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Background: Sepsis is a severe global health problem, with high morbidity and mortality. In sepsis, one of the main affected organs is the liver. Hepatic alterations characterize a negative prognostic. Omega-3 fatty acids (ω3), eicosapentaenoic acid, and docosahexaenoic acid, are part of the main families of polyunsaturated fatty acids. ω3 has been used in studies as sepsis treatment and as a treatment for non-alcoholic liver disease., Aim: We aimed to evaluate the effects of treatment with fish oil (FO) rich in ω3 on liver changes and damage resulting from experimental sepsis., Methodology: A model of severe sepsis in Wistar rats was used. Oxidative stress in the liver tissue was evaluated by means of tests of thiobarbituric acid reactive substances, 2,7-dihydrodichlorofluorescein diacetate , catalase, and glutathione peroxidase, in the serum TBARS, DCF, thiols and, to assess liver dysfunction, alanine aminotransferase and aspartate aminotransferase. Hepatic tissue damage was evaluated using H&E histology., Results: In assessments of oxidative stress in liver tissue, a protective effect was observed in the tests of TBARS, DCF, CAT, and GPx, when compared the sepsis versus sepsis+ω3 groups. Regarding the oxidative stress in serum, a protective effect of treatment with ω3 was observed in the TBARS, DCF, and thiols assays, in the comparison between the sepsis and sepsis+ω3 groups. ω3 had also a beneficial effect on biochemical parameters in serum in the analysis of ALT, creatinine, urea, and lactate, observed in the comparison between the sepsis and sepsis+ω3 groups., Conclusion: The results suggest ω3 as a liver protector during sepsis with an antioxidant effect, alleviating injuries and dysfunctions., (© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Abstract: Phyllanthus niruri L. (Euphorbiaceae) (P. niruri) is a well-known hepatoprotective herbal plant. In the present study, hepatoprotective potential of the protein isolate of P. niruri was investigated against carbon tetrachloride (CCl4) induced liver damage in vivo. Protein isolate of P. niruri was intraperitoneally injected in mice either prior to (preventive) or after the induction of toxicity (curative). Levels of different liver marker enzymes in serum and different anti-oxidant enzymes, as well as lipid peroxidation products and glutathione (GSH) in liver homogenates were measured in normal, control (toxicity induced) and protein isolate treated mice. Administration of CCl4 increased the serum glutamate pyruvate transaminase (GPT) and alkaline phosphatase (ALP) levels of mice sera along with increased lipid peroxidation and reduced levels of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the liver. Treatment with the protein isolate of P. niruri significantly altered these changes to almost normal. The protein isolate also showed protective properties as was evidenced in histopathological studies. Results suggest that the protein isolate of P. niruri protects liver tissues against oxidative damage and somehow helps stimulating repair mechanism present in liver. It could be used as an effective hepatoprotector against CCl4 induced liver damage. [Copyright &y& Elsevier]

Abstract: Polyphenols are ubiquitous substances in the diet. Their anti-oxidative, anti-inflammatory and anti-viral effects are of interest for human health, and polyphenols such as luteolin are used at high concentrations in food supplements. The aim of this project was to determine the intrinsic effects of luteolin in H4IIE rat hepatoma cells. Luteolin is relatively toxic, cell death was caused via induction of apoptosis as detected by DNA-ladder formation, by nuclear fragmentation and activation of apoptotic enzymes (caspase-2, -3/7, -9 and -8/10). Luteolin (250μM, 24h) increased the caspase-3/7 activity four-fold and the caspase-9 activity six-fold. In a time course experiment caspase-9 is activated after 6h, while caspase-2 and -3/7 are activated after 12h. After 24h, caspase-8/10 also displays activation. We found a concentration-dependent increase in malondialdehyde release suggesting a prooxidative effect of luteolin. Furthermore, we analysed DNA strand break formation by luteolin and found a distinct increase of DNA strand breaks after incubation for 3h with 100μM luteolin, a concentration which induces oligonucleosomal DNA cleavage at 24h. In conclusion, the sequence of events is compatible with the assumption that luteolin triggers the mitochondrial pathway of apoptosis, probably by inducing DNA damage. [Copyright &y& Elsevier]

