SH-PRO extract alleviates benign prostatic hyperplasia via ROS-mediated activation of PARP/caspase 3 and inhibition of FOXO3a/AR/PSA signaling in vitro and in vivo.

To target benign prostatic hyperplasia (BPH) as a common urinary disease in old men, in the current study, the antiproliferative and apoptotic mechanism of SH-PRO, a mixture of Angelica gigas and Astragalus membranaceus (2:1), was evaluated in BPH-1 cells and rats with testosterone-induced BPH. Herein, SH-PRO significantly reduced the viability of BPH-1 cells and dihydrotestosterone (DHT)-treated RWPE-1 cells. Also, SH-PRO increased the sub-G1 population in BPH-1 cells and consistently attenuated the expression of pro-PARP, pro-caspase 3, Bcl2, FOXO3a, androgen receptor (AR), and prostate-specific antigen (PSA) in BPH-1 cells and DHT-treated RWPE-1 cells. Of note, SH-PRO generated reactive oxygen species (ROS) in BPH-1 cells, while ROS inhibitor N-acetyl-l-cysteine (NAC) disturbed the ability of SH-PRO to reduce the expression of pro-PARP, FOXO3a, catalase, SOD, and increase sub-G1 population in BPH-1 cells. Furthermore, oral treatment of SH-PRO significantly abrogated the weight of the prostate in testosterone-treated rats compared to BPH control with the reduced expression of AR, PSA, and DHT and lower plasma levels of DTH, bFGF, and EGF with no toxicity. Overall, these findings highlight the antiproliferative and apoptotic potential of SH-PRO via ROS-mediated activation of PARP and caspase 3 and inhibition of FOXO3a/AR/PSA signaling as a potent anti-BPH candidate.

Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells.

Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells.

Passion fruit (Passiflora edulis) leaf extract modulates the oxidative metabolism of rat peritoneal neutrophils in a model of inflammation

This study was conducted to evaluate the effect of extracts of Passiflora edulis Sims leaves on the oxidative metabolism of rat peritoneal neutrophils using a model of acute inflammation. The extract was obtained by maceration in 70% ethanol, evaporation under reduced pressure and lyophilisation. Total phenolic content (TP) was determined by the Folin-Ciocalteu assay. The P. edulis extract, in different doses, was administered by gavage 1 h prior to inflammation induction by carrageenan (8 mg/kg, i.p.); five hours later, the neutrophils were obtained by intraperitoneal lavage. The tests performed in neutrophils were cytochrome C and chemiluminescence assay as well as myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. The administration of the extract reduced the number of neutrophils recruited to the site of inflammation; however, the extract did not alter the activity of NADPH oxidase as well as SOD activity in these cells. The MPO and CAT activities in peritoneal neutrophils of rat treated with extract was lower than in the control group, and the GPx activity was increased. Based on the experimental model utilised, the anti-inflammatory potential of P. edulis leaf extract could be related to the presence of phenolic compounds in the extract.

Extender Supplementation with Antioxidants Selected after the Evaluation of Sperm Susceptibility to Oxidative Challenges in Goats.

This study aimed to detect the most deleterious ROS for goat sperm and then supplemented the extender with a proper antioxidant. For this, 12 adult goats (aged 1-7) were used. Fresh samples were submitted to challenge with different ROS (superoxide anion, hydrogen peroxide, and hydroxyl radical) and malondialdehyde (MDA-toxic product of lipid peroxidation). After experiment 1, sperms were cryopreserved in extenders supplemented to glutathione peroxidase (Control: 0 UI/mL; GPx1: 1 UI/mL; GPx5: 5 UI/mL, and GPx10: 10 UI/mL) and catalase (Control: 0 UI/mL; CAT60: 60 UI/mL; CAT120: 120 UI/mL, and CAT240: 240 UI/mL). Each sample was evaluated by motility, plasma membrane integrity (eosin/nigrosin), acrosome integrity (fast green/rose bengal), sperm morphology, assay of the sperm chromatin structure, mitochondrial activity (3,3-diaminobenzidine), and measurement of lipid peroxidation (thiobarbituric acid reactive substances [TBARS]). It was possible to observe a mitochondrial dysfunction (DAB-Class IV) and low membrane integrity after hydrogen peroxide action. However, the high rates of TBARS were observed on hydroxyl radical. CAT240 presents the lower percentage of plasma membrane integrity. It was possible to attest that hydrogen peroxide and hydroxyl radical are the more harmful for goat sperm. Antioxidant therapy must be improving perhaps using combination between antioxidants.

