Markers Malondialdehyde Research Articles

Anti-Inflammatory and Antioxidant Effects of Gundelia tournefortii Aqueous Extract on the Liver and Kidney of PCOS Mice.

Polycystic Ovarian Syndrome (PCOS) is an endocrine disorder associated with increased risk of kidney and liver damage. Current treatments have shown contradictory outcomes, and their long-term use causes unwanted side effects. G. tournefortii could serve as a complementary medicine to current PCOS treatments. This study evaluates the effect of G. tournefortii in alleviating liver and kidney damage induced by PCOS via the regulation of oxidative stress pathways. PCOS was induced in female Balb/c mice using dehydroepiandrosterone over 21 days. They included a Sham group, a Vehicle group, a group treated with the extract only, and an untreated PCOS mice group. Positive Controls were treated with Metformin. The other PCOS groups were either co-treated while inducing PCOS or treated with the extract post-disease induction. Histological analysis was performed. Serum liver and kidney biochemical markers, levels of oxidative stress, and two pro-inflammatory markers were measured. NLRP3 and its associated genes (caspase-1 and ASC) gene expression was assessed. The extract restored normal kidney and liver histology post-PCOS induction. It decreased ALT and AST levels by 50% and the oxidant marker malondialdehyde (MDA) by 65% (P < .05). Superoxide dismutase (SOD)/catalase (CAT) activities were normalized in PCOS treated group. IL-1β/TNF-α significantly decreased (80% and 68%, respectively, P < .05) in the post-treated group. NLRP3 genes decreased in kidney tissues post-treatment with G. tournefortii extract. G. tournefortii reduced oxidative stress by modifying the ASC/caspase-1/IL-1β signaling pathway, thus protecting livers and kidneys highlighting the herb as a potential preventative and complementary agent in mitigating PCOS associated damage.

Effect of olive olive extracts in myocardial and vascular function of patients with chronic cononary syndromes

Abstract Introduction In a recent study, we demonstrated that the administration of an olive oil supplement enriched with HT (Olivomed) reduces oxidative stress and inflammatory biomarkers, improves endothelial and arterial function, and facilitates the diastolic function of the left ventricle after a short treatment period in patients with chronic coronary syndromes. Objetive Wehypothesized that the administration of an oral supplement, Olivomed SMART, containing olive oil extract enriched with oleuropein (OL), hydroxytyrosol (HT) and oleocanthal (OLEO), can reduce oxidative burden and further improve cardiac and vascular markers in patients with chronic coronary syndromes. Method Thus, in a prospective, randomized, crossover, double-blind, placebo-controlled clinical trial, we randomized 15 patients with chronic coronary syndromes to an oral supplement of olive oil extract enriched with OL, HT, and OLEO in a ratio of 2:1:3 or a placebo for one month. We measured before treatment, one month after using the placebo, and one month after administering the olive supplement: a) the Perfused Boundary Region (PBR) related inversely to the thickness of the endothelial glycocalyx in sublingual arterioles (range 5–25 μm), a marker inversely related to glycocalyx thickness, b) endothelial-dependent vasodilation (FMD) of the brachial artery, c) flow reserve in the anterior descending (CFR) with Doppler echocardiography, d) pulse wave velocity (PWV), central systolic blood pressure (cSBP), e) concentration of malondialdehyde (MDA), an oxidative stress marker. Results It appears that the administration of the Olivomed SMART supplement significantly improves vascular markers FMD and CFR compared to baseline, while no changes are induced by the placebo (Table 1). Olivomed SMART improves diastolic function, as shown by improved values of E’, E/e’, DT, LVGLS. No significant no marker indicates any difference compared to baseline (Table 2). The administration of the Olivomed SMART supplement significantly reduced levels of the oxidative stress marker MDA and oxidized LDL cholesterol in serum compared to baseline. In contrast, no statistically significant changes were observed after placebo administration (Table 3). Comparing the action of Olivomed and Olivomed SMART on the main vascular, echocardiographic, and biochemical markers relative to baseline values before treatment, the following table (Table 4) shows significant changes after the administration of Olivomed SMART in left ventricular longitudinal strain values and glycocalyx integrity in vessels ranging 20-25 μm. Conclusion Comparing Olivomed and Olivomed SMART, it appears that the beneficial effects on vascular and cardiac properties are largely due to the action of HT, while the newer combined formulation seems to provide additional benefits in endothelial function of arterioles, coronary artery function, and myocardial strain through the reduction of oxidative stress.

Predictive Value and Potential of Targeting Complement Factor C3 in Patients with Renal Injury in Preeclampsia.

