.05). After treatment, the levels of COMP, CTX-II, and MMP-3 in the two groups decreased, and the levels of COMP, CTX-II, and MMP-3 in the observation group were lower than those in the control group (P < 0.05). After treatment, the levels of SOD and GSHPx increased, while the levels of MDA and NO decreased in the two groups. The levels of SOD and GSHPx in the observation group were higher than those in the control group, while the levels of MDA and NO were lower than those in the control group (P < 0.05). After treatment, the TLR4 level in the observation group was lower than that of the control group, and the level of TGF-ß in the observation group was higher than that of the control group (P < 0.05). Conclusion: Compared with arthroscopic surgery alone, combined with modified Duhuo Jisheng Decoction can better alleviate the clinical symptoms of patients with KOA, improve their bone metabolism, oxidative stress indicators, and serum TLR4 and TGF-ß 1 level, and reduce the inflammatory injury of knee joint.

Sinomenine pretreatment alleviates hepatic ischemia/reperfusion injury through activating Nrf-2/HO-1 pathway.

INTRODUCTION: Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated. METHODS: This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury. RESULTS: Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the downregulated activities of serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-α, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects. CONCLUSIONS: Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.

The effects of butyrate supplementation on glycemic control, lipid profile, blood pressure, nitric oxide level and glutathione peroxidase activity in type 2 diabetic patients: A randomized triple -blind, placebo-controlled trial.

BACKGROUND: This study aimed to investigate the effects of oral NaBut on metabolic parameters, blood pressure, and oxidative stress indices including glutathione peroxidase (GPx) and nitric oxide (NO) status in type 2 diabetic patients. METHODS: In the current interventional trial, 42 patients with type 2 diabetes mellitus (T2DM) were randomly allocated into either NaBut (n = 21) or placebo (n = 21) group for six weeks. Serum concentrations of metabolic parameters, GPx, NO as well as blood pressure were assessed before and after the intervention. RESULTS: Within-group findings demonstrated that NaBut administration significantly reduced systolic and diastolic blood pressure (p = 0.016 and p = 0.002, respectively). Blood sugar 2-hr postprandial (BS2hpp) was also significantly decreased in the intervention and placebo groups (p = 0.016 and p = 0.019, respectively), but the between-group differences were not statistically significant. Differences in homeostatic model assessment of insulin resistance (HOMA-IR) were not significant between groups after adjustment for potential confounders (p = 0.061). NaBut supplementation was also found to significantly increase total cholesterol (p = 0.001), low-density lipoprotein cholesterol (p = 0.005), and insulin levels (p = 0.047) compared to the baseline, while decreased NO levels (p = 0.040). However, there were no significant between-group differences in these parameters. No significant differences were also found in other parameters. CONCLUSIONS: We observed significant within-group decreases in systolic and diastolic blood pressure as well as BS2hpp following oral butyrate treatment. While no or even adverse changes in other biochemical parameters were found. Further investigations with longer durations are warranted to more vividly elucidate the effects of NaBut supplementation on patients with T2DM. Registered under Iranian Registry of Clinical Trials website (http://www.irct.ir), Identifier no. IRC T20090609002017N33.

Ascorbic acid and hydrocortisone synergistically inhibit septic organ injury via improving oxidative stress and inhibiting inflammation.

