Elevated GSH Research Articles

The effect of TFAP2A/ANXA8 axis on ferroptosis of cervical squamous cell carcinoma (CESC) in vitro.

Potential role and associated mechanisms of Annexin A8 (ANXA8), a member of the Annexins family, in cervical squamous cell carcinoma (CESC) are still unclear, despite being upregulated in various malignant tumors. Here, we observed a notably elevated expression of ANXA8 in CESC cells. The inhibition of ANXA8 amplified the susceptibility of CESC cells to Erastin and sorafenib-induced ferroptosis, whereas it exerted minimal influence on DPI7 and DPI10-induced ferroptosis. The results from the Fe2+ concentration assay showed no significant correlation between ANXA8 gene knockdown and intracellular Fe2+ concentration induced by ferroptosis inducers. Western blot analysis demonstrated that the knockdown of ANXA8 did not alter ACSL4 and LPCAT levels under ferroptosis-inducing conditions, but it did result in a reduction in intracellular GSH levels induced by the ferroptosis inducer. Subsequently, we identified TFAP2A as an upstream transcription factor of ANXA8, which plays a role in regulating cell ferroptosis. The knockdown of TFAP2A significantly elevated MDA levels and depressed GSH levels in the presence of a ferroptosis inducer, thereby inhibiting cell ferroptosis. However, this inhibitory effect could be reversed by ANXA8 overexpression. Therefore, our research suggests that the TFAP2A/ANXA8 axis exerts regulatory control over ferroptosis in CESC cells by mediating GSH synthesis in System Xc.

Administration of Momordica charantia Linnaeus Extracts for the Treatment of Hypothyroidism Induced Obesity in Mice and Study of Related Biochemical Parameters and Thyroid Histology

Background:: Hypothyroidism is marked by increased Thyroid Stimulating Hormone (TSH) levels and decreased T3 (tri-iodothyronine) and T4 (tetra-iodothyronine/thyroxine) levels. Hypothyroidism-induced obesity has been linked to various metabolism-related abnormalities like slowed down basal metabolic rate (BMR). Momordica charantia Linn. fruit has traditionally been used for reducing obesity. Objective:: Administration of Momordica charantia Linnaeus extracts for the treatment of hypothy-roidism-induced obesity in mice and study of related biochemical parameters and thyroid histology. Methods:: Hypothyroidism-induced obesity was induced by administering methimazole to the mice for 21 consecutive days and then investigating the disease reversal properties of Momordica char-antia aqueous extract, alcoholic extracts, and standard drug thyroxine following their administration to mice for 21 consecutive days. Blood sampling was done to obtain the biochemical parameters normal values, hypothyroidism-induced obesity levels, and levels after treatment with the test ex-tracts. Various biochemical parameters like thyroid profile {TSH, T3, and T4} and lipid profile {Total cholesterol (TC), total triglycerides (TGs), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL)} and physical parameters like body weight, waist circumference, and food and water intake were measured. Liver and heart were dissected from the mice of each group for oxidative stress measurement by estimation of serum Glutathione (GSH), Malondialdehyde (MDA), and Catalase levels. The thyroid gland was dissected from the mice of each group for histopathological analysis. Results:: Serum MDA levels had significantly increased (p<0.001), whereas the values of GSH and catalase had decreased significantly (0.001) in hypothyroid obese mice. The standard and test groups showed attenuation of MDA levels (p<0.0001) and elevation of GSH (p<0.0001) and cata-lase levels (p<0.0001) back toward normal measurements. After the induction of hypothyroid obe-sity, the thyroid profile and lipid profile both had disturbed significantly and the levels of TSH, TC, TGs, and VLDL elevated, whereas the levels of T3, T4 hormones, and HDL decreased significantly. After the treatment with the test plant extracts and standard drug, the levels of TSH, (p<0.0001) TC (p<0.05), TGs (0.0001), and VLDL (p<0.0001) attenuated and the levels of T3 (p<0.0001), T4 (p<0.0001), and HDL (p<0.0001) elevated back towards the normal range. Histopathological anal-ysis and the hypothyroid obese group thyroid showed significant shrinkage of thyroid globule size wise and a significant decrease in colloid levels when compared with the control group, whereas the standard and test groups showed reversal of the thyroid globule size back towards normal. Conclusion:: The plant extracts can be used as a safe herbal treatment for hypothyroid obesity.

Functional mechanism of baicalein in alleviating severe acute pancreatitis-acute lung injury by blocking the TLR4/MyD88/TRIF signaling pathway.

