Lipid Peroxide Formation Research Articles

Synergistic effect of folic acid and galantamine against experimentally induced oxidative stress in IMR 32 cells

Galantamine is an active constituent obtained from Galanthus nivalis L., a traditional herb known for its pharmacological properties, particularly nootropic effect. Folic acid is a dietary supplement that enhances neuronal activity. Effect of galantamine and folic acid on human neuronal cells is well known. In the present study, we explored the protective effect of galantamine and folic acid, both independently as well as in combination, over antioxidant defence system and nootropic effects on human neuroblastoma cells IMR-32. The treatment galantamine, folic acid and their combination was given for 24 h and cytotoxicity study was carried out by trypan blue dye exclusion assay. Apoptosis and necrosis were observed using Propidium iodide (PI) and Hoechst double staining method. Biochemical assays viz. total protein, protein carbonyl, lipid peroxidation and glutathione were analyzed along with super oxide dismutase and catalase. Result of cytotoxicity showed dose dependent increase in percent viability and significant decrease was observed in apoptosis and necrosis. Moreover, exposure to Galantamine, Folic acid and their combination significantly decreased lipid peroxidation and protein carbonyl formation along with the enhancement in antioxidant defence mechanism. Findings of these dose reliant toxicity study of Galantamine , Folic acid and their combination suggest that these has higher potency when given together and shows synergistic effect. They also causes repair of human neuronal cells IMR-32 cells enhancing the cell viability and consumption of Galantamine and Folic acid together will help in prevention of CNS disorders and neurodegeneration.

Comparative Toxic Effect of Bulk Copper Oxide (CuO) and CuO Nanoparticles on Human Red Blood Cells.

Destruction of red blood cell is associated with anemia and other pathological status; hence, the hemolytic effects of all chemicals and particles which come into contact with blood components must be considered. Nanomaterials and nanoparticles are potential substitutes for common material and particles, and assessment of their effect on blood components is a necessary part of their safety evaluation. High surface-to-volume ratio of nanoparticles may cause their toxic effects differ from those observed for bulk material. The aim of this study was to compare the hemolytic effects of CuO nanoparticles and bulk CuO. Red blood cells were isolated from blood of healthy subjects and hemolytic effects assayed following treatment of cells with 0.005-0.25mM of CuO (bulk and nanoparticles) for 6h. For assessment of other parameters, cells were incubated with 0.01, 0.05, and 0.25mM of CuO nanoparticles and bulk CuO for 1, 2, and 3h. Our results demonstrate that CuO nanoparticles, in particular, caused toxic hemolytic effects in concentration-dependent manner, and this effect maybe through formation of ROS, glutathione depletion, and lipid peroxidation. In conclusion, CuO nanoparticles are shown to effectively destruct human red blood cells in comparison to bulk CuO.

5-Aminolevulinic Acid and 24-Epibrassinolide Improve the Drought Stress Resilience and Productivity of Banana Plants.

Plant growth, development, and productivity are adversely affected under drought conditions. Previous findings indicated that 5-aminolevulinic acid (ALA) and 24-epibrassinolide (EBL) play an important role in the plant response to adverse environmental conditions. This study demonstrated the role of ALA and EBL on oxidative stress and photosynthetic capacity of drought-stressed ‘Williams’ banana grown under the Egyptian semi-arid conditions. Exogenous application of either ALA or EBL at concentrations of 15, 30, and 45 mg·L−1 significantly restored plant photosynthetic activity and increased productivity under reduced irrigation; this was equivalent to 75% of the plant’s total water requirements. Both compounds significantly reduced drought-induced oxidative damages by increasing antioxidant enzyme activities (superoxide dismutase ‘SOD’, catalase ‘CAT’, and peroxidase ‘POD’) and preserving chloroplast structure. Lipid peroxidation, electrolyte loss and free non-radical H2O2 formation in the chloroplast were noticeably reduced compared to the control, but chlorophyll content and photosynthetic oxygen evolution were increased. Nutrient uptake, auxin and cytokinin levels were also improved with the reduced abscisic acid levels. The results indicated that ALA and EBL could reduce the accumulation of reactive oxygen species and maintain the stability of the chloroplast membrane structure under drought stress. This study suggests that the use of ALA or EBL at 30 mg·L−1 can promote the growth, productivity and fruit quality of drought-stressed banana plants.

Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity and Promote Programmed Cell Death.

The nanocatalytic activity of nanozymes provides a vision for tumor treatment. However, the glutathione (GSH)-related antioxidant defense system (ADS) formed on the basis of excessive GSH in the tumor microenvironment limits its catalytic activity. Here, dendritic mesoporous silica nanoparticles (DMSNs) were employed as nanocarrier; ultrasmall Fe3O4 nanoparticles, Mn2+ ions, and glutaminase inhibitor Telaglenastat (CB-839) were subsequently integrated into large mesopores of DMSNs, forming DMSN/Fe3O4-Mn@CB-839 (DFMC) nanomedicine. This nanomedicine exhibits peroxidase mimicking activities under acidic conditions, which catalyzes the decomposition of hydrogen peroxide (H2O2) into hydroxyl radical (•OH). This also promotes the formation of lipid peroxides, which is required for ferroptosis. Furthermore, this nanomedicine can effectively deplete the existing GSH, thereby enhancing reactive oxygen species (ROS)-mediated tumor catalytic therapy. Moreover, the introduced CB-839 blocks the endogenous synthesis of GSH, further enhancing GSH depletion performance, which reduces the excretion of oxaliplatin (GSH-related resistance) from tumor cells, thereby restoring the chemical sensitivity of oxaliplatin. The dual GSH depletion property significantly weakens the GSH-related ADS and restores the chemical sensitivity of oxaliplatin, leading to the high DFMC-induced apoptosis and ferroptosis of tumor cells. Our developed nanomedicine based on integrated nanotechnology and clinical drug may aid the development of tumor treatment.

Protective Effect of GIP against Monosodium Glutamate-Induced Ferroptosis in Mouse Hippocampal HT-22 Cells through the MAPK Signaling Pathway

The effect of glucose-dependent insulinotropic polypeptide (GIP) on cells under oxidative stress induced by glutamate, a neurotransmitter, and the underlying molecular mechanisms were assessed in the present study. We found that in the pre-treatment of HT-22 cells with glutamate in a dose-dependent manner, intracellular ROS were excessively generated, and additional cell damage occurred in the form of lipid peroxidation. The neurotoxicity caused by excessive glutamate was found to be ferroptosis and not apoptosis. Other factors (GPx-4, Nrf2, Nox1 and Hspb1) involved in ferroptosis were also identified. In other words, it was confirmed that GIP increased the activity of sub-signalling molecules in the process of suppressing ferroptosis as an antioxidant and maintained a stable cell cycle even under glutamate-induced neurotoxicity. At the same time, in HT-22 cells exposed to ferroptosis as a result of excessive glutamate accumulation, GIP sustained cell viability by activating the mitogen-activated protein kinase (MAPK) signalling pathway. These results suggest that the overexpression of the GIP gene increases cell viability by regulating mechanisms related to cytotoxicity and reactive oxygen species production in hippocampal neuronal cell lines.

Oxidative stress-mediated inflammation promotes the pathogenesis of amyotrophic lateral sclerosis

Neuroinflammation in amyotrophic lateral sclerosis (ALS) is characterized by activation of monocytes/macrophages and T lymphocytes in the periphery and microglia and astrocytes within the central nervous system. This review emphasizes the role of oxidative stress in promoting systemic inflammation and the early stages of neurodegeneration. Motor axon terminals of ALS patients have significantly increased intraluminal calcium and dysfunctional mitochondria, increasing the formation of lipid peroxides and ferroptosis programmed cell death. Serum lipid peroxides and acute phase proteins are elevated, and regulatory T lymphocytes (Tregs) are dysfunctional, impairing immune-mediated neuroprotection. Macrophages are pro-inflammatory; the expression of genes involved in inflammation is increased in peripheral monocytes/macrophages of ALS patients. Suppressing these multiple components of inflammation is an important therapeutic goal and provides an opportunity to interrupt the self-propagating cytotoxic cycle. Two clinical trials with autologous infusions of ex vivo expanded Tregs have been safe and well tolerated, with promising clinical results associated with suppression of pro-inflammatory lipid peroxides.

