Inhibition Of Antioxidant Systems Research Articles

Characteristics of streptozotocin-induced and okadaic acid-induced models of Alzheimer's disease

alzheimer's disease is the main cause of dementia in people over the age of 65, which affects millions of patients worldwide. Since the prevalence of this pathology increases significantly with the increase in life expectancy, the societal consequences of Alzheimer's disease will be dire if no effective therapy is developed in the near future. Fundamental experimental work is a mandatory and necessary stage of preclinical research for the safe and effective development of new approaches to the treatment of dementia as part of clinical trials in the future. Streptozotocin is a natural chemical obtained from Streptomyces achromogenes, primarily classified as an antibiotic, the introduction of which leads to the activation of oxidative stress and damage to the myelin sheath. This chemical compound promotes the accumulation of characteristic abnormal proteins, called β-amyloid and tau protein, which leads to imitation of neuropathological, behavioral, metabolic and molecular symptoms that resemble human Alzheimer's disease. Okadaic acid is a C38 fatty acid polyester phycotoxin, which is a powerful and selective inhibitor of serine/threonine phosphatases: PP-1c, PP1, PP2A and PP2B, which leads to a decrease in dephosphorylation of phosphorylated tau protein and, accordingly, to hyperphosphorylation of tau protein. Hyperphosphorylation of tau protein is responsible for the deposition of neurofibrillary tangles in vivo and in vitro, which ultimately causes synaptic dysfunction and neuronal death. In addition, okadaic acid activates kinases that regulate tau protein phosphorylation: GSK3β, CDK5, MAPK, ERK1/2, AMPK. The activation of kinases significantly contributes to the phosphorylation of tau protein. Okadain administration is also reported to significantly activate the expression of BACE1, one of the key enzymes in the amyloidogenic cascade. The mechanisms of molecular and morphological changes of the Alzheimer's type in the brain of experimental animals when streptozotocin and okadaic acid are administered are similar in many respects. These include induction and activation of neurodegeneration, apoptosis and necrosis of neurons, development of oxidative stress and inhibition of antioxidant systems, deficiency of neurotransmitters and mitochondrial dysfunction, etc. Both proposed toxins effectively contribute to the simulation of dementia of the Alzheimer's type in the experiment.

Lead induced thymic immunosuppression in Japanese quail (Coturnix japonica) via oxidative stress-based T cell receptor pathway signaling inhibition

The human-induced lead (Pb) contamination brings about serious environmental issues around the world and it also poses severe risks to wildlife including birds. Avian thymus is one of primary lymphoid organs and it plays an important role in regulating T cell-based cellular immunity. Therefore, in this study, we tried to examine toxic effects and potential molecular mechanism of Pb on avian thymus using a biological model species-Japanese quail (Coturnix japonica). One-week-old Japanese quails were exposed to 0, 50, 500 and 1000 ppm Pb concentrations in drinking water for three weeks when thymus reached developmental climax. The results showed body weight, thymus weight and thymic size were reduced significantly by Pb exposure. Meanwhile, histopathological changes including vacuolation, cortex atrophy and nuclear debris were detected in thymic cells of Pb exposure. In addition, ultrastructural alterations such as mitochondrial damage, chromatin condensation, and nuclear destruction were found in the thymus of Pb treatments. The increase of reactive oxygen species (ROS) and Malondialdehyde (MDA) as well as the inhibition of antioxidant system indicated that Pb exposure caused oxidative damages in the thymus. Pb exposure also increased thymic cell apoptosis. Moreover, RNA-Seq analysis revealed that thymic functional pathways were disrupted by Pb exposure. Especially, Pb exposure disturbed T cell differentiation and led to T helper type 1 (Th1) /T helper type 2 (Th2) imbalance by interfering with T cell receptor signaling and cytokine signaling. This study implied that Pb caused thymic immunosuppression through causing morphological deformation, structural destruction, oxidation and molecular signaling disruption.