The activation of the complement system is accompanied by the occurrence and development of preeclampsia, as well as kidney diseases. Here, the role of complement C3 [C3] in renal injury in preeclampsia was explored, and its potential application as an early diagnostic biomarker or drug target to ameliorate kidney injury induced by preeclampsia was preliminarily evaluated. A total of 48 subjects were included in the present study, and the complement C3 levels and renal function were analyzed. Patients with preeclampsia with severe features [sPe] had poorer renal function compared with the patients with preeclampsia. Urinary C3 levels could be used to distinguish between healthy controls, patients with preeclampsia, and patients with sPe. Increased renal inflammation and oxidative stress were notably increased in the preeclampsia mice with impaired renal function and attenuation of C3 activity using a C3 receptor antagonist, which reduced Pe-like symptoms and renal impairment, decreased serum blood urea nitrogen, creatinine, and urinary albumin levels, and decreased expression of the oxidative stress marker malondialdehyde, whilst increasing superoxide dismutase activity. In addition, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 ([HO-1) pathway was involved in the inhibition of complement C3 in the kidney. Higher urinary C3 levels could be used to predict kidney damage as it was found that the activation of the Nrf2/HO-1 pathway attenuated C3 levels, and this resulted in increased renal impairment in preeclampsia.

The effect of Ramadan intermittent fasting on anthropometric, hormonal, metabolic, inflammatory, and oxidative stress markers in pre-and post-menopausal women: a prospective cohort of Saudi women.

The menopausal transition significantly affects cardiometabolic health, primarily due to changes in reproductive hormones, particularly decreased estrogen levels and relative androgen excess. Adult Muslim women, both pre-and post-menopausal, are mandated to observe Ramadan intermittent fasting (RIF) every year. Therefore, the current study was designed to investigate RIF's effects on pre-menopausal (PRE-M) and post-menopausal (POST-M) healthy women's cardiometabolic health markers. This study further evaluated the relationship between tested markers and the participant's basic variables, such as BMI and body fatness. Due to differences in physiological and metabolic biomarkers between groups, RIF is likely to impact PRE-M and POST-M women differently. This study included 62 healthy women (31 PRE-M, aged 21-42 years, and 31 POST-M, aged 43-68 years) who observed RIF. Anthropometrics, sex hormones, lipid profile, pro-inflammatory (TNF-α), anti-inflammatory (IL-10) cytokines, the oxidative stress markers malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidase (GPx), and aging biomarker insulin-like growth factor-1 (IGF-1); all were tested 1 week before and at the fourth week of Ramadan. Body weight, BMI, waist circumference, body fat percentage (BFP), fat mass, fat mass index, triglycerides, and diastolic blood pressure significantly (p < 0.05) decreased at the end of Ramadan in both groups in comparison to the pre-fasting period. Contrarily, HDL, SOD, GPx, and IL-10 significantly (p < 0.05) increased in both groups. Estrogen levels significantly (p < 0.05) decreased in PRE-M women, whereas significantly (p < 0.05) increased in POST-M women. The progesterone levels, TAC, MDA, and IGF-1 remained unchanged in both groups. TNF-α significantly decreased in both groups, but the magnitude of reduction was higher in PRE-M women. Sex hormones and some metabolic biomarkers, especially in POST-M women, variably exhibited positive or negative relationships to BMI and BFP. RIF may influence the levels of estrogen, TNF-α, and IL-10 through improvements in metabolic health, reductions in body fat, activation of autophagy, modulation of immune responses, and changes in hormonal regulation. The RIF was generally associated with improved anthropometric, metabolic, inflammatory, and oxidative stress markers in both PRE-M and POST-M healthy women. Adhering to healthy dietary and lifestyle guidelines by pre-and post-menopausal women during Ramadan may foster the health benefits gained.

Sildenafil and Vitamin E Alone or in Combination Suppresses Cyclophosphamide-Induced Hepatotoxicity in Rats Through Antioxidant Mechanisms