Non-suicidal intentional ingestion of iron tablets and severe intoxication: the result of adolescent boy’s impulsive risky behaviour in the school

Acute iron poisoning is a potentially fatal intoxication in children. As the Iron preparations are commonly administered to pregnant women, lactating mothers, toddlers, it is easily available at home. So younger children are prone to consume it accidently. Although iron is a therapeutic drug in recommended dosages, excessive iron in the free state can produce toxicity by affecting multiple cellular processes by catalysing redox reactions with lipid peroxidation and free radical formation. The severity of intoxication depends on the amount of elemental iron ingested. Serious toxicity is usually associated with a dose of >40 mg/kg of elemental iron. Levels more than 100 mg/kg are almost always fatal. We report a case where a 12-year male child intentionally taken 60 tablets of iron (ferrous fumarate) at his school as a part of competition or bet to other schoolmate and presented with acute iron poisoning with hepatic encephalopathy to us. Important initial laboratory parameters were AST-4,879 U/L, Prothrombin time-60 sec and Iron level-213 microgram/dl. With timely specific management i.e., deferoxamine infusion along with all required intensive care supportive management in PICU the patient was discharged successfully. We chose to report this case to highlight the risky behaviour of adolescence who usually grows physically and emotionally earlier but their prefrontal lobes are yet immature to take proper and correct decision. Thus, impulse activity may prove fatal for them.

Ferroptosis as a Major Factor and Therapeutic Target for Neuroinflammation in Parkinson's Disease.

Mounting evidence suggests that ferroptosis is not just a consequence but also a fundamental contributor to the development and progression of Parkinson’s disease (PD). Ferroptosis is characterized as iron-dependent regulated cell death caused by excessive lipid peroxidation, leading to plasma membrane rupture, release of damage-associated molecular patterns, and neuroinflammation. Due to the crucial role of intracellular iron in mediating the production of reactive oxygen species and the formation of lipid peroxides, ferroptosis is intimately controlled by regulators involved in many aspects of iron metabolism, including iron uptake, storage and export, and by pathways constituting the antioxidant systems. Translational and transcriptional regulation of iron homeostasis and redox status provide an integrated network to determine the sensitivity of ferroptosis. We herein review recent advances related to ferroptosis, ranging from fundamental mechanistic discoveries and cutting-edge preclinical animal studies, to clinical trials in PD and the regulation of neuroinflammation via ferroptosis pathways. Elucidating the roles of ferroptosis in the survival of dopaminergic neurons and microglial activity can enhance our understanding of the pathogenesis of PD and provide opportunities for the development of novel prevention and treatment strategies.

Antitumor and Antioxidant Activity of S-Methyl Methionine Sulfonium Chloride against Liver Cancer Induced in Wistar Albino Rats by Diethyl Nitrosamine and Carbon Tertrachloride

Liver disease, especially liver cancer, has become a threat facing the world. Now, antioxidant products are garnering great attention for the treatment and prevention of many diseases. S-Methyl methionine sulfonium chloride (MMSC) is a methionine derivative and is present in many vegetables and has anti-inflammatory effects and antioxidants. This is the first study aiming to investigate the antitumor activity of the MMSC. This study was carried out on 60 male Wistar albino rats (4–6 weeks old age) and divided into four groups, with the first group as normal control, second group as hepatocarcinoma induced by diethyl nitrosamine and carbon tetrachloride (DEN/CCL4) group, third group as normal rats treated with MMSC, and fourth group as hepatocellular carcinoma (HCC) induced rats treated with MMSC. Our findings revealed that MMSC administration after HCC induction significantly improved (p < 0.05) the liver function biomarkers, including AST, GGT, albumin, globulin, and albumin/globulin ratio (A/G), in comparison with those in the HCC group. Moreover, the histopathological changes of the liver tissue in the HCC group were improved by MMSC treatment. Likewise, the expression levels of tumor necrosis factor-alpha (TNF-α), induced nitric oxide synthase (iNOS), transforming growth factor (TGF-1β), and glypican 3 (GP3) were downregulated by MMSC treatment after HCC induction in comparison with those in the HCC-induced group. In conclusion, MMSC showed antitumor activity against HCC induction by DEN/CCl4 through decreasing lipid peroxide formation, the expression level of an inflammatory cytokines such as (TNF-α), immunoregulatory cytokines such as (TGF-1β), induced nitric oxide synthase, and glypican 3.

