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1.
J Cell Sci ; 135(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414166

RESUMO

Ferroptosis is a regulated, non-apoptotic form of cell death, characterized by hydroxy-peroxidation of discrete phospholipid hydroperoxides, particularly hydroperoxyl (Hp) forms of arachidonoyl- and adrenoyl-phosphatidylethanolamine, with a downstream cascade of oxidative damage to membrane lipids, proteins and DNA, culminating in cell death. We recently showed that human trophoblasts are particularly sensitive to ferroptosis caused by depletion or inhibition of glutathione peroxidase 4 (GPX4) or the lipase PLA2G6. Here, we show that trophoblastic ferroptosis is accompanied by a dramatic change in the trophoblast plasma membrane, with macro-blebbing and vesiculation. Immunofluorescence revealed that ferroptotic cell-derived blebs stained positive for F-actin, but negative for cytoplasmic organelle markers. Transfer of conditioned medium that contained detached macrovesicles or co-culture of wild-type target cells with blebbing cells did not stimulate ferroptosis in target cells. Molecular modeling showed that the presence of Hp-phosphatidylethanolamine in the cell membrane promoted its cell ability to be stretched. Together, our data establish that membrane macro-blebbing is characteristic of trophoblast ferroptosis and can serve as a useful marker of this process. Whether or not these blebs are physiologically functional remains to be established.


Assuntos
Ferroptose , Feminino , Humanos , Peroxidação de Lipídeos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Placenta , Gravidez , Trofoblastos
2.
Anal Chem ; 93(34): 11758-11764, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34410685

RESUMO

The detection of SO2 and its derivatives is indispensable for monitoring atmospheric, water quality, and biological fluctuation of oxidative stress and metabolism of biothiols within native cellular contexts. In this article, the brush copolymer nanoreactors containing amine-terminated PDMS were used to encapsulate the fluorescent indicator C11-BDP, forming sulfite-sensitive nanoreactors (ssNRs). Surprisingly, the ssNRs were found to be highly selective to sulfite over a range of reactive oxygen/nitrogen/sulfur species and anions, which was not observed with freely dissolved indicators. The ssNRs showed a rapid response (t95 = 65 s), an excellent detection limit (0.7 µM), and a very high sensitivity (ca. 1000-fold ratiometric intensity change) to sulfite. For cellular studies, the ssNRs exhibited negligible toxicity and could be endocytosed into endosomes and lysosomes. Finally, the ssNRs allowed us to visualize the different responses of three different types of cells (pre-adipocytes, RAW264.7, and HeLa cells) to external stimuli in the culture media with sulfites and lipopolysaccharides.


Assuntos
Corantes Fluorescentes , Sulfitos , Células HeLa , Humanos , Peroxidação de Lipídeos , Nanotecnologia
3.
Nutrients ; 13(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34444911

RESUMO

Plant-derived conjugated linolenic acids (CLnA) have been widely studied for their preventive and therapeutic properties against diverse diseases such as cancer. In particular, punicic acid (PunA), a conjugated linolenic acid isomer (C18:3 c9t11c13) present at up to 83% in pomegranate seed oil, has been shown to exert anti-cancer effects, although the mechanism behind its cytotoxicity remains unclear. Ferroptosis, a cell death triggered by an overwhelming accumulation of lipid peroxides, has recently arisen as a potential mechanism underlying CLnA cytotoxicity. In the present study, we show that PunA is highly cytotoxic to HCT-116 colorectal and FaDu hypopharyngeal carcinoma cells grown either in monolayers or as three-dimensional spheroids. Moreover, our data indicate that PunA triggers ferroptosis in carcinoma cells. It induces significant lipid peroxidation and its effects are prevented by the addition of ferroptosis inhibitors. A combination with docosahexaenoic acid (DHA), a known polyunsaturated fatty acid with anticancer properties, synergistically increases PunA cytotoxicity. Our findings highlight the potential of using PunA as a ferroptosis-sensitizing phytochemical for the prevention and treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Ácidos Linolênicos/farmacologia , Carcinoma/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Células HCT116 , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos
4.
Yonsei Med J ; 62(9): 843-849, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34427071

