Reactive Oxygen Species In Brain Research Articles

Exposure to the Natural Compound Climacostol Induces Cell Damage and Oxidative Stress in the Fruit Fly Drosophila melanogaster.

The ciliate Climacostomum virens produces the metabolite climacostol that displays antimicrobial activity and cytotoxicity on human and rodent tumor cells. Given its potential as a backbone in pharmacological studies, we used the fruit fly Drosophila melanogaster to evaluate how the xenobiotic climacostol affects biological systems in vivo at the organismal level. Food administration with climacostol demonstrated its harmful role during larvae developmental stages but not pupation. The midgut of eclosed larvae showed apoptosis and increased generation of reactive oxygen species (ROS), thus demonstrating gastrointestinal toxicity. Climacostol did not affect enteroendocrine cell proliferation, suggesting moderate damage that does not initiate the repairing program. The fact that climacostol increased brain ROS and inhibited the proliferation of neural cells revealed a systemic (neurotoxic) role of this harmful substance. In this line, we found lower expression of relevant antioxidant enzymes in the larvae and impaired mitochondrial activity. Adult offsprings presented no major alterations in survival and mobility, as well the absence of abnormal phenotypes. However, mitochondrial activity and oviposition behavior was somewhat affected, indicating the chronic toxicity of climacostol, which continues moderately until adult stages. These results revealed for the first time the detrimental role of ingested climacostol in a non-target multicellular organism.

Rosiglitazone inhibits acyl-CoA synthetase long-chain family number 4 and improves secondary brain injury in a rat model of surgical brain injury.

Ferroptosis is a recently discovered non-apoptotic form of cellular death. Acyl-CoA synthetase long-chain family number 4 (ACSL4) is necessary for iron-dependent cellular death, and reactive oxygen species (ROS) produced by ACSL4 are the executioners of ferroptosis. Rosiglitazone improves ferroptosis by inhibiting ACSL4. There is no research indicating whether ACSL4 plays a role in cell death after surgical brain injury (SBI). This study aimed to investigate the role of ACSL4 in SBI via the ferroptosis pathway. Ninety male Sprague-Dawley rats were examined using a model of SBI. Subsequently, the inhibitory effect of rosiglitazone on ACSL4 was assessed via western blot, real-time polymerase chain reaction (PCR), immunofluorescence, fluoro-jade C staining, Perl's staining, ROS assay, and neurological scoring. The results showed that compared with the Sham group, the protein levels of ACSL4 and transferrin were significantly increased after SBI. Administration of rosiglitazone significantly reduced neuronal necrosis, iron deposition, brain water content and ROS in brain tissue and ameliorated neurological deficits at 48 h after SBI, which was concomitant with decreased transferrin expression. These findings demonstrate that SBI-induced upregulation of ACSL4 may be partly mediated by the ferroptosis pathway, which can be reversed by rosiglitazone administration.

Brain Iron Metabolism, Redox Balance and Neurological Diseases.

The incidence of neurological diseases, such as Parkinson's disease, Alzheimer's disease and stroke, is increasing. An increasing number of studies have correlated these diseases with brain iron overload and the resulting oxidative damage. Brain iron deficiency has also been closely linked to neurodevelopment. These neurological disorders seriously affect the physical and mental health of patients and bring heavy economic burdens to families and society. Therefore, it is important to maintain brain iron homeostasis and to understand the mechanism of brain iron disorders affecting reactive oxygen species (ROS) balance, resulting in neural damage, cell death and, ultimately, leading to the development of disease. Evidence has shown that many therapies targeting brain iron and ROS imbalances have good preventive and therapeutic effects on neurological diseases. This review highlights the molecular mechanisms, pathogenesis and treatment strategies of brain iron metabolism disorders in neurological diseases.

Is NADPH Critical to Maintain Redox Homeostasis in Hypoxia-Tolerant Naked Mole-Rat Brain?