Tat-p27 Ameliorates Neuronal Damage Reducing α-Synuclein and Inflammatory Responses in Motor Neurons After Spinal Cord Ischemia.

p27Kip1(p27) regulates the cell cycle by inhibiting G1 progression in cells. Several studies have shown conflicting results on the effects of p27 against cell death in various insults. In the present study, we examined the neuroprotective effects of p27 against H2O2-induced oxidative stress in NSC34 cells and against spinal cord ischemia-induced neuronal damage in rabbits. To promote delivery into NSC34 cells and motor neurons in the spinal cord, Tat-p27 fusion protein and its control protein (Control-p27) were synthesized with or without Tat peptide, respectively. Tat-p27, but not Control-27, was efficiently introduced into NSC34 cells in a concentration- and time-dependent manner, and the protein was detected in the cytoplasm. Tat-p27 showed neuroprotective effects against oxidative stress induced by H2O2 treatment and reduced the formation of reactive oxygen species, DNA fragmentation, and lipid peroxidation in NSC34 cells. Tat-p27, but not Control-p27, ameliorated ischemia-induced neurological deficits and cell damage in the rabbit spinal cord. In addition, Tat-p27 treatment reduced the expression of α-synuclein, activation of microglia, and release of pro-inflammatory cytokines such as interleukin-1β and tumor necrosis factor-α in the spinal cord. Taken together, these results suggest that Tat-p27 inhibits neuronal damage by decreasing oxidative stress, α-synuclein expression, and inflammatory responses after ischemia.

Towards Aldehydomics: Untargeted Trapping and Analysis of Reactive Diet-Related Carbonyl Compounds Formed in the Intestinal Lumen.

Lipid peroxidation and subsequent formation of toxic aldehydes, such as 4-hydroxynonenal, is known to be involved in numerous pathophysiological processes, possibly including the development of colorectal cancer. This work aimed at the development of an untargeted approach using high-performance liquid chromatography coupled with high-resolution mass spectrometry (HPLC–HRMS) for tracking aldehydes in both suspect screening and untargeted methods in fecal water, representing the aqueous environment of colon epithelial cells. This original approach is based on the introduction of a characteristic isotopic labeling by selective derivatization of the carbonyl function using a brominated reagent. Following a metabolomics workflow, the developed methodology was applied to the characterization of aldehyde compounds formed by lipid peroxidation in rats fed two different diets differentially prone to lipoperoxidation. Derivatized aldehydes were first selectively detected on the basis of their isotopic pattern, then annotated and finally identified by tandem mass spectrometry. This original approach allowed us to evidence the occurrence of expected aldehydes according to their fatty acid precursors in the diet, and to characterize other aldehydes differentiating the different diets.

Anti-pollution effects of two antioxidants and a chelator-Ex vivo electron spin resonance and in vivo cigarette smoke model assessments in human skin.

Skin damage arising from pollutants in gaseous and particulate matter forms is mainly mediated by oxidative stress. The pollutants directly or indirectly generate free radicals on and in the skin, leading, for example, to MMP up-regulation and damage of collagen fibers. Antioxidants and chelators are used in anti-pollution cosmetics to reduce the harmful effects of free radical generation. We investigated the efficacy of two antioxidants and one chelator in an anti-pollution cigarette smoke model. Free radical generation was measured directly after UV and cigarette smoke exposure ex vivo on pig skin (slaughterhouse waste), by use of Electron Spin Resonance (ESR). Effects of cigarette smoke were compared to those of Urban Dust (NIST-standard). ESR was also used to measure the copper chelation activity of the test products. Following cigarette smoke application in vivo, two markers of lipid peroxidation malondialdehyde (MDA), and squalene monohydroperoxide (SQOOH), were measured from swab solutions taken from the smoke-exposed skin sites. EDTA generated no effect and the non-chelator antioxidant Tocopherol only small antioxidant effects after exposed to cigarette smoke ex vivo as well as in vivo. Only the hydrophilic phenylethanoid H1 showed significant effects. A clear reduction of free radicals ex vivo and further a significant reduction of in vivo lipid peroxide formation was measured. The cigarette smoke model is an ideal method for in vivo assessment of anti-pollution efficacy of topical products with close relation to the real situation of subjects exposed to urban pollution. Further research is required to better understand the role of chelators in anti-pollution cosmetics.