Objectives: The objective of this study was to test the predictive value of an oxidative stress biomarker in 634 patients from the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). Background: Oxidative stress contributes to mechanisms of atherosclerosis and plaque instability. Biomarkers of oxidation, such as malondialdehyde (MDA), may represent independent indicators of risk for patients with stable coronary artery disease (CAD). Methods: Serum MDA levels were measured as thiobarbituric acid reactive substances (TBARS) in 634 patients with documented CAD using reverse-phase high-performance liquid chromatography and spectrophotometric approaches. Results: During the three-year study, there were 51 major vascular events such as fatal/nonfatal myocardial infarction, 149 hospitalizations for nonfatal vascular events, and 139 patients underwent a major vascular procedure. At baseline, patients with TBARS levels in the highest quartile had a relative risk (RR) of 3.30 (95% confidence interval [CI] 1.47 to 7.42; p = 0.038) for major vascular events, RR of 4.10 (95% CI 2.55 to 6.60; p < 0.0001) for nonfatal vascular events, and RR of 3.84 (95% CI 2.56 to 5.76; p < 0.0001) for major vascular procedures. The effect of TBARS on events and procedures was also seen in a multivariate model adjusted for inflammatory markers (C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6), and other risk factors (age, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, body mass index, and blood pressure). This analysis showed an independent effect of TBARS on major vascular events (p = 0.0149), nonfatal vascular events (p < 0.0001), major vascular procedures (p < 0.001), and all vascular events and procedures (p < 0.0001). Conclusions: Serum levels of TBARS were strongly predictive of cardiovascular events in patients with stable CAD, independently of traditional risk factors and inflammatory markers. [Copyright &y& Elsevier]

Thapsigargin addition to thymocytes increased cytosolic Ca2+ by a factor of 8.5 with a time for half maximal effect (t1/2) of 2.5 min. Calcium signaling increased mitocondrial and endoplasmic reticulum nitric oxide synthase (NOS) activities by five and six times, with t1/2 of 16 and 48 min, respectively, followed by increases of 140% in intracellular [H2O2], 73% in hydroperoxide content, and 250% in thiobarbituric reactive substance content, with t1/2 of 13, 27, and 30 min, respectively. Mitochondrial dysfunction followed, and was characterized by decreased respiratory control, membrane depolarization, and decrease cytochrome c content release, processes with t½ of 101, 129, and 133 min, respectively. Increased UDP-GT gene expression, observed by mRNA synthesis, and the enzymatic activity of this protein had t½ of 52 and 187 min, respectively. These events were followed by caspase-3 activation (t½=210 min) and DNA laddering (t½=260 min) at the completion of the cell death program. Preincubation of thymocytes with NOS inhibitors (NG-methyl-l-arginine and l-Nω-nitro-l-arginine methylester) halted the whole process through inhibition of mitochondrial and endoplasmic reticulum NOS activities and of DNA laddering. [Copyright &y& Elsevier]

Chronic hyperglycemia in diabetes is a major causative factor of free radical generation which further leads to many secondary diabetic complications via the damage to cellular proteins, membrane lipids, nucleic acids and eventually to cell death. Recently we have reported on the hypoglycemic efficacy of a new macrocyclic binuclear oxovanadium complex and its non-toxic nature. This study focuses on the effect of the above complex in ameliorating oxidative stress in the pancreas of diabetic rats. Streptozotocin induced diabetic rats were treated orally with the vanadium complex (5mg/kg body weight) for 30 days and the level of pancreatic antioxidants and lipid peroxides were determined. Treatment with the macrocyclic binuclear oxovanadium complex decreased the lipid peroxides and the antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase to near control levels. Histological examinations also revealed the protective effect of the complex on pancreatic beta cells. The results demonstrate the protective effect of the macrocyclic binuclear oxovanadium complex on the pancreatic antioxidant status. [Copyright &y& Elsevier]

The ability of dopamine to induce apoptosis in a variety of cell types, including PC12 cells and neurons, has been well documented. Under non-reducing conditions, dopamine can be oxidized to semi-quinone and quinone species, which have the ability to arylate proteins and lead to the formation of covalent adducts. Potentially, it is the arylation of substrates critical to cell survival and/or the formation of toxic adducts which leads to the death observed after dopamine treatment. We have previously described the ability of a substituted monohydroxy-tetra-hydronaphthalene (DATN) to bind proteins that are susceptible to arylation by dopamine and related catecholamines. As DATN can prevent the covalent incorporation of dopamine into substrate molecules, we hypothesized that this compound could have a protective effect on cells that undergo apoptotic death in response to dopamine exposure. We report here that DATN prevents the dopamine-induced apoptotic death of PC12 cells in a dose-dependent manner. DATN did not prevent the oxidative stress associated with dopamine treatment, as lipid peroxide production was not influenced by DATN treatment. The ability of DATN to prevent dopamine-induced cell death was selective for this insult, as this compound did not influence the death of PC12 cells induced by hydrogen peroxide (H2O2). Consistent with this finding, DATN did not alter lipid peroxidation, nor oxidation of intracellular dichlorodihydrofluorescein subsequent to H2O2 treatment. Consistent with a reduction in apoptotic death, the increase in caspase-3 activity associated with dopamine treatment was also prevented by DATN. These observations suggest that DATN may act to prevent one of the pathways linking dopamine and oxidative stress to caspase-3 activation. We propose that the inhibition of substrate arylation by the products of dopamine oxidation may provide a useful strategy for the prevention of dopamine-induced cell death. [Copyright &y& Elsevier]