Severe acute pancreatitis-acute lung injury (SAP-ALI) is a disease with high mortality. This study aims to explore the mechanism of baicalein on SAP-ALI in rats by blocking toll-like receptor-4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) signal pathway. The SAP-ALI rat model was established by intraperitoneal injection of 3% pentobarbital sodium (30 mg/kg), with pancreas and intestines turned over, injected with 3.5% sodium taurocholate backward into the bile-pancreatic duct at 0.1 mL/100 g for 12h, and treated with baicalein, lipopolysaccharide (LPS), miR-182 agomir, or miR-182 antagomir. The TLR4/MyD88/TRIF pathway was activated using LPS in SAP-ALI rats after baicalein treatment. Baicalein attenuated inflammatory cell infiltration, alveolar wall edema, decreased W/D ratio and levels of TLR4, MyD88, and TRIF in the lung tissues, reduced levels of inflammatory factors in pancreatic and lung tissues and BALF, diminished ROS, and elevated GSH, SOD and CAT in pancreatic and lung tissues of SAP-ALI rats. Activation of the TLR4/MyD88/TRIF pathway partly abrogated baicalein-mediated improvements in inflammation and oxidative stress in SAP-ALI rats. miR-182 targeted TLR4. miR-182 suppressed inflammation and oxidative stress in SAP-ALI rats by targeting TLR4. Inhibition of miR-182 partly nullified baicalein-mediated attenuation on inflammation and oxidative stress in SAP-ALI rats. In conclusion, baicalein can inhibit the TLR4/MyD88/TRIF pathway and alleviate inflammatory response and oxidative stress in SAP-ALI rats by upregulating miR-182 and suppressing TLR4, thus ameliorating SAP-ALI.

Impact of Saussurea lappa against foodborne parasite Trichinella spiralis experimental infections induced variation in DNA damage, oxidative stress and PCNA expression in rat skeletal muscles.

Trichinellosis is a parasite zoonosis that is spread through ingesting raw or undercooked meat that contains the Trichinella spiralis (T. spiralis) infective larvae. It has three clinical phases: intestinal, migratory, and muscular. Kuth root, also known as Costus (Saussurea lappa) roots, is used in many traditional medical systems all over the world to treat a variety of illnesses, such as dyspepsia, diarrhoea, vomiting, and inflammation. Current study assessed the therapeutic Potential of costus roots extract (CRE) treatment on experimental trichinellosis induce changes in DNA damage, oxidative stress and Proliferating cell nuclear antigen (PCNA) expression in muscle fibers in male rats. A total of 60 male Sprague Dawley rats were divided into 6 groups (Gps) [Gp1, Negative control; Gp2, Costus (CRE); Gp3, Positive control or Infected rats with T. spiralis, Gp4; Pre-treated infection with CRE; Gp5 & Gp6, Post treated infection with CRE for one and two weeks respectively]. Current results revealed that; Trichinella spiralis experimentally infection induced significant elevation in tissue malondialdehyde (MDA), DNA damage, PCNA expression and significant depletion in tissue glutathione (GSH), superoxide dismutase (SOD) and catalase (Cat) activities. Pre or/and post CRE treated infected rats with T. spiralis (Gp4-Gp6) induced improvements and depletion in DNA damage, PCNA expression, MDA and elevation in GSH, SOD, catalase as compared to infected rats with T. spiralis (Gp3) with best results for the pretreatments (Gp4). Trichinella spiralis experimental infection induced DNA damage and oxidative stress in rat skeletal muscles and treatments with costus roots extract modulates these changes.

Acid and Glutathione Dual-Responsive, Injectable and Self-Healing Hydrogels for Controlled Drug Delivery.