Nicotinamide adenine dinucleotide phosphate (NADPH) is a ubiquitous electron donor and a key reducing agent in numerous biochemical reactions. Among other important cellular roles, NADPH activity is central to the maintenance of redox homeostasis in eukaryotic cells. NADPH increases markedly during acute in vivo hypoxia in the brain of naked mole-rats, which are among the most hypoxia-tolerant mammals, and which do not exhibit imbalances in redox homeostasis or increased reactive oxygen species (ROS)-mediated damage during bouts of hypoxia-reoxygenation in brain. Conversely, NADPH does not increase in the brain of hypoxia-intolerant mice, which are prone to deleterious ROS bursts during perturbations in oxygen availability. Although the importance of NADPH in mediating ROS homeostasis has been demonstrated in the brain of other mammals, little is known about the source of NADPH changes in hypoxic naked mole-rat brain, nor about the mechanisms via which NADPH may provide neuroprotection in this species. Elucidating the underlying mechanisms that support the remarkably stable ROS profile in naked mole-rat brain may provide insight into novel mechanisms to ameliorate the deleterious impact of ROS bursts in the brains of hypoxia-intolerant mammals, such as occur during stroke and other diseases. In this review, we discuss what is known regarding the management of ROS and NADPH in naked mole-rat brain, examine potential cellular sources of NADPH that may underlie the large hypoxic increase in this molecule during acute hypoxic exposure, and propose experiments to advance our understanding of the role NADPH has in maintaining naked mole-rat brain redox balance. (First online: December 28, 2022)

Therapeutic targeting of microglia mediated oxidative stress after neurotrauma.

Inflammation is a primary component of the central nervous system injury response. Traumatic brain and spinal cord injury are characterized by a pronounced microglial response to damage, including alterations in microglial morphology and increased production of reactive oxygen species (ROS). The acute activity of microglia may be beneficial to recovery, but continued inflammation and ROS production is deleterious to the health and function of other cells. Microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), mitochondria, and changes in iron levels are three of the most common sources of ROS. All three play a significant role in post-traumatic brain and spinal cord injury ROS production and the resultant oxidative stress. This review will evaluate the current state of therapeutics used to target these avenues of microglia-mediated oxidative stress after injury and suggest avenues for future research.

Neuropharmacological Alterations by a Rice Contaminant Stenotrophomonas maltophilia: a Detailed Bio-molecular and Mechanistic Landscape.

Contaminated rice is a major source of food poisoning in human communities where our earlier study showed Stenotrophomonas maltophilia, a Gram-negative bacillus, has been a major contaminant of the stored rice. In the present study, mono- and di-unsaturated fatty acids (UFAs) such as 18:1 ω 7 c, 16:1 ω 6 c, 16:1 ω 7 c, and 18:2 ω 6,9 c long-chain fatty acids have been found as the chief constituents of S. maltophilia boiled cell lysate. Throughout the study, both acute and chronic exposure of the cell lysate showed a decrease in the locomotor activity and a time-dependent increase of the depression (p < 0.001-0.0001, two-way ANOVA), supported by bioamine (dopamine, noradrenaline, adrenaline, serotonin, and GABA) depletion in rodents' brain possibly due to UFA-amino acid decarboxylase interaction favoring bioamine depletion as revealed by our study. Furthermore, the UFA-rich cell lysate revealed dose-dependent inhibition of murine brain microglial cell viability in vitro with concomitant increase of reactive oxygen species (ROS) inside the cell. Destruction of neuroprotective and neurotrophin releasing microglial cells, augmentation of brain ROS, and inflaming brain tissue resulting in infiltration of polymorphonuclear leucocytes also suggest to cause neurotoxicity by UFA derived from Stenotrophomonas maltophilia.

Therapeutic Effects of Hydrogen Gas Inhalation on Trimethyltin-Induced Neurotoxicity and Cognitive Impairment in the C57BL/6 Mice Model.