Mammalian testes are highly sensitive to oxidative free radical damage. Acute scrotum is a clinical syndrome mainly caused by torsion of the spermatic cord that constitutes a surgical emergence affecting newborns, children and adolescents. This syndrome often leads to infertility of the ipsilateral (torted) and contralateral (not torted) testis, an outcome that makes surgical intervention mandatory. There is a controversy involving the effects of ischemia and reperfusion on ipsilateral and contralateral testes after unilateral torsion and detorsion of the spermatic cord. Conflicting reports have led to two distinct and opposite recommendations regarding surgical intervention: detortion and preservation of the ipsilateral testis, or ipsilateral orchiectomy to preserve contralateral fertility. Early detortion surgery in humans preserves fertility, but after prolonged torsion periods followed by preservation of the ipsilateral fertility of both testis is jeopardized. Lowered contralateral blood flow after unilateral testicular torsion is associated with reactive oxygen species (ROS) overgeneration and therefore with the corresponding tissue damage. Reperfusion time appears to be determinant of contralateral testes damage due to the consequent oxidative insult that accompanies the rise in ROS following ischemia–reperfusion. Nevertheless, more investigations on the molecular mechanisms and the antioxidant status in testis are necessary to ascertain the contribution of ROS to the tissue damage produced by spermatic cord torsion in experimental animals and humans. [Copyright &y& Elsevier]

The scientific establishment has been discussing the relationship between aging and oxidative stress for quite some time now. While we are still far from a general agreement about this subject, there is an impressive amount of data collected that can be used to draw a compelling picture of the events that take place during the human aging process and their correlation with the oxidant status of the organism. In this review, we bring forth the results of some key studies that can help to elucidate the aging-oxidative stress puzzle, as well as to explain which are the fundamental events in this interplay and why their causal relationships remain so elusive. We also put forward here data on the systemic oxidative stress status of a group of 503 healthy human subjects. The data consist of the plasma levels of TBARS and of the nutritional antioxidants, α-tocopherol, β-carotene and ascorbic acid, and of the activity of the antioxidant enzymes, Cu, Zn-superoxide dismutase, catalase and glutathione peroxidase, of red blood cells. The data indicate that a moderate situation of oxidative stress gradually develops during human aging. [Copyright &y& Elsevier]

Background/Aims: Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats.Methods: Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA.Results: Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P<0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P<0.001). The increased nuclear binding of nuclear factor κB in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P<0.01), indicating decreased oxidative stress and inflammation.Conclusions: In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress. [Copyright &y& Elsevier]

This paper evaluates the ability of organoselenium compounds [ebselen, selenocystine N-ethyl-carbamate (SeCis), bis-4-isopropyl-2-oxazolinyl phenyl diselenide (AASe)] to prevent HgCl2 toxicity. Rats were injected with HgCl2 (0 or 17 μmol/kg, sc) 6 h after organoselenium compounds had been injected (0 or 50 μmol/kg, sc). In vivo, HgCl2 inhibited renal ALA-D activity (∼48%), increased TBARS level in kidney (∼52%) and reduced the hepatic content of non-protein thiol groups (∼40%), but organoselenium compounds did not prevent such effects. SeCis, per se, increased renal TBARS level (∼42%), while AASe increased hepatic content of ascorbic acid (∼38%). In vitro, renal and hepatic ALA-D activity was inhibited by HgCl2 (&ges;25 μm), ebselen (&ges;12 μm) and SeCis (&ges;4 μm). HgCl2 (400 μm) significantly increased TBARS production in renal and hepatic tissue preparations in vitro, and this effect was completely or partially prevented by organoselenium compounds. Ebselen exhibited thiol peroxidase activity in our assay conditions, while SeCis exhibited thiol-oxidizing properties regardless of the presence of peroxide. AASe had no effect on thiol oxidation. Results suggest that organoselenium compounds could not prevent mercury toxicity in vivo. The protective effect of these compounds against mercury-induced increase of TBARS production in vitro is probably related to an antioxidant action rather than to mercury binding. [Copyright &y& Elsevier]

Background/Aims: We explored the involvement of cell types, cytokines and lipid peroxidation in a rat dietary model of fibrosing steatohepatitis.Methods: Male rats were fed a high fat diet deficient in methionine and choline (MCD) for up to 17 weeks. Whole liver, hepatocytes and non-parenchymal cells were analysed for reduced glutathione (GSH) levels, products of lipid peroxidation (thiobarbituric acid reactive substances, TBARS), liver injury, and fibrosis.Results: MCD diet-fed rats developed hepatic steatosis at week 2 and focal necroinflammatory change by week 5, while pericellular fibrosis evolved and progressed between weeks 12 and 17. Collagen α1(1) gene expression was upregulated by week 5 and increased fivefold by week 17. Stellate cells were the unique source of collagen gene expression. TIMP-1 and -2 were increased at week 12. Livers of MCD diet-fed rats exhibited lowered levels of GSH and elevated TBARS. Hepatocytes were the source of lipid peroxidation, and mRNA levels for TGFβ1 were increased only in this cell type.Conclusions: The MCD model of ‘fibrosing steatohepatitis’ replicates the histologic features of human steatohepatitis, and the sequence of steatosis, inflammatory cell injury and fibrogenesis. The temporal sequence is consistent with a concept for involvement of oxidative injury in inflammatory recruitment and pathogenesis of hepatic fibrogenesis. [Copyright &y& Elsevier]