Hyperbaric oxygen inhibits production of CD3+ T cells in the thymus and facilitates malignant glioma cell growth.

Objective Hyperbaric oxygen (HBO) is an emerging complementary alternative medical approach in glioma treatment. However, its mode of action is unknown, so this was investigated in the present study. Methods We constructed an intracranial glioma model of congenic C57BL/6J mice. Glioma growth under HBO stimulation was assessed by bioluminescent imaging and magnetic resonance imaging. Flow cytometry assessed direct effects of HBO on reactive oxygen species (ROS) signaling of transplanted glioma cells and organs, and quantified mature T cells and subgroups in tumors, the brain, and blood. Results HBO promoted the growth of transplanted GL261-Luc glioma in the intracranial glioma mouse model. ROS signaling of glioma cells and brain cells was significantly downregulated under HBO stimulation, but thymus ROS levels were significantly upregulated. CD3+ T cells were significantly downregulated, while both Ti/Th cells (CD3+CD4+) and Ts/Tc cells (CD3+CD8+) were inhibited in tumors of the HBO group. The percentage of regulatory T cells in Ti/Th (CD3+CD4+) cells was elevated in the tumors and thymuses of the HBO group. Conclusion HBO induced ROS signaling in the thymus, inhibited CD3+ T cell generation, and facilitated malignant glioma cell growth in vivo in the intracranial glioma mouse model.

Blood pressure lowering and anti-inflammatory effects of hesperidin in type 2 diabetes; a randomized double-blind controlled clinical trial.

Elevated levels of reactive oxygen species under diabetic condition lead to vascular complications and inflammation. This study aimed to examine the effects of hesperidin supplement on blood pressure and inflammatory markers in type 2 diabetes. In this research, 64 patients were randomly allocated to receive 500 mg/day hesperidin or placebo capsules for 6 weeks. Data on systolic blood pressure (SBP), diastolic blood pressure, serum total antioxidant capacity (TAC), tumor necrosis factor alpha, interleukin 6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) were collected at the baseline and at the end of the study. In the hesperidin group, SBP (122.7 ± 8.5 vs. 119.0 ± 7.4; p = .005), mean arterial blood pressure (94.2 ± 5.5 vs. 91.8 ± 5.5; p = .009), IL-6 (8.3 ± 2.1 vs. 7.4 ± 1.8; p = .001), and hs-CRP (1.9 ± 1.2 vs. 1.1 ± 0.9; p < .000) decreased whereas TAC increased (0.74 ± 0.1 vs. 0.82 ± 0.1; p < .000) in comparison to the baseline values. There was a significant difference in mean percent change of SBP, diastolic blood pressure, mean arterial blood pressure, serum TAC, and inflammatory markers (tumor necrosis factor alpha, IL-6, and hs-CRP) between hesperidin and control groups following intervention in adjusted models (p < .05). These results suggest that hesperidin may have antihypertensive and anti-inflammatory effects in type 2 diabetes.

Hot topics in reactive oxygen therapy: Antimicrobial and immunological mechanisms, safety and clinical applications.

Reactive oxygen species (ROS), when combined with various delivery mechanisms, has the potential to become a powerful novel therapeutic agent against difficult-to-treat infections, especially those involving biofilm. It is important in the context of the global antibiotic resistance crisis. ROS is rapidly active in vitro against all Gram-positive and Gram-negative bacteria tested. ROS also has antifungal and antiviral properties. ROS prevents the formation of biofilms caused by a range of bacterial species in wounds and respiratory epithelium. ROS has been successfully used in infection prevention, eradication of multiresistant organisms, prevention of surgical site infection, and intravascular line care. This antimicrobial mechanism has great potential for the control of bioburden and biofilm at many sites, thus providing an alternative to systemic antibiotics on epithelial/mucosal surfaces, for wound and cavity infection, chronic respiratory infections and possibly recurrent urinary infections as well as local delivery to deeper structures and prosthetic devices. Its simplicity and stability lend itself to use in developing economies as well.

Encapsulated platelets modulate kupffer cell activation and reduce oxidative stress in a model of acute liver failure.

