Elevated Malondialdehyde Levels Research Articles

HINT2 deficiency deteriorates oxidative stress in a mouse model of myocardial infarction.

Myocardial infarction (MI) is one of the serious diseases with great mortality over the world. Myocardial mitochondrial oxidative stress has been implicated as a key player in MI. The histidine triad nucleotide-binding protein 2 (HINT2) is a nucleotide hydrolase and transferase located in mitochondria. HINT2 has multiple functions such as regulating mitochondrial lipid metabolism and respiration and glucose homeostasis. Although HINT2 has been shown to protect against MI, the underlying mechanisms were not fully elucidated. In this study, the effects of HINT2 on oxidative stress during MI were explored. MI mouse models in both wild-type and HINT2-deficient mice were established. The expression of HINT2 in HINT2-deficient mice was determined by quantitative real-time PCR and western blot. The levels of oxidative stress were measured, including the levels of malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione (GSH). The myocardial functions, as indicated by left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS), were monitored. Both mRNA and protein expressions of HINT2 in the myocardial tissues were significantly down-regulated in MI mice starting at 6h post-MI. MI induced oxidative stress 6h post-MI in myocardial tissues of wild-type mice, as suggested by the enhanced MDA and NO levels and decreased SOD and GSH levels. The expression of HINT2 was negatively correlated to the MDA and NO levels and positively correlated to the SOD and GSH levels. HINT2-deficient MI mice had significantly elevated levels of MDA and NO and significantly decreased levels of SOD and GSH when compared with wild-type MI mice. HINT2-deficient MI mice had higher LVEDD and LVESD and lower LVEF and LVFS compared with wild-type MI mice, indicating that HINT2 deficiency exacerbated myocardial dysfunction. HINT2 deficiency causes deteriorative oxidative stress in MI mice, leading to exacerbated myocardial dysfunction.

Therapeutic Potential of Selenium Nanoparticles on Letrozole-Induced Polycystic Ovarian Syndrome in Female Wistar Rats.

Polycystic ovarian syndrome (PCOS) is considered the most frequent gynecological endocrine disorder that causes anovulatory infertility. The current study aimed to investigate the potential significance of selenium nanoparticles (SeNPs), an IL-1 inhibitor, in the treatment of letrozole-induced PCOS in rats that satisfied the metabolic and endocrine parameters found in PCOS patients. Letrozole (2ppm, per orally, p.o.) was given orally to female Wistar rats for 21days to develop PCOS. After PCOS induction, rats were given SeNPs (25ppm/day, p.o.), SeNPs (50ppm/day, p.o.), or metformin (2ppm/day, p.o.) for 14days. PCOS was associated with an increase in body weight, ovarian weight, ovarian size, and cysts, as well as an increase in blood testosterone, luteinizing hormone (LH), and insulin, glycaemia, and lipid profile levels. The SeNP administration decreased all of these variables. Furthermore, SeNPs significantly reduced letrozole-induced oxidative stress in the ovaries, muscles, and liver by decreasing elevated levels of malondialdehyde and total nitrite while raising suppressed levels of superoxide dismutase and catalase. SeNPs increased the amounts of the protective proteins Kelch-like ECH-associated protein 1 (Keap-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and OH-1. It was depicted from the study that SeNPs reduce the upregulation of inflammatory cytokines that are interleukin 6 (IL-6), tumour necrosis factor α (TNF-α), and the interleukin 1 (IL-1). Our findings show that SeNPs, through their antioxidant and anti-inflammatory characteristics, alleviate letrozole-induced PCOS.

Asprosin aggravates vascular endothelial dysfunction via disturbing mitochondrial dynamics in obesity models.

The aim of the study was to investigate the contribution of asprosin (ASP), a fasting-induced hormone involved in metabolic disorders, to vascular endothelial dysfunction in obesity models. Primary rat thoracic aortic endothelial cells treated with palmitic acid and mice fed with a high-fat diet (HFD) were used as the obesity models. The role and mechanism of ASP in endothelial dysfunction were investigated by the means of morphologic, functional, and genetic analysis. ASP aggravated the endothelial dysfunction induced by either palmitic acidin vitro or an HFD in vivo, characterized as the impairment of endothelium-dependent vasodilation, reduction of nitric oxide levels, elevation of malondialdehyde levels, and inhibition of phosphoinositide 3-kinase-AKT-endothelial nitric oxide synthase signaling. However, adipose conditional knockout of ASP or ASP neutralization significantly alleviated the endothelial dysfunction induced by an HFD. Mechanistically, ASP enhanced mitochondrial fission, and inhibition of the fission through knockdown of dynamin-related protein 1 (a fission-hallmark factor) rescued the endothelial dysfunction and the disturbance to mitochondrial dynamics induced by ASP. The findings demonstrate that ASP causes and even exacerbates vascular endothelial dysfunction through promoting mitochondrial fission in obesity, suggesting that ASP can act as an early predictive marker of blood vessel dysfunction and become a novel potential therapeutic target for obesity-related cardiovascular diseases.

