Uncontrolled Oxidative Stress Research Articles

A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury

Uncontrolled oxidative stress contributes to the secondary neuronal death that promotes long-term neurological dysfunction following traumatic brain injury (TBI). Surprisingly, both NADPH oxidase 2 (NOX2) that increases and transcription factor Nrf2 that decreases reactive oxygen species (ROS) are induced after TBI. As the post-injury functional outcome depends on the balance of these opposing molecular pathways, we evaluated the effect of TBI on the motor and cognitive deficits and cortical contusion volume in NOX2 and Nrf2 knockout mice. Genetic deletion of NOX2 improved, while Nrf2 worsened the post-TBI motor function recovery and lesion volume indicating that decreasing ROS levels might be beneficial after TBI. Treatment with either apocynin (NOX2 inhibitor) or TBHQ (Nrf2 activator) alone significantly improved the motor function after TBI, but had no effect on the lesion volume, compared to vehicle control. Whereas, the combo therapy (apocynin + TBHQ) given at either 5 min/24 h or 2 h/24 h improved motor and cognitive function and decreased cortical contusion volume compared to vehicle group. Thus, both the generation and disposal of ROS are important modulators of oxidative stress, and a combo therapy that prevents ROS formation and potentiates ROS disposal concurrently is efficacious after TBI.

OLR1 and Loxin Expression in PBMCs of Women with a History of Unexplained Recurrent Miscarriage: A Pilot Study.

The aim of this study was to evaluate the expression of OLR1 and its alternative splicing isoform Loxin in unexplained recurrent miscarriage (uRM). Sixty-three women of reproductive age were recruited and were divided into four groups: 18 pregnant and 23 non-pregnant women with uRM, and 12 pregnant and 10 non-pregnant women with physiological pregnancies. Complementary DNA derived from peripheral blood mononuclear cells (PBMCs) was analyzed by quantitative real-time PCR to evaluate the expression of OLR1 and Loxin. Oxidized low-density lipoproteins (ox-LDLs) were assayed from serum by a commercially available kit. Pregnant uRM women presented with a higher, though not significant, OLR1/Loxin ratio and a higher ox-LDLs serum level (p ≤ 0.05) compared with pregnant control women. OLR1 and Loxin levels were significantly decreased in non-pregnant uRM women compared with the control (OLR1: 0.00018 vs. 0.00043, p ≤ 0.005; Loxin: 0.00018 vs. 0.00060, p ≤ 0.005, respectively). Loxin expression decreased by about two-thirds (p ≤ 0.005) in pregnant women compared with non-pregnant control women. A higher expression of OLR1 in pregnant women compared with non-pregnant women with uRM (p ≤ 0.05) was observed, but no variation in Loxin expression was observed. The results of this study show an association of peripheral OLR1 and Loxin expression levels in uRM women, and they suggest the possible existence of an uncontrolled oxidative stress in these women in the first trimester of pregnancy.

Isolation and characterization of a spotted leaf 32 mutant with early leaf senescence and enhanced defense response in rice

Leaf senescence is a complex biological process and defense responses play vital role for rice development, their molecular mechanisms, however, remain elusive in rice. We herein reported a rice mutant spotted leaf 32 (spl32) derived from a rice cultivar 9311 by radiation. The spl32 plants displayed early leaf senescence, identified by disintegration of chloroplasts as cellular evidence, dramatically decreased contents of chlorophyll, up-regulation of superoxide dismutase enzyme activity and malondialdehyde, as physiological characteristic, and both up-regulation of senescence-induced STAY GREEN gene and senescence-associated transcription factors, and down-regulation of photosynthesis-associated genes, as molecular indicators. Positional cloning revealed that SPL32 encodes a ferredoxin-dependent glutamate synthase (Fd-GOGAT). Compared to wild type, enzyme activity of GOGAT was significantly decreased, and free amino acid contents, particularly for glutamate and glutamine, were altered in spl32 leaves. Moreover, the mutant was subjected to uncontrolled oxidative stress due to over-produced reactive oxygen species and damaged scavenging pathways, in accordance with decreased photorespiration rate. Besides, the mutant showed higher resistance to Xanthomonas oryzae pv. Oryzae than its wild type, coupled with up-regulation of four pathogenesis-related marker genes. Taken together, our results highlight Fd-GOGAT is associated with the regulation of leaf senescence and defense responses in rice.