Oxidative stress (OS) is one of the causative factors in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s disease (AD) and cognitive dysfunction. In the present study, we investigated the effects of hydrogen (H2) gas inhalation in trimethyltin (TMT)-induced neurotoxicity and cognitive dysfunction in the C57BL/6 mice. First, mice were divided into the following groups: mice without TMT injection (NC), TMT-only injection group (TMT only), TMT injection + lithium chloride-treated group as a positive control (PC), and TMT injection + 2% H2 inhalation-treated group (H2). The TMT injection groups were administered a single dosage of intraperitoneal TMT injection (2.6 mg/kg body weight) and the H2 group was treated with 2% H2 for 30 min once a day for four weeks. Additionally, a behavioral test was performed with Y-maze to test the cognitive abilities of the mice. Furthermore, multiple OS- and AD-related biomarkers such as reactive oxygen species (ROS), nitric oxide (NO), calcium (Ca2+), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase, inflammatory cytokines, apolipoprotein E (Apo-E), amyloid β (Aβ)-40, phospho-tau (p-tau), Bcl-2, and Bcl-2- associated X (Bax) were investigated in the blood and brain. Our results demonstrated that TMT exposure alters seizure and spatial recognition memory. However, after H2 treatment, memory deficits were ameliorated. H2 treatment also decreased AD-related biomarkers, such as Apo-E, Aβ-40, p-tau, and Bax and OS markers such as ROS, NO, Ca2+, and MDA in both serum and brain. In contrast, catalase and GPx activities were significantly increased in the TMT-only group and decreased after H2 gas treatment in serum and brain. In addition, inflammatory cytokines such as granulocyte colony-stimulating factors (G-CSF), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) were found to be significantly decreased after H2 treatment in both serum and brain lysates. In contrast, Bcl-2 and vascular endothelial growth factor (VEGF) expression levels were found to be enhanced after H2 treatment. Taken together, our results demonstrated that 2% H2 gas inhalation in TMT-treated mice exhibits memory enhancing activity and decreases the AD, OS, and inflammatory-related markers. Therefore, H2 might be a candidate for repairing neurodegenerative diseases with cognitive dysfunction. However, further mechanistic studies are needed to fully clarify the effects of H2 inhalation on TMT-induced neurotoxicity and cognitive dysfunction.

Hydrogen-rich saline alleviates early brain injury through inhibition of necroptosis and neuroinflammation via the ROS/HO-1 signaling pathway after traumatic brain injury.

Traumatic brain injury (TBI) has been recognized as a serious public health issue and a key contributor to disability and death, with a huge economic burden worldwide. Hydrogen, which is a slight and specific cytotoxic oxygen radical scavenger, has been demonstrated to ameliorate early brain injury (EBI) through reactive oxygen species (ROS), oxidative stress injury, apoptosis and necroptosis. Necroptosis refers to a type of programmed cell death process that has a vital function in neuronal cell death following TBI. The specific function of necroptosis in hydrogen-mediated neuroprotection after TBI, however, has yet to be determined. The present study aimed to examine the neuroprotective effects and possible molecular basis that underly hydrogen-rich saline in TBI-stimulated EBI by examining neural necroptosis in the C57BL/6 mouse model. The brain water content, neurological score, neuroinflammatory cytokines (NF-κΒ, TNF-α, IL-6 and IL-1β) and ROS were evaluated using flow cytometry. Malondialdehyde, superoxide dismutase (SOD) and glutathione (GSH) levels were evaluated using a biochemical kit. Receptor-interacting protein kinase (RIP)1, RIP3, Nrf2 and Heme oxygenase-1 (HO-1) were evaluated using western blotting. mRNA of Nrf2 and HO-1 were evaluated using quantitative PCR. Neuronal death was evaluated by TUNEL staining. The outcomes illustrated that hydrogen-rich saline treatment considerably enhanced the neurological score, increased neuronal survival, decreased the levels of serum MDA and brain ROS, increased the levels of serum GSH and SOD. In addition the protein expression levels of RIP1 and RIP3 and the cytokines NF-κB, TNF-α, IL-1β and IL-6 were downregulated compared with the TBI group, which demonstrated that hydrogen-rich saline-induced inhibition of necroptosis and neuroinflammation ameliorated neuronal death following TBI. The neuroprotective capacity of hydrogen-rich saline was demonstrated to be partly dependent on the ROS/heme oxygenase-1 signaling pathway. Taken together, the findings of the present study indicated that hydrogen-rich saline enhanced neurological outcomes in mice and minimized neuronal death by inducing protective effects against neural necroptosis as well as neuroinflammation.

