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1.
J Cancer Res Clin Oncol ; 145(9): 2261-2271, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31367836

RESUMO

PURPOSE: To investigate the role of sonic hedgehog (Shh) signaling and epithelial-mesenchymal transition (EMT) in bladder cancer progression and invasion. METHODS: We cultured three bladder cancer cell lines, muscle-invasive T24 and 5637, and non-muscle-invasive KK47, in the presence of a recombinant-Shh (r-Shh) protein or cyclopamine, a Shh signaling inhibitor, to investigate proliferation and expression of EMT markers. Wound-healing assays and transwell assay were performed to evaluate cell invasion and migration. Mice were then inoculated with bladder cancer cells and treated with cyclopamine. Mouse tumor samples were stained for Shh signaling and EMT markers. RESULTS: R-Shh protein enhanced cell proliferation, whereas cyclopamine significantly suppressed cell proliferation, especially in invasive cancer (5637 and T24) (p < 0.05). R-Shh protein promoted EMT, suppressed E-cadherin and enhanced N-cadherin and vimentin and Gli1, an Shh downstream molecule, while cyclopamine blocked EMT, especially in 5637 and T24. Cyclopamine also inhibited cell invasion and migration in vitro. In the animal study, intraperitoneal injection of cyclopamine significantly suppressed tumor growth in 5637 and T24 in mice (p = 0.01 and p = 0.004, respectively) and slightly suppressing KK47 tumor growth (p = 0.298). Significant cyclopamine-induced suppression of Gli1 in 5637 and T24 mouse tumors (both p = 0.03) was seen, suggesting that muscle-invasive bladder cancer may be more dependent on Shh signaling than non-muscle-invasive bladder cancer. CONCLUSIONS: Shh signaling and EMT were especially enhanced in muscle-invasive bladder cancer progression and invasion, and suppressed by the inhibition of Shh signaling.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Proteínas Hedgehog/fisiologia , Neoplasias Musculares/secundário , Neoplasias da Bexiga Urinária/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Musculares/metabolismo , Invasividade Neoplásica , Transdução de Sinais/fisiologia , Neoplasias da Bexiga Urinária/metabolismo
2.
J Cancer Res Clin Oncol ; 145(9): 2169-2197, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401674

RESUMO

BACKGROUND: Recent studies have shown that the short-chain fatty acids (SCFAs) produced by the gut microbiota play a positive role in the development of colorectal cancer (CRC). AIMS: This study aims to elucidate the "food-microorganism-SCFAs" axis and to provide guidance for prevention and intervention in CRC. METHODS: The PubMed, Embase and Cochrane databases were searched from their inceptions to August 2018, and 75 articles and 25 conference abstracts were included and analysed after identification and screening. RESULTS: The concentrations of SCFAs in CRC patients and individuals with a high risk of CRC were higher than those in healthy individuals. The protective mechanism of SCFAs against CRC has been described in three aspects: epigenetics, immunology and molecular signalling pathways. Many food and plant extracts that were fermented by microorganisms produced SCFAs that play positive roles with preventive and therapeutic effects on CRC. The "food-microorganism-SCFAs" axis was constructed by summarizing the pertinent literature. CONCLUSIONS: This study provides insight into the basic research and practical application of SCFAs by assessing the protective effect of SCFAs on CRC.


Assuntos
Neoplasias Colorretais/prevenção & controle , Ácidos Graxos Voláteis/fisiologia , Comportamento Alimentar/fisiologia , Microbioma Gastrointestinal/fisiologia , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/microbiologia , Ácidos Graxos Voláteis/uso terapêutico , Alimentos , Humanos , Padrões de Prática Médica/tendências , Probióticos/uso terapêutico , Fatores de Risco , Transdução de Sinais/fisiologia
3.
Biol Res ; 52(1): 41, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387634