Inhibiting aggregation and deposition of amyloid β-peptide (Aβ) in brain is a therapeutic strategy for Alzheimer’s disease (AD). A Congo-red-like molecule, X-34, is reported to bind to Aβ deposits. Oxidative stress associated with Aβ is hypothesized to be critical for the neurotoxic properties of this peptide. The present study was undertaken to test the hypothesis that X-34, with its salicylate groups, would act as an antioxidant. When challenged by hydroxyl or peroxyl free radicals or Aβ(1–42), oxidative stress and neurotoxicity occurred in neural systems as assessed by several indices. However, pretreatment of synaptosomes and primary neuronal cell culture with X-34 greatly ameliorated lipid peroxidation induced by these free radicals and Aβ(1–42). Protein oxidation was not prevented by X-34. These results are discussed in terms of potential therapeutic use of X-34 and related compounds in AD. [Copyright &y& Elsevier]

Free iron is capable of stimulating the production of free radicals which cause oxidative damage such as lipid peroxidation. One of the most important mechanisms of antioxidant defense is thus the sequestration of iron in a redox-inactive form by transferrin. In diabetes mellitus, increased oxidative stress and lipid peroxidation contribute to chronic complications but it is not known if this is related to abnormalities in transferrin function. In this study we investigated the role of transferrin concentration and glycation. The antioxidant capacity of apotransferrin to inhibit lipid peroxidation by iron-binding decreased in a concentration-dependent manner from 89% at ≥2 mg/ml to 42% at 0.5 mg/ml. Pre-incubation of apotransferrin with glucose for 14 days resulted in a concentration-dependent increase of glycation: 1, 5 and 13 μmol fructosamine/g transferrin at 0, 5.6 and 33.3 mmol/l glucose respectively, p <0.001. This was accompanied by a decrease in the iron-binding antioxidant capacity of apotransferrin. In contrast, transferrin glycation by up to 33.3 mmol/l glucose did not affect chemiluminescence-quenching antioxidant capacity, which is iron-independent. Colorimetric evaluation of total iron binding capacity in the presence of an excess of iron (iron/transferrin molar ratio=2.4) also decreased from 0.726 to 0.696 and 0.585 mg/g transferrin after 0, 5.6 and 33.3 mmol/l glucose, respectively, p <0.01. In conclusion, these results suggest that lower transferrin concentration and its glycation can, by enhancing the pro-oxidant effects of iron, contribute to the increased lipid peroxidation observed in diabetes. [ABSTRACT FROM AUTHOR]

In this study we show that micromolar Ca2+ concentrations (>10 μM) strongly stimulate the release of reactive oxygen species (ROS) in rotenone-treated isolated rat forebrain mitochondria. Ca2+-stimulated mitochondrial ROS release was associated with membrane lipid peroxidation and was directly correlated with the degree of complex I inhibition by rotenone. On the other hand, Ca2+ did not increase mitochondrial ROS release in the presence of the complex I inhibitor 1-methyl-4-phenylpyridinium. Cyclosporin A had no effect on Ca2+-stimulated mitochondrial ROS release in the presence of rotenone, indicating that mitochondrial permeability transition is not involved in this process. We hypothesized that Ca2+-induced mitochondrial oxidative stress associated with partial inhibition of complex I may be an important factor in neuronal cell death observed in the neurodegenerative disorder Parkinson’s disease. [Copyright &y& Elsevier]

Here we show that homocysteine stimulates low density lipoprotein (LDL) oxidation at copper(II) concentrations causing only a slight oxidation of LDL lipids. LDL oxidation by homocysteine and copper(II) is further enhanced in the presence of cystine, although cystine alone does not stimulate LDL oxidation with copper(II). Similarly, a combination of cysteine with homocysteine provoked a more than additive increase of oxidation. Simultaneous presence of cysteine and homocystine also resulted in a more than additive oxidative effect which was not statistically significant, however. Stimulation of LDL oxidation in the presence of homocysteine by cystine was also observed with iron(III) at acidic pH and when LDL oxidation was initiated by azo-compound generated peroxyl radicals. At pH 7.4 histidine is able to prevent LDL oxidation by copper(II) in a thiol mixture similar to the one found in human plasma if present in tenfold excess over homocysteine, but loses its inhibitory effect at higher homocysteine concentrations. The synergistic effect on metal-catalyzed LDL oxidation observed with mixtures of homocysteine and cystine or cysteine sustains the hypothesis that the epidemiological association between raised homocysteine levels and risk of cardiovascular disease is caused by an increase in oxidative stress. [Copyright &y& Elsevier]