Ferroptosis-Related Gene Signature Promotes Ovarian Cancer by Influencing Immune Infiltration and Invasion.

Ovarian cancer is a kind of gynecological malignancy with high mortality. Ferroptosis is a new type of iron-dependent cell death characterized by the formation of lipid peroxides and excessive accumulation of reactive oxygen species. Studies have shown that ferroptosis modulates tumor genesis, progression, and invasion, including ovarian cancer. Based on the mRNA expression data from TCGA, we construct a scoring system using consensus clustering analysis, univariate Cox regression analysis, and least absolute selection operator. Then, we systematically evaluate the relationship between score and clinical characteristics of ovarian cancer. The result from the prediction of biofunction pathways shows that score serves as an independent prognostic marker for ovarian cancer and affects tumor progression by modulating tumor metastasis. Moreover, immunocytes such as activated CD4 T cell, activated CD8 T cell, regulatory T cells, macrophage, and stromal cells, including adipocytes, epithelial cells, and fibroblast infiltrate more in the tumor microenvironment in a high-score group, indicating ferroptosis can also affect tumor immune landscape. Critically, four potentially sensitive drugs, including staurosporine, epothilone B, DMOG, and HG6-64-1 based on the scores, are predicted, and DMOG is recognized as a novel targeted drug for ovarian cancer. In general, we construct the scoring system based on ferroptosis-related genes that can predict the prognosis of ovarian cancer patients and propose that ferroptosis may affect ovarian cancer progression by mediating tumor metastasis and immune landscape. Novel drugs to target ovarian cancer are also predicted.

Physiological and molecular responses of flax (Linum usitatissimum L.) cultivars under a multicontaminated technosol amended with biochar.

Soil pollution is a worldwide issue and has a strong impact on ecosystems. Metal(loid)s have toxic effects on plants and affect various plant life traits. That is why metal(loid) polluted soils need to be remediated. As a remediation solution, phytoremediation, which uses plants to reduce the toxicity and risk of polluted soils, has been proposed. Moreover, flax (Linum usitatissimum L.) has been suggested as a potential phytoremediation plant, due to its antioxidant systems, which can lower the production of reactive oxygen species and can also chelate metal(loid)s. However, the high metal(loid) toxicity associated with the low fertility of the polluted soils render vegetation difficult to establish. Therefore, amendments, such as biochar, need to be applied to improve soil conditions and immobilize metal(loid)s. Here, we analyzed the growth parameters and oxidative stress biomarkers (ROS production, membrane lipid peroxidation, protein carbonylation and 8-oxoGuanine formation) of five different flax cultivars when grown on a real contaminated soil condition, and in the presence of a biochar amendment. Significant correlations were observed between plant growth, tolerance to oxidative stress, and reprogramming of phytochemical accumulation. A clear genotype-dependent response to metal(loid) stress was observed. It was demonstrated that some phenylpropanoids such as benzoic acid, caffeic acid, lariciresinol, and kaempferol played a key role in the tolerance to the metal(loid)-induced oxidative stress. According to these results, it appeared that some flax genotypes, i.e., Angora and Baikal, could be well adapted for the phytoremediation of metal(loid) polluted soils as a consequence of their adaptation to oxidative stress.

Association of measures of body fat with serum alpha-tocopherol and its metabolites in middle-aged individuals

Background and aimsThe accumulation of fat increases the formation of lipid peroxides, which are partly scavenged by alpha-tocopherol (α-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary α-TOH metabolites in middle-aged individuals. Methods and resultsIn this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N = 511, 53% women; mean [SD] age of 55 [6.1] years), serum α-TOH and α-TOH metabolites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (α-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (α-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were assessed using magnetic resonance imaging. Using multivariable-adjusted linear regression analyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary α-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum α-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. ConclusionsOpposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized α-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead.

