RÉSUMÉ
BACKGROUND: Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance-associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery. METHODS: Our study utilized whole-exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2-24C > T (rs717620) point mutation and conducting dual-luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss-of-function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function. RESULTS: ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss-of-function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2-high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2-mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient-derived organoids and patient-derived tumor-like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression. CONCLUSIONS: Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression. HIGHLIGHTS: ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux. The ABCC2 24C > T polymorphism is a key factor influencing its expression. These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.
Sujet(s)
Ferroptose , Glutathion , Protéine-2 associée à la multirésistance aux médicaments , Protéines associées à la multirésistance aux médicaments , Tumeurs de l'estomac , Humains , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/génétique , Tumeurs de l'estomac/anatomopathologie , Ferroptose/génétique , Protéines associées à la multirésistance aux médicaments/génétique , Protéines associées à la multirésistance aux médicaments/métabolisme , Glutathion/métabolisme , Animaux , Souris , Lignée cellulaire tumorale , Mâle , FemelleRÉSUMÉ
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated. METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy. RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP. CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
Sujet(s)
Autophagie , Modèles animaux de maladie humaine , Ferroptose , Peroxydation lipidique , Pancréatite , Rat Sprague-Dawley , Animaux , Pancréatite/métabolisme , Pancréatite/anatomopathologie , Rats , Mâle , Adénine/analogues et dérivés , Adénine/pharmacologie , Phospholipid hydroperoxide glutathione peroxidase/métabolisme , Acide taurocholique , Cyclohexylamines/pharmacologie , Pancréas/anatomopathologie , Pancréas/métabolisme , Phénylènediamines/pharmacologie , Malonaldéhyde/métabolisme , Espèces réactives de l'oxygène/métabolisme , Maladie aigüe , Glutathion/métabolisme , Fer/métabolismeRÉSUMÉ
BACKGROUND: Extensive research has been conducted on embryonic developmental disorders linked to Polycystic Ovary Syndrome (PCOS), a pathological condition that affects 5-10% of women and is characterized by irregularities in the menstrual cycle and infertility. By employing RNA sequencing (RNA-seq), we performed an in-depth investigation of PCOS-related changes in gene expression patterns at the mouse blastocyst stage. METHODS: The zygotes of female B6D2 mice were obtained and then differentiated into blastocysts in K + Simplex Optimised Medium (KSOM) cultures containing exo-NC (negative control for exosomes) or exo-LIPE-AS1 (a novel exosomal marker of PCOS). Subsequently, blastocysts were collected for RNA-seq. The bioinformatics was performed to analyze and compare the differences of gene expression profile between blastocysts of control and PCOS group. RESULTS: There were 1150 differentially expressed genes (DEGs) between the two groups of mouse blastocysts; 243 genes were upregulated and 907 downregulated in the blastocysts of the exo-LIPE-AS1 group compared to those of the exo-NC group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the genes involved in amino acid synthesis and glutathione metabolic pathways were down-regulated in exo-LIPE-AS1 group. CONCLUSION: This study has revealed that blastocyst developmental retardation may be associated with the downregulation of amino acid synthesis and glutathione metabolism, which may affect energy metabolism, biosynthesis, cellular osmotic pressure, antioxidant synthesis, ROS clearance or mitochondrial function, and ultimately cause blastocyst cell development abnormalities. Our research offers encouraging data on the mechanisms underlying aberrant embryonic development in patients with PCOS as well as potential treatment strategies.
Sujet(s)
Acides aminés , Blastocyste , Développement embryonnaire , Glutathion , Syndrome des ovaires polykystiques , Animaux , Syndrome des ovaires polykystiques/métabolisme , Syndrome des ovaires polykystiques/génétique , Syndrome des ovaires polykystiques/anatomopathologie , Femelle , Souris , Blastocyste/métabolisme , Développement embryonnaire/génétique , Glutathion/métabolisme , Acides aminés/métabolisme , Analyse de séquence d'ARN , Modèles animaux de maladie humaine , Régulation de l'expression des gènes au cours du développementRÉSUMÉ
The study included 40 patients of both genders who underwent skin transplantation after a hand injury. The study aims to evaluate the oxidative stress parameters in patients' blood and serum levels of galectin-3 in order to investigate gender differences pre- and post- skin transplantation. The results of the study suggest a significant increase in superoxide anion radical levels, catalase activity, and reduced glutathione levels in females before skin transplantation. The surgical treatment caused significant increase in superoxide anion radical and hydrogen peroxide levels as prooxidants in males, while superoxide dismutase and catalase activity were also increased 7 days after the procedure. In females, superoxide anion radical and TBARS levels increased after surgical procedure as well as the activity of catalase. Regarding galectin-3 levels, a significant interaction between gender and time was observed (gender×time; p=0.000). Correlation analysis of different oxidative stress markers with gal-3 revealed the existence of a significant negative correlation of superoxide anion radical, catalase, and reduced glutathione with gal-3, but only in female patients. It can be concluded that OS as well as galectin-3 play important roles at least in the first 7 days of the postoperative period.
