Increased Lipid Peroxidation Research Articles

TMET-30. ONCOLYTIC HSV REWIRES METABOLISM TO PROMOTE ANTITUMOR IMMUNITY THROUGH REDUCTIVE CARBOXYLATION AND FERROPTOSIS

Abstract Cancer cells autonomously rewire metabolism to meet increased bioenergetic demands. Oncolytic HSVs (oHSVs) are attenuated Herpes simplex type 1 derived viruses that lyse tumor cells releasing damage-associated molecules triggering antitumor immunity. Currently one oHSV-1 derived virus is approved for melanoma treatment in the USA and another for recurrent GBM in Japan. While several other viruses are being evaluated in clinical trials for safety and efficacy, an understanding of the impact of oHSV therapy on cancer cell metabolism is largely unexplored. A detailed understanding of how oHSV impact tumor cell metabolism and oxidative stress is important to understand the unique susceptibilities that can further be exploited to improve the therapeutic index. Here, we analyzed transcriptomic changes in tumor biopsies of recurrent high-grade glioma patients treated with oHSV. RNA-seq data obtained from pre- and post-G207 treated biopsies from phase-Ib study patients (NCT00028158) revealed enrichment in pathways related to citric acid cycle, oxidative phosphorylation, and glutamate metabolism. We confirmed these changes by RNA sequencing of oHSV-infected patient derived GBM cells. Mechanistically, oHSV hijacked cellular glucose metabolism to increase oxidative phosphorylation and modulated cellular glutamine metabolism towards reductive carboxylation and reduced free glutathione, collectively contributing to increased ROS generation. Kinome profiling revealed PKC activation upon treatment with oHSV. Increased ROS combined with reduced glutathione, and PKC activation promoted ferroptotic cell death characterized by increased lipid peroxidation and smaller, ruptured mitochondria, and contributed to immunotherapy by this treatment. IDH mutant tumors that block reductive carboxylation were resistant to oHSV-induced ferroptotic cell death and did not benefit from oHSV-induced antitumor benefit. Together, this study presents avenues to enhance antitumor immunity by oHSV therapy.

Evaluation of Gender-Specific Variation in Lead-induced Nephrotoxicity in Wistar Rats

The kidney is sensitive to heavy metals because of its intensive metabolic activity and multiple functions namely those of excretion and pollutants concentration. The study aimed to evaluate the gender-specific variation in lead-induced nephrotoxicity in Wistar rats. 10 male and 10 female Wistar rats (180-220g) were each divided into 2 groups (n=5 each): Control (M), Lead alone (M), Control (F), Lead alone (F). Male and female rats of the experimental groups were administered a daily dose of 100 mg/kg/bw of lead acetate dispersed in distilled water for 21 days. All rats were anesthetized and sacrificed 24 hours after the last administration. Blood samples were collected via cardiac puncture for biochemical analysis, kidney tissues were harvested, homogenized, and analyzed for antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and lipid peroxidation (measured by malondialdehyde levels). Results indicated a significantly (p<0.01) lower weight gain in the lead-only female (F) group compared to the lead-only male (M) group. Lead acetate exposure caused oxidative damage, evidenced by significantly reduced antioxidant enzyme levels and increased lipid peroxidation in both male and female groups, with the effects being more pronounced in females (p<0.05). Serum creatinine and Urea levels in the lead alone (M) and lead alone (F) group were increased when compared to their respective control groups (p<0.05) however serum creatinine was significantly (p<0.001) higher in lead alone (F) than lead alone (M). The electrolyte function increased significantly in this study (p<0.05) when compared with their control groups. Sodium ion in lead alone (F) increased significantly (p<0.01) when compared to lead alone (M). The study concludes that lead exposure induced nephrotoxicity in both male and female rats, but more significantly pronounced in females than the males. This increased severity may have been mediated by the higher lead-induced oxidative stress observed in the female rats compared to males.

Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma

Enhancer of zeste homolog 2 (EZH2), a key protein implicated in various cancers including hepatocellular carcinoma (HCC), is recognized for its association with epigenetic dysregulation and pathogenesis. Despite clinical explorations into EZH2-targeting therapies, the mechanisms underlying its role in gene suppression in HCC have remained largely unexplored. Here, we integrate epigenomic and transcriptomic analyses to uncover the transcriptional landscape modulated by selective EZH2 inhibition in HCC. By reanalyzing transcriptomic data of HCC patients, we demonstrate that EZH2 overexpression correlates with poor patient survival. Treatment with the EZH2 inhibitor tazemetostat restored expression of genes involved in cysteine-methionine metabolism and lipid homeostasis, while suppressing angiogenesis and oxidative stress-related genes. Mechanistically, we demonstrate EZH2-mediated H3K27me3 enrichment at cis-regulatory elements of transsulfuration pathway genes, which is reversed upon inhibition, leading to increased chromatin accessibility. Among 16 EZH2-targeted candidate genes, BHMT and CDO1 were notably correlated with poor HCC prognosis. Tazemetostat treatment of HCC cells increased BHMT and CDO1 expression while reducing levels of ferroptosis markers FSP1, NFS1, and SLC7A11. Functionally, EZH2 inhibition dose-dependently reduced cell viability and increased lipid peroxidation in HCC cells. Our findings reveal a novel epigenetic mechanism controlling lipid peroxidation and ferroptosis susceptibility in HCC, providing a rationale for exploring EZH2-targeted therapies in this malignancy.

GLUT1 and prorenin receptor mediate differential regulation of TGF-β and CTGF in renal inner medullary collecting duct cells during high glucose conditions

BackgroundDuring diabetes, prorenin is highly produced by the renal collecting ducts. The binding of prorenin to (pro)renin receptor (PRR) on the apical plasma membrane triggers intracellular profibrotic genes, including TGF-β and CTGF. However, the underlying mechanisms contributing to the stimulation of these pathways remain unclear. Hence, we hypothesize that the glucose transporter-1 (GLUT1) favors the PRR-dependent stimulation of TGF-β and CTGF in the distal nephron segments during high glucose (HG) conditions.MethodsTo test this hypothesis, primary cultured renal inner medullary collecting duct (IMCD) cells were treated with normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) for 48 h in the presence or absence of the GLUT1-specific inhibitor BAY 876 (2 nM). Additionally, IMCD cells were treated with the PRR antagonist PRO20. The expression of TGF-β and CTGF was quantified by immunoblot and qRT-PCR.ResultsHG increased GLUT1 mRNA and protein abundance, while BAY 876 inhibited these responses. HG treatment upregulated PRR, but the concomitant treatment with BAY 876 partially prevented this effect. TGF-β and CTGF expressions were augmented in IMCD cells treated with HG. However, PRO20 prevented the increases in TGF-β but not those of CTGF. GLUT1 inhibition partially prevented the increases in reactive oxygen species (ROS) during HG while PRO20 did not. ROS scavenging impaired CTGF upregulation during HG conditions. Additionally, long-term exposure to HG increases lipid peroxidation and reduced cell viability.ConclusionsThe data indicate that glucose transportation via GLUT1 is implicated in the PRR-dependent upregulation of TGF-β while CTGF is mediated mainly via a mechanism depending on ROS formation in renal medullary collecting duct cells.

4‑Methoxydalbergione inhibits the tumorigenesis and metastasis of lung cancer through promoting ferroptosis via the DNMT1/system Xc‑/GPX4 pathway.