Background: Cyclophosphamide (CP) can induce severe hepatotoxicity in certain patients by generating oxidative molecules and increasing reactive oxygen species (ROS). There are limited reports on the antioxidant and anti-inflammatory properties of Sildenafil. Objectives: This study aimed to evaluate the effect of Sildenafil on CP-induced hepatotoxicity. Methods: Animals were randomly divided into five groups (n = 6): Group I (control) received water distillate by gavage. Group II received CP (200 mg/kg) intraperitoneally to induce hepatotoxicity. Group III was orally administered Sildenafil (75 mg/kg) along with CP (200 mg/kg), while Group IV received vitamin E (500 mg/kg) and CP (200 mg/kg). Group V was administered 75 mg/kg of Sildenafil, 200 mg/kg of CP, and 500 mg/kg of vitamin E. At the end of the experiment, blood samples were collected from the animals' hearts to measure serum levels of liver enzymes, including aspartate transaminase (AST) and alanine aminotransferase (ALT), as well as oxidative stress markers malondialdehyde (MDA), nitric oxide (NO), and ferric reducing antioxidant power (FRAP). Liver tissue was also collected for assessment of antioxidant enzyme activity, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), along with histological examination. Results: The CP-treated group exhibited significant increases in AST, ALT, MDA, and NO levels, while CAT, SOD, GPx, and FRAP levels were markedly lower in the CP group compared to the saline group (P ≤ 0.01). Administration of sildenafil, alone and in combination with vitamin E, significantly reduced levels of AST, ALT, MDA, and NO. Meanwhile, antioxidant enzyme activity was markedly enhanced following sildenafil and vitamin E intake (P ≤ 0.01). Additionally, histological analysis confirmed Sildenafil's hepatoprotective properties. Conclusions: This study demonstrated that Sildenafil, both alone and in combination with vitamin E, was effective in reducing CP-induced liver toxicity through antioxidant mechanisms. Therefore, these findings suggest that Sildenafil, especially when combined with vitamin E, may serve as a complementary therapy to mitigate the hepatotoxic effects of CP.

Morin Ameliorates Lipopolysaccharides-Induced Sepsis-Associated Encephalopathy and Cognitive Impairment in Albino Mice

Sepsis-associated encephalopathy is a common neurological complication of sepsis that is characterized by neuroinflammation, oxidative stress and apoptosis, which results in cognitive impairments in septic survivors. Despite numerous treatment options for this condition, none of them are definite. Therefore, this study aimed to investigate the impact of morin, a flavone known for its neuroprotective and anti-inflammatory effects, against lipopolysaccharides-induced sepsis-associated encephalopathy in albino mice for 7 days. Mice were divided into 4 groups: Negative control, morin, septic, and septic morin-treated mice. Sepsis was induced by a single injection of lipopolysaccharides (5 mg/kg, intraperitoneally), morin (50 mg/kg b. wt.) was given orally, starting from 5 h after sepsis induction, then daily for 4 other days. Morin ameliorated septic structural and functional alternations as manifested by improving the survival rate, the behavioral functions, in addition to preserving and protecting the brain tissue. This was accompanied with the augmentation of the total antioxidant capacity, as well as the suppression of tissue levels of the lipid peroxidation marker malondialdehyde, apoptosis (cleaved-caspase-3), glial fibrillary acidic protein, and the proinflammatory cytokine tumor necrosis factor. In conclusion, morin has a promising ameliorative effect to counteract the sepsis-associated encephalopathy via its anti-inflammatory and antioxidant effects and to prevent the associated cognitive impairments.

Sertraline as a Multi-Target Modulator of AChE, COX-2, BACE-1, and GSK-3β: Computational and In Vivo Studies.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with the dysregulation of several key enzymes, including acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2), glycogen synthase kinase 3β (GSK-3β), β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), and caspase-3. In this study, machine learning algorithms such as Random Forest (RF), Gradient Boost (GB), and Extreme Gradient Boost (XGB) were employed to screen US-FDA approved drugs from the ZINC15 database to identify potential dual inhibitors of COX-2 and AChE. The models were trained using molecules obtained from the ChEMBL database, with 5039 molecules for AChE and 3689 molecules for COX-2. Specifically, 1248 and 3791 molecules were classified as active and inactive for AChE, respectively, while 858 and 2831 molecules were classified as active and inactive for COX-2. The three machine learning models achieved prediction accuracies ranging from 92% to 95% for both AChE and COX-2. Virtual screening of US-FDA drugs from the ZINC15 database identified sertraline (SETL) as a potential dual inhibitor of AChE and COX-2. Further docking studies of SETL in the active sites of AChE and COX-2, as well as BACE-1, GSK-3β, and caspase-3, revealed strong binding affinities for all five proteins. In vivo validation was conducted using a lipopolysaccharide (LPS)-induced rat model pretreated with SETL for 30 days. The results demonstrated a significant decrease in the levels of AChE (p < 0.001), BACE-1 (p < 0.01), GSK-3β (p < 0.05), and COX-2 (p < 0.05). Additionally, the downstream effects were evaluated, showing significant decreases in the apoptosis marker caspase-3 (p < 0.05) and the oxidative stress marker malondialdehyde (MDA) (p < 0.001), indicating that SETL is clinically localized in its effectiveness, mitigating both enzymatic activity and the associated pathological changes of cognitive impairment and AD.