Deteriorating insulin resistance due to WL15 peptide from cysteine and glycine-rich protein 2 in high glucose-induced rat skeletal muscle L6 cells.

This study investigates the antioxidant and antidiabetic activity of the WL15 peptide derived from Channa striatus on regulating the antioxidant property in the rat skeletal muscle cell line (L6) and enhancing glucose uptake via glucose metabolism. Increased oxidative stress plays a major role in the development of diabetes and its complications. Strategies are needed to mitigate the oxidative stress that can reduce these pathogenic processes. Our results showed that with treatment with WL15 peptide, the reactive oxygen species significantly decreased in L6 myotubes in a dose-dependent manner, and increased antioxidant enzymes help to prevent the formation of lipid peroxidation in L6 myotubes. The cytotoxicity of WL15 is evaluated in the L6 cells and found to be non-cytotoxic at the tested concentration. Also, for the analysis of glucose uptake activity in L6 cells, the 2-(N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl]amino)-2-deoxy- d -glucose assay was performed in the presence of wortmannin and genistein inhibitors. WL15 demonstrated antidiabetic activities through a dose-dependent increase in glucose uptake (64%) and glycogen storage (7.8 mM). The optimal concentration for the maximum activity was found to be 50 µM. In addition, studies of gene expression in L6 myotubes demonstrated upregulation of antioxidant genes and genes involved in the pathway of insulin signaling. In cell-based assays, WL15 peptide decreased intracellular reactive oxygen species levels and demonstrated insulin mimic activity by enhancing the primary genes involved in the insulin signaling pathway by increased glucose uptake indicatingthat glucose transporter type 4 (GLUT4) is regulated from the intracellular pool to the plasma membrane.

Reduced Flow during Ex-Situ Heart Perfusion Provides Superior Function Preservation and Less Edema Formation

PurposeEx-situ heart perfusion (ESHP) allows continuous functional and metabolic resuscitation of donor hearts before transplantation. Evidence indicates that hearts that are perfused under physiologic conditions lose the normal vasomotor tone and fail in a few hours. We aim to evaluate the reduced coronary flow during ex situ heart perfusion on cardiac function and coronary vascular resistance.MethodsPorcine hearts (n=6 each group) were perfused in working mode for 6 hours either by constant diastolic pressure perfusion (40 mmHg) or constant coronary blood flow rate perfusion (500mL/min). Cardiac functional parameters, coronary vascular resistance (CVR) and metabolism were monitored continuously. Myocardial injury parameter of cardiac troponin I and lipid peroxidation marker oxidized low-density lipoprotein were evaluated in the perfusate. These parameters were compared between groups at different time.ResultsCardiac function was better preserved in the flow control group at 5 hours (T5) of perfusion, indicated by higher stroke work and cardiac index (p<0.05, Figure AC). After perfusion the flow control group showed less edema than the pressure control group (p<0.001, Figure B). Both groups have a significant decrease of CVR, with relative higher in the flow control group (p<0.01, Figure D). cTnI was lower in the flow control group starting at T3, indicating less myocardial injury (p<0.05, Figure E). oxLDL increased in both groups, indicating lipid peroxidation formation; the level in the flow control group was significantly lower in comparison to the pressure control group (p<0.01, Figure F), suggesting less oxidative stress in this group.ConclusionReduced coronary flow during ex-situ heart perfusion decreased edema formation, showed less myocardial damage and oxidative stress which may contribute to better cardiac function preservation. The relative higher coronary vascular resistance induced by reduced coronary flow perfusion may help to maintain the cardiac function. Ex-situ heart perfusion (ESHP) allows continuous functional and metabolic resuscitation of donor hearts before transplantation. Evidence indicates that hearts that are perfused under physiologic conditions lose the normal vasomotor tone and fail in a few hours. We aim to evaluate the reduced coronary flow during ex situ heart perfusion on cardiac function and coronary vascular resistance. Porcine hearts (n=6 each group) were perfused in working mode for 6 hours either by constant diastolic pressure perfusion (40 mmHg) or constant coronary blood flow rate perfusion (500mL/min). Cardiac functional parameters, coronary vascular resistance (CVR) and metabolism were monitored continuously. Myocardial injury parameter of cardiac troponin I and lipid peroxidation marker oxidized low-density lipoprotein were evaluated in the perfusate. These parameters were compared between groups at different time. Cardiac function was better preserved in the flow control group at 5 hours (T5) of perfusion, indicated by higher stroke work and cardiac index (p<0.05, Figure AC). After perfusion the flow control group showed less edema than the pressure control group (p<0.001, Figure B). Both groups have a significant decrease of CVR, with relative higher in the flow control group (p<0.01, Figure D). cTnI was lower in the flow control group starting at T3, indicating less myocardial injury (p<0.05, Figure E). oxLDL increased in both groups, indicating lipid peroxidation formation; the level in the flow control group was significantly lower in comparison to the pressure control group (p<0.01, Figure F), suggesting less oxidative stress in this group. Reduced coronary flow during ex-situ heart perfusion decreased edema formation, showed less myocardial damage and oxidative stress which may contribute to better cardiac function preservation. The relative higher coronary vascular resistance induced by reduced coronary flow perfusion may help to maintain the cardiac function.