Nutraceutical Strategy to Counteract Eye Neurodegeneration and Oxidative Stress in Drosophila melanogaster Fed with High-Sugar Diet.

Aberrant production of reactive oxygen species (ROS) is a common feature of damaged retinal neurons in diabetic retinopathy, and antioxidants may exert both preventive and therapeutic action. To evaluate the beneficial and antioxidant properties of food supplementation with Lisosan G, a powder of bran and germ of grain (Triticum aestivum) obtained by fermentation with selected lactobacillus and natural yeast strains, we used an in vivo model of hyperglycemia-induced retinal damage, the fruit fly Drosophila melanogaster fed with high-sucrose diet. Lisosan G positively affected the visual system of hyperglycemic flies at structural/functional level, decreased apoptosis, and reactivated protective autophagy at the retina internal network. Also, in high sucrose-fed Drosophila, Lisosan G reduced the levels of brain ROS and retina peroxynitrite. The analysis of oxidative stress-related metabolites suggested 7,8-dihydrofolate, uric acid, dihydroorotate, γ-L-glutamyl-L-cysteine, allantoin, cysteinyl-glycine, and quinolate as key mediators of Lisosan G-induced inhibition of neuronal ROS, along with the upregulation of glutathione system. Of note, Lisosan G may impact oxidative stress and the ensuing retinal cell death, also independently from autophagy, although the autophagy-ROS cross-talk is critical. This study demonstrated that the continuous supplementation with the alimentary integrator Lisosan G exerts a robust and multifaceted antioxidant effect on retinal neurons, thus providing efficacious neuroprotection of hyperglycemic eye.

An inhibitory and beneficial effect of chlorpromazine and promethazine (C + P) on hyperglycolysis through HIF-1α regulation in ischemic stroke

BackgroundAfter ischemic stroke, the increased catabolism of glucose (hyperglycolysis) results in the production of reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). A depressive or hibernation-like effect of C + P on brain activity was reported to induce neuroprotection. The current study assesses the effect of C + P on hyperglycolysis and NOX activation. MethodsAdult male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion. At the onset of reperfusion, rats received C + P with or without temperature control, or phloretin [glucose transporter (GLUT)-1 inhibitor], or cytochalasin B (GLUT-3 inhibitor). We detected brain ROS, apoptotic cell death, and ATP levels along with HIF-1α expression. Cerebral hyperglycolysis was measured by glucose, protein expression of GLUT-1/3, and phosphofructokinase-1 (PFK-1), as well as lactate and lactate dehydrogenase (LDH) at 6 and 24 h of reperfusion. The enzymatic activity of NOX and protein expression of its subunits (gp91phox) were detected. Neural SHSY5Y cells were placed under 2 h of oxygen-glucose deprivation (OGD) followed by reoxygenation for 6 and 24 h with C + P treatment. Cell viability and protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured. A HIF-1α overexpression vector was transfected into the cells, and then protein levels of HIF-1α, GLUT-1/3, PFK-1, and LDH were quantitated. In sham-operated rats and control cells, the protein levels of HIF-1α, GLUT-1/3, PFK-1, LDH, and gp91phox were measured at 6 and 24 h after C + P administration. ResultsC + P reduced the protein elevations after stroke in HIF-1α, glycolytic enzymes, as well as in ROS, cell death, glucose and lactate, but raised ATP levels in the brain. In ischemic rats exposed to GLUT-1/3 inhibitors, ROS, cell death, glucose, and lactate were all decreased, as well as GLUT-1, GLUT-3, LDH, and PFK-1 protein levels. C + P decreased ischemia-induced NOX activation by reducing the enzymatic activity and protein expression of the NOX subunit gp91phox, as was observed in the presence of GLUT-1/3 inhibitors. These markers were significantly decreased following C + P administration with the induced hypothermia, while C + P administration with temperature control at 37 °C induced lesser protection after ischemia stroke. In the OGD/reoxygenation model, C + P treatment increased cell viability and diminished protein levels of HIF-1α, GLUT-1, GLUT-3, PFK-1, LDH, and gp91phox. However, in OGD with HIF-1α overexpression, C + P was unable to effectively reduce the upregulated GLUT-1, GLUT-3, and LDH. In normal conditions, C + P reduced HIF-1α and the levels of key glycolytic enzymes depending on its pharmacological effect. ConclusionC + P, partially depending on hypothermia, attenuates hyperglycolysis and NOX activation through HIF-1α regulation.