RESUMO

BACKGROUND: Di-N-butyl-phthalate (DBP) is an endocrine disrupting substance. We investigated the adverse effect of DBP on testis of male rat and reveal its potential mechanism of MAPK signaling pathway involved this effect in vivo and in vitro. Gonadal hormone, sperm quality, morphological change and the activation status of JNK, ERK1/2 and p38 was determined in vivo. Primary Sertoli cell was established and cultivated with JNK, ERK1/2 inhibitors, then determine the cell viability, apoptosis and the expression of p-JNK, p-ERK1/2. Data in this study were presented as mean ± SD and determined by one-way analysis of variance (ANOVA) followed by Bonferroni's test. Difference was considered statistically significant at P < 0.05. RESULTS: In vivo experiment, DBP impaired the normal structure of testicular tissue, reduced testosterone levels in blood serum, decreased sperm count and increased sperm abnormality, p-ERK1/2 and p-JNK in rat testicular tissue increased in a dose-dependent manner. In vitro studies, DBP could decrease the viability of Sertoli cells and increase p-ERK1/2 and p-JNK. Cell apoptosis in SP600125 + DBP group was significantly lower than in DBP group (P < 0.05). p-JNK was not significantly decreased in SP600125 + DBP group, while p-ERK1/2 was significantly decreased in U0126 + DBP group. CONCLUSIONS: These results suggest that DBP can lead to testicular damage and the activation of ERK1/2 and JNK pathways, the JNK signaling pathway may be primarily associated with its effect.


Assuntos
Dibutilftalato/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/fisiologia , Testículo/lesões , Testículo/metabolismo , Animais , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos
5.
Hum Genet ; 138(8-9): 937-955, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359131

RESUMO

Ocular developmental anomalies are among the most common causes of severe visual impairment in newborns (combined incidence 1-2:10,000). They comprise a wide range of inborn errors of eye development with a spectrum of overlapping phenotypes and they are frequently associated with extraocular malformations, neuropsychomotor developmental delay and/or intellectual disabilities. Many studies from model organisms have demonstrated the role of retinoic acid (RA) during organogenesis, including eye development, and have revealed the wide spectrum of malformations that can arise from defective RA signaling. However, genes coding for homeobox proteins and morphogenetic factors were implicated in anomalies of ocular development long before genes coding for RA-signaling proteins. The purpose of this review is to discuss current knowledge about the highly complex genetic architecture of RA-signaling-associated ocular developmental anomalies in humans. Despite less than a dozen genes identified thus far, all steps of RA-signaling, from vitamin A transport to target cells to transcriptional activation of RA targets, have been implicated. Furthermore, the majority of these genetic disorders are associated with both dominant and recessive inheritance patterns and a wide spectrum of ocular malformations, which can dominate the phenotype or represent one of many features. Although some genotype-phenotype correlations are described, in many cases, the variability of clinical expression cannot be accounted for by the genotype alone. This observation and the large number of unsolved cases suggest that the relationship between RA signaling and eye development deserves further investigation.


Assuntos
Olho/metabolismo , Transdução de Sinais/fisiologia , Tretinoína/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Genótipo , Proteínas de Homeodomínio/metabolismo , Humanos , Fenótipo
6.
Braz J Med Biol Res ; 52(7): e8732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314855

RESUMO

Inflammation plays an important role in the development of cardiovascular diseases (CVDs), suggesting that the immune system is a target of therapeutic interventions used for treating CVDs. This study evaluated mechanisms underlying inflammatory response and cardiomyocyte hypertrophy associated with bacterial lipopolysaccharide (LPS)- or heat shock protein 60 (HSP60)-induced Toll-like receptor (TLR) stimulation and the effect of a small interfering RNA (siRNA) against Ca2+/calmodulin-dependent kinase II delta B (CaMKIIδB) on these outcomes. Our results showed that treatment with HSP60 or LPS (TLR agonists) induced cardiomyocyte hypertrophy and complement system C3 and factor B gene expression. In vitro silencing of CaMKIIδB prevented complement gene transcription and cardiomyocyte hypertrophy associated with TLR 2/4 activation but did not prevent the increase in interleukin-6 and tumor necrosis factor-alfa gene expression in primary cultured cardiomyocytes. Moreover, CaMKIIδB silencing attenuated nuclear factor-kappa B expression. These findings supported the hypothesis that CaMKIIδB acts as a link between inflammation and cardiac hypertrophy. Furthermore, the present study is the first to show that extracellular HSP60 activated complement gene expression through CaMKIIδB. Our results indicated that a stress stimulus induced by LPS or HSP60 treatment promoted cardiomyocyte hypertrophy and initiated an inflammatory response through the complement system. However, CaMKIIδB silencing prevented the cardiomyocyte hypertrophy independent of inflammatory response induced by LPS or HSP60 treatment.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Miócitos Cardíacos/patologia , Receptores Toll-Like/metabolismo , Animais , Chaperonina 60/farmacologia , Expressão Gênica , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , RNA Interferente Pequeno , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia
7.
Nat Commun ; 10(1): 2572, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189917

