Increased GSH Levels Research Articles

Evaluation of the Effect of Gum Arabic on the Histological and Physiological Changes in the Liver of Albino Rats Exposed to Bisphenol A

We designed this work in order to study the protective effect of aqueous extract of gum arabic (GA) from oxidative damage induced by bisphenol A(BPA). This study was conducted on 35 male laboratory Albino rats of Sprague Dawley strain (165-210 grams) and divided into five groups. Each group included 7 rats. The experiment was performed at the animal house of Biology (College of Education for Pure Sciences). The experiment continued for 90 days under conditions Standard laboratory, as follows: The first group was the control; the second group had GA taken orally; the third group had BPA taken orally; the fourth group had GA taken first, followed by BPS, and the fifth group had BPA taken first, followed by GA. According to the above results clearly, Serum levels of AST, ALT and Lipid profile (Cholesterol, Triglyceride) indicated a highly significant increase in these parameters at group 3, While the fourth and fifth groups show significant reductions in AST, ALT, cholesterol, triglycerides, and MDA, also significant increases in GSH levels, While the histological changes in the third group were represented by the presence of a state of blood congestion with depletion of glycoprotein and degeneration of some cells, in addition to the presence of a state of necrosis of liver cells, while it was not observed severe histological changes when compared to third group in both fourth and fifth groups. In Short, the above results indicated that GA treatment for BPA-induced liver injury had Therapeutic effect through anti-free radical formation and functional role as free scavenger.

Glutathione and Selenium Supplementation Attenuates Liver Injury in Diethylnitrosamine-Induced Hepatocarcinogenic Mice by Enhancing Glutathione-Related Antioxidant Capacities

Excess oxidative stress and inadequate antioxidant capacities are critical features in the development of hepatocellular carcinoma. This study aimed to determine whether supplementation with glutathione (GSH) and/or selenium (Se), as antioxidants, attenuates diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. C57BL/6J male mice were randomly assigned to control, DEN, DEN + GSH, DEN + Se, and DEN + GSH + Se groups for 20 weeks. Daily supplementation with GSH and/or Se commenced in the first experimental week and continued throughout the study. DEN was administered in weeks 2–9 and 16–19 of the experimental period. DEN administration induced significant pathological alterations of hepatic foci, evidenced by elevated levels of liver function, accompanied by high malondialdehyde (MDA) levels; low GSH levels; and glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) activities. Supplementation with GSH and Se significantly ameliorated liver pathological changes, reducing liver function and MDA levels while increasing GSH levels and GPx, GR, and GST activities. Notably, combined supplementation with GSH and Se more effectively increased the GSH/glutathione disulfide ratio and GPx activity than individual supplementation. Supplementation with GSH and Se attenuated liver injury in DEN-induced hepatocarcinogenic mice by enhancing GSH and its related antioxidant capacities, thereby mitigating oxidative damage.

Trans-chalcone ameliorates CCl4-induced acute liver injury by suppressing endoplasmic reticulum stress, oxidative stress and inflammation

