• Journal of Yeungnam Medical Science
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• v.34 no.2
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• pp.174-181
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• 2017

Ferroptosis is a newly recognized type of cell death that results from iron-dependent lipid peroxidation and is different from other types of cell death, such as apoptosis, necrosis, and autophagic cell death. This type of cell death is characterized by mitochondrial shrinkage with an increased mitochondrial membrane density and outer mitochondrial membrane rupture. Ferroptosis can be induced by a loss of activity of system $X_c{^-}$ and the inhibition of glutathione peroxidase 4, followed by the accumulation of lipid reactive oxygen species (ROS). In addition, inactivation of the mevalonate and transsulfuration pathways is involved in the induction of ferroptosis. Moreover, nicotinamide adenine dinucleotide phosphate oxidase and p53 promote ferroptosis by increasing ROS production, while heat shock protein beta-1 and nuclear factor erythroid 2-related factor 2 inhibit ferroptosis by reducing iron uptake. This article outlines the molecular mechanisms and signaling pathways of ferroptosis regulation, and explains the roles of ferroptosis in human disease.

• Journal of Microbiology and Biotechnology
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• v.33 no.8
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• pp.992-997
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• 2023

Ferroptosis is a new kind of programmed cell death of which occurrence in microorganisms is not clearly verified. The elevated level of reactive oxygen species (ROS) influences cellular metabolisms through highly reactive hydroxyl radical formation under the iron-dependent Fenton reaction. Iron contributes to ROS production and acts as a cofactor for lipoxygenase to catalyze poly unsaturated fatty acid (PUFA) oxidation, exerting oxidative damage in cells. While ferroptosis is known to take place only in mammalian cells, recent studies discovered the possible ferroptosis-like death in few specific microorganisms. Capacity of integrating PUFA into intracellular membrane phospholipid has been considered as a key factor in bacterial or fungal ferroptosis-like death. Vibrio species in bacteria and Saccharomyces cerevisiae in fungi exhibited certain characteristics. Therefore, this review focus on introducing the occurrence of ferroptosis-like death in microorganisms and investigating the mode of action underlying the cells based on contribution of lipid peroxidation and iron-dependent reaction.

• Molecular Medicine Reports
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• v.20 no.4
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• pp.3933-3941
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• 2019

The microbiome has recently attracted research interest in a variety of subjects, including cancer. In the present study, it was determined that reinforced clostridium media (RC M) for microbiome culture, exerts antitumor effects on renal cell carcinoma cells when compared to the microbiome 'X'. The antitumor effects of RC M were investigated for all ingredients of RC M, and the results revealed that yeast extract could be a candidate for the ingredient driving this phenomenon. Further experiments including MTT assay, cell counting, cell death analysis, cell cycle analysis and western blotting were conducted with yeast extract on renal cell carcinoma cells (Caki-1 and Caki-2) and normal human proximal tubular cells (HK-2). As a result, yeast extract exhibited dose-dependent antitumor effects on Caki-1 and Caki-2, but only slight effects on HK-2. In addition, yeast extract only exhibited slight effects on necrosis, autophagy, or apoptosis of Caki-1 and Caki-2. Yeast extract produced cell cycle arrest with an increased G0/G1 fraction and a decreased S fraction, and this was considered to be related to the decreased cyclin D1. Although yeast extract treatment increased anti-oxidant activities, the antitumor effects of yeast extract were also related to iron metabolism, based on the decreased transferrin receptor and increased ferritin. In addition, decreased GPX4 may be related to iron-dependent cell death, particularly in Caki-2. These results revealed that yeast extract may inhibit proliferation of renal cell carcinoma cells by regulating iron metabolism. Since an increased iron requirement is a classic phenomenon of cancer cells, yeast extract may be a candidate for adjuvant treatment of renal cell carcinoma.

• Korean Journal of Clinical Laboratory Science
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• v.43 no.4
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• pp.161-170
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• 2011

Quercetin is one of the most distributed flavonoids in the plant kingdom and occurs naturally in a wide range of fruits and vegetables. This study was undertaken to determine whether quercetin exerts beneficial effect against necrotic and apoptotic cell death induced by hydrogen peroxide ($H_2O2$) in intestinal cells using the human-derived cultured T84 colonic epithelial cell line. Necrotic cell death was induced by exposing cells to 0.5 mM $H_2O_2$ for 2 h and apoptosis was induced by incubating cells in normal culture medium for 18 h following exposure of cells to 0.5 mM $H_2O2$ for 2 h. Cell viability was evaluated by the trypan blue exclusion assay and apoptosis was assessed by Hoechst 33258 staining and flow cytometry. $H_2O_2$ induced necrotic cell death in a time and dose-dependent fashion. Both necrotic and apoptotic cell deaths were not prevented by the antioxidants N,N'-diphenyl-p-phenylenediamine(DPPD) and Trolox, whereas both cell deaths induced by the organic hydroperoxide t-butylhydroperoxide (tBHP) were prevented by DPPD, suggesting that $H_2O_2$ induces cell death through a lipid peroxidation-independent mechanism. $H_2O2$-induced necrotic death was prevented by deferoxamine and 3-aminobenzamide, while the apoptotic cell death was not affected by these agents. Quercetin prevented both necrotic and apoptotic cell deaths induced by $H_2O_2$ in a dose-dependent manner. $H_2O_2$ caused activation of poly (ADP-ribose) polmerase (PARP), which was inhibited by deferoxamine, 3-aminobenzamide, and quercetin, but not DPPD. These results indicate that quercetin inhibits both necroticand apoptotic deaths of T84 cells. The anti-necrotic effect of quercetin may be attributed to its iron chelator activity rather than a direct $H_2O_2$ scavenging capacity and antioxidant. The present study suggests that quercetin may play a therapeutic role in the treatment of human gastrointestinal diseases mediated by oxidants.