Changes in the activities of antioxidant enzymes superoxide dismutase, catalase (CAT), glutathione peroxidase and heme oxygenase (HO) and changes in lipid peroxidation and reduced glutathione (GSH) levels were measured in the livers of control and Lewis lung carcinoma (LLC)-bearing mice 24 h after a single injection of cisplatin or CoCl2. Treatment with cisplatin induced the same degree of lipid peroxidation and GSH depletion as did CoCl2 but the antioxidant enzymes were differently involved in cisplatin- and cobalt-induced oxidative stress responses. In cobalt-treated mice the activities of these enzymes were either inhibited or not changed significantly and only the HO activity was increased (5-fold) as a main protective enzyme. In cisplatin-treated animals the antioxidant enzymes were activated but the enhancement of HO and CAT was greater in LLC-inoculated mice. It is suggested that these two enzymes represent the protective response against cisplatin toxicity in the livers of tumor-bearing animals. [Copyright &y& Elsevier]

The effects of sulfur dioxide (SO2) on levels of thiobarbituric acid reactive substances (TBARS), levels of reduced glutathione(GSH) and the activities of Cu,Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were investigated in brains and livers of Kunming albino mice of both sexes. SO2 at different concentrations (22, 56 and 112 mg/m3) was administered to animals of SO2 groups in different exposure chambers for 6 h/day for 7 days, while control groups were exposed to filtered air in the same condition. Our results show that SO2 caused lipid peroxidation and changes of antioxidative status in brains and livers of mice. Exposure to SO2 at all concentrations tested caused significantly the increase of TRARS levels in brains and livers of mice. For the brains, activities of these antioxidant enzymes and levels of GSH were significantly unaltered by SO2 at low concentrations, except significant increase of GSH levels in the brains of male mice; however, SO2 at higher concentrations caused significantly decreases of GSH levels and activities of these antioxidant enzymes. For livers, SO2 at all concentrations tested decreased significantly activities of SOD relative to control animals; SO2 tended to decrease activities of GPx and CAT, but only the decreases of GPx and CAT activities caused by SO2 exposures of higher concentrations (56 and 112 mg/m3) were statistically significant. SO2 also tended to decrease levels of GSH, but only at 112 mg/m3 caused significantly decrease of GSH levels in livers of both sexual mice. Unexpectedly, the decreases of activities of these antioxidative enzymes caused by SO2 at different concentrations in brains and livers of mice did not follow a linear dose–response curves. In many respects, the decreased percentages of the activities of each antioxidative enzyme (SOD or GPx or CAT) caused by SO2 at 22, 56 and 112 mg/m3 in brains and livers of mice were similar. These results lead to conclusion that SO2 exposure can caused oxidative damage to brains and livers of mice, and SO2 is a toxin to brain and liver of mammals, not only to respiratory system. Further work is required to understand toxicological role of SO2 on multiply or even all organs in human and animal. [Copyright &y& Elsevier]

Elevated levels of reactive α,β-unsaturated aldehydes (e.g. malondialdehyde, 4-hydroxynonenal and acrolein) in the affected tissues of various degenerative conditions suggest these substances are active propagators of the disease process. One experimental approach to attenuating damage by these intermediates employs ‘aldehyde-sequestering drugs’ as sacrificial nucleophiles, thereby sparing cell macromolecules and perhaps slowing disease progression. Drugs with demonstrated trapping activity toward lipid-derived aldehydes include various amine compounds such as aminoguanidine, carnosine and pyridoxamine. We have focused on identifying scavengers of acrolein, perhaps the most toxic aldehyde formed during lipid peroxidation cascades. Various phthalazine compounds (hydralazine and dihydralazine) were found to trap acrolein readily, forming hydrazone derivatives in a rapid Schiff-type reaction. These compounds strongly protect against acrolein-mediated toxicity in isolated hepatocytes. [Copyright &y& Elsevier]

Age- and sex-associated differences in lipid peroxidation (LPO), and total sialic acid content (TSA) in response to abuse of drugs have been reported both in humans and experimental animals. However, no data on the influence of gender and age on these parameters have been reported for methionine-enkephalin (MENK). In this study we examined the influence of age and gender on MENK-induced LPO levels in the liver and TSA content in splenocytes of CBA mice. LPO production, which was age- and gender-associated was differentially regulated by MENK at a dose of 10 mg or 2.5 mg/kg body weight. At the higher dose, MENK stimulated LPO production in younger males and females but suppressed only in older male mice. At the lower dose, MENK induced strong suppression in males while being without any effect in females. In TSA levels, the age-associated increase was greater in males and much lower in females, with higher TSA levels in younger (2.5, 4.5 months) and decreased levels in older female mice (9 months) being observed. Contrary to the effect on LPO level, TSA level in MENK-treated mice was suppressed in both sexes but only in young 2.5-month-old mice. These data provide evidence that some immunomodulatory properties of MENK are age- and gender-associated which may be relevant to the potential use of MENK as adjuvant therapy in patients with immunocompromised status. [Copyright &y& Elsevier]