Considering the complexity of physiological microenvironments and the risks of surgical infection, there still remains critical demand to develop a hydrogel as a drug release platform with multifunctional properties, including good neutral stability and sensitive multiple stimuli-responsive behaviors, as well as injectable and self-healing properties. Herein, we present a facile preparation of injectable, self-healing hydrogels with acid and glutathione (GSH) dual-responsiveness for controlled drug delivery. Initially, the anticancer drug camptothecin (CPT) was premodified with disulfide bonds and attached to poly(ethylenimine) (PEI) via the Schiff base reaction, resulting in PEI-CPT. Subsequently, OSA-IR780 was synthesized through the Schiff base reaction involving IR780 with amine groups (IR780-NH2) and oxidized sodium alginate with aldehyde groups (OSA). The formation of PEI-CPT/OSA-IR780 hydrogels with various solid contents occurred rapidly within 40 s through a simple mixing process of the aqueous solution of PEI-CPT and OSA-IR780. These hydrogels exhibited remarkable stability under neutral conditions and controlled release of CPT upon exposure to simulated tumor environments characterized by acidic conditions and elevated GSH concentrations. Furthermore, they had significant injectable and self-healing properties due to the dynamically imine-cross-linked networks. In addition, the prepared hydrogels exhibited long-term biodegradability and biocompatibility. Collectively, these features indicate the great potential of PEI-CPT/OSA-IR780 hydrogels as therapeutic delivery vehicles.

Faecal Microbiota Transplantation Alleviates Ferroptosis after Ischaemic Stroke

Ischaemic stroke can induce changes in the abundance of gut microbiota constituents, and the outcome of stroke may also be influenced by the gut microbiota. This study aimed to determine whether gut microbiota transplantation could rescue changes in the gut microbiota and reduce ferroptosis after stroke in rats. Male Sprague-Dawley rats (6 weeks of age) were subjected to ischaemic stroke by middle cerebral artery occlusion (MCAO). Fecal samples were collected for 16S ribosomal RNA (rRNA) sequencing to analyze the effects of FMT on the gut microbiota. Neurological deficits were evaluated using the Longa score. triphenyl tetrazolium chloride (TTC) staining was performed in the brain, and kits were used to measure malondialdehyde (MDA), iron, and glutathione (GSH) levels in the ipsilateral brain of rats. Western blotting was used to detect the protein expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and the transferrin receptor 2 (TFR2) in the ipsilateral brain of rats. Stroke induced significant changes in the gut microbiota, and FMT ameliorated these changes. TTC staining results showed that FMT reduced cerebral infarct volume. In addition, FMT diminished MDA and iron levels and elevated GSH levels in the ipsilateral brain. Western blot analysis showed that FMT increased GPX4 and SLC7A11 protein expression and decreased TFR2 protein expression in the ipsilateral brain after stroke. FMT can reverse gut microbiota dysbiosis, reduce cerebellar infarct volume, and decrease ferroptosis after stroke.

Metabolomic modelling and neuroprotective effects of carvacrol against acrylamide toxicity in rat's brain and sciatic nerve.

The study aimed to investigate the harmful effects of acrylamide (AA), which forms in carbohydrate-rich foods at temperatures above 120°C, on the central and peripheral nervous systems and to evaluate the potential neuroprotective effects of carvacrol (CRV). Male Wistar Albino rats were subjected to AA (40 mg/kg/bw/day) and CRV (50 mg/kg/bw/day) for 15 days. Following the last administration, evaluations revealed disrupted gait, heightened thermal sensitivity and altered paw withdrawal thresholds in AA-exposed rats. Notably, AA reduced glutathione (GSH) and raised malondialdehyde (MDA) levels in both brain and sciatic nerve tissues. AA raised nuclear factor erythroid 2-related factor 2 (Nrf2), caspase 3 and nuclear factor κB (NF-κB) gene expressions while decreasing NR4A2. CRV co-administration mitigated gait abnormalities, elevated GSH levels and lowered MDA levels in both tissues. CRV also modulated gene expression, reducing Nrf2 and NF-κB while increasing NR4A2. Histopathological signs of AA-induced neurodegeneration and elevated glial fibrillary acidic protein levels observed in brain and sciatic nerve tissues were rectified with simultaneous administration of CRV, thereby demonstrating neuroprotective efficacy in both regions. This study is pioneering in demonstrating CRV's neuroprotective potential against AA-induced neurotoxicity in both central and peripheral nervous systems, effectively addressing limitations in the literature. In conclusion, the study revealed AA-induced neurodegeneration in the brain and sciatic nerve, with CRV significantly mitigating this neurotoxicity. This novel research underscores CRV's promise as a neuroprotective agent against AA-induced adverse effects in both the central and peripheral nervous systems.

Lipid Carrier Nanostructured Astilbin Ameliorates Rotenone-Induced Neurodegeneration in Mice Brain via Modulation of GSK3β-Nrf2 Signaling Pathways.

