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1.
Organelle-specific regulation of ferroptosis.
Chen, X, Kang, R, Kroemer, G, Tang, D
Cell death and differentiation. 2021;(10):2843-2856
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Abstract
Ferroptosis, a cell death modality characterized by iron-dependent lipid peroxidation, is involved in the development of multiple pathological conditions, including ischemic tissue damage, infection, neurodegeneration, and cancer. The cellular machinery responsible for the execution of ferroptosis integrates multiple pro-survival or pro-death signals from subcellular organelles and then 'decides' whether to engage the lethal process or not. Here, we outline the evidence implicating different organelles (including mitochondria, lysosomes, endoplasmic reticulum, lipid droplets, peroxisomes, Golgi apparatus, and nucleus) in the ignition or avoidance of ferroptosis, while emphasizing their potential relevance for human disease and their targetability for pharmacological interventions.
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Tomato powder is more effective than lycopene to alleviate exercise-induced lipid peroxidation in well-trained male athletes: randomized, double-blinded cross-over study.
Gholami, F, Antonio, J, Evans, C, Cheraghi, K, Rahmani, L, Amirnezhad, F
Journal of the International Society of Sports Nutrition. 2021;(1):17
Abstract
BACKGROUND Consumption of nutritional supplements to optimize recovery is gaining popularity among athletes. Tomatoes contain micronutrients and various bioactive components with antioxidant properties. Many of the health benefits of tomatoes have been attributed to lycopene encouraging athletes to consume pure lycopene supplements. The aim of this study was to compare the effect of tomato powder and lycopene supplement on lipid peroxidation induced by exhaustive exercise in well-trained male athletes. METHODS Eleven well-trained male athletes participated in a randomized, double-blinded, crossover study. Each subject underwent three exhaustive exercise tests after 1-week supplementation of tomato powder (each serving contained 30 mg lycopene, 5.38 mg beta-carotene, 22.32 mg phytoene, 9.84 mg phytofluene), manufactured lycopene supplement (30 mg lycopene), or placebo. Three blood samples (baseline, post-ingestion and post-exercise) were collected to assess total anti-oxidant capacity (TAC) and variables of lipid peroxidation including malondialdehyde (MDA) and 8-isoprostane. Data were analyzed using repeated-measures of ANOVA at P < 0.05. RESULTS Tomato powder enhanced total antioxidant capacity (12% increase, P = 0.04). Exhaustive exercise, regardless of supplement/ placebo, elevated MDA and 8-isoprostane levels (P < 0.001). The elevation of 8-isoprostane following exhaustive exercise was lower in the tomato powder treatment compared to the placebo (9% versus 24%, p = 0.01). Furthermore, following exhaustive exercise MDA elevated to a lower extent in tomatoe powder treatment compared to the placebo (20% versus 51%, p = 0.009). However, such differences were not indicated between lycopene and placebo treatments (p > 0.05). CONCLUSION Beneficial effects of tomato powder on antioxidant capacity and exercise-induced lipid peroxidation may be brought about by a synergistic interaction of lycopene with other bioactive nutrients rather than single lycopene.
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Cytochrome P450 reductase (POR) as a ferroptosis fuel.
Koppula, P, Zhuang, L, Gan, B
Protein & cell. 2021;(9):675-679
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Myriocin modulates the altered lipid metabolism and storage in cystic fibrosis.
Signorelli, P, Pivari, F, Barcella, M, Merelli, I, Zulueta, A, Dei Cas, M, Rosso, L, Ghidoni, R, Caretti, A, Paroni, R, et al
Cellular signalling. 2021;:109928
Abstract
Cystic fibrosis (CF) is a hereditary disease mostly related to ΔF508 CFTR mutation causing a proteinopathy that is characterized by multiple organ dysfunction, primarily lungs chronic inflammation, and infection. Defective autophagy and accumulation of the inflammatory lipid ceramide have been proposed as therapeutic targets. Accumulation of lipids and cholesterol was reported in the airways of CF patients, together with altered triglycerides and cholesterol levels in plasma, thus suggesting a disease-related dyslipidemia. Myriocin, an inhibitor of sphingolipids synthesis, significantly reduces inflammation and activates TFEB-induced response to stress, enhancing fatty acids oxidation and promoting autophagy. Myriocin ameliorates the response against microbial infection in CF models and patients' monocytes. Here we show that CF broncho-epithelial cells exhibit an altered distribution of intracellular lipids. We demonstrated that lipid accumulation is supported by an enhanced synthesis of fatty acids containing molecules and that Myriocin is able to reduce such accumulation. Moreover, Myriocin modulated the transcriptional profile of CF cells in order to restore autophagy, activate an anti-oxidative response, stimulate lipid metabolism and reduce lipid peroxidation. Moreover, lipid storage may be altered in CF cells, since we observed a reduced expression of lipid droplets related proteins named perilipin 3 and 5 and seipin. To note, Myriocin up-regulates the expression of genes that are involved in lipid droplets biosynthesis and maturation. We suggest that targeting sphingolipids de novo synthesis may counteract lipids accumulation by modulating CF altered transcriptional profile, thus restoring autophagy and lipid metabolism homeostasis.