Effect of long term soil salinity was studied in wheat cvs, Kharchia 65 (tolerant) and KRL 19 (moderately tolerant) under control and two levels of salinity (ECe=5.4 and 10.6 dS m−1). Salinity stress decreased relative water content (RWC), chlorophyll (CHL), carotenoids (CAR), membrane stability index (MSI), biomass and grain yield, and increased hydrogen peroxide (H2O2), thiobarbituric acid reactive substances (TBARS), proline, glycine-betaine (GB), soluble sugars, superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) activity in both the genotypes and at all the stages. Salinity induced decrease in RWC, CHL, CAR, MSI, biomass and grain yield were significantly higher in KRL 19 than more tolerant Kharchia 65. Kharchia 65 recorded higher activity of SOD, CAT, GR, as well as contents of proline, soluble sugar, GB and K, and comparatively lower H2O2 and TBARS contents compared with KRL 19. KRL 19 also showed higher Na and Na/K ratio. Results show that salinity tolerance of Kharchia 65 as manifested by lower decrease in biomass and grain yield is associated with higher antioxidant activity, osmolyte concentration and potassium contents, and lower H2O2, TBARS and sodium contents than KRL 19. [Copyright &y& Elsevier]

Oxidative modifications of low density lipoprotein (LDL) convert LDL into a ligand recognized by a variety of scavenger receptors (SR) in mammals. This oxidized LDL (oxLDL) activate several cell types, and have been shown to induce expression of a variety of genes in mammals. Lipoproteins of poikilothermic animals like salmonid fishes contain high levels of polyunsaturated fatty acids susceptible to oxidative modifications. We have investigated, and found trout LDL to be susceptible to oxidation in the presence of Cu2+. When oxidized or acetylated trout LDL was injected intravenously, the clearance rate was increased compared to that of native LDL. Modified LDL was taken up almost exclusively in the kidney, whereas native LDL was also taken up in the liver. Uptake of both oxLDL and acetylated LDL in the kidney was significantly inhibited by lipoteichoic acid (LTA) and formaldehyde treated BSA (fBSA), both of which are known ligands of SR. [Copyright &y& Elsevier]

Oxidative modification of lipids, proteins and DNA by reactive oxygen species in the organism and imbalance between the concentrations of free radicals and the antioxidant defenses may be related to processes such as aging and diseases (cardiovascular, neurodegenerative, cancer, etc.). Although the relationship between oxidant status and antioxidant defence in aging of different species, organs or sexes has been investigated extensively, the studies have produced conflicting results. In order to determine the extent of age-associated alteration, oxidant production and antioxidant status were measured in tissues of CBA and AKR mice of both sexes. At the same time we will focus on lipid peroxidation (LPO) process and superoxide dismutase activity (SOD) of AKR mice related to ontogeny of thymic lymphoma in mice of different age and sex. Male and female CBA and AKR mice aged 3, 6, 12 or 18 months were used. Lipid-bound sialic acid (LSA) content was determined as a malignancy marker. LPO processes of CBA and AKR mice were monitored according to the presence of thiobarbituric acid reactive substances (TBARS) in liver and thymus, and antioxidant status as SOD activity in whole blood. TBARS concentration increased significantly with age in the liver of CBA and AKR mice of both sexes, but only in male thymuses of both strains. TBARS concentration in female thymuses of both strains was unchanged during aging. Thus, age-associated LPO processes of tumor-free mice of both strains were tissue-dependent. In the liver of tumor-bearing CBA and AKR mice as well as in thymuses of AKR mice, TBARS concentration significantly decreased and was neither sex nor tissue related. SOD activity was strain-dependent but independent of sex. However, SOD activity in mice with developed thymomas was drastically reduced in comparison to tumor-free mice. Our data indicate that age associated LPO processes in both strains are only tissue-dependent and SOD activity mainly strain-dependent in tumor-free mice. In tumor-bearing mice LPO processes and SOD activity were not tissue, sex or strain dependent. [Copyright &y& Elsevier]

Effects of long term, medium level (electrical conductivity of extract (ECe)=6.85 dS m−1) sodium chloride (NaCl) salinity were studied in tolerant (Kharchia 65) and susceptible (HD 2687) wheat genotypes. NaCl salinity caused decrease in relative water content (RWC), chlorophyll (CHL), membrane stability index (MSI) and ascorbic acid (AA) content, and increased the contents of hydrogen peroxide (H2O2), thiobarbituric acid reactive substances (TBARS) (measure of lipid peroxidation) and activities of superoxide dismutase (SOD), its various isozymes, ascorbate peroxidase (APOX) and glutathione reductase (GR) in wheat genotypes Kharchia 65 (tolerant) and HD 2687 (susceptible). Salinity tolerant wheat cv. Kharchia 65 showed less decline in RWC, CHL, MSI estimated in whole tissue than salt sensitive HD 2687. Kharchia 65 also exhibited less decrease in AA content, less increase in H2O2, TBARS contents and higher increase in SOD and its isozymes, APOX and GR in all sub-cellular fractions than salt sensitive HD 2687. H2O2, TBARS contents and AA contents were higher in chloroplastic fraction. Chloroplastic fraction showed higher total SOD, APOX and GR activity, followed by mitochondrial fraction in case of total SOD and GR, while cytosolic fraction was in second place in case of APOX activity. Though Mn–SOD activity was highest in mitochondrial fraction, but residual activity was also observed in cytosolic fraction. Cu/Zn–SOD and Fe–SOD were observed in all the sub-cellular fractions, however, the activities were higher in chloroplastic fraction for both the isoforms. Total Cu/Zn–SOD activity, sum of activity observed in all the fractions, was higher than other SOD isoforms. Susceptibility of HD 2687 to long-term salinity stress seems to be due to relatively less induction of SOD isozymes, no induction in chloroplastic and mitochondrial APOX and cytosolic GR and decrease in chloroplastic GR under salt stress resulting in higher oxidative stress in the form of H2O2 and TBARS contents and decrease in MSI and CHL. [Copyright &y& Elsevier]