Ent-Kaurane diterpenoids induce apoptosis and ferroptosis through targeting redox resetting to overcome cisplatin resistance

Reactive oxygen species (ROS) induction is an effective mechanism to kill cancer cells for many chemotherapeutics, while resettled redox homeostasis induced by the anticancer drugs will promote cancer chemoresistance. Natural ent-kaurane diterpenoids have been found to bind glutathione (GSH) and sulfhydryl group in antioxidant enzymes covalently, which leads to the destruction of intracellular redox homeostasis. Therefore, redox resetting destruction by ent-kaurane diterpenoids may emerge as a viable strategy for cancer therapy. In this study, we isolated 30 ent-kaurane diterpenoids including 20 new samples from Chinese liverworts Jungermannia tetragona Lindenb and studied their specific targets and possible application in cancer drug resistance through redox resetting destruction. 11β-hydroxy-ent-16-kaurene-15-one (23) possessed strong inhibitory activity against several cancer cell lines. Moreover, compound 23 induced both apoptosis and ferroptosis through increasing cellular ROS levels in HepG2 cells. ROS accumulation induced by compound 23 was caused by inhibition of antioxidant systems through targeting peroxiredoxin I/II (Prdx I/II) and depletion of GSH. Furthermore, compound 23 sensitized cisplatin (CDDP)-resistant A549/CDDP cancer cells in vitro and in vivo by inducing apoptosis and ferroptosis. Thus, the ent-kaurane derivative showed potential application for sensitizing CDDP resistance by redox resetting destruction through dual inhibition of Prdx I/II and GSH in cancer chemotherapy.

Inhibition of Thioredoxin Reductase by Triosmium Carbonyl Clusters.

Tumor cells are characterized by increased reactive oxygen species production in parallel with an enhanced antioxidant system to avoid oxidative damage. The inhibition of antioxidant systems is an effective way to kill cancer cells, and the thioredoxin system or, more specifically, the cytosolic selenocysteine-containing enzyme thioredoxin reductase (TrxR) has become an interesting target for cancer therapy. We show here that the known cytotoxic and apoptosis-inducing osmium carbonyl cluster Os3(CO)10(NCCH3)2 (1) is a nonsubstrate inhibitor of mammalian TrxR, with an IC50 of 5.3 ± 0.9 μM. It inhibits TrxR selectively over the closely related glutathione reductase (GR) and in the presence of excess reduced glutathione (GSH). This inhibition has also been demonstrated in cell lysates, suggesting that TrxR inhibition is a potential apoptotic pathway for 1.

The potential effects of dietary flavones on diabetic nephropathy; a review of mechanisms

Diabetes as a chronic metabolic disorder affects the worldwide population with high incidence of morbidity and mortality. Different complications such as nephropathy, neuropathy, ocular diseases, and cardiovascular disease are common in patients with diabetes that threaten the patient’s lifestyle. Diabetic nephropathy (DN) usually is related to some major structural alterations in the kidney which characterized by generation of toxic reactive oxygen species (ROS) or inhibition of antioxidant systems in kidney tissue. Different natural agents have been introduced to be used as a complementary treatment to prevent diabetic kidney disease. Flavones (apigenin, luteolin, nobiletin and chrysin) as a subgroup of flavonoids are natural occurring substances which have several pharmacological activates, including antioxidant, antiapoptotic, anti-inflammatory, and anti-tumor efficacy. Recent evidence indicated that flavones may be effective for prevention and treatment of diabetes complications in experimental models. The present study was designed to review the relationship between flavones administration and diabetes and diabetic kidney disease by focusing on the possible molecular pathway. The findings indicate that flavones have protective effects against diabetic kidney disease by modulation of different pathways related to oxidative stress, inflammation, and apoptosis in animal models. Therefore, more clinical investigations are suggested to be conducted to find the protective effects of flavones in patients with diabetes.