BACKGROUND: The current study aimed to investigate the effect of the combination of ascorbic acid (AscA) and hydrocortisone (Hyd) on septic organ injury and its potential mechanism. METHOD: Sepsis was induced in mice by a single intraperitoneal injection of lipopolysaccharides. RESULTS: AscA and Hyd combined showed more effective protection of the injured liver and kidney in septic mice by decreasing alanine aminotransferase, aspartate aminotransferase, serum urea nitrogen, and serum creatinine and ameliorating pathological manifestations than Hyd or AscA alone. AscA showed a mild inhibitory effect on the secretion of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6)). However, Hyd showed a weak regulatory effect on septic oxidative stress markers (malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)). However, the combination of AscA and Hyd showed a more powerful inhibitory effect on the septic inflammatory response and oxidative stress than Hyd or AscA alone by decreasing TNF-α, IL-1ß, and IL-6 and regulating MDA, SOD, and GSH. In an in vitro study, cotreatment of RAW 264.7 macrophages with Hyd and AscA sharply reduced reactive oxygen species (ROS) generation and synergistically inhibited TNF-α, IL-1ß, and IL-6 secretion, which could be abolished by additional stimulation with the ROS donor 3-nitropropionic acid (3-NP). As expected, cotreatment of macrophages with Hyd and AscA synergistically inhibited the activation of p38 MAPK and p-p65, and the effect could be reversed by additional stimulation with 3-NP. CONCLUSIONS: AscA and Hyd synergistically protect the kidney and liver from injury by inhibiting the inflammatory response and oxidative stress. The powerful inhibitory effects of AscA on oxidative stress contribute to the synergistic anti-inflammatory action.

Synergistic ferroptosis-gemcitabine chemotherapy of the gemcitabine loaded carbonaceous nanozymes to enhance the treatment and magnetic resonance imaging monitoring of pancreatic cancer.

Pancreatic adenocarcinoma (PDAC) is one of the deadliest cancers, and it is resistant to most conventional antineoplastic therapies. To address this challenge, gemcitabine (Gem)-loaded carbonaceous nanoparticles (MFC-Gem) as nanozymes and a theranostic platform were fabricated and used for MR-guided ferroptosis-chemo synergetic therapy of PDAC. As a biocompatible carrier, MFC-Gem nanoparticles are regarded as peroxidase-like and glutathione peroxidase-like nanozymes that promote ferroptosis therapy by effectively generating ROS and consuming GSH. Meanwhile, the combination of MnFe2O4 and Gem can markedly enhance synergetic therapy by both ferroptosis and Gem chemotherapy. MFC-Gem has higher magnetic susceptibility and was used for simultaneous magnetic resonance imaging (MRI) monitoring of the PDAC treatment. In conclusion, these salient features unequivocally indicate that this biocompatible nanotheranostic system has cooperative and enhancing chemotherapy effects for anti-PDAC therapy with simultaneous MRI monitoring. STATEMENT OF SIGNIFICANCE: Pancreatic adenocarcinoma (PDAC) is one of the deadliest cancers, and it is resistant to most conventional antineoplastic therapies. To address this challenge, gemcitabine (Gem)-loaded carbonaceous nanoparticles (MFC-Gem) as nanozymes and a theranostic platform were fabricated and used for MR-guided ferroptosis-chemo synergetic therapy of PDAC. i) MFC nanoparticles are regarded as peroxidase-like and glutathione peroxidase-like nanozymes that enhance ferroptosis therapy by effectively generating ROS and consuming GSH. ii) The combination of MnFe2O4 and Gem can markedly enhance synergetic therapy by both ferroptosis and Gem chemotherapy. iii) MFC-Gem has higher magnetic susceptibility and was used for simultaneous magnetic resonance imaging (MRI) monitoring of the PDAC treatment.

Sex-Specific Association between Antioxidant Defense System and Therapeutic Response to Risperidone in Schizophrenia: A Prospective Longitudinal Study.