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American Ginseng Attenuates Eccentric Exercise-Induced Muscle Damage via the Modulation of Lipid Peroxidation and Inflammatory Adaptation in Males.
Lin, CH, Lin, YA, Chen, SL, Hsu, MC, Hsu, CC
Nutrients. 2021;(1)
Abstract
Exercise-induced muscle damage (EIMD) is characterized by a reduction in functional performance, disruption of muscle structure, production of reactive oxygen species, and inflammatory reactions. Ginseng, along with its major bioactive component ginsenosides, has been widely employed in traditional Chinese medicine. The protective potential of American ginseng (AG) for eccentric EIMD remains unclear. Twelve physically active males (age: 22.4 ± 1.7 years; height: 175.1 ± 5.7 cm; weight: 70.8 ± 8.0 kg; peak oxygen consumption [V˙O2peak] 54.1 ± 4.3 mL/kg/min) were administrated by AG extract (1.6 g/day) or placebo (P) for 28 days and subsequently challenged by downhill (DH) running (-10% gradient and 60% V˙O2peak). The levels of circulating 8-iso-prostaglandin F 2α (PGF2α), creatine kinase (CK), interleukin (IL)-1β, IL-4, IL-10, and TNF-α, and the graphic pain rating scale (GPRS) were measured before and after supplementation and DH running. The results showed that the increases in plasma CK activity induced by DH running were eliminated by AG supplementation at 48 and 72 h after DH running. The level of plasma 8-iso-PGF2α was attenuated by AG supplementation immediately (p = 0.01 and r = 0.53), 2 h (p = 0.01 and r = 0.53) and 24 h (p = 0.028 and r = 0.45) after DH running compared with that by P supplementation. Moreover, our results showed an attenuation in the plasma IL-4 levels between AG and P supplementation before (p = 0.011 and r = 0.52) and 72 h (p = 0.028 and r = 0.45) following DH running. Our findings suggest that short-term supplementation with AG alleviates eccentric EIMD by decreasing lipid peroxidation and promoting inflammatory adaptation.
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Investigating the effects of vitamins E and C on oxidative stress and hematological parameters among power plant workers: A double-blind randomized controlled clinical trial.
Hosseinabadi, MB, Khanjani, N, Norouzi, P, Mirzaii, M, Biganeh, J, Nazarkhani, F
Toxicology and industrial health. 2020;(2):99-109
Abstract
The present study aimed to determine the effect of taking antioxidant vitamins including vitamins E and C in reducing oxidative stress levels and improving blood parameters. This double-blind randomized controlled trial study was conducted among the employees working in different parts of a power plant in Semnan, Iran, in 2017. A total of 91 employees were randomly allocated to four groups including vitamin E (400 units per day), vitamin C (1000 mg per day), vitamin E + C for 90 days, and control. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (Cat), and total antioxidant capacity (TAC) in plasma, and hematological parameters were measured in the participants before and after the intervention. A significant increase was seen in the mean level of SOD, Cat, and TAC in the vitamin-treated groups as well as a significant decrease in mean MOD in vitamin C and vitamin E groups after the intervention. In the intervention groups, the number of red blood cells, hematocrit, and the level of mean corpuscular hemoglobin (MCH) and MCH concentration significantly increased. After the intervention, the mean levels of MDA, SOD, and Cat in vitamin E group were significantly lower than the control group. The mean level of TAC decreased only in the vitamin C group compared to the control group. Taking vitamins E and C as nonenzymatic scavengers of free radicals appears to decrease lipid peroxidation and increase the level of antioxidant enzymes, which can be imbalanced by exposure to extremely low-frequency electromagnetic fields in power plant employees. Furthermore, some hematological parameters can be improved by consuming these vitamins.
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4-HNE Immunohistochemistry and Image Analysis for Detection of Lipid Peroxidation in Human Liver Samples Using Vitamin E Treatment in NAFLD as a Proof of Concept.
Podszun, MC, Chung, JY, Ylaya, K, Kleiner, DE, Hewitt, SM, Rotman, Y
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 2020;(9):635-643
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Abstract
Lipid peroxidation is a common feature of liver diseases, especially non-alcoholic fatty liver disease (NAFLD). There are limited validated tools to study intra-hepatic lipid peroxidation, especially for small specimen. We developed a semi-quantitative, fully automated immunohistochemistry assay for the detection of 4-hydroxynoneal (4-HNE) protein adducts, a marker of lipid peroxidation, for adaptation to clinical diagnostics and research. We used Hep G2 cells treated with 4-HNE to validate specificity, sensitivity, and dynamic range of the antibody. Staining and semi-quantitative automated readout were confirmed in human needle-biopsy liver samples from subjects with NAFLD and normal liver histology. The ability to detect changes in lipid peroxidation was tested in paired liver biopsies from NAFLD subjects, obtained before and after 4 weeks of treatment with the antioxidant vitamin E (ClinicalTrials.gov NCT01792115, n=21). The cellular calibrator was linear and NAFLD patients had significantly higher levels of 4-HNE adducts compared to controls (p=0.02). Vitamin E treatment significantly decreased 4-HNE (p=0.0002). Our findings demonstrate that 4-HNE quantification by immunohistochemistry and automated image analysis is feasible and able to detect changes in hepatic lipid peroxidation in clinical trials. This method can be applied to archival and fresh samples and should be considered for use in assessing NAFLD histology.