Effect of Achyranthes Aspera Linn. Leaves Extract on Reactive Oxygen Species (ROS) in Diabetes-induced Rats by Flow cytometry and Possible Molecular Mechanism through Molecular Docking

Background::Oxidative stress is caused due to the overproduction of the reactive oxygen species (ROS) and the disturbance developed in the antioxidant potential of biochemical processes. ROS mostly form in the brain due to the high consumption of oxygen and the insufficiency of endogenous antioxidant resistance mechanisms. Cytochrome P450 2E1 has an excessive percentage of NADPH oxidase activity, which causes the production of ROS and increases oxidative stress.Objectives::We have studied the effect of ethyl acetate extract of Achyranthes Aspera (EAAA) on ROS in the brain of diabetes-induced rats. We have also investigated the possible molecular mechanism of reduction in ROS through molecular docking.Methods:To study the oxidative stress induced by ROS in diabetic rats, we estimated the ROS in rat brain through flow cytometry. The oral dose of EAAA 50mg/kg and 100 mg/kg was given to diabetesinduced rats. Results were articulated as mean ± standard deviation (SD). Data were analyzed using analysis of variance (ANOVA) followed by Bonferroni as a post hoc test. We performed molecular docking of flavonoids on CYP2E1 to study the inhibitory potential.Results::The results have shown that EAAA reduces the generation of ROS in the diabetes-induced rat in a dose-dependent manner. The oral dose of EAAA 50mg/kg and 100 mg/kg was given to the rats and the ROS generation got affected accordingly. Luteolin, quercetin, and apigenin inhibited the CYP2E1 very effectively. Luteolin formed 4 hydrogen bonds with CYP2E1, which indicated its potential inhibition. Although, luteolin and apigenin showed a very good binding affinity with the enzyme.Conclusion::From the present work, we have concluded that the ethyl acetate extract of achyrantesaspera can effectively inhibit the ROS generation in the diabetes-induced rats by inhibiting the activity of CYP2E1.

Hydrogen-rich saline alleviates early brain injury through regulating of ER stress and autophagy after experimental subarachnoid hemorrhage.

ABSTRACTPurpose:Subarachnoid hemorrhage (SAH) is a common complication of cerebral vascular disease. Hydrogen has been reported to alleviate early brain injury (EBI) through oxidative stress injury, reactive oxygen species (ROS), and autophagy. Autophagy is a programmed cell death mechanism that plays a vital role in neuronal cell death after SAH. However, the precise role of autophagy in hydrogen-mediated neuroprotection following SAH has not been confirmed.Methods:In the present study, the objective was to investigate the neuroprotective effects and potential molecular mechanisms of hydrogen-rich saline in SAH-induced EBI by regulating neural autophagy in the C57BL/6 mice model. Mortality, neurological score, brain water content, ROS, malondialdehyde (MDA), and neuronal death were evaluated.Results:The results show that hydrogen-rich saline treatment markedly increased the survival rate and neurological score, increased neuron survival, downregulated the autophagy protein expression of Beclin-1 and LC3, and endoplasmic reticulum (ER) stress. That indicates that hydrogen-rich saline-mediated inhibition of autophagy and ER stress ameliorate neuronal death after SAH. The neuroprotective capacity of hydrogen-rich saline is partly dependent on the ROS/Nrf2/heme oxygenase-1 (HO-1) signaling pathway.Conclusions:The results of this study demonstrate that hydrogen-rich saline improves neurological outcomes in mice and reduces neuronal death by protecting against neural autophagy and ER stress.

Astaxanthin Decreases Spatial Memory and Glutamate Transport Impairment Induced by Fluoride.