Lung cancer is responsible for the highest number of tumor‑related deaths worldwide. A flavonoid extracted from the heartwood of Dalbergia sissoo Roxb., 4‑methoxydalbergione (4‑MD), exhibits potent anticancer activity in multiple malignancies; however, the potential anticancer activity of 4‑MD in lung cancer has not yet been elucidated. In the present study, A549 cells were treated with increasing concentrations of 4‑MD, and cell viability was assessed using a Cell Counting Kit‑8 assay. In addition, colony formation, 5‑ethynyl‑2'‑deoxyuridine, wound healing and Transwell assays were conducted to evaluate cell proliferation, migration and invasion, respectively. Cell morphology was observed using transmission electron microscopy, and ferroptosis was determined using thiobarbituric acid reactive substance, lipid reactive oxygen species (ROS) and iron assays. Moreover, molecular docking was used to verify the potential interaction between 4‑MD and DNA methyltransferase 1 (DNMT1). Tumor‑bearing mice were established and treated with 10 or 30 mg/kg 4‑MD, and tumor volume and weight were recorded. Immunohistochemistry and Prussian blue staining were conducted to examine Ki‑67 expression and iron deposition in tumor tissues, and protein expression was further explored using western blot analysis. The results of the present study revealed that 4‑MD significantly inhibited cell proliferation, migration, invasion and epithelial‑mesenchymal transition in a concentration‑dependent manner. Notably, 4‑MD induced ferroptosis via increased lipid peroxidation, lipid ROS and Fe2+ levels. In addition, it was revealed that 4‑MD can directly bind to DNMT1 to inhibit expression, and inhibit solute carrier family 7 member 11 (SLC7A11; also known as cystine‑glutamate antiporter) and glutathione peroxidase 4 expression. Following DNMT1 overexpression, the observed antitumor activity and ferroptosis‑promoting effects of 4‑MD were partially reversed. Furthermore, 4‑MD significantly inhibited tumor growth in vivo, and reduced tumor volume and weight. In addition, Ki‑67 expression was reduced while iron deposition was increased in the tumor tissues of mice following treatment with 4‑MD. In conclusion, 4‑MD may exhibit anticancer activity through the promotion of DNMT1‑mediated cell ferroptosis. Thus, 4‑MD may have potential as a novel therapeutic agent in the treatment of lung cancer.

Experimental Periodontitis Increases Anxious Behavior and Worsens Cognitive Aspects and Systemic Oxidative Stress in Wistar Rats.

Periodontitis (PD) has the potential to induce systemic changes that affect both physical and behavioral aspects. These alterations may be associated with changes in both the inflammatory profile and the oxidative stress status of individuals with PD. Therefore, we aimed to evaluate the effects of PD on oxidative stress, as well as on behavioral parameters and cognitive impairment, in a preclinical model. Twenty-four male Wistar rats were randomly assigned to PD and sham groups. PD was induced by the ligature protocol for 14 days. Behavioral tests were initiated on the 9th day of the experiment to evaluate anxious behavior and cognition (learning and memory). After euthanasia, oxidative stress was evaluated in the gums, blood, hippocampus, and amygdala. Alveolar bone loss, bone microstructure, and elemental compositions of the mandibular bone were also assessed. PD increased alveolar bone loss, reduced the calcium and phosphorus content in the mandibular bone, and increased anxiety-like behavior and cognitive decline (p < 0.05). Furthermore, PD significantly affected the redox balance, as evidenced by increased total antioxidant capacity (TAC) in the gingiva and hippocampus (p < 0.05). It also led to increased lipid peroxidation in the gingiva and erythrocytes (p < 0.05), decreased antioxidant defenses in erythrocytes (superoxide dismutase) and the hippocampus (catalase), and increased antioxidant activity (catalase) in the amygdala (p < 0.05). PD resulted in cognitive alterations, including impairments in spatial learning and memory, as well as increased anxious behavior, likely due to redox imbalance in rats.

In-Depth Analysis of Olea europaea L. Leaf Extract: Alleviating Pulmonary Histological Disturbances, Pro-Inflammatory Responses, and Oxidative Stress from Isolated or Combined Exposure to Inhaled Toluene and Noise in Rats

The primary objective of this study was to investigate the pulmonary damage resulting from isolated or combined exposure to inhaled toluene (300 ppm) and noise 85 dB (A), with a focus on evaluating the potential protective effects of Olea europaea L. leaf extract (OLE). Forty-eight male Wistar rats were divided into eight groups: control (C), OLE treatment (O), noise exposure (N), noise exposure with OLE treatment (N+OLE), toluene exposure (T), toluene exposure with OLE treatment (T + OLE), co-exposure to toluene and noise (NT), and co-exposure with OLE treatment (NT + OLE). OLE (40 mg/kg/day) was administered daily for six weeks via oral gavage. Exposure to toluene and noise resulted in significant disruption of the pulmonary tissue structure, accompanied by oxidative stress, as evidenced by increased lipid peroxidation, diminished catalase and superoxide dismutase activities, and elevated pro-inflammatory cytokines IL6, IL-β, and TNF-α. Notably, the administration of OLE effectively mitigated oxidative stress and inflammation and preserved pulmonary histology. In conclusion, exposure to toluene and its combination with noise significantly elevated oxidative stress, inflammatory responses, and histological disruptions in the lung tissue. In contrast, noise exposure alone is characterized by minimal effects, although it is still associated with an inflammatory response. Notably, Olea europaea L. leaf extract (OLE) exhibits a substantial protective role, effectively mitigating the adverse effects of combined exposure and highlighting its potential as a therapeutic agent for lung health.