Sujet(s)
Catalase , Galectine -3 , Glutathion , Blessures de la main , Stress oxydatif , Transplantation de peau , Adulte , Femelle , Humains , Mâle , Adulte d'âge moyen , Jeune adulte , Protéines du sang , Catalase/sang , Catalase/métabolisme , Galectine -3/sang , Galectine -3/métabolisme , Galectines , Glutathion/sang , Glutathion/métabolisme , Blessures de la main/chirurgie , Blessures de la main/sang , Blessures de la main/métabolisme , Peroxyde d'hydrogène/sang , Peroxyde d'hydrogène/métabolisme , Caractères sexuels , Facteurs sexuels , Superoxide dismutase/sang , Superoxide dismutase/métabolisme , Superoxydes/métabolisme , Superoxydes/sang , Substances réactives à l'acide thiobarbiturique/métabolismeRÉSUMÉ
Introduction: Heme oxygenase-1 (HO-1) is a stress-inducible heat shock protein (HSP32) that exerts cytoprotective effects against oxidative stress and inflammation, and is involved in the maintenance of cellular homeostasis. This study aimed to evaluate the expression of HO-1 in natural killer (NK) cells from individuals of different age groups after stimulation with various factors, and to analyze the relationships between the concentration of this cytoprotective protein and parameters corresponding to oxidative stress and inflammation, that is, NOD-like receptor protein 3 (NLRP3), glutathione (GSH), GSH disulfide (GSSG), and interleukin 6 (IL-6). Methods: The study population comprised three age groups: young adults (age range, 19-23 years), older adults aged under 85 years (age range, 73-84 years), and older adults aged over 85 years (age range, 85-92 years). NLRP3, GSH, and GSSG concentrations were measured in serum, whereas the HO-1 concentration and IL-6 expression were studied in NK cells cultivated for 48 h and stimulated with IL-2, lipopolysaccharide (LPS), or phorbol 12-myristate 13-acetate (PMA) with ionomycin. Results: The analysis of serum NLRP3, GSH, and GSSG concentrations revealed no statistically significant differences among the studied age groups. However, some typical trends of aging were observed, such as a decrease in GSH concentration and an increase in both GSSG level, and GSSG/GSH ratio. The highest basal expression of IL-6 and lowest basal content of HO-1 were found in NK cells of adults over 85 years of age. The NK cells in this age group also showed the highest sensitivity to stimulation with the applied factors. Moreover, statistically significant negative correlations were observed between HO-1 and IL-6 expression levels in the studied NK cells. Conclusions: These results showed that NK cells can express HO-1 at a basal level, which was significantly increased in activated cells, even in the oldest group of adults. The reciprocal relationship between HO-1 and IL-6 expression suggests a negative feedback loop between these parameters.
Sujet(s)
Vieillissement , Heme oxygenase-1 , Cellules tueuses naturelles , Stress oxydatif , Humains , Heme oxygenase-1/métabolisme , Vieillissement/immunologie , Sujet âgé de 80 ans ou plus , Sujet âgé , Cellules tueuses naturelles/immunologie , Cellules tueuses naturelles/métabolisme , Mâle , Jeune adulte , Femelle , Glutathion/métabolisme , Interleukine-6/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , AdulteRÉSUMÉ
Diabetic nephropathy, characterized by inflammation and oxidative stress, poses a management challenge. This study investigates the effect of Polygonum hyrcanicum extract on diabetic nephropathy in alloxan-induced diabetic mice. In this experimental animal study, the P. hyrcanicum extract was prepared using continuous macerations. Thirty male Albino mice, divided into five groups, were induced with alloxan-induced diabetes. They received intraperitoneal injections of the plant extract (100 and 200 mg/kg) and metformin (300 mg/kg) for four weeks. Kidney and blood samples were collected to assess protein carbonyl, glutathione, lipid peroxidation, TNF-α and IL-6 levels. The amount of total flavonoid and phenolic content in the hydroalcoholic extract of P. hyrcanicum were 7.5 ± 0.3 mg of quercetin and 88.2 ± 1.3 mg gallic acid per gram of extract respectively. The antioxidant activity level of the hydroalcoholic extract was determined to be 1.78 ± 0.51 mM equivalent per gram of extract. Alloxan administration resulted in a significant reduction in glutathione levels and a significant increase in protein carbonyl, lipid peroxidation, TNF-α, and IL-6 levels. Hydroalcoholic extract of P. hyrcanicum effectively reduced oxidative stress markers and inflammatory cytokines (TNF-α, IL-6), indicating its potential in mitigating diabetic nephropathy. However, no significant difference in efficacy was observed between the 100 mg/kg and 200 mg/kg doses in terms of reducing these toxicities.