Excessive exposure to the sources of fluoride in drinking water, oral care products, and food is a widespread problem. Fluoride is associated with impairment in child intelligence development. It causes DNA damage, oxidative stress, and mitochondrial dysfunction, mainly due to the production of reactive oxygen species (ROS). It has been postulated that the use of antioxidants such as astaxanthin, may alleviate fluoride’s adverse effects. This study assessed the effects of fluoride on cellular ROS content and rat’s learning and memory ability and investigated the protective potency of astaxanthin with emphasis on the role of glutamate using the Morris Water Maze test, glutamate concentration determination, and western blot techniques. The fluoride treatment of cells results in an increment of cellular ROS, whereas astaxanthin inhibits lipid peroxidation. Fluoride significantly decreases the cellular glutamate uptake and glutamate transporter, protein level, possibly due to the disruption of mitochondrial energy metabolism and defect of the transporter recycle, respectively. The in-vivo study indicated that the treatment of rats with fluoride led to a loss of learning, while astaxanthin improved memory dysfunction. Measurement of ROS and glutamate levels of rat brain hippocampus showed that fluoride increased the ROS but decreased the glutamate. On the other hand, the utilization of astaxanthin decreased the brain ROS content and increased the glutamate level. It seems that fluoride disrupts the normal function of neurons via increment of ROS production and decrement of glutamate level, whereas astaxanthin has neuroprotective potency due to the ROS scavenging ability.

Role of Muscle-Specific Histone Methyltransferase (Smyd1) in Exercise-Induced Cardioprotection against Pathological Remodeling after Myocardial Infarction.

Pathological remodeling is the main detrimental complication after myocardial infarction (MI). Overproduction of reactive oxygen species (ROS) in infarcted myocardium may contribute to this process. Adequate exercise training after MI may reduce oxidative stress-induced cardiac tissue damage and remodeling. SET and MYND domain containing 1 (Smyd1) is a muscle-specific histone methyltransferase which is upregulated by resistance training, may strengthen sarcomere assembly and myofiber folding, and may promote skeletal muscles growth and hypertrophy. However, it remains elusive if Smyd1 has similar functions in post-MI cardiac muscle and participates in exercise-induced cardioprotection. Accordingly, we investigated the effects of interval treadmill exercise on cardiac function, ROS generation, Smyd1 expression, and sarcomere assembly of F-actin in normal and infarcted hearts. Adult male rats were randomly divided into five groups (n = 10/group): control (C), exercise alone (EX), sham-operated (S), MI induced by permanent ligation of left anterior descending coronary artery (MI), and MI with interval exercise training (MI + EX). Exercise training significantly improved post-MI cardiac function and sarcomere assembly of F-actin. The cardioprotective effects were associated with increased Smyd1, Trx1, cTnI, and α-actinin expression as well as upregulated ratio of phosphorylated AMP-activated protein kinase (AMPK)/AMPK, whereas Hsp90, MuRF1, brain natriuretic peptide (BNP) expression, ROS generation, and myocardial fibrosis were attenuated. The improved post-MI cardiac function was associated with increased Smyd1 expression. In cultured H9C2 cardiomyoblasts, in vitro treatment with H2O2 (50 µmol/L) or AMP-activated protein kinase (AMPK) agonist (AICAR, 1 mmol/L) or their combination for 4 h simulated the effects of exercise on levels of ROS and Smyd1. In conclusion, we demonstrated a novel role of Smyd1 in association with post-MI exercise-induced cardioprotection. The moderate level of ROS-induced upregulation of Smyd1 may be an important target for modulating post-MI cardiac function and remodeling.

����� ����������� ?-���������� �� ������������� ����� �� �������� ������������� ���� � � ����� ���

Anthropogenic pollution of natural waters by pesticides became a global problem with the beginning of their widespread use in the 1960s of the twentieth century. The most studied cells’ response to the pesticides is an increase in the content of reactive oxygen species (ROS) and, as a consequence, the development of oxidative stress. The proliferative activity of cells is regulated by various factors and largely depends on the expression of proteins involved in the DNA replication. Among such proteins are replicative proteins A (RPA), which binds single-stranded DNA (ssDNA) of eukaryotes. Disruption of RPA-associated cellular activity initiates genomic imbalance, so the expression and content of RPA1 serves as a marker not only of the cell cycle stability, but also the relevant response to DNA damage caused by ecotoxicants.The aim of our study is to determine the oxidative stress development and the RPA1 protein state as a response of rainbow trout’s brain cells to the influence of sublethal concentrations of the lambda-cyhalothrin. A model experiment on the neurotoxicity of lambda-cyhalothrin was performed on the rainbow trout (Oncorhynchus mykiss) under experimental conditions in a la-boratory. The obtained results indicate that sublethal concentrations of lambda-cyhalothrin in the water induce a significant increase in ROS generation in the rainbow trout’s brain. It was found that the content of ROS in the fish brain in all experimental groups depends on both the lambda-cyhalothrin concentration and the duration of exposure to the pesticide. Oxidative stress under the influence of lambda-cyhalothrin increases the content of stress-regulating protein RPA1 in the fish brain, inhibits transcriptional activity and limits the DNA breaks repair, which, in turn, can lead to genomic instability and activation of apoptosis. This indicates a high sensitivity of the mechanism of DNA replication to the neurotoxic effect of synthetic pyrethroids. Thus, the detected increased expression of RPA1 protein may be an adequate biomarker of cellular response to the toxic effects of synthetic pyrethroids in the brain of fish. Further studies of the effect of pyrethroids on key proteins of the aquatic organisms’ reaction to intoxication are of great importance for the determination of indicative biomarkers of pesticide pollution and its potential risk

Comparative evaluation of enzymatic and non-enzymatic antioxidants in alzheimer dementia

The senile dementia is a neurodegenerative disease characterized by loss of memory, attention and cognitive functions. The oxidants- antioxidant plays important role by several mechanism by reducing toxic Amyloid-β in neurons The Alzheimer's disease is due to Amyloid-β deposition in the brain and production of neurofibrillary tangles. Amyloid-β induces reactive oxygen species in brain of Alzheimer dementia patients. In the present study we evaluated the levels of Superoxide dismutase, Glutathione peroxidase, Catalase, Vitamin C and Vitamin E and Vitamin B6 in Alzheimer dementia patients. It has been observed lower levels of Enzymatic, Non-Enzymatic Antioxidants and increased serum levels of malondialdehyde significantly in Alzheimer's dementia patients as compared to healthy controls (p &amp;#60; 0.001). Thus, altered oxidative stress markers may play important role in neurodegenerative diseases like Senile dementia. Serum levels of Superoxide dismutase, Glutathione peroxidase, Catalase, Vitamin C and Vitamin E and Vitamin B6 and Malondialdehyde (indicator of Lipid peroxidation) were measured using standard methods in 50 healthy controls and 50 Alzheimer's dementia patients.

A Conditionally Releasable “Do not Eat Me” CD47 Signal Facilitates Microglia‐Targeted Drug Delivery for the Treatment of Alzheimer's Disease

AbstractEfficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting “do not eat me” signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable “do not eat me” CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.

Diphenyl diselenide dietary supplementation protects against fumonisin B1-induced oxidative stress in brains of the silver catfish Rhamdia quelen

The trend toward using plant-based ingredients in aquafeeds has raised important concerns for aquaculture owing to the negative impacts of mycotoxins on fish health; with emphasis for contamination by fumonisin B1 (FB1). The brain is an important target of FB1; however, study of the pathways linked to brain damage is limited to an analysis of histopathological alterations. Reports have demonstrated the protective effects of dietary supplementation with diphenyl diselenide (Ph2Se2) in the brains of fish subjected to several environmental insults; nevertheless, its neuroprotective effects in fish fed with diets contaminated with FB1 remain unknown. Therefore, the aim of this study was to evaluate whether oxidative damage may be a pathway associated with FB1-induced neurotoxicity, as well as to evaluate whether dietary supplementation with Ph2Se2 prevents or reduces FB1-mediated brain oxidative damage in silver catfish. Brain reactive oxygen species (ROS), lipid peroxidation (LOOH) and protein carbonylation increased on day 30 post-feeding in animals that received FB1-contaminated diets compared to the control group, while brain antioxidant capacity against peroxyl radicals (ACAP) levels and catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities were lower. Diphenyl diselenide dietary supplementation avoid increases in brain ROS levels, as well minimizing the augmentation of LOOH levels. Furthermore, Ph2Se2 prevented impairment of brain ACAP levels, as well as GPx and GST activities elicited by FB1-contaminated diets. These data suggest that dietary supplementation with 3 mg/kg Ph2Se2 prevented FB1-induced brain damage in silver catfish, and this protective effect occurred through avoided of excessive ROS production, as well as via prevention of brain lipid damage. Furthermore, Ph2Se2 exerted its neuroprotective effects via ameliorative effects on the enzymatic and non-enzymatic antioxidant defense systems, and may be an approach to prevent FB1-induced brain oxidative stress; however, is not an alternative to prevent the impairment on performance caused by FB1.