BackgroundAcute liver injury serves as a crucial marker for detecting liver damage due to toxic, viral, metabolic, and autoimmune exposures. Due to the response to adverse external stimuli and various cellular homeostasis, Endoplasmic reticulum stress (ERS), Oxidative stress, and Inflammation have great potential for treating liver injury. Trans-chalcones (TC) is a polyphenolic compound derived from a natural plant with anti-oxidative and anti-inflammatory abilities. Here, TC was aimed to attenuate liver injury by triggering ER stress, oxidative stress, inflammation, and apoptosis. A single dose of carbon tetrachloride (CCl4) 1 mL/kg was administered intraperitoneally into C57BL6 mice to construct an in vivo NAFLD model, whereas AML12 cells were treated with lipopolysaccharides (LPS) to construct an in vitro NAFLD model. The mice used in the experiment were randomly assigned to two groups: a 12-hour set and a 24-hour set. Forty-nine mice were randomly divided into seven groups, the control group (Group I), TC group (Group II) 10 mg/kg TC, negative control group (Group III) CCl4, TC + CCl4 groups (Groups IV−VI), mice were subcutaneously treated with (5, 10, and 20) mg/kg of TC for three consecutive days before the CCl4 injection and the positive control group (Group VII) received 10 mg/kg Silymarin. After the experiment, serum transaminase, liver histological pathology, hepatic expression levels ERS, oxidative stress, and inflammation-related markers were assessed. TC pre-treatment significantly alleviates the expression of ER stress, oxidative stress, inflammatory cytokines, and apoptosis in both in vivo and in vitro models of liver injury. TC treatment significantly reduced serum transaminase levels (ALT and AST), and improved liver histopathological scores. TC administration also led to a reduction in MDA levels and the suppression of ROS generated by CCl4 in hepatic tissue, which contributed to an increase in GSH levels. The protective effect of TC on the liver injury mouse model was achieved by inhibiting hepatocyte apoptosis. Moreover, TC pre-treatment dramatically decreased the protein levels of ER stress indicators such as CHOP, Bip, Ero-Lα, IRE1α, PERK, Calnexin, and PDI when compared to the CCl4-only treated group. TC exerts hepatoprotective effects against CCl4-induced acute liver injuries in mice by modulating ERS, oxidative stress, and inflammation. These results suggest that TC pre-treatment at a dose of (20 mg/kg BW) was as effective as silymarin (10 mg/kg) in preventing CCl4-induced acute liver injury. Further investigations are necessary to elucidate the precise molecular mechanisms underlying the hepatoprotective effects of TC and to explore its therapeutic potential in clinical trials.

Effects of long-term Tai Chi vs. aerobic exercise on antioxidant activity and cognitive function in individuals with Parkinson’s disease

An imbalance between the generation of reactive oxygen species and the body’s antioxidant defense mechanisms is closely related to the development and progression of Parkinson’s disease (PD). Considering that physical exercise is a potential therapeutic intervention for modulating oxidative stress markers and cognitive function in PD, the primary purpose of this study was to compare the effects of different long-term exercise modalities on antioxidants and cognitive performance in patients with PD. In addition, the secondary purpose was to explore whether changes in the levels of these biochemical markers are associated with alterations in cognitive performance pre- and post-intervention. In all, 61 participants were randomly divided into the aerobic exercise (AE, n=20), Tai Chi exercise (TCE, n=21), or control (n=20) group. Blood samples were collected before and after a 12-week intervention period for the analysis of antioxidant markers [leukocyte 8-hydroxydeoxyguanosine (8-OHdG), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px), oxidized glutathione (GSSG), superoxide dismutase (SOD), and uric acid (UA)]. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Although no significant changes were observed in the activity of 8-OhdG, GSH-Px, GSSG, GSH:GSSG ratio, SOD, and cognitive performance in the AE and TCE groups, the 12-week AE intervention led to a significant increase in CAT and GSH levels, along with a significantly decrease in UA levels among individuals with PD. Conversely, the TCE intervention resulted in a significant increase in GSH levels. However, SOD activity and MMSE scores were significantly decreased after 12 weeks in the control group. The correlations between changes in MMSE scores and changes in the levels of GSH and UA prior to and after the intervention reached significance in the AE group. Thus, long-term AE and TCE might serve as effective strategies for reducing oxidative damage and preserving cognitive function in PD, with AE exhibiting greater benefits compared with TCE. These findings hold potential clinical relevance as complementary measures to standard medical treatments and alternative therapies, such as antioxidant supplements and dietary adjustments, particularly for individuals in the early stages of PD.