BACKGROUND: There are various differences in response to different antipsychotics and antioxidant defense systems (ADS) by sex. Previous studies have shown that several ADS enzymes are closely related to the treatment response of patients with antipsychotics-naïve first-episode (ANFE) schizophrenia. OBJECTIVE: Therefore, the main goal of this study was to assess the sex difference in the relationship between changes in ADS enzyme activities and risperidone response. METHODS: The plasma activities of glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and total antioxidant status (TAS) were measured in 218 patients and 125 healthy controls. Patients were treated with risperidone for 3 months, and we measured PANSS for psychopathological symptoms and ADS biomarkers at baseline and at the end of 3 months of treatment. We compared sex-specific group differences between 50 non-responders and 168 responders at baseline and at the end of the three months of treatment. RESULTS: We found that female patients responded better to risperidone treatment than male patients. At baseline and 3-month follow-up, there were no significant sex differences in TAS levels and three ADS enzyme activities. Interestingly, only in female patients, after 12 weeks of risperidone treatment, the GPx activity of responders was higher than that of non-responders. CONCLUSION: These results indicate that after treatment with risperidone, changes in GPx activity were associated with treatment response, suggesting that changes in GPx may be a predictor of response to risperidone treatment in female patients with ANFE schizophrenia.

B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis.

Aerobic organisms need to maintain cellular redox homeostasis. Glutathione peroxidase-4 (Gpx4) has the unique ability to protect cells against lipid peroxidation. Here, we show that Gpx4 is absolutely required to prevent ferroptosis during development, maintenance, and responses of innate-like B cells, namely, the B1 and marginal zone (MZ) B cells. In contrast, Gpx4 is dispensable for the development, germinal center reactions, and antibody responses of follicular B2 cells. Mechanistically, we show increased lipid metabolism and sensitivity to lipid peroxidation and ferroptosis in B1 and MZ B cells compared to follicular B2 cells, consistent with the requirement of Gpx4 in innate-like B cells. This high sensitivity to ferroptosis of innate-like B cells may be used to therapeutically target Gpx4 in certain forms of B cell malignancies involving B1 cells.

Is plasma selenium correlated to transthyretin levels in critically ill patients? / ¿Se correlacionan los niveles plasmáticos de selenio con los de prealbúmina en los pacientes críticos?

Background: Selenium is an essential trace element, but critically ill patients using total parenteral nutrition (PN) do not receive selenium because this mineral is not commonly offered. Threfore, the evaluation of plasma selenium levels is very important for treating or preventing this deficiency. Recent studies have shown that transthyretin may reflect the selenium intake and could be considered a biomarker. However, this issue is still little explored in the literature. Objective: This study aims to investigate the correlation of transthyretin with the plasma selenium of critically ill patients receiving PN. Method: This was a prospective cohort study with 44 patients using PN without selenium. Blood samples were carried out in 3 stages: initial, 7th and 14th day of PN. In order to evaluate the clinical condition and the inflammatory process, albumin, C-reactive protein (CRP), transthyretin, creatinine and HDL cholesterol levels were observed. To assess the selenium status, plasma selenium and glutathione peroxidase (GPx) in whole blood were measured. Descriptive analyses were performed and the ANOVA, Mann-Whitney and Spearman’s coefficient tests were conducted; we assumed a significance level of 5%. Results: A positive correlation of selenium with the GPx levels (r = 0.46; p = 0.03) was identified. During two weeks, there was a positive correlation of transthyretin with plasma selenium (r = 0.71; p = 0.05) regardless of the CRP values. Conclusion: Transthyretin may have reflected plasma selenium, mainly because the correlation was verified after the acute phase (AU)