Acute liver failure (ALF) is characterized by massive hepatocyte cell death. Kupffer cells (KC) are the first cells to be activated after liver injury. They secrete cytokines and produce reactive oxygen species, leading to apoptosis of hepatocytes. In a previous study, we showed that encapsulated platelets (PLTs) increase survival in a model of ALF. Here, we investigate how PLTs exert their beneficial effect. Wistar rats submitted to 90% hepatectomy were treated with PLTs encapsulated in sodium alginate or empty capsules. Animals were euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy, and livers were collected to assess oxidative stress, caspase activity, and gene expression related to oxidative stress or liver function. The number of KCs in the remnant liver was evaluated. Interaction of encapsulated PLTs and KCs was investigated using a coculture system. PLTs increase superoxide dismutase and catalase activity and reduce lipid peroxidation. In addition, caspase 3 activity was reduced in animals receiving encapsulated PLTs at 48 and 72 hours. Gene expression of endothelial nitric oxide synthase and nuclear factor kappa B were elevated in the PLT group at each time point analyzed. Gene expression of albumin and factor V also increased in the PLT group. The number of KCs in the PLT group returned to normal levels at 12 hours but remained elevated in the control group until 72 hours. Finally, PLTs modulate interleukin (IL) 6 and IL10 expression in KCs after 24 hours of coculture. In conclusion, these results indicate that PLTs interact with KCs in this model and exert their beneficial effect through reduction of oxidative stress that results in healthier hepatocytes and decreased apoptosis. Liver Transplantation 22 1562-1572 2016 AASLD.

The benefits of respective and combined use of green tea polyphenols and ERK inhibitor on the survival and neurologic outcomes in cardiac arrest rats induced by ventricular fibrillation.

BACKGROUND: Cerebral injury is a main factor contributing to a high mortality after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR). OBJECTIVE: We sought to evaluate the effect of green tea polyphenols (GTPs) and ERK1/2 inhibitor PD98059 (PD) on the survival and neurologic outcomes after CA/CPR in rats. METHODS: First, rats were subjected to CA after CPR. The rats that restored spontaneous circulation were blindly allocated to the saline group (saline, IV, n = 12), the GTP group (GTPs, 10 mg/kg, IV, n = 12), the PD group (PD, 0.3 mg/kg, IV, n = 12), and the GTPs + PD group (GTPs, 10 mg/kg; PD, 0.3 mg/kg, IV, n = 12). Another 12 rats without experiencing CA and CPR were served as a sham group. Survival and the neurologic deficit score were observed for 72 hours after restoration of spontaneous circulation. Second, same experimental procedures were performed, and in 1 of 5 groups, animals were divided into 4 subgroups further according to the different time points (12, 24, 48, and 72 hours after restoration of spontaneous circulation [ROSC], n = 6/group). Brain tissues were harvested at relative time points for the morphologic evaluation as well as reactive oxygen species (ROS), malonylaldehyde, and superoxide dismutase (SOD) measurement. RESULTS: Green tea polyphenols, PD, and a combination of GTPs and PD used after ROSC alleviated the morphologic changes of the cerebrum. These 3 treatments also decreased the productions of ROS and malonylaldehyde, increased SOD activities in cerebral tissues, and improved the neurologic deficit and survival rates at 12, 24, 48, and 72 hours after ROSC. CONCLUSIONS: Administration of GTPs and PD after ROSC can alleviate cerebral injury, improve the survival and neurologic outcomes via reduction of ROS, and increase of SOD activity in a rat CA/CPR model.

Dietary fats significantly influence the survival of penumbral neurons in a rat model of chronic ischemic by modifying lipid mediators, inflammatory biomarkers, NOS production, and redox-dependent apoptotic signals.