RESUMO

PURPOSE: Temozolomide is used in first-line treatment for glioblastoma. However, chemoresistance to temozolomide is common in glioma patients. In addition, mechanisms for the anti-tumor effects of temozolomide are largely unknown. Ferroptosis is a form of programmed cell death triggered by disturbed redox homeostasis, overloaded iron, and increased lipid peroxidation. The present study was performed to elucidate the involvement of ferroptosis in the anti-tumor mechanisms of temozolomide. MATERIALS AND METHODS: We utilized the CCK8 assay to evaluate cytotoxicity. Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), iron, and glutathione (GSH) were measured. Flow cytometry and fluorescence microscope were used to detect the production of reactive oxygen species (ROS). Western blotting, RT-PCR and siRNA transfection were used to investigate molecular mechanisms. RESULTS: Temozolomide increased the levels of LDH, MDA, and iron and reduced GSH levels in TG905 cells. Furthermore, we found that ROS levels and DMT1 expression were elevated in TG905 cells treated with temozolomide and were accompanied by a decrease in the expression of glutathione peroxidase 4, indicating an iron-dependent cell death, ferroptosis. Our results also showed that temozolomide-induced ferroptosis is associated with regulation of the Nrf2/HO-1 pathway. Conversely, DMT1 knockdown by siRNA evidently blocked temozolomide-induced ferroptosis in TG905 cells. CONCLUSION: Taken together, our findings indicate that temozolomide may suppress cell growth partly by inducing ferroptosis by targeting DMT1 expression in glioblastoma cells.


Assuntos
Ferroptose , Glioblastoma , Glioblastoma/tratamento farmacológico , Humanos , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio , Temozolomida/farmacologia
5.
Nat Immunol ; 22(9): 1127-1139, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34413521

RESUMO

Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of TFH cell survival remains unclear. Here we report that TFH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for TFH cell survival. The deletion of GPX4 in T cells selectively abrogated TFH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased TFH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.


Assuntos
Ferroptose/fisiologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/farmacologia , Células T Auxiliares Foliculares/fisiologia , Adolescente , Adulto , Animais , Sobrevivência Celular/imunologia , Criança , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Imunidade Humoral/imunologia , Vacinas contra Influenza/imunologia , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/fisiologia , Ovalbumina , Células T Auxiliares Foliculares/imunologia , Vacinação , Adulto Jovem
6.
FASEB J ; 35(9): e21808, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390515

RESUMO

The link between serum uric acid (SUA) and the risk of venous thromboembolism (VTE) is well established. Recent data suggested a causative role of UA in endothelial cells (ECs) dysfunction. However, the molecular mechanism of high UA on thrombogenesis is unknown. We investigate whether high UA induce phosphatidylserine (PS) externalization and microparticle (MP) shedding in cultured EC, and contribute to UA-induced hypercoagulable state. In the present study, we demonstrate that UA induces PS exposure and EMP release of EC in a concentration- and time-dependent manner, which enhances the procoagulant activity (PCA) of EC and inhibited over 90% by lactadherin in vitro. Furthermore, hyperuricemic rat model was used to evaluate the development of thrombi following by flow stasis in the inferior vena cava (IVC). Hyperuricemia group is more likely to form large and hard thrombi compared with control. Importantly, we found that TMEM16F expression is significantly upregulated in UA-treated EC, which is crucial for UA-induced PS exposure and MP formation. Additionally, UA increases the generation of reactive oxygen species (ROS), lipid peroxidation, and cytosolic Ca2+ concentration in EC, which might contribute to increased TMEM16F expression. Using confocal microscopy, we also observed disruption of the actin cytoskeleton, suggesting that depolymerization of actin filaments might be required for TMEM16F activation and followed by PS exposure and membrane blebbing in UA-treated EC. Our results demonstrate a thrombotic role of EC in hyperuricemia through TMEM16F-mediated PS exposure and MPs release.


Assuntos
Anoctaminas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/metabolismo , Hiperuricemia/metabolismo , Fosfatidilserinas/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperuricemia/sangue , Peroxidação de Lipídeos/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Ácido Úrico/sangue
7.
Ceska Slov Farm ; 70(3): 102-108, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34418947

RESUMO

In this experimental study, the effects of the combined herbal drug Pancreo-Plant® at a dose of 72 mg/kg and the comparison drug silymarin at a dose of 25 mg/ kg on animal mortality, cytolysis activity, free radical oxidation, and functional activity of the liver in the conditions of acute experimental ischemia have been studied. A pronounced antioxidant effect of the studied agent has been found which was manifested in the reduction of the lipid peroxidation products content, namely thiobarbituric acid products and diene conjugates and normalization of the enzymatic and non-enzymatic chains of endogenous antioxidant protection (reduced glutathione, catalase). In the case of acute liver failure, Pancreo-Plant® exhibited a significant anti-cytolytic effect, restored carbohydrate metabolism and protein-synthetic function of the liver. It was found that the total hepatoprotective activity of the combined herbal drug Pancreo-Plant® exceeded the activity of the comparison drug silymarin.


Assuntos
Antioxidantes , Silimarina , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Isquemia/metabolismo , Peroxidação de Lipídeos , Fígado , Silimarina/metabolismo , Silimarina/farmacologia
8.
BMC Res Notes ; 14(1): 298, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344447

RESUMO

OBJECTIVE: In present study, the effects of the leaf extract of Pyrus biossieriana Buhse on tert-Butyl hydroperoxide (t-BHP) induced toxicity in the HepG2 cell line were investigated. RESULTS: HepG2 cells were exposed to different concentrations of both extract (1.5, 2.0, and 2.5 mg/mL) and t-BHP (100, 150, and 200 µM). The total flavonoid and phenolic contents, the cell viability, lipid peroxidation, NO generation, and the total antioxidant capacity in cell media were assessed. The amount of arbutin was estimated 12.6% of the dry weight of leaves (equivalent to 126 mg/g). Additionally, the amounts of flavonoids and phenols in extract were estimated 119 mg/g and 418 mg/g, respectively. The cells incubated with t-BHP showed a significant decrease in survival (p < 0.001). Preincubation with extract (1.5 mg/mL and 2.0 mg/mL) attenuated the t-BHP toxicity and increased the cell viability in cells exposed even to the highest concentration of t-BHP (200 µM) (p value < 0.001, and p value = 0.035) respectively. Additionally, treatment with extract reduced the cell growth suppression caused by t-BHP. The P. biossieriana Buhse leaf extract at concentrations of 1.5 and 2.0 mg/mL is capable of attenuating t-BHP-induced cytotoxicity in HepG2 cells.


Assuntos
Pyrus , Sobrevivência Celular , Células Hep G2 , Humanos , Peroxidação de Lipídeos , Estresse Oxidativo , Extratos Vegetais/farmacologia , terc-Butil Hidroperóxido/toxicidade
9.
Adv Exp Med Biol ; 1301: 25-40, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370286

RESUMO

Iron is an ancient, essential and versatile transition metal found in almost all living organisms on Earth. This fundamental trace element is used in the synthesis of heme and iron-sulfur (Fe-S) containing proteins and other vital cofactors that are involved in respiration, redox reactions, catalysis, DNA synthesis and transcription. At the same time, the ability of iron to cycle between its oxidized, ferric (Fe3+) and its reduced, ferrous (Fe2+) state contributes to the production of free radicals that can damage biomolecules, including proteins, lipids and DNA. In particular, the regulated non-apoptotic cell death ferroptosis is driven by Fe2+-dependent lipid peroxidation that can be prevented by iron chelation or genetic inhibition of cellular iron uptake. Therefore, iron homeostasis must be tightly regulated to avoid iron toxicity. This review provides an overview of the origin and chemistry of iron that makes it suitable for a variety of biological functions and addresses how organisms evolved various strategies, including their scavenging and antioxidant machinery, to manage redox-associated drawbacks. Finally, key mechanisms of iron metabolism are highlighted in human diseases and model organisms, underlining the perils of dysfunctional iron handlings.


Assuntos
Ferro , Radicais Livres , Homeostase , Humanos , Peroxidação de Lipídeos , Oxirredução
10.
Adv Exp Med Biol ; 1301: 59-79, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370288

RESUMO

Ferroptosis is a distinct form regulated necrotic cell death mainly characterized by the accumulation of toxic lipid peroxides. The importance of this form of cell death has been recognized in several diseases. An imbalance between free radicals and antioxidant molecules has been reported to play role in several pathologies and is commonly associated with worse outcomes of these maladies. Emerging evidence suggests that ferroptosis and/or its regulators may modulate other forms of cell death leading to the induction of necro-inflammatory response and consequently organ failure. Herein, we review the major forms of necrotic cell death triggered by pathogens highlighting mechanisms in which oxidative stress and cellular antioxidants may limit or favor pathogen dissemination defining host cell fate. Specially, we discuss the role of ferroptosis and how its molecular components may modulate disease progression.


Assuntos
Doenças Transmissíveis , Ferroptose , Antioxidantes , Morte Celular , Humanos , Peroxidação de Lipídeos
11.
Adv Exp Med Biol ; 1301: 81-121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370289

RESUMO

Ferroptosis is a dedicated mode of cell death involving iron, reactive oxygen species and lipid peroxidation. Involved in processes such as glutathione metabolism, lysosomal iron retention or interference with lipid metabolism, leading either to activation or inhibition of ferroptosis. Given the implications of ferroptosis in diseases such as cancer, aging, Alzheimer and infectious diseases, new molecular mechanisms underlying ferroptosis and small molecules regulators that target those mechanisms have prompted a great deal of interest. Here, we discuss the current scenario of small molecules modulating ferroptosis and critically assess what is known about their mechanisms of action.


Assuntos
Ferroptose , Morte Celular , Humanos , Ferro , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio
12.
Stomatologiia (Mosk) ; 100(4): 7-15, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34357721

RESUMO

The purpose of the study was to examine the condition of the pro-antioxidant balance of the homogenates of tissues of the oral mucosal wound surface in vivo experiment under the photodynamic action of combined two-wave radiation to eliminate its damaging effect on the structures of cell membranes. MATERIALS AND METHODS: On the mucous membrane of the cheeks of sexually mature female autocrats of Wistar rats (n=72) experimental models of wound surfaces with a diameter of 3 mm were formed. The animals were divided into groups: control (n=36) and experimental (n=36). In the experimental group, a single photodynamic exposure was carried out for the 1st postoperative day with a sequential combined light radiation at two wavelengths (660 nm and 405 nm) with a total dose of 15 J/cm2. Wound management was carried out traditionally in the control group of animals. The observation periods were 3, 7 and 14 days. RESULTS: Macroscopic examination of the wound surface indicated complete epithelialization of the wound on the 7th day in the experimental group of animals and on the 14th day in the control group. Significant and sharp decline in free-radical oxidation processes (Imax, S, Z index) intensity was recorded in the experimental animals at earlier periods in comparison with the initial data and control results, when analyzing the results of studies of homogenates of animal tissues. A similar pattern was observed in the evaluation of lipid peroxidation products, especially in the early days of observations. The reported results were supported by the activation of antioxidant enzymes in the experimental group compared to control data and baseline data. CONCLUSION: Thus, a combined photodynamic action using two wavelengths with a combined dose of 15 J/cm2 provides safety and low invasiveness for use on the oral mucous membrane and, may be used to stimulate regeneration of the wound surface, which requires further experimental testing.


Assuntos
Mucosa Bucal , Cicatrização , Animais , Feminino , Peroxidação de Lipídeos , Oxirredução , Ratos , Ratos Wistar
13.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443459

RESUMO

Antioxidants remain interesting molecules of choice for suppression of the toxic effects of free radicals in foods and human systems. The current practice involves the use of mainly synthetic molecules as potent antioxidant agents. However, due to the potential negative impact on human health, there is an intensive effort within the research community to develop natural alternatives with similar antioxidant efficacy but without the negative side effects of synthetic molecules. Still, the successful development of new molecules depends on the use of reliable chemical or cell culture assays to screen antioxidant properties. Chemical antioxidant assays include the determination of scavenging ability against free radicals such as DPPH, superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and nitric oxide. Other antioxidant tests include the ability of compounds to bind and sequester prooxidant metal cations, reduce ferric iron, and attenuate the rate of lipid oxidation. Ex vivo tests utilize cell cultures to confirm entry of the molecules into cells and the ability to quench synthetic intracellular free radicals or to stimulate the increased biosynthesis of endogenous antioxidants. In order to assist researchers in their choice of antioxidant evaluation methods, this review presents background scientific information on some of the most commonly used antioxidant assays with a comparative discussion of the relevance of published literature data to food science and human nutrition applications.


Assuntos
Antioxidantes/metabolismo , Bioensaio/métodos , Células/metabolismo , Antioxidantes/química , Membrana Celular/metabolismo , Humanos , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio/metabolismo
14.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445561

RESUMO

Among numerous contaminants, the ubiquitous occurrence of nonsteroidal anti-inflammatory drugs (NSAIDs) in the environment and their plausible harmful impact on nontarget organisms have made them one of the most important areas of concern in recent years. Crop plants can also potentially be exposed to NSAIDs, since the concentration of these pharmaceuticals is constantly rising in the surface water and soil. Our goal was to evaluate the stress response of two crop plants, maize and tomato, to treatment with selected NSAIDs, naproxen and diclofenac. The focus of the research was on the growth response, photosynthetic efficiency, selected oxidative stress factors (such as the H2O2 level and the rate of lipid peroxidation) as well as the total phenolic content, which represents the non-enzymatic protectants against oxidative stress. The results indicate that susceptibility to the NSAIDs that were tested is dependent on the plant species. A higher sensitivity of tomato manifested in growth inhibition, a decrease in the content of the photosynthetic pigments and a reduction in the maximum quantum efficiency of PSII and the activity of PSII, which was estimated using the Fv/Fm and Fv/F0 ratios. Based on the growth results, it was also possible to reveal that diclofenac had a more toxic effect on tomato. In contrast to tomato, in maize, neither the content of the photosynthetic pigments nor growth appeared to be affected by DFC and NPX. However, both drugs significantly decreased in maize Fv and Fm, which are particularly sensitive to stress. A higher H2O2 concentration accompanied, in most cases, increasing lipid peroxidation, indicating that oxidative stress occurred in response to the selected NSAIDs in the plant species that were studied. The higher phenolic content of the plants after NSAIDs treatment may, in turn, indicate the activation of defense mechanisms in response to the oxidative stress that is triggered by these drugs.


Assuntos
Diclofenaco/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lycopersicon esculentum/efeitos dos fármacos , Naproxeno/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Zea mays/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Peróxido de Hidrogênio/farmacologia , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/metabolismo , Oxidantes/farmacologia , Fenóis/farmacologia , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo
15.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361067

RESUMO

Carotenoids and phenylpropanoids play a dual role of limiting and countering photooxidative stress. We hypothesize that their "antioxidant" function is prominent in plants exposed to summer drought, when climatic conditions exacerbate the light stress. To test this, we conducted a field study on Phillyrea latifolia, a Mediterranean evergreen shrub, carrying out daily physiological and biochemical analyses in spring and summer. We also investigated the functional role of the major phenylpropanoids in different leaf tissues. Summer leaves underwent the most severe drought stress concomitantly with a reduction in radiation use efficiency upon being exposed to intense photooxidative stress, particularly during the central hours of the day. In parallel, a significant daily variation in both carotenoids and phenylpropanoids was observed. Our data suggest that the morning-to-midday increase in zeaxanthin derived from the hydroxylation of ß-carotene to sustain non-photochemical quenching and limit lipid peroxidation in thylakoid membranes. We observed substantial spring-to-summer and morning-to-midday increases in quercetin and luteolin derivatives, mostly in the leaf mesophyll. These findings highlight their importance as antioxidants, countering the drought-induced photooxidative stress. We concluded that seasonal and daily changes in photosynthetic and non-photosynthetic pigments may allow P. latifolia leaves to avoid irreversible photodamage and to cope successfully with the Mediterranean harsh climate.


Assuntos
Antioxidantes/farmacologia , Oleaceae/efeitos dos fármacos , Fenilpropionatos/farmacologia , Folhas de Planta/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Estações do Ano , Estresse Fisiológico , Carotenoides/farmacologia , Secas , Luz , Peroxidação de Lipídeos , Oleaceae/crescimento & desenvolvimento , Oleaceae/efeitos da radiação , Estresse Oxidativo , Fotossíntese , Pigmentação , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/efeitos da radiação
16.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360671

RESUMO

Regulated cell death (RCD) is a fundamental process common to nearly all living beings and essential for the development and tissue homeostasis in animals and humans. A wide range of molecules can induce RCD, including a number of viral proteolytic enzymes. To date, numerous data indicate that picornaviral 3C proteases can induce RCD. In most reported cases, these proteases induce classical caspase-dependent apoptosis. In contrast, the human hepatitis A virus 3C protease (3Cpro) has recently been shown to cause caspase-independent cell death accompanied by previously undescribed features. Here, we expressed 3Cpro in HEK293, HeLa, and A549 human cell lines to characterize 3Cpro-induced cell death morphologically and biochemically using flow cytometry and fluorescence microscopy. We found that dead cells demonstrated necrosis-like morphological changes including permeabilization of the plasma membrane, loss of mitochondrial potential, as well as mitochondria and nuclei swelling. Additionally, we showed that 3Cpro-induced cell death was efficiently blocked by ferroptosis inhibitors and was accompanied by intense lipid peroxidation. Taken together, these results indicate that 3Cpro induces ferroptosis upon its individual expression in human cells. This is the first demonstration that a proteolytic enzyme can induce ferroptosis, the recently discovered and actively studied type of RCD.


Assuntos
Proteases Virais 3C/metabolismo , Núcleo Celular/patologia , Ferroptose , Mitocôndrias/patologia , Proteases Virais 3C/genética , Células A549 , Núcleo Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Técnicas In Vitro , Peroxidação de Lipídeos , Mitocôndrias/metabolismo
17.
BMC Plant Biol ; 21(1): 361, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34364372

RESUMO

BACKGROUND: Priming of seed prior chilling is regarded as one of the methods to promote seeds germination, whole plant growth, and yield components. The application of biostimulants was reported as beneficial for protecting many plants from biotic or abiotic stresses. Their value was as important to be involved in improving the growth parameters of plants. Also, they were practiced in the regulation of various metabolic pathways to enhance acclimation and tolerance in coriander against chilling stress. To our knowledge, little is deciphered about the molecular mechanisms underpinning the ameliorative impact of biostimulants in the context of understanding the link and overlap between improved morphological characters, induced metabolic processes, and upregulated gene expression. In this study, the ameliorative effect(s) of potassium silicate, HA, and gamma radiation on acclimation of coriander to tolerate chilling stress was evaluated by integrating the data of growth, yield, physiological and molecular aspects. RESULTS: Plant growth, yield components, and metabolic activities were generally diminished in chilling-stressed coriander plants. On the other hand, levels of ABA and soluble sugars were increased. Alleviation treatment by humic acid, followed by silicate and gamma irradiation, has notably promoted plant growth parameters and yield components in chilling-stressed coriander plants. This improvement was concomitant with a significant increase in phytohormones, photosynthetic pigments, carbohydrate contents, antioxidants defense system, and induction of large subunit of RuBisCO enzyme production. The assembly of Toc complex subunits was maintained, and even their expression was stimulated (especially Toc75 and Toc 34) upon alleviation of the chilling stress by applied biostimulators. Collectively, humic acid was the best the element to alleviate the adverse effects of chilling stress on growth and productivity of coriander. CONCLUSIONS: It could be suggested that the inducing effect of the pretreatments on hormonal balance triggered an increase in IAA + GA3/ABA hormonal ratio. This ratio could be linked and engaged with the protection of cellular metabolic activities from chilling injury against the whole plant life cycle. Therefore, it was speculated that seed priming in humic acid is a powerful technique that can benefit the chilled along with non-chilled plants and sustain the economic importance of coriander plant productivity.


Assuntos
Resposta ao Choque Frio/fisiologia , Coriandrum/crescimento & desenvolvimento , Reguladores de Crescimento de Plantas/farmacologia , Sementes/crescimento & desenvolvimento , Aclimatação , Antioxidantes/metabolismo , Metabolismo dos Carboidratos , Carboidratos/análise , Proteínas de Cloroplastos/metabolismo , Resposta ao Choque Frio/efeitos dos fármacos , Resposta ao Choque Frio/efeitos da radiação , Coriandrum/efeitos dos fármacos , Coriandrum/efeitos da radiação , Enzimas/metabolismo , Raios gama , Substâncias Húmicas , Peroxidação de Lipídeos , Pigmentos Biológicos/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Compostos de Potássio/química , Compostos de Potássio/farmacologia , Sementes/efeitos dos fármacos , Sementes/efeitos da radiação
18.
Nutrients ; 13(8)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34444734