Fluorescent gold nanoclusters possess multiple actions against atherosclerosis

Atherosclerosis caused major morbidity and mortality worldwide. Molecules possessing lipid-lowering and/or anti-inflammatory properties are potential druggable targets against atherosclerosis. We examined the anti-atherosclerotic effects of fluorescent gold nanoclusters (FANC), which were dihydrolipoic acid (DHLA)-capped 2-nm gold nanoparticles. We evaluated the 8-week effects of FANC in Western-type diet-fed ApoE-deficient mice by either continuous intraperitoneal delivery (20 μM, 50 μl weekly) or via drinking water (300 nM). FANC reduced aortic atheroma burden, serum total cholesterol, and oxidative stress markers malondialdehyde and 4-hydroxynonenal levels. FANC attenuated hepatic lipid deposit, with changed expression of lipid homeostasis-related genes HMGCR, SREBP, PCSK9, and LDLR in a pattern similar to mice treated with ezetimibe. FANC also inhibited intestinal cholesterol absorption, resembling the action of ezetimibe. The lipid-lowering and anti-atherosclerotic effects of FANC reappeared in Western-type diet-fed LDLr-deficient mice. FANC bound insulin receptor β (IRβ) via DHLA, leading to AKT activation. However, unlike insulin, which also bound IRβ to activate AKT to induce HO-1, activation of AKT by FANC was independent of HO-1 expression in human aortic endothelial cells (HAECs). Alternatively, FANC up-regulated NRF2, interfered the binding of KEAP1 to NRF2, and promoted KEAP1 degradation to free NRF2 for nuclear entry to induce HO-1 that suppressed the expression of ICAM-1 and VCAM-1. Consistently, FANC suppressed ox-LDL-induced enhanced attachment of THP-derived macrophages onto HAECs. In macrophages, FANC up-regulated ABCA1, and reversed ox-LDL-induced suppression of cholesterol efflux. FANC effected in vitro at nano moles. In conclusion, our findings showed novel actions and multiple mechanisms of FANC worked coherently against atherosclerosis.

Klotho relieves H2O2-induced lens epithelial cell damage via suppression of NOX4.

Age-related cataract (ARC) is a common eye disease and represents a common contributing factor to visual damage and loss. Klotho is a longevity gene and has been reported to participate in aging-related disorders. This work aims to investigate the potential role of klotho in ARC. In human lens epithelial cells (HLECs) induced by varying concentrations of hydrogen peroxide (H2O2), CCK-8 assay was used to detect cell viability. DCFH-DA probe was used to detect reactive oxygen species (ROS) level. Western blot was used to detect klotho expression. JC-1 fluorochrome assay was used to detect mitochondrial membrane potential (MMP). The concentrations of oxidative stress markers malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by related assay kits. Flow cytometry analysis, immunofluorescence staining and western blot were used to detect cell apoptosis. SA-β-gal staining and western blot were used to detect cell senescence. Klotho expression was decreased in HLECs induced by increasing concentrations of H2O2. Overexpression of klotho significantly inhibited ROS generation, decreased MDA content, increased SOD content, promoted cell viability and suppressed cell apoptosis and senescence in H2O2-induced HLECs. Furthermore, klotho down-regulated NOX4 expression and NOX4 elevation partially reversed the effects of klotho on H2O2-induced HLECs. To sum up, klotho may down-regulate NOX4 to protect against H2O2-induced HLECs damage. This finding suggested the potential therapeutic use of klotho in ARC, which needs further investigation.

A Randomized Double-Blind Placebo-Controlled Study on the Safety and Efficacy of Probiotics for Insulin Resistance and Oxidative Stress Markers in Diabetic Patients With End-Stage Renal Disease on Hemodialysis.

Chronic kidney disease (CKD) is a progressive loss of kidney function that can lead to end-stage renal disease (ESRD), requiring renal replacement therapy. Patients on chronic hemodialysis are at a higher risk of developing cardiovascular disease. This study aimed to investigate the effect of 12-week probiotic supplementation on insulin resistance, oxidative stress, and lipid profiles in diabetic patients with ESRD undergoing hemodialysis. This is a prospective, randomized, parallel-group, double-blind, placebo-controlled study with efficacy parameters including changes in insulin resistance assessed by homeostatic model assessment for insulin resistance (HOMA-IR); oxidative stress markers malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH); glycemic control (fasting blood sugar (FBS), glycosylated hemoglobin); and lipid profile over 12 weeks of probiotic supplementation in diabetic patients with ESRD on hemodialysis compared to placebo. The study included a total of 47 subjects, 30 men and 17 women with a mean age of 52.68 years, and observed a significant reduction in HOMA-IR with a mean difference of 0.66; improvements in MDA, NO, and GSH with mean differences of 0.92, 6.16, and 24.37 µmol/L, respectively; and a significant improvement in FBS and hemoglobin A1c (HbA1c). Minor self-limiting gastrointestinal adverse events like bloating and constipation were associated with probiotics. Probiotic supplementation can improve insulin resistance in patients with diabetes and ESRD undergoing regular hemodialysis. However, further research is needed to explore its effects on clinical outcomes.