Interaction between the plant ApDef1 defensin and Saccharomyces cerevisiae results in yeast death through a cell cycle- and caspase-dependent process occurring via uncontrolled oxidative stress

BackgroundPlant defensins were discovered at beginning of the 90s'; however, their precise mechanism of action is still unknown. Herein, we studied ApDef1-Saccharomyces cerevisiae interaction. MethodsApDef1-S. cerevisiae interaction was studied by determining the MIC, viability and death kinetic assays. Viability assay was repeated with hydroxyurea synchronized-yeast and pretreated with CCCP. Plasma membrane permeabilization, ROS induction, chromatin condensation, and caspase activation analyses were assessed through Sytox green, DAB, DAPI and FITC-VAD-FMK, respectively. Viability assay was done in presence of ascorbic acid and Z-VAD-FMK. Ultrastructural analysis was done by electron microscopy. ResultsApDef1 caused S. cerevisiae cell death and MIC was 7.8μM. Whole cell population died after 18h of ApDef1 interaction. After 3h, 98.76% of synchronized cell population died. Pretreatment with CCCP protected yeast from ApDef1 induced death. ApDef1-S. cerevisiae interaction resulted in membrane permeabilization, H2O2 increased production, chromatin condensation and caspase activation. Ascorbic acid prevented yeast cell death and membrane permeabilization. Z-VAD-FMK prevented yeast cell death. ConclusionsApDef1-S. cerevisiae interaction caused cell death through cell cycle dependentprocess which requires preserved membrane potential. After interaction, yeast went through uncontrolled ROS production and accumulation, which led to plasma membrane permeabilization, chromatin condensation and, ultimately, cell death by activation of caspase-dependent apoptosis via. General significanceWe show novel requirements for the interaction between plant defensin and fungi cells, i.e. cell cycle phase and membrane potential, and we indicate that membrane permeabilization is probably caused by ROS and therefore, it would be an indirect event of the ApDef1-S. cerevisiae interaction.

A Role for the Fifth G-Track in G-Quadruplex Forming Oncogene Promoter Sequences during Oxidative Stress: Do These "Spare Tires" Have an Evolved Function?

Uncontrolled inflammation or oxidative stress generates electron-deficient species that oxidize the genome increasing its instability in cancer. The G-quadruplex (G4) sequences regulating the c-MYC, KRAS, VEGF, BCL-2, HIF-1α, and RET oncogenes, as examples, are targets for oxidation at loop and 5′-core guanines (G) as showcased in this study by CO3•– oxidation of the VEGF G4. Products observed include 8-oxo-7,8-dihydroguanine (OG), spiroiminodihydantoin (Sp), and 5-guanidinohydantoin (Gh). Our previous studies found that OG and Gh, when present in the four G-tracks of the solved structure for VEGF and c-MYC, were not substrates for the base excision repair (BER) DNA glycosylases in biologically relevant KCl solutions. We now hypothesize that a fifth G-track found a few nucleotides distant from the G4 tracks involved in folding can act as a “spare tire,” facilitating extrusion of a damaged G-run into a large loop that then becomes a substrate for BER. Thermodynamic, spectroscopic, and DMS footprinting studies verified the fifth domain replacing a damaged G-track with OG or Gh at a loop or core position in the VEGF G4. These new “spare tire”-containing strands with Gh in loops are now found to be substrates for initiation of BER with the NEIL1, NEIL2, and NEIL3 DNA glycosylases. The results support a hypothesis in which regulatory G4s carry a “spare-tire” fifth G-track for aiding in the repair process when these sequences are damaged by radical oxygen species, a feature observed in a large number of these sequences. Furthermore, formation and repair of oxidized bases in promoter regions may constitute an additional example of epigenetic modification, in this case of guanine bases, to regulate gene expression in which the G4 sequences act as sensors of oxidative stress.