Nicorandil attenuates lithocholic acid-induced hepatotoxicity in mice through impeding oxidative stress, inflammation and apoptosis

This study was performed to explore the beneficial protective impact of nicorandil (Nico) against lithocholic acid (LCA)-induced hepatotoxicity. Materials and methods: Mice received Nico (50 and 100 mg/kg. orally) for 7 days and LCA (125 mg/kg, i.p.) was injected for the last 4 days two times daily. Results: Nico improved both structural and functional abnormalities induced by LCA. Nico significantly decreased serum levels of transaminases, ALP, GGT and markedly elevated albumin levels. Additionally, Nico mitigated oxidative stress; it decreased contents of MDA and NO and increased GSH level and SOD activity. Moreover, Nico markedly decreased the elevated levels of TNF-α, JNK, Bax, Caspase-3 and iNOS, and increased the levels of eNOS in hepatic tissues. Furthermore, Nico substantially decreased the expression of NFκBp65 in hepatic tissues. Histopathological and transmission electron microscopy findings further supported these biomarkers. Conclusion: Nico might be used as an adjuvant medication to prevent LCA-induced hepatotoxicity, pending further clinical research, through impeding oxidative stress, inflammation and apoptosis.

Dietary inclusion of cyanobacteria Arthrospira (Spirulina platensis) spp. decreases the aggravating effect of hemin from red meat in a rat colorectal carcinogenesis model

Colorectal cancer (CRC) risk, associated with a high intake of red/processed meat, may be related to hemin. A potential chemopreventive agent, Arthrospira (Spirulina platensis) spp. (AP) is a cyanobacteria employed as a functional food with the potential to reduce malnutrition in developing countries. Thus, we assessed the effects of dietary AP against hemin-promoting effects in a dimethylhydrazine (DMH)-induced colorectal carcinogenesis model. Male Sprague-Dawley rats were allocated into five groups. G1–G4 received four subcutaneous DMH injections (40 mg/kg body weight, twice a week for 2 weeks) and G5 received DMH vehicle. At weeks 4 to 16, groups were fed a balanced diet (BD, G1 and G5), BD containing 2 % AP (20 g powder/kg chow, G2), BD containing hemin (0.32 g/kg chow, G3) or BD containing hemin+2 % AP (G4), respectively. Hemin group (G3) increased aberrant crypt foci (ACF) development, malondialdehyde (MDA), and Nox-1 levels and reduced glutathione (GSH) and GSH-Px levels in colonic mucosa when compared to DMH group (G1). In contrast, the dietary hemin+2 % AP regimen (G4), reduced both preneoplastic lesion development and MDA levels while increased GSH levels, compared to the DMH+hemin group (G3). Dietary AP may reduce hemin-promoting effects by modulating oxidative stress and ACF lesions.

Glutathione regulates CIA-activated splenic-lymphocytes via NF-κB/MMP-9 and MAPK/PCNA pathways manipulating immune response

Reduced glutathione (GSH) is an antioxidant involved in redox homeostasis, and recently regarded as an inducer of Reductive stress. Its immune-regulatory effects on lymphocytes have not been extensively studied. This study is based on the finding that much increased GSH level in collagen-induced arthritis (CIA) rat spleen, and aimed to investigate the effects of GSH (0, 1, 10, 100 mM) on normal and immune-stimulated spleen lymphocytes respectively. The elevated GSH level is associated with the increased levels of inflammatory factors; especially the increased DPP1 activity indicated immune-granulocytes activation in CIA rat spleen. Exogenous GSH had different influences on normal and CIA lymphocytes, affecting intracellular levels of GSH, Glutathione-S-transferases (GSTs) and Reactive oxygen species (ROS); as well as the expressions of NF-κB, MMP-9, Bcl-2, GST, P38, PCNA and TLR4. The increased extracellular GSH level disturbed redox homeostasis and induces reductive stress to spleen lymphocytes, which decreased intracellular GSH concentration and influenced the MAPK/PCNA and NF-κB/MMP-9 signaling pathways, as well as cell cycles respectively, leading to cell senescence/ferroptosis /apoptosis. This study also revealed the multiple faces of GSH in regulating spleen lymphocytes, which depends on its levels in tissue or in cells, and the activation status of lymphocytes. These findings indicate the immune-regulatory role of GSH on spleen-lymphocytes, and the high level GSH in CIA rat spleens may contribute to CIA development.