Sujet(s)
Antioxydants , Diabète expérimental , Néphropathies diabétiques , Stress oxydatif , Extraits de plantes , Polygonum , Animaux , Stress oxydatif/effets des médicaments et des substances chimiques , Extraits de plantes/pharmacologie , Extraits de plantes/composition chimique , Diabète expérimental/traitement médicamenteux , Diabète expérimental/métabolisme , Néphropathies diabétiques/traitement médicamenteux , Néphropathies diabétiques/métabolisme , Souris , Mâle , Antioxydants/pharmacologie , Polygonum/composition chimique , Alloxane , Peroxydation lipidique/effets des médicaments et des substances chimiques , Facteur de nécrose tumorale alpha/métabolisme , Glutathion/métabolisme , Rein/effets des médicaments et des substances chimiques , Rein/métabolisme , Rein/anatomopathologie , Interleukine-6/métabolisme , Interleukine-6/sangRÉSUMÉ
In the development and progression of cervical cancer, oxidative stress plays an important role within the cells. Among them, Solute Carrier Family 7 Member 11 (SLC7A11/xCT) is crucial for maintaining the synthesis of glutathione and the antioxidant system in cervical cancer cells. In various tumor cells, studies have shown that SLC7A11 inhibits ferroptosis, a form of cell death, by mediating cystine uptake and maintaining glutathione synthesis. Additionally, SLC7A11 is also involved in promoting tumor metastasis and immune evasion. Therefore, inhibiting the SLC7A11/xCT axis has become a potential therapeutic strategy for cervical cancer. In this study, through structure-based high-throughput virtual screening, a compound targeting the SLC7A11/xCT axis named compound 1 (PubChem CID: 3492258) was discovered. In vitro experiments using HeLa cervical cancer cells as the experimental cell model showed that compound 1 could reduce intracellular glutathione levels, increase glutamate and reactive oxygen species (ROS) levels, disrupt the oxidative balance within HeLa cells, and induce cell death. Furthermore, molecular dynamics simulation results showed that compound 1 has a stronger binding affinity with SLC7A11 compared to the positive control erastin. Overall, all the results mentioned above indicate the potential of compound 1 in targeting the SLC7A11/xCT axis and treating cervical cancer both in vitro and in silico.
Sujet(s)
Système y+ de transport d'acides aminés , Glutathion , Simulation de dynamique moléculaire , Espèces réactives de l'oxygène , Tumeurs du col de l'utérus , Humains , Système y+ de transport d'acides aminés/métabolisme , Système y+ de transport d'acides aminés/antagonistes et inhibiteurs , Cellules HeLa , Glutathion/métabolisme , Espèces réactives de l'oxygène/métabolisme , Tumeurs du col de l'utérus/traitement médicamenteux , Tumeurs du col de l'utérus/métabolisme , Tumeurs du col de l'utérus/anatomopathologie , Stress oxydatif/effets des médicaments et des substances chimiques , Simulation de docking moléculaire , Femelle , Découverte de médicament/méthodes , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Simulation numérique , Ferroptose/effets des médicaments et des substances chimiquesRÉSUMÉ
The most abundant tripeptide-glutathione (GSH)-and the major GSH-related enzymes-glutathione peroxidases (GPxs) and glutathione S-transferases (GSTs)-are highly significant in the regulation of tumor cell viability, initiation of tumor development, its progression, and drug resistance. The high level of GSH synthesis in different cancer types depends not only on the increasing expression of the key enzymes of the γ-glutamyl cycle but also on the changes in transport velocity of its precursor amino acids. The ability of GPxs to reduce hydroperoxides is used for cellular viability, and each member of the GPx family has a different mechanism of action and site for maintaining redox balance. GSTs not only catalyze the conjugation of GSH to electrophilic substances and the reduction of organic hydroperoxides but also take part in the regulation of cellular signaling pathways. By catalyzing the S-glutathionylation of key target proteins, GSTs are involved in the regulation of major cellular processes, including metabolism (e.g., glycolysis and the PPP), signal transduction, transcription regulation, and the development of resistance to anticancer drugs. In this review, recent findings in GSH synthesis, the roles and functions of GPxs, and GST isoforms in cancer development are discussed, along with the search for GST and GPx inhibitors for cancer treatment.
Sujet(s)
Glutathione transferase , Glutathion , Tumeurs , Transduction du signal , Humains , Glutathion/métabolisme , Tumeurs/métabolisme , Tumeurs/anatomopathologie , Tumeurs/traitement médicamenteux , Glutathione transferase/métabolisme , Animaux , Glutathione peroxidase/métabolismeRÉSUMÉ
The spatial organization characteristics and redox status of the extracellular space (ECS) are crucial in the development of brain diseases. However, it remains a challenge to simultaneously capture dynamic changes in microstructural features and redox states at the submicron level within the ECS. Here, we developed a reversible glutathione (GSH)-responsive nanoprobe (RGN) for mapping the spatial organization features and redox status of the ECS in brain tissues with nanoscale resolution. The RGN is composed of polymer nanoparticles modified with GSH-responsive molecules and amino-functionalized methoxypoly(ethylene glycol), which exhibit exceptional single-particle brightness and excellent free diffusion capability in the ECS of brain tissues. Tracking single RGNs in acute brain slices allowed us to dynamically map spatial organizational features and redox levels within the ECS of brain tissues in disease models. This provides a powerful super-resolution imaging method that offers a potential opportunity to study the dynamic changes in the ECS microenvironment and to understand the physiological and pathological roles of the ECS in vivo.
Sujet(s)
Encéphale , Espace extracellulaire , Glutathion , Nanoparticules , Oxydoréduction , Encéphale/métabolisme , Encéphale/imagerie diagnostique , Animaux , Espace extracellulaire/métabolisme , Espace extracellulaire/composition chimique , Glutathion/composition chimique , Glutathion/métabolisme , Nanoparticules/composition chimique , Souris , Polyéthylène glycols/composition chimiqueRÉSUMÉ
OBJECTIVE: Exploring the changes in cerebellar ferroptosis in hypertensive mice after lead exposure. METHODS: Twenty-five healthy C57 male mice were selected to construct a hypertensive model by intraperitoneal injection of angiotensin II(Ang II) at a concentration of 0.05 mg/kg for 7 consecutive days. After a systolic blood pressure of 140 mmHg, 20 hypertensive mice were randomly divided into a hypertensive control group and a hypertensive lead exposure group. Twenty C57 mice with normal blood pressure were randomly divided into a blood pressure normal control group and a blood pressure normal lead exposure group. The mice in the normal blood pressure control group and the hypertensive control group drank water freely. Mice in the lead exposure group with normal blood pressure and the lead exposure group with hypertension drank lead acetate water containing 250 mg/L. Ang II was injected intraperitoneally every two days in the hypertensive control group and hypertensive lead exposed group mice. Each group of mice was poisoned for 12 weeks. Using open field experiments and balance beam experiments to detect motor dysfunction in mice. Using a reagent kit to detect the levels of divalent iron(Fe~(2+)), malondialdehyde(MDA), and glutathione(GSH) in the cerebellum of different groups of mice. Western blot was used to determine the protein expression of member 11 of the solute carrier family 7(SLC7A11), glutathione peroxidase 4(GPX4), nuclear receptor coactivator 4(NCOA4), microtubule associated protein 1 light chain 3B(LC3B), and ferritin heavy chain 1(FTH1) in mouse cerebellar tissue. RESULTS: The result of the open field experiment showed that the activity distance(1013.04 cm) of mice in the hypertensive lead exposure group was significantly lower than that of the hypertensive control group(1351.18 cm) and the lead exposure group with normal blood pressure(1287.35 cm). And the lead exposure group with hypertension also extended the time through the balance beam, which was 29.40 seconds(P<0.05). In addition, the Fe~(2+)content in the cerebellum of mice in the hypertensive lead exposure group was 3.33 µmol/g prot, which was 1.54 times that of the hypertensive control group and 1.14 times that of the lead exposure group with normal blood pressure. The MDA content was 4.71 nmol/mg prot, higher than that of the hypertensive control group and the lead exposure group with normal blood pressure. The GSH content was 5.36 µmol/g prot, lower than that of the hypertensive control group and the lead exposure group with normal blood pressure(P<0.05). Western blot result showed that compared with the hypertensive control group and the lead exposure group with normal blood pressure, the protein expression of SLC7A11 and GPX4 in the hypertensive lead exposure group was significantly reduced(P<0.05). In addition, compared with the control group with normal blood pressure, the expression of NCOA4 and LC3B proteins in the cerebellum of mice in the hypertension control group and lead exposure group with normal blood pressure increased, while the expression of FTH1 protein decreased(P<0.05). The expression of NCOA4 and LC3B proteins in the hypertensive lead exposure group was higher than that in the hypertensive control group and the lead exposure group with normal blood pressure, while the expression of FTH1 protein decreased(P<0.05). CONCLUSION: Lead exposure can exacerbate iron death in the cerebellar tissue of hypertensive mice, and iron autophagy may be involved in its occurrence and development.
Sujet(s)
Angiotensine-II , Cervelet , Ferroptose , Hypertension artérielle , Plomb , Souris de lignée C57BL , Animaux , Ferroptose/effets des médicaments et des substances chimiques , Souris , Mâle , Hypertension artérielle/induit chimiquement , Hypertension artérielle/métabolisme , Plomb/toxicité , Cervelet/métabolisme , Cervelet/effets des médicaments et des substances chimiques , Malonaldéhyde/métabolisme , Glutathione peroxidase/métabolisme , Système y+ de transport d'acides aminés/métabolisme , Fer/métabolisme , Glutathion/métabolismeRÉSUMÉ
Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is one of the most important neglected diseases in Latin America. The limited use of the current nitro-derivative-based chemotherapy highlights the need for alternative drugs and the identification of their molecular targets. In this study, we investigated the trypanocidal effect of the sesquiterpene lactone dehydroleucodine (DhL) and its derivatives, focusing on the antioxidative defense of the parasites. DhL and two derivatives, at lesser extent, displayed antiproliferative effect on the parasites. This effect was blocked by the reducing agent glutathione (GSH). Treated parasites exhibited increased intracellular ROS concentration and trypanothione synthetase activity, accompanied by mitochondrial swelling. Although molecular dynamics studies predicted that GSH would not interact with DhL, 1H-NMR analysis confirmed that GSH could protect parasites by interacting with the lactone. When parasites overexpressing mitochondrial tryparedoxin peroxidase were incubated with DhL, its effect was attenuated. Overexpression of cytosolic tryparedoxin peroxidase also provided some protection against DhL. These findings suggest that DhL induces oxidative imbalance in T. cruzi, offering new insights into potential drug targets against this parasite.
Sujet(s)
Lactones , Espèces réactives de l'oxygène , Sesquiterpènes , Trypanosoma cruzi , Trypanosoma cruzi/effets des médicaments et des substances chimiques , Trypanosoma cruzi/métabolisme , Sesquiterpènes/pharmacologie , Lactones/pharmacologie , Espèces réactives de l'oxygène/métabolisme , Trypanocides/pharmacologie , Glutathion/métabolisme , Maladie de Chagas/traitement médicamenteux , Maladie de Chagas/parasitologie , Protéines de protozoaire/métabolisme , Animaux , Mitochondries/métabolisme , Mitochondries/effets des médicaments et des substances chimiques , Amide synthasesRÉSUMÉ
BACKGROUND: The neurobiological underpinnings of Autism Spectrum Disorder (ASD) are diverse and likely multifactorial. One possible mechanism is increased oxidative stress leading to altered neurodevelopment and brain function. However, this hypothesis has mostly been tested in post-mortem studies. So far, available in vivo studies in autistic individuals have reported no differences in glutathione (GSH) levels in frontal, occipital, and subcortical regions. However, these studies were limited by the technically challenging quantification of GSH, the main brain antioxidant molecule. This study aimed to overcome previous studies' limitations by using a GSH-tailored spectroscopy sequence and optimised quantification methodology to provide clarity on GSH levels in autistic adults. METHODS: We used spectral editing proton-magnetic resonance spectroscopy (1H-MRS) combined with linear combination model fitting to quantify GSH in the dorsomedial prefrontal cortex (DMPFC) and medial occipital cortex (mOCC) of autistic and non-autistic adults (male and female). We compared GSH levels between groups. We also examined correlations between GSH and current autism symptoms, measured using the Autism Quotient (AQ). RESULTS: Data were available from 31 adult autistic participants (24 males, 7 females) and 40 non-autistic participants (21 males, 16 females); the largest sample to date. The GSH levels did not differ between groups in either region. No correlations with AQ were observed. CONCLUSION: GSH levels as measured using 1H-MRS are unaltered in the DMPFC and mOCC regions of autistic adults, suggesting that oxidative stress in these cortical regions is not a marked neurobiological signature of ASD.
Sujet(s)
Trouble du spectre autistique , Trouble autistique , Glutathion , Lobe occipital , Humains , Mâle , Femelle , Glutathion/métabolisme , Glutathion/analyse , Adulte , Lobe occipital/métabolisme , Lobe occipital/imagerie diagnostique , Trouble du spectre autistique/métabolisme , Trouble autistique/métabolisme , Jeune adulte , Spectroscopie par résonance magnétique du proton , Lobe frontal/métabolisme , Stress oxydatif , Adulte d'âge moyen , Cortex préfrontal/métabolisme , Cortex préfrontal/imagerie diagnostiqueRÉSUMÉ
We have prepared a novel assembly with copper nanoclusters (CuNCs) and imidazolium-based gemini surfactants (different chain lengths). These novel mimic enzymes formed through the assembly of nanocluster-gemini surfactants have been utilized in creating colorimetric sensors to detect biomolecules. Yet, understanding the method for detecting glutathione (GSH) and its sensing mechanism using this specific assembly-based colorimetric sensor poses a significant challenge. Because of the role of surface ligands, the complexes of cysteine-capped CuNCs (Cys-CuNCs) and gemini surfactants exhibit strong amphiphilicity, enabling them to self-assemble like a molecular amphiphile. We have investigated the kinetics and catalytic capabilities of this Cys-CuNCs@gemini surfactant assembly through peroxidase-like activity. Additionally, a sensitive and simple-to-use colorimetric sensing approach for glutathione (GSH) is also disclosed here, demonstrating a low limit of detection, by using this peroxidase-like activity of Cys-CuNCs@gemini surfactant assemblies. Thus, the remarkable advantages of the Cys-CuNCs@gemini surfactant nanozyme make it suitable for the precise colorimetric detection of GSH, demonstrating excellent sensitivity and reliable selectivity. Additionally, it performs well in detecting GSH in various soft drinks.
Sujet(s)
Colorimétrie , Cuivre , Cystéine , Glutathion , Nanoparticules métalliques , Tensioactifs , Cuivre/composition chimique , Glutathion/analyse , Glutathion/composition chimique , Colorimétrie/méthodes , Tensioactifs/composition chimique , Cystéine/analyse , Cystéine/composition chimique , Nanoparticules métalliques/composition chimique , Imidazoles/composition chimique , Myeloperoxidase/composition chimique , Myeloperoxidase/métabolismeRÉSUMÉ
In this paper, we demonstrated the biological effects of acute low-dose neutrons on the whole body of rats and investigated the impact of that level of neutron dose to induce an in vivo radio-adaptive response. To understand the radio-adaptive response, the examined animals were exposed to acute neutron radiation doses of 5 and 10 mSv, followed by a 50 mSv challenge dose after 14 days. After irradiation, all groups receiving single and double doses were kept in cages for one day before sampling. The electron paramagnetic resonance (EPR) method was used to estimate the radiation-induced radicals in the blood, and some hematological parameters and lipid peroxidation (MDA) were determined. A comet assay was performed beside some of the antioxidant enzymes [catalase enzyme (CAT), superoxide dismutase (SOD), and glutathione (GSH)]. Seven groups of adult male rats were classified according to their dose of neutron exposure. Measurements of all studied markers are taken one week after harvesting, except for hematological markers, within 2 h. The results indicated lower production of antioxidant enzymes (CAT by 1.18-5.83%, SOD by 1.47-17.8%, and GSH by 11.3-82.1%). Additionally, there was an increase in red cell distribution width (RDW) (from 4.61 to 25.19%) and in comet assay parameters such as Tail Length, (from 6.16 to 10.81 µm), Tail Moment, (from 1.17 to 2.46 µm), and percentage of DNA in tail length (DNA%) (from 9.58 to 17.32%) in all groups exposed to acute doses of radiation ranging from 5 to 50 mSv, respectively. This emphasizes the ascending harmful effect with the increased acute thermal neutron doses. The values of the introduced factor of radio adaptive response for all markers under study reveal that the lower priming dose promotes a higher adaptation response and vice versa. Ultimately, the results indicate significant variations in DNA%, SOD enzyme levels, EPR intensity, total Hb concentration, and RDWs, suggesting their potential use as biomarkers for acute thermal neutron dosimetry. Further research is necessary to validate these measurements as biodosimetry for radiation exposure, including investigations involving the response impact of RAR with varied challenge doses and post-irradiation behavior.
Sujet(s)
Marqueurs biologiques , Neutrons , Animaux , Rats , Mâle , Marqueurs biologiques/métabolisme , Superoxide dismutase/métabolisme , Peroxydation lipidique/effets des radiations , Radiométrie/méthodes , Relation dose-effet des rayonnements , Altération de l'ADN/effets des radiations , Adaptation physiologique/effets des radiations , Catalase/métabolisme , Glutathion/métabolisme , Glutathion/sang , Test des comètes , Stress oxydatif/effets des radiations , Spectroscopie de résonance de spin électronique/méthodesRÉSUMÉ
Salivary proteins of insect herbivores can suppress plant defenses, but the roles of many remain elusive. One such protein is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the saliva of the Recilia dorsalis (RdGAPDH) leafhopper, which is known to transmit rice gall dwarf virus (RGDV). Here we show that RdGAPDH was loaded into exosomes and released from salivary glands into the rice phloem through an exosomal pathway as R. dorsalis fed. In infected salivary glands of R. dorsalis, the virus upregulated the accumulation and subsequent release of exosomal RdGAPDH into the phloem. Once released, RdGAPDH consumed H2O2 in rice plants owing to its -SH groups reacting with H2O2. This reduction in H2O2 of rice plant facilitated R. dorsalis feeding and consequently promoted RGDV transmission. However, overoxidation of RdGAPDH could cause potential irreversible cytotoxicity to rice plants. In response, rice launched emergency defense by utilizing glutathione to S-glutathionylate the oxidization products of RdGAPDH. This process counteracts the potential cellular damage from RdGAPDH overoxidation, helping plant to maintain a normal phenotype. Additionally, salivary GAPDHs from other hemipterans vectors similarly suppressed H2O2 burst in plants. We propose a strategy by which plant viruses exploit insect salivary proteins to modulate plant defenses, thus enabling sustainable insect feeding and facilitating viral transmission.
Sujet(s)
Hemiptera , Peroxyde d'hydrogène , Oryza , Maladies des plantes , Salive , Animaux , Hemiptera/virologie , Peroxyde d'hydrogène/métabolisme , Oryza/virologie , Oryza/métabolisme , Maladies des plantes/virologie , Salive/métabolisme , Salive/virologie , Glyceraldehyde 3-phosphate dehydrogenases/métabolisme , Glandes salivaires/virologie , Glandes salivaires/métabolisme , Protéines d'insecte/métabolisme , Protéines d'insecte/génétique , Vecteurs insectes/virologie , Phloème/virologie , Phloème/métabolisme , Reoviridae/physiologie , Glutathion/métabolisme , Protéines et peptides salivaires/métabolisme , Virus des plantes/physiologie , Défense des plantes contre les herbivoresRÉSUMÉ
Despite the prevalent of hexagonal, tetragonal, and triangular pore structures in two-dimensional covalent organic frameworks (2D COFs), the pentagonal pores remain conspicuously absent. We herein present the Cairo pentagonal tessellated COFs, achieved through precisely chosen geometry and metrics of the linkers, resulting in unprecedented mcm topology. In each pentagonal structure, porphyrin units create four uniform sides around 15.5 Å with 90° angles, while tetrabiphenyl unit establish a bottom edge about 11.6 Å with 120° angles, aligning precisely with the criteria of Cairo Pentagon. According to the narrow bandgap and strong near-infrared (NIR) absorbance, as-synthesized COFs exhibit the efficient singlet oxygen (1O2) generation and photothermal conversion, resulting in NIR photothermal combined photodynamic therapy to guide cancer cell apoptosis. Mechanistic studies reveal that the good 1O2 production capability upregulates intracellular lipid peroxidation, leading to glutathione depletion, low expression of glutathione peroxidase 4, and induction of ferroptosis. The implementation of pentagonal Cairo tessellations in this work provides a promising strategy for diversifying COFs with new topologies, along with multimodal NIR phototherapy.
Sujet(s)
Apoptose , Rayons infrarouges , Photothérapie dynamique , Oxygène singulet , Humains , Oxygène singulet/métabolisme , Oxygène singulet/composition chimique , Photothérapie dynamique/méthodes , Réseaux organométalliques/composition chimique , Porphyrines/composition chimique , Animaux , Peroxydation lipidique , Lignée cellulaire tumorale , Ferroptose , Photothérapie/méthodes , Souris , Glutathion/composition chimique , Glutathion/métabolisme , Photosensibilisants/composition chimique , Tumeurs/thérapie , Tumeurs/métabolismeRÉSUMÉ
This study examined the impact of dietary guanidino acetic acid (GAA) and rumen-protected methionine (RPM) on beef quality in Simmental bulls. For 140 days, forty-five bulls (453.43 ± 29.05 kg) were randomly divided into control (CON), 0.1% GAA (GAA), and 0.1% GAA + 0.1% RPM (GAM) groups with 15 bulls in each group and containing 3 pen with 5 bulls in each pen. Significant improvements in eye muscle area, pH48h, redness (a*) value, and crude protein (CP) content of longissimus lumborum (LL) muscles were observed in the GAA and GAM groups (P < 0.05). Conversely, the lightness (L*) value, drip loss, cooking loss, and moisture contents decreased (P < 0.05). Additionally, glutathione (GSH) and glutathione peroxidase (GSH-PX) concentrations of LL muscles in GAM were higher (P < 0.05), while malondialdehyde (MDA) content of LL muscles in GAA and GAM groups were lower (P < 0.05). Polyunsaturated fatty acids (PUFA) profiles were enriched in beef from GAM group (P < 0.05). The addition of GAA and RPM affected the expression of genes in LL muscle, such as HMOX1, EIF4E, SCD5, and NOS2, which are related to hypoxia metabolism, protein synthesis, and unsaturated fatty acid synthesis-related signaling pathways. In addition, GAA and RPM also affected the content of a series of metabolites such as L-tyrosine, L-tryptophan, and PC (O-16:0/0:0) involved in amino acid and lipid metabolism-related signaling pathways. In summary, GAA and RPM can improve the beef quality and its nutritional composition. These changes may be related to changes in gene expression and metabolic pathways related to protein metabolism and lipid metabolism in beef.
Sujet(s)
Aliment pour animaux , Glycine , Méthionine , Muscles squelettiques , Viande rouge , Rumen , Animaux , Bovins , Mâle , Muscles squelettiques/composition chimique , Muscles squelettiques/métabolisme , Viande rouge/analyse , Aliment pour animaux/analyse , Rumen/métabolisme , Glycine/analogues et dérivés , Régime alimentaire/médecine vétérinaire , Glutathion/métabolisme , Compléments alimentaires , Acides gras insaturés/analyse , Glutathione peroxidase/métabolisme , Malonaldéhyde/métabolisme , Malonaldéhyde/analyse , CouleurRÉSUMÉ
The physiological and clinical importance of Glutathione and Cysteamine is emphasized by their participation in a range of conditions, such as diabetes, cancer, renal failure, Parkinson's disease, and hypothyroidism. This necessitates the requirement for accessible, expedited, and cost-efficient testing that can facilitate clinical diagnosis and treatment options. This article examines numerous techniques used to detect both glutathione and cysteamine. The discussed methods include electroanalytical techniques such as voltammetry and amperometry, which are examined for their sensitivity and ability to provide real-time analysis. Furthermore, this study investigates the accuracy of gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC) in measuring the concentrations of glutathione and cysteamine. Additionally, the potential of new nanotechnology-based methods, such as plasmonic nanoparticles and quantum dots, to improve the sensitivity of detecting glutathione and cysteamine is emphasized.
Sujet(s)
Marqueurs biologiques , Mercaptamine , Glutathion , Mercaptamine/composition chimique , Glutathion/analyse , Humains , Marqueurs biologiques/analyse , Chromatographie en phase liquide à haute performance , Techniques électrochimiques , Chromatographie gazeuse-spectrométrie de masse , Thiols/analyseRÉSUMÉ
BACKGROUND Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of perinatal and postnatal morbidity and mortality worldwide. Catalase (CAT) activity detection is used to determine levels of inflammation and oxidative stress. Glutathione (GSH) is the most critical non-enzymatic endogenous antioxidant. Lipid peroxidation levels marked after hypoxia can be detected based on the level of malondialdehyde (MDA). Ischemia-modified albumin (IMA) is considered a biomarker for cardiac ischemia and is known to increase in the liver, brain, and kidney in states of insufficient oxygenation. We aimed to explain the results and relations between the oxidant and antioxidants to detail oxidant-antioxidant balance and cellular mechanisms. MATERIAL AND METHODS Serum levels of IMA and MDA, as an oxidative stress marker, and CAT and GSH, as antioxidant enzymes, were measured in first blood samples of 59 neonates diagnosed with HIE, with pH <7, base excess >12, and APGAR scores. RESULTS Neonates who were ≥37 weeks of gestation and had hypoxia were included. Compared with healthy newborns (n=32), CAT was statistically significantly lower in the hypoxia group (P=0.0001), while MDA serum levels were significantly higher in neonates with hypoxia (P=0.01). There was no difference between hypoxic and healthy neonates in GSH and IMA measurements (P=0.054, P=0.19 respectively). CONCLUSIONS HIE pathophysiology involves oxidative stress and mitochondrial energy production failure. Explaining the pathways between oxidant-antioxidant balance and cell death, which explains the pathophysiology of HIE, is essential to develop treatment strategies that will minimize the effects of oxygen deprivation on other body organs, especially the brain.
Sujet(s)
Antioxydants , Marqueurs biologiques , Hypoxie-ischémie du cerveau , Malonaldéhyde , Stress oxydatif , Humains , Nouveau-né , Hypoxie-ischémie du cerveau/métabolisme , Hypoxie-ischémie du cerveau/sang , Hypoxie-ischémie du cerveau/physiopathologie , Marqueurs biologiques/sang , Marqueurs biologiques/métabolisme , Antioxydants/métabolisme , Femelle , Mâle , Malonaldéhyde/sang , Malonaldéhyde/métabolisme , Glutathion/sang , Glutathion/métabolisme , Sérum-albumine humaine/métabolisme , Catalase/sang , Catalase/métabolisme , Peroxydation lipidiqueRÉSUMÉ
Ferroptosis is an iron-dependent form of programmed cell death triggered by the excessive accumulation of lipid peroxides on the cell membrane. Recent studies have found that ferroptosis can be induced by exposure of the testis tissue and germ cells to some high-risk factors, accompanied by various characteristic reproductive system injuries, including changes in cell morphology, ferroptosis-related physicochemical indicators and gene expressions. This review focuses on the association of ferroptosis with male reproductive system diseases from three key aspects: iron metabolism abnormalities, Cystine/GSH/GPX4 axis imbalance, and lipid peroxidation.