A Novel Role of Protein Disulfide Isomerase in Calpain Regulated Hypoxia Induced Prothrombotic Phenotype

Introduction The increased risk of thromboembolic events under low oxygen environments such as high altitude regions is a well known phenomenon but with little knowledge about molecular events underlying its pathogenesis. We have recently reported the proteomic changes in hyperreactive platelets under hypoxia and demonstrated that increased activity of protease calpain is crucial for the induction of prothrombotic phenotype under hypoxic environment (Tyagi et al, 2014). However, considering the complex nature of hemostatic reactions, multiple aspects of the regulation of hemostatic balance under hypoxia need to be understood. Hypoxic environment creates oxidative stress in biological system which needs to be contained by counteractive factors. One of such factor, the Protein disulfide isomerase (PDI), which catalyzes the formation and rearrangements of disulfide bonds on proteins, has been found to be upregulated in multiple cell types and is believed to be protective under oxidative stress. The extracellular PDI has been recently reported to play a key role in initial thrombotic events in vivo and in vitro, but whether it affects the hemostasis under hypoxia remains unknown. We analyzed the role played by PDI in calpain regulated hypoxia induced prothrombotic phenotype by using specific PDI inhibitor Quercetin-3-rutinoside (Q-3R) in an animal model.Method:The Sprague-Dawley male rats were exposed to simulated hypobaric hypoxia in a specially designed animal decompression chamber maintained at pressure of 366 torr (equivalent to altitude of 6096m) for 3h duration. The exposed group of animals was infused with either Q-3R or vehicle, via tail vein injection prior to hypoxia exposure. The effect of PDI inhibitor on coagulation was analyzed by measuring clotting time and Prothrombin time. The PDI activity was measured in plasma by insulin reduction assay. The plasma calpain activity was measured by fluorescence based assay. The status of oxidative damage was assessed by measuring MDA levels which are hallmark of oxidative stress. We also analyzed the factor V activity in plasma of animals by standard clot based assay using factor V deficient plasma.Results: As previously reported by us, the animals exposed to hypoxic conditions demonstrated prothrombotic tendency as evident in significant shortening of clotting times (PT 84% of control, p < .03) as compared to control animals. The exposed animals preinfused with PDI inhibitors demonstrated further reductions in clotting times. The preinfusion of Q-3R (0.25 to 1.5 mg/kg body wt) significantly shortened the Prothrombin times (71%, p < .01) as compared to respective vehicle control. The hypercoagulative tendency triggered by Q-3R was also evident in drastically reduced activated clotting times in whole blood. Hypoxia induced the activation of PDI which was reflected by significantly elevated activity as compared to control animals. The dose dependent PDI inhibition in Q-3R preinfused animals was confirmed by the fallen activity of PDI in plasma from exposed animals. The calpain activity remained elevated in hypoxic animals (compared to controls) as observed previously. The oxidative damage as measured by MDA levels, was found to be much higher in exposed animals preinfused with Q-3R as compared to the vehicle group. Interestingly, the active factor V was observed to be significantly higher in case of PDI inhibition with largest activity increase in animals infused with highest dose of Q-3R.Conclusion:These results demonstrate the critical role of PDI in regulation of hypoxia induced prothrombotic state. The prevention of increase in activity of PDI in hypoxic animals by using specific PDI inhibitor accelerated the prothrombotic effect of hypoxia. These results appear to be in contrast with recently reported in vivo antithrombotic effect of PDI inhibition. However, as PDI upregulation is considered largely as a protective mechanism, this prothrombotic effect of PDI inhibition under hypoxia seems to be in part due to uncontrolled oxidative stress as shown by higher MDA levels. Also, as factor V activity was shot up by PDI inhibitors, this shows the activation of factor V to be under control of PDI, which can also be explained by role of disulfide linkages in activation of released factor V. Together, these results suggests a novel role of PDI, along with calpain, in regulating hypoxia induced prothrombotic phenotype. DisclosuresNo relevant conflicts of interest to declare.

Preoxiredoxin family members (Prx3 and Prx4) and pregnancy disorder (recurrent pregnancy loss).

Placenta is a pregnancy unique tissue, and proper formation of placenta is a key phenomenal step for success of a pregnancy. Peroxiredoxins (Prxs) are a family of antioxidant proteins. This family is composed of six members, among which Peroxiredoxin 3 (Prx3) and Peroxiredoxin 4 (Prx4) are expressed by cytotrophoblast cells and play an important role in the implantation and a normal placentation through their antioxidant activities. Although the presence of autoantibody against several peroxiredoxin family members was reported before, there was no report regarding the presence of antibodies against Prx3 or Prx4 in human pregnancy miscarriage. So for the first time we hypothesize and indicate that uncontrolled oxidative stress, due to anti-peroxiredoxins antibodies, may affect the proper formation of the placenta and lead to placentation-related pregnancy disorders such as miscarriage. Our results indicate that two placental proteins, Prx3 and Prx4, may act as new placental immune targets. Considering the role of antioxidant defense in the protection of placenta from oxidative stress, production of antibodies against peroxiredoxins 3 and 4 may introduce a new autoimmune hypothesis for miscarriages, which is needed to be tested in the future works.