Astilbin is a flavanonol, found in St John's wort (Hypericum perforatum) and many other plants. It has been demonstrated that astilbin contains anti-inflammatory, antioxidant, and immune-suppressive properties. However, the bioavailability of astilbin remains a question for which drug delivery-based nanoparticles can be utilized. We formulated a nanostructured lipid carrier loaded with astilbin (NLC-AS) and tested its effects on the rotenone exposed PC12 cells and in a neurodegenerative mice model of Parkinson's disease (PD) induced by rotenone. Results show that rotenone caused dose-dependent inhibition of PC12 cell growth with about 50% cell death at 2 µM rotenone. Rotenone caused apoptosis in PC12 cells which was reduced to a notable level by NLC-AS through suppression of oxidative stress, especially via elevation of GSH and total antioxidant capacity, and inhibition of monoamine oxidase. Rotenone significantly augmented neurodegeneration in mouse brains by triggering apoptosis and oxidative damage, while NLC-AS treatment halted these processes. Rotenone-exposed mice showed neuronal deficits and impaired neurocognitive functions like loss of memory and learning restrictions which were restored to a remarkable level by NLC-AS administration. The protective effect of NLC-AS was mediated through the inhibition of GSK3β and induction of Nrf2 genes in the brain tissues. These findings suggest that NLC-AS administration may efficiently regulate the signs of PD in mice and prevent neurodegeneration and neurocognitive dysfunctions.

Quercetin Attenuates Oxidative Stress and Apoptosis in Brain Tissue of APP/PS1 Double Transgenic AD Mice by Regulating Keap1/Nrf2/HO-1 Pathway to Improve Cognitive Impairment.

Objective: The objective of the study is to investigate whether quercetin ameliorates Alzheimer's disease (AD)-like pathology in APP/PS1 double transgenic mice and its hypothesized mechanism, contributing to the comprehension of AD pathogenesis. Methods: A total of 30 APP/PS1 transgenic mice were randomized into model group (APP/PS1), quercetin group (APP/PS1+Q), and donepezil hydrochloride group (APP/PS1+DON). Simultaneously, there were 10 C57 mice of the same age served as a control group. Three months posttreatment, the effects of quercetin on AD mice were evaluated using the Morris water maze (MWM) test, Y maze experiment, immunohistochemistry, immunofluorescence, and western blotting. Results: Results from the water maze and Y maze indicated that quercetin significantly improved cognitive impairment in APP/PS1 transgenic AD mice. Additionally, serum enzyme-linked immunosorbent assay (ELISA) results demonstrated that quercetin elevated MDA, superoxide dismutase (SOD), CAT, GSH, acetylcholine (ACh), and acetylcholinesterase (AChE) levels in AD mice. Hematoxylin-eosin (HE) staining, Nissl staining, and hippocampal tissue thioflavine staining revealed that quercetin reduced neuronal damage and Aβ protein accumulation in AD mice. Western blot validated protein expression in the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathway associated with oxidative stress and apoptosis, confirming quercetin's potential molecular mechanism of enhancing AD mouse cognition. Furthermore, western blot findings indicate that quercetin significantly alters protein expression in the Keap1/Nrf2/HO-1 pathway. Moreover, molecular docking analysis suggests that Keap1, NQO1, HO-1, caspase-3, Bcl-2, and Bax proteins in the Keap1/Nrf2/HO-1 pathway may be potential regulatory targets of quercetin. These findings will provide a molecular basis for quercetin's clinical application in AD treatment. Conclusion: Quercetin can improve cognitive impairment and AD-like pathology in APP/PS1 double transgenic mice, potentially related to quercetin's activation of the Keap1/Nrf2/HO-1 pathway and reduction of cell apoptosis.

Effects of supplementation with mature coconut water on oxidative stress, semen quality, reproductive hormone levels, and sexual behavior in Boer bucks

AbstractMature coconut water (MCW) has been demonstrated to contain bioactive compounds with antioxidant properties. In vivo research showed that MCW supplementation increased semen quality in rats, suggesting that it may boost reproductive performance. This study investigated the impact of MCW on the reproduction of Boer bucks. Two groups of 12 sexually mature bucks were given either plain water (control) or MCW at 5 mL/kg of body weight daily for 60 days. Sexual behaviors were studied using the focal observation technique, whereas semen was collected for quality assessment. Oxidative stress markers, namely, malondialdehyde (MDA) and glutathione (GSH), along with reproductive hormones, specifically luteinizing hormone (LH), follicle‐stimulating hormone (FSH), and testosterone, were quantified in blood serum samples via enzyme‐linked immunosorbent assay (ELISA). The oxidative stress analysis showed elevated GSH and reduced MDA levels, accompanied by enhanced sperm quality, including superior motility, concentration, viability, and fewer morphological abnormalities (p < 0.05), in the group receiving MCW. Moreover, there was a rise in LH, FSH, and testosterone levels with improved sexual behaviors (p < 0.05), including a reduced latency to the first mount, increased mount attempts, higher libido, and prolonged kicking and sniffing durations. In conclusion, MCW may improve reproductive health and fertility in Boer bucks.