The behavior of the antioxidant defense system was studied in sunflower cotyledons subjected to ultraviolet-B (UV-B) radiation. The two doses assayed (15.0 and 30.0 kJ m−2) induced oxidative damage, as evidenced by an increase in lipid peroxidation and a decrease in both chlorophyll content and superoxide dismutase activity. However, the reduced glutathione/oxidized glutathione ratio was significantly increased and ascorbate/dehydroascorbate ratio was not affected by UV-B treatments. In addition, the activity of the antioxidant enzymes catalase, glutathione dehydrogenase and guaiacol peroxidase were increased at the two doses of UV-B radiation used, while ascorbate peroxidase and glutathione reductase activities were not altered under the two irradiation treatments. These results suggest that UV-B radiation undoubtedly induces antioxidant defense system in sunflower cotyledons, allowing plant survival in spite of the oxidative stress generation. However, more research is necessary to elucidate the precise role that the antioxidant system plays under UV-B stress. [Copyright &y& Elsevier]

Rat liver microsomal suspension (1 mg protein per ml) was incubated at 37 °C with 5 mM salicylic acid and 0.2 mM NADPH. The amounts of thiobarbituric acid reactive substances (TBARS) and 2,5-dihydroxybenzoic acid (2,5-DHB), an oxidative metabolite of salicylic acid increased with the incubation time. Simultaneously spontaneous chemiluminescence (CL) was found to be generated there. The addition of SKF-525A, an inhibitor of cytochrome P450 (P450), to the reaction mixture inhibited the CL generation together with the inhibition of the oxidative metabolism. The anti-oxidants and singlet oxygen scavengers like N,N-diphenylphenylenediamine (DPPD) and histidine suppressed the CL generation. The addition of 1,4-diazabicyclo [2.2.2] octane (DABCO), a singlet oxygen quencher, to the reaction mixture generating CL enhanced CL transiently and then CL decreased markedly. Thus CL observed here may possibly originate from the singlet oxygen. The CL generation was suggested to be closely related with salicylic acid-induced lipid peroxidation, and to be coupled with the oxidative metabolism mediated by P450 in rat liver microsomes. [Copyright &y& Elsevier]

Hypercholesterolemia impairs endothelial function. However, the production/release of nitric oxide from the hypercholesterolemic aorta is reported to be enhanced rather than impaired in animal studies. l-arginine improves endothelial function in hypercholesterolemic subjects. The goal of the present study was to investigate the effects of l-arginine on endothelial function and oxidative stress in hypercholesterolemic subjects. In 17 hypercholesterolemic male subjects (mean age 41.7 years, mean total cholesterol 264.3±5.9 mg/dl) and 17 age-matched healthy men as controls (mean total cholesterol 187.1±6.8 mg/dl), we measured flow-mediated endothelium-dependent vasodilation of the brachial artery during saline infusion and after saline plus l-arginine infusion (30 g for 1 h) with ultrasound technique. In addition, we measured the levels of thiobarbituric acid reactive substances (TBARS), as a marker of lipid peroxide. The flow-mediated vasodilation was lower and the TBARS concentration was higher in the hypercholesterolemic group than in the control group during the saline infusion. The addition of l-arginine increased flow-mediated vasodilation and decreased TBARS concentration in the hypercholesterolemic group (from 3.92±0.58 to 7.27±0.53% [P<0.01 by analysis of variance (ANOVA)], from 7.74±0.46 to 5.71±0.35 nmol/ml [P<0.01 by ANOVA], respectively), but not in the control group (from 7.74±0.40 to 8.21±0.47%, from 5.45±0.43 to 4.83±0.35 nmol/ml, respectively). The endothelial function is blunted, and the oxidative stress is increased in hypercholesterolemic subjects. l-arginine improves endothelial function with decreasing oxidative stress. The augmentation of nitric oxide production/release induced by l-arginine may act as an antioxidant, and contributes to the improvement of endothelial function in hypercholesterolemic subjects. [Copyright &y& Elsevier]