Oxidative stress and its biomarkers in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease whose etiology remains largely unknown. The uncontrolled oxidative stress in SLE contributes to functional oxidative modifications of cellular protein, lipid and DNA and consequences of oxidative modification play a crucial role in immunomodulation and trigger autoimmunity. Measurements of oxidative modified protein, lipid and DNA in biological samples from SLE patients may assist in the elucidation of the pathophysiological mechanisms of the oxidative stress-related damage, the prediction of disease prognosis and the selection of adequate treatment in the early stage of disease. Application of these biomarkers in disease may indicate the early effectiveness of the therapy. This review is intended to provide an overview of various reactive oxygen species (ROS) formed during the state of disease and their biomarkers linking with disease. The first part of the review presents biochemistry and pathophysiology of ROS and antioxidant system in disease. The second part of the review discusses the recent development of oxidative stress biomarkers that relates pathogenesis in SLE patients and animal model. Finally, this review also describes the reported clinical trials of antioxidant in the disease that have evaluated the efficacy of antioxidant in the management of disease with ongoing conventional therapy.

A lipid-rich gestational diet predisposes offspring to nonalcoholic fatty liver disease: a potential sequence of events

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. It affects 20%–30% of the US population, and it is increasing worldwide. Recently, the role of lipid-rich maternal gestational nutrition in spurring the development of NAFLD among offspring has been indicated. Fetal predisposition to NAFLD involves numerous physiological reroutings that are initiated by increased delivery of nonesterified fatty acids to the fetal liver. Hampered β-oxidation, uncontrolled oxidative stress, increased triacylglycerol synthesis, and the endoplasmic reticulum unfolded protein response are all implicated in sculpting a hepatic phenotype with a propensity to develop NAFLD in the postnatal state. This review suggests a mechanism that integrates outcomes reported by a variety of studies conducted in an analysis of fetal hepatic metabolic capacity amid the maternal consumption of a high-fat diet. Potential preventive measures and therapies for use both as part of prenatal nutrition and for those at risk for the development of NAFLD are also discussed.

Pathogenic microbes, the microbiome, and Alzheimer's disease (AD).

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of cognitive and behavioral impairment in industrialized societies. The cause of AD is unknown and the major risk factor for AD is age. About 5% of all AD cases have a genetic or familial cause however the vast majority of all AD cases (~95%) are of sporadic origin. Both the familial and the sporadic forms of AD share a common disease phenotype involving at least eight characteristic features including (i) evidence of uncontrolled oxidative stress; (ii) up-regulated pro-inflammatory signaling; (iii) changes in innate-immune signaling; (iv) the progressive accumulation of lesions including neurofibrillary tangles (NFT) and amyloid beta (Aβ)-containing senile plaques (SP); (v) significant synaptic signaling deficits; (vi) neurite and brain cell atrophy; (vii) progressively altered gene expression patterns that are different from healthy brain aging; and (viii) progressive cognitive impairment and dementia in the host. There is currently no cure or adequate clinical treatment for AD, and it remains unclear how AD originates and propagates throughout the brain and central nervous system (CNS). Results from recent genome-wide association studies (GWAS) indicate that a significant portion of AD-relevant gene signals are not located within gene coding regions suggesting the contribution of epigenetic or environmental factors to AD risk. The potential contribution of pathogenic microbes to aging and AD is becoming increasingly recognized (Miklossy, 2011; Cho and Blaser, 2012; Bhattacharjee and Lukiw, 2013; Poole et al., 2013; Heintz and Mair, 2014; Huang et al., 2014; Mancuso et al., 2014). Importantly, most of the changes seen in AD, such as inflammation, brain cell atrophy, immunological aberrations, amyloidogenesis, altered gene expression and cognitive deficits are also seen as a consequence of microbial infection (Cho and Blaser, 2012; Yatsunenko et al., 2012; Bhattacharjee and Lukiw, 2013; Foster and McVey Neufeld, 2013; Kim et al., 2013; Heintz and Mair, 2014; Mancuso et al., 2014). This brief communication will review some recent observations on the potential contribution of pathogens to neurological dysfunction, with specific reference to AD wherever possible.

