1.Ferroptosis in acute leukemia.
Tianxin LYU ; Xudong LI ; Yongping SONG
Chinese Medical Journal 2023;136(8):886-898
Ferroptosis is an iron-dependent cell death pathway that is different from apoptosis, pyroptosis, and necrosis. The main characteristics of ferroptosis are the Fenton reaction mediated by intracellular free divalent iron ions, lipid peroxidation of cell membrane lipids, and inhibition of the anti-lipid peroxidation activity of intracellular glutathione peroxidase 4 (GPX4). Recent studies have shown that ferroptosis can be involved in the pathological processes of many disorders, such as ischemia-reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of acute leukemia still need to be more fully and deeply studied. This article reviews the characteristics of ferroptosis and the regulatory mechanisms promoting or inhibiting ferroptosis. More importantly, it further discusses the role of ferroptosis in acute leukemia and predicts a change in treatment strategy brought about by increased knowledge of the role of ferroptosis in acute leukemia.
Humans
;
Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism*
;
Ferroptosis
;
Cell Death
;
Iron/metabolism*
;
Leukemia, Myeloid, Acute
2.New perspectives on ferroptosis and its role in hepatocellular carcinoma.
Tianhao CONG ; Yingen LUO ; Yan FU ; Yu LIU ; Yujie LI ; Xiao LI
Chinese Medical Journal 2022;135(18):2157-2166
For a long time, the morbidity and mortality rates of hepatocellular carcinoma (HCC) have remained high. Since the concept of ferroptosis was introduced in 2012, researchers' perspectives have shifted toward finding novel ferroptosis-related treatment strategies, especially for tumors that are resistant to apoptosis. In recent years, there have been an increasing number of studies on ferroptosis, and these studies have found that ferroptosis has great potential and promise for cancer treatment. Ferroptosis is a kind of regulated cell death (RCD); unlike apoptosis, ferroptosis is an iron-dependent type of RCD driven by lipid peroxidation. The whole process of ferroptosis mainly revolves around three pathways (system xc-/ glutathione peroxidase 4 [GPX4]), lipid peroxidation, and iron metabolism), which are also regulated by various metabolic factors. This review will attempt to analyze the relationship between the system xc-/GPX4 pathway, lipid peroxidation, iron metabolism, and ferroptosis from three aspects (triggering, execution, and regulation), and the regulatory factors for ferroptosis will be summarized. In this review, we will also illustrate the relationship between ferroptosis and tumors as well as its application in tumors from the perspective of HCC. Finally, we will summarize the current limitations and needs and provide perspectives related to the focus of development in the future.
Humans
;
Ferroptosis
;
Carcinoma, Hepatocellular/metabolism*
;
Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism*
;
Cell Death
;
Liver Neoplasms/metabolism*
;
Lipid Peroxidation
;
Iron/metabolism*
3.Lycium barbarum Polysaccharides Promotes Mitochondrial Biogenesis and Energy Balance in a NAFLD Cell Model.
Yan-Nan ZHANG ; Yi-Qiong GUO ; Yan-Na FAN ; Xiu-Juan TAO ; Qing-Han GAO ; Jian-Jun YANG
Chinese journal of integrative medicine 2022;28(11):975-982
OBJECTIVE:
To explore the protective effect and underlying mechanism of Lycium barbarum polysaccharides (LBP) in a non-alcoholic fatty liver disease (NAFLD) cell model.
METHODS:
Normal human hepatocyte LO2 cells were treated with 1 mmol/L free fatty acids (FFA) mixture for 24 h to induce NAFLD cell model. Cells were divided into 5 groups, including control, model, low-, medium- and high dose LBP (30,100 and 300 µg/mL) groups. The monosaccharide components of LBP were analyzed with high performance liquid chromatography. Effects of LBP on cell viability and intracellular lipid accumulation were assessed by cell counting Kit-8 assay and oil red O staining, respectively. Triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), adenosine triphosphate (ATP) and oxidative stress indicators were evaluated. Energy balance and mitochondrial biogenesis related mRNA and proteins were determined by quantitative real-time polymerase chain reaction and Western blot, respectively.
RESULTS:
Heteropolysaccharides with mannose and glucose are the main components of LBP. LBP treatment significantly decreased intracellular lipid accumulation as well as TG, ALT, AST and malondialdehyde levels (P<0.05 or P<0.01), increased the levels of superoxide dismutase, phospholipid hydroperoxide glutathione peroxidase, catalase, and ATP in NAFLD cell model (P<0.05). Meanwhile, the expression of uncoupling protein 2 was down-regulated and peroxisome proliferator-activated receptor gamma coactivator-1α/nuclear respiratory factor 1/mitochondrial transcription factor A pathway was up-regulated (P<0.05).
CONCLUSION
LBP promotes mitochondrial biogenesis and improves energy balance in NAFLD cell model.
Humans
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Non-alcoholic Fatty Liver Disease/drug therapy*
;
Lycium/metabolism*
;
Catalase/metabolism*
;
Organelle Biogenesis
;
Alanine Transaminase
;
Uncoupling Protein 2
;
Fatty Acids, Nonesterified
;
Mannose
;
Nuclear Respiratory Factor 1/metabolism*
;
PPAR gamma/metabolism*
;
Phospholipid Hydroperoxide Glutathione Peroxidase
;
Drugs, Chinese Herbal/pharmacology*
;
Malondialdehyde/metabolism*
;
Superoxide Dismutase/metabolism*
;
Polysaccharides/pharmacology*
;
Triglycerides
;
RNA, Messenger
;
Aspartate Aminotransferases
;
Glucose
;
Adenosine Triphosphate
4.Shenmai Injection Attenuates Myocardial Ischemia/Reperfusion Injury by Targeting Nrf2/GPX4 Signalling-Mediated Ferroptosis.
Sheng-Lan MEI ; Zhong-Yuan XIA ; Zhen QIU ; Yi-Fan JIA ; Jin-Jian ZHOU ; Bin ZHOU
Chinese journal of integrative medicine 2022;28(11):983-991
OBJECTIVE:
To examine the effect of Shenmai Injection (SMJ) on ferroptosis during myocardial ischemia reperfusion (I/R) injury in rats and the underlying mechanism.
METHODS:
A total of 120 SPF-grade adult male SD rats, weighing 220-250 g were randomly divided into different groups according to a random number table. Myocardial I/R model was established by occluding the left anterior descending artery for 30 min followed by 120 min of reperfusion. SMJ was injected intraperitoneally at the onset of 120 min of reperfusion, and erastin (an agonist of ferroptosis), ferrostatin-1 (Fer-1, an inhibitor of ferroptosis) and ML385 (an inhibitor of nuclear factor erythroid-2 related factor 2 (Nrf2)) were administered intraperitoneally separately 30 min before myocardial ischemia as different pretreatments. Cardiac function before ischemia, after ischemia and after reperfusion was analysed. Pathological changes in the myocardium and the ultrastructure of cardiomyocytes were observed, and the myocardial infarction area was measured. Additionally, the concentration of Fe2+ in heart tissues and the levels of creatine kinase-MB (CK-MB), troponin I (cTnl), malondialdehyde (MDA) and superoxide dismutase (SOD) in serum were measured using assay kits, and the expressions of Nrf2, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were examined by Western blot.
RESULTS:
Compared with the sham group, I/R significantly injured heart tissues, as evidenced by the disordered, ruptured and oedematous myocardial fibres; the increases in infarct size, serum CK-MB, cTnI and MDA levels, and myocardial Fe2+ concentrations; and the decreases in SOD activity (P<0.05). These results were accompanied by ultrastructural alterations to the mitochondria, increased expression of ACSL4 and inhibited the activation of Nrf2/GPX4 signalling (P<0.05). Compared with I/R group, pretreatment with 9 mL/kg SMJ and 2 mg/kg Fer-1 significantly reduced myocardial I/R injury, Fe2+ concentrations and ACSL4 expression and attenuated mitochondrial impairment, while 14 mg/kg erastin exacerbated myocardial I/R injury (P<0.05). In addition, cardioprotection provided by 9 mL/kg SMJ was completely reversed by ML385, as evidenced by the increased myocardial infarct size, CK-MB, cTnI, MDA and Fe2+ concentrations, and the decreased SOD activity (P<0.05).
CONCLUSIONS
Ferroptosis is involved in myocardial I/R injury. Pretreatment with SMJ alleviated myocardial I/R injury by activating Nrf2/GPX4 signalling-mediated ferroptosis, thereby providing a strategy for the prevention and treatment of ischemic heart diseases.
Animals
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Male
;
Rats
;
Coenzyme A
;
Creatine Kinase
;
Ferroptosis
;
Ligases
;
Malondialdehyde
;
Myocardial Infarction/drug therapy*
;
Myocardial Ischemia/drug therapy*
;
Myocardial Reperfusion Injury/pathology*
;
Myocytes, Cardiac/metabolism*
;
NF-E2-Related Factor 2/metabolism*
;
Phospholipid Hydroperoxide Glutathione Peroxidase
;
Rats, Sprague-Dawley
;
Superoxide Dismutase/metabolism*
;
Troponin I