Obesity difference on association blood malondialdehyde level and diastolic hypertension in the elderly population: a cross-sectional analysis

AimsAlthough increased production of malondialdehyde (MDA), an end product of lipid oxidation caused by reactive oxygen species (ROS), has been found be elevated in hypertensive population, whether MDA contributed to a changed risk of hypertension is uncertain. We aimed to investigate whether elevated blood levels of MDA contribute to increased risk of hypertension and obesity has a modified effect on the association in an older Chinese population.MethodsData were obtained from 2011 to 2012 of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a national cohort of older adults in China. Associations between blood MDA level and systolic and diastolic blood pressure (BP) and risk of hypertension were performed by multivariable linear regression and logistic regression analysis.ResultsThe results of smooth curve revealed a gradual upward trend on association of blood MDA level with diastolic BP (P < 0.001), but not with systolic BP (P > 0.05). Logistic regression analysis suggested that elevated blood MDA levels were associated with increased risk of diastolic hypertension (OR = 1.079, 95% CI 1.039–1.122, P < 0.001) rather than systolic hypertension (OR = 0.978, 95% CI 0.943–1.015, P = 0.247) after adjustments of related confounding factors were made. Furthermore, we found the significant modification effect of obesity on the association between MDA level and risk of diastolic hypertension evaluated by body mass index (BMI, interaction P = 0.015) and by waist circumference (interaction P = 0.016).ConclusionOur results firstly identified that increased blood MDA levels were associated with elevated risk of diastolic hypertension, rather than systolic hypertension in the non-obese old population.

Modeling and optimization of malondialdehyde (MDA) absorbance behavior through response surface methodology (RSM) and artificial intelligence network (AIN): An endeavor to estimate lipid peroxidation by determination of MDA

AbstractOxidative stress (OS) associated with reactive oxygen species (ROS) attacks many biomolecules, leading to cell death, lipid peroxidation (LP), and physiological mechanism damage in the human body because of its reaction with nucleotides, membrane lipids, and proteins. Malondialdehyde (MDA) is one of the end products of polyunsaturated fatty acids peroxidation. The elevated level of MDA is widely known as a biomarker for the indirect measurement of OS during LP. Although several derivatizations' approaches and successful commercial kits are available, their analytical validity and reliability in clinical studies require further attention to obtain robust quantitation and high‐quality data. Also, re‐evaluation and development of new analytical methods with high sensitivity and selectivity in response to free MDA and total MDA, DNA and protein adducts are not well‐characterized. Here, response surface methodology (RSM) and artificial neural network (ANN) were proposed to model, predict, and optimize MDA detection. This paper introduced a novel, simple, and fast modeling method using a new reagent (para methoxy aniline or PMA) for the first time to convert MDA to an adduct which could be detectable by UV‐Vis spectroscopy. Based on the interactions between MDA and PMA at times and temperatures, RSM and artificial intelligence network (AIN) were then applied to forecast the absorbance rate of MDA‐PMA. The optimum mode for the highest absorbance rate of MDA‐PMA is at the temperature of 74.99°C with a PMA concentration of 499.87 μM and MDA concentration of 49.98 μM. The best structure with five hidden layers, including 5,5,5,9,4 neurons with the transfer function logsig for each layer, was selected for the MLP‐ANN model. The maximum error rate of the MLP‐ANN model was 2.08%.Our new approach is an improvement over existing assay kits, overcoming limitations such as time, temperature, and reliability with a bright future to target increased MDA level in human samples.