Cardioprotective effects of Ficus religiosa in neonatal streptozotocin-induced diabetic cardiomyopathy in rats

Diabetes mellitus is one of the major problems. In developing as well as developed countries. Uncontrolled blood glucose level and oxidative stress plays a vital role in pathogenesis of the diabetic cardiomyopathy. The present study was aimed to investigate the effect of Ficus religiosa in STZ-induced diabetic cardiomyopathy in rats. Streptozotocin (90mg/kg i.p.), administered to 2 days old neonates (10–12g), resulted in significant increase in fasting blood glucose, HbA1c, cardiac hypertrophic index, TGF-β1, TNFα, malondialdehyde, LDH, CK-MB, BNP and caspase-3, blood pressure. It caused significant reduction in plasma insulin, heart rate and superoxide dismutase. The eight-week treatment of F. religiosa started after induction of six weeks of diabetes, the treatment significantly improved diabetic markers, oxidative stress, inflammatory and cardiac markers. Results of the present study suggest that the cardioprotective effect of F. religiosa may be mediated through the control of diabetes, modulation of oxidative marker and cytokine (TGF-β1, TNFα).

Olive leaf down-regulates the oxidative stress and immune dysregulation in streptozotocin-induced diabetic mice

Type 1 diabetes is an endocrinologic disorder characterized by uncontrolled glucose regulation and oxidative stress. Olive leaves have been studied extensively for their antioxidant activity and capacity to improve immune function. We hypothesized that olive leaf powder supplementation will be effective in inhibiting the oxidative stress and immune dysregulation in streptozotocin (STZ)-induced diabetic mice. Mice were assigned to 1 of 5 groups: control (C), STZ-induced diabetes (D), and STZ-induced diabetes supplemented with very low dose (VLOL), low dose (LOL), or high dose of olive leaf powder (HOL). Blood glucose in the VLOL and LOL groups was lower than that in the D group (P < .05). Insulin levels were increased in all experimental groups in comparison with that in the D group, (P < .05). Superoxide dismutase, glutathione peroxidase, and catalase activities were shown to decrease in the D group, whereas these were increased in the VLOL and LOL groups. Nitric oxide levels decreased in the VLOL and LOL groups, as compared with the D group. The messenger RNA expression levels of inducible nitric oxide synthase were significantly decreased in the VLOL and HOL groups, and interferon-γ levels were significantly decreased in the liver of the VLOL, LOL, and HOL groups compared with the levels in the D group. Interleukin-17 levels were significantly decreased in the VLOL and HOL groups. Th1 and Th17 cytokine levels were increased in the D group but decreased in all the experimental groups. Th2 cytokine levels were increased in all olive leaf–supplemented groups compared with those in the D group. These results indicate a reduction in the levels of proinflammatory cytokines, suggesting that olive leaves have the potential to provide therapeutic inhibition of diabetic complications.

FABP5 deficiency enhances susceptibility to H1N1 influenza A virus-induced lung inflammation

The early inflammatory response to influenza A virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which inflammatory cells invade the respiratory tract remain unclear. Uncontrolled inflammation and oxidative stress cause lung damage in response to influenza A infection. We have previously shown that the fatty acid binding protein 5 (FABP5) has anti-inflammatory properties. We speculate that, as a transporter of fatty acids, FABP5 plays an important protective role against oxidative damage to lipids during infection as well. Using FABP5-/- and wild-type (WT) mice infected with influenza A virus, we showed that FABP5-/- mice had increased cell infiltration of macrophages and neutrophils compared with WT mice. FABP5-/- mice presented lower viral burden but lost as much weight as WT mice. The adaptive immune response was also increased in FABP5-/- mice as illustrated by the accumulation of T and B cells in the lung tissues and increased levels of H1N1-specific IgG antibodies. FABP5 deficiency greatly enhanced oxidative damage and lipid peroxidation following influenza A infection and presented with sustained tissue inflammation. Interestingly, FABP5 expression decreased following influenza A infection in WT lung tissues that corresponded to a decrease in the anti-inflammatory molecule PPAR-γ activity. In conclusion, our results demonstrate a previously unknown contribution of FABP5 to influenza A virus pathogenesis by controlling excessive oxidative damage and inflammation. This property could be exploited for therapeutic purposes.