Mitochondrial damage precedes the changes of glutathione metabolism in CdCl2 treated neuronal SH-SY5Y cells

Cadmium crosses the blood-brain barrier inducing damage to neurons. Cell impairment is predominantly linked to oxidative stress and glutathione (GSH) depletion. On the other hand, several reports have described an increase of GSH levels in neuronal cells after CdCl2 exposure. Therefore, the aim of the present report was to investigate the relation between changes in GSH levels and mitochondrial damage in neuronal cells after CdCl2 treatment. To characterize neuronal impairment after CdCl2 treatment (0–200 μM) for 1–48 h, we used the SH-SY5Y cell line. We analyzed GSH metabolism and determined mitochondrial activity using high-resolution respirometry. CdCl2 treatment induced both the decreases and increases of GSH levels in SH-SY5Y cells. GSH concentration was significantly increased in cells incubated with up to 50 μM CdCl2 but only 100 μM CdCl2 induced GSH depletion linked to increased ROS production. The overexpression of proteins involved in GSH synthesis increased in response to 50 and 100 μM CdCl2 after 6 h. Finally, strong mitochondrial impairment was detected even in 50 μM CdCl2 treated cells after 24 h. We conclude that a significant decrease in mitochondrial activity can be observed in 50 μM CdCl2 even without the occurrence of GSH depletion in SH-SY5Y cells.

Neuroprotective effect of Myrtus communis against ionizing radiation-induced brain injury: Insights from histopathological and biochemical analysis in rats: TROD-GROG 005

AimTo investigate the potential radioprotective effects of Myrtus communis on brain tissue. MethodsThirty female rats were divided into four groups. The control group (C) was applied with oral saline solution (SF) for four days. Myrtus communis (MC) groups started to receive MC (100 mg/kg, oral) either four days before (R + preMC) or immediately after (R + MC) irradiation for four days. Irradiation was applied 10 Gy in a single fraction. All rats were sacrificed on the fourth day of irradiation. Malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels, myeloperoxidase (MPO), superoxide dismutase (SOD), and tissue factor activities (TFa) were determined for biochemical analysis. Hematoxylin&Eosin staining was done for histopathological analyses, and electrophoretic analyses were performed. ResultsNO, MDA, and MPO levels were higher in all irradiated groups compared with the C group. MC administration decreased NO, MDA, and MPO levels in R + preMC and R + MC groups. MC administration increased GSH levels. TFa activity decreased in R groups but did not change with MC administration compared to the C group. Radiation-induced brain tissue injury decreased, and morphologically normal neurons were observed in both MC-added groups. ConclusionMyrtus communis has a potential neuroprotective effect on brain tissue, attributed to its antioxidative, anti-inflammatory, and anti-lipid peroxidative properties.

Effects of in utero benzo[a]pyrene exposure on the testis of rats during puberty and the protective effect of atorvastatin.