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Subacute Ingestion of Caffeine and Oolong Tea Increases Fat Oxidation without Affecting Energy Expenditure and Sleep Architecture: A Randomized, Placebo-Controlled, Double-Blinded Cross-Over Trial.
Zhang, S, Takano, J, Murayama, N, Tominaga, M, Abe, T, Park, I, Seol, J, Ishihara, A, Tanaka, Y, Yajima, K, et al
Nutrients. 2020;(12)
Abstract
Ingesting oolong tea or caffeine acutely increases energy expenditure, and oolong tea, but not caffeine, stimulates fat oxidation. The acute effects of caffeine, such as increased heart rate and interference with sleep, diminish over 1-4 days, known as caffeine tolerance. During each 14-day session of the present study, 12 non-obese males consumed oolong tea (100 mg caffeine, 21.4 mg gallic acid, 97 mg catechins and 125 mg polymerized polyphenol), caffeine (100 mg), or placebo at breakfast and lunch. On day 14 of each session, 24-h indirect calorimetry and polysomnographic sleep recording were performed. Caffeine and oolong tea increased fat oxidation by ~20% without affecting energy expenditure over 24-h. The decrease in the respiratory quotient by oolong tea was greater than that by caffeine during sleep. The effect of oolong tea on fat oxidation was salient in the post-absorptive state. These findings suggest a role of unidentified ingredients in oolong tea to stimulate fat oxidation, and this effect is partially suppressed in a postprandial state. Two weeks of caffeine or oolong tea ingestion increased fat oxidation without interfering with sleep. The effects of subacute ingestion of caffeine and oolong tea differed from the acute effects, which is a particularly important consideration regarding habitual tea consumption.
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Adjunct N-Acetylcysteine Treatment in Hospitalized Patients With HIV-Associated Tuberculosis Dampens the Oxidative Stress in Peripheral Blood: Results From the RIPENACTB Study Trial.
Safe, IP, Amaral, EP, Araújo-Pereira, M, Lacerda, MVG, Printes, VS, Souza, AB, Beraldi-Magalhães, F, Monteiro, WM, Sampaio, VS, Barreto-Duarte, B, et al
Frontiers in immunology. 2020;:602589
Abstract
Tuberculosis (TB) still causes significant morbidity and mortality worldwide, especially in persons living with human immunodeficiency virus (HIV). This disease is hallmarked by persistent oxidative stress and systemic inflammation. N-acetylcysteine (NAC), a glutathione (GSH) precursor, has been shown in experimental models to limit Mycobacterium tuberculosis infection and disease both by suppression of the host oxidative response and through direct antimicrobial activity. In a recent phase II randomized clinical trial (RIPENACTB study), use of NAC as adjunct therapy during the first two months of anti-TB treatment was safe. Whether adjunct NAC therapy of patients with TB-HIV coinfection in the context of anti-TB treatment could directly affect pro-oxidation and systemic inflammation has not been yet formally demonstrated. To test this hypothesis, we leveraged existing data and biospecimens from the RIPENACTB trial to measure a number of surrogate markers of oxidative stress and of immune activation in peripheral blood of the participants at pre-treatment and at the day 60 of anti-TB treatment. Upon initiation of therapy, we found that the group of patients undertaking NAC exhibited significant increase in GSH levels and in total antioxidant status while displaying substantial reduction in lipid peroxidation compared to the control group. Only small changes in plasma concentrations of cytokines were noted. Pharmacological improvement of the host antioxidant status appears to be a reasonable strategy to reduce TB-associated immunopathology.
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Posttranslational Modifications in Ferroptosis.
Wei, X, Yi, X, Zhu, XH, Jiang, DS
Oxidative medicine and cellular longevity. 2020;:8832043
Abstract
Ferroptosis was first coined in 2012 to describe the form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. To date, ferroptosis has been implicated in many diseases, such as carcinogenesis, degenerative diseases (e.g., Huntington's, Alzheimer's, and Parkinson's diseases), ischemia-reperfusion injury, and cardiovascular diseases. Previous studies have identified numerous targets involved in ferroptosis; for example, acyl-CoA synthetase long-chain family member 4 (ACSL4) and p53 induce while glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1) inhibit ferroptosis. At least three major pathways (the glutathione-GPX4, FSP1-coenzyme Q10 (CoQ10), and GTP cyclohydrolase-1- (GCH1-) tetrahydrobiopterin (BH4) pathways) have been identified to participate in ferroptosis regulation. Recent advances have also highlighted the crucial roles of posttranslational modifications (PTMs) of proteins in ferroptosis. Here, we summarize the recently discovered knowledge regarding the mechanisms underlying ferroptosis, particularly the roles of PTMs in ferroptosis regulation.