Methyl Parathion Exposure Induces Development Toxicity and Cardiotoxicity in Zebrafish Embryos

Methyl parathion (MP) has been widely used as an organophosphorus pesticide for food preservation and pest management, resulting in its accumulation in the aquatic environment. However, the early developmental toxicity of MP to non-target species, especially aquatic vertebrates, has not been thoroughly investigated. In this study, zebrafish embryos were treated with 2.5, 5, or 10 mg/L of MP solution until 72 h post-fertilization (hpf). The results showed that MP exposure reduced spontaneous movement, hatching, and survival rates of zebrafish embryos and induced developmental abnormalities such as shortened body length, yolk edema, and spinal curvature. Notably, MP was found to induce cardiac abnormalities, including pericardial edema and decreased heart rate. Exposure to MP resulted in the accumulation of reactive oxygen species (ROS), decreased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, elevated malondialdehyde (MDA) levels, and caused cardiac apoptosis in zebrafish embryos. Moreover, MP affected the transcription of cardiac development-related genes (vmhc, sox9b, nppa, tnnt2, bmp2b, bmp4) and apoptosis-related genes (p53, bax, bcl2). Astaxanthin could rescue MP-induced heart development defects by down-regulating oxidative stress. These findings suggest that MP induces cardiac developmental toxicity and provides additional evidence of MP toxicity to aquatic organisms.

Exposure of combination of environmental pollutant, lead (Pb) and β-amyloid peptides causes mitochondrial dysfunction and oxidative stress in human neuronal cells.

Exposure to the environmental pollutant lead (Pb) has been linked to Alzheimer's disease (AD), in which mitochondrial dysfunction is a pathological consequence of neuronal degeneration. The toxicity of Pb in combination with β-amyloid peptides (1-40) and (25-35) causes selective death in neuronal cells. However, the precise mechanism through which Pb induces Alzheimer's disease, particularly mitochondrial damage, is unknown. Changes in mitochondrial mass, membrane potential, mitochondrial complex activities, mitochondrial DNA and oxidative stress were examined in neuronal cells of human origin exposed to Pb and β-amyloid peptides (1-40) and (25-35) individually and in different combinations. The results showed depolarization of mitochondrial membrane potential, decrease in mitochondrial mass, ATP levels and mtDNA copy number in Pb and β-amyloid peptides (1-40) and (25-35) exposed cells. Also, significant reductions in the expression of mitochondrial electron transport chain (ETC) complex proteins (ATP5A, COXIV, UQCRC2, SDHB, NDUFS3), as well as down regulation of ETC complex gene expressions such as COXIV, ATP5F1 and NDUFS3 and antioxidant gene expressions like MnSOD and Gpx4 were observed in exposed cells. Furthermore, Pb and β-amyloid peptides exposure resulted in elevated mitochondrial malondialdehyde levels and a decrease in mitochondrial GSH levels. Our findings suggest that Pb toxicity could be one of the causative factors for the mitochondrial dysfunction and oxidative stress in Alzheimer's disease progression.

Differences of semen microbiota among breeding boars with different reproductive ages.

In this study, we investigated 18 healthy and fertile Duroc boars, dividing them into two groups based on their reproductive age: 9 boars aged 18 mo and 9 boars aged 36 mo. Prior to semen sampling, all boars were raised together under identical management conditions for a period of 3 mo. Our findings revealed that older boars exhibited lower sperm motility and a higher proportion of abnormal sperm morphology compared to younger boars. Furthermore, older boars demonstrated lower anti-oxidant capacity in their semen, as indicated by elevated levels of malondialdehyde and decreased levels of superoxide dismutase and glutathione peroxidase. Microbiota analysis utilizing the 16S rRNA technique showed that the semen microbiota of older boars had reduced alpha-diversity and beta-diversity in comparison to younger boars. We identified the Streptococcus genus and Streptococcus gallolyticus subsp macedonicus species served as biomarkers for semen from younger breeding boars, while the Bacteroides pyogenes species as a biomarker for semen from older breeding boars. Additionally, the semen from older boars exhibited a higher abundance of Aerococcus, Gallicola, Ulvibacter, and Proteiniphilum compared to younger boars. Spearman correlation analysis showed that these four bacteria were negatively correlated with semen quality. The abundance of Gallicola and Proteiniphilum were negatively correlated with semen anti-oxidant capacity. Additionally, the reduction of semen anti-oxidant capacity was correlated to the decrease of semen quality. Based on these findings, we concluded that the semen of older boars contains a higher abundance of harmful bacteria, which contributes to the observed reduction in semen anti-oxidant capacity and overall semen quality in this group.