Introducción: el selenio es un oligoelemento esencial. Sin embargo, los pacientes críticos con nutrición parenteral (NP) no reciben selenio de forma habitual. La evaluación de los niveles plasmáticos de selenio se vuelve imprescindible en este contexto, para prevenir las deficiencias. Algunos estudios recientes han demostrado que los niveles de prealbúmina pueden reflejar los aportes de selenio y servir como biomarcador del estado de selenio. Esta posibilidad se ha evaluado de una forma insuficiente. Objetivo: investigar la correlación entre los niveles plasmáticos de selenio y de prealbúmina en el paciente crítico. Método: estudio prospectivo de una cohorte de 44 pacientes que recibían NP sin selenio. Se extrajeron muestras de sangre en el momento del inicio y a los 7 y 14 días de NP. Para evaluar la situación clínica y el proceso inflamatorio, se midieron también los niveles de albúmina, proteína C reactiva (PCR), prealbúmina, creatinina y colesterol HDL. Para evaluar el estado de selenio, se midieron los niveles de selenio y de glutation peroxidasa (GPx) en sangre completa. Se realizó un análisis descriptivo así como los siguientes estudios estadísticos: ANOVA, Mann-Whitney y coeficiente de correlación de Spearman, asumiendo un nivel de significación estadística del 5%. Resultados: se encontró una correlación positiva con los niveles de GPX (r = 0,46; p = 0,03). Durante las dos semanas de estudio, hubo correlación entre los niveles plasmático de selenio y de prealbúmina (r = 0,71; p = 0,05), con independencia de los niveles de PCR. Conclusión: la prealbúmina puede reflejar los niveles plasmáticos de selenio, al demostrar una buena correlación tras la fase aguda de la agresión (AU)

Glutathione peroxidase-1 as a novel therapeutic target for COPD.

Oxidative stress plays a role in a variety of diseases but it is even more pertinent in chronic obstructive pulmonary disease (COPD) given the increased oxidant burden in smokers. The increased oxidant burden results from the fact that cigarette smoke contains over 4700 different chemical compounds and more than 10(15) oxidants/free radicals per puff. Other factors, such as air pollutants, infections, and occupational dusts that may exacerbate COPD, also have the potential to produce oxidative stress. These oxidants give rise to Reactive Oxygen Species (ROS) that are generated enzymatically by inflammatory and epithelial cells within the lung as part of an inflammatory immune response towards a pathogen or irritant. Thus, while ROS are necessary for host defence against invading pathogens, increased levels of ROS have been implicated in initiating inflammatory responses in the lungs through the activation of transcriptional factors, signal transduction pathways, chromatin remodelling and gene expression of pro-inflammatory mediators. However, the normal lung has developed defences to ROS-mediated damage, which include antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. In this review we consider the therapeutic potential of the antioxidant enzyme glutathione peroxidase-1 for the treatment of cigarette smoke-induced lung inflammation and damage.

Vasospasm after subarachnoid hemorrhage in haptoglobin 2-2 mice can be prevented with a glutathione peroxidase mimetic.

Vasospasm after subarachnoid hemorrhage (SAH) is attributable to inflammation and oxidative stress associated with extracellular hemoglobin (Hb). Haptoglobin (Hp) binds free Hb and the Hp-Hb complex is cleared by macrophages, and the Hp-2 isoform of Hp is associated with more oxidative stress and more severe vasospasm. We hypothesized that treatment with an anti-oxidant, the glutathione peroxidase mimetic SYI-2074, would reduce vasospasm after SAH in Hp-2 mice. We found that SAH induced significant vasospasm in Hp-2 mice (lumen patency reduced to 65.9%), but no vasospasm was seen in mice that received SYI-2074 after SAH (lumen patency of 98.7%). We conclude that vasospasm after SAH in Hp-2 mice can be prevented with SYI-2074, suggesting that oxidative stress contributes significantly to vasospasm.

Dopaminergic neurotoxicity of HIV-1 gp120: reactive oxygen species as signaling intermediates.