Tenofovir alafenamide compared to tenofovir disoproxil fumarate, induces dysglycemia, and dyslipidemia in Wistar rats.

To determine the metabolic effects of tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) in vivo . Male Wistar rats ( Rattus novergicus , 250-300 g body weight) were divided into three groups ( n = 8) and orally treated daily with 1.0 ml distilled water (group 1), TAF (0.42 mg/kg) (group 2), or TDF (5.0 mg/kg) (group 3), respectively, for 56 days. Glucose tolerance tests were done before the animals were sacrificed by halothane overdose, and blood was collected by cardiac puncture for the analysis of plasma lipids, electrolytes, and insulin. The kidney and pancreatic tissues were excised and homogenized to measure oxidative stress. Compartmentation of TAF and TDF was determined in NRK-52 and peripheral blood mononuclear cells (PBMCs). There were no significant differences in weight gain among controls, TAF- or TDF-treated rats. TAF-treated rats had significantly increased fasting blood glucose (FBG), fasting plasma insulin (FPI), insulin resistance, impaired glucose tolerance, and dyslipidemia compared to control or TDF-treated rats, respectively. There was increased lipid peroxidation in the pancreas of TAF-treated compared to TDF-treated or control animals, respectively. TDF- treated rats presented with symptoms of Fanconi syndrome compared to TAF-treated or control animals, respectively. Kidney homogenates from TDF-treated animals had significantly reduced antioxidant enzyme activity compared to TAF-treated animals or controls, respectively. Intracellular concentrations of TAF were significantly higher than TDF in both NRK-52E cells and PBMC, respectively. TAF treatment is weight-neutral and causes dysglycemia, and dyslipidemia but not Fanconi syndrome compared to TDF.

A natural protopanaxatriol from Panax notoginseng enhances osteosarcoma sensitivity to ferroptosis via ASCL4 upregulation

Current treatments for osteosarcoma, the most common primary bone cancer, including surgery, radiotherapy, and chemotherapy, are largely ineffective against metastatic and chemo-resistant cases, emphasizing the need for novel therapies. In this study, we investigated (20S)-Protopanaxatriol [(20S)-PPT], a natural product from Panax notoginseng, an herb used both as food and medicine, for its ability to enhance osteosarcoma sensitivity to ferroptosis induced by inducers such as RSL3, ML210, and IKE. Specifically, (20S)-PPT increased lipid peroxidation in osteosarcoma cells exposed to RSL3. This effect was mediated by ACSL4 upregulation, as ACSL4 knockdown reversed (20S)-PPT-sensitized ferroptosis. Importantly, (20S)-PPT significantly reduced tumor growth in xenograft models when combined with IKE. Collectively, our study confirms that combining (20S)-PPT with ferroptosis inducers offers a promising novel strategy for treating osteosarcoma.

The intricate interplay between ferroptosis and efferocytosis in cancer: unraveling novel insights and therapeutic opportunities.