Toxic effect of carpet dust on the biochemical indices and histological structure of the lung in rats: the potential role of cytochrome P450 2E1 and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways

Background: Carpet dust exposure in the carpet industry causes various respiratory hazards that lead to permanent loss of lung function. This study investigated the potentially toxic effects of knotted and tufted carpet dust on rat lungs and the possible involvement of cytochrome P450 2E1 (CYP2E1) and extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathways in the induced toxicity, as well as histological changes in the lung induced by carpet dust. Methods: This study divided 48 adult rats into six groups: group I was the control group, group II (vehicle group) received phosphate buffer saline (50 µL/rat), groups III and IV received knotted dust (2.5 and 5 mg/kg, respectively), and groups V and VI received tufted dust (2.5 and 5 mg/kg, respectively). All treatments were intranasally administered once a day for 7 days. Results: Both dust types significantly decreased the lung content of GSH compared with the control. Significantly elevated malondialdehyde (MDA) and nitric oxide (NO) lung contents were observed with an increased CYP2E1, interleukin (IL)-6, nuclear factor kappa B (NF-κβ), and ERK/MAPK. The histological lung structure was moderately affected with a moderately increased number of CD68-positive macrophages in the lung parenchyma of knotted dust-exposed rats, whereas tufted dust exposure severely affected the lung tissue with significantly increased CD68-positive macrophages. Conclusions: Carpet dust exposure could induce oxidative stress and inflammatory response in the lung tissue via induction of CYP2E1 that stimulates ERK/MAPK signalling pathway proteins, resulting in elevated MDA, NO and IL-6 levels in the lung tissue with suppressed GSH content. Tufted dust could possess a more toxic response than knotted ones.

Exploring the Impacts of Different Music Genres on Oxidative Stress in Rat Brain and Serum

Music reduces emotional stress, relieves anxiety, and is utilized while treating various diseases. The present study explored the impacts of various music genres at different decibels on the oxidation state in the brain tissue and serum. We carried out the study on 42 male Wistar Albino rats. The rats were randomized (six rats in each cage) as a control group and groups exposed to noise, rock music, and slow music at different decibels for 21 days and 4 hours a day. At the end of the experiment, we studied oxidant [malondialdehyde (MDA), nitric oxide, protein carbonyl (PC)] and antioxidant [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)] parameters in the cerebral cortex, cerebellum, and serum. In the cortex, while MDA levels were low in the 100 dB(A) slow music group, the 50 dB(A) noise and rock music groups had elevated SOD, GSH-Px, and MDA levels when compared to the control group and higher MDA and GSH-Px levels when compared to the 50 dB(A) slow music group. In the cerebellum, although SOD levels did not significantly change, we found MDA and GSH-Px to increase in the 50 dB(A) and 100 dB(A) rock music groups and the 50 dB(A) noise group. Finally, we determined MDA and PC levels to be low and SOD levels to be high in the 50 dB(A) slow music group. Overall, that high dB rock music created oxidative stress in cerebellar tissue, that low dB rock music and noise created oxidative stress in the cortex and cerebellum, and that high and low dB slow music may have positive impacts on oxidative stress.

Alamandine alleviates methotrexate-induced nephrotoxicity in rats by targeting oxidative stress and inflammation

Aim: Nephrotoxicity due to the use of methotrexate (Mtx) is one of the most important problems associated with chemotherapy. Oxidative stress and inflammation are the major pathomechanisms of Mtx-induced nephrotoxicity. Alamandine (Ala), a new member of the renin-angiotensin system (RAS), is an important peptide with antioxidant and anti-inflammatory capacities. In this study, it was investigated whether Ala ameliorates Mtx-induced kidney damage by reducing oxidative stress and inflammation. Materials and Methods: Male Wistar albino rats were assigned into three groups: control group, Mtx group, and Mtx+Ala group. At the end of the experiment, kidney tissues were quickly removed. Glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative state in kidney tissues. In addition, tissue samples were assessed as histopathological and immunohistochemical for heat shock protein 60 (HSP60), caspase-3, tumor necrosis factor-α (TNF-α), and receptor-interacting protein kinase-3 (RIPK3). Results: Mtx treatment resulted in reduced GSH content, elevated MDA level, increased heat shock protein 60 (HSP60), and caspase-3 expression. These changes in kidney tissues of rats treated with Mtx triggered oxidative stress characterized by apoptosis and kidney damage. Mtx also markedly increased the expression of TNF-α, an inflammation marker, and RIPK3, a marker of necroptosis. However, Ala administration significantly alleviated Mtx-induced kidney damage by reducing apoptosis and necroptosis by suppressing oxidative stress and inflammation. Conclusion: Taken together, our results support that Ala treatment can serve as a new and promising therapeutic strategy against Mtx-induced nephrotoxicity. Keywords: Alamandine; methotrexate; oxidative stress; inflammation; apoptosis; necroptosis; nephrotoxicity