We examined the role of reactive oxygen species (ROS) in loss of dopaminergic neurons (DNs) from the substantia nigra (SN) in neuroAIDS. The frequency of Parkinson-like symptomatology, and DN loss, in neuroAIDS is often attributed to nonspecific DN fragility to oxidative stress. Cultured DN are more sensitive to ROS than non-dopaminergic neurons (RN): DN underwent apoptosis at far lower H(2)O(2) concentrations than RN. Gene delivery of glutathione peroxidase (GPx1), which detoxifies H(2)O(2), largely protected both neuron types. HIV-1 envelope, gp120, which elicits oxidative stress in neurons, caused apoptosis more readily in DN than in RN. However, unlike apoptosis caused by H(2)O(2), gp120-induced DN apoptosis was specific: DNs were specifically more sensitive than RN to receptor-mediated [Ca(2+)](i) fluxes triggered by gp120. Gp120-induced Ca(2+) signaling in both neuron types was inhibited by GPx1 or Cu/Zn superoxide dismutase (SOD1), implicating superoxide and peroxide in ligand (gp120)-induced signaling upstream of Ca(2+) release from intracellular stores. In vivo, rats given 10 ng of gp120 stereotaxically showed rapid DN loss within the SN, while loss of RN in the SN and caudate-putamen (CP) was slower and required > or =100 ng of gp120. Furthermore, gp120 injected into the CP was transported axonally retrograde to the SN, causing delayed DN loss there. This, too, was prevented by SOD1 or GPx1. DNs are therefore specifically hypersensitive to gp120-induced apoptosis, signaling for which involves ROS intermediates. These findings may help explain why DN loss and Parkinson's-like dysfunction predominate in neuroAIDS and may apply to other neurodegenerative diseases involving the SN.

Hydrogen sulfide protects from intestinal ischaemia-reperfusion injury in rats.

OBJECTIVES: Hydrogen sulfide (H2S) is an endogenously gaseous mediator, regulating many pathophysiological functions in mammalian cells. H2S has been shown to inhibit myocardial ischaemia-reperfusion (I/R) injury. However, little is known about whether H2S could modulate intestinal I/R injury. This study aimed to investigate the effect of H2S on intestinal I/R injury and potential mechanism(s) underlying the action of H2S in regulating the development of intestinal I/R injury in rats. METHODS: Following surgical induction of intestinal I/R injury for 1 h, groups of Sprague-Dawley rats were treated with, or without, tetramethylpyrazine (8 mg/kg), or sodium hydrosulfide (NaHS, an H2S donor at 7 or 14 micromol/kg) 30 min after occlusion. All rats were sacrificed immediately after the reperfusion. Their intestinal injury, together with that of sham-control rats, was histologically examined and their sera and intestinal malondialdehyde (MDA), superoxide dismutase (SOD), peroxidase (GSH-Px) activities were characterized by biochemical analysis. KEY FINDINGS: The results showed that NaHS significantly reduced intestinal I/R injury and the levels of sera and intestinal MDA activity, and dramatically increased the levels of serum and intestinal SOD and GSH-Px activity. CONCLUSIONS: The results suggest that H2S protects from intestinal I/R injury in rats, which is associated with increase in the activity of antioxidant enzymes.

Estrés oxidativo en la retina de la rata inducido por la administración crónica de etanol: tratamiento con el antioxidante ebselen / Chronic ethanol feeding induces oxidative stress in the rat retina: treatment with the antioxidant ebselen

Objetivo: Establecer la existencia de cambios bioquímicos y funcionales en la retina tras la administración crónica de etanol en ratas adultas, y estudiar la capacidad del antioxidante ebselen para corregir estos efectos. Métodos: Se utilizaron ratas macho Sprague-Dawley, que fueron alimentadas con una dieta líquida con etanol, mientras el grupo control recibió una dieta isocalórica libre de etanol. Después de seis semanas, los ojos fueron extraídos y homogenizados sin cristalino, y se determinaron parámetros relevantes en la modulación del estrés oxidativo, tales como el contenido de glutation (GSH) y de malondialdehído (MDA) como antioxidante intracelular y producto de la peroxidación de lípidos, respectivamente. Además, se comprobó la funcionalidad de la retina mediante electrorretinograma (ERG). Resultados: La concentración de MDA en la retina fue significativamente mayor en el grupo alimentado con etanol, mientras el contenido de GSH fue significativamente menor en este grupo, al compararlo con el grupo control. El etanol también indujo una disminución de la onda b del ERG. El tratamiento con ebselen fue capaz de corregir los valores de MDA, GSH y la amplitud de la onda b en el ERG hasta valores control. Conclusión: Estos resultados indican que la ingesta crónica de etanol como único factor etiológico, altera el estado redox de la retina así como su función (ERG), descartando la influencia del estado nutricional. Aun así, son necesarios nuevos estudios para confirmar el mecanismo protector del ebselen en este modelo del alcoholismo crónico