Dysregulation of choline metabolism and therapeutic potential of citicoline in Huntington's disease.

Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti-apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies.

Effect of green coffee on miR-133a, miR-155 and inflammatory biomarkers in obese individuals

ObjectivesMetabolic syndrome is a cluster of conditions that increases the risk of atherosclerotic cardiovascular diseases. The current study was a randomized, double blind, placebo-controlled study that aimed to determine the impact of green coffee (GC) in obese patients with metabolic syndrome through analysis of miRNA-155, miRNA-133a and the inflammatory biomarkers such as resistin, TNF-α, total sialic acid, homocysteine, high sensitivity C-reactive protein (hs-CRP), and the anti-inflammatory cytokine, adiponectin.MethodsOne hundred-sixty obese patients were randomly supplemented either with GC capsules (800 mg) or placebo daily for six months. Both groups were advised to take a balanced diet. Blood samples were collected at baseline and after six months of supplementation.ResultsGC supplementation for 6 months reduced BMI (p = 0.002), waist circumference (p = 0.038), blood glucose (p = 0.002), HbA1c% (p = 0.000), Insulin (p = 0.000), systolic blood pressure (p = 0.005), diastolic BP (p = 0.001) compared with placebo. GC significantly decreased total cholesterol (TC, p = 0.000), LDL-C (p = 0.001), triglycerides (TG, p = 0.002) and increased HDL-C (p = 0.008) compared with placebo group. In addition, GC significantly (p ≤ 0.005) reduced total sialic acid, homocysteine, resistin, TNF-α, hs-CRP and the oxidative stress marker malondialdehyde (MDA), but increased serum adiponectin (p = 0.000) compared to placebo group. There was a significant reduction in the gene expression of miR-133a (p = 0.000) in GC group as compared with baseline levels and with the control placebo group (p = 0.001) after 6 months.ConclusionGC administration modulated metabolic syndrome by decreasing BMI, high BP, blood glucose, dyslipidemia, miRNA-133a and inflammatory biomarkers that constitute risk factors for cardiovascular diseases.ClinicalTrials.gov registration No. is NCT05688917.Graphical

The Role of Arginase and some Parameters in Diabetic Type 2 Patients with and without Retinopathy

Background: Oxidative stress plays a major role in the pathogenesis of diabetes mellitus by damaging cellular organelles and enzymes in blood such as arginase1, insulin and glutathione s-transferase; increasing lipid peroxidation such as malondialdehyde and increasing insulin resistance which can lead to diabetic complications such as diabetic retinopathy. Objectives: To explore the relationship of oxidative stress to the development of diabetic retinopathy by measuring the levels of Arginase1, the activity of glutathione s-transferase enzyme, and the levels of malondialdehyde as a secondary product of lipid peroxidation (biomarker for oxidative stress). Patients and MethodsThis study was conducted from November 2022 to January 2023 at the Ibn Al-Haitham Teaching Eye Hospital in Baghdad, the University of Baghdad / Department of Chemistry and the National Diabetes Centre for Treatment and Research at Al-Mustansyrriah University. This study was conducted on 120 subjects distributed as follows: 40 non-diabetic obese controls, 40 type 2 diabetics with no retinopathy, and 40 type 2 diabetic retinopathy patients, between 30 and 65 years of age. All groups were subjected to tests: measuring fasting blood glucose (FBG), HbA1c, lipid profile (cholesterol, triglycerides, HDL- cholesterol, LDL- cholesterol, and VLDL cholesterol), serum total arginase1, malondialdehyde glutathione s -transferase, body mass index (BMI), and waist-to-hip ratio. Results: Mean arginase1 levels were significantly higher in diabetic patients than in diabetic retinopathy and control groups (p ≤ 0.05). The mean xidative stress marker malondialdehyde concentration was significantly higher in diabetic retinopathy patients than in type 2 diabetics and the control group (P ≤ 0.05). The mean glutathione s-transferase activity in diabetic retinopathy patients was significantly higher than in the control group and type 2 diabetics (P ≤ 0.05). Conclusion: There is a relationship between oxidative stress and the development of diabetic retinopathy, where the levels of arginase1 and malondialdehyde increased and the activity of glutathione s –transferase enzyme increased as a result of oxidative stress and inflammation associated with complications of type 2 diabetes.