Benzo[a]pyrene (BaP) is a contaminant that is generated in the environment through processes such as smoke, incomplete combustion of fossil fuels, vehicle exhaust emissions, entry into the body is through inhalation, and consumption of contaminated food. It is an omnipresent environmental pollutant with unavoidable exposure. BaP metabolites are observed in the male reproductive system, especially in the testes and epididymis of animals, and are responsible for reduced testicular and epididymal function. The protective effect of atorvastatin (ATV) on testicular damage was investigated previously. The aim of the present study was to investigate the protective effect of ATV on testicular toxicity induced by benzo[a]pyrene (BaP) during pregnancy in Wistar rats. This experimental laboratory study involved 40 adult rats, divided into seven groups and maintained under standard environmental conditions. The groups received different diets [control, corn oil, ATV (10 mg/kg), BaP (10 and 20 mg/kg), and ATV + BaP (10 and 20 mg/kg)] at gestation Days 7-16, orally. Male offspring were examined 10 weeks after birth. Testis and serum samples were collected, and testosterone level, malondialdehyde (MDA), and glutathione (GSH) were measured. Histological and immunohistochemical assays were performed under a light microscope. Statistical analysis was conducted using SPSS, with analysis of variance and Tukey tests to assess significant differences between groups. ATV significantly reduced MDA, a marker of lipid peroxidation and oxidative stress in rat testes following BaP administration. Treatment with ATV at doses of 10 mg/kg increased GSH levels, correcting disruptions in the antioxidant system caused by BaP. Testosterone concentration in rats treated with ATV and BaP substantially prevented the decrease induced by BaP. Histomorphometry revealed that ATV significantly prevented the detrimental effects of BaP on the thickness of spermatogenic epithelium and the diameter of seminiferous tubules. Under ATV treatment, testicular tissue histopathology improved, and spermatogenesis returned to a almost back to normal state. Caspase-3 expression decreased, and apoptosis activity in testicular tissue improved under ATV treatment, indicating a positive effect of ATV in reducing apoptotic damage caused by BaP. In conclusion, exposure to BaP can induce oxidative stress-related damage to testicular tissue, as evidenced by an increase in MDA levels, which ATV treatment can mitigate. Additionally, ATV enhances intracellular antioxidant GSH and protects the testes against BaP-induced damage while increasing testosterone levels, which are reduced due to exposure to BaP.

Abstract Tu138: Tandem Mass Tagging (TMT)-based Identification of Proteome Signatures for Ischemia-Reperfusion Injury in Swine

Background: The composition of proteins in blood plasma mirrors the physical changes occurring in the course of disease pathogenesis. Currently available clinical markers are insufficient to predict the actual damage and the redox changes in response to ischemia. Hence, we identified novel redox markers for ischemia/reperfusion (I/R) in swine using TMT-proteomics. Methodology: We employed TMT-10plex isobaric labeling-based quantitative proteomics to track the plasma proteome in Sus Scorfa pigs subjected to surgical I/R at different time points. Plasma samples were collected before ischemia, at 1-hr after ischemia (baseline), and 4-hr, 24-hrs, and 7 days following reperfusion. Results: An average of 4853 spectra and a total of 457 proteins were identified, ensuring a 1% false discovery rate for peptides and proteins with at least two distinct peptides. Pre-ischemia plasma samples served as the control group in all the analyses. TMT analysis revealed temporal changes in the plasma proteome with a prominent shift at 4 hours after I/R insult. To investigate the significantly changed proteins (>1.5 fold), a temporal analysis was carried out. Notably, endopin-1, a serpin protein family member, and fibronectin B were detectable in the plasma following 4 hours of ischemia-reperfusion, indicating the release of these proteins in the circulation during the ischemia-reperfusion. A positive correlation was observed between the redox proteins (i.e., catalase and glutathione peroxidase) with the serpin proteins in the plasma. Biochemical analysis of circulating glutathione, a small-molecular antioxidant, revealed a reductive redox after 60 minutes of Ischemia (hypoxic condition) but this was shifted to an oxidative milieu at 4hrs following reperfusion (hyperoxia) in the adult pigs subjected to I/R insult. Interestingly, we noticed a significant increase in GSH levels and a decrease in catalase levels at 24 hours following I/R, suggesting a compensatory biochemical response in association with repair after I/R insult/injury in the heart. These results correlated with the increased circulating LDH levels indicating the rate of tissue damage following I/R. Conclusion: The present study reveals the presence of a previously unexplored Serpin protein member, endopin-1, during I/R. Understanding the kinetics of endopin-1 expression along with the shift in redox state can help unravel its role in the progression and resolution phases of I/R injury.