Evaluation of Testicular Function and Structural Changes of Wistar Rats Following Antiretroviral Exposure: Protective Role of Cyperus Esculentus.

Long-term antiretroviral drug toxicity may exacerbate the impact of HAART-Cyperus esculentus (C. esculentus) interactions on testicular function in HIV-infected individuals. This study examined the ability of C. esculentus plants to treat testicular dysfunction, which is thought to be a probable side effect of antiretroviral toxicity. Adult Wistar male rats weighing 90-110 g were divided into six groups and administered the prescribed treatments. In addition to testicular histology and stereological parameters, testosterone levels, follicle-stimulating hormone levels, antioxidant markers, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione levels were also evaluated. The adverse consequences of highly active antiretroviral therapy (HAART) include considerable loss of germ cells, enlargement of the tubular lumen, widening of interstitial gaps, and severe hypocellularity. Compared to the other treatment groups, MDA levels dramatically increased, whereas GSH and antioxidant enzyme (SOD) levels significantly decreased. Testicular architecture was largely conserved after treatment with C. esculentus, with a notable increase in the cellular densities of germinal and interstitial cells and a notable decrease in the tubular lumen. Vacuolation, architectural malformations, and hypoplastic changes were reduced. Significant improvements were also observed in C. esculentus in terms of elevated antioxidant SOD and GSH levels and decreased MDA levels. C. esculentus reduced architectural distortions and testicular dysfunction caused by HAART, and improved testicular morphology. Further exploration of these pathways is required.

Glutathione-triggered prodrugs: Design strategies, potential applications, and perspectives.

The burgeoning prodrug strategy offers a promising avenue towardimproving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of the tumor microenvironment. Considering the pivotal involvement of elevated GSH in the tumorigenic process, a diverse repertoire of GSH-triggered prodrugs has been developed for cancer therapy, facilitating the attenuation of deleterious side effects associated with conventional chemotherapeutic agents and/or the attainment of more efficacious therapeutic outcomes. These prodrug formulations encompass a spectrum of architectures, spanning from small molecules to polymer-based and organic-inorganic nanomaterial constructs. Although the GSH-triggered prodrugs have been gaining increasing interests, a comprehensive review of the advancements made in the field is still lacking. To fill the existing lacuna, this review undertakes a retrospective analysis of noteworthy research endeavors, based on a categorization of these molecules by their diverse recognition units (i.e., disulfides, diselenides, Michael acceptors, and sulfonamides/sulfonates). This review also focuses on explaining the distinct benefits of employing various chemical architecture strategies in the design of these prodrug agents. Furthermore, we highlight the potential for synergistic functionality by incorporating multiple-targeting conjugates, theranostic entities, and combinational treatment modalities, all of which rely on the GSH-triggering. Overall, an extensive overview of the emerging field is presented in this review, highlighting the obstacles and opportunities that lie ahead. Our overarching goal is to furnish methodological guidance for the development of more efficacious GSH-triggered prodrugs in the future. By assessing the pros and cons of current GSH-triggered prodrugs, we expect that this review will be a handful reference for prodrug design, and would provide a guidance for improving the properties of prodrugs and discovering novel trigger scaffolds for constructing GSH-triggered prodrugs.

Combined quercetin and simvastatin attenuate hepatic fibrosis in rats by modulating SphK1/NLRP3 pathways