Silencing miR-155–5p expression improves intestinal damage through inhibiting inflammation and ferroptosis in necrotizing enterocolitis

BackgroundNecrotizing enterocolitis (NEC) is a condition characterized by acquired damage to the mucosal lining, predominantly affecting premature infants. Bioinformatics assessments uncovered a notable rise in miR-155–5p expression in the intestinal tissues of infants suffering from NEC. Nevertheless, the development of NEC's underlying mechanisms and the role of miR-155–5p are still not well understood. This research aimed to explore the role of miR-155–5p in NEC and to elucidate its underlying mechanisms. MethodsTo replicate NEC in vitro, lipopolysaccharide (LPS) was employed, whereas an in vivo rat model of NEC was established using formula feeding and exposure to hypoxia. Subsequently, levels of inflammatory cytokines, cell survival, and apoptosis rates were assessed. Various biochemical indicators such as glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured utilizing a purchased diagnostic kit. For the assessment of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) within FHC cells, analysis by flow cytometry was conducted. Additionally, the technique of Western blotting was utilized to analyze the levels of ferroptosis-associated proteins. Moreover, hematoxylin and eosin (H&E) staining was carried out to observe the histopathological alterations in the intestinal tissue samples from rats with necrotizing enterocolitis (NEC). ResultsReducing miR-155–5p improved the survival of FHC cells exposed to LPS, decreased cell apoptosis, inflammation, and ferroptosis, and mitigated intestinal damage in NEC rats. Furthermore, SLC7A11 was found to be a direct target of miR-155–5p. The inhibition of miR-155–5p decreased LPS-induced inflammation and ferroptosis in both FHC cells and NEC rats by promoting SLC7A11 expression. This effect was evidenced by increased levels of ferroptosis-related proteins FTH1 and GPX4, decreased COX-2 and ACSL4 levels, lower lipid peroxidation marker MDA, reduced antioxidant markers GSH, SOD, and CAT, fewer IL-6 and TNF-α, and suppression of the IκBα/NF-κB p65 signaling pathway. ConclusionsIn conclusion, reducing miR-155–5p could improve intestinal damage in NEC by inhibiting inflammation and ferroptosis. These findings may provide theoretical insights for the development of new therapies for NEC.

Betahistine's Neuroprotective Actions against Lipopolysaccharide-Induced Neurotoxicity: Insights from Experimental and Computational Studies.

Histamine H3 receptor (H3R) antagonists, such as betahistine (BHTE), have shown significant potential in treating central nervous system (CNS) disorders due to their neuroprotective properties. This study investigated BHTE's effects on lipopolysaccharide (LPS)-induced neurotoxicity, which is associated with neuroinflammation and neurodegeneration. Rats were divided into groups and pre-treated with BHTE (5 or 10 mg/kg, p.o.) for 30 days, followed by LPS administration (1 mg/kg, i.p.) for 4 consecutive days to induce neurotoxicity. LPS exposure resulted in cognitive impairment, as evidenced by performance deficits in maze tests, and a significant reduction in brain acetylcholine (ACh) levels. Additionally, LPS led to increased neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Pre-treatment with BHTE effectively counteracted these effects, improving cognitive performance and restoring ACh levels. BHTE significantly reduced LPS-induced increases in pro-inflammatory markers (COX-2, TNF-α, and IL-6) while enhancing anti-inflammatory cytokines (IL-10 and TGF-β1). Furthermore, BHTE improved mitochondrial function by increasing enzyme levels (MRCC-I, II, and IV) and boosted anti-apoptotic (Bcl-2) and antioxidant defenses (GSH and catalase). BHTE also reduced apoptosis markers, including pro-apoptotic protein caspase-3, and oxidative stress marker malondialdehyde (MDA). Molecular modeling studies revealed that BHTE effectively binds to key enzymes involved in neuroinflammation and apoptosis (AChE, COX-2, and caspase-3), with binding free energies between 4 and 5 kcal/mol, interacting with critical residues. These findings underscore BHTE's multifaceted neuroprotective effects against LPS-induced neurotoxicity, offering potential therapeutic avenues for managing neuroinflammation and related neurodegenerative disorders.

Evaluation of Endoplasmic Reticulum Stress in an Experimental Intestinal Ischemia-Reperfusion Model in Rats: The Role of Ozone Therapy and Trimetazidine.