RESUMO

Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.


Assuntos
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Retroalimentação Fisiológica/fisiologia , Chaperonas Moleculares/metabolismo , Ataxias Espinocerebelares/patologia , Animais , Retroalimentação Fisiológica/efeitos dos fármacos , Fibroblastos , Células HEK293 , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Hipocampo/patologia , Holoenzimas/metabolismo , Humanos , Leupeptinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Nucleosídeos de Purina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ataxias Espinocerebelares/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia
8.
Nat Commun ; 10(1): 2738, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227696

RESUMO

The breeding of cereals with altered gibberellin (GA) signaling propelled the 'Green Revolution' by generating semidwarf plants with increased tiller number. The mechanism by which GAs promote shoot height has been studied extensively, but it is not known what causes the inverse relationship between plant height and tiller number. Here we show that rice tiller number regulator MONOCULM 1 (MOC1) is protected from degradation by binding to the DELLA protein SLENDER RICE 1 (SLR1). GAs trigger the degradation of SLR1, leading to stem elongation and also to the degradation of MOC1, and hence a decrease in tiller number. This discovery provides a molecular explanation for the coordinated control of plant height and tiller number in rice by GAs, SLR1 and MOC1.


Assuntos
Regulação da Expressão Gênica de Plantas/fisiologia , Giberelinas/metabolismo , Oryza/fisiologia , Proteínas de Plantas/metabolismo , Brotos de Planta/fisiologia , Grão Comestível , Giberelinas/genética , Mutação , Melhoramento Vegetal/métodos , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Proteólise , Transdução de Sinais/fisiologia
9.
Nat Commun ; 10(1): 2757, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227697

RESUMO

Inappropriate expansion of the adipose cells in the subcutaneous adipose tissue (SAT) is a characteristic of hypertrophic obesity and of individuals with genetic predisposition for T2D (first-degree relatives; FDR). It is associated with insulin resistance, a dysfunctional, adipose tissue and reduced adipogenesis. We examined the regulation of adipogenesis in human SAT precursor cells and found ZNF521 to be a critical regulator of early adipogenic commitment and precursor cells leaving the cell cycle. However, neither altered upstream signalling nor lack of SAT progenitor cells could explain the reduced adipogenesis in hypertrophic obesity. Instead, we show that progenitor cells undergoing poor differentiation are characterized by senescence, inability to suppress p53/P16INK4 and secretion of factors reducing adipogenesis in non-senescent cells. We found aging, FDR and established T2D to be associated with increased progenitor cell senescence, reduced adipogenesis and hypertrophic expansion of the SAT adipose cells.


Assuntos
Adipogenia , Senescência Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Obesidade/patologia , Gordura Subcutânea/patologia , Adipócitos , Adulto , Idoso , Envelhecimento/fisiologia , Biópsia por Agulha , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Humanos , Hipertrofia/patologia , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Cultura Primária de Células , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Gordura Subcutânea/citologia , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
10.
Nat Neurosci ; 22(7): 1075-1088, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209379

RESUMO

Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remain a key open question. Here we show that whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. This synapse elimination is dependent on signaling by CX3CR1, the receptor for microglial fractalkine (also known as CXCL1), but not complement receptor 3. Furthermore, mice deficient in CX3CL1 have profound defects in synapse elimination. Single-cell RNA sequencing revealed that Cx3cl1 is derived from cortical neurons, and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and in microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies Cx3cr1-/- and Cx3cl1-/- synapse elimination defects. Together, these results identify neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal that context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.