Abstract 4372: Effects of high glucose and DCA on ROS production and viability of breast cancer cells with disrupted antioxidant systems

Abstract A goal of this study was to determine if disruption of protective cellular antioxidant systems would sensitize cancer cells to dichloroacetate (DCA), a compound affecting mitochondrial metabolism (reversing the Warburg Effect). DCA shifts the metabolism of glucose back to mitochondrial oxidative phosphorylation, with subsequent production of reactive oxygen species (ROS) (Bonnet et al., 2007). While cancer cells consume large amounts of glucose to meet energy demands and provide substrates necessary for protein and nucleic acid biosynthesis, they utilize aerobic glycolytic pathways (Warburg metabolism) instead of oxidative phosphorylation. Glutathione (GSH) and thioredoxin (Trx) are among the antioxidants produced to protect cells from oxidative damage; oxidative stress occurs when the production of ROS overwhelms these systems. Biosynthesis of GSH and Trx were inhibited by treating cells with low levels of buthionine sulfoximine (BSO) and auranofin (AUR) to deplete GSH and Trx, respectively. Through its stimulation of ROS production, DCA should enhance the cytotoxic effects in cells with diminished antioxidant systems. A second goal was to investigate the effects of these compounds on cells grown in either low or high glucose media (1 g/L vs 4.5 g/L). Cells grown under high glucose conditions were expected to produce more ROS and exhibit greater sensitivity to the combination of DCA, BSO and AUR. The experiments were conducted using MDA-MB-231 and MCF-7, breast cancer cell lines with known differences in metabolism and responses to chemotherapeutic drugs. BSO led to a dramatic decrease of GSH levels. AUR, at concentrations above 0.5 µM, significantly reduced cell viability when in combination with BSO. DCA alone reduced viability, but its effects were significantly enhanced when used in conjunction with BSO/AUR. Levels of ROS were quantified using a luminescence-based assay. In low glucose media, BSO/AUR and DCA had no effect on ROS production. In contrast, a high glucose environment led to elevated ROS production under all conditions, with the highest levels being induced by DCA in the cells having disrupted antioxidant systems. In the presence of BSO/AUR, MDA-MB-231 cells produced more ROS than MCF-7 cells. Overall, inhibition of antioxidant systems sensitized cells to DCA, increasing ROS and reducing viability.Previous studies have reported metabolic differences between cell lines (Gatenby and Gillies, 2004). MDA-MB-231 cells rely on aerobic glycolysis while MCF-7 cells are more reliant on mitochondrial oxidative phosphorylation. Therefore, MCF-7 cells have developed increased protection against ROS as compared to MDA-MB-231 cells (Theodossiou et al., 2017). These findings support the observed differences in response to BSO/AUR between the two cell lines. Paradoxically, MCF-7 cells were more sensitive to BSO/AUR than MDA-MB-231 cells in colony formation assays. Citation Format: Radek Buss, Collin Ellenbecker, Emily Minton, Lauren Gray, Mona Nolte, Aysiah Jaeke, Russ Feirer. Effects of high glucose and DCA on ROS production and viability of breast cancer cells with disrupted antioxidant systems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4372.

Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems

Piperlongumine (PL), naturally synthesized in long pepper, is known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis. ROS are the primary effector molecules of radiation, and increase of ROS production by pharmacological modulation is known to enhance radioresponse. We therefore investigated the radiosensitizing effect of PL in colorectal cancer cells (CT26 and DLD-1) and CT26 tumor-bearing mice. Firstly, we found that PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase. Secondly, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells, linked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration. Finally, the radiosensitizing effect of PL was verified in vivo. PL improved the tumor response to both single and fractionated radiation, resulting in a significant increase of survival rate of tumor-bearing mice, while it was ineffective on its own. In line with in vitro findings, enhanced radioresponse is associated with inhibition of antioxidant systems. In conclusion, our results suggest that PL could be a potential radiosensitizer in colorectal cancer.