OBJECTIVE: Brain stroke is the third most important cause of death in developed countries. We studied the effect of different dietary lipids on the outcome of a permanent ischemic stroke rat model. METHODS: Wistar rats were fed diets containing 7% commercial oils (S, soybean; O, olive; C, coconut; G, grape seed) for 35 d. Stroke was induced by permanent middle cerebral artery occlusion. Coronal slices from ischemic brains and sham-operated animals were supravitally stained. Penumbra and core volumes were calculated by image digitalization after 24, 48, and 72 h poststroke. Homogenates and mitochondrial fractions were prepared from different zones and analyzed by redox status, inflammatory markers, ceramide, and arachidonate content, phospholipase A2, NOS, and proteases. RESULTS: Soybean (S) and G diets were mainly prooxidative and proinflammatory by increasing the liberation of arachidonate and its transformation into prostaglandins. O was protective in terms of redox homeostatic balance, minor increases in lipid and protein damage, conservation of reduced glutathione, protective activation of NOS in penumbra, and net ratio of anti-to proinflammatory cytokines. Apoptosis (caspase-3, milli- and microcalpains) was less activated by O than by any other diet. CONCLUSION: Dietary lipids modulate NOS and PLA2 activities, ceramide production, and glutathione import into the mitochondrial matrix, finally determining the activation of the two main protease systems involved in programmed cell death. Olive oil appears to be a biological source for the isolation of protective agents that block the expansion of brain core at the expense of penumbral neurons.

Antiinflammatory and antioxidant effects of H2O2 generated by natural sources in Il1ß-treated human endothelial cells.

Specific reactive oxygen species (ROS) from different sources, might lead to different and even opposite, cellular effects. We studied the production of specific ROS resulting from the exposure of human umbilical veins endothelial cells (HUVEC) to H2O2 derived from the natural antioxidant epigallocathechin gallate (EGCG) or from the exposure to IL-1ß using a fluorogenic probe and flow cytometry, and evaluated by western blot analysis and immunocytochemistry the associated expression of transcription factors sensitive to both inflammatory and oxidative stress, such as NF-κB and Nrf2, and some downstream activated genes such as cyclooxygenase-2 (COX-2) and hemeoxygenase 1 (HO-1). The results obtained showed that exogenously-generated H2O2 induce anti-inflammatory and antioxidant effects in HUVECs counteracting the pro-inflammatory and pro-oxidant effect of IL-1ß related to the production of superoxide anions. The underlying mechanisms resulting from the extracellular production of H2O2, include (1) Nrf2 nuclear translocation and the enhanced expression of antioxidant enzymes such as HO-1, and (2) the previously unreported inhibition of NF-κB and COX-2 expression. Overall, these findings provide evidence that the production of specific reactive oxygen species finely tunes endothelial cell function and might be relevant for the reappraisal of the effects of exogenous antioxidants in the context of cardiovascular diseases.

Flavonoids identified from Korean Scutellaria baicalensis induce apoptosis by ROS generation and caspase activation on human fibrosarcoma cells.

The effects of flavonoids from Korean Scutellaria baicalensis on fibrosarcoma HT1080 cells and their underlying molecular mechanism were investigated in this study. Flavonoids affected HT1080 cell proliferation by interrupting cell cycle progress, obviously augmenting the proportion of sub-G1 and diminishing that of G1 phase, and undergoing apoptosis at the tested dosage (100-400 µg/mL). In addition, the mediated apoptosis was mainly caused by total reactive oxygen species (ROS) generation and by up-regulating the ratio of Bax/Bcl-xL, triggering caspase cascades (caspase-3, -9 and -8), and inactivating PARP, dose-dependently. The proteomics results showed that AP-4, ARID 5B, HNRNP K, PLOG, Prdx6, and myosin-1, associated with cell growth, differentiation and development, and overexpressed in gastric cancer, colorectal cancer, pancreatic cancer, etc., were statistically down-regulated after the flavonoids treatment. Taken together, our data demonstrated that flavonoids from Korean S. baicalensis induced apoptosis in HT1080 cells, which involved a hierarchy of cellular pathways and multiple signal proteins, and might be a potential anticancer therapeutic agent.

Is nicotine still the bad guy? Summary of the effects of smoking on patients with head and neck cancer in the postoperative period and the uses of nicotine replacement therapy in these patients.

Smoking has long been implicated in the development and progression of numerous postoperative complications. The cause is largely thought to be the presence of reactive oxygen species (ROS) in cigarette smoke, which attenuates inflammation and affects neutrophil function. Wound healing is further compromised by deficiencies in vitamins C and E, which result from a higher vitamin turnover secondary to the oxidative stress produced by smoking. However, studies recently have found that the effects of nicotine may benefit healing if used in isolation. We summarise the effects that smoking and abstaining from smoking can have on inflammation and wound healing, and describe the possible benefits that nicotine replacement and antioxidant supplements can give.