Assuntos
Proteína ADAM10/fisiologia , Secretases da Proteína Precursora do Amiloide/fisiologia , Receptor 1 de Quimiocina CX3C/fisiologia , Quimiocina CX3CL1/fisiologia , Proteínas de Membrana/fisiologia , Microglia/fisiologia , Córtex Sensório-Motor/fisiopatologia , Tato/fisiologia , Vibrissas/lesões , Proteína ADAM10/antagonistas & inibidores , Proteína ADAM10/genética , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Animais , Receptor 1 de Quimiocina CX3C/deficiência , Receptor 1 de Quimiocina CX3C/genética , Contagem de Células , Feminino , Regulação da Expressão Gênica , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas Analíticas Microfluídicas , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Córtex Sensório-Motor/metabolismo , Córtex Sensório-Motor/patologia , Transdução de Sinais/fisiologia , Análise de Célula Única , Transcriptoma , Vibrissas/fisiologia
11.
Spine (Phila Pa 1976) ; 44(12): E707-E714, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150368

RESUMO

STUDY DESIGN: The effect of triptolide on spinal cord injury (SCI) and inflammatory response was observed by establishing SCI rat model. And in vitro experiments were conducted to determine the underlying mechanism of triptolide-mediated in murine microglial cell line BV2. OBJECTIVE: To determine the underlying mechanism of triptolide in suppressing the microglia activation to improve SCI. SUMMARY OF BACKGROUND DATA: Triptolide, as a major active ingredient of Chinese herb Tripterygium wilfordii, can promote spinal cord repair through inhibiting microglia activation, but the underlying mechanism is not clear. METHODS: Locomotion recovery was accessed by Basso, Beattie, and Bresnahan score, the number of footfalls, stride length, and angle of rotation analysis. Expressions of microRNA 96 (miR-96), microglia activation marker Iba-1, and IκB kinase (IKKß)/nuclear factor (NF)-κB-related proteins were detected by qRT-PCR or western blot. Inflammatory cytokines tumor necrosis factor-α and interleukin -1ß were measured by enzyme-linked immuno sorbent assay. The regulation of miR-96 on IKKß was confirmed by dual luciferase reporter assay. RESULTS: Triptolide promoted locomotion recovery of SCI rats, upregulated the expression of miR-96, decreased microglia activation marker Iba-1 and IKKß/NF-κB-related proteins, and inhibited inflammatory cytokines tumor necrosis factor-α and interleukin-1ß levels in spinal cord tissues and lipopolysaccharide -induced microglia. Triptolide suppressed the microglia activation and inflammatory cytokines secretion in BV2 cells through up-regulating miR-96. We confirmed the interaction between miR-96 and IKKß, and IKKß expression was negatively regulated by miR-96. Finally, we determined that triptolide suppressed the microglia activation and inflammatory cytokines secretion through miR-96/IKKß pathway. CONCLUSION: Triptolide suppressed microglia activation after SCI through miR-96/IKKß/NF-κB pathway. LEVEL OF EVIDENCE: N/A.


Assuntos
Diterpenos/uso terapêutico , Quinase I-kappa B/biossíntese , MicroRNAs/biossíntese , Microglia/metabolismo , NF-kappa B/biossíntese , Fenantrenos/uso terapêutico , Traumatismos da Medula Espinal/metabolismo , Animais , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Quinase I-kappa B/antagonistas & inibidores , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Fenantrenos/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico
12.
Sheng Wu Gong Cheng Xue Bao ; 35(5): 766-774, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31222995

RESUMO

Iron is one of the essential mineral micronutrients for plants. Low concentrations of effective iron in soil can easily increase risk of plant iron deficiency. Several members of bHLH transcription factors family participate in the response to iron deficiency and play an important role in iron regulation of plants. In order to better understand the mechanism of iron deficiency response, an overview of the structure, classification, function and regulatory mechanism of bHLH transcription factors was given in this review as well as signaling pathway triggered by iron deficiency. It will provide theoretical basis and design strategies for cultivating iron deficiency tolerant or iron-rich crops using bHLH transcription factors.