The objective of the study was to assess the impact of ozone (O3) and trimetazidine on the intestines following ischemia-reperfusion (I/R) injury through the investigation of endoplasmic reticulum stress. Forty Sprague Dawley rats were separated into five groups. The groups were named as follows: control, O3, I/R, I/R + trimetazidine (TMZ), and I/R + O3. The control group had laparotomy and exploration of the superior mesenteric artery (SMA) only. Furthermore, alongside laparotomy and SMA exploration, an intraperitoneal (i.p.) administration of a 0.7 mg/kg ozone-oxygen (O3-O2) combination was given to the O3 group. In the experimental groups, the SMA was blocked with the silk suture ligation technique for a duration of 1 h and then restored to normal blood flow for another hour. In the I/R + O3 group, ozone was delivered i.p. at a dosage of 0.7 mg/kg, 30 min after ischemia. In the I/R + TMZ group, a dose of 20 mg/kg/day of trimetazidine was administered orally via gavage for a duration of 7 days, beginning 1 week prior to the induction of ischemia. Intestinal tissues were taken to assess indicators of intestinal mucosal injury and oxidative stress. The level of the lipid peroxidation marker malondialdehyde (MDA) was significantly reduced in the experimental groups as compared to the I/R group (p < 0.05). The experimental groups had considerably greater levels of glutathione (GSH), which reflects antioxidant capacity, compared to the I/R group (p < 0.05). Nevertheless, the concentration of GSH was observed to be increased in the I/R + O3 group in comparison to the I/R + TMZ group (p < 0.05). The histopathological damage score showed a substantial decrease in the experimental groups as compared to the I/R group (p < 0.05). The I/R + O3 group had the lowest injury score. The experimental groups exhibited significantly reduced positivity of the endoplasmic reticulum (ER) stress markers C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP)-78 compared to the I/R group (p < 0.05). The findings provide evidence for the potential advantages of utilizing ozone therapy in the treatment of intestinal ischemia-reperfusion injury. Additionally, they propose that ozone should be assessed in more extensive clinical trials in the future as a therapeutic agent that can disrupt endoplasmic reticulum stress.

Benchmark Dose of Melamine Exposure for a Renal Injury Marker Mediated by Oxidative Stress: Examples in Patients with Urolithiasis and Occupational Workers.

Establishing a safe exposure level from epidemiological studies while providing direct hazard characterization in humans often faces uncertainty in causality, especially cross-sectional data. With advances in molecular epidemiology, it is reasonable to integrate identified intermediate biomarkers into health risk assessment. In this study, by considering the mediation of the oxidative stress marker malondialdehyde (MDA), we explored the exposure threshold of melamine on the early renal injury marker N-acetyl-β-D glucosaminidase (NAG). The benchmark dose (BMD) was derived from model averaging of the composite direct effect of melamine exposure and the indirect effect through the mediation of MDA on NAG levels. As illustrative examples, we analyzed 309 adult patients with calcium urolithiasis and 80 occupational workers for the corresponding exposure thresholds. The derived threshold was subpopulation-dependent, with the one-sided lower bound BMDL10 for the patients with urolithiasis with (without) the mediator MDA for the patients with kidney stones and the occupational workers being 0.88 (0.96) μg/kg_bw/day and 22.82 (18.09) μg/kg_bw/day, respectively. The derived threshold levels, considering the oxidative stress marker MDA, were consistent with those without adjusting for the mediation effect. However, the study outcomes were further supported by the suggested mechanism pathway. The threshold for the patients with urolithiasis was up to two orders lower than the current tolerable daily intake level of 200 μg/kg_bw/day recommended by the WHO (EFSA).

Regulation of the p53/SLC7A11/GPX4 Pathway by Gentamicin Induces Ferroptosis in HEI-OC1 Cells.

Gentamicin is a commonly used aminoglycoside antibiotic, with ototoxicity as a significant side effect. Ferroptosis, an iron-dependent form of cell death, has been implicated in a variety of disorders. Whether ferroptosis impacts gentamicin ototoxicity is not yet known. The current work used an in-vitro model to examine the influence of gentamicin-induced ferroptosis on cochlear hair cell damage and probable molecular biological pathways. House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated with different concentrations of gentamicin for 24 hours, with or without ferrostatin-1 pretreatment, to observe gentamicin-induced ferroptosis. The role of p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling in gentamicin-induced ferroptosis was explored by pretreating cells with the p53 inhibitor pifithrin-α (PFT-α). We investigated the effect of gentamicin on cells by assessing cell viability. Cellular proteins were isolated and Western blots were performed to detect changes in the expression of p53, SLC7A11, and GPX4. Fluorescence staining was used to assess levels of reactive oxygen species. An enzymatic detection kit was used to detect glutathione, Fe, and malondialdehyde markers. Gentamicin reduced cell viability, glutathione content, and SLC7A11 and GPX4 protein levels, and increased levels of p53 protein, reactive oxygen species, malondialdehyde, and Fe. These effects were largely blocked by pretreatment with ferrostatin-1. Pretreatment with the p53 inhibitor PFT-α prevented the gentamicin-induced reduction in SLC7A11 and GPX4, which alleviated several features of ferroptosis including glutathione depletion, iron overload, and lipid peroxidation build-up. Gentamicin induces ferroptosis in the HEI-OC1 cell line, and the mechanism may be related to the p53/SLC7A11/GPX4 signaling pathway.