Liver fibrosis involves several signalling pathways working in concert regulating the deposition of extracellular matrix. In this study, we evaluated the effect of quercetin and simvastatin alone and their combination on the treatment of experimentally induced hepatic fibrosis in rats. To decipher the potential mechanisms involved, liver fibrosis was induced in rats by administration of 40 % carbon tetrachloride (CCl4) (1 μl/g rat, i.p., twice weekly) for 6 weeks. Quercetin (50 mg/kg, orally), simvastatin (40 mg/kg, orally) either individually or combined were administered for another 4 weeks. The three treatment groups ameliorated hepatic dysfunction and altered parameters of sphingolipid and pyroptosis pathways. Yet, the combined group showed a more pronounced effect. Treatments lowered serum levels of GOT, GPT, ALP and elevated albumin and total protein levels. Histopathological and electron microscope examination of liver tissue revealed diminished fibrosis and inflammation. Protein expression levels of α-SMA, IL-1β, PPAR-γ, TGF-β1, caspase-1 and caspase-3 expression in liver tissues were reduced. Additionally, hepatic mRNA levels of SphK1 and NLRP3 decreased after treatment. Furthermore, the three groups lowered MDA levels and elevated total antioxidant capacity, GSH and Nrf2 expression levels. Treatments downregulated sphingolipid pathway and NLRP3-mediated pyroptosis and stimulated an anti-apoptotic, anti-proliferative and antioxidant activity. This suggests that targeting the SphK1/NLRP3 pathway could be a prospective therapeutic strategy against liver fibrosis.

Evaluation of the Antiparasitic, Antihepatotoxicity, and Antioxidant Efficacy of Quercetin and Chitosan, Either Alone or in Combination, against Infection Induced by Giardia lamblia in Male Rats.

Giardia lamblia (G. lamblia) is one of the most common protozoal infections and a key cause of malabsorption, some cases of mental developmental issues in children, and reduced body weight. The known antiparasitic medications, which are the standard drugs used for parasitic treatment, have several side effects and sometimes exhibit low efficacy. Therefore, the current study aimed to evaluate the treatment with quercetin (QC) or chitosan (CH), either alone or in combination, as possible alternative therapeutic agents that may alleviate the side effects of G. lamblia infections and restore the normal architecture of the intestinal muscles. They are investigated as alternatives to other routinely administered drugs that may gradually lose their efficacy due to human resistance to therapeutic agents. This study was carried out on 50 male albino rats that were divided into five groups with 10 rats in each group: the control group (Group I), the infected non-treated group (Group II), the infected group treated with QC (Group III), the infected treated group with CH (Group IV), and the infected group treated with a combination of QC and CH (Group V). The effect was first evaluated by counting the G. lamblia fecal cysts in the stool, examining histopathological sections of the intestine with the appearance of trophozoites in the infected group, and conducting a transmission electron microscopic examination of the tissues of the small intestine. Alterations in the biochemical parameters of liver and kidney function and the antioxidant enzymes in the liver tissues of SOD, CAT, and GSH, and non-enzymatic markers of lipid peroxidation (MDA) were evaluated. The results showed a significant decline in the number of parasites in the stool samples, with a marked elevation in the number of trophozoites in the intestinal sections of the infected non-treated group as compared to the infected treated groups. The last group, which was treated with a combination of QC and CH, showed the best results in terms of a decline in the infection rate of G. lamblia in stool samples, with a marked and clear improvement in the intestinal mucosa, regular muscles with normal enteric ganglions, and reduced rates of intestinal injuries caused by G. lamblia trophozoites. Both QC and CH had non-toxic effects on the biochemical parameters of the liver and kidneys, as well as pronounced antioxidant activities due to the elevation of SOD, CAT, and GSH in conjunction with a decline in the levels of MDA. A combination of QC and CH can be considered a potent antiparasitic, anti-hepatotoxic, and antioxidant therapeutic agent; it could constitute a promising alternative treatment agent against G. lamblia infection.

Hesperetin protects hippocampal neurons from the neurotoxicity of Aflatoxin B1 in mice

Aflatoxin B1 (AFB1) is a major food and feed pollutant that endangers public health. Previous studies have shown that exposure to AFB1 causes neurotoxicity in the body. However, the mechanism of neurotoxicity caused by AFB1 is not well understood, and finding a workable and practical method to safeguard animals from AFB1 toxicity is essential. This study confirmed that AFB1 caused endoplasmic reticulum stress (ER stress) and apoptosis in hippocampal neurons using C57BL/6 J mice and HT22 cells as models. In vitro experiments showed that the aryl hydrocarbon receptor (AHR) plays a significant role in the cytotoxicity of AFB1. Finally, we assessed how hesperetin protecting against the neurotoxicity caused by AFB1. Our findings demonstrated that AFB1 increased the levels of BAX and Cleaved-Caspase3 proteins, while decreasing the levels of BCL2 protein in the CA1 and CA3 regions of the hippocampus. The AFB1 increased the expression of AHR and activated nuclear translocation. It also elevated the expression levels of Chop, GRP78, p-IRE1/ Xbp1s, and p-PERK/p-EIF2a. Importantly, we also discovered for the first time that blocking AHR in HT22 cells dramatically reduced the level of ER stress and apoptosis caused by AFB1. In vivo and in vitro studies, supplementation of hesperetin effectively reversed AFB1-induced cytotoxicity. We have demonstrated that hesperetin effectively restored the imbalance in the GSH/GST system in HT22 cells treated with AFB1. Furthermore, we observed that elevated GSH levels facilitated the formation of AFB1-GSH complexes, which enhanced the excretion of AFB1. Therefore, hesperetin improves ER stress-induced apoptosis by reducing AFB1 activation of AHR.