Diphenyl diselenide dietary supplementation alleviates behavior impairment and brain damage in grass carp (Ctenopharyngodon idella) exposed to methylmercury chloride

Mercury (Hg) induces neurobehavioral disorders through reactive oxygen species (ROS) elevation and impairment of brain key enzyme activities. Nevertheless, the therapeutic and toxic selenium concentrations for fish are very close; diphenyl diselenide (Ph2Se2), an organoselenium compound with neuroprotective effects, may be an alternative to elemental Se. Therefore, the aim of this study was to determine whether dietary supplementation with Ph2Se2 prevented or reduced the neurobehavioral alterations and oxidative damage elicited by CH3HgCl in grass carp Ctenopharyngodon idella. Fish exposed to CH3HgCl exhibited significantly reduced distance travelled and swimming speed compared to the control group, as well as augmented cortisol and ROS levels and xanthine oxidase (XO) activities. CH3HgCl exposure significantly increased lipid peroxidation (LOOH) and protein carbonylation (PC) levels compared to those of the control group, while acetylcholinesterase (AChE) and sodium-potassium pump (Na+, K+-ATPase) activities were inhibited. Dietary supplementation with 3 mg/kg Ph2Se2 ameliorated locomotor activity impairment and prevented the augmented brain cortisol and ROS levels as well as XO activity. The supplement reduced lipid and protein damage elicited by CH3HgCl and exerted protective effects on brain AChE and Na+, K+-ATPase activities. Exposure to an environmental concentration of CH3HgCl elicited neurobehavioral alterations linked to reduced locomotor activity, a finding that can be explained by oxidative damage and reduced activity of AChE and Na+, K+-ATPase in telencephalon and mesencephalon structures. Dietary supplementation with Ph2Se2 prevented CH3HgCl-induced locomotor impairment. This effect appeared to be mediated by antioxidant action. Ph2Se2 may be a viable approach to prevention or reduction CH3HgCl-mediated neurotoxic effects.

Activation of the phagocyte NADPH oxidase/NOX2 and myeloperoxidase in the mouse brain during pilocarpine-induced temporal lobe epilepsy and inhibition by ketamine.

Excessive reactive oxygen species (ROS) production can induce tissue injury involved in a variety of neurodegenerative disorders such as neurodegeneration observed in pilocarpine-induced temporal lobe epilepsy. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist has beneficial effects in pilocarpine-induced temporal lobe epilepsy, when administered within minutes of seizure to avoid the harmful neurological lesions induced by pilocarpine. However, the enzymes involved in ROS productions and the effect of ketamine on this process remain less documented. Here we show that during pilocarpine-induced epilepsy in mice, the expression of the phagocyte NADPH oxidase NOX2 subunits (NOX2/gp91phox, p22phox, and p47phox) and the expression of myeloperoxidase (MPO) were dramatically increased in mice brain treated with pilocarpine. Interestingly, treatment of mice with ketamine before or after pilocarpine administration decreased this process, mainly when injected before pilocarpine. Finally, our results showed that pilocarpine induced p47phox phosphorylation and H2O2 production in mice brain and ketamine was able to inhibit these processes. Our results show that pilocarpine induced NOX2 activation to produce ROS in mice brain and that administration of ketamine before or after the induction of temporal lobe epilepsy by pilocarpine inhibited this activation in mice brain. These results suggest a key role of the phagocyte NADPH oxidase NOX2 and MPO in epilepsy and identify a novel effect of ketamine.