The Development of Subcutaneous Sarcomas in Rodents Exposed to Peroxisome Proliferators Agonists

Peroxisome proliferator-activated receptors (PPARs) represent therapeutic targets for the management of type 2 diabetes mellitus and dyslipidemia. Rodent carcinogenicity studies have revealed a link between γ and dual γ/α PPAR agonist treatment and the increased incidence of subcutaneous (SC) liposarcomas/fibrosarcomas or hemangiosarcomas, but very little has been reported for potent and selective PPARα agonists. We present a mode of action framework for the development of SC mesenchymal tumors in rodents given PPAR agonists. (1) Tumor promotion results from pharmacologically mediated recruitment (proliferation and differentiation), thermogenesis and adipogenesis of stromovascular cells, and subsequent generation of oxidative free radicals. (2) Tumor initiation consists of chemotype-driven mitochondrial dysfunction causing uncontrolled oxidative stress and permanent DNA damage. Promotion is characterized by enhanced adipogenesis in the SC adipose tissue, where the baseline PPARγ expression and responsiveness to PPARγ ligands is the highest, and by thermogenesis through expression of the uncoupling protein 1 (UCP-1) and the PPARγ co-activator 1 α (PGC-1α), two factors more highly expressed in brown versus white adipose tissue. Initiation is supported by the demonstration of mitochondrial uncoupling and OXPHOS Complexes dysfunction (Complexes III, IV and V) by compounds associated with increased incidences of sarcomas (muraglitazar and troglitazone), but not others lacking malignant tumor effects (pioglitazone, rosiglitazone).

MiR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1

Uncontrolled oxidative stress impairs bone formation and induces age-related bone loss in humans. The FoxO family is widely accepted to play an important role in protecting diverse cells from reactive oxygen species (ROS). Activation of FoxO1, the main FoxO in bone, stimulates proliferation and differentiation as well as inhibits apoptosis of osteoblast lineage cells. Despite the important role of FoxO1, little is known about how FoxO1 expression in bone is regulated. Meanwhile, several recent studies reported that microRNAs (miRNAs) could play a role in osteoblast differentiation and bone formation by targeting various transcriptional factors. Here, we identified one additional crucial miRNA, miR-182, which regulates osteoblastogenesis by repressing FoxO1 and thereby negatively affecting osteogenesis. Overexpression of miR-182 in osteoblast lineage cells increased cell apoptosis and inhibited osteoblast differentiation, whereas in vivo overexpression of miR-182 in zebrafish impaired bone formation. From in silico analysis and validation experiments, FoxO1 was identified as the target of miR-182, and restoration of FoxO1 expression in miR-182-overexpressing osteoblasts rescued them from the inhibitory effects of miR-182. These results indicate that miR-182 functions as a FoxO1 inhibitor to antagonize osteoblast proliferation and differentiation, with a subsequent negative effect on osteogenesis. To treat bone aging, an antisense approach targeting miR-182 could be of therapeutic value.

Bromocriptine as a new therapeutic agent for peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a poorly understood, rare disorder in which left ventricular systolic dysfunction and symptoms of heart failure occur between the last month of pregnancy and the first 5 months postpartum. Recent data suggest that uncontrolled oxidative stress leads to the activation of the prolactin cleaving enzyme cathepsin D that in turn leads to an increase in a cleaved 16 kDa prolactin. This cleaved form that has an angiostatic and proapoptotic role appears to drive the disease by adversely impacting the endothelium and cardiomyocyte. Bromocriptine that reduces the prolactin production by dopamine agonist actions may improve outcomes in patients with peripartum cardiomyopathy by eliminating the cleaved form of prolactin despite the activation of the cleaving enzyme. In limited case reports and proof of concept studies use of bromocriptine in the early stages has been shown to improve outcomes in patients with peripartum cardiomyopathy. However, larger randomized control study is still awaited.

Neurodegenerative diseases: exercising toward neurogenesis and neuroregeneration.

Currently, there is still no effective therapy for neurodegenerative diseases (NDD) such as Alzheimer's disease (AD) and Parkinson's disease (PD) despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician's and the scientist's needs, and to highlight current research investigating exercise as a therapeutic or preventive measure.