Intraperitoneal hepato-renal toxicity of zinc oxide and nickel oxide nanoparticles in male rats: biochemical, hematological and histopathological studies.

In recent years, zinc oxide (ZnO) and nickel oxide (NiO) nanoparticles (NPs) have become more prevalent in commercial and industrial products. However, questions have been raised regarding their potential harm to human health. Limited studies have been conducted on their intraperitoneal toxicity in rats, and their co-exposure effects remain uncertain. Therefore, this study aimed to investigate some biological responses induced by a single intraperitoneal injection of ZnO-NPs (200 mg/kg) and/or NiO-NPs (50 mg/kg) in rats over time intervals. Blood and organ samples were collected from 36 male rats for hematological, biochemical, oxidative stress, and histological analysis. Results showed that the administration of NPs reduced the body and organ weights as well as red blood cell (RBC) indices and altered white blood cell (WBC) and platelet (PLT) counts. The experimental groups exhibited elevated levels of aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine (CREA), urea, lipid profile, glucose (GLU), total protein (TP), albumin (ALB) and malondialdehyde (MDA), and decreased uric acid (UA), superoxide dismutase (SOD), and glutathione (GSH). Histological observations also revealed architectural damages in liver and kidneys. These alterations were time-dependent and varied in their degree of toxicity. Co-exposure of NPs initially lessened the damage but increased it afterwards compared to individual exposure. In conclusion, intraperitoneal injection of ZnO-NPs and/or NiO-NPs alters biological processes and induces oxidative stress in rats' liver and kidneys in a time-dependent manner, with NiO-NPs being more potent than ZnO-NPs. Furthermore, co-exposed NPs initially appeared to be antagonistic to one another while further aiming toward synergism.

Relation between blood levels of heavy metals and some markers of oxidative stress among boys with neuropathic bladder and posterior urethral valve

BackgroundThe status of heavy metals in children with lower urinary tract pathology that may harm the upper tract, e.g., neuropathic bladder and posterior urethral valve and its relationship with oxidative stress has not been adequately investigated. Therefore, the object of the current work was to evaluate the concentrations of copper, zinc, cadmium and lead and their relations with levels of catalase (CAT), malondialdehyde (MDA) and glutathione (GSH) in boys with neuropathic bladder and posterior urethral valve. MethodsThirty-six children with neuropathic bladder, 35 children with posterior urethral valve and 33 health controls were included in the study. In addition to routine laboratory tests, blood samples were collected from patients and controls to assess levels of Cu, Zn, Cd and Pb in addition to plasma concentrations of CAT, MDA and GSH. ResultsSignificantly elevated levels of Cu, Pb, CAT, MDA and GSH and significantly lower concentration of blood Zn were found in the studied groups compared to the controls. In the posterior urethral valve group, blood level of Cu was positively correlated with GSH while a significantly negative relation was observed between blood Zn and CAT activity among the neuropathic bladder patients. ConclusionNeuropathic bladder and posterior urethral valve may lead to abnormalities in the blood levels of heavy metals (i.e. Cu, Pb and Zn) and markers of oxidative stress (CAT, MDA and GSH). Therefore, the levels of theses metal ions should be monitored during the treatment course of neuropathic bladder and posterior urethral valve patients to prevent or minimize long-term oxidative injury.

Secondary iron overload induces chronic pancreatitis and ferroptosis of acinar cells in mice.

