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1.
Environ Sci Pollut Res Int ; 31(10): 15946-15957, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38308781

RESUMO

Nitrogen forms can affect metal accumulation in plants and tolerance to metals, but a few published studies on the effects on Cu toxicity and Cu accumulation in plants are scarce. Thus, the objective of this study was to evaluate the responses of Liriodendron chinense to different nitrogen forms, by the oxidative stress, antioxidant enzymes system, GSH-AsA cycle, Cu uptake, translocation, and accumulation under Cu stress. We found that Cu-induced growth inhibiting was alleviated by added exclusive NO3--N. Adding N as NH4+-N with or without NO3--N was aggravated as evidenced by significantly elevated malonaldehyde (MDA) and hydrogen peroxide (H2O2) compared to N-Null. Cu exposure and adding NH4+-N inhibited superoxide dismutase activity, but remarkably stimulated the activities of catalase and peroxidase, the efficiency of glutathione-ascorbate (GSH-AsA) cycle, and the activity of glutathione reductase and nitrate reductase, with respect to the control. However, adding exclusive NO3--N progressively restored the alteration of antioxidant to prevent Cu-induced oxidative stress. Additionally, adding exclusive NO3--N significantly promoted the Cu uptake and accumulation in roots, but reduced Cu concentration in leaves, accompanied by the inhibited Cu translocation factor from roots to shoots by 36.7%, when compared with N-Null. Overall, adding NO3--N alleviated its Cu toxicity by preventing Cu-induced oxidative stress and inhibiting Cu translocation from roots to shoots, which provides an effective strategy for phytostabilization in Cu-contaminated lands.


Assuntos
Cobre , Liriodendron , Cobre/toxicidade , Antioxidantes/metabolismo , Nitratos/farmacologia , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo , Glutationa/metabolismo , Nitrogênio/farmacologia , Raízes de Plantas/metabolismo
2.
J Agric Food Chem ; 72(8): 3937-3948, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38354096

RESUMO

Resistance to the herbicide pyroxasulfone has slowly but steadily increased in agricultural weeds. The evolved resistance of one Lolium rigidum population has been attributed to the conjugation of pyroxasulfone to reduced glutathione, mediated by glutathione transferase (GST) activity. To determine if GST-based metabolism is a widespread mechanism of pyroxasulfone resistance in L. rigidum, a number of putative-resistant populations were screened for GST activity toward pyroxasulfone, the presence of GSTF13-like isoforms (previously implicated in pyroxasulfone conjugation in this species), tissue glutathione concentrations, and response to inhibitors of GSTs and oxygenases. Although there were no direct correlations between pyroxasulfone resistance levels and these individual parameters, a random forest analysis indicated that GST activity was of primary importance for L. rigidum resistance to this herbicide.


Assuntos
Herbicidas , Lolium , Sulfonas , Resistência a Herbicidas , Herbicidas/farmacologia , Herbicidas/metabolismo , Isoxazóis/farmacologia , Glutationa/metabolismo
3.
Biochem Soc Trans ; 52(1): 269-278, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38372426

RESUMO

Recent evidence highlights the importance of trace metal micronutrients such as zinc (Zn) in coronary and vascular diseases. Zn2+ plays a signalling role in modulating endothelial nitric oxide synthase and protects the endothelium against oxidative stress by up-regulation of glutathione synthesis. Excessive accumulation of Zn2+ in endothelial cells leads to apoptotic cell death resulting from dysregulation of glutathione and mitochondrial ATP synthesis, whereas zinc deficiency induces an inflammatory phenotype, associated with increased monocyte adhesion. Nuclear factor-E2-related factor 2 (NRF2) is a transcription factor known to target hundreds of different genes. Activation of NRF2 affects redox metabolism, autophagy, cell proliferation, remodelling of the extracellular matrix and wound healing. As a redox-inert metal ion, Zn has emerged as a biomarker in diagnosis and as a therapeutic approach for oxidative-related diseases due to its close link to NRF2 signalling. In non-vascular cell types, Zn has been shown to modify conformations of the NRF2 negative regulators Kelch-like ECH-associated Protein 1 (KEAP1) and glycogen synthase kinase 3ß (GSK3ß) and to promote degradation of BACH1, a transcriptional suppressor of select NRF2 genes. Zn can affect phosphorylation signalling, including mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinases and protein kinase C, which facilitate NRF2 phosphorylation and nuclear translocation. Notably, several NRF2-targeted proteins have been suggested to modify cellular Zn concentration via Zn exporters (ZnTs) and importers (ZIPs) and the Zn buffering protein metallothionein. This review summarises the cross-talk between reactive oxygen species, Zn and NRF2 in antioxidant responses of vascular cells against oxidative stress and hypoxia/reoxygenation.


Assuntos
Fator 2 Relacionado a NF-E2 , Zinco , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Zinco/metabolismo , Células Endoteliais/metabolismo , Estresse Oxidativo , Oxirredução , Glutationa/metabolismo
4.
Int J Mol Sci ; 25(4)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38396960

RESUMO

Active vitamin D derivatives (VDDs)-1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs-are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells restored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1.


Assuntos
Abietanos , Leucemia Mieloide Aguda , Fator de Transcrição AP-1 , Humanos , Fator de Transcrição AP-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Vitamina D/uso terapêutico , Vitaminas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Receptores de Calcitriol/metabolismo , Diferenciação Celular , Transdução de Sinais , Glutationa/metabolismo
5.
Int Immunopharmacol ; 129: 111657, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38335655

RESUMO

BACKGROUND: Epilepsy is a severe neurological disorder associated with substantial morbidity and mortality. Vanillin (Van) is a natural phenolic aldehyde with beneficial pharmacological properties. This study investigated the neuroprotective effects of Van in epilepsy and elucidated its mechanism of action. METHODS: Swiss albino mice were divided into the following five groups: "normal group", 0.9 % saline; "pentylenetetrazole (PTZ) group", intraperitoneal administration of 35 mg/kg PTZ on alternate days up to 42 days; and "PTZ + Van 20", "PTZ + Van 40", and "PTZ + sodium valproate (Val)" groups received PTZ injections in conjunction withVan 20 mg, Van 40 mg/kg, and Val 300 mg/kg, respectively. Behavioural tests and hippocampal histopathological analysis were performed in all groups. The Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways, oxidative stress, neuro-inflammation, and apoptotic markers were analysed. Furthermore, brain acetylcholinesterase (AChE) activity and levels of dopamine (DA), gamma-aminobutyric acid GABA, and serotonin 5-HT were assessed. RESULTS: Van prolonged seizure manifestations and improved electroencephalogram (EEG)criteriain conjunction with 100 mg/kg PTZ once daily. Van administration increased Nrf2/HO-1/NQO1 levels, with subsequent attenuation of malondialdehyde (MDA) and nitric oxide (NO) levels with elevated glutathione (GSH) levels and intensified superoxide dismutase (SOD) and catalase activities. Van reduced the gene and protein expression of HMGB1/RAGE/TLR4/NFκB and decreased the levels of inflammatory and apoptotic markers. In addition, Van reduced AChE activity, and elevated glial fibrillary acidic proteins (GFAP) increased neurotransmitter and brain-derived neurotrophic factors (BDNF). CONCLUSION: By increasing Nrf2/HO-1/NQO1 levels and downregulating the HMGB1/RAGE/TLR4/ NFκB pathway, Van offered protection in PTZ-kindled mice with subsequent attenuation in lipid peroxidation, upregulation in antioxidant enzyme activities, and reduction in inflammation and apoptosis.


Assuntos
Benzaldeídos , Epilepsia , Proteína HMGB1 , Camundongos , Animais , Pentilenotetrazol , Fator 2 Relacionado a NF-E2/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteína HMGB1/metabolismo , Acetilcolinesterase/metabolismo , Epilepsia/induzido quimicamente , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Estresse Oxidativo , Transtornos da Memória , Glutationa/metabolismo , Inflamação
6.
Theranostics ; 14(4): 1683-1700, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38389839

RESUMO

Background: Pancreatic ductal adenocarcinoma (PDAC) is an insidious, rapidly progressing malignancy of the gastrointestinal tract. Due to its dense fibrous stroma and complex tumor microenvironment, neither of which is sensitive to radiotherapy, pancreatic adenocarcinoma is one of the malignancies with the poorest prognosis. Therefore, detailed elucidation of the inhibitory microenvironment of PDAC is essential for the development of novel therapeutic strategies. Methods: We analyzed the association between cancer-associated fibroblasts (CAFs) and resistance to ferroptosis in PDAC using conditioned CAF medium and co-culture of pancreatic cancer cells. Abnormal cysteine metabolism was observed in CAFs using non-targeted metabolomics analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The regulatory effects of cysteine were investigated in PDAC cells through measurement of cell cloning, cell death, cell function, and EdU assays. The effects of exogenous cysteine intake were examined in a mouse xenograft model and the effects of the cysteine pathway on ferroptosis in PDAC were investigated by western blotting, measurement of glutathione and reactive oxygen species levels, among others. Results: It was found that CAFs played a critical role in PDAC metabolism by secreting cysteine, which could increase tumor resistance to ferroptosis. A previously unrecognized function of the sulfur transfer pathway in CAFs was identified, which increased the extracellular supply of cysteine to support glutathione synthesis and thus inducing ferroptosis resistance. Cysteine secretion by CAFs was found to be mediated by the TGF-ß/SMAD3/ATF4 signaling axis. Conclusion: Taken together, the findings demonstrate a novel metabolic relationship between CAFs and cancer cells, in which cysteine generated by CAFs acts as a substrate in the prevention of oxidative damage in PDAC and thus suggests new therapeutic targets for PDAC.


Assuntos
Adenocarcinoma , Fibroblastos Associados a Câncer , Carcinoma Ductal Pancreático , Ferroptose , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Neoplasias Pancreáticas/patologia , Cisteína/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Adenocarcinoma/patologia , Cromatografia Líquida , Espectrometria de Massas em Tandem , Carcinoma Ductal Pancreático/patologia , Glutationa/metabolismo , Microambiente Tumoral
7.
Ann Med ; 56(1): 2319853, 2024 12.
Artigo em Inglês | MEDLINE | ID: mdl-38373208

RESUMO

Propyl gallate (PG) has been found to exert an inhibitory effect on the growth of different cell types, including lung cancer cells. However, little is known about the cytotoxicological effects of PG specifically on normal primary lung cells. The current study examined the cellular effects and cell death resulting from PG treatment in human pulmonary fibroblast (HPF) cells. DNA flow cytometry results demonstrated that PG (100-1,600 µM) had a significant impact on the cell cycle, leading to G1 phase arrest. Notably, 1,600 µM PG slightly increased the number of sub-G1 cells. Additionally, PG (400-1,600 µM) resulted in the initiation of cell death, a process that coincided with a loss of mitochondrial membrane potential (MMP; ΔΨm). This loss of MMP (ΔΨm) was evaluated using a FACS cytometer. In PG-treated HPF cells, inhibitors targeting pan-caspase, caspase-3, caspase-8, and caspase-9 showed no significant impact on the quantity of annexin V-positive and MMP (ΔΨm) loss cells. The administration of siRNA targeting Bax or caspase-3 demonstrated a significant attenuation of PG-induced cell death in HPF cells. However, the use of siRNAs targeting p53, Bcl-2, or caspase-8 did not exhibit any notable effect on cell death. Furthermore, none of the tested MAPK inhibitors, including MEK, c-Jun N-terminal kinase (JNK), and p38, showed any impact on PG-induced cell death or the loss of MMP (ΔΨm) in HPF cells. In conclusion, PG induces G1 phase arrest of the cell cycle and cell death in HPF cells through apoptosis and/or necrosis. The observed HPF cell death is mediated by the modulation of Bax and caspase-3. These findings offer insights into the cytotoxic and molecular effects of PG on normal HPF cells.


Assuntos
Glutationa , Galato de Propila , Humanos , Galato de Propila/metabolismo , Galato de Propila/farmacologia , Caspase 8/metabolismo , Caspase 8/farmacologia , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia , Caspase 3/metabolismo , Caspase 3/farmacologia , Glutationa/metabolismo , Glutationa/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Morte Celular , Apoptose , Pulmão , Fibroblastos/metabolismo
8.
Mol Cell ; 84(4): 616-618, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38364779

RESUMO

Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.


Assuntos
Ferro , Mitocôndrias , Ferro/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Glutationa/metabolismo
9.
Chem Biol Drug Des ; 103(2): e14480, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38369620

RESUMO

Cerebral ischaemia-reperfusion (CIR) injury occurs in stroke patients after the restoration of cerebral perfusion. Sinigrin, a phytochemical found in cruciferous vegetables, exhibits strong antioxidant activity. This study investigated the role of sinigrin in oxidative stress using a CIR injury model. The effects of sinigrin were studied in middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-injured SH-SY5Y cells. Sinigrin treatment improved brain injury and neurological deficits induced by MCAO surgery in rats. Sinigrin inhibited apoptosis in brain tissues and SH-SY5Y cells following OGD/R induction. Additionally, sinigrin elevated the levels of superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) levels. Furthermore, sinigrin inhibited the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signalling pathway. The anti-apoptotic and antioxidant activities of sinigrin in OGD/R-injured SH-SY5Y cells were reversed by TLR4 overexpression. In conclusion, sinigrin inhibits oxidative stress in CIR injury by suppressing the TLR4/MyD88 signalling pathway.


Assuntos
Isquemia Encefálica , Glucosinolatos , Neuroblastoma , Traumatismo por Reperfusão , Humanos , Ratos , Animais , Receptor 4 Toll-Like/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Glutationa/metabolismo , Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Apoptose
10.
Drug Des Devel Ther ; 18: 453-462, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38374827

RESUMO

Introduction: Methotrexate (MTX) is one of the most widely used drugs in cancer chemotherapy and treating rheumatoid arthritis. The hepatotoxicity of MTX is one of its major side effects. Roflumilast (ROF) has been recognized to have antioxidant and anti-inflammatory activity in in-vivo and in-vitro models. The present study aimed to explore the potential protective effects of roflumilast against MTX-induced liver toxicity in male Wistar rats. Methods: High dose of 5 mg/kg for 4 consecutive days subcutaneous (S.C) injection of methotrexate for induction of acute liver injury. A total of 24 Wistar rats, rats were used in four different groups. The NS injections were given S.C to the control group once a day for 4 consecutive days. SC injections of MTX (5 mg/kg) were given to the MTX group daily for four days. At 5 mg/kg once daily for four days, the roflumilast group was given daily oral roflumilast. An injection of MTX and oral roflumilast were given to the MTX + roflumilast group once daily for four consecutive days. Results: Administration of high dose MTX (5 mg/kg) today 4 produced a significant decrease in hepatic glutathione (GSH) levels and a significant increase in ALT and AST liver enzymes, hepatic malondialdehyde (MDA), tumor suppressor protein (p53), interleukin 6, interleukin 1 levels compared to the control group. Treatment with roflumilast for 4 days significantly attenuated unfavorable changes in these parameters. According to histopathological findings, Roflumilast significantly reduced MTX-induced inflammation and degeneration in the liver. In conclusion, the findings indicate that roflumilast may have a potential therapeutic benefit in treating rats with MTX-induced liver toxicity by mitigating its effects. Purpose: The aim of this study is to investigate the potential protective effects of roflumilast against MTX-induced liver toxicity in Wistar rats.


Assuntos
Aminopiridinas , Benzamidas , Doença Hepática Induzida por Substâncias e Drogas , Metotrexato , Ratos , Masculino , Animais , Metotrexato/toxicidade , Ratos Wistar , Estresse Oxidativo , Peroxidação de Lipídeos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Glutationa/metabolismo , Fígado , Ciclopropanos
11.
Cell Death Dis ; 15(2): 145, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360744

RESUMO

Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.


Assuntos
Cistina , Ferroptose , Cistina/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Glutationa/metabolismo , Lipídeos
12.
ACS Appl Mater Interfaces ; 16(6): 6859-6867, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38299497

RESUMO

The rapid development of nanomedicine has considerably advanced precision therapy for cancer treatment. Superior to traditional chemotherapy, emerging theranostic nanoprodrugs can effectively realize inherent self-tracking, targeted drug delivery, stimuli-triggered drug release, and reduced systemic toxicity of chemotherapeutic drugs. However, theranostic nanoprodrugs with real-time drug release monitoring have remained rare so far. In this work, we developed a new glutathione-responsive theranostic nanoprodrug with a high drug-loading content of 59.4 wt % and an average nanoscale size of 46 nm, consisting of the anticancer drug paclitaxel and a fluorescent imaging probe with a high fluorescence quantum yield, which are linked by a disulfide-based glutathione-sensitive self-immolating linker. The strong fluorescence emission of the fluorophore enables efficacious self-tracking and sensitive fluorescence "ON-OFF" glutathione sensing. Upon encountering high-level glutathione in cancer cells, the disulfide bond is cleaved, and the resulting linker halves spontaneously collapse into cyclic small molecules at the same pace, leading to the simultaneous release of the therapeutic drug and the fluorescence-OFF imaging probe. Thereby, the drug release process is efficiently monitored by the fluorescence change in the nanoprodrug. The nanoprodrugs exerted high cytotoxicity toward various cancer cells, especially for A549 and HEK-293 cells, in which the nanoprodrugs generated better therapeutic effects than free paclitaxel. Our work demonstrated a new modality of smart theranostic nanoprodrugs for precise cancer therapy.


Assuntos
Nanopartículas , Neoplasias , Humanos , Medicina de Precisão , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Elétrons , Células HEK293 , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Nanomedicina Teranóstica/métodos , Imagem Óptica/métodos , Glutationa/metabolismo , Dissulfetos/uso terapêutico , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
13.
FASEB J ; 38(3): e23453, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38318639

RESUMO

During early development, both genome-wide epigenetic reprogramming and metabolic remodeling are hallmark changes of normal embryogenesis. However, little is known about their relationship and developmental functions during the preimplantation window, which is essential for the acquisition of totipotency and pluripotency. Herein, we reported that glutathione (GSH), a ubiquitous intracellular protective antioxidant that maintains mitochondrial function and redox homeostasis, plays a critical role in safeguarding postfertilization DNA demethylation and is essential for establishing developmental potential in preimplantation embryos. By profiling mitochondria-related transcriptome that coupled with different pluripotency, we found GSH is a potential marker that is tightly correlated with full pluripotency, and its beneficial effect on prompting developmental potential was functionally conformed using in vitro fertilized mouse and bovine embryos as the model. Mechanistic study based on preimplantation embryos and embryonic stem cells further revealed that GSH prompts the acquisition of totipotency and pluripotency by facilitating ten-eleven-translocation (TET)-dependent DNA demethylation, and ascorbic acid (AsA)-GSH cycle is implicated in the process. In addition, we also reported that GSH serves as an oviductal paracrine factor that supports development potential of preimplantation embryos. Thus, our results not only advance the current knowledge of functional links between epigenetic reprogramming and metabolic remodeling during preimplantation development but also provided a promising approach for improving current in vitro culture system for assisted reproductive technology.


Assuntos
Desmetilação do DNA , Metilação de DNA , Animais , Bovinos , Camundongos , Blastocisto/metabolismo , Células-Tronco Embrionárias/metabolismo , Glutationa/metabolismo , Desenvolvimento Embrionário/genética
14.
Drug Res (Stuttg) ; 74(2): 67-76, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38346682

RESUMO

Parkinson's disease is the loss of dopaminergic neurons in the substantial nigra part of the brain leading to neurodegeneration. Whereas, reactive oxygen species and mitochondrial impairment are considered to be the major pathophysiology of neurodegeneration. The benzylidene-based 2-chloroquinolin derivatives were synthesized and characterized by FT-IR, NMR, and MS spectrometry which were screened using various in-silico approaches. The designed compounds were further assessed using in-vitro cytotoxicity assay by the MTT method, DPPH assay, and Glutathione measurements in the SHSY5Y neuroblastoma cell lines. The compounds JD-7 and JD-4 were found to have a binding affinity of - 7.941 and - 7.633 kcal/mol with an MMGBSA score of - 64.614 and - 62.817 kcal/mol. The compound JD-7 showed the highest % Cell viability of 87.64% at a minimal dose of 125 µg/mL by the MTT method. The neurotoxicity effects were observed at increasing concentrations from 0 to 125, 250, and 500 µg/mL. Further, free radical scavenging activity for the JD-7 was found to be 36.55 at lowest 125 µg/mL concentrations. At 125 µg/mL, GSH % and GSSG % were found to be increasing in rotenone treatment, whereas JD-7 and JD-4 were found in the downregulation of glutathione level in the pre-treated rotenone SHSY5Y neuroblastoma cell lines. The benzylidene-based chloroquinolin derivatives were synthesized, and among the compounds JD-1 to JD-13, the compounds JD-7, and JD-4 were found to have having highest % cell viability, free radical scavenging molecules, and glutathione levels in the SHSY5Y neuroblastoma cell lines and could be used as free radical scavengers in Parkinson's disease.


Assuntos
Neuroblastoma , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/química , Rotenona , Espectroscopia de Infravermelho com Transformada de Fourier , Espécies Reativas de Oxigênio/metabolismo , Glutationa/metabolismo
15.
J Biochem Mol Toxicol ; 38(2): e23658, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38348719

RESUMO

Vinpocetine (VIN) is a synthetic drug derived from the natural alkaloid vincamine. The antioxidation and anti-inflammation effects of VIN allow it to be used for multiple therapeutic purposes. So, the research aims to discover the possibility of using VIN to improve the nephrotoxicity of acrylamide (ACR). Twenty-four male albino rats were used in the trial: rats in the control group received 0.5 mL of oral saline, rats in the VIN group received an oral dose of VIN (5 mg/kg), rats in the ACR group received an oral dose of ACR (38.27 mg/kg), and rats in the VIN + ACR group received VIN and then ACR 1 h later. Rat blood and kidneys were collected 10 days after the experiment began to assess biochemical parameters and to examine both renal histopathological and immunohistochemistry. The ACR-treated rats showed high levels of serum kidney function biomarkers (creatinine, urea, and uric acid), serum protein biomarkers (total protein, albumin, and globulin), renal kidney injury molecule (KIM)-1, renal malondialdehyde (MDA), and renal caspase-3 immunoexpression. Moreover, ACR lowed both renal superoxide dismutase (SOD) activity and renal glutathione (GSH) level and caused renal histological alterations. While administration of VIN improved serum kidney function biomarkers, serum protein biomarkers, renal KIM-1, renal oxidative stress biomarkers (MDA, SOD, and GSH), renal caspase-3 immunoexpression, and renal histological alterations induced by ACR. The study confirmed the ability of VIN to reduce the nephrotoxic effects of ACR, which was evident through the results of biochemical parameters and histological and immunohistochemical examinations of the kidney tissues.


Assuntos
Acrilamida , Insuficiência Renal , Alcaloides de Vinca , Ratos , Masculino , Animais , Caspase 3/metabolismo , Acrilamida/toxicidade , Rim , Antioxidantes/farmacologia , Estresse Oxidativo , Glutationa/metabolismo , Superóxido Dismutase/metabolismo , Proteínas Sanguíneas/metabolismo , Biomarcadores/metabolismo , Malondialdeído/metabolismo
16.
Ren Fail ; 46(1): 2313863, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38345031

RESUMO

BACKGROUND: The effect of tacrolimus (TAC) on oxidative stress after kidney transplantation (KT) is unclear. This study aimed to evaluate the influence of TAC trough levels of oxidative stress status in Tunisian KT patients during the post-transplantation period (PTP). METHODS: A prospective study including 90 KT patients was performed. TAC whole-blood concentrations were measured by the microparticle enzyme immunoassay method and adjusted according to the target range. Plasma levels of oxidants (malondialdehyde (MDA) and advanced oxidation protein products (AOPP)) and antioxidants (ascorbic acid, glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) were measured using spectrophotometry. The subjects were subdivided according to PTP into three groups: patients with early, intermediate, and late PT. According to the TAC level, they were subdivided into LL-TAC, NL-TAC, and HL-TAC groups. RESULTS: A decrease in MDA levels, SOD activity, and an increase in GSH levels and GPx activity were observed in patients with late PT compared to those with early and intermediate PT (p < 0.05). Patients with LL-TAC had lower MDA levels and higher GSH levels and GPx activity compared with the NL-TAC and HL-TAC groups (p < 0.05). CONCLUSION: Our results have shown that in KT patients, despite the recovery of kidney function, the TAC reduced but did not normalize oxidative stress levels in long-term therapy, and the TAC effect significantly depends on the concentration used.


Assuntos
Transplante de Rim , Tacrolimo , Humanos , Tacrolimo/uso terapêutico , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Estresse Oxidativo , Antioxidantes/farmacologia , Glutationa/metabolismo , Superóxido Dismutase/metabolismo , Rim/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/farmacologia
17.
J Hazard Mater ; 466: 133578, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38306837

RESUMO

Phytoremediation is widely considered as a cost-effective method for managing heavy metal soil pollution. Leersia hexandra Swartz shows a promising potential for the remediation of heavy metals pollution, including chromium (Cr), copper (Cu), and nickel (Ni). It is vital to understand the physiological and biochemical responses of L. hexandra to Ni stress to elucidate the mechanisms underlying Ni tolerance and accumulation. Here, we examined the metabolic and transcriptomic responses of L. hexandra exposed to 40 mg/L Ni for 24 h and 14 d. After 24-h Ni stress, gene expression of glutathione metabolic cycle (GSTF1, GSTU1 and MDAR4) and superoxide dismutase (SODCC2) was significantly increased in plant leaves. Furthermore, after 14-d Ni stress, the ascorbate peroxidase (APX7), superoxide dismutase (SODCP and SOD1), and catalase (CAT) gene expression was significantly upregulated, but that of glutathione metabolic cycle (EMB2360, GSTU1, GSTU6, GSH2, GPX6, and MDAR2) was downregulated. After 24-h Ni stress, the differentially expressed metabolites (DEMs) were mainly flavonoids (45%) and flavones (20%). However, after 14-d Ni stress, the DEMs were mainly carbohydrates and their derivatives (34%), amino acids and derivatives (15%), and organic acids and derivatives (8%). Results suggest that L. hexandra adopt distinct time-dependent antioxidant and metal detoxification strategies likely associated with intracellular reduction-oxidation balance. Novel insights into the molecular mechanisms responsible for Ni tolerance in plants are presented.


Assuntos
Metais Pesados , Poluentes do Solo , Níquel/toxicidade , Antioxidantes/metabolismo , Poluentes do Solo/toxicidade , Poluentes do Solo/metabolismo , Metais Pesados/toxicidade , Metais Pesados/metabolismo , Poaceae/metabolismo , Glutationa/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Mecanismos de Defesa
18.
Cell Biochem Funct ; 42(2): e3958, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38396357

RESUMO

Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.


Assuntos
Acetilcisteína , Sobrecarga de Ferro , Ratos , Masculino , Animais , Acetilcisteína/farmacologia , Acetilcisteína/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Regulação para Cima , Regulação para Baixo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/farmacologia , Nestina/genética , Nestina/metabolismo , Nestina/farmacologia , Dextranos/metabolismo , Dextranos/farmacologia , Estresse Oxidativo , Ferro/metabolismo , Ferro/farmacologia , Glutationa/metabolismo , Caspases/metabolismo , Hipocampo/metabolismo , Claudinas/genética , Giro Denteado/metabolismo
19.
Ecotoxicol Environ Saf ; 272: 116055, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38340597

RESUMO

2-Methyl-1-butanol (2MB) and 3-Methyl-1-butanol (3MB) are microbial volatile organic compounds (VOCs) and found in indoor air. Here, we applied rice as a bioindicator to investigate the effects of these indoor microbial volatile pollutants. A remarkable decrease in germination percentage, shoot and root elongation, as well as lateral root numbers were observed in 3MB. Furthermore, ROS production increased by 2MB and 3MB, suggesting that pentanol isomers could induce cytotoxicity in rice seedlings. The enhancement of peroxidase (POD) and catalase (CAT) activity provided evidence that pentanol isomers activated the enzymatic antioxidant scavenging systems, with a more significant effect observed in 3MB. Furthermore, 3MB induced higher activity levels of glutathione (GSH), oxidized glutathione (GSSG), and the GSH/GSSG ratio in rice compared to the levels induced by 2MB. Additionally, qRT-PCR analysis showed more up-regulation in the expression of glutaredoxins (GRXs), peroxiredoxins (PRXs), thioredoxins (TRXs), and glutathione S-transferases (GSTUs) genes in 3MB. Taking the impacts of pentanol isomers together, the present study suggests that 3MB exhibits more cytotoxic than 2MB, as such has critical effects on germination and the early seedling stage of rice. Our results provide molecular insights into how isomeric indoor microbial volatile pollutants affect plant growth through airborne signals.


Assuntos
Poluentes Ambientais , Oryza , Antioxidantes/metabolismo , Plântula , Oryza/metabolismo , Pentanóis/metabolismo , Pentanóis/farmacologia , 1-Butanol/metabolismo , 1-Butanol/farmacologia , Poluentes Ambientais/metabolismo , Dissulfeto de Glutationa/metabolismo , Estresse Oxidativo , Glutationa/metabolismo , Raízes de Plantas/metabolismo
20.
Ecotoxicol Environ Saf ; 272: 116053, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38306815

RESUMO

Organic UV filters, which are often found in the environment, have been the focus of much public health concern. 2-ethylhexyl-4-methoxycinnamate (EHMC) is one of the most common organic UV filters present in the environment. However, few studies have investigated its developmental neurotoxic (DNT) effects and the underlying molecular mechanisms. In the present study, zebrafish embryos were exposed to low concentration of EHMC (0, 0.01, 0.1, 1 mg/L) in static water starting from 6 h post-fertilization (hpf). Results showed that EHMC exposure caused a reduction in somite count at 13 hpf, a diminishment in head-trunk angle at 30 hpf, a delay in hatching at 48 hpf, and a decrease in head depth and head length at both 30 and 48 hpf. Additionally, EHMC led to abnormal motor behaviors at various developmental stages including altered spontaneous movement at both 23 and 24 hpf, and decreased touch response at 30 hpf. Consistent with these morphological changes and motor behavior deficits, EHMC inhibited axonal growth of primary motor neurons at 30 and 48 hpf, and yielded subtle changes in muscle fiber length at 48 hpf, suggesting the functional relevance of structural changes. Moreover, EHMC exposure induced excessive cell apoptosis in the head and spinal cord regions, increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and reduced the level of glutathione (GSH). Defects of lateral line system neuromasts were also observed, but no structural deformity of blood vessels was seen in developing zebrafish. Abnormal expression of axonal growth-related genes (gap43, mbp, shha, and α1-tubulin) and apoptosis-related genes (bax/bcl-2 and caspase-3) revealed potential molecular mechanisms regarding the defective motor behaviors and aberrant phenotype. In summary, our findings indicate that EHMC induced developmental neurotoxicity in zebrafish, making it essential to assess its risks and provide warnings regarding EHMC exposure.


Assuntos
Perciformes , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Cinamatos/farmacologia , Cinamatos/toxicidade , Glutationa/metabolismo , Perciformes/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fertilização , Embrião não Mamífero , Larva
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