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1.
ACS Chem Neurosci ; 12(16): 3049-3059, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34340312

RESUMO

Diabetic peripheral neuropathy (DPN) is a complication of diabetes whose pathophysiology is linked to altered mitochondrial bioenergetics (mtBE). KU-596 is a small molecule neurotherapeutic that reverses symptoms of DPN, improves sensory neuron mtBE, and decreases the pro-oxidant protein, thioredoxin-interacting protein (Txnip) in a heat shock protein 70 (Hsp70)-dependent manner. However, the mechanism by which KU-596 improves mtBE and the role of Txnip in drug efficacy remains unknown. Mitophagy is a quality-control mechanism that selectively targets damaged mitochondria for degradation. The goal of this study was to determine if KU-596 therapy improved DPN, mtBE, and mitophagy in an Hsp70- and Txnip-dependent manner. Mito-QC (MQC) mice express a mitochondrially targeted mCherry-GFP fusion protein that enables visualizing mitophagy. Diabetic MQC, MQC × Hsp70 knockout (KO), and MQC × Txnip KO mice developed sensory and nerve conduction dysfunctions consistent with the onset of DPN. KU-596 therapy improved these measures, and this was dependent on Hsp70 but not Txnip. In MQC mice, diabetes decreased mtBE and increased mitophagy and KU-596 treatment reversed these effects. In contrast, KU-596 was unable to improve mtBE and decrease mitophagy in MQC × Hsp70 and MQC × Txnip KO mice. These data suggest that Txnip is not necessary for the development of the sensory symptoms and mitochondrial dysfunction induced by diabetes. KU-596 therapy may improve mitochondrial tolerance to diabetic stress to decrease mitophagic clearance in an Hsp70- and Txnip-dependent manner.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Animais , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Metabolismo Energético , Proteínas de Choque Térmico HSP70/metabolismo , Camundongos , Mitocôndrias/metabolismo , Mitofagia , Células Receptoras Sensoriais/metabolismo , Tiorredoxinas/metabolismo
2.
Ann Clin Lab Sci ; 51(4): 494-502, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452887

RESUMO

OBJECTIVE: Gastric cancer is one of the most common gastrointestinal malignancies. miRNAs (microRNAs) have been reported to play a pivotal role in the tumorigenesis of gastric cancer. However, the role of miR-643 in gastric cancer is not fully understood. METHODS: The expression of miR-643 in gastric cancer cell lines was detected by qRT-PCR (quantitative reverse transcription PCR). Cell viability, apoptosis, migration, and invasion were assessed using the Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and wound scratch and Transwell assays, respectively. The target gene of miR-643 was predicted by bioinformatics analysis and validated using luciferase reporter assay. RESULTS: The expression level of miR-643 in gastric cancer cell lines was lower than in the normal gastric epithelium cell line (GES-1). Overexpression of miR-643 inhibited cell viability and colony formation but promoted cell apoptosis in gastric cancer. Transwell invasion assay and in vitro scratch assay evidenced that miR-643 overexpression inhibited gastric cancer cell migration and invasion. Bioinformatics analysis revealed that miR-643 could directly target TXNDC9 (Thioredoxin domain containing 9), and luciferase reporter assay validated this result. Further analysis showed that miR-643 mimics caused a significant reduction of TXNDC9 in gastric cancer cells. Moreover, TXNDC9 overexpression reversed the effects of miR-643 mimics on gastric cancer cell viability, invasion, and migration. CONCLUSION: miR-643 functions as a potential tumor suppressor in gastric cancer by inhibiting cell viability, colony formation, migration, and invasion via targeting TXNDC9, which provides a novel target for the diagnostic treatment of gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/patologia , Tiorredoxinas/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Transição Epitelial-Mesenquimal , Humanos , Invasividade Neoplásica , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tiorredoxinas/genética , Células Tumorais Cultivadas
3.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199590

RESUMO

In living cells Reactive Oxygen Species (ROS) participate in intra- and inter-cellular signaling and all cells contain specific systems that guard redox homeostasis. These systems contain both enzymes which may produce ROS such as NADPH-dependent and other oxidases or nitric oxide synthases, and ROS-neutralizing enzymes such as catalase, peroxiredoxins, thioredoxins, thioredoxin reductases, glutathione reductases, and many others. Most of the genes coding for these enzymes contain sequences targeted by micro RNAs (miRNAs), which are components of RNA-induced silencing complexes and play important roles in inhibiting translation of their targeted messenger RNAs (mRNAs). In this review we describe miRNAs that directly target and can influence enzymes responsible for scavenging of ROS and their possible role in cellular redox homeostasis. Regulation of antioxidant enzymes aims to adjust cells to survive in unstable oxidative environments; however, sometimes seemingly paradoxical phenomena appear where oxidative stress induces an increase in the levels of miRNAs which target genes which are supposed to neutralize ROS and therefore would be expected to decrease antioxidant levels. Here we show examples of such cellular behaviors and discuss the possible roles of miRNAs in redox regulatory circuits and further cell responses to stress.


Assuntos
Antioxidantes/metabolismo , Homeostase/genética , MicroRNAs/genética , Estresse Oxidativo/genética , Glutationa Redutase/genética , Glutationa Redutase/metabolismo , Humanos , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Oxirredução , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
4.
Biomed Pharmacother ; 139: 111688, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243612

RESUMO

Cardiac hypertrophy is a current, major, global health challenge. Oxidative stress is an important mechanism that contributes to the pathogenesis of cardiac hypertrophy. Schisandra chinensis polysaccharides (SCP), the primary active constituent in Schisandra chinensis, have antioxidative properties. Here, we investigated the role played by SCP in a cardiac hypertrophy model mouse induced by transverse aortic constriction (TAC). We found that SCP treatment improved cardiac function by inhibiting myocardial hypertrophy and oxidative stress. Angiotensin II was used to induce cardiomyocyte hypertrophy and oxidative stress in vitro. We discovered that the antioxidant effects of SCP were mediated through the regulation of the thioredoxin-interacting protein (TXNIP)/Thioredoxin-1 (Trx-1) pathway. Using molecular docking, we found that SCP binds to Arg207, Ser169, Lys166, Lys286 and Ser285 in TXNIP through hydrogen bonds. TXNIP is an endogenous inhibitor of Trx-1, and the binding SCP with TXNIP may restrict or interfere with the binding between TXNIP and Trx-1, resulting in Trx-1 activation. In conclusion, our findings demonstrated that the potential use of SCP as a TXNIP inhibitor to attenuate oxidative stress, suggesting that TXNIP might represent a potential therapeutic target for the treatment of cardiac hypertrophy.


Assuntos
Cardiomegalia/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Schisandra/metabolismo , Tiorredoxinas/metabolismo , Angiotensina II/farmacologia , Animais , Antioxidantes/fisiologia , Cardiomegalia/metabolismo , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular/métodos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos
5.
Lab Invest ; 101(9): 1142-1152, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34103662

RESUMO

Numerous studies have revealed that hyperglycemia is a pivotal driver of diabetic vascular complications. However, the mechanisms of hyperglycemia-induced endothelial dysfunction in diabetes remain incompletely understood. This study aims to expound on the underlying mechanism of the endothelial dysfunction induced by hyperglycemia from the perspective of long non-coding RNAs (lncRNA). In this study, a downregulation of SNHG15 was observed in the ischemic hind limb of diabetic mice and high glucose (HG)-treated HUVECs. Functionally, the overexpression of SNHG15 promoted cell proliferation, migration, and tube formation, and suppressed cell apoptosis in HG-treated HUVECs. Mechanistically, SNHG15 reduced thioredoxin-interacting protein (TXNIP) expression by enhancing ITCH-mediated ubiquitination of TXNIP. TXNIP overexpression abrogated the protective effect of lncRNA SNHG15 overexpression on HG-induced endothelial dysfunction. The following experiment further confirmed that SNHG15 overexpression promoted angiogenesis of the ischemic hind limb in diabetic mice. In conclusion, SNHG15 is a novel protector for hyperglycemia-induced endothelial dysfunction via decreasing TXNIP expression.


Assuntos
Proteínas de Transporte , Hiperglicemia/metabolismo , RNA Longo não Codificante , Tiorredoxinas , Ubiquitinação/genética , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/citologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
6.
Arq Bras Cardiol ; 116(5): 970-978, 2021 05.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34008824

RESUMO

BACKGROUND: Vitamin D (VD) has been shown to play an important role in cardiac function. However, this vitamin exerts a biphasic "dose response" curve in cardiovascular pathophysiology and may cause deleterious effects, even in non-toxic doses. VD exerts its cellular functions by binding to VD receptor. Additionally, it was identified that the thioredoxin-interacting protein (TXNIP) expression is positively regulated by VD. TXNIP modulate different cell signaling pathways that may be important for cardiac remodeling. OBJECTIVE: To evaluate whether VD supplementation lead to cardiac remodeling and if TXNIP and thioredoxin (Trx) proteins are associated with the process. METHODS: A total of 250 Male Wistar rats were allocated into three groups: control (C, n=21), with no VD supplementation; VD3 (n = 22) and VD10 (n=21), supplemented with 3,000 and 10,000 IU of VD/ kg of chow respectively, for two months. The groups were compared by one-way analysis of variance (ANOVA) and Holm-Sidak post hoc analysis, (variables with normal distribution), or by Kruskal-Wallis test and Dunn's test post hoc analysis. The significance level for all tests was 5%. RESULTS: TXNIP protein expression was higher and Trx activity was lower in VD10. The animals supplemented with VD showed increased lipid hydroperoxide and decreased superoxide dismutase and glutathione peroxidase. The protein Bcl-2 was lower in VD10. There was a decrease in fatty acid ß-oxidation, tricarboxylic acid cycle and electron transport chain with shift to increase in glycolytic pathway. CONCLUSION: VD supplementation led to cardiac remodeling and this process may be modulated by TXNIP and Trx proteins and consequently oxidative stress.


Assuntos
Tiorredoxinas , Remodelação Ventricular , Animais , Proteínas de Ciclo Celular , Suplementos Nutricionais , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Tiorredoxinas/metabolismo , Vitamina D
8.
Aging (Albany NY) ; 13(11): 15100-15113, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34032607

RESUMO

Osteoarthritis (OA) is a chronic disease characterized by progressive loss of cartilage and failure of the diarthrodial joint. Circular RNAs (circRNAs) are known to participate in the pathogenesis of multiple diseases, including OA. We investigated the functions of hsa_circ_0032131, a circRNA upregulated in OA, using CHON-001 cells and an in vivo OA rat model. CHON-001 cells were treated with interleukin (IL)-1ß to mimic OA in vitro. IL-1ß-induced inhibition of CHON-001 growth was reversed by silencing hsa_circ_0032131. In addition, hsa_circ_0032131 knockdown reversed IL-1ß-induced activation of Trx1, Cyclin D and PRDX3, whereas overexpression of PRDX3, a direct target of miR-502-5p, reversed this effect. Hsa_circ_0032131 served as a competing endogenous RNA for miR-502-5p. Moreover, knockdown of hsa_circ_0032131 attenuated OA symptoms in vivo by inactivating the STAT3 signaling pathway. Thus, silencing of hsa_circ_0032131 inhibited the progression of OA by inactivating the miR-502-5p/PRDX3/Trx1/STAT3 axis, which highlights its potential as a therapeutic target for OA.


Assuntos
Técnicas de Silenciamento de Genes , MicroRNAs/metabolismo , Osteoartrite/genética , Osteoartrite/patologia , Peroxirredoxina III/metabolismo , RNA Circular/metabolismo , Animais , Apoptose/genética , Sequência de Bases , Linhagem Celular , Proliferação de Células/genética , Progressão da Doença , Interleucina-1beta/metabolismo , MicroRNAs/genética , Modelos Biológicos , Peroxirredoxina III/genética , RNA Circular/genética , RNA Interferente Pequeno/metabolismo , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Tiorredoxinas/metabolismo
9.
Phytomedicine ; 87: 153586, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34044253

RESUMO

BACKGROUND: Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases. PURPOSE: The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis. STUDY DESIGN: Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin. METHODS: Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury. RESULTS: The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1ß (IL-1ß) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro. CONCLUSIONS: These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inflamassomos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Luteolina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Tiorredoxinas/antagonistas & inibidores , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatite/tratamento farmacológico , Hepatite/etiologia , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Inflamassomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
10.
Chem Biol Interact ; 344: 109529, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34029542

RESUMO

Ganoderic acid A (GAA), one of the major triterpenoid components extracted from Ganoderma mushroom has been shown to possess numerous important pharmacological activities. The present study was aimed to investigate the mechanisms of GAA on carbon tetrachloride (CCl4)-induced kidney inflammation, fibrosis and oxidative stress in mice. The male mice were treated with 25 and 50 mg/mg GAA after stimulated with CCl4. Our results showed that GAA improved renal damage by decreasing the serum levels of creatinine, urea, uric acid and alleviating kidney fibrosis. GAA ameliorated CCl4-induced indices of inflammation. GAA suppressed oxidative stress by regulating the glutathione antioxidant system and the thioredoxin antioxidant system. GAA increased the activations of thioredoxin reductase (TrxR), Trx, GSH, SOD, GPx. Furthermore, GAA supplementation inhibited the JAK and STAT3 pathway. GAA inhibited the activations of RhoA, ROCK, NF-κB, TGF-ß and Smad3. Thus, this study demonstrated that GAA possesses immune-protective properties through regulating the Trx/TrxR, JAK2/STAT3 and RhoA/ROCK pathways.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Fibrose/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Nefropatias/tratamento farmacológico , Lanosterol/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono , Fibrose/induzido quimicamente , Fibrose/patologia , Janus Quinase 2/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/patologia , Lanosterol/uso terapêutico , Masculino , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Proteína Smad3/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Quinases Associadas a rho/metabolismo
11.
Lab Invest ; 101(7): 837-850, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33875790

RESUMO

Accumulating evidences have suggested that extracellular vesicles (EVs) are crucial players in the pathogenesis of ischemic brain injury. This study was designed to explore the specific functions of M2 phenotype microglia-derived EVs in ischemic brain injury progression. The expression of microRNA-135a-5p (miR-135a-5p) in M2 microglia-derived EVs was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), followed by the identification of expression relationship among miR-135a-5p, thioredoxin-interacting protein (TXNIP), and nod-like receptor protein 3 (NLRP3) by dual luciferase reporter gene assay. After construction of an oxygen-glucose deprivation/reperfusion (OGD/R) cell model, the effects of miR-135a-5p on the biological characteristics of HT-22 cells were assessed by cell counting kit 8 (CCK-8) assay and flow cytometry. Finally, a mouse model of transient middle cerebral artery occlusion (tMCAO) was established and cerebral infarction volume was determined by triphenyltetrazolium chloride (TTC) staining and the expression of IL-18 and IL-1ß in the brain tissue was determined by enzyme-linked immunosorbent assay (ELISA). We found that M2 microglia-derived EVs had high expression of miR-135a-5p, and that miR-135a-5p in M2 microglia-derived EVs negatively regulated the expression of NLRP3 via TXNIP. Overexpression of miR-135a-5p promoted the proliferation but inhibited the apoptosis of neuronal cells, and inhibited the expression of autophagy-related proteins. M2 microglia-derived EVs delivered miR-135a-5p into neuronal cells to inhibit TXNIP expression, which further inhibited the activation of NLRP3 inflammasome, thereby reducing neuronal autophagy and ischemic brain injury. Hence, M2 microglia-derived EVs are novel therapeutic targets for ischemic brain injury treatment.


Assuntos
Isquemia Encefálica/metabolismo , Proteínas de Transporte/metabolismo , Vesículas Extracelulares , MicroRNAs/metabolismo , Microglia/química , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tiorredoxinas/metabolismo , Animais , Proteínas de Transporte/genética , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Tiorredoxinas/genética
12.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803178

RESUMO

Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.


Assuntos
Proteínas de Transporte/metabolismo , Síndrome Metabólica , Neoplasias , Doenças do Sistema Nervoso , Proteínas Supressoras de Tumor/metabolismo , Animais , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/terapia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Síndrome Metabólica/terapia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/terapia , Proteínas Nucleares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/metabolismo , Tiorredoxinas/metabolismo
13.
Nat Commun ; 12(1): 2048, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824345

RESUMO

Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC.


Assuntos
Ferroptose , Tumores Neuroendócrinos/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Animais , Antioxidantes/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos Nus , Modelos Biológicos , Necroptose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeos/metabolismo , Prognóstico , Tiorredoxinas/metabolismo
14.
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
15.
Oxid Med Cell Longev ; 2021: 6672693, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868574

RESUMO

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting both skin and mucous membranes. Its pathogenesis is related to IgG autoantibodies primarily targeting the cellular adhesion protein desmoglein (Dsg) 3, one of the major desmosome components. Impaired redox regulation is considered a major player in the pathogenesis of autoimmune diseases such as pemphigus by enhancing inflammation and breakdown of immunological tolerance by structural protein modifications. Despite many recent advances, local and systemic redox profiles that characterize the immune response in pemphigus are virtually unknown but potentially crucial in further advancing our understanding of redox-dependent modifications that eventually lead to clinical manifestation. Here, we have analyzed the individual expression pattern of four major redox enzymes that are members of the thioredoxin (Trx) fold superfamily (peroxiredoxins (Prxs) 1 and 4, glutaredoxin (Grx) 2, and Trx1) in serum and PBMCs as well as their distribution in the skin of pemphigus patients compared to healthy controls. We show that in groups of five pemphigus patients, Prx1 is upregulated in both serum and PBMCs, while its epithelial distribution remains within the spinous epithelial layer. Expression of Grx2 and Prx4 is both reduced in serum and PBMCs, while their distinct and similar expression in the skin changes from an even distribution throughout the basal layer (healthy) to ubiquitous nuclear localization in pemphigus patients. In PV patients, Trx1 is secreted into serum, and cellular distribution appears membrane-bound and cytosolic compared to healthy controls. We furthermore showed that a 3D ex vivo human skin model can indeed be used to reproduce similar changes in the protein levels and distribution of redox enzymes by application of cold atmospheric plasma. Deciphering the relationship between redox enzyme expression and autoimmunity in the context of pemphigus could be critical in elucidating key pathogenic mechanisms and developing novel interventions for clinical management.


Assuntos
Pênfigo/enzimologia , Tiorredoxinas/metabolismo , Humanos , Oxirredução
16.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916181

RESUMO

We have synthesized new magnetic resonance imaging (MRI) T1 contrast agents (CA1 and CA2) that permit the activatable recognition of the cellular vicinal thiol motifs of the protein thioredoxin. The contrast agents showed MR relaxivities typical of gadolinium complexes with a single water molecule coordinated to a Gd3+ center (i.e., ~4.54 mM-1s-1) for both CA1 and CA2 at 60 MHz. The contrast agent CA1 showed a ~140% relaxivity enhancement in the presence of thioredoxin, a finding attributed to a reduction in the flexibility of the molecule after binding to thioredoxin. Support for this rationale, as opposed to one based on preferential binding, came from 1H-15N-HSQC NMR spectral studies; these revealed that the binding affinities toward thioredoxin were almost the same for both CA1 and CA2. In the case of CA1, T1-weighted phantom images of cancer cells (MCF-7, A549) could be generated based on the expression of thioredoxin. We further confirmed thioredoxin expression-dependent changes in the T1-weighted contrast via knockdown of the expression of the thioredoxin using siRNA-transfected MCF-7 cells. The nontoxic nature of CA1, coupled with its relaxivity features, leads us to suggest that it constitutes a first-in-class MRI T1 contrast agent that allows for the facile and noninvasive monitoring of vicinal thiol protein motif expression in live cells.


Assuntos
Rastreamento de Células/métodos , Meios de Contraste , Espectroscopia de Ressonância Magnética , Compostos de Sulfidrila , Tiorredoxinas , Linhagem Celular Tumoral , Meios de Contraste/síntese química , Meios de Contraste/química , Humanos , Imagens de Fantasmas , Compostos de Sulfidrila/metabolismo , Tiorredoxinas/metabolismo
17.
Arch Biochem Biophys ; 706: 108857, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-33781769

RESUMO

Accumulating evidence has demonstrated that cellular antioxidant systems play essential roles in retarding oxidative stress-related diseases, such as Parkinson's disease. Because nuclear factor erythroid 2-related factor 2 (Nrf2) is a chief regulator of cellular antioxidant systems, small molecules with Nrf2-activating ability may be promising neuroprotective agents. Avenanthramide-2c (Aven-2c), avenanthramide-2f (Aven-2f) and avenanthramide-2p (Aven-2p) are the most abundant avenanthramides in oats, and they have been documented to possess multiple pharmacological benefits. In this work, we synthesized these three compounds and evaluated their cytoprotective effect against oxidative stress-induced PC12 cell injuries. Aven-2c displayed the best protective potency among them. Aven-2c conferred protection on PC12 cells by scavenging free radicals and activating the Nrf2-ARE signaling pathway. Pretreatment of PC12 cells with Aven-2c efficiently enhanced Nrf2 nuclear accumulation and evoked the expression of a set of cytoprotective molecules. The mechanistic study also supports that Nrf2 activation is the molecular basis for the cellular action of Aven-2c. Collectively, this study demonstrates that Aven-2c is a potent Nrf2 agonist, shedding light on the potential usage of Aven-2c in the treatment of neuroprotective diseases.


Assuntos
Elementos de Resposta Antioxidante , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/genética , ortoaminobenzoatos/farmacologia , Animais , Avena/química , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/antagonistas & inibidores , Oxidopamina/farmacologia , Células PC12 , Extratos Vegetais/química , Ratos , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
18.
Phytomedicine ; 88: 153454, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33663922

RESUMO

BACKGROUND: The damage of pancreatic ß cells is a major pathogenesis of the development and progression of type 2 diabetes and there is still no effective therapy to protect pancreatic ß cells clinically. In our previous study, we found that Quzhou Fructus Aurantii (QFA), which is rich in flavanones, had the protective effect of pancreatic ß cells in diabetic mice. However, the underlying mechanism is still unclear. PURPOSE: In the current study, we administered naringenin and hesperetin, two major active components of QFA, to protect pancreatic ß cells and to investigate the underlying molecular mechanism focusing on the epigenetic modifications. METHODS: We used diabetic db/db mouse and INS-1 pancreatic ß cell line as in vivo and in vitro models to investigate the protective effect of naringenin and hesperetin on pancreatic ß cells under high glucose environment and the related mechanism. The phenotypic changes were evaluatedby immunostaining and the measurement of biochemical indexes. The molecular mechanism was explored by biological techniques such as western blotting, qPCR, ChIP-seq and ChIP-qPCR, flow cytometry and lentivirus infection. RESULTS: We found that naringenin and hesperetin had an inhibitory effect on histone acetylation. We showed that naringenin and hesperetin protected pancreatic ß cells in vivo and in vitro, and this effect was independent of their direct antioxidant capacity. The further study found that the inhibition of thioredoxin-interacting protein (Txnip) expression regulated by histone acetylation was critical for the protective role of naringenin and hesperetin. Mechanistically, the histone acetylation inhibition by naringenin and hesperetin was achieved through regulating AMPK-mediated p300 inactivation. CONCLUSION: These findings highlight flavanones and the phytomedicine rich in flavanones as important dietary supplements in protecting pancreatic ß cells in advanced diabetes. In addition, targeting histone acetylation by phytomedicine is a potential strategy to delay the development and progression of diabetes.


Assuntos
Proteínas de Transporte/metabolismo , Flavanonas/farmacologia , Hesperidina/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Células Secretoras de Insulina/efeitos dos fármacos , Tiorredoxinas/metabolismo , Acetilação/efeitos dos fármacos , Animais , Proteínas de Transporte/genética , Citrus/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Tiorredoxinas/genética
19.
Expert Opin Ther Pat ; 31(8): 745-758, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33666133

RESUMO

Introduction: Thioredoxin reductase (TrxR) is a selenocysteine-containing enzyme which is responsible - as a part of the thioredoxin system - for maintaining redox homeostasis in cells. It is upregulated in cancerous state as a defense against oxidative stress. TrxR has been mostly considered an anticancer drug target although it has applications in other therapeutic areas such as neurodegeneration, inflammation, microbial infections, and neonatal hyperoxic lung injury.Areas covered: The present review covers the patent literature that appeared in the period 2017-2020, i.e. since the publication of the previous expert opinion patent review on TrxR inhibitors. The recent additions to the following traditional classes of inhibitors are discussed: metal complexes, Michael acceptors as well as arsenic and selenium compounds. At the same time, a novel group of nitro (hetero)aromatic compounds have emerged which likely acts via covalent inhibition mechanism. Several miscellaneous chemotypes are grouped under Miscellaneous subsection.Expert opinion: While specificity over glutathione reductase is achieved easily, TrxR is still moving toward the later stages of development at a very slow rate. Michael acceptors, particularly based on TRXR substrate-mimicking scaffolds, are gaining impetus and so are dual and hybrid compounds. The development prospects of the emerging nitro (hetero)aromatic chemotypes remain uncertain.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Desenvolvimento de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Patentes como Assunto , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/metabolismo
20.
Mol Biol Rep ; 48(3): 2929-2934, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33660093

RESUMO

Thioredoxin-like protein-1 (TXNL1; also known as thioredoxin-related 32 kDa protein, TRP32) is a thioredoxin involved in the regulation of oxidative stress, which protects cells from damage through redox balance. Studies have shown that TXNL1 has a variety of functions, including cell signal transduction, cell cycle regulation, protein synthesis, modification and degradation, vesicle transport, transcriptional regulation, cell apoptosis, virus replication and oxidative stress regulation, etc., and plays an important role in the occurrence and development of human diseases. Therefore, TXNL1 has a strong correlation with the treatment of cancer and oxidative stress diseases. In this paper, the basic structure, function and potential application value of TXNL1 in diseases are reviewed, so as to open up new targets for the treatment of cancer and oxidative stress-related diseases.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo , Tiorredoxinas/metabolismo , Animais , Epilepsia/patologia , Humanos , Neoplasias/terapia , Traumatismos da Medula Espinal/patologia , Tiorredoxinas/química
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