Disruption of iron homeostasis is associated with multiple diseases. It has been found that patients with genetic iron overload develop massive iron deposition in the pancreas. However, few studies have focused on the effect of secondary iron overload on the pancreas. The objective of the present study was to investigate the pathogenic consequences of secondary iron overload in mice. An iron overload mouse model was constructed by intraperitoneal injection of 120mg/kg body weight of iron dextran every other week for 12weeks. Iron deposition, immunocyte infiltration, fibrosis, oxidative stress and ferroptosis were assessed using Prussian blue staining, immunohistochemical analysis, Masson staining, Sirius red staining, RT‑qPCR analysis and western blot analysis. It was found that iron‑overloaded mice showed pancreatic iron overload, together with elevated gene expression of the iron storage factor ferritin H, and decreased expression of the iron transportation mediator divalent metal transporter 1, ferroportin 1 and transferrin receptor. Iron‑overloaded mice developed mild pancreatitis with increased serum amylase and lipase activities, as well as elevated gene expression levels of pro‑inflammatory cytokines, including interleukin (IL)‑1β, IL‑6 and inducible nitric oxide synthase. Acinar atrophy, massive immunocyte infiltration and pancreatic fibrosis were noted in the iron‑overloaded mice. As an underlying mechanism, iron‑overloaded mice showed increased pancreatic oxidative stress, with an elevated malondialdehyde level, and decreased SOD and glutathione peroxidase activity. Furthermore, iron overload led to ferroptosis with promoted expression of cytochrome c oxidase subunit II, and decreased transcripts of glutathione peroxidase 4 and solute carrier family 7 member 11. These results provided evidence that multiple intraperitoneal injections of iron dextran in mice lead to iron overload‑induced chronic pancreatitis, which suggested that secondary iron overload is a risk factor for pancreatitis and highlights the importance of iron in maintaining the normal functions of the pancreas.

Gelsemine Exerts Neuroprotective Effects on Neonatal Mice with Hypoxic-Ischemic Brain Injury by Suppressing Inflammation and Oxidative Stress via Nrf2/HO-1 Pathway.

Given that the role of Gelsemine in neuroinflammation has been demonstrated, this research aimed to investigate the effect of Gelsemine on neonatal hypoxic-ischemic (HI) brain injury. An in vivo HI brain injury neonatal mouse model and an in vitro oxygen-glucose deprivation (OGD) cell model were established and pretreated with Gelsemine. The brain infarct volume, neuronal loss and apoptosis, as well as spatial learning and memory were examined by TTC staining, Nissl's staining, TUNEL staining and Morris water maze test. Immunohistochemical staining was applied to detect the microglia cells and astrocytes in the mouse brain tissue. The cell viability was analyzed by CCK-8 assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), TNF-α, IL-1β, and IL-6 were determined via ELISA. The lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) level in OGD-treated cells were detected by colorimetry and DCFH-DA staining. Nrf2, HO-1, and inflammation-related factors were analyzed by immunofluorescence, qRT-PCR, or western blot. Gelsemine reduced the infarct volume and neuronal loss and apoptosis, yet improved spatial learning and memory impairment of HI-injured mice. Gelsemine inhibited the elevated MDA, TNF-α, IL-1β, IL-6, LDH and ROS levels, promoted the reduced SOD level and viability, and strengthened the up-regulation of HO-1 and Nrf2 in brain tissues and OGD-treated cells. However, Nrf2 silencing reversed the effects of Gelsemine on the Nrf2/HO-1 pathway, inflammation, and oxidative stress in OGD-treated cells. Gelsemine produces neuroprotective effects on neonatal mice with HI brain injury by suppressing inflammation and oxidative stress via Nrf2/HO-1 pathway.

Modulation of the p38 MAPK Pathway by Anisomycin Promotes Ferroptosis of Hepatocellular Carcinoma through Phosphorylation of H3S10.