The complex interplay between ferroptosis and efferocytosis in cancer has attracted significant interest recently. Efferocytosis, the process of eliminating apoptotic cells, is essential for preserving tissue homeostasis and reducing inflammation. However, dysregulation of efferocytosis can have profound effects on cancer. Apoptotic cells accumulate because of impaired efferocytosis, which triggers chronic inflammation and the release of pro-inflammatory chemicals. Surprisingly, accumulating evidence suggests that dysregulation of ferroptosis- a form of controlled cell death characterized by lipid peroxidation and the buildup iron-dependent reactive oxygen species (ROS)-can influence efferocytic activities within the tumor microenvironment. Dysfunctional iron metabolism and increased lipid peroxidation, are associated with ferroptosis, resulting in inadequate apoptotic cell clearance. Conversely, apoptotic cells can activate ferroptotic pathways, increasing oxidative stress and inducing cell death in cancer cells. This reciprocal interaction emphasizes the complex relationship between efferocytosis and ferroptosis in cancer biology. Understanding and managing the delicate balance between cell clearance and cell death pathways holds significant therapeutic potential in cancer treatment. Targeting the efferocytosis and ferroptosis pathways may offer new opportunities for improving tumor clearance, reducing inflammation, and sensitizing cancer cells to therapeutic interventions. Further research into the interaction between efferocytosis and ferroptosis in cancer will provide valuable insights for the development of novel therapies aimed at restoring tissue homeostasis and improving patient outcomes.

Synergistic Effect of Flavonoid-rich Ethanolic Extract of Coccinia indica and Hesperidin in Diabetes Induced Neuropathic Rat Model

Degeneration of neuronal function and diminished sensation characterize diabetic neuropathy, the foremost prevalent complication connected with diabetes mellitus. This research focuses on investigating the combined impact of flavonoid rich ethanolic extract of Coccinia indica extract (CIE) and hesperidin in diabetes induced neuropathy. Male sprague dawley rats were instigated with diabetic neuropathy (DN), following 14 days of high fat diet treatment along with streptozotocin (35 mg/kg, i.p), then the animals were maintained for 4 weeks to allow the development of DN. In accordance to the previous research identifying increased lipid peroxidation and reduced enzymatic antioxidants (superoxide dismutase, catalase, and reduced glutathione) as hallmark indicators of diabetic neuropathy (DN), our study demonstrated a similar biochemical profile. Treatment with CIE (200 mg/kg) alone and in combination with hesperidin at doses (25, 50 mg/kg), orally were conducted for eight weeks, which produced substantial reduction in blood sugar and restored antioxidant levels. Models for neurological pain (Eddy’s hot plate and Tail immersion) were utilized to assess the levels of antinociception. Post third week, the combined therapy of CIE and hesperidin exhibited significant (p&lt;0.001) antinociception due to their ability to improve the insulin sensitivity (Increase in glucose tolerance) when compared with metformin. As CIE, hesperidin, and metformin are all known to activate AMP-activated protein kinase (AMPK), which subsequently leads to the inhibition of nuclear factor-kappa B (NF-κB) and other pertinent signaling pathways. This cascade ultimately results in the suppression of gluconeogenesis, inflammatory cytokines while enhancing insulin sensitivity and elevating antioxidant levels. This signifies that combination therapy with CIE+hesperidin is equivalent to metformin in delaying the progression of diabetes induced neuropathy. Histological examinations confirmed the absence of sciatic nerve damage. Combined therapy of CIE along with hesperidin yielded notable depletion in blood sugar concentration and prevented further development of diabetic neuropathy.

Effects of circuit weight training by intensity on stress hormones and antioxidant capacity in high-school wrestlers.

We aimed to investigate the effects of 8-week circuit weight training by intensity on blood stress hormones and antioxidant capacity in high-school wrestlers. This study involved 27 male wrestlers with >2 years of wrestling experience who were randomly assigned to either a low intensity (n=13) or a high-intensity circuit weight training group (n=14). The participants performed circuit weight training for 60 min per session, 3 times per week for 8 weeks. The low- and high-intensity circuit weight training exercises were performed at 50%-60% and 70%-80% of one-repetition maximum for 10 stations, respectively, and 8-15 repeated sessions per station were performed in order. No changes were observed in adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine levels between the two training groups. When compared to levels before the training, ACTH and epinephrine levels decreased, whereas cortisol levels increased. However, no difference was observed in norepinephrine levels. Further, no differences were observed in malondialdehyde (MDA) and glutathione peroxidase (GPX) levels between the two groups. However, MDA and GPX levels were increased from those before training. Changes in superoxide dismutase levels were observed between the two groups, but the change was significant only in the high-intensity circuit weight training group. Long-term training did not increase lipid peroxidation, but increased the activity of antioxidant enzymes that defend against oxidative stress. The antioxidant defense system in tissues can be regulated by exercise intensity as well as physical training status.

