Analysis of Influencing Factors on the Occurrence and Development of Gastric Cancer in High-Incidence Areas of Digestive Tract Tumors Based on High Methylation of GPX3 Gene

Stomach cancer is the second largest cause of cancer-related mortality globally, and it continues to be a reason for worry today. Inhalation of the stomach cancer risk factor H. pylori produces large levels of reactive oxygen species (ROS). When combined with glutathione reductase, glutathione peroxidase 3 (GPX3) catalyzes the reduction of hydrogen peroxide and lipid peroxides. To get a better understanding of the GPX3 gene’s role in the illness, the researchers used quantitative real-time RT-PCR to examine the gene’s expression and regulation in gastric cancer cell lines, original gastric cancer samples, and 45 normal stomach mucosa adjacent to malignancies. According to the research, GPX3 expression was decreased or silenced in eight of nine cancer cell lines and 83 percent of gastric cancer samples (90/108) as compared to normal gastric tissues in the vicinity of the tumor ( P < 0.0001 ). It was found that 60 percent of stomach cancer samples exhibited DNA hypermethylation after analyzing the GPX3 promoter ( P = 0.007 ) (a methylation level of more than 10 percent, as measured by bisulfite pyrosequencing). In stomach tumors, we found a statistically significant reduction in the amount of GPX3 DNA copies ( P < 0.001 ). The gene expression of SNU1 and MKN28 cells was restored after treatment with 5-Aza-2′ Deoxycytidine to reduce GPX3 promoter methylation. Genetic and epigenetic alterations lead GPX3 to be dysfunctional in gastric cancer. This indicates that the systems that regulate ROS have been disrupted, and GPX3 may be implicated in the development of gastric cancer, as shown by our results when evaluated alone and in combination.

Can Polyphenols Inhibit Ferroptosis?

Polyphenols, a diverse group of naturally occurring molecules commonly found in higher plants, have been heavily investigated over the last two decades due to their potent biological activities—among which the most important are their antioxidant, antimicrobial, anticancer, anti-inflammatory and neuroprotective activities. A common route of polyphenol intake in humans is through the diet. Since they are subjected to excessive metabolism in vivo it has been questioned whether their much-proven in vitro bioactivity could be translated to in vivo systems. Ferroptosis is a newly introduced, iron-dependent, regulated mode of oxidative cell death, characterized by increased lipid peroxidation and the accumulation of toxic lipid peroxides, which are considered to be toxic reactive oxygen species. There is a growing body of evidence that ferroptosis is involved in the development of almost all chronic diseases. Thus, ferroptosis is considered a new therapeutic target for offsetting many diseases, and researchers are putting great expectations on this field of research and medicine. The aim of this review is to critically analyse the potential of polyphenols to modulate ferroptosis and whether they can be considered promising compounds for the alleviation of chronic conditions.

The Role of Peroxiredoxins in the Regulation of Sepsis

Oxidative stress, a result of a disturbance in redox homeostasis, is considered to be one of the main aggravating events in the pathogenesis of immune disorders. Peroxiredoxins (Prdxs) are an enzyme family that catalyzes the reduction of peroxides, including hydrogen peroxide, lipid peroxides, and nitrogen peroxides. Although the maintenance of cellular redox homeostasis through Prdxs is essential for surviving in adverse environments, Prdxs also participate in the regulation of cellular signal transduction by modulating the activities of a panel of molecules involved in the signal transduction process. Although Prdxs were discovered as intracellular anti-oxidative enzymes, recent research has revealed that Prdxs also play important roles in the extracellular milieu. Indeed, Prdxs have been shown to have the capacity to activate immune cells through ligation with innate immune receptors such as toll-like receptors (TLRs). In this review, we will summarize the intracellular as well as extracellular roles of Prdxs for and against the pathogenesis of inflammatory disorders including sepsis, hemorrhagic shock, and drug-induced liver injury.

Attenuation of hyperglycemia and amadori products by aminoguanidine in alloxan-diabetic rabbits occurs via enhancement in antioxidant defenses and control of stress