Paralysie faciale périphérique : penser à rechercher un niveau sensitif du tronc et évoquer la maladie de Lyme

Kwashiorkor and marasmus are two clinical syndromes observed in severe acute malnutrition. In this review, we highlighted the differences between these two syndromes by reviewing the data comparing kwashiorkor and marasmus in literature, combined with recent microbiological findings and meta-analysis. Depletion of antioxidants, vitamins and minerals were more severe in kwashiorkor than marasmus. This was consistent with the severe and uncontrolled oxidative stress associated with the depletion of gut anaerobes and the relative proliferation of aerotolerant gut pathogens. This relative proliferation and invasion of gut microbes belonging to the aerotolerant Proteobacteria phylum and pathogens suggested a specific microbial process critical in the pathogenesis of kwashiorkor. Liver mitochondrial and peroxisomal dysfunction could be secondary to toxic microbial compounds produced in the gut such as ethanol, lipopolysaccharides and endotoxins produced by Proteobacteria, particularly Klebsiella pneumoniae, and aflatoxin produced by Aspergillus species. The gut-liver axis alteration is characterized by oedema and a fatty and enlarged liver and was associated with a dramatic depletion of methionine and glutathione, an excessive level of free circulating iron and frequent lethal bacteraemia by enteric pathogens. This was consistent with the fact that antibiotics improved survival only in children with kwashiorkor but not marasmus. The specific pathogenic characteristics of kwashiorkor identified in this review open new avenues to develop more targeted and effective treatments for both marasmus and/or kwashiorkor. Urgent correction of plasma glutathione depletion, alongside supply of specific essential amino acids, particularly methionine and cysteine, early detection of pathogens and an antibiotic more efficient than amoxicillin in supressing gut Proteobacteria including K. pneumoniae, and probiotics to restore the human gut anaerobic mature microbiota could save many more children with kwashiorkor.

Alpha-lipoic Acid Attenuates Exercise-induced Oxidative Stress And Enhances Heat Shock Protein Responses

Uncontrolled oxidative stress, a state where the increased production of ROS overwhelms endogenous antioxidant protection, may result in macromolecular damage and perturbation of redox control of signalling and cellular events. The heat shock proteins (HSPs) respond to a wide variety of stress, including oxidative stress. HSPs function primarily as molecular chaperones, but also control protein synthesis and trafficking, as well as regulate cellular adaptation and survival. PURPOSE: Several antioxidant supplementation strategies have been used to cope with exercise-induced oxidative stress and to facilitate adaptations to exercise. While antioxidant supplementation diminishes exercise-induced oxidative stress, there is also a risk of decreasing the normal response of tissues to exercise and blunting the adaptations. In this study we examined the protective role of natural thiol antioxidant, alpha-lipoic acid (LA) supplementation at rest, after exercise and at different recovery points in skeletal muscle in horses. METHODS: Six standardbred trotters were examined on the treadmill and exercised 75 min at individually defined aerobic level. Blood and muscle biopsy samples were taken before and immediately after treadmill exercise, as well as after 2-, 6-, 24- and 48-hour recovery. RESULTS: LA supplementation (25 mg kg-1 day-1) for five weeks increased the resting levels of HSP90 and the recovery levels of inducible HSP70 in gluteus medius muscle. In addition, following LA-supplementation, we observed a significant decrease in exercise-induced protein oxidation in plasma and free radical formation in muscle, measured by EPR signals. CONCLUSION: Our findings suggest that LA enhances HSP levels and decreases exercise-induced oxidative stress in skeletal muscle.

How to Keep Oxidative Stress Under Control?

An excessive production of oxidants disturbs the normal intracellular equilibrium, and can lead to an “oxidative stress”. Recent data indicate that several components of the regular diet as well as chemical compounds and drugs can modulate the so-called “oxidative stress” both via anti-oxidant effects and via inhibition or activation of the enzymes involved in reactive nitrogen oxygen species (RNOS). We will describe in this review article the biochemistry of oxygen, the physiological roles and regulation of oxidative stress. The clinical relevance of uncontrolled oxidative stress will be presented as well as the results of therapeutic trials with antioxidants. New promising strategies which modulate the activities of the RNOS generating enzymes, with selected catalytic inhibitors will be discussed.