Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.943
Filtrar
1.
Nat Commun ; 12(1): 2042, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824329

RESUMO

Daytime warm temperature elicits thermomorphogenesis in Arabidopsis by stabilizing the central thermoregulator PHYTOCHROME INTERACTING transcription FACTOR 4 (PIF4), whose degradation is otherwise promoted by the photoreceptor and thermosensor phytochrome B. PIF4 stabilization in the light requires a transcriptional activator, HEMERA (HMR), and is abrogated when HMR's transactivation activity is impaired in hmr-22. Here, we report the identification of a hmr-22 suppressor mutant, rcb-101, which surprisingly carries an A275V mutation in REGULATOR OF CHLOROPLAST BIOGENESIS (RCB). rcb-101/hmr-22 restores thermoresponsive PIF4 accumulation and reverts the defects of hmr-22 in chloroplast biogenesis and photomorphogenesis. Strikingly, similar to hmr, the null rcb-10 mutant impedes PIF4 accumulation and thereby loses the warm-temperature response. rcb-101 rescues hmr-22 in an allele-specific manner. Consistently, RCB interacts directly with HMR. Together, these results unveil RCB as a novel temperature signaling component that functions collaboratively with HMR to initiate thermomorphogenesis by selectively stabilizing PIF4 in the daytime.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Morfogênese , Temperatura , Tiorredoxinas/metabolismo , Sequência de Aminoácidos , Arabidopsis/genética , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Clorofila/metabolismo , Cloroplastos/metabolismo , Cloroplastos/efeitos da radiação , Genes Supressores , Luz , Modelos Biológicos , Morfogênese/efeitos da radiação , Fotoperíodo , Estabilidade Proteica/efeitos da radiação , Plântula/metabolismo , Plântula/efeitos da radiação , Tiorredoxinas/química , Tiorredoxinas/genética , Fatores de Transcrição/metabolismo
2.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466919

RESUMO

Redox (reduction-oxidation) reactions control many important biological processes in all organisms, both prokaryotes and eukaryotes. This reaction is usually accomplished by canonical disulphide-based pathways involving a donor enzyme that reduces the oxidised cysteine residues of a target protein, resulting in the cleavage of its disulphide bonds. Focusing on human vitamin K epoxide reductase (hVKORC1) as a target and on four redoxins (protein disulphide isomerase (PDI), endoplasmic reticulum oxidoreductase (ERp18), thioredoxin-related transmembrane protein 1 (Tmx1) and thioredoxin-related transmembrane protein 4 (Tmx4)) as the most probable reducers of VKORC1, a comparative in-silico analysis that concentrates on the similarity and divergence of redoxins in their sequence, secondary and tertiary structure, dynamics, intraprotein interactions and composition of the surface exposed to the target is provided. Similarly, hVKORC1 is analysed in its native state, where two pairs of cysteine residues are covalently linked, forming two disulphide bridges, as a target for Trx-fold proteins. Such analysis is used to derive the putative recognition/binding sites on each isolated protein, and PDI is suggested as the most probable hVKORC1 partner. By probing the alternative orientation of PDI with respect to hVKORC1, the functionally related noncovalent complex formed by hVKORC1 and PDI was found, which is proposed to be a first precursor to probe thiol-disulphide exchange reactions between PDI and hVKORC1.


Assuntos
Domínios Proteicos , Dobramento de Proteína , Tiorredoxinas/química , Vitamina K Epóxido Redutases/química , Algoritmos , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Simulação de Dinâmica Molecular , Oxirredução , Proteína Dissulfeto Redutase (Glutationa)/química , Proteína Dissulfeto Redutase (Glutationa)/genética , Proteína Dissulfeto Redutase (Glutationa)/metabolismo , Isomerases de Dissulfetos de Proteínas/química , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Homologia de Sequência de Aminoácidos , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Vitamina K Epóxido Redutases/genética , Vitamina K Epóxido Redutases/metabolismo
3.
PLoS One ; 15(12): e0244060, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338048

RESUMO

Ataxia-Telangiectasia (A-T), a pleiotropic chromosomal breakage syndrome, is caused by the loss of the kinase Ataxia-telangiectasia mutated (ATM). ATM is not only involved in the response to DNA damage, but also in sensing and counteracting oxidative stress. Since a disturbed redox balance has been implicated in the pathophysiology of A-T lung disease, we aimed to further explore the interplay between ATM and oxidative stress in lung cells. Using a kinetic trapping approach, we could demonstrate an interaction between the trapping mutant TRX1-CS and ATM upon oxidative stress. We could further show that combined inhibition of thioredoxin reductase (TrxR) and ATM kinase activity, using Auranofin and KU55933 respectively, induced an increase in cellular reactive oxygen species (ROS) levels and protein oxidation in lung cells. Furthermore, ATM inhibition sensitized lung cells to Auranofin-induced cell death that could be rescued by ROS scavengers. As a consequence, targeted reduction of ATM by TRX1 could serve as a regulator of oxidative ATM activation and contribute to the maintenance of the cellular redox homeostasis. These results highlight the importance of the redox-active function of ATM in preventing ROS accumulation and cell death in lung cells.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Auranofina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Células A549 , Animais , Morte Celular/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pironas/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
4.
Int J Mol Sci ; 21(24)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327533

RESUMO

The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor ß-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1). Txnip-/- (KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (S. aureus) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.


Assuntos
Proteínas de Transporte/metabolismo , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Tiorredoxinas/metabolismo , Animais , Proteínas de Transporte/genética , Ensaio de Imunoadsorção Enzimática , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Células Matadoras Naturais/imunologia , Lipopeptídeos/farmacologia , Camundongos , Camundongos Knockout , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/patogenicidade , Tiorredoxinas/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
5.
Nat Commun ; 11(1): 4055, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792504

RESUMO

Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.


Assuntos
Cromatina/metabolismo , Glucose/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Transporte Biológico/genética , Transporte Biológico/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Reprogramação Celular/genética , Reprogramação Celular/fisiologia , Imunoprecipitação da Cromatina , Epigênese Genética/genética , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/genética , Fosfogluconato Desidrogenase/genética , Fosfogluconato Desidrogenase/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
6.
Nat Commun ; 11(1): 4254, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848143

RESUMO

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFß1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFß1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.


Assuntos
Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Deleção de Genes , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isomerases de Dissulfetos de Proteínas/genética , Dobramento de Proteína , Estabilidade Proteica , Fibrose Pulmonar/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Transdução de Sinais , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Regulação para Cima
7.
PLoS One ; 15(6): e0235475, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603381

RESUMO

Sea barley Hordeum marinum is an important germplasm resource. However, the origin of this tetraploid H. marinum subsp. gussoneanum is still unclear, which has caused great perplexity to the exploration and utilization of germplasm resources. We used two single-copy nuclear genes, thioredoxin-like gene (TRX) and waxy1 gene encoding granule-bound starch synthase (WAXY1) to analyze 41 accessions of Hordeum marinum. The phylogenies of different genes told different story of evolution of tetraploids of H. marinum subsp. gussoneanum. The phylogenetic trees showed that two distinct copies of sequences from both genes were detected for some accessions of the tetraploids of H. marinum subsp. gussoneanum, and diploid marinum might also contribute to the origin and evolution of the tetraploid gussoneanum. Our findings suggested that tetraploid more likely originated from the diploids of H. marinum subsp. gussoneanum and another ancestor that might be an extinct unknown diploid species. Homogenization of gene in tetraploids also occurred after polyploidization as both TRX and WAXY1 sequences in some accessions of tetraploid H. marinum subsp. gussoneanum cannot be distinguished, indicating the complicated evolution of this tetraploid.


Assuntos
Hordeum/genética , Filogenia , Evolução Biológica , Genes de Plantas , Genoma de Planta , Poliploidia , Sintase do Amido/genética , Tetraploidia , Tiorredoxinas/genética
8.
Proc Natl Acad Sci U S A ; 117(28): 16283-16291, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32611810

RESUMO

The difficulty of achieving robust functional expression of insect nicotinic acetylcholine receptors (nAChRs) has hampered our understanding of these important molecular targets of globally deployed neonicotinoid insecticides at a time when concerns have grown regarding the toxicity of this chemotype to insect pollinators. We show that thioredoxin-related transmembrane protein 3 (TMX3) is essential to enable robust expression in Xenopus laevis oocytes of honeybee (Apis mellifera) and bumblebee (Bombus terrestris) as well as fruit fly (Drosophila melanogaster) nAChR heteromers targeted by neonicotinoids and not hitherto robustly expressed. This has enabled the characterization of picomolar target site actions of neonicotinoids, findings important in understanding their toxicity.


Assuntos
Proteínas de Insetos/metabolismo , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Acetilcolina/farmacologia , Animais , Abelhas/metabolismo , Relação Dose-Resposta a Droga , Drosophila melanogaster/metabolismo , Proteínas de Insetos/agonistas , Proteínas de Insetos/genética , Oócitos/metabolismo , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/genética , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Xenopus laevis
9.
Medicine (Baltimore) ; 99(21): e20294, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481311

RESUMO

BACKGROUND: The aim of this study is to explore the effect of grelin on TRX expression (TRXE) in chronic heart failure tissue (CHFT). METHODS: We will search electronic databases from inception to the March 1, 2020 in MEDLINE, EMBASE, Cochrane Library, CINAHL, PEDro, the Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. We will not apply any limitations to the language and publication status. Any randomized controlled trials (RCTs) that studied the effect of grelin on TRXE in CHFT will be included. Study quality will be checked by Cochrane risk of bias and evidence quality will be appraised by Grading of Recommendations Assessment Development and Evaluation. All extracted data will be analyzed by RevMan 5.3 Software. RESULTS: This study will summarize the present RCTs to assess the effect of grelin on TRXE in CHFT. CONCLUSION: The results of this study will provide conclusive evidence of the effect of grelin on TRXE in CHFT. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040078.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/terapia , Medicina Tradicional Chinesa/métodos , Tiorredoxinas/genética , DNA/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Tiorredoxinas/biossíntese
10.
Vet Res ; 51(1): 38, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32156317

RESUMO

Rhodococcus equi is an intracellular veterinary pathogen that is becoming resistant to current antibiotherapy. Genes involved in preserving redox homeostasis could be promising targets for the development of novel anti-infectives. Here, we studied the role of an extracellular thioredoxin (Etrx3/REQ_13520) in the resistance to phagocytosis. An etrx3-null mutant strain was unable to survive within macrophages, whereas the complementation with the etrx3 gene restored its intracellular survival rate. In addition, the deletion of etrx3 conferred to R. equi a high susceptibility to sodium hypochlorite. Our results suggest that Etrx3 is essential for the resistance of R. equi to specific oxidative agents.


Assuntos
Infecções por Actinomycetales/veterinária , Proteínas de Bactérias/genética , Macrófagos/microbiologia , Fagocitose , Rhodococcus equi/genética , Tiorredoxinas/genética , Infecções por Actinomycetales/imunologia , Animais , Proteínas de Bactérias/metabolismo , Camundongos , Mutação , Tiorredoxinas/metabolismo
11.
Biochem J ; 477(6): 1083-1087, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32187349

RESUMO

Thioredoxins are a family of conserved oxidoreductases responsible for maintaining redox balance within cells. They have also served as excellent model systems for protein design and engineering studies particularly through ancestral sequence reconstruction methods. The recent work by Gamiz-Arco et al. [Biochem J (2019) 476, 3631-3647] answers fundamental questions on how specific sequence differences can contribute to differences in folding rates between modern and ancient thioredoxins but also among a selected subset of modern thioredoxins. They surprisingly find that rapid unassisted folding, a feature of ancient thioredoxins, is not conserved in the modern descendants suggestive of co-evolution of better folding machinery that likely enabled the accumulation of mutations that slow-down folding. The work thus provides an interesting take on the expected folding-stability-function constraint while arguing for additional factors that contribute to sequence evolution and hence impact folding efficiency.


Assuntos
Evolução Molecular , Dobramento de Proteína , Tiorredoxinas/metabolismo , Animais , Humanos , Engenharia de Proteínas/tendências , Termodinâmica , Tiorredoxinas/química , Tiorredoxinas/genética
12.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165716, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061776

RESUMO

Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), also known as Rhodanese, is a mitochondrial enzyme which catalyzes the transfer of sulfur in several molecular pathways. After its initial identification as a cyanide detoxification enzyme, it was found that its functions also include sulfur metabolism, modification of iron­sulfur clusters and the reduction of antioxidants glutathione and thioredoxin. TST deficiency was shown to be strongly related to the pathophysiology of metabolic diseases including diabetes and obesity. This review summarizes research related to the enzymatic properties and functions of TST, to then explore the association between the effects of TST on mitochondria and development of diseases such as diabetes and obesity.


Assuntos
Antioxidantes/metabolismo , Doenças Metabólicas/genética , Enxofre/metabolismo , Tiossulfato Sulfurtransferase/genética , Glutationa/metabolismo , Humanos , Proteínas com Ferro-Enxofre/genética , Doenças Metabólicas/enzimologia , Doenças Metabólicas/patologia , Selênio/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Tiossulfato Sulfurtransferase/metabolismo
13.
Fish Shellfish Immunol ; 99: 495-504, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32081809

RESUMO

Thioredoxin (Trx) is a small ubiquitous multifunctional protein with a characteristic WCGPC thiol-disulfide active site that is conserved through evolution. Trx plays a crucial role in the antioxidant defense system. Further, it is involved in a variety of biological functions including gene expression, apoptosis, and growth regulation. Trx exists in several forms, with the cytosolic (Trx-1) and mitochondrial (Trx-2) forms being the most predominant. In this study, the mitochondrial Trx protein (HaTrx-2), from the big-belly seahorse (Hippocampus abdominalis) was characterized, and its molecular features and functional properties were investigated. The cDNA sequence of HaTrx-2 consists of a 519 bp ORF, and it encodes a polypeptide of 172 amino acids. This protein has a calculated molecular mass of 18.8 kDa and a calculated isoelectric point (pI) of 7.80. The highest values of identity (78.7%) and similarity (86.2%) were observed with Fundulus heteroclitus Trx-2 from the pairwise alignment results. The phylogenetic analysis revealed that HaTrx-2 is closely clustered with teleost fishes. The qPCR results showed that HaTrx-2 was prevalently expressed at various levels in all the tissues examined. The ovary showed the highest expression, followed by the brain and kidney. HaTrx-2 showed varying mRNA expression levels during the immune challenge experiment, depending on the type of tissue and the time interval. Our results confirmed the antioxidant property of HaTrx-2 by performing the MCO assay, DPPH radical scavenging activity, and cell viability assays. Further, an insulin disulfide reduction assay revealed the dithiol remove the enzymatic activity of HaTrx-2. Altogether these results indicate that HaTrx-2 plays indispensable roles in the regulation of oxidative stress and immune response in the seahorse.


Assuntos
Infecções Bacterianas/veterinária , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Smegmamorpha/imunologia , Tiorredoxinas/imunologia , Animais , Infecções Bacterianas/imunologia , DNA Complementar/genética , Doenças dos Peixes/microbiologia , Proteínas de Peixes/imunologia , Regulação da Expressão Gênica , Imunidade Inata , Filogenia , Smegmamorpha/genética , Tiorredoxinas/genética
14.
Biochem Biophys Res Commun ; 524(4): 876-882, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32057359

RESUMO

Sepsis is a progressive disease characterized by excessive inflammatory responses, severe tissue injury and organ dysfunction, ultimately leading to mortality. In this study, we demonstrated that thioredoxin-2 (TRX-2) expression is reduced in macrophages stimulated with lipopolysaccharide (LPS). Overexpression of TRX-2 significantly attenuated interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) production induced by LPS. TRX-2 inhibited LPS-induced inflammatory responses through suppressing activation of the NF-κB and MAPK signaling pathways. Furthermore, TRX-2 induced a significant decrease in mortality in mouse sepsis models in association with reduced inflammatory cytokine production and attenuation of organ injury. Our data collectively support a role of TRX-2 as a critical regulator of sepsis that influences survival by protecting the host from excessive inflammatory damage.


Assuntos
Macrófagos Peritoneais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , Choque Séptico/genética , Tiorredoxinas/genética , Animais , Regulação da Expressão Gênica , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Choque Séptico/induzido quimicamente , Choque Séptico/mortalidade , Choque Séptico/patologia , Transdução de Sinais , Análise de Sobrevida , Tioglicolatos/farmacologia , Tiorredoxinas/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
15.
Biochem Biophys Res Commun ; 524(3): 582-588, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32029274

RESUMO

Colorectal cancer (CRC) is the third most commonly malignancy worldwide. The incidence of CRC is on the rise and leads to indisputable society burden due to the high cost of cancer treatments. Resistance to oxaliplatin-chemotherapy is the major cause for treatment failure and CRC-related death. In this study, we anticipated that TXNDC9 might demonstrate a protective role in oxaliplatin-resistant CRC cells. TXNDC9 was found significantly upregulated when treated with oxaliplatin. Manipulation of TXNDC9 expression largely affected the oxaliplatin-induced cell death. Moreover, TXNDC9 regulates autophagy and apoptosis in response to oxaliplatin treatment in HT29 cells via the Nrf2 pathway. Taken together, our findings explore the biological role of TXNDC9 in oxaliplatin resistance in CRC cells and may identify a novel therapeutic target to counteract drug resistance to oxaliplatin in CRC.


Assuntos
Adenocarcinoma/patologia , Apoptose , Autofagia , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Oxaliplatina/farmacologia , Tiorredoxinas/metabolismo , Adenocarcinoma/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Tiorredoxinas/genética , Regulação para Cima/efeitos dos fármacos
16.
Sci Rep ; 10(1): 3009, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080212

RESUMO

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) have been investigated as triple-negative breast cancer (TNBC) biomarkers. Reduced EGFR levels can be compensated by increases in HER3; thus, assaying EGFR and HER3 together may improve prognostic value. In a multi-institutional cohort of 510 TNBC patients, we analyzed the impact of HER3, EGFR, or combined HER3-EGFR protein expression in pre-treatment samples on breast cancer-specific and distant metastasis-free survival (BCSS and DMFS, respectively). A subset of 60 TNBC samples were RNA-sequenced using massive parallel sequencing. The combined HER3-EGFR score outperformed individual HER3 and EGFR scores, with high HER3-EGFR score independently predicting worse BCSS (Hazard Ratio [HR] = 2.30, p = 0.006) and DMFS (HR = 1.78, p = 0.041, respectively). TNBCs with high HER3-EGFR scores exhibited significantly suppressed ATM signaling and differential expression of a network predicted to be controlled by low TXN activity, resulting in activation of EGFR, PARP1, and caspases and inhibition of p53 and NFκB. Nuclear PARP1 protein levels were higher in HER3-EGFR-high TNBCs based on immunohistochemistry (p = 0.036). Assessing HER3 and EGFR protein expression in combination may identify which adjuvant chemotherapy-treated TNBC patients have a higher risk of treatment resistance and may benefit from a dual HER3-EGFR inhibitor and a PARP1 inhibitor.


Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Receptor ErbB-3/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Estadiamento de Neoplasias , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Prognóstico , Receptor ErbB-3/metabolismo , Análise de Sobrevida , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
17.
Sci Adv ; 6(1): eaax8358, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911946

RESUMO

Irreversible oxidation of Cys residues to sulfinic/sulfonic forms typically impairs protein function. We found that persulfidation (CysSSH) protects Cys from irreversible oxidative loss of function by the formation of CysSSO1-3H derivatives that can subsequently be reduced back to native thiols. Reductive reactivation of oxidized persulfides by the thioredoxin system was demonstrated in albumin, Prx2, and PTP1B. In cells, this mechanism protects and regulates key proteins of signaling pathways, including Prx2, PTEN, PTP1B, HSP90, and KEAP1. Using quantitative mass spectrometry, we show that (i) CysSSH and CysSSO3H species are abundant in mouse liver and enzymatically regulated by the glutathione and thioredoxin systems and (ii) deletion of the thioredoxin-related protein TRP14 in mice altered CysSSH levels on a subset of proteins, predicting a role for TRP14 in persulfide signaling. Furthermore, selenium supplementation, polysulfide treatment, or knockdown of TRP14 mediated cellular responses to EGF, suggesting a role for TrxR1/TRP14-regulated oxidative persulfidation in growth factor responsiveness.


Assuntos
Cisteína/genética , Oxirredução/efeitos dos fármacos , Tiorredoxina Redutase 1/genética , Tiorredoxinas/genética , Animais , Cisteína/química , Fator de Crescimento Epidérmico/genética , Proteínas de Choque Térmico HSP90/genética , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/genética , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Camundongos , PTEN Fosfo-Hidrolase/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Selênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfetos/metabolismo , Sulfetos/farmacologia , Tiorredoxina Redutase 1/química , Tiorredoxinas/química
18.
Cancer Sci ; 111(4): 1165-1179, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31994822

RESUMO

Luteolin is a natural flavonoid with strong anti-oxidative properties that is reported to have an anti-cancer effect in several malignancies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin-1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell-cycle arrest, p21 upregulation and downregulation of phospho(p)-S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p-S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67-labeling index and p-S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin-3'-O-glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin-3'-glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product-derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling.


Assuntos
Luteolina/farmacologia , Serina-Treonina Quinases TOR/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Proteínas rho de Ligação ao GTP/genética , Animais , Apoptose/efeitos dos fármacos , Butilidroxibutilnitrosamina/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Antígeno Ki-67/genética , Luteolina/metabolismo , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Tiorredoxinas/genética , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Food Microbiol ; 87: 103389, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31948630

RESUMO

To overcome the deleterious effects of hydrogen peroxide, Lactobacillus plantarum elicits an adaptive response to oxidative stress. In this study, global transcriptomic analysis revealed that L. plantarum CAUH2 expanded its carbon source utilizing profile and enhanced glycolysis to produce more ATP to confront with H2O2 stress. Some antioxidant enzymes including NADH peroxidase, thioredoxin reductase and glutathione peroxidase were 6.11, 36.76 and 6.23-fold up-regulated at transcription level for H2O2 scavenging. Meanwhile, free ferrous iron (Fe2+) was maintained at low concentrations in the cytoplasm, which could limit Fenton reaction and reduce the production of hydroxyl radicals. To repair DNA lesion caused by H2O2, both base excision repair system and recombinational DNA repair pathway were employed by L. plantarum CAUH2. In addition, the expression of methionine sulfoxide reductases and thioredoxin were up-regulated to repair oxidized proteins. It is noteworthy that some transcriptional regulators (Spx, CcpA and MarR1) were predicted to participate in the adaptive response to H2O2 stress, suggesting that L. plantarum CAUH2 utilized a wide array of sensors to monitor oxidative stress and modulated the transcriptional regulation network under H2O2 stress. These findings provide novel insight into the protective mechanisms developed by L. plantarum to cope with oxidative stress.


Assuntos
Proteínas de Bactérias/genética , Peróxido de Hidrogênio/farmacologia , Lactobacillus plantarum/efeitos dos fármacos , Lactobacillus plantarum/genética , Proteínas de Bactérias/metabolismo , Perfilação da Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Lactobacillus plantarum/enzimologia , Lactobacillus plantarum/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidases/genética , Peroxidases/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Transcriptoma/efeitos dos fármacos
20.
Int Immunopharmacol ; 80: 106141, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982825

RESUMO

Neuroinflammation significantly contributes to brain injury and neurological deterioration following intracerebral hemorrhage (ICH). MicroRNA-152(miR-152) was reported to be downregulated in ICH patients and to possess anti-inflammatory properties in other diseases. In this study, we aimed to explore the role of miR-152 in ICH, and the underlying mechanisms, using a collagenase-induced rat ICH model and hemin-exposure as a cell model. We first confirmed that miR-152 was consistently downregulated in both models. Overexpression of miR-152 in microglial BV2 cells reduced hemin-induced inflammatory response and reactive oxygen species (ROS) generation, thus protecting co-cultured neuronal HT22 cells. Moreover, overexpression of miR-152 by intracerebroventricular lentivirus injection in ICH rats significantly alleviated neurodecifits, brain edema, and hematoma. These changes were associated with a marked reduction in ICH-induced neuronal death, as detected by co-staining of NeuN and TUNEL, and ICH-induced neuroinflammation, as revealed by inflammatory cytokine levels as well as by the number of Iba1 positive-stained cells in the perihematomal region. Mechanistically, miR-152 significantly inhibited ICH-induced TXNIP expression, and its overexpression blocked the interaction between TXNIP and NOD-like receptor pyrin domain containing 3(NLRP3), thus inhibiting NLRP3-driven inflammasome activation to attenuate neuroinflammation in vivo and in vitro. Moreover, the results of si-TXNIP transfection further confirmed that TXNIP inhibition was involved in the reduction of NLRP3 inflammasome activation by the overexpression of miR-152. Collectively, the present study demonstrates that miR-152 confers protection against ICH-induced neuroinflammation and brain injury by inhibiting TXNIP-mediated NLRP3 inflammasome activation, indicating a potential strategy for ICH treatment.


Assuntos
Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Hemorragia Cerebral Intraventricular/genética , Inflamassomos/imunologia , MicroRNAs/metabolismo , Tiorredoxinas/genética , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Hemorragia Cerebral Intraventricular/induzido quimicamente , Hemorragia Cerebral Intraventricular/imunologia , Hemorragia Cerebral Intraventricular/patologia , Ventrículos Cerebrais/imunologia , Ventrículos Cerebrais/patologia , Técnicas de Cocultura , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Técnicas de Silenciamento de Genes , Hemina/imunologia , Humanos , Inflamassomos/metabolismo , Injeções Intraventriculares , Masculino , Camundongos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Colagenase Microbiana/administração & dosagem , Colagenase Microbiana/toxicidade , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios , Ligação Proteica/genética , Ligação Proteica/imunologia , RNA Interferente Pequeno/metabolismo , Ratos , Tiorredoxinas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...