Функціональний стан прооксидантної та антиоксидантної систем у легенях при екcпериментальному алергічному альвеоліті за умов іммобілізаційного стресу і корекція його порушень корвітином

Introduction. Experimental allergic alveolitis (EAA) takes an important part among the diseases of the allergic genesis of the bronchopulmonary unit. The sharp deterioration of the socioeconomic situation in Ukraine, the high psycho-emotional stress in society, the long-term systematic impact of adverse factors are often combined, causing a stressful situation in the body.The aim of the study – to learn the functional state of the prooxidant and antioxidant system in the lungs of the mollusks under the conditions of the development of experimental immobilization stress and experimental allergic alveolitis and their correction with corvethene.Research Methods. The object – 80 guinea pigs (females) divided into 8 experimental groups, with 10 animals in each. 1st group – intact animals; 2, 3, 4 groups – the experimental model of allergic alveolitis (1st, 2nd, 34th day)to the treatment of K.5, 6, 7 groups – EAA under conditions of experimental immobilization stress (EIS ) (1st, 2nd, 34th day) to C treatment. Group 8 – EAA in the conditions of EIS (34th day) after treatment C, which for 10 days was administered intravaginal drug "Corvitin" (Borshchahivskyi Chemical and Pharmaceutical factory) in dose of 40 mg/kg. The animals then decapitated and determined in the lungs the content of the LPO products and the activity of the enzymes AOC. The content of diene conjugates (DK) – method of V. H. Havrylov, V. I. Mishkorudna, malone dialdehyde (MDA) – E. N. Korobeinikov, superoxide dismutase activity (SOD) – by R. Fried method, catalase activity (CT) – by B. Holmes, C. Masters. Immobilization stress – by the method of PID Horizon [10]. Experimental AA – by the method of O. Orekhov, Yu. A. Kyrilov. Statistical processing of digital data – Styuden's method. Statistically reliable results were considered, for which p≤0.05.Results and Discussion. During experimental studies, there was a change in the activity of antioxidant protection and lipid peroxidation in the dynamics of EAA development. There are changes in the equilibrium between the prooxidant and antioxidant systems in the direction of the growth of prooxidant and inhibition of antioxidant systems. According to the results, there is a significant activation of antioxidant mechanisms before the first day, with a gradual exhaustion up to 34 days of the disease and an increase in the processes of lipoperoxidation up to 34 days. Under conditions of combined pathological processes – experimental AA and immobilization stress, there is a significant stimulation of the antioxidant and prooxidant antioxidant systems. After treatment for ten days, mullahs with experimental AA in the conditions of EIS and treated K, which was administered at a dose of 40 mg/kg. there is a significant inhibition of LPO, and an increase in the activity of the antioxidant system – superoxide dismutase.Conclusions. The obtained results of the study showed the failure of the antioxidant system to dispose of the products of the LPA in the experimental AA under stress and its exhaustion in early periods of the disease. With theuse of corvetone, which has membrane-stabilizing, immune-regulating, anti-inflammatory and anti-ischemic effects, there was a decrease in the damaging effect of LPO and a significant increase in antioxidant defense, which in turn indicates the corrective effect of corvetane on the parameters of prooxidant and antioxidant systems and provides an opportunity for further study and experimental researches.

Forskolin Effect on FOXO1 Expression and Relationship of FOXO1 Activation to Oxidative Stress: From Molecular to Therapeutic Strategy