Influence of Aframomum sceptrum Treatment on Hepatic Toxicity Induced by Monosodium Glutamate in Albino Rats

Monosodium glutamate (MSG) is commonly used as a culinary flavouring, although research suggest that it is toxic to people and laboratory animals, especially in high dosages. The study goal is to determine the impact of Aframomum sceptrum (ataiko) treatment on hepatic induced toxicity by MSG. Thirty-six albino rats (male) with weight of 120 to 210 g were used for the study. The rats were separated into 6 groups in which each group contains six rats. Group 1: normal control. Group 2: MSG only. Group 3 and 4 were given MSG and then treated with 250 and 350 mg/kg b.wt of A. sceptrum extract respectively. Group 5 and 6 were administered only 250 and 350 mg/kg b.wt of A. sceptrum extract, respectively. The MSG groups were given intra-peritoneal injection of MSG solution at single dose of 4253 mg/kg b.wt. A. sceptrum extract was administered three times a week for four weeks beginning two days after the MSG induction. Liver function markers such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and oxidative stress markers such as reduced glutathione (GSH) and malondialdehyde (MDA) were determined in serum and liver. Also, glucose was determined in the serum. The results showed that there were significant (p < 0.05) increased in glucose, AST, ALT and MDA in serum and liver, and decreased in GSH level in the liver of rats given MSG only when compared with normal control. However, A. sceptrum administration significantly (p < 0.05) decreased glucose, AST, ALT and MDA in the serum and liver, and increased GSH level in the liver when compared with MSG only. In conclusion, aqueous extract of A. sceptrum may have beneficial effect in MSG induced toxicity in rats by improving GSH level as well as liver function markers in a dose dependent manner.

Resveratrol attenuates doxorubicin-induced toxicity during in vitro culture of mouse-isolated preantral follicles.

The aims of this study were to evaluate the doxorubicin concentration that induces toxic effects on in vitro culture of isolated mouse secondary follicles and to investigate whether resveratrol can inhibit or reduce this toxicity. Secondary follicles were isolated and cultured for 12 days in control medium (α-MEM+) or in α-MEM+ supplemented with doxorubicin (0.1 µg/ml) or different concentrations of resveratrol (0.5, 2, or 5 µM) associated with doxorubicin (0.1 µg/ml) (experiment 1). For experiment 2, follicles were cultured in α-MEM+ alone or supplemented with doxorubicin (0.3 µg/ml) or different concentrations of resveratrol (5 or 10 µM) associated or not with doxorubicin (0.3 µg/ml) (experiment 2). The endpoints analyzed were morphology (survival), antrum formation, follicular diameter, mitochondrial activity, glutathione (GSH) levels and DNA fragmentation. In the first experiment, doxorubicin (0.1 µg/ml) maintained survival and antrum formation similar to the control, while 5 µM resveratrol showed increased parameters, maintained mitochondrial activity and increased GSH levels compared to the control. In the second experiment, doxorubicin (0.3 µg/ml) reduced survival, antrum formation and follicular diameter compared to the control. Resveratrol at a concentration of 10 µM attenuated the damage caused by doxorubicin by improving follicular survival and did not present DNA fragmentation. In conclusion, supplementation of the in vitro culture medium with 0.3 µg/ml doxorubicin reduced the survival and impaired the development of mouse-isolated preantral follicles. Resveratrol at 10 µM reduced doxorubicin-induced follicular atresia, without DNA fragmentation in the follicles.

Honey and levodopa comparably preserved substantia nigra pars compacta neurons through the modulation of nuclear factor erythroid 2-related factor 2 signaling pathway in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease model.