Purpose: To assess the involvement of biochemical and functional changes to the retina after chronic ethanol intake in adult rats, and the capacity of the antioxidant ebselen to prevent these changes. Methods: Male Sprague-Dawley rats were used in the study. They were fed an ethanol-containing liquid diet, whereas a control group was given an ethanol-free isocaloric diet. After six weeks of experiment, the eyes were extracted and homogenized without the lens, and markers of oxidative stress were assayed, i.e., glutathione (GSH) and malondialdehyde (MDA) as an intracellular antioxidant and a lipid peroxidation product, respectively. Moreover, retinal function was assessed by electroretinogram (ERG). Results: The retinal MDA concentration was significantly increased in the ethanol-fed animals compared to controls, whereas the GSH content was significantly reduced in the ethanol-fed group compared to controls. Ethanol also induced a decrease in ERG b-wave amplitude. Ebselen treatment restored the MDA and GSH concentrations and ERG bwave amplitude to control values. Conclusion: These results indicate that chronic alcohol consumption alone and without the influence of nutritional factors alters the retinal redox status as well as its function (ERG). Further studies are required to better understand the protective mechanism of ebselen in this experimental model of chronic alcoholism

Role of reactive oxygen species in mediating hepatic ischemia-reperfusion injury and its therapeutic applications in liver transplantation.

Increasing evidence has shown that reactive oxygen species (ROS) are important mediators in liver ischemia/reperfusion injury(IRI). ROS include hydrogen peroxide (H(2)O(2)), superoxide anion (O(-2)), and hydroxyl radical (HO(-)), which may be generated by activated Kupffer cells in the liver, contributing to reperfusion injury. Hepatic IRI is a multistep process that damages liver graft function. To establish a series of therapeutic strategies to improve the outcome of liver transplantation, a good understanding of the mechanisms of IRI is essential. However, the detail mechanisms of how ROS lead to hepatocyte damage in IRI remains unclear. The aim of this review was to describe recent developments in the field of oxidative stress research. The first part of this review focused on the key roles and possible mechanisms of ROS in hepatic IRI. The second part of this review summarizes some findings including novel and classic antioxidant methods to ameliorate the hepatocyte damage during IRI.

Compounds for the prevention and treatment of noise-induced hearing loss.

Noise-induced hearing loss (NIHL) is the leading occupational disease and a major contributor to the development of age-related hearing loss. The pharmacological prevention and treatment of NIHL has been under preclinical investigation for the past 20 years. Promising treatments have now been identified and entered into clinical development. Within the next five years, safe and effective drugs could be approved as the first generation of otoprotectants. This review covers strategies that are under investigation for NIHL. Drugs that effectively prevent and treat NIHL will have a significant impact on medical costs, disability compensation and several issues affecting the quality of life.

Impact of nutritional rehabilitation on enzymatic antioxidant levels in protein energy malnutrition.

To assess the role of enzymatic antioxidants in the pathogenesis of protein energy malnutrition (PEM) and the effect of nutritional rehabilitation, we studied 30 infants with PEM (mean age 10.63 +/- 4.39 months: 10 marasmic; 8 with kwashiorkor; 12 with marasmic kwashiorkor) and 15 controls. All underwent clinical examination and laboratory investigations, including superoxide dismutase (SOD) and glutathione peroxidase (GPx) estimation before and after nutrition rehabilitation. SOD and GPx were significantly lower in all malnourished infants compared to controls, and significantly increased after nutritional rehabilitation. These significant correlations suggest that antioxidants could be introduced during PEM nutritional rehabilitation to decrease morbidity and mortality.