Mitochondria-targeted antioxidant, mito-TEMPO mitigates initiation phase of N-Nitrosodiethylamine-induced hepatocarcinogenesis

Targeting mitochondrial oxidative stress during initial stages of hepatocarcinogenesis can be an effective and promising strategy to prevent hepatocellular carcinoma (HCC). In the present study, mitochondria targeted antioxidant, mito-TEMPO was administered to male BALB/c mice at a dosage 0.1 mg/kg b.w. (intraperitoneal) twice a week, followed by single N-Nitrosodiethylamine (NDEA) intraperitoneal injection (10 mg/kg b.w.). After 24 h of NDEA administration, animals were sacrificed, blood and liver tissue were collected. Liver injury markers, histoarchitecture, antioxidant defence status, mitochondrial reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial dysfunction analysis, and mitochondrial membrane potential were investigated. Mito-TEMPO pre-treatment protected animals from the damaging effects of NDEA as observed by normalization of liver injury markers. NDEA metabolism resulted in a significantly increased intracellular and mitochondrial ROS generation with concomitant increase in LPO formation. The activity of mitochondrial complex I, complex II, malate dehydrogenase were significantly reduced and mitochondrial membrane potential was increased. Mito-TEMPO effectively scavenged NDEA-induced ROS generation and reduced LPO formation. A significant improvement was also observed in the activity of mitochondrial complex I, complex II, malate dehydrogenase and normalisation of mitochondrial membrane potential. Results suggested that mito-TEMPO had significant impact on the initiation phase of hepatocarcinogensis which could be one of the reason for its reported chemopreventive effect.

Thioredoxin-1 Rescues MPP+/MPTP-Induced Ferroptosis by Increasing Glutathione Peroxidase 4.

Parkinson's disease (PD), a common neurodegenerative disease, is typically associated with the loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc). Ferroptosis is a newly identified cell death, which associated with iron accumulation, glutathione (GSH) depletion, lipid peroxidation formation, reactive oxygen species (ROS) accumulation, and glutathione peroxidase 4 (GPX4) reduction. It has been reported that ferroptosis is linked with PD.Thioredoxin-1 (Trx-1) is a redox regulating protein and plays various roles in regulating the activity of transcription factors and inhibiting apoptosis. However, whether Trx-1 plays the role in regulating ferroptosis involved in PD is still unknown. Our present study showed that 1-methyl-4-phenylpyridinium (MPP+) decreased cell viability, GPX4, and Trx-1, which were reversed by Ferrostatin-1 (Fer-1) in PC 12 cells and SH-SY5Y cells. Moreover, the decreased GPX4 and GSH, and increased ROS were inhibited by Fer-1 and Trx-1 overexpression. We further repeated that behavior deficits resulted from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were improved in Trx-1 overexpression transgenic mice. Trx-1 reversed the decreases of GPX4 and tyrosine hydroxylase (TH) induced by MPTP in the substantia nigra pars compacta (SNpc). Our results suggest that Trx-1 inhibits ferroptosis in PD through regulating GPX4 and GSH.

The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy.

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.