Background: Reactive Oxygen Species (ROS) production has been established as an essential contributor in the development cardiotoxicity. The increase of ROS production simultaneously leads to the inhibition of anti-oxidant systems. Forkhead transcription factor O1 (FOXO1) plays an important role in regulating metabolism and oxidant stress. Clozapine was used to induce cardiotoxicity. Forskolin the well-known anti-oxidant and anti-inflammatory agent was used to modulate the effect on both FOXO1 gene and its target gene catalase and to what extent it may protect against clozapine-induced cardiotoxicity. Methods: The animals were classified into: control group, forskolin group; forskolin was administered for 8 weeks; clozapine group, and forskolin + clozapine group; forskolin was pre-administered for 5 weeks then continued along with clozapine for the last 3 weeks. RT-qPCR and gel electrophoresis were done. We analyzed the relation between FoxO1 gene and oxidative stress. Results: These effects are achieved by the ability of Forskolin to modulate the expression of Foxo-1 and catalase, the levels of CKMB, troponin I, GST, MDA, and TNF- α, Caspase-3 were decreased, histopathological changes were improved. Forskolin reduce cardiomyocytes damage, and improve cardiac function by decreasing oxidative stress. Conclusion: Forkolin with its biological activities and anti-oxidative effects control cardiotoxicity induced by ROS in addition to its anti-inflammatory activity. This may be considered as therapy in cardiac problems management.

Selective inhibition of endogenous antioxidants with Auranofin causes mitochondrial oxidative stress which can be countered by selenium supplementation

Auranofin is a thiol-reactive gold (I)-containing compound with potential asa chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants. Significant inhibition of TrxR was observed at 20nM Auranofin with inhibition of GPx from 10µM. Significant increases in reactive oxygen species (ROS) were associated with antioxidant inhibition at Auranofin concentrations of 100nM (TrxR inhibition) and 10µM (TrxR and GPx inhibition), respectively. Evaluation of mitochondrial respiration demonstrated significant reductions in routine and maximal respiration at both 100nM and 10μM Auranofin. Auranofin treatment at concentrations of 10μM and higher concentrations resulted in a ∼68% decrease in cellular viability and was associated with elevations in pro-apoptotic markers cytochrome c flux control factor (FCFc) at concentration of 100nM and mitochondrial Bax at 10μM. The supplementation of selenium (100nM) prior to treatment had a generalized protective affect through the restoration of antioxidant activity with a significant increase in TrxR and GPx activity, a significant reduction in ROS and associated improvement in mitochondrial respiration and cellular viability (10µM ∼48% increase). Selenium supplementation reduced the FCFc at low doses of Auranofin (<10μM) however no effect was noted on either FCFc or Bax at concentrations above 10μM. The inhibition of antioxidant systems in non-cancerous cells by Auranofin is strongly dose dependent, and this inhibition can be altered by selenium exposure. Therefore, Auranofin dose and the selenium status of patients are important considerations in the therapeutic use of Auranofin as an agent of chemosensitization.

Response of antioxidant and biotransformation systems of selected freshwater mussels (Dreissena polymorpha, Anadonta cygnea, Unio tumidus, and Corbicula javanicus) to the cyanobacterial neurotoxin β-N-methylamino-L-alanine

Response of selected biotransformation and antioxidant enzymes (glutathione S-transferase (GST), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx)) of four different freshwater mussel species (Dreissena polymorpha, Corbicula javanicus, Anadonta cygnea, and Unio tumidus) was compared after a static exposure to 100 μg L−1 β-N-methylamino-L-alanine (BMAA) for 24 or 48 hours. Whereas D. polymorpha and A. cygnea did not show significant alteration in the activity of the selected enzymes, C. javanicus reacted with increased GST and GR activity after 24 hours and decreased CAT and GPx activity after 48 hours. U. tumidus displayed increased CAT and GR activity after 24 hours. Comparison between the concentration-dependent reaction of invasive D. polymorpha and native U. tumidus (exposure to 10, 100, and 500 μg L−1 BMAA) suggested a greater susceptibility of U. tumidus to BMAA. A further experiment on the time-dependent response to BMAA in U. tumidus gave an insight into the progression of the enzymatic response(s). An increase in CAT activity occurred after merely four hours, while a decrease of GPx activity was in turn only considerable after a longer exposure, for four or seven days. The data suggest that the BMAA exposure in freshwater mussels provokes changes in selected oxidative stress enzymes, which could result in the enhancement or inhibition of antioxidant systems.