Interactions of 27 steroids, among them 17 derivatives such as ethers, sulfates and amidosulfonates derived from 17β- and 17α-estradiol, from testosterone and α- and β-dihydrotesosterone and from dehydroepiandrosterone with rat liver microsomal cytochromes P450 (P450) were investigated in vitro by assessing binding to P450 and effects on P450 mediated monooxygenase functions as measured by different model reactions: ethoxyresorufin O-deethylation (EROD), ethoxycoumarin O-deethylation (ECOD) and ethylmorphine N-demethylation (EMND). With the exception of 17α-estradiol-3-dimethylamidosulfonate, estrone, its -3-methylether and -3-amidosulfonate and testosterone, all other steroids displayed type I or reverse type I binding to P450. All steroids inhibited EROD activity in micromolar concentrations. An additional strong inhibition of ECOD and EMND activities was only demonstrated for the androgens and progestins. Estriol, estrone and mestranol displayed less inhibitory actions on the model reactions than estradiol. No major differences in comparison to the parent compounds were noted with the other derivatives. The only exceptions were 17β-(8,9-dehydro-14α,15α-methylene)estradiol, which displayed stronger effects than estradiol, and dehydroepiandrosterone-3-sulfate, which was less effective than dehydroepiandrosterone. Possible antioxidant properties of the steroids were examined by the stimulated lipid peroxidation (LPO), H2O2 production, and lucigenin (LC) and luminol (LM) amplified chemiluminescence (CL) using rat liver microsomes. Additionally, the influence on rat whole blood chemiluminescence (WB-CL) was assessed. All the estrogens, but not their methylethers and amidosulfonates inhibited LPO in micromolar concentrations. The effects on the other oxidase model reactions or on WB-CL were less distinct. Only ethinylestradiol and 17β-(8,9-dehydro-14α,15α-methylene)estradiol displayed a strong inhibitory action on all model reactions. With the exception of dehydroepiandrosterone-3-sulfate, which in general had only weak effects, the androgen and progestin derivatives, in contrast, strongly decreased H2O2 formation and LM- and LC-CL, but were mostly ineffective on LPO and WB-CL. [Copyright &y& Elsevier]

Changes in the activity of so-called oxidative stress defensive enzymes, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and heme oxygenase, as well as changes in lipid peroxidation and reduced glutathione levels, were measured in guinea pig and rat liver after acute cobalt loading. Cobalt chloride administration produced a much higher degree of lipid peroxidation in guinea pig than in rat liver compared with the control animals. The intrahepatic reduced glutathione content in control guinea pig was higher than that in rat, but was equally decreased in both species after cobalt administration. The enzymatic scavengers of free radicals, superoxide dismutase, catalase and glutathione peroxidase, were significantly decreased in rat liver after acute cobalt loading, and as a compensatory reaction, the heme oxygenase activity was increased (seven-fold). In guinea pig liver, only superoxide dismutase activity was depleted in response to cobalt-induced oxidative stress, while catalase and glutathione peroxidase were highly activated and the heme oxygenase activity was dramatically increased (13-fold). It is assumed that enhanced heme oxygenase activity may have important antioxidant significance by increasing the liver oxidative-stress defense capacity. [Copyright &y& Elsevier]

Significance: Electronic cigarettes (e-cigarettes) have become a popular way to smoke all over the world. Chronic exposure to e-cigarette aerosol may influence lung health. This study uses an animal model to explore the time course of the effect of exposure to e-cigarette aerosols on the lung., Methods: Lung samples were collected after exposure of Balb/c mice to e-cigarette aerosols for 1 h/day (6 times/week) for 1, 2 and 4 weeks and compared to sham-exposed controls. Examined biomarkers including inflammatory cells, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD), and Thiobarbituric acid reactive substances (TBARS)., Results: Exposure of animals to e-cigarette aerosols induced significant increases (P < 0.05) in total inflammatory cells, eosinophils, macrophages and TNFα in the lung tissue after 1, 2 and 4 weeks of exposure. Furthermore, level of IL-10 significantly decreased, whereas levels of neutrophils and basophils significantly increased (P < 0.05) after 1 week of exposure. Exposure of animals to e-cigarette aerosol also induced significant decreases (P < 0.05) in the GSH/GSSG ratio, and GPx levels after 2 and 4 weeks of exposures. The activity of catalase was also reduced (P < 0.05) after 4 weeks of exposure. Level of TBARS showed a trend of elevation with time and it reached a significant elevation after 4 weeks (P < 0.01)., Conclusion: Current results indicate that inhalation of unflavored e-cigarette aerosol might be associated with inflammation in lung tissue that worsen as the duration of exposure increases. Further experiments including more time points, histopathology and pulmonary physiology experiments are needed to confirm the current results., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Eissenberg and Shihadeh are paid consultants in litigation against the tobacco industry and also the electronic cigarette industry and are named on one patent for a device that measures the puffing behavior of electronic cigarette users. Dr. Eissenberg is also named on another patent application for a smartphone app that determines electronic cigarette device and liquid characteristics, and a third patent application for a smoking cessation intervention. Other authors have no conflict of interest., (© 2022 The Authors.)