Comparison of the Effects of Rosmarinic Acid and Electromagnetic Radiation-Induced Cardiotoxicity on Rats.

Electromagnetic radiation (EMR) causes stable aggregation of reactive oxygen species (ROS), producing oxidative stress. Rosmarinic acid (RA), a plant-origin antioxidant, has been proposed against the side effects of cell phone and ultrahigh-frequency waves. Forty-two male Wistar rats were randomly divided into 6 groups. Group 1 (controls) received 5 mL of normal saline with the gavage method, Group 2 received 915 MHz radiation, Group 3 received 2450 MHz radiation, Group 4 received RA plus 915 MHz radiation, Group 5 received RA plus 2450MHz radiation, and Group 6 received oral RA (5 mg/kg). Treatment and radiation (1 hour per day) continued for up to 30 days. EMR significantly reduced the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), the content of glutathione (GSH), and the level of total antioxidant capacity (TAC) and significantly increased oxidative stress indices, such as the levels of malondialdehyde (MDA) and nitric oxide (NO), and the content of protein carbonyl (PC). In contrast, RA significantly elevated TAC level (all groups), GSH content (the RA/cell phone radiation group), GPx activity (the RA/ultrahigh-frequency radiation group), SOD activity (all groups), and CAT activity (RA/ultrahigh-frequency radiation group) and conversely reduced MDA level (all groups), NO level (all groups), and PC content (all groups) in the RA/cell phone and RA/ultrahigh-frequency radiation groups compared with the NS/cell phone and NS/ultrahigh-frequency radiation groups, respectively. The administration of RA resulted in a significant reversal of cardiac markers in EMR-intoxicated rats. RA treatment showed a significant protective effect against EMR-induced cardiotoxicity.

Inhibition of the glutamate-cysteine ligase catalytic subunit with buthionine sulfoximine enhances the cytotoxic effect of doxorubicin and cyclophosphamide in Burkitt lymphoma cells

Burkitt lymphoma (BL) is a highly aggressive lymphoma that mainly affects children and young adults. Chemotherapy is effective in young BL patients but the outcome in adults is less satisfactory. Therefore, there is a need to enhance the cytotoxic effect of drugs used in BL treatment. Glutathione (GSH) is an important antioxidant involved in processes such as regulation of oxidative stress and drug detoxification. Elevated GSH levels have been observed in many cancers and were associated with chemoresistance. We previously identified GCLC, encoding an enzyme involved in GSH biosynthesis, as an essential gene in BL. We now confirm that knockout of GCLC decreases viability of BL cells and that the GCLC protein is overexpressed in BL tissues. Moreover, we demonstrate that buthionine sulfoximine (BSO), a known inhibitor of GCLC, decreases growth of BL cells but does not affect control B cells. Furthermore, we show for the first time that BSO enhances the cytotoxicity of compounds commonly used in BL treatment, doxorubicin, and cyclophosphamide. Given the fact that BSO itself was not toxic to control cells and well-tolerated in clinical trials, combination of chemotherapy with BSO may allow reduction of the doses of cytotoxic drugs required to obtain effective responses in BL patients.

Flower-shaped covalent organic framework synthesis and its anticancer drug delivery application