системи глутатіону крові щурів та морфологічні зміни підшлункової залози в умовах експериментального гострого та хронічного панкреатиту

In experiment on laboratory rats the models of acute and chronic pancreatitis were developed to study the changes of lipoperoxidation-antioxidant protection system depending on morphological changes of the pancreas. The acute and chronic pancreatitis is accompanied with intensification of lipoperoxidation and gradual inhibition of antioxidant system due to development of subsequent chronization of the pathological process.

The ameliorating effect of Acadian marine plant extract against ionic liquids-induced oxidative stress and DNA damage in marine macroalga Ulva lactuca

Ionic liquids (ILs) are generally considered as the green replacement for conventional volatile organic solvents. Nonetheless, their high solubility in water with proven toxic effects on aquatic biota has questioned their green credentials. In the present study, the detoxification potential of Acadian marine plant extract powder (AMPEP) prepared from the brown alga Ascophyllum nodosum was investigated against the 1-alkyl-3-methylimidazolium bromide [C12mim]Br ionic liquid-induced toxicity and oxidative stress in marine macroalga Ulva lactuca. The IL ([C12mim]Br) at LC50 (70 μM) exposure triggered the generation of reactive oxygen species (ROS) such as O2·−, H2O2 and OH· causing membrane and DNA damage together with inhibition of antioxidant systems in the alga. The supplementation of AMPEP (150 μg mL−1) to the culture medium significantly reduced the accumulation of ROS and lipid peroxidation together with the inhibition of lipoxygenase (LOX) activity specially LOX-2 and LOX-3 isoforms. This is for the first time wherein comet assay was performed to ascertain the protective role of AMPEP against DNA damage in algal tissue grown in medium supplemented with IL and AMPEP. The AMPEP showed protective role against DNA damage (5–45 % tail DNA) when compared to those of grown in IL alone (45–70 % tail DNA). Further, specific isomorphs of different antioxidant enzymes such as superoxide dismutase (Mn-SOD-1, ~150 kDa), ascorbate peroxidase (APX-4, ~55 kDa), glutathione peroxidase (GSH-Px-2, ~55 kDa) and glutathione reductase (GR-1, ~180 kDa) responded specifically to AMPEP supplementation. It is evident from these findings that AMPEP could possibly be used for circumventing the negative effects arising from ILs-induced toxicity in marine ecosystem.

Динаміка зміни показників системи ПОЛ-АОЗ, вуглеводного та ліпідного обміну в крові експериментальних щурів при переході гострого панкреатиту у хронічну форму

In consequence of ligation of the main duct in pancreatic tail section of male rats the acute pancreatitis had developed but it gradually turned into a chronic form. In the blood of experimental animals processes of lipid peroxidation (LPO), the state of antioxidant protection system (AOP), carbohydrate and lipid metabolism were studied. In rats with chronic pancreatitis the significant intensification of lipid peroxidation, inhibition of antioxidant system, hyperglycaemia, and hyperlipidaemia were found.

Selenium and spermine alleviate cadmium induced toxicity in the red seaweed Gracilaria dura by regulating antioxidants and DNA methylation