Parkinson's disease (PD) affects about 8.5 million individuals worldwide. Oxidative and inflammatory cascades are implicated in the neurological sequels, that are mostly unresolved in PD treatments. However, proper nutrition offers one of the most effective and least costly ways to decrease the burden of many diseases and their associated risk factors. Moreover, prevention may be the best response to the progressive nature of PD, thus, the therapeutic novelty of honey and levodopa may be prospective. This study aimed to investigate the neuroprotective role of honey and levodopa against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress. Fifty-four adult male Swiss mice were divided into control and PD model groups of 27 mice. Each third of the control mice either received phosphate buffered saline, honey, or levodopa for 21 days. However, each third of the PD models was either pretreated with honey and levodopa or not pretreated. Behavioral studies and euthanasia were conducted 2 and 8 days after MPTP administration respectively. The result showed that there were significantly (P<0.05) higher motor activities in the PD models pretreated with the honey as well as levodopa. furthermore, the pretreatments protected the midbrain against the chromatolysis and astrogliosis induced by MPTP. The expression of antioxidant markers (glutathione [GSH] and nuclear factor erythroid 2-related factor 2 [Nrf2]) was also significantly upregulated in the pretreated PD models. It is thus concluded that honey and levodopa comparably protected the substantia nigra pars compacta neurons against oxidative stress by modulating the Nrf2 signaling molecule thereby increasing GSH level to prevent MPTP-induced oxidative stress.

Cerebroprotective Potential of Andrographolide Nanoparticles: In silico and In vivo Investigations.

Ischemic stroke remains the leading cause of death and disability, while the main mechanisms of dominant neurological damage in stroke contain oxidative stress and inflammation. Docking studies revealed a binding energy of - 6.1 kcal/mol for AG, while the co-crystallized ligand (CCl) exhibited a binding energy of - 7.3 kcal/mol with NOS. AG demonstrated favourable hydrogen bond interactions with amino acids ASN A:354 and ARG A:388 and hydrophobic interactions with GLU A:377. Molecular dynamics simulations throughout 100 ns indicated a binding affinity of - 27.65±2.88 kcal/mol for AG, compared to - 18.01±4.02 kcal/mol for CCl. These findings suggest that AG possesses a superior binding affinity for NOS compared to CCl, thus complementing the stability of NOS at the docked site.AG has limited applications owing to its low bioavailability, poor water solubility, and high chemical and metabolic instability.The fabrication method was employed in the preparation of AGNP, SEM analysis confirmed spherical shape with size in 19.4±5 nm and investigated the neuroprotective effect in cerebral stroke rats induced by 30 min of carotid artery occlusion followed by 4 hr reperfusion, evaluated by infarction size, ROS/RNS via GSH, MPO, NO estimationand AchE activity, and monitoring EEG function. Cortex and hippocampal histology were compared between groups. AGNP treatment significantly decreased Infarction size and increased GSH levels (p<0.01**), decreased MPO (p<0.01**), NO (p<0.01**), AchE (p<0.01**), restored to normal EEG amplitude, minimizing unsynchronized polyspikes and histological data revealed that increased pyramidal cell layer thickness and decreased apoptotic neurons in hippocampus, cortex appeared normal neurons with central large vesicular nuclei, containing one or more nucleoli in compared to AG treatment. Based on brain biochemical, histopathology reports AGNP exhibited significant cerebroprotective activity compared to AG on ischemic rats.

A new neuroprotective candidate TJ1 targeting amyloidogenesis in 5xFAD Alzheimer’s disease mice

As one of the main pathmechanisms of Alzheimer’s disease (AD), amyloid-β (Aβ) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aβ42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aβ42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aβ42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aβ42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2– and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood–brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aβ42 by acting on Aβ oligomerization and fibrilization. Besides, TJ1 reversed Aβ-, H2O2– and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aβ42 and Aβ plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.

Mechanism of Prunella vulgaris L. and luteolin in restoring Tfh/Tfr balance and alleviating oxidative stress in Graves' disease

BackgroundThe pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PurposeThis study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). MethodsHigh-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. ResultsA total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. ConclusionXKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.

Sappanone a alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis via activating the SIRT1/Nrf2 signaling pathway.

Osteoarthritis (OA) is a common degenerative joint disease that cause pain and disability in adults. Chondrocyte ferroptosis is found to be involved in OA progression. Sappanone A has been found as an anti-inflammatory and antioxidative agent in several diseases. This study aims to investigate the effects of sappanone A on OA progression and chondrocyte ferroptosis.IL-1β-induced chondrocytes and destabilization of the medial meniscus (DMM)-induced rats were respectively used as the OA model in vitro and in vivo. The effects of sappanone A on inflammation, extracellular matrix (ECM) metabolism, and ferroptosis were determined.Our results showed thatin IL-1β-induced chondrocytes, sappanone A suppressed the production of NO, PGE2, TNF-α, IL-6, iNOS, and COX2. Sappanone A also inhibited the expression of MMP3, MMP13, and ADAMTS5, while increasing collagen II expression. Moreover, sappanone A alleviated cytotoxicity and decreased the levels of intracellular ROS, lipid ROS, MDA, and iron, while increasing GSH levels. Additionally, sappanone A increased the protein expression of SLC7A11 and GPX4. Administration of ferroptosis activator reversed the inhibitory effects of sappanone A on IL-1β-induced inflammation and ECM degradation. More importantly, Sappanone A activated the Nrf2 signaling by targeting SIRT1. The inhibition of sappanone A on ferroptosis was greatly eliminated due to the addition of SIRT1 inhibitor. Furthermore, intra-articular injection of sappanone A mitigated cartilage destruction and ferroptosis in DMM-induced OA rats.In conclusion,sappanone A protects against inflammation and ECM degradation in OA via decreasing chondrocyte ferroptosis by activating the SIRT1/Nrf2 signaling. These findings deepen our understanding of chondrocyte ferroptosis in OA and highlight the therapeutic potential of sappanone A for OA.

Epigallocatechin-3-gallate-synthesized gold nanoparticles modulate reactive oxygen species and antioxidant parameters in brain and heart tissues using a chicken embryo model

Chemically synthesized gold nanoparticles (AuNPs) come with drawbacks, such as biological toxicity and ecological imbalances. Nonetheless, a knowledge gap remains regarding their impact on oxidative and antioxidant parameters. Here, environmentally friendly AuNPs were synthesized using epigallocatechin-3-gallate (AuNPs-EGCG). The successful synthesis of AuNPs-EGCG were confirmed using ultraviolet–visible spectroscopy, Fourier-transform infrared spectroscopy, atomic force microscopy, and dynamic light scattering. Antioxidant activity was assessed using free radical 2,2-diphenyl-1-picrylhydrazyl, oxygen radical absorbance capacity, and ferric reducing antioxidant power assays, while cytotoxicity properties were evaluated in the NIH3T3 fibroblast cells. Furthermore, the impact of AuNPs-EGCG on oxidative stress was investigated in the hearts and brains of chicken embryos. AuNPs-EGCG exhibited no cytotoxicity and was not toxic for chicken embryos at higher concentrations. However, exposure to lower concentrations (100 and 30 μg/mL) caused an increase in reactive oxygen species (ROS) levels and a decrease in total antioxidant capacity in the heart and brain, resulting in a disturbance in the redox balance attributed to a reduction in catalase activity and glutathione (GSH) content, and an increase in glutathione peroxidase activity. In contrast, AuNPs-EGCG at 300 μg/mL promoted an increase in GSH levels and modulation of ROS, while also reducing vascular density in the chorioallantoic membrane. Furthermore, AuNPs-EGCG did not cause lipid or protein oxidation. The present study offers evidence that supports the investigation of how AuNPs-EGCG can modulate antioxidant defense mechanisms and assess the safety of phytoantioxidant-functionalized nanoparticles in vivo. This may lead to new and innovative strategies for the utilization of nanomaterials in biological systems.

Quetiapine attenuates cadmium neurotoxicity by suppressing oxidative stress, inflammation, and pyroptosis.

Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied. QTP was administered in 10 and 20mg/kg doses, while Cd was given in a dose of 6.5mg/kg. In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and β-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO2 and neuronal cytokines TNF-α and IL-1β and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels. In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals.