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1.
Adv Exp Med Biol ; 1325: 117-135, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495532

RESUMO

O-Linked glycosylation such as O-fucose, O-glucose, and O-N-acetylglucosamine are considered to be unusual. As suggested by the high levels of evolutional conservation, these O-glycans are fundamentally important for life. In the last two decades, our understanding of the importance of these glycans has greatly advanced. In particular, identification of the glycosyltransferases responsible for the biosynthesis of these glycans has accelerated basic research on the functional significance and molecular mechanisms by which these O-glycans regulate protein functions as well as clinical research on human diseases due to changes in these types of O-glycosylation. Notably, Notch receptor signaling is modified with and regulated by these types of O-glycans. Here, we summarize the current view of the structures and the significance of these O-glycans mainly in the context of Notch signaling regulation and human diseases.


Assuntos
Fucose , Receptores Notch , Glucose , Glicosilação , Humanos , Polissacarídeos , Receptores Notch/metabolismo , Transdução de Sinais
2.
Nat Cell Biol ; 23(9): 953-966, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34475534

RESUMO

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Following damage, interleukin-1ß (IL-1ß) signalling-dependent modulation of Jag1 and Jag2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives the reprogramming and acquisition of differentiation plasticity. We identify the transcription factor Fosl2 (also known as Fra2) for secretory cell fate conversion to alveolar type 2 cells that retain the distinct genetic and epigenetic signatures of secretory lineages. We also reveal that human secretory cells positive for KDR (also known as FLK-1) display a conserved capacity to generate alveolar type 2 cells via Notch inhibition. Our results demonstrate the functional role of an IL-1ß-Notch-Fosl2 axis in the fate decision of secretory cells during injury repair, proposing a potential therapeutic target for human lung alveolar regeneration.


Assuntos
Diferenciação Celular/fisiologia , Antígeno 2 Relacionado a Fos/metabolismo , Interleucina-1beta/metabolismo , Receptores Notch/metabolismo , Regeneração/fisiologia , Animais , Antígeno 2 Relacionado a Fos/genética , Regulação da Expressão Gênica/fisiologia , Interleucina-1beta/genética , Camundongos , Sistema Respiratório/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo
3.
Medicine (Baltimore) ; 100(31): e26623, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397798

RESUMO

BACKGROUND: Cyclin F (CCNF) dysfunction has been implicated in various forms of cancer, offering a new avenue for understanding the pathogenic mechanisms underlying hepatocellular carcinoma (HCC). We aimed to evaluate the role of CCNF in HCC using publicly available data from The Cancer Genome Atlas (TCGA). METHOD: We used TCGA data and Gene Expression Omnibus (GEO) data to analyze the differential expression of CCNF between tumor and adjacent tissues and the relationship between CCNF and clinical characteristics. We compared prognosis of patients with HCC with high and low CCNF expression and constructed receiver operating characteristic (ROC) curves. In addition, we also explored the types of gene mutations in relevant groups and conducted Gene Set Enrichment Analysis (GSEA). RESULTS: The expression of CCNF in liver cancer tissues was significantly increased compared with that in adjacent tissues, and patients with high CCNF expression had a worse prognosis than those with low CCNF expression. Patients with high CCNF expression also had more somatic mutations. High expression of CCNF hampers the prognosis independently. The GSEA showed that the "http://www.gsea-msigdb.org/gsea/msigdb/cards/BIOCARTA_WNT_PATHWAY" Wnt pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/BIOCARTA_P53_PATHWAY" P53 pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_PI3K_AKT_MTOR_SIGNALING" PI3K/Akt/mTOR pathway, "http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_NOTCH_SIGNALING" Notch pathway were enriched in patients with the high CCNF expression phenotype. CONCLUSION: High CCNF expression can be seen as an independent risk factor for poor survival in HCC. Its expression may serve as a target for the diagnosis and treatment of liver cancer.


Assuntos
Carcinoma Hepatocelular/genética , Ciclinas/genética , Neoplasias Hepáticas/genética , Transdução de Sinais/genética , Carcinoma Hepatocelular/metabolismo , Ciclinas/metabolismo , Bases de Dados Genéticas , Feminino , Expressão Gênica , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Receptores Notch/metabolismo , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt/genética
4.
Biomed Res Int ; 2021: 8463161, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337053

RESUMO

Meso-Xanthin (Meso-Xanthin F199™) is a highly active antiaging injection drug of the latest generation. The main acting compound is fucoxanthin, supplemented with several growth factors, vitamins, and hyaluronic acid. Previous examination of fucoxanthin on melanocytes showed its ability to inhibit skin pigmentation through different signaling pathways focused on suppression of melanogenic-stimulating receptors. In turn, the anticancer property of fucoxanthin is realized through MAPK and PI3K pathways. We aimed to evaluate the effect of fucoxanthin and supplemented growth factors on melanocyte growth and transformation at a proteomic level. The effect of fucoxanthin on melanocytes cultivated in three-dimensional (3D) condition was examined using high-throughput proteomic and system biology approaches to disclose key molecular events of the targeted action. Our results demonstrated significant inhibition of cell differentiation and ubiquitination processes. We found that the negative regulation of PSME1 and PTGIS largely determines the inhibition of NF-κB and MAPK2. Besides, fucoxanthin selectively inhibits cell differentiation via negative regulation of Raf signaling and the upstream activation of IL-1 signaling. It is assumed that inhibition of Raf influences the Notch-4 signaling and switches off the MAPK/MAPK2 cascade. Blockage of MAPK/MAPK2 is feasible due to suppression of Ras and NF-κB by the addressed action of IKKB, IKK2, and TRAF6. Suggestively, Meso-Xanthin F199™ can manage processes of proliferative activity and inhibition of apoptosis due to composition of fucoxanthin and growth-stimulating factors, which may increase the risk of skin cancer development under certain condition.


Assuntos
Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células , Sistema de Sinalização das MAP Quinases , Melanócitos/citologia , Melanócitos/metabolismo , Receptores Notch/metabolismo , Xantina/farmacologia , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanócitos/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteoma/metabolismo
5.
Arterioscler Thromb Vasc Biol ; 41(9): e427-e439, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34261328

RESUMO

Objective: Atheromatous fibrous caps are produced by smooth muscle cells (SMCs) that are recruited to the subendothelial space. We tested whether the recruitment mechanisms are the same as in embryonic artery development, which relies prominently on Notch signaling to form the subendothelial medial SMC layers. Approach and Results: Notch elements were expressed in regions of fibrous cap in human and mouse plaques. To assess the causal role of Notch signaling in cap formation, we studied atherosclerosis in mice where the Notch pathway was inactivated in SMCs by conditional knockout of the essential effector transcription factor RBPJ (recombination signal-binding protein for immunoglobulin kappa J region). The recruitment of cap SMCs was significantly reduced without major effects on plaque size. Lineage tracing revealed the accumulation of SMC-derived plaque cells in the cap region was unaltered but that Notch-defective cells failed to re-acquire the SMC phenotype in the cap. Conversely, to analyze whether the loss of Notch signaling is required for SMC-derived cells to accumulate in atherogenesis, we studied atherosclerosis in mice with constitutive activation of Notch signaling in SMCs achieved by conditional expression of the Notch intracellular domain. Forced Notch signaling inhibited the ability of medial SMCs to contribute to plaque cells, including both cap SMCs and osteochondrogenic cells, and significantly reduced atherosclerosis development. Conclusions: Sequential loss and gain of Notch signaling is needed to build the cap SMC population. The shared mechanisms with embryonic arterial media assembly suggest that the cap forms as a neo-media that restores the connection between endothelium and subendothelial SMCs, transiently disrupted in early atherogenesis.


Assuntos
Aterosclerose/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica , Receptores Notch/metabolismo , Túnica Média/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Artérias/metabolismo , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Linhagem da Célula , Células Cultivadas , Progressão da Doença , Fibrose , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Ratos , Receptores Notch/genética , Transdução de Sinais , Túnica Média/patologia
6.
Aging (Albany NY) ; 13(12): 16471-16484, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34230221

RESUMO

BACKGROUND: Increasing reports have revealed that dysregulated expression of long non-coding RNAs (lncRNAs) is involved in pancreatic carcinoma progression. This study intends to explore the function and molecular mechanism of lncRNA HLA complex group 11 (HCG11) in pancreatic carcinoma. METHODS: The expression profiles of HCG11 in pancreatic carcinoma samples were detected by qPCR. Bioinformatics analysis was applied to detect the associations among HCG11/miR-579-3p/MDM2. The malignant properties of pancreatic carcinoma cells were measured by numerous biological assays. Xenograft model was exploited to detect the effect of HCG11 on tumor growth. RESULTS: A significant increase of HCG11 was occurred in pancreatic carcinoma samples. Knockdown of HCG11 suppressed the progression of pancreatic carcinoma cells. Bioinformatics analysis revealed that HCG11 upregulated MDM2 expression by competitively targeting miR-579-3p. The rescue assays showed that miR-579-3p reversed cell behaviors caused by HCG11, and MDM2 reversed cell properties induced by miR-579-3p. The Notch1 intracellular domain (NICD) and Hes1 protein levels were increased by overexpression of HCG11/MDM2. The tumor growth was suppressed after depletion of HCG11, followed by suppressing Ki67, PCNA and Vimentin expression, increasing TUNEL-positive cells and E-cadherin expression. CONCLUSIONS: Our observations highlighted that HCG11 contributed to the progression of pancreatic carcinoma by promoting growth and aggressiveness, and inhibiting apoptosis via miR-579-3p/MDM2/Notch/Hes1 axis.


Assuntos
MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Longo não Codificante/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Fatores de Transcrição HES-1/metabolismo , Animais , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética , Reprodutibilidade dos Testes , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cell Death Dis ; 12(7): 677, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226515

RESUMO

Muscular dystrophies are debilitating neuromuscular disorders for which no cure exists. As this disorder affects both cardiac and skeletal muscle, patients would benefit from a cellular therapy that can simultaneously regenerate both tissues. The current protocol to derive bipotent mesodermal progenitors which can differentiate into cardiac and skeletal muscle relies on the spontaneous formation of embryoid bodies, thereby hampering further clinical translation. Additionally, as skeletal muscle is the largest organ in the human body, a high myogenic potential is necessary for successful regeneration. Here, we have optimized a protocol to generate chemically defined human induced pluripotent stem cell-derived mesodermal progenitors (cdMiPs). We demonstrate that these cells contribute to myotube formation and differentiate into cardiomyocytes, both in vitro and in vivo. Furthermore, the addition of valproic acid, a clinically approved small molecule, increases the potential of the cdMiPs to contribute to myotube formation that can be prevented by NOTCH signaling inhibitors. Moreover, valproic acid pre-treated cdMiPs injected in dystrophic muscles increase physical strength and ameliorate the functional performances of transplanted mice. Taken together, these results constitute a novel approach to generate mesodermal progenitors with enhanced myogenic potential using clinically approved reagents.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Mesoderma/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Receptores Notch/metabolismo , Ácido Valproico/farmacologia , Animais , Linhagem da Célula , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Masculino , Mesoderma/citologia , Mesoderma/metabolismo , Mesoderma/transplante , Camundongos , Camundongos Knockout , Contração Muscular , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/transplante , Força Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/fisiopatologia , Distrofias Musculares/cirurgia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/transplante , Fenótipo , Ratos , Transdução de Sinais
8.
Phytomedicine ; 90: 153640, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34330066

RESUMO

BACKGROUND: Diabetic neuropathic pain (DNP), a complication of diabetes, has serious impacts on human health. As the pathogenesis of DNP is very complex, clinical treatments for DNP is limited. Koumine (KM) is an active ingredient extracted from Gelsemium elegans Benth. that exerts an inhibitory effect on neuropathic pain (NP) in several animal models. PURPOSE: To clarify the anti-NP effect of KM on rats with DNP and the molecular mechanisms involving the Notch- Jκ recombination signal binding protein (RBP-Jκ) signaling pathway. METHODS: Male Sprague-Dawley rats were administered streptozocin (STZ) by intraperitoneal injection to induce DNP. The effect of KM on mechanical hyperalgesia in rats with DNP was evaluated using the Von Frey test. Microglial polarization in the spinal cord was examined using western blotting and quantitative real-time PCR. The Notch-RBP-Jκ signaling pathway was analysed using western blotting. RESULTS: KM attenuated DNP during the observation period. In addition, KM alleviated M1 microglial polarization in STZ-induced rats. Subsequent experiments revealed that Notch-RBP-Jκ signaling pathway was activated in the spinal cord of rats with DNP, and the activation of this pathways was decreased by KM. Additionally, KM-mediated analgesia and deactivation of the Notch-RBP-Jκ signaling pathway were inhibited by the Notch signaling agonist jagged 1, indicating that the anti-DNP effect of KM may be regulated by the Notch-RBP-Jκ signaling pathway. CONCLUSIONS: KM is a potentially desirable candidate treatment for DNP that may inhibit microglial M1 polarization through the Notch-RBP-Jκ signaling pathway.


Assuntos
Diabetes Mellitus , Alcaloides Indólicos/farmacologia , Microglia/efeitos dos fármacos , Neuralgia , Transdução de Sinais/efeitos dos fármacos , Animais , Polaridade Celular , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Masculino , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores Notch/metabolismo
9.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069142

RESUMO

Bone healing is a complex, well-organized process. Multiple factors regulate this process, including growth factors, hormones, cytokines, mechanical stimulation, and aging. One of the most important signaling pathways that affect bone healing is the Notch signaling pathway. It has a significant role in controlling the differentiation of bone mesenchymal stem cells and forming new bone. Interventions to enhance the healing of critical-sized bone defects are of great importance, and stem cell transplantations are eminent candidates for treating such defects. Understanding how Notch signaling impacts pluripotent stem cell differentiation can significantly enhance osteogenesis and improve the overall healing process upon transplantation. In Rancourt's lab, mouse embryonic stem cells (ESC) have been successfully differentiated to the osteogenic cell lineage. This study investigates the role of Notch signaling inhibition in the osteogenic differentiation of mouse embryonic and induced pluripotent stem cells (iPS). Our data showed that Notch inhibition greatly enhanced the differentiation of both mouse embryonic and induced pluripotent stem cells.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Osteogênese/genética , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Proteínas de Ciclo Celular/genética , Diferenciação Celular/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Dexametasona/farmacologia , Diaminas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/fisiologia , Mesoderma/citologia , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteogênese/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Receptores Notch/metabolismo , Tiazóis/farmacologia , Fatores de Transcrição HES-1/genética , Vitamina D/farmacologia
10.
PLoS Comput Biol ; 17(6): e1009034, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34061834

RESUMO

Increasing interest has emerged in new mathematical approaches that simplify the study of complex differentiation processes by formalizing Waddington's landscape metaphor. However, a rational method to build these landscape models remains an open problem. Here we study vulval development in C. elegans by developing a framework based on Catastrophe Theory (CT) and approximate Bayesian computation (ABC) to build data-fitted landscape models. We first identify the candidate qualitative landscapes, and then use CT to build the simplest model consistent with the data, which we quantitatively fit using ABC. The resulting model suggests that the underlying mechanism is a quantifiable two-step decision controlled by EGF and Notch-Delta signals, where a non-vulval/vulval decision is followed by a bistable transition to the two vulval states. This new model fits a broad set of data and makes several novel predictions.


Assuntos
Caenorhabditis elegans/citologia , Modelos Biológicos , Animais , Teorema de Bayes , Diferenciação Celular , Fator de Crescimento Epidérmico/metabolismo , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Receptores Notch/metabolismo , Projetos de Pesquisa , Vulva/crescimento & desenvolvimento
11.
Elife ; 102021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34099102

RESUMO

Chromosome 4q deletion is one of the most frequently detected genomic imbalance events in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions without known CHD genes suggests unknown CHD genes within these intervals. Here, we have shown that knockdown of SORBS2, a 4q interval gene, disrupted sarcomeric integrity of cardiomyocytes and caused reduced cardiomyocyte number in human embryonic stem cell differentiation model. Molecular analyses revealed decreased expression of second heart field (SHF) marker genes and impaired NOTCH and SHH signaling in SORBS2-knockdown cells. Exogenous SHH rescued SORBS2 knockdown-induced cardiomyocyte differentiation defects. Sorbs2-/- mouse mutants had atrial septal hypoplasia/aplasia or double atrial septum (DAS) derived from impaired posterior SHF with a similar expression alteration. Rare SORBS2 variants were significantly enriched in a cohort of 300 CHD patients. Our findings indicate that SORBS2 is a regulator of SHF development and its variants contribute to CHD pathogenesis. The presence of DAS in Sorbs2-/- hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Diferenciação Celular , Transtornos Cromossômicos/genética , Cardiopatias Congênitas/genética , Células-Tronco Embrionárias Humanas/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 4/genética , Bases de Dados Genéticas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Células HEK293 , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Células-Tronco Embrionárias Humanas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Miócitos Cardíacos/patologia , Fenótipo , Proteínas de Ligação a RNA/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais
12.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946266

RESUMO

Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-ß, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores Notch/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
13.
J Biomed Sci ; 28(1): 36, 2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-33966637

RESUMO

Fibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibrogenic process, often in a context-dependent manner. However, the pathogenetic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibroproliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-ß1, and therapeutic strategies under development.


Assuntos
Cicatriz Hipertrófica/genética , Fibrose/genética , Receptores Notch/metabolismo , Escleroderma Sistêmico/genética , Transdução de Sinais , Cicatriz Hipertrófica/patologia , Fibrose/patologia , Escleroderma Sistêmico/patologia , Pele/patologia
14.
Development ; 148(10)2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33999996

RESUMO

Movement of epithelial cells in a tissue occurs through neighbor exchange and drives tissue shape changes. It requires intercellular junction remodeling, a process typically powered by the contractile actomyosin cytoskeleton. This has been investigated mainly in homogeneous epithelia, where intercalation takes minutes. However, in some tissues, intercalation involves different cell types and can take hours. Whether slow and fast intercalation share the same mechanisms remains to be examined. To address this issue, we used the fly eye, where the cone cells exchange neighbors over ∼10 h to shape the lens. We uncovered three pathways regulating this slow mode of cell intercalation. First, we found a limited requirement for MyosinII. In this case, mathematical modeling predicts an adhesion-dominant intercalation mechanism. Genetic experiments support this prediction, revealing a role for adhesion through the Nephrin proteins Roughest and Hibris. Second, we found that cone cell intercalation is regulated by the Notch pathway. Third, we show that endocytosis is required for membrane removal and Notch activation. Taken together, our work indicates that adhesion, endocytosis and Notch can direct slow cell intercalation during tissue morphogenesis.


Assuntos
Adesão Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila/embriologia , Endocitose/fisiologia , Receptores Notch/metabolismo , Retina/embriologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Actomiosina/metabolismo , Junções Aderentes/fisiologia , Animais , Padronização Corporal/fisiologia , Moléculas de Adesão Celular Neuronais/metabolismo , Comunicação Celular , Proteínas de Drosophila/genética , Células Epiteliais/citologia , Proteínas do Olho/metabolismo , Adesões Focais/fisiologia , Proteínas de Membrana/metabolismo , Miosina Tipo II/metabolismo , Receptores Notch/genética , Transdução de Sinais/fisiologia
15.
Nat Commun ; 12(1): 2564, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963183

RESUMO

Endothelial to mesenchymal transition (EndMT) is a leading cause of fibrosis and disease, however its mechanism has yet to be elucidated. The endothelium possesses a profound regenerative capacity to adapt and reorganize that is attributed to a population of vessel-resident endovascular progenitors (EVP) governing an endothelial hierarchy. Here, using fate analysis, we show that two transcription factors SOX9 and RBPJ specifically affect the murine EVP numbers and regulate lineage specification. Conditional knock-out of Sox9 from the vasculature (Sox9fl/fl/Cdh5-CreER RosaYFP) depletes EVP while enhancing Rbpj expression and canonical Notch signalling. Additionally, skin wound analysis from Sox9 conditional knock-out mice demonstrates a significant reduction in pathological EndMT resulting in reduced scar area. The converse is observed with Rbpj conditionally knocked-out from the murine vasculature (Rbpjfl/fl/Cdh5-CreER RosaYFP) or inhibition of Notch signaling in human endothelial colony forming cells, resulting in enhanced Sox9 and EndMT related gene (Snail, Slug, Twist1, Twist2, TGF-ß) expression. Similarly, increased endothelial hedgehog signaling (Ptch1fl/fl/Cdh5-CreER RosaYFP), that upregulates the expression of Sox9 in cells undergoing pathological EndMT, also results in excess fibrosis. Endothelial cells transitioning to a mesenchymal fate express increased Sox9, reduced Rbpj and enhanced EndMT. Importantly, using topical administration of siRNA against Sox9 on skin wounds can substantially reduce scar area by blocking pathological EndMT. Overall, here we report distinct fates of EVPs according to the relative expression of Rbpj or Notch signalling and Sox9, highlighting their potential plasticity and opening exciting avenues for more effective therapies in fibrotic