The micro- and macro-complications in diabetes mellitus (DM) mainly arise from the damage induced by Amadori and advanced glycation end products, as well as the released free radicals. The primary goal of DM treatment is to reduce the risk of micro- and macro-complications. In this study, we looked at the efficacy of aminoguanidine (AG) to prevent the production of early glycation products in alloxan-diabetic rabbits. Type1 DM was induced in rabbits by a single intravenous injection of alloxan (90 mg/kg body weight). Another group of rabbits was pre-treated with AG (100 mg/kg body weight) prior to alloxan injection; this was followed by weekly treatment with 100 mg/kg of AG for eight weeks. Glucose, insulin, and early glycation products (HbA1C and fructosamine) were measured in control, diabetic and AG treated diabetic rabbits. The effects of hyperglycemia on superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx), reduced glutathione (rGSH), nitric oxide, lipid peroxides, and protein carbonyl were investigated. Alloxan-diabetic rabbits had lower levels of SOD, CAT, Gpx, and rGSH than control rabbits. Nitric oxide levels were considerably greater. AG administration restored the activities of SOD, CAT, Gpx enzymes up to 70–80% and ameliorated the nitric oxide production. HbA1c and fructosamine levels were considerably lower in AG-treated diabetic rabbits. The observed control of hyperglycemia and amadori adducts in alloxan-diabetic rabbits by AG may be attributed to decrease of stress and restoration of antioxidant defenses.

Active-passive Strategy for Enhanced Synergistic Photothermal-Ferroptosis Therapy in NIR-I/II Biowindows

Ferroptosis therapy (FT) is an attractive strategy to selectively damage cancer cells by lipid peroxides (LPO) over accumulation. However, this therapy suffers from poor therapeutic efficacy due to the limited...

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.

Lactose and Casein Cause Changes on Biomarkers of Oxidative Damage and Dysbiosis in an Experimental Model of Multiple Sclerosis

Background and Objectives: Experimental autoimmune encephalomyelitis (EAE) in rats closely reproduces multiple sclerosis (MS), a disease characterized by neuroinflammation and oxidative stress, that also appears to extend to other organ compartments. The origin of MS is a matter for discussion, but it would seem that altering certain bacterial populations present in the gut may lead to a proinflammatory condition due to the bacterial lipopolysaccharides (LPS) in the so-called brain-gut axis. The casein and lactose in milk confer anti-inflammatory properties and immunomodulatory effects. The objectives of this study were: to evaluate the effects of administration of casein and lactose on the oxidative damage and the clinical status caused by EAE, and to verify whether both, casein and lactose, had any effect on the LPS and its transport protein -LBP-. Methods: Twenty male dark Agouti rats were divided into: control rats (control), EAE rats and EAE rats to which casein and lactose, EAE+casein and EAE+lactose, respectively, were administered. Fifty-one days after casein and lactose administration, the rats were sacrificed and different organs were studied (brain, spinal cord, blood, heart, liver, kidney, small and large intestine). In the latter, products derived from oxidative stress were studied (lipid peroxides and carbonylated proteins) as well as the glutathione redox system, various inflammation factors (total nitrite, Nuclear Factor-kappa B p065, the Rat Tumour Necrosis Factor-α) and the LPS and LBP values. Results and Conclusion: Casein and lactose administration improved the clinical aspect of the disease at the same time as reducing inflammation and oxidative stress, exerting its action on the glutathione redox system or increasing GPx levels.

Pharmacological Targeting of Ferroptosis in Cancer Treatment

: Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.

Lauric Acid, a Dietary Saturated Medium-Chain Fatty Acid, Elicits Calcium-Dependent Eryptosis

Cardiovascular diseases (CVD) are a leading cause of mortality worldwide, and dietary habits represent a major risk factor for dyslipidemia; a hallmark of CVD. Saturated fatty acids contribute to CVD by aggravating dyslipidemia, and, in particular, lauric acid (LA) raises circulating cholesterol levels. The role of red blood cells (RBCs) in CVD is increasingly being appreciated, and eryptosis has recently been identified as a novel mechanism in CVD. However, the effect of LA on RBC physiology has not been thoroughly investigated. RBCs were isolated from heparin-anticoagulated whole blood (WB) and exposed to 50–250 μM of LA for 24 h at 37 °C. Hemoglobin was photometrically examined as an indicator of hemolysis, whereas eryptosis was assessed by Annexin V-FITC for phosphatidylserine (PS) exposure, Fluo4/AM for Ca2+, light scatter for cellular morphology, H2DCFDA for oxidative stress, and BODIPY 581/591 C11 for lipid peroxidation. WB was also examined for RBC, leukocyte, and platelet viability and indices. LA caused dose-responsive hemolysis, and Ca2+-dependent PS exposure, elevated erythrocyte sedimentation rate (ESR), cytosolic Ca2+ overload, cell shrinkage and granularity, oxidative stress, accumulation of lipid peroxides, and stimulation of casein kinase 1α (CK1α). In WB, LA disrupted leukocyte distribution with elevated neutrophil-lymphocyte ratio (NLR) due to selective toxicity to lymphocytes. In conclusion, this report provides the first evidence of the pro-eryptotic potential of LA and associated mechanisms, which informs dietary interventions aimed at CVD prevention and management.

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.