A Self-Amplifying Nanodrug to Manipulate Janus-Faced Nature of Ferroptosis for Tumor Therapy

Ferroptosis, an unusual nonapoptotic cell death caused by iron-dependent accumulation of lipid peroxide, enables flexible design of antitumor platform. Specifically, as a positive role, ferroptosis can induce immune response accompanied...

Oxidative Effects in Streptozotocin-induced Male and Female Mice: The Effect of Garlic Oil and Melatonin

Background: Recent studies have revealed that a hyperglycemia-induced overproduction of superoxide can be the first event in the activation of all pathways involved in the pathogenesis of complications of diabetes. Supplementation of garlic was found to decrease diabetes-induced oxidative stress complications. Studies shown also that melatonin attenuates diabetes‐induced oxidative stress in diabetic induced rabbits and rats. Objective: In this present study, oxidative stress in diabetic model and the effect of garlic oil or melatonin treatment were examined in both genders' male and females' mice. Methods: 96 mice were randomly divided into 5 groups including control (C), diabetic (D), melatonin 10 mg/kg (D+M), garlic extract 100 mg/kg (D+G) and combined melatonin and garlic (D+M+G). All treatments were given orally daily for 16 weeks after induction of hyperglycemia by streptozocin (STZ). Fasting blood glucose and antioxidant levels were estimated. Results: Streptozotocin induced diabetic mice, showed a significant increase of plasma glucose, lipid peroxide and uric acid. Accordingly, significant decreases in the levels of antioxidants ceruloplasmin were found in the plasma of diabetic mice. Treatment of diabetic mice with garlic oil or melatonin for 16 weeks significantly increased plasma levels of ceruloplasmin activities. Lipid peroxides, uric acid, blood glucose was decreased significantly after treatment with garlic oil or melatonin. Conclusion: The results suggest that garlic oil or melatonin may effectively normalize the impaired antioxidants status in streptozotocin induced diabetes in both males and females mice.

The Emerging Role of Ferroptosis in Liver Diseases

Ferroptosis is a newly discovered type of cell death mediated by iron-dependent lipid peroxide. The disturbance of iron metabolism, imbalance of the amino acid antioxidant system, and lipid peroxide accumulation are considered distinct fingerprints of ferroptosis. The dysregulation of ferroptosis has been intensively studied in recent years due to its participation in various diseases, including cancer, kidney injury, and neurodegenerative diseases. Notably, increasing evidence indicates that ferroptosis plays different roles in a wide spectrum of liver diseases. On the one hand, inhibiting ferroptosis may counteract the pathophysiological progression of several liver diseases, such as alcoholic liver injury, nonalcoholic steatosis hepatitis and fibrosis. On the other hand, inducing ferroptosis may restrict the emergence of secondary resistance to current medicines, such as sorafenib, for hepatocellular carcinoma (HCC) therapy. Here, we summarize the biological characteristics and regulatory signalling pathways of ferroptosis involved in liver disease. The current available medical agents targeting ferroptosis, including inducers or inhibitors applied in liver diseases, are also reviewed. This work aims to provide new insight into the emerging role of pathogenesis and therapeutic approaches for liver diseases.

Influence of Polyunsaturated Fatty Acid Intake on Kidney Functions of Rats with Chronic Renal Failure

Arachidonic acid (ARA), an omega-6 (ω-6) polyunsaturated fatty acid (PUFA), is involved in the development and maintenance of renal functions, whereas docosahexaenoic acid (DHA) is an omega-3 (ω-3) PUFA that has anti-inflammatory effects and attenuates nephropathy. However, their effects on the progression of chronic kidney disease (CKD) remain unknown. The aim of this study was to assess the effects of feeding ARA, DHA, and ARA and DHA-containing diets on rats with 5/6 nephrectomized kidneys. Urine and feces were collected every 4 weeks, and the kidneys were collected at 16 weeks after surgery. Urinary albumin (U-ALB) excretion increased gradually with nephrectomy, but the U-ALB excretion was attenuated by feeding the rats with an ARA + DHA-containing diet. Reactive oxygen species (ROS) levels in the kidneys were lower in the ARA + DHA group than in the other groups. At 4 weeks after surgery, the lipid peroxide (LPO) levels in the plasma of the ARA + DHA groups decreased significantly after surgery compared to the control CKD group, but this did not happen at 16 weeks post-surgery. There was a significant negative correlation between LPO levels in the plasma at 4 weeks and creatinine clearance, and a positive correlation with urinary albumin levels. These results suggest that the combination of ARA and DHA inhibit the progress of early stage CKD.