Assuntos
Arabidopsis , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Regulação da Expressão Gênica de Plantas , Ferro , Arabidopsis/genética , Arabidopsis/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ferro/deficiência , Transdução de Sinais/fisiologia
13.
Biochemistry (Mosc) ; 84(Suppl 1): S206-S224, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31213203

RESUMO

Reactive carbonyl compounds (RCC) are a group of compounds with clearly pronounced electrophilic properties that facilitate their spontaneous reactions with numerous nucleophilic reaction sites in proteins, lipids, and nucleic acids. The biological functions of RCC are determined by their concentration and governed by the hormesis (biphasic reaction) principle. At low concentrations, RCC act as signaling molecules activating defense systems against xenobiotics and oxidizers, and at high concentrations, they exhibit the cytotoxic effect. RCC participate in the formation of cell adaptive response via intracellular signaling pathways involving regulation of gene expression and cytoplasmic mechanisms related to the structure-functional rearrangements of proteins. Special attention in this review is given to the functioning of electrophiles as mediators of cell general adaption syndrome manifested as the biphasic response. The hypothesis is proposed that electrophilic signaling can be a proto-signaling system.


Assuntos
Aldeídos/metabolismo , Radicais Livres/metabolismo , Cetonas/metabolismo , Mutagênese/fisiologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , Animais , Humanos , Oxirredução , Processamento de Proteína Pós-Traducional
14.
Cell Prolif ; 52(4): e12637, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168899

RESUMO

OBJECTIVES: Chondrocyte proliferation and differentiation are crucial for endochondral ossification, but their regulatory mechanism remains unclear. The present study aimed to determine the physiological function of TGFß1 signalling in the proliferation and differentiation of antler chondrocytes and explore its relationship with Notch, Shh signalling and Foxa. MATERIALS AND METHODS: Immunofluorescence, Western blot, MTS assay, flow cytometry, RNA interference and real-time PCR were used to analyse the function and regulatory mechanisms of TGFß1 signalling in antler chondrocyte proliferation and differentiation. RESULTS: TGFß1, TGFBR1 and TGFBR2 were highly expressed in antler cartilage. TGFß1 promoted chondrocyte proliferation, increased the proportion of S-phase cells and induced the expression of hypertrophic chondrocyte markers Col X, Runx2 and Alpl. However, this induction was weakened by TGFß receptor inhibitor SB431542 and Smad3 inhibitor SIS3. Simultaneously, TGFß1 activated Notch and Shh signalling whose blockage attenuated the above effects of rTGFß1, whereas addition of rShh rescued the defects in chondrocyte proliferation and differentiation elicited by SB431542 and SIS3. Further analysis revealed that inhibition of Notch signalling impeded TGFß1 activation of the Shh pathway. Knockdown of Foxa1, Foxa2 and Foxa3 abrogated the effects of TGFß1 on chondrocyte differentiation. Notch and Shh signalling mediated the regulation of Foxa transcription factors by TGFß1. CONCLUSIONS: TGFß1 signalling could induce the proliferation and differentiation of antler chondrocytes through Notch-Shh-Foxa pathway.


Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Chifres de Veado , Benzamidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Dioxóis/farmacologia , Proteínas Hedgehog/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Isoquinolinas/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Notch/metabolismo , Fase S/efeitos dos fármacos , Fase S/fisiologia , Transdução de Sinais/efeitos dos fármacos
15.
Cell Prolif ; 52(4): e12649, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31199047

RESUMO

Mycobacterium tuberculosis (Mtb) leads to approximately 1.5 million human deaths every year. In pulmonary tuberculosis (TB), Mtb must drive host tissue destruction to cause pulmonary cavitation and dissemination in the tissues. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading all components of pulmonary extracellular matrix (ECM). It is well established that Mtb infection leads to upregulation of MMPs and also causes disturbance in the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thus altering the extracellular matrix deposition. In TB, secretion of MMPs is mainly regulated by NF-κB, p38 and MAPK signalling pathways. In addition, recent studies have demonstrated the immunomodulatory roles of MMPs in Mtb pathogenesis. Researchers have proposed a new regimen of improved TB treatment by inhibition of MMP activity to hinder matrix destruction and to minimize the TB-associated morbidity and mortality. The proposed regimen involves adjunctive use of MMP inhibitors such as doxycycline, marimastat and other related drugs along with front-line anti-TB drugs to reduce granuloma formation and bacterial load. These findings implicate the possible addition of economical and well-tolerated MMP inhibitors to current multidrug regimens as an attractive mean to increase the drug potency. Here, we will summarize the recent advancements regarding expression of MMPs in TB, their immunomodulatory role, as well as their potential as therapeutic targets to control the deadly disease.


Assuntos
Metaloproteinases da Matriz/metabolismo , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia , Animais , Matriz Extracelular/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Transdução de Sinais/fisiologia
16.
Cancer Sci ; 110(8): 2471-2484, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187548

RESUMO

Endoplasmic reticulum stress (ERS) plays a key role in the pathogenesis and development of tumors and protects tumor cells from radiation damage and drug-induced stress. We previously demonstrated that EGFR confers radioresistance in human papillomavirus (HPV)-negative human oropharyngeal carcinoma by activating ERS signaling through PERK and IRE1α. In addition, PERK confers radioresistance by activating the inflammatory cytokine NF-κB. However, the effect of IRE1 on radiosensitivity has not yet been fully elucidated. Here, we clarified that IRE1 overexpression was associated with poor outcome in HPV-negative patients treated with radiotherapy (P = 0.0001). In addition, a significantly higher percentage of radioresistant HPV-negative patients than radiosensitive HPV-negative patients exhibited high IRE expression (66.7% vs 27.8%, respectively; P = 0.001). Silencing IRE1 and XBP1 increased DNA double-strand break (DSB) and radiation-induced apoptosis, thereby increasing the radiosensitivity of HPV-negative oropharyngeal carcinoma cells. IRE1-XBP1 silencing also inhibited radiation-induced IL-6 expression at both the RNA and protein levels. The regulatory effect of IRE1-XBP1 silencing on DNA DSB-induced and radiation-induced apoptosis was inhibited by pretreatment with IL-6. These data indicate that IRE1 regulates radioresistance in HPV-negative oropharyngeal carcinoma through IL-6 activation, enhancing X-ray-induced DNA DSB and cell apoptosis.


Assuntos
Endorribonucleases/metabolismo , Interleucina-6/metabolismo , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Tolerância a Radiação/fisiologia , Proteína 1 de Ligação a X-Box/metabolismo , Apoptose/fisiologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Humanos , NF-kappa B/metabolismo , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
17.
Plant Sci ; 285: 34-43, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203892

RESUMO

Seed germination is a critical stage during the initiation of the plant lifecycle and is strongly affected by endogenous phytohormones and environmental stress. High temperature (HT) upregulates endogenous abscisic acid (ABA) to suppress seed germination, and ABA-INSENSITIVE 5 (ABI5) is the key positive regulator in the ABA signal-mediated modulation of seed germination. In plants, hydrogen sulfide (H2S) is a small gas messenger that participates in multiple physiological processes, but its role in seed germination thermotolerance has not been thoroughly elucidated to date. In this study, we found that H2S enhanced the seed germination rate under HT. Moreover, HT accelerates the efflux of the E3 ligase CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1) from the nucleus to the cytoplasm, which results in increased nuclear accumulation of ELONG HYPCOTYL 5 (HY5) to activate the expression of ABI5 and thereby suppress seed germination. However, the H2S signal reversed the HT effect, as characterized by increased COP1 in the nucleus, which resulted in increased degradation of HY5 and reduced expression of ABI5 and thereby enhanced the seed germination thermotolerance. Thus, our findings reveal a novel role for the H2S signal in the modulation of seed germination thermotolerance through the nucleocytoplasmic partitioning of COP1 and the downstream HY5 and ABI5 pathways.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Germinação/fisiologia , Sulfeto de Hidrogênio/metabolismo , Proteínas Nucleares/metabolismo , Sementes/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ácido Abscísico/metabolismo , Ácido Abscísico/fisiologia , Arabidopsis/fisiologia , Proteínas de Arabidopsis/fisiologia , Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Núcleo Celular/enzimologia , Núcleo Celular/metabolismo , Giberelinas/metabolismo , Giberelinas/fisiologia , Temperatura Alta , Proteínas Nucleares/fisiologia , Reguladores de Crescimento de Planta/fisiologia , Plantas Geneticamente Modificadas , Reação em Cadeia da Polimerase em Tempo Real , Sementes/fisiologia , Transdução de Sinais/fisiologia , Termotolerância , Ubiquitina-Proteína Ligases/fisiologia
18.
Cancer Sci ; 110(8): 2408-2420, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215094

RESUMO

Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC-DR, established from a metastatic thoracic lesion. ESCC-DRtca2M was prepared by treating ESCC-DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose-6-phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF-κB) (p65) and O-linked N-Acetylglucosamine (O-GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O-GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line-based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF-κB (p65) and O-GlcNAc were expressed more highly in ESCC-DRtca2M than in the other cell lines. Moreover, ESCC-DRtca2M cells had additional chromosomal abnormalities in excess of ESCC-DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF-κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line-based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF-κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.


Assuntos
Ácidos e Sais Biliares/metabolismo , Vias Biossintéticas/fisiologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Hexosaminas/metabolismo , Via de Pentose Fosfato/fisiologia , Acetilglucosamina/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Glucose/análogos & derivados , Glucose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
19.
Cancer Sci ; 110(8): 2520-2528, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215118

RESUMO

Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of ApcΔ716 mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC. Laser capture microdissection and in situ hybridization analysis show almost exclusive expression of Dio2 in the stroma of ApcΔ716 polyps in the proximity of the COX-2-positive areas. Treatment with iopanoic acid, a deiodinase inhibitor, or chemical thyroidectomy suppresses tumor formation in ApcΔ716 mice, accompanied by reduced tumor cell proliferation and angiogenesis. Dio2 expression in ApcΔ716 polyps is strongly suppressed by treatment with the COX-2 inhibitor meloxicam. Analysis of The Cancer Genome Atlas data shows upregulation of DIO2 in CRC clinical samples and a close association of its expression pattern with the stromal component, consistently with almost exclusive expression of DIO2 in the stroma of human CRC as revealed by in situ hybridization. These results indicate essential roles of stromal DIO2 and thyroid hormone signaling in promoting the growth of intestinal tumors.


Assuntos
Proliferação de Células/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Iodeto Peroxidase/metabolismo , Polipose Adenomatosa do Colo/tratamento farmacológico , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Humanos , Pólipos Intestinais/tratamento farmacológico , Pólipos Intestinais/metabolismo , Pólipos Intestinais/patologia , Camundongos , Camundongos Knockout , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Hormônios Tireóideos/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
20.
Cancer Sci ; 110(8): 2507-2519, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215741

RESUMO

Abnormal tumor microenvironment and the epithelial-mesenchymal transition (EMT) are important features of tumor metastasis. However, it remains unknown how signals can form complicated networks to regulate the sustainability of the EMT process. The aim of our study is to explore the possible interaction between tumor-associated macrophages and tumor cells in the EMT process mediated by microRNA (miR)-362-3p. In this study, we found that by releasing TGF-ß, M2 macrophages mediate binding of Smad2/3 to miR-362-3p promoter, leading to overexpression of miR-362-3p. MicroRNA-362-3p maintains EMT by regulating CD82, one of the most important members of the family of tetraspanins. Our finding suggests that miR-362-3p can serve as a core factor mediating cross-talk between the TGF-ß pathway in tumor-associated macrophages and tetraspanins in tumor cells, and thus facilitates the EMT process.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/fisiologia , Proteína Kangai-1/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Macrófagos/patologia , Camundongos , Camundongos Nus , Transdução de Sinais/fisiologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Tetraspaninas/metabolismo
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