Extremely Low-Frequency Electromagnetic Field (ELF-EMF) Increases Mitochondrial Electron Transport Chain Activities and Ameliorates Depressive Behaviors in Mice.

Compromised mitochondrial electron transport chain (ETC) activities are associated with depression in humans and rodents. However, the effects of the enhancement of mitochondrial ETC activities on depression remain elusive. We recently reported that an extremely low-frequency electromagnetic field (ELF-EMF) of as low as 10 μT induced hormetic activation of mitochondrial ETC complexes in human/mouse cultured cells and mouse livers. Chronic social defeat stress (CSDS) for 10 consecutive days caused behavioral defects mimicking depression in mice, and using an ELF-EMF for two to six weeks ameliorated them. CSDS variably decreased the mitochondrial ETC proteins in the prefrontal cortex (PFC) in 10 days, which were increased by an ELF-EMF in six weeks. CSDS had no effect on the mitochondrial oxygen consumption rate in the PFC in 10 days, but using an ELF-EMF for six weeks enhanced it. CSDS inactivated SOD2 by enhancing its acetylation and increased lipid peroxidation in the PFC. In contrast, the ELF-EMF activated the Sirt3-FoxO3a-SOD2 pathway and suppressed lipid peroxidation. Furthermore, CSDS increased markers for mitophagy, which was suppressed by the ELF-EMF in six weeks. The ELF-EMF exerted beneficial hormetic effects on mitochondrial energy production, mitochondrial antioxidation, and mitochondrial dynamics in a mouse model of depression. We envisage that an ELF-EMF is a promising therapeutic option for depression.

Immunomodulatory microneedle patch for enhanced Ferroptosis and immunogenic cell death in postoperative tumor therapy

Microneedle technologies have emerged as a promising transdermal drug delivery platform for postoperative tumor therapy. Despite their potential, enhancing intracellular drug delivery to tumor cells and boosting the therapeutic efficiency of microneedles pose significant challenges. Herein, we develop a nanomedicine-loaded microneedle to enhance the induction of ferroptosis and immunogenic cell death for postoperative tumor therapy. This advancement is achieved by pre-formulating small molecule drugs with transition metal and protein templates into nanomedicine. Upon insertion into the tumors, the microneedle rapidly dissolves, facilitating the release and subsequent cellular uptake of the nanomedicine by tumor cells. Notably, the nanomedicine can release Mn ions and ferroptosis-inducer sulfasalazine (SAS) under acidic conditions. Furthermore, the released Mn ions can produce reactive oxygen species, which decrease the levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4) with increased lipid peroxidation and enhanced induction of ferroptosis. Besides, the treatment stimulates immunogenic cell death through the cell surface exposure of calreticulin (CRT) and release of high-mobility group box 1 (HMGB1), which further stimulates dendric cell maturation, T cell infiltration, and macrophage polarization towards the M1 phenotype. Consequently, this strategy significantly inhibits postoperative tumor regrowth and extends overall survival. Our study indicates the potential of the combination of nanomedicine and microneedle to improve postoperative therapeutic efficiency.

Astaxanthin Supplementation Effects in Right Ventricle of Rats Exposed to Chronic Intermittent Hypobaric Hypoxia.

Thirty two male Wistar rats were randomly assigned to the following groups (n = 8 per group): the normoxia with vehicle (NX), normoxia with astaxanthin (NX + AS), chronic intermittent hypobaric hypoxia with vehicle (CIHH), and chronic intermittent hypobaric hypoxia with astaxanthin (CIHH + AS) groups. CIHH was simulated by 2 days in a hypobaric chamber followed by 2 days at sea level for 29 days. Exposure to CIHH induced RVH and increased lipid peroxidation (MDA), Nox2 expression, and SOD activity, however, it decreased pro-IL-1β expression. Astaxanthin restored oxidative stress markers (Nox2 and MDA), increased GPx activity, and decreased RVH compared to CIHH. Astaxanthin alleviates RVH and reduces Nox2 and MDA levels while increasing GPx activity in rats subjected to CIHH. These findings provide new insights of astaxanthin as a new nutraceutical against high-altitude effects.