Evaluation of Paromomycin Loaded Chitosan Nanoparticles and Oxidative Stress Activities against Entamoeba Histolytica

This investigation was carried out to estimate the antiparasitic potential of chitosan nanoparticles loaded with paromomycin against Entamoeba histolytica infected. After rats inoculated orally in a dose 103 viable cysts for acute infection; then treated with paromomycin, chitosan nanoparticles as a single or combined therapy given for seven days. Stool examination revealed a significant decrease in the number of Entamoeba histolytica cysts in all treated infected rats compared with infected non-treated. Combined treatment provided better results than single treatment. The best effect was observed in the group of rats treated with chitosan nanoparticles loaded with paromomycin. Also, the oxidative stress markers Glutathione (GSH) and Lipid Peroxide (Malondialdehyde) (MDA) were assessed in liver tissue homogenate. The current work is the first time of using chitosan nanoparticles loaded with paromomycin as therapeutic agents against experimental amoebiasis. It was shown that the highest degree of effectiveness attained by the synergistic action of paromomycin and chitosan nanoparticles as was indicated by lower parasite count and GSH, MDA concentration.

FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis

Background Ferroptosis is a newly identified type of programmed cell death, which preferentially targets iron-rich cancer cells such as hepatocellular carcinoma (HCC). Ferritin heavy chain (FTH) is a major iron storing nanocage to store redox-inactive iron, and harbors ferroxidase activity to prevent the iron-mediated production of ROS. Our previous studies have demonstrated that FTH acts as a protective role to increase the cellular resistance to ferroptosis. However, the specific role of FTH in the development of HCC and ferroptosis resistance remains unclear. Methods The indicated databases were used for bioinformatics analysis. The abilities of cell proliferation, migration were measured by cell proliferation assay, transwell assay and wound healing assay. The levels of reactive oxygen species (ROS), lipid peroxide, free iron, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were determined by DCF-DA, C11-BODIPY, mitoSOX, mitoTracker, JC-10 and TMRM staining, respectively. The mitochondrial oxygen consumption rate was monitored by the Seahorse XF24 Analyzer. Results The pan-cancer analysis was performed and showed that FTH expression is upregulated in multiple cancers, such as LIHC, CHOL, HNSC, compared to corresponding normal tissues. In addition, the level of serum ferritin is positively associated with the progression of hepatitis, cirrhosis liver and hepatocellular carcinoma. Further investigation shed light on the strong correlation between FTH expression and tumor grades, cancer stages and prognosis of HCC. Importantly, the proteins interaction network elucidated that FTH is involved in iron homeostasis maintenance and lysosomal-dependent degradation. Enforced expression of FTH accelerates proliferation, migration and endows HCC cells specifically resistant to ferroptosis, but does not protect against cell death caused by cytotoxic compounds like oxaliplatin, irinotecan, and adriamycin. Mechanically, FTH reconstituted cells exhibit diminished peroxides accumulation, reduce mitochondrial ROS level, attenuate the impaired mitochondrial respiratory and rescue the mitochondrial homeostasis. Notably, FTH expression boosts tumorigenic potential in vivo with increased PCNA staining and lesser lipid peroxides generation. Conclusion These results provide new insights that FTH acts as an oncogene in the carcinogenesis and progression of HCC, and is hopeful to be a potential target for therapeutic intervention through ferroptosis.

An osmium-peroxo complex for photoactive therapy of hypoxic tumors

Its limited therapeutic effect on hypoxic and refractory solid tumors has hindered the practical application of photodynamic therapy (PDT). Herein, we report our investigation of an osmium-peroxo complex (Os2), which is inactive in the dark, but upon light irradiation, can release a peroxo ligand O2•−, and is transformed into a cytotoxic osmium complex (Os1). The osmium-peroxo complex Os2 produces O2•− under light irradiation even in the absence of oxygen, and retains its phototoxicity in hypoxic tumors. Os1 is cytotoxic in the presence or absence of irradiation, behaves as a chemotherapeutic drug. The light-activated Os2 induces distinct ferroptosis, which is mediated by GSH degradation, lipid peroxide accumulation and down-regulation of glutathione peroxidase 4 (GPX4). In addition, Os2 causes photocatalytic oxidation of endogenous 1,4-dihydronicotinamide adenine dinucleotide (NADH) in living cancer cells, leading to ferroptosis. In vivo studies have confirmed that the Os2 can effectively inhibit the growth of solid hypoxic tumors in mice. A new strategy is proposed for the treatment of hypoxic tumors with metal-based drugs.

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

Intracerebral hemorrhage (ICH) is a highly fatal type of stroke that leads to various types of neuronal death. Recently, ferroptosis, a form of cell death resulting from iron-dependent lipid peroxide accumulation, was observed in a mouse ICH model. N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine (HET0016), which inhibits synthesis of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), has shown a protective effect after ICH. However, the underlying mechanisms of the neuroprotective effect need further investigation. We explored whether 20-HETE participates in ICH-induced ferroptosis ex vivo by using hemoglobin-treated organotypic hippocampal slice cultures (OHSCs) and in vivo by using a collagenase-induced ICH mouse model. Ex vivo, we found that the 20-HETE synthesis inhibitor HET0016 and antagonist 20-6,15-HEDGE reduced hemoglobin-induced cell death, iron deposition, and lipid reactive oxygen species levels in OHSCs. Furthermore, 20-HETE inhibition in OHSCs increased the expression of glutathione peroxidase (GPX) 4, an antioxidant enzyme that serves as a main regulator of ferroptosis. In contrast, exposure of OHSCs to the 20-HETE stable mimetic 20-5,14-HEDGE induced cell death that was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. In vivo, HET0016 treatment ameliorated focal deficits, reduced lesion volume, and decreased iron accumulation around the lesion at day 3 and 7 after ICH. In addition, lipid peroxidation was decreased and expression of GPX4 was increased in the HET0016-treated ICH group. The mitogen-activated protein kinase pathway also was inhibited by HET0016 in vivo. These results indicate that 20-HETE contributes to ICH-induced acute brain injury in part by activating ferroptosis pathways, thereby providing an upstream target for inhibiting ferroptosis.

E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme

Aims: E-cigarette aerosol containing aldehydes, including acetaldehyde, are metabolized by the enzyme aldehyde dehydrogenase 2 (ALDH2). However, little is known how aldehyde exposure from e-cigarettes, when coupled with an inactivating ALDH2 genetic variant, ALDH2*2 (present in 8% of the world population), affects cardiovascular oxidative stress. The aim of this study was to determine how e-cigarette aerosol exposure, when coupled with genetics, impacts cardiovascular oxidative stress in wild type ALDH2 and ALDH2*2 knock-in mice. Methods and Results: Using selective ion flow mass spectrometry, we determined that e-cigarette aerosol contains acetaldehyde that are 10-fold higher than formaldehyde or acrolein. Next, using wild type ALDH2 and ALDH2*2 knock-in rodents, we identified organ-specific differences in ALDH2 with the heart having 1.5-fold less ALDH2 enzyme activity relative to the liver and lung. In isolated cardiac myocytes, acetaldehyde exposure (30seconds, 0.1-1μM) caused a 4-fold greater peak in calcium levels for ALDH2*2 relative to ALDH2 cardiomyocytes. ALDH2*2 cardiomyocytes exposed to acetaldehyde also demonstrated a 2-fold increase in ROS production and 2.5-fold increase in 4HNE protein adducts relative to ALDH2 cardiomyocytes. For intact rodents, ALDH2*2 knock-in mice exposed to e-cigarette aerosol had an increased heart rate beginning 5 days after exposure compared to wild type ALDH2 mice (775±30bpm versus 679±33bpm, respectively, *p<0.01, n=7-8 per group). E-cigarette aerosol exposure also exacerbated oxidative stress in ALDH2*2 heart homogenates, including a 1.3-fold higher protein carbonyl level, a 1.7-fold higher lipid peroxide level and 1.5-fold greater phosphorylation of NF-κB relative to wild type ALDH2 homogenates. Conclusions: The increased oxidative stress from e-cigarette aerosol aldehydes triggers the proinflammatory NF-κB pathway. As ALDH2 expression and activity is lower in the heart relative to the lung, the heart could be more susceptible to increases in cardiovascular oxidative stress from e-cigarette aerosol; particularly for those carrying an ALDH2*2 genetic variant which limits acetaldehyde metabolism.