Elevated snail expression mediates tumor progression in areca quid chewing-associated oral squamous cell carcinoma via reactive oxygen species.

BACKGROUND: Snail is an important transcription factor implicated in several tumor progression and can be induced by reactive oxygen species (ROS). Areca quid chewing is a major risk factor of oral squamous cell carcinoma (OSCC). Therefore, we hypothesize that the major areca nut alkaloid arecoline may induce Snail via ROS and involve in the pathogenesis of areca quid chewing-associated OSCC. METHODOLOGY/PRINCIPAL FINDING: Thirty-six OSCC and ten normal oral epithelium specimens were examined by immunohistochemistry and analyzed by the clinico-pathological profiles. Cytotoxicity, 2', 7'-dichlorofluorescein diacetate assay, and western blot were used to investigate the effects of arecoline in human oral keratinocytes (HOKs) and oral epithelial cell line OECM-1 cells. In addition, antioxidants N-acetyl-L-cysteine (NAC), curcumin, and epigallocatechin-3 gallate (EGCG) were added to find the possible regulatory mechanisms. Initially, Snail expression was significantly higher in OSCC specimens (p<0.05). Elevated Snail expression was associated with lymph node metastasis (p = 0.031) and poor differentiation (p = 0.017). Arecoline enhanced the generation of intracellular ROS at the concentration higher than 40 µg/ml (p<0.05). Arecoline was also found to induced Snail expression in a dose- and time-dependent manner (p<0.05). Treatment with NAC, curcumin, and EGCG markedly inhibited arecoline induced Snail expression (p<0.05). CONCLUSION/SIGNIFICANCE: Our results suggest that Snail overexpression in areca quid chewing-associated OSCC is associated with tumors differentiation and lymph node metastasis. Arecoline-upregulated Snail expression may be mediated by ROS generation. In addition, arecoline induced Snail expression was downregulated by NAC, curcumin, and EGCG.

A review on antioxidants, prooxidants and related controversy: natural and synthetic compounds, screening and analysis methodologies and future perspectives.

Many studies have been conducted with regard to free radicals, oxidative stress and antioxidant activity of food, giving antioxidants a prominent beneficial role, but, recently many authors have questioned their importance, whilst trying to understand the mechanisms behind oxidative stress. Many scientists defend that regardless of the quantity of ingested antioxidants, the absorption is very limited, and that in some cases prooxidants are beneficial to human health. The detection of antioxidant activity as well as specific antioxidant compounds can be carried out with a large number of different assays, all of them with advantages and disadvantages. The controversy around antioxidant in vivo benefits has become intense in the past few decades and the present review tries to shed some light on research on antioxidants (natural and synthetic) and prooxidants, showing the potential benefits and adverse effects of these opposing events, as well as their mechanisms of action and detection methodologies. It also identifies the limitations of antioxidants and provides a perspective on the likely future trends in this field.

Addition of erythrocytes to in vitro culture medium attenuates the detrimental effects of reactive oxygen species on bovine preimplantation embryo development.

Erythrocytes were recently found to improve the early development of mice embryos by their antioxidant effect. The purpose of the present study was to examine the effect of erythrocytes on the in vitro development of bovine in vitro fertilized (IVF) embryos in medium supplemented with reactive oxygen species (ROS). IVF embryos were cultured in CR1aa medium supplemented with oxidizing agents, 0.5mmol/L hypoxanthine and 0.01U/mL xanthine oxidase (HX/XOD), in the presence and absence of erythrocytes (5×10(4) , 5×10(5) , 5×10(6) and 5×10(7) erythrocytes/mL). After 8 days, blastocysts were examined with a stereomicroscope. HX/XOD blocked development to the blastocyst stage (HX/XOD: 0%, control: 33%), but in the presence of both erythrocytes and HX/XOD, blastocyst development was restored to about one-third to two-thirds the normal rate (5×10(5) to 5×10(7) erythrocytes/mL: 12 to 23%). Furthermore, adding erythrocytes or erythrocyte hemolysate to medium without HX/XOD increased the blastocyst rate. These results suggest that the addition of erythrocytes can attenuate the detrimental effects of ROS on embryo development in bovine species as well as in mice.

Dual effects of curcumin on neuronal oxidative stress in the presence of Cu(II).