Dynamics of Free Radical Oxidative Processes During the Latent Period of Experimental Metastasizing to the Liver

Purpose — to investigate the dynamics of the content of antioxidant enzymes superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPO1), glutathione reductase (GR) and lipid peroxidation products diene conjugates (DC), malondialdehyde (MDA) in the spleen and liver during the latent period of growth and metastasis of experimental tumor.Materials and methods. Using 28 white male rats, a model of hematogenous liver metastasis was created by transplanting sarcoma 45 cells (S45) into the spleen, previously lead out under the skin 3 weeks before. Previously, was determined that a tumor visualized in the spleen at 5 weeks, and liver metastases at 7 weeks after transplantation S45. Levels of SOD1, GPO1, GR and MDA were determined using ELISA and DC by biochemical method in spleen and liver homogenates during the latent period of tumor growth and metastasis (1–2 weeks post-transplantation).Results. Significant changes (1.5–5.2 times, р &lt; 0.050–0.001) in studied factors levels were observed compared to intact rats and rats with the spleen lead out. Activation of lipid peroxidation and antioxidant system was noted in the spleen (tumor-carrying organ) during tumor growth and metastasis. At the same time, in the liver (the target organ of metastasis) observed also increased lipid peroxidation but simultaneously a pronounced decreased GR levels (5 times, p &lt; 0.001) without affecting SOD1 levels.Conclusion. Liver tissue exhibited the inferiority of antioxidant protection and the formation of pro-oxidant condition during the latent period of tumor growth, which may prepare the soil for metastasis.

Polydatin Prevents Electron Transport Chain Dysfunction and ROS Overproduction Paralleled by an Improvement in Lipid Peroxidation and Cardiolipin Levels in Iron-Overloaded Rat Liver Mitochondria.

Increased intramitochondrial free iron is a key feature of various liver diseases, leading to oxidative stress, mitochondrial dysfunction, and liver damage. Polydatin is a polyphenol with a hepatoprotective effect, which has been attributed to its ability to enhance mitochondrial oxidative metabolism and antioxidant defenses, thereby inhibiting reactive oxygen species (ROS) dependent cellular damage processes and liver diseases. However, it has not been explored whether polydatin is able to exert its effects by protecting the phospholipid cardiolipin against damage from excess iron. Cardiolipin maintains the integrity and function of electron transport chain (ETC) complexes and keeps cytochrome c bound to mitochondria, avoiding uncontrolled apoptosis. Therefore, the effect of polydatin on oxidative lipid damage, ETC activity, cytochrome levels, and ROS production was explored in iron-exposed rat liver mitochondria. Fe2+ increased lipid peroxidation, decreased cardiolipin and cytochromes c + c1 and aa3 levels, inhibited ETC complex activities, and dramatically increased ROS production. Preincubation with polydatin prevented all these effects to a variable degree. These results suggest that the hepatoprotective mechanism of polydatin involves the attenuation of free radical production by iron, which enhances cardiolipin levels by counteracting membrane lipid peroxidation. This prevents the loss of cytochromes, improves ETC function, and decreases mitochondrial ROS production.

Genotype-Dependent Variations in Oxidative Stress Markers and Bioactive Proteins in Hereford Bulls: Associations with DGAT1, LEP, and SCD1 Genes.

The objective of this study is to assess the influence of genetic polymorphisms in DGAT1, LEP, and SCD1 on the oxidative stress biomarkers and bioactive protein levels in Hereford bulls. A total of sixty-eight bulls were analyzed at 22 months of age to assess growth metrics and carcass quality, with a focus on polymorphisms in these genes. The key markers of oxidative stress, including malondialdehyde (MDA), and the activities of antioxidant enzymes such as glutathione reductase (GluRed), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were measured, alongside bioactive compounds like taurine, carnosine, and anserine. The results show that the TT genotype of DGAT1 is linked to significantly higher MDA levels, reflecting increased lipid peroxidation, but is also associated with higher GluRed and GPx activities and elevated levels of taurine, carnosine, and anserine, suggesting an adaptive response to oxidative stress. The LEP gene analysis revealed that the CC genotype had the highest MDA levels but also exhibited increased GPx and SOD activities, with the CT genotype showing the highest SOD activity and the TT genotype the highest total antioxidant status (TAS). The SCD1 AA genotype displayed the highest activities of GluRed, GPx, and SOD, indicating a more effective antioxidant defence, while the VA genotype had the highest MDA levels and the VV genotype showed lower MDA levels, suggesting protective effects against oxidative damage. These findings highlight genotype specific variations in the oxidative stress markers and bioactive compound levels, providing insights into the genetic regulation of oxidative stress and antioxidant defences, which could inform breeding strategies for improving oxidative stress resistance in livestock and managing related conditions.

Deubiquitylase USP52 Promotes Bladder Cancer Progression by Modulating Ferroptosis through Stabilizing SLC7A11/xCT.

Bladder cancer (BLCA) is a prevalent cancer with high case-fatality rates and a substantial economic burden worldwide. Understanding its molecular underpinnings to guide clinical management is crucial. Ferroptosis, a recently described non-apoptotic form of cell death, is initiated by the lethal accumulation of iron-dependent lipid peroxidation products. Despite growing interest, the roles and vulnerabilities determining ferroptosis sensitivity in BLCA remain unclear. Re-analysis of single-cell RNA data reveals a decrease in high-ferroptosis cancer cells as BLCA advances. USP52/PAN2 is identified as a key regulator of ferroptosis in BLCA through an unbiased siRNA screen targeting 96 deubiquitylases (DUBs). Functionally, USP52 depletion impedes glutathione (GSH) synthesis by promoting xCT protein degradation, increasing lipid peroxidation and ferroptosis susceptibility, thus suppressing BLCA progression. Mechanistically, USP52 interacts with xCT and enzymatically cleaves the K48-conjugated ubiquitin chains at K4 and K12, enhancing its protein stability. Clinical BLCA samples demonstrate a positive correlation between USP52 and xCT expression, with high USP52 levels associated with aggressive disease progression and poor prognosis. In vivo, USP52 depletion combined with ferroptosis triggers imidazole ketone Erastin (IKE) synergistically restrains BLCA progression by inducing ferroptosis. These findings elucidate the role of the USP52-xCT axis in BLCA and highlight the therapeutic potential of targeting USP52 and ferroptosis inducers in BLCA.

Synergistic ferroptosis in triple-negative breast cancer cells: Paclitaxel in combination with Erastin induced oxidative stress and Ferroportin-1 modulation in MDA-MB-231 cells.

Ferroptosis is an important regulated cell death mechanism characterized by iron-dependent lipid peroxidation and oxidative stress. In this study, we examined the ferroptosis-inducing effect of the combined use of Paclitaxel, a microtubule-stabilizing agent, and Erastin, a ferroptosis inducer, in breast cancer cells. In this context, the combination of the compounds in question was applied to the cells and the presence of a synergistic effect was determined by calculating the combination index. Glutathione (GSH) levels and glutathione peroxidase (GPX) activity were determined by commercial assay kits, and the effect of the compounds on lipid peroxidation was determined by measurement of malondialdehyde (MDA) levels. Additionally, the effect of combination treatment on ferroptotic protein expression was determined by western blot. Our findings revealed that the combination treatment caused a significant change in mitochondrial function by causing an increase in the depolarized/viable cell population. Additionally, there was a significant increase in intracellular reactive oxygen species (ROS) levels compared to single applications of the compounds. The significant increase observed in malondialdehyde (MDA) levels revealed that the combination treatment increased lipid peroxidation. Moreover, intracellular GSH levels and glutathione peroxidase (GPX) activity significantly decreased by Paclitaxel-Erastin combination. The expression of ferroptosis-regulating proteins was significantly downregulated. The findings showed that the Paclitaxel-Erastin combination synergistically contributed to the accumulation of lipid reactive oxygen species and induced the ferroptotic cell death pathway in breast cancer cells.