• BMB Reports
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• v.41 no.2
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• pp.164-169
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• 2008

The tumor suppressor gene p53 regulates apoptotic cell death and the cell cycle. In this study, we investigated the role of p53 in nitric oxide (NO)-induced apoptosis in vascular smooth muscle cells (VSMCs). We found that the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) increased apoptotic cell death in p53-deficient VSMCs compared with wild-type cells. The heme oxygen-ase (HO) inhibitor tin protoporphyrin IX reduced the resistance of wild-type VSMCs to SNAP-induced cell death. SNAP promoted HO-1 expression in both cell types. HO-2 protein was increased only in wild-type VSMCs following SNAP treatment; however, similar levels of HO-2 mRNA were detected in both cell types. SNAP significantly increased the levels of non-heme-iron and dinitrosyl iron-sulfur clusters in wild-type VSMCs compared with p53-deficient VSMCs. Moreover, pretreatment with FeSO4 and the carbon monoxide donor CORM-2, but not biliverdin, significantly protected p53-deficient cells from SNAP-induced cell death compared with normal cells. These results suggest that wild-type VSMCs are more resistant to NO-mediated apoptosis than p53-deficient VSMCs through p53-dependent up-regulation of HO-2.

• The Journal of Korean Medicine
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• v.25 no.4
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• pp.61-78
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• 2004

Objective : This study was undertaken to determine whether Gamibaegi-eum (BGU) in vitro and in vivo exerts a beneficial effect against cell injury induced by reactive oxygen species (ROS) in the human intestine. Methods : Effects of BGU in vitro on cell injury were examined using Caco-2 cells, cultured human intestinal cell line. Exposure of cells to H₂O₂ induced increases in the loss of cell viability in a time and dose-dependent fashion. Results : BGU prevented H₂O₂-induced cell death and its effect was dose-dependent over a concentration range of 0.05­1%. H₂O₂-induced cell death was prevented by catalase, the hydrogen peroxide scavenger enzyme, and deferoxamine, the iron chelator. However, the potent antioxidant DPPD did not affect H₂O₂-induced cell death. H₂O₂ increased lipid peroxidation, which was inhibited by BGU and DPPD. H₂O₂ caused DNA damage in a dose-dependent manner, which was prevented by BGU, catalase, and deferoxamine, but not DPPD. BGU restored ATP depletion induced by H₂O₂. BGU inhibited generation of superoxide and H₂O₂ and scavenged directly H₂O₂. Oral administration of mepirizole in vivo at a dose of 200mg/kg resulted in ulcer lesions in the stomach and the proximal duodenum. Pretreatment of BGU(0.1%/kg, orally) and catalase (800Units/kg, i.v.) significantly decreased the size of ulcers. Mepirizole increased lipid peroxidation in the mucosa of the duodenum, suggesting an involvement of ROS. Pretreatment of BGU and catalase significantly inhibited lipid peroxidation induced by mepirizole. Morphological studies showed that mepirizole treatment causes duodenal injury and its effect is prevented by BGU. Conclusion : These results indicate that BGU exerts a protective effect against cell injury in vitro and in vivo through antioxidant action. The present study suggests that BGU may playa therapeutic role in the treatment of human gastrointestinal diseases mediated by ROS.

• Journal of Acupuncture Research
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• v.17 no.3
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• pp.208-218
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• 2000

This study was undertaken to determine if Salviae Radix (SR) exerts protective effect against oxidant-induced inhibition of phosphate uptake in renal proximal tubular cells. Membrane transport function and cell death were evaluated by measuring phosphate uptake and trypan blue exclusion, respectively, in opossum kidney (OK) cells, an established proximal tubular cell line. $H_2O_2$ was used as a model oxidant. $H_2O_2$ inhibited the phosphate uptake in a dose-dependent manner over the concentration range of 0.1-0.5 mM. Similar fashion was observed in cell death. However, the phosphate uptake was more vulnerable to $H_2O_2$ than cell death, suggesting that $H_2O_2$-induced inhibition of phosphate uptake is not totally attributed to cell death. Decreasedphosphate uptake was associated with ATP depletion and inhibition of $Na^+$-pump activity as determined by direct inhibition of $N^+-K^+$-ATPase activity. When cells were treated with $H_2O_2$ in the presence of 0.05% SR, the inhibition of phosphate uptake and cell death induced by $H_2O_2$ was significantly attenuated. SR restored ATP depletion and decreased $Na^+-K^+$-ATPase activity, and this is likely responsible for the protective effect of SR on decreased phosphate uptake. The protective effect of SR was similar to the $H_2O_2$ scavenger catalase. SR reacts directly with $H_2O_2$ to reduce the effective concentration of the oxidant. The iron chelator deferoxamine prevented the inhibition of phosphate uptake and cell death induced by $H_2O_2$, suggesting that $H_2O_2$-induced cell injury is resulted from an iron-dependent mechanism. These results indicate that SR exerts the protective effect against $H_2O_2$-induced inhibition of phosphate uptake by reacting directly with $H_2O_2$ like the $H_2O_2$scavenger enzyme catalase, in OK cells. However, the underlying mechanism remains to be explored.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.159-164
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• 2023

Ferroptosis is a type of regulated cell death recently discovered, characterized by the accumulation of iron-dependent lipid peroxides in the cell membrane, and it involves a complex network of signaling pathways, including iron metabolism, lipid peroxidation, and redox regulation. The dysregulation of these pathways can lead to the induction of ferroptosis and the development of liver diseases, such as alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis, and liver cancer. Studies have demonstrated that targeting key molecules involved in iron metabolism, lipid peroxidation, and redox regulation can reduce liver injury and improve liver function in different liver diseases by inhibiting ferroptosis. Thus, modulation of ferroptosis presents a promising therapeutic target for treating liver diseases. However, further research is required to gain a more comprehensive understanding of the mechanisms underlying the role of ferroptosis in liver diseases and to develop more effective and targeted treatments.

• Tuberculosis and Respiratory Diseases
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• v.56 no.2
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• pp.187-197
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• 2004

Background : Nitric Oxide (NO) is a multi-faceted molecule with dichotomous regulatory roles in many areas of biology. NO can promote apoptosis in some cells, whereas it inhibits apoptosis in other cell types. This study was performed to characterize NO-induced cell death in lung epithelial cells and to investigate the roles of cell death regulators including iron, bcl-2 and p53. Methods : A549 cells were used for lung epithelial cells. SNP (sodium nitroprusside) and SNAP (S-nitroso-N-acetyl- penicillamine) were used for NO donor. Cytoxicity assay was done by MTT assay and crystal violet assay. Apoptotic assay was done by fluorescent microscopy after double staining with propidium iodide and hoecst 33342. Iron inhibition study was done with RBCs and FeSO4. For bcl-2 study, bcl-2 overexpressing cells (A549-bcl-2) were used and for p53 study, Western blot analysis and p53 functionally knock-out cells (A549-E6) were used. Results : SNP and SNAP induced dose-dependent cell death in A549 cells and fluorescent microscopy revealed that SNAP induced apoptosis in low doses but necrosis in high doses while SNP induced exclusively necrotic cell death. Iron inhibition study using RBCs and FeSO4 significantly blocked SNAP-induced cell death. And also SNAP-induced cell death was blocked by bcl-2 overexpression. Finally, we found that SNAP activate p53 by Western blot analysis and that SNAP-induced cell death was decreased in the abscence of p53. Conclusion : In lung epithelial cells, NO can induce cell death, more precisely apoptosis in low doses and necrosis in high doses. And iron, bcl-2, and p53 play important roles in NO-induced cell death.

• Clinical Nutrition Research
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• v.12 no.2
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• pp.154-167
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• 2023

Hepatic encephalopathy (HE) associated with liver failure is accompanied by hyperammonemia, severe inflammation, depression, anxiety, and memory deficits as well as liver injury. Recent studies have focused on the liver-brain-inflammation axis to identify a therapeutic solution for patients with HE. Lipocalin-2 is an inflammation-related glycoprotein that is secreted by various organs and is involved in cellular mechanisms including iron homeostasis, glucose metabolism, cell death, neurite outgrowth, and neurogenesis. In this study, we investigated that the roles of lipocalin-2 both in the brain cortex of mice with HE and in Neuro-2a (N2A) cells. We detected elevated levels of lipocalin-2 both in the plasma and liver in a bile duct ligation mouse model of HE. We confirmed changes in cytokine expression, such as interleukin-1β, cyclooxygenase 2 expression, and iron metabolism related to gene expression through AKT-mediated signaling both in the brain cortex of mice with HE and N2A cells. Our data showed negative effects of hepatic lipocalin-2 on cell survival, iron homeostasis, and neurite outgrowth in N2A cells. Thus, we suggest that regulation of lipocalin-2 in the brain in HE may be a critical therapeutic approach to alleviate neuropathological problems focused on the liver-brain axis.