Fabrication of covalent organic frameworks (COFs) at room temperature is necessary due to their easy preparation, practical scale-up, and low cost to overcome the limitations of solvothermal and high-temperature synthesis. Herein, we fabricated flower-shaped COFs (FSCOFs) that were synthesized in various ratios of ortho-xylene and butanol mixture solvents. The FSCOFs exhibited excellent crystallinity with a pore size of approximately 10 nm, which was confirmed by PXRD and BET measurements. To utilize the FSCOFs as a drug carrier, doxorubicin (DOX) was loaded, followed by encapsulation of hyaluronic acid to increase the colloidal stability of FSCOFs in a physiological environment (FSCOFs-DOX-HA). The encapsulation efficiency and the drug loading capacity of FSCOFs-DOX-HA were 21.23 % and 29.82 %, respectively. Moreover, 92 % and 59 % of DOX is released in acidic environments and elevated GSH environments, proving the sensitivity of the FSCOFs as carriers. The excellent drug release mechanism of FSCOFs-HA-DOX is demonstrated by FSCOFs imine nitrogen protonation under acidic environment confirmed by its zeta potential changes under various physiological environments. The designed FSCOFs-DOX-HA was demonstrated to be a pH-sensitive drug carrier to deliver anticancer drugs into cancer cells. The MTT and drug internalization data demonstrated sustained DOX release from FSCOFs-DOX-HA. Finally, the real-time fluorescence demonstrates the effectiveness of the FSCOFs-DOX-HA upon cellular uptake and release of the anticancer drug. Thus, the FSCOFs system reported here opens a new path in COF research for drug carrier systems.

Prefrontal Glutathione Levels in Major Depressive Disorder Are Linked to a Lack of Positive Affect.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders, with symptoms including persistent sadness and loss of interest. MDD is associated with neurochemical alterations in GABA, glutamate, and glutamine levels but, to date, few studies have examined changes in glutathione (GSH) in MDD. This study investigated changes in GSH in an unmedicated group of young adults, including 46 participants with current (n = 12) or past MDD (n = 34) and 20 healthy controls. Glutathione levels were assessed from GSH-edited magnetic resonance (MR) spectra, acquired from a voxel in the left prefrontal cortex, and depressive symptoms were evaluated with validated questionnaires and clinical assessments. Cortisol levels were also assessed as a marker for acute stress. Participants with current MDD demonstrated elevated GSH in comparison to participants with past MDD and controls, although the results could be influenced by differences in tissue composition within the MRS voxel. In addition, participants with both current and past MDD showed elevated cortisol levels in comparison to controls. No significant association was observed between GSH and cortisol levels, but elevated GSH levels were associated with a decrease in positive affect. These results demonstrate for the first time that elevated GSH in current but not past depression may reflect a state rather than a trait neurobiological change, related to a loss of positive affect.

Increasing glutathione levels by a novel posttranslational mechanism inhibits neuronal hyperexcitability

Glutathione (GSH) depletion, and impaired redox homeostasis have been observed in experimental animal models and patients with epilepsy. Pleiotropic strategies that elevate GSH levels via transcriptional regulation have been shown to significantly decrease oxidative stress and seizure frequency, increase seizure threshold, and rescue certain cognitive deficits. Whether elevation of GSH per se alters neuronal hyperexcitability remains unanswered. We previously showed that thiols such as dimercaprol (DMP) elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme. Here, we asked if elevation of cellular GSH by DMP altered neuronal hyperexcitability in-vitro and in-vivo. Treatment of primary neuronal-glial cerebrocortical cultures with DMP elevated GSH and inhibited a voltage-gated potassium channel blocker (4-aminopyridine, 4AP) induced neuronal hyperexcitability. DMP increased GSH in wildtype (WT) zebrafish larvae and significantly attenuated convulsant pentylenetetrazol (PTZ)-induced acute ‘seizure-like’ swim behavior. DMP treatment increased GSH and inhibited convulsive, spontaneous ‘seizure-like’ swim behavior in the Dravet Syndrome (DS) zebrafish larvae (scn1Lab). Furthermore, DMP treatment significantly decreased spontaneous electrographic seizures and associated seizure parameters in scn1Lab zebrafish larvae. We investigated the role of the redox-sensitive mammalian target of rapamycin (mTOR) pathway due to the presence of several cysteine-rich proteins and their involvement in regulating neuronal excitability. Treatment of primary neuronal-glial cerebrocortical cultures with 4AP or l-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of GSH biosynthesis, significantly increased mTOR complex I (mTORC1) activity which was rescued by pre-treatment with DMP. Furthermore, BSO-mediated GSH depletion oxidatively modified the tuberous sclerosis protein complex (TSC) consisting of hamartin (TSC1), tuberin (TSC2), and TBC1 domain family member 7 (TBC1D7) which are critical negative regulators of mTORC1. In summary, our results suggest that DMP-mediated GSH elevation by a novel post-translational mechanism can inhibit neuronal hyperexcitability both in-vitro and in-vivo and a plausible link is the redox sensitive mTORC1 pathway.