The protective role of exogenously supplied selenium (Se) and polyamines (PAs) such as putrescine (Put) and spermine (Spm) in detoxifying the cadmium (Cd) induced toxicity was studied in the marine red alga Gracilaria dura in laboratory conditions. The Cd exposure (0.4 mM) impede the growth of alga while triggering the reactive oxygen species (ROS viz. O(2)(•-) and H(2)O(2)) generation, inhibition of antioxidant system, and enhancing the lipoxygenase (LOX) activity, malondialdehyde (MDA) level and demethylation of DNA. Additions of Se (50 μM) and/or Spm (1 mM) to the culture medium in contrast to Put, efficiently ameliorated the Cd toxicity by decreasing the accumulation of ROS and MDA contents, while restoring or enhancing the level of enzymatic and nonenzymatic antioxidants and their redox ratio, phycobiliproteins and phytochelatins, over the controls. The isoforms of antioxidant enzymes namely superoxide dismutase (Mn-SOD, ~150 kDa; Fe-SOD ~120 kDa), glutathione peroxidase (GSH-Px, ~120 and 140 kDa), glutathione reductase (GR, ~110 kDa) regulated differentially to Se and/or Spm supplementation. Furthermore, it has also resulted in enhanced levels of endogenous PAs (specially free and bound insoluble Put and Spm) and n-6 PUFAs (C20-3, n-6 and C20-4, n-6). This is for the first time wherein Se and Spm were found to regulate the stabilization of DNA methylation by reducing the events of cytosine demethylation in a mechanism to alleviate the Cd stress in marine alga. The present findings reveal that both Se and Spm play a crucial role in controlling the Cd induced oxidative stress in G. dura.

Toxic Effects of Imidazolium Ionic Liquids on the Green Seaweed Ulva lactuca: Oxidative Stress and DNA Damage

The green credentials of ionic liquids (ILs) are being increasingly questioned due to the growing evidence of their toxicity to aquatic ecosystems, although the mechanisms of toxicity are unknown. This study provides insights into the mechanism of toxicity and biological effects of 1-alkyl-3-methylimidazolium bromide [C(n)mim]Br (n = 4 to 16) on the marine macroalga Ulva lactuca. The cell viability of this alga during IL exposure was found to be negatively correlated to the chain length of the alkyl group. The IL ([C(12)mim]Br) exposure triggers the generation of reactive oxygen species (ROS viz. O(2)(•-), H(2)O(2), and OH(•)), damage of the membrane and DNA, and inhibition of antioxidant systems in the alga. The enhanced production of ROS and lipid peroxidation in the alga subjected to LC(50) concentration for 4 days was largely attributed to lipoxygenase (LOX) activity coupled with the induction of two LOX isoforms (~80 kDa and ~55 kDa). Pretreatment of the algal thallus with enzyme inhibitors such as diphenylene iodonium, sodium azide, cantharidin, and oxadiazoloquinoxalin-1-one, prior to [C(12)mim]Br exposure showed the regulation of ROS by the activation of membrane bound NADPH-oxidase and cytochrome oxidase. The IL exposure resulted in the accumulation of n-3 and n-6 fatty acids at 0.5 LC(50) concentration indicating the induction of desaturase enzymes. Furthermore, antioxidant enzyme activities such as superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR) were enhanced by 1.3-2.0-fold, while glutathione peroxidase (GSH-Px) diminished, together with a higher regeneration rate of reduced ascorbate and glutathione. The isoforms of antioxidant enzymes, namely, Mn-SOD (~85 kDa), APX (~125 and 45 kDa), and GR (~135 kDa) regulated differentially to IL exposure. The comet assay performed for the first time for seaweeds revealed the significant induction of DNA damage (>50-70% increase in % tail DNA over control) in alga exposed to ≥ LC(50) concentration.

Noopept Reduces the Postischemic Functional and Metabolic Disorders in the Brain of Rats with Different Sensitivity to Hypoxia

Chronic cerebral ischemia was induced by ligation of both common carotid arteries in Wistar rats, divided by sensitivity to hypoxia into highly sensitive and low-sensitive. Noopept (peptide preparation), injected (0.5 mg/kg) during 7 days after occlusion of the carotid arteries, reduced the neurological disorders in rats with high and low sensitivity to hypoxia and improved their survival during the postischemic period. Noopept normalized behavior disordered by cerebral ischemia (according to the open field and elevated plus maze tests), prevented accumulation of LPO products and inhibition of antioxidant systems in the brain of rats with high and low sensitivity to hypoxia. Hence, noopept exhibited a neuroprotective effect in cerebral ischemia.