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Elevated copper (Cu) ions are thought to link AD pathology. Curcumin is suggested to treat AD because of its high anti-oxidative activity and coordination to transitional metal ions. In this study, the protective effect of curcumin against the Cu(II)-induced oxidative damage was investigated in primary rat cortical neurons. The neuronal damage was assessed by morphological observation, cell viability, and oxidative stress level. The results showed that curcumin at low dosage protected primary cultured neurons from the 20 µM Cu(II)-induced damage. Low dosage of curcumin depressed oxidative stress levels exacerbated by Cu(II). However, high dosage of curcumin failed to decrease the Cu(II)-induced oxidative stress. When Cu(II) was presented in primary neurons, curcumin at high dosage resulted in chromosomal aberration and cell damage. These results suggest that curcumin, in a concentration-dependent manner, plays both anti-oxidative and pro-oxidative roles in primary neurons treated with Cu(II).

Oxidative insults to neurons and synapse are prevented by aged garlic extract and S-allyl-L-cysteine treatment in the neuronal culture and APP-Tg mouse model.

Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly. In AD patients, ß-amyloid peptide (Aß) plaques and neurofibrillary tangles are common features observed in the CNS. Aß deposition results in the production of reactive oxygen species (ROS) leading to the hyperphosphorylation of tau that are associated with neuronal damage. Cholinesterase inhibitors and a partial NMDA receptor antagonist (memantine) have been identified as potential treatment options for AD. However, clinical studies have found that these drugs fail to prevent the disease progression. From ancient times, garlic (Allium sativum) has been used to treat several diseases. By 'aging' of garlic, some adverse reactions of garlic can be eliminated. Recent findings suggest that 'aged garlic extract' (AGE) may be a therapeutic agent for AD because of its antioxidant and Aß lowering properties. To date, the molecular properties of AGE have been sparsely studied in vitro or in vivo. The present study tested specific biochemical and molecular effects of AGE in neuronal and AD rodent models. Furthermore, we identified S-allyl-L-cysteine (SAC) as one of the most active chemicals responsible for the AGE-mediated effect(s). We observed significant neuroprotective and neurorescue properties of AGE and one of its ingredients, SAC, from ROS (H(2)O(2))-mediated insults to neuronal cells. Treatment of AGE and SAC were found to protect neuronal cells when they were independently co-treated with ROS. Furthermore, a novel neuropreservation effect of AGE was detected in that pre-treatment with AGE alone protected ∼ 80% neuronal cells from ROS-mediated damage. AGE was also found to preserve pre-synaptic protein synaptosomal associated protein of 25 kDa (SNAP25) from ROS-mediated insult. For example, treatment with 2% AGE containing diet and SAC (20 mg/kg of diet) independently increased (∼70%) levels of SNAP25 and synaptophysin in Alzheimer's amyloid precursor protein-transgenic mice, of which the latter was significantly decreased in AD. Taken together, the neuroprotective, including preservation of pre-synaptic proteins by AGE and SAC can be utilized in future drug development in AD.

Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders.

The homodimeric flavohemeprotein endothelial nitric oxide synthase (eNOS) oxidizes l-arginine to l-citrulline and nitric oxide (NO), which acutely vasodilates blood vessels and inhibits platelet aggregation. Chronically, eNOS has a major role in the regulation of blood pressure and prevention of atherosclerosis by decreasing leukocyte adhesion and smooth muscle proliferation. However, a disturbed vascular redox balance results in eNOS damage and uncoupling of oxygen activation from l-arginine conversion. Uncoupled eNOS monomerizes and generates reactive oxygen species (ROS) rather than NO. Indeed, eNOS uncoupling has been suggested as one of the main pathomechanisms in a broad range of cardiovascular and pulmonary disorders such as atherosclerosis, ventricular remodeling, and pulmonary hypertension. Therefore, modulating uncoupled eNOS, in particular eNOS-dependent ROS generation, is an attractive therapeutic approach to preventing and/or treating cardiopulmonary disorders, including protective effects during cardiothoracic surgery. This review provides a comprehensive overview of the pathogenetic role of uncoupled eNOS in both cardiovascular and pulmonary disorders. In addition, the related therapeutic possibilities such as supplementation with the eNOS substrate l-arginine, volatile NO, and direct NO donors as well as eNOS modulators such as the eNOS cofactor tetrahydrobiopterin and folic acid are discussed in detail.