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide. Ferroptosis is emerging as an effective target for tumor treatment as it has been shown to potentiate cell death in some malignancies. However, it remains unclear whether histone phosphorylation events, an epigenetic mechanism that regulates transcriptional expression, are involved in ferroptosis. Our study found that supplementation with anisomycin, an agonist of p38 mitogen-activated protein kinase (MAPK), induced ferroptosis in HCC cells, and the phosphorylation of histone H3 on serine 10 (p-H3S10) was participated in anisomycin-induced ferroptosis. To investigate the anticancer effects of anisomycin-activated p38 MAPK in HCC, we analyzed cell viability, colony formation, cell death, and cell migration in Hep3B and HCCLM3 cells. The results showed that anisomycin could significantly suppress HCC cell colony formation and migration and induce HCC cell death. The hallmarks of ferroptosis, such as abnormal accumulation of iron and elevated levels of lipid peroxidation and malondialdehyde, were detected to confirm the ability of anisomycin to promote ferroptosis. Furthermore, coincubation with SB203580, an inhibitor of activated p38 MAPK, partially rescued anisomycin-induced ferroptosis. And the levels of p-p38 MAPK and p-H3S10 were successively increased by anisomycin treatment. The relationship between p-H3S10 and ferroptosis was revealed by ChIP sequencing. The reverse transcription PCR and immunofluorescence results showed that NCOA4 was upregulated both in mRNA and protein levels after anisomycin treatment. And by C11-BODIPY staining, we found that anisomycin-induced lipid reactive oxygen species was reduced after NCOA4 knockdown. In conclusion, the anisomycin-activated p38 MAPK promoted ferroptosis of HCC cells through H3S10 phosphorylation.

Neuroprotective potential of cinnamoyl derivatives against Parkinson’s disease indicators in Drosophila melanogaster and in silico models

Parkinson's disease (PD) is a movement disorder resulting from the loss of dopaminergic neurons over time. While there is no cure for PD, available conventional therapies aid to manage the motor symptoms. Natural products (NPs) derived from plants are among the most potent alternative therapies for PD. This study explored the neuroprotective potential of selected cinnamoyl derivatives namely toussaintine A (1), E-toussaintine E (2), asperphenamate (3) and julocrotine (4) against PD indicators using rotenone-challenged Drosophila melanogaster and in silico models. The compounds were first assessed for their toxicity preceding treatment experiments. Adult flies (aged 1–4 days) were exposed to varying concentrations of the compounds for 7 days. During the experiment, the mortality of flies was observed, and the lethal concentration (LC50) of each tested compound was determined. The LC50 values were found to be 50.1, 55.6, 513.5, and 101.0 µM for compounds 1, 2, 3, and 4, respectively. For seven days, we exposed flies to 500 µM of rotenone and co-fed with a chosen dose of 40 µM of each test compound in the diet. Using a negative geotaxis test, rotenone-challenged flies exhibited compromised climbing ability in comparison to control flies, the condition that was reversed by the action of studied compounds. Rotenone exposure also elevated malondialdehyde levels in the brain tissues, as measured by lipid peroxidation, when compared to control flies. In flies exposed to rotenone and co-fed with the compounds, this effect was lessened. In flies exposed to rotenone, mRNA levels of antioxidant enzymes such as superoxide dismutase and catalase were raised but were normalized in flies treated with the investigated compounds. Moreover, in-silico studies examined the inhibitory ability of compounds 1–4 against selected PD molecular targets, revealing the strong power of toussaintine A (1) against Adenosine receptor 2 (A2AR) and monoamine oxidase B. Thus, our findings suggest that cinnamoyl derivatives have neuroprotective potential via reducing the oxidative burden and improving locomotor ability after toxin invectives. In particular, compound 1 at lower doses can simultaneously be a potential inhibitor of A2AR and an anti-oxidative mediator in the development of anti-PD agents.

Determination of Metabolomics Profiling in BPA-Induced Impaired Metabolism.

Exposure to bisphenol A (BPA) is unavoidable and it has far-reaching negative effects on living systems. This study aimed to explore the toxic effects of BPA in an experimental animal model through a metabolomics approach that is useful in measuring small molecule perturbations. Beside this, we also examined the ameliorative effects of resveratrol (RSV) against BPA-induced disturbances in experimental mice. This study was conducted for 28 days, and the results showed that BPA indeed induced an impairment in amino acid metabolism, taking place in the mitochondria by significantly (p &lt; 0.05) decreasing the levels of certain amino acids, i.e., taurine, threonine, asparagine, leucine, norleucine, and glutamic acid in the mice plasma. However, the administration of RSV did prove effective against the BPA-induced intoxication and significantly (p &lt; 0.05) restored the level of free amino acids. Lipid metabolites, L-carnitine, sphinganine, phytosphingosine, and lysophosphatidylcholine were also determined in the mice serum. A significant (p &lt; 0.05) decline in glutathione peroxidase (GPx), superoxide dismutase (SOD,) glutathione, and catalase levels and an elevation in malondialdehyde level in the BPA group confirmed the generation of oxidative stress and lipid peroxidation in experimental mice exposed to BPA. The expression of Carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II (CPT-II), lecithin-cholesterol acyltransferase (LCAT), carnitine O-octanoyltransferase (CROT), carnitine-acylcarnitine translocase (CACT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) genes was significantly upregulated in the liver tissue homogenates of experimental mice exposed to BPA, although RSV regulated the expression of these genes when compared with BPA treated experimental mice. CPT-I, CPT-II, and CACT genes are located in the mitochondria and are involved in the metabolism and transportation of carnitine. Hence, this study confirms that BPA exposure induced oxidative stress, upregulated gene expression, and impaired lipid and amino acid metabolism in experimental mice.