Antiparkinson potential of khellin on rotenone-induced Parkinson's disease in a zebrafish model: targeting MAO, inflammatory, and oxidative stress markers with molecular docking, MD simulations, and histopathology evidence

In this study, the antiparkinson effect of khellin (KL) on rotenone-induced Parkinson's disease (PD) was examined in zebrafish. Initially, In silico evaluations, such as drug likeness and ADME/T analysis, confirmed the pharmacological viability of KL. Molecular docking and molecular dynamics (MD) analysis revealed stable binding interactions between KL and monamine oxidase B (MAO-B). Molecular docking results for KL and pioglitazone (CCl) revealed binding energies of −6.5 and −10.4 kcal/mol, respectively. Later, molecular dynamics (MD) studies were performed to assess the stability of these complexes, which yielded binding energies of −36.04 ± 55.21 and −56.2 ± 80.63 kJ/mol for KL and CCl, respectively. These results suggest that KL exhibits considerable binding affinity for MAO-B. In In vitro studies, according to the DPPH free radical scavenging assay, KL exhibited significant antioxidant effects, indicating that it can promote redox balance with an IC50 value of 22.68 ± 0.5 μg/ml. In vivo studies and evaluation of locomotor activity, social interaction, histopathology and biochemical parameters were conducted in KL-treated zebrafish to measure SOD and GSH antioxidant activity, the oxidative stress marker malondialdehyde (MDA), the inflammatory marker myeloperoxidase (MPO) and MAO-B. However, while the locomotor and social interaction abilities of the rotenone-treated zebrafish were significantly reduced, KL treatment significantly improved locomotor activity (p < 0.001) and social interaction (p < 0.001). KL alleviated PD symptoms, as indicated by significant increases in SOD (p < 0.01), GSH (p < 0.001), MDA (p < 0.001), MAO-B (p < 0.001) and MPO (p < 0.001) in rotenone-induced PD fish (p<0.001) significantly reduced activities. Histopathological studies revealed that rotenone-induced brain hyperintensity and abnormal cellularity of the periventricular gray matter in the optic tectum were significantly reduced by KL treatment. This study provides a strong basis for developing KL as a new candidate for the treatment of Parkinson's disease, with the prospect of improved safety profiles and efficacy.

Lambda-cyhalothrin induces heart injury in chickens by regulating cytochrome P450 enzyme system and inhibiting Nrf2/HO-1 pathway

Lambda-cyhalothrin (LCT) is a common pyrethroid insecticide widely used for ectoparasite control and hygiene pest prevention in poultry and this study aimed to investigate the mechanisms of LCT-induced cardiac injury in chickens. Low, medium, and high-dose LCT exposure models in chickens were established and hematoxylin and eosin (H&E) staining, dihydroethidium (DHE) staining, TUNEL staining, immunofluorescence, biochemical analysis, and gene expression analysis were used to study the effects of LCT exposure on the chicken heart. The results showed that LCT exposure increased the serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH), led to muscle fiber breakage and inflammatory cell infiltration and caused cardiac tissue damage. The DHE staining and biochemical analysis revealed that LCT exposure resulted in the excessive accumulation of ROS, decreased activities/levels of catalase (CAT), total superoxide dismutase (T-SOD), and glutathione (GSH), and increased levels of the oxidative damage marker malondialdehyde (MDA). The TUNEL staining indicated that LCT exposure increased apoptosis possibly through the elevated expression of pro-apoptotic genes in the mitochondrial pathway, the reduced expression of anti-apoptotic genes, the upregulation of pro-inflammatory factors and the downregulation of anti-inflammatory factors. Here, LCT exposure significantly inhibited the expression of genes in the Nrf2/HO-1 pathway and activated the expression of genes in the CYP450 enzyme system. Compared to the low-dose group, the high-dose LCT exposure group showed lower levels of apoptosis and inflammation, possibly related to the low oxidative stress levels mediated by the decreased expression of the CYP450 enzyme system. In conclusion, LCT exposure induces oxidative stress, apoptosis, and inflammation in chicken hearts, which may be associated with the inhibition of the Nrf2/HO-1 pathway and activation of the CYP450 enzyme system. This study provides a theoretical basis for the safer use of insecticides in poultry production.