RESUMO

Seeds of industrial hemp (Cannabis sativa L.) contain a large amount of protein (26.3%), dietary fiber (27.5%), and fatty acids (33.2%), including linoleic, α-linolenic, and some amount of γ-linolenic acid. In our study, obese male Zucker rats (n = 6) at 8 weeks of age were supplemented for a further 4 weeks with either ground hemp seeds (12% diet) or lipid fractions in the form of hemp seed oil (4% diet). Hemp oil decreased blood plasma HDL-cholesterol (x0.76, p ≤ 0.0001), triglycerides (x0.55, p = 0.01), and calculated atherogenic parameters. Meanwhile, hemp seeds decreased HDL-cholesterol (x0.71, p ≤ 0.0001) and total cholesterol (x0.81, p = 0.006) but not the atherogenic index. The plasma antioxidant capacity of water-soluble compounds was decreased by the seeds (x0.30, p = 0.0015), which in turn was associated with a decrease in plasma uric acid (x0.18, p = 0.03). Dietary hemp seeds also decreased plasma urea (x0.80, p = 0.02), while the oil decreased the plasma total protein (x0.90, p = 0.05). Hemp seeds and the oil decreased lipid peroxidation in the blood plasma and in the heart (reflected as malondialdehyde content), improved contraction to noradrenaline, and up-regulated the sensitivity of potassium channels dependent on ATP and Ca2+. Meanwhile, acetylcholine-induced vasodilation was improved by hemp seeds exclusively. Dietary supplementation with ground hemp seeds was much more beneficial than the oil, which suggests that the lipid fractions are only partially responsible for this effect.


Assuntos
Cannabis , Fenômenos Fisiológicos Cardiovasculares , Suplementos Nutricionais , Obesidade/fisiopatologia , Extratos Vegetais , Sementes , Animais , Antioxidantes , Glicemia , Pressão Sanguínea , Proteínas Sanguíneas/análise , Peroxidação de Lipídeos , Lipídeos/sangue , Masculino , Miocárdio/metabolismo , Ratos , Ratos Zucker , Tromboxano A2/análise , Vasoconstrição , Vasodilatação
19.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360999

RESUMO

CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Peroxidação de Lipídeos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Fígado Gorduroso Alcoólico/patologia , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-34444074

RESUMO

Smoking and lead (Pb) exposure increased oxidative stress in human body, and people with some gene variants may be susceptible to Pb and smoking via oxidative stress. The aim of this study is to evaluate oxidative stress by measuring thiobarbituric acid reactive substances (TBARS) and the relationship of lipid peroxidation markers in Pb workers with different gene polymorphisms (rs4673 and rs1050450) in both smokers and nonsmokers. Blood samples were collected from 267 Pb workers who received their annual health examination in the Kaohsiung Medical University Hospital. Glutathione peroxidase 1 (GPx-1) rs1050450 and cytochrome B-245 Alpha Chain (CYBA) rs4673 single-nucleotide polymorphisms (SNP) were analyzed by specific primer-probes using Real-Time PCR methods. The interaction between blood Pb and smoking increased serum levels of TBARS and the ratio of oxidative low-density lipoprotein and low-density lipoprotein (oxLDL/LDL). Analysis of workers with rs1050450 SNPs showed higher blood Pb levels in the workers with CC genotype than those with CT genotype. Smokers had significantly higher blood Pb, alanine transaminase (ALT), TBARS, and OxLDL levels than nonsmokers. TBARS increased 0.009 nmol/mL when blood Pb increased one µg/dL in smokers compared to nonsmokers. The ratio of OxLDL/LDL increased 0.223 when blood Pb increased one µg/dL in smokers compared to nonsmokers. TBARS levels and the ratio of OxLDL/LDL were positively correlated and interacted between blood Pb and smoking after the adjustment of confounders, suggesting that smoking cessation is an important issue in the Pb-exposed working environment.


Assuntos
Chumbo , Estresse Oxidativo , Fumar/efeitos adversos , Humanos , Chumbo/efeitos adversos , Peroxidação de Lipídeos , Estresse Oxidativo/genética , Substâncias Reativas com Ácido Tiobarbitúrico
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