Heme induces intestinal epithelial cell ferroptosis via mitochondrial dysfunction in transfusion-associated necrotizing enterocolitis.

Transfusion-associated necrotising enterocolitis (TANEC) is a life-threatening disease with a poor prognosis in preterm infants. This study explored whether and how heme induces ferroptosis in TANEC gut injury. A TANEC mouse model and a cell culture system for heme and Caco-2 cells were established. Ferroptosis was assessed by measuring iron and malondialdehyde (MDA) levels and mitochondrial morphology in intestinal tissues and Caco-2 cells. Mitochondrial dysfunction was evaluated by measuring mitochondrial reactive oxygen species (ROS) production and membrane potential using JC-1. The intestinal injury grade was higher in the anemia-transfusion group than in the control group (p < .0001). Higher intestinal iron concentration (p < .0001), elevated levels of lipid peroxidation MDA (p=.0021), and ferroptotic mitochondrial morphological changes were found in mice of the anemia-transfusion group; specific ferroptosis inhibitor could alleviate anemia-transfusion gut injury, suggesting that ferroptosis play a role in the TANEC gut injury. Next, we explored whether heme released by hemolysis of erythrocytes induces ferroptosis in intestinal epithelial cells in vitro. The viability of Caco-2 cells significantly decreased after heme treatment (p < .0001). Iron accumulation, MDA elevated levels, and mitochondrial dysfunction also existed in the co-culture system, which ferroptosis inhibitors could reduce. In summary, ferroptosis was discovered in TANEC, and heme could induce ferroptosis in intestinal epithelial cells via mitochondrial dysfunction. Heme-inducing ferroptosis may be a possible mechanism and therapeutic target for TANEC.

Oxidative imbalance increases the risk for colonic polyp and colorectal cancer development.

The role of oxidative stress in the pathogenesis of colorectal carcinoma (CRC) has garnered considerable interest recently. Specific oxidative factors have been implicated in the pathogenesis of adenomatous polyps and ultimately adenocarcinoma. To evaluate the effect of oxidative imbalance as quantified by specific serological markers in the development of sporadic colon adenocarcinoma. A total of 170 patients that underwent endoscopy of the lower gastrointestinal tract in a tertiary center within 3 years were included in the study. They were allocated in three groups; those with sporadic colon adenocarcinoma (n = 56, 32.9%), those with colonic polyps (n = 33, 19.4%) and healthy controls (n = 81, 47.7%). All patients were evaluated for oxidant activity and antioxidant capacity with serum measurements of specific markers such as vitamins A, 25(OH) D3, E, C, B12, folic acid, glutathione, selenium (Se), zinc (Zn), free iron (Fe2+), and malondialdehyde and results were compared between groups. Serum levels of vitamins C, E, D, Se, Zn, vitamin B12 and total antioxidant capacity were significantly lower in the combined neoplasia/polyp group than in the control group (P = 0.002, P = 0.009, P < 0.001, P < 0.001, P < 0.001, P = 0.020 and P < 0.001, correspondingly). Increased levels of vitamin E (P = 0.004), vitamin D (P < 0.001), Se (P < 0.001) and Zn (P < 0.001) seem to bestow a protective effect on the development of CRC. For vitamin D (P < 0.001) and Zn (P = 0.036), this effect seems to extend to the development of colon polyps as well. On the other hand, elevated serum levels of malondialdehyde are associated with a higher risk of CRC (OR = 2.09 compared to controls, P = 0.004). Regarding colonic polyp development, increased concentrations of vitamin Α and Fe2+ are associated with a higher risk, whereas lower levels of malondialdehyde with a lower risk. Increased oxidative stress may play an important role in the pathogenesis and progression of CRC. Antioxidants' presence may exert a protective effect in the very early stages of colon carcinogenesis.