Ferroptosis is a type of regulated cell death driven by iron-dependent lipid peroxidation that has received extensive attention in recent years. A growing body of evidence suggests that ferroptosis contributes to the progression of drug-induced liver injury. Therefore, the role and mechanism of ferroptosis in the process of drug-induced liver injury deserve further extensive and in-depth exploration, which will aid in the discovery of novel biomarkers as well as the identification of potential approches of targeting ferroptosis to intervene in drug-induced liver injury.
Humans ; Biomarkers/metabolism* ; Chemical and Drug Induced Liver Injury ; Ferroptosis ; Iron/metabolism* ; Lipid Peroxidation/physiology*

The testis is an immune-privileged organ susceptible to oxidative stress and inflammation, two major factors implicated in male infertility. A reduction in the concentration and activities of testicular function biomarkers has been shown to correlate with impaired hypothalamic-pituitary-testicular axis and oxidative stress. However, the use of natural products to ameliorate these oxidative stress-induced changes may be essential to improving male reproductive function. Quercetin possesses several pharmacological activities that may help to combat cellular reproduction-related assaults, such as altered sperm function and reproductive hormone dysfunction, and dysregulated testicular apoptosis, oxidative stress, and inflammation. Studies have shown that quercetin ameliorates testicular toxicity, largely by inhibiting the generation of reactive oxygen species, with the aid of the two antioxidant pharmacophores present in its ring structure. The radical-scavenging property of quercetin may alter signal transduction of oxidative stress-induced apoptosis, prevent inflammation, and increase sperm quality in relation to the hormonal concentration. In this review, the therapeutic potential of quercetin in mediating male reproductive health is discussed.
Antioxidants/pharmacology* ; Apoptosis ; Humans ; Inflammation/drug therapy* ; Lipid Peroxidation ; Male ; Oxidative Stress ; Quercetin/pharmacology* ; Semen ; Testis

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*

OBJECTIVE: To investigate evodiamine (EVO)-induced hepatotoxicity and the underlying mechanism. METHODS: HepG2 cells were treated with EVO (0.04-25 μmol/L) for different time intervals, and the cell survival rate was examined by cell counting kit-8 (CCK-8) method. After HepG2 cells were treated with EVO (0.2, 1 and 5 μmol/L) for 48 h, the alanine transaminase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) activities and total bilirubin (TBIL) content of supernatant were detected. A multifunctional microplate reader was used to detect the intracellular superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in HepG2 cells to evaluate the level of cell lipid peroxidation damage. The interactions between EVO and apoptosis, autophagy or ferroptosis-associated proteins were simulated by molecular docking. The HepG2 cells were stained by mitochondrial membrane potential (MMP) fluorescent probe (JC-10) and annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI), and MMP and apoptosis in HepG2 cells were detected by flow cytometry. The protein expression levels of caspase-9, caspase-3, bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) were detected by Western blot. RESULTS: The cell survival rate was significantly reduced after the HepG2 cells were exposed to EVO (0.04-25 μmol/L) in a time- and dose-dependent manner. The half maximal inhibitory concentration (IC50) of the HepG2 cells treated with EVO for 24, 48 and 72 h were 85.3, 6.6 and 4.7 μmol/L, respectively. After exposure to EVO (0.2, 1 and 5 μmol/L) for 48 h, the ALT, AST, LDH, ALP activities and TBIL content in the HepG2 cell culture supernatant, and the MDA content in the cells were increased, and SOD enzyme activity was decreased. Molecular docking results showed that EVO interacted with apoptosis-associated proteins (caspase-9 and caspase-3) better. JC-10 and Annexin V-FITC/PI staining assays demonstrated that EVO could decrease MMP and promote apoptosis in the HepG2 cells. Western blot results indicated that the protein expressions of cleaved caspase-9 and cleaved caspase-3 were upregulated in the HepG2 cell treated with EVO for 48 h. In contrast, the protein expressions of pro-caspase-3, BSEP and MRP2 were downregulated. CONCLUSION These results suggested that 0.2, 1 and 5 μmol/L EVO had the potential hepatotoxicity, and the possible mechanism involved lipid peroxidation damage, cell apoptosis, and cholestasis.
ATP Binding Cassette Transporter, Subfamily B, Member 11 ; Apoptosis ; Caspase 3 ; Caspase 9 ; Cholestasis ; Hep G2 Cells/drug effects* ; Humans ; Lipid Peroxidation ; Liver/drug effects* ; Molecular Docking Simulation ; Multidrug Resistance-Associated Protein 2 ; Quinazolines/toxicity*

Ferroptosis is a newly discovered non-apoptotic form of regulated cell death driven by iron-dependent lipid peroxidation. The present studies have shown that many metabolic processes and homeostasis are affected by ferroptosis. It is related to many lung diseases, including acute lung injury, chronic obstructive pulmonary disease and pulmonary fibrosis, etc. Currently, the research on ferroptosis is still in its infancy. Previous studies have confirmed that ferroptosis is regulated by a variety of genes, and the mechanism is complex, mainly involving iron homeostasis and lipid peroxidation metabolism. This review summarizes some regulation networks of metabolic processes associated with ferroptosis and discusses the roles of ferroptosis in the pathophysiological progression of many lung diseases. We expected to provide new ideas and references for the treatment of these diseases.
Ferroptosis ; Humans ; Iron ; Lipid Peroxidation ; Metabolic Networks and Pathways ; Pulmonary Disease, Chronic Obstructive

Oxidative stress is considered a major contributor in the pathogenesis of diabetic neuropathy and in diabetes complications, such as nephropathy and cardiovascular diseases. Diabetic neuropathy, which is the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. This study aimed to investigate whether 7,8-dihydroxyflavone (7,8-DHF) protects SH-SY5Y neuronal cells against high glucose-induced toxicity. In the current study, we found that diabetic patients exhibited higher lipid peroxidation caused by oxidative stress than healthy subjects. 7,8-DHF exhibits superoxide anion and hydroxyl radical scavenging activities. High glucose-induced toxicity severely damaged SH-SY5Y neuronal cells, causing mitochondrial depolarization; however, 7,8-DHF recovered mitochondrial polarization. Furthermore, 7,8-DHF effectively modulated the expression of pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) under high glucose, thus inhibiting the activation of caspase signaling pathways. These results indicate that 7,8-DHF has antioxidant effects and protects cells from apoptotic cell death induced by high glucose. Thus, 7,8-DHF may be developed into a promising candidate for the treatment of diabetic neuropathy.
Antioxidants ; Autonomic Pathways ; Cardiovascular Diseases ; Cell Death ; Diabetes Complications ; Diabetic Neuropathies ; Glucose ; Healthy Volunteers ; Humans ; Hydroxyl Radical ; Lipid Peroxidation ; Neurons* ; Oxidative Stress* ; Superoxides

In vitro prediction of hepatotoxicity can enhance the performance of non-clinical animal testing for identifying chemical hazards. In this study, we assessed high-content analysis (HCA) using multi-parameter cell-based assays as an in vitro hepatotoxicity testing model using various hepatotoxicants and human hepatocytes such as HepG2 cells and human primary hepatocytes (hPHs). Both hepatocyte types were exposed separately to multiple doses of ten hepatotoxicants associated with liver injury whose mechanisms of action have been described. HCA data were obtained using fluorescence probes for nuclear size (Hoechst), mitochondrial membrane potential (TMRM), cytosolic free calcium (Fluo-4AM), and lipid peroxidation (BODIPY). Cellular alterations were observed in response to all hepatotoxicants tested. The most sensitive parameter was TMRM, with high sensitivity at a low dose, next was BODIPY, followed by Fluo-4AM. HCA data from HepG2 cells and hPHs were generally concordant, although some inconsistencies were noted. Both hepatocyte types showed mild or severe mitochondrial impairment and lipid peroxidation in response to several hepatotoxicants. The results demonstrate that the application of HCA to in vitro hepatotoxicity testing enables more efficient hazard identification, and further, they suggest that certain parameters could serve as sensitive endpoints for predicting the hepatotoxic potential of chemical compounds.
Animals ; Calcium ; Cytosol ; Fluorescence ; Hep G2 Cells ; Hepatocytes ; Humans ; In Vitro Techniques ; Lipid Peroxidation ; Liver ; Membrane Potential, Mitochondrial

Obesity is a substantial public health challenge across the globe. The use of resistant starch has been proposed as a probable management strategy for complications of obesity. We investigated the effects of resistant starch intake on lipid profiles, glucose metabolism, antioxidant status, lipid peroxidation marker, blood pressure, and anthropometric variables in subjects with overweight or obesity. In this 12-week, randomized, double-blind, placebo-controlled, 2 × 2 crossover trial, 21 Participants (mean age, 35 ± 7.0 years; body mass index, 32.4 ± 3.5 kg/m²) were given 13.5 g Hi-Maize 260 or placebo daily for 4 weeks, separated by a 4-week washout period. Changes in total antioxidant status (p = 0.04) and serum concentrations of insulin in 52.4% participants with insulin levels above 16 µIU/mL at the baseline (p = 0.04) were significantly different in the three phases. In addition, the mean of serum high-density lipoprotein cholesterol after the intervention was significantly higher than after baseline value (p = 0.04). We found no significant differences in serum concentrations of total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, fasting blood sugar, insulin, homeostatic model assessment of insulin resistance, quantitative insulin sensitivity check index, superoxide dismutase activity, malondialdehyde, blood pressure, and anthropometric variables in the three phases of baseline, after intervention with resistant starch and after placebo. Resistant starch consumption improved serum insulin concentrations, lipid profiles, and antioxidant status in subjects with overweight or obesity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01992783
Adult ; Blood Glucose ; Blood Pressure ; Body Mass Index ; Cholesterol ; Dietary Fiber ; Fasting ; Glucose ; Humans ; Insulin ; Insulin Resistance ; Lipid Metabolism ; Lipid Peroxidation ; Lipoproteins ; Malondialdehyde ; Metabolism ; Obesity ; Overweight ; Oxidative Stress ; Public Health ; Starch ; Superoxide Dismutase ; Triglycerides

The purpose of this study was to investigate the effects of isoflavone on serum lipids and antioxidant enzymes activities in growing rats fed high lard diet. Twenty four female Sprague-Dawley rats (body weight 50–60 g) were divided into three groups, control, high fat (HF, lard 200 g/kg diet) and high fat + isoflavone (HFI, lard 200 g/kg diet + isoflavone 310.9 mg/kg diet) for 4 weeks. The results of study indicated that body weight gain was not different by isoflavone diet. Mean intake was significantly lower in HF group and HFI group than control group. Food efficiency ratio was significantly higher in HF group and HFI group than control group. The level of serum triglyceride and total cholesterol were significantly lower in HFI group than control group and HF group. The level of high-density lipoprotein cholesterol, was significantly higher in control group than HF group and HFI group. The level of low-density lipoprotein cholesterol was not significantly different by experimental diets, but atherogenic index (AI) was significantly lower in control group and HFI group than HF group. Contents of total cholesterol and triglyceride in liver tissues were found to be insignificant. The concentration of lipid peroxidation, malondialdehyde was significantly lower in control groups and HFI group than HF group. And antioxidant enzymes in liver tissue were not significantly different by lard and isoflavone supplemented diets. In conclusion, it seems possible that isoflavone supplemented high fat diet may produce positive results on level of serum triglyceride, serum total cholesterol, AI and concentration of malondialdyhyde.
Animals ; Antioxidants ; Body Weight ; Cholesterol ; Control Groups ; Diet ; Diet, High-Fat ; Female ; Humans ; Isoflavones ; Lipid Peroxidation ; Lipoproteins ; Liver ; Malondialdehyde ; Rats ; Rats, Sprague-Dawley ; Triglycerides

BACKGROUND: Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS: A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS: Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μmol/L to 1.91 ± 0.72 μmol/L; P = 0.002) but not in the non-responder group. CONCLUSION: The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.
Antioxidants ; Blood Pressure ; Creatinine ; Diabetic Nephropathies ; Dialysis ; Humans ; Indican ; Korea ; Lipid Peroxidation ; Oxidative Stress ; Prospective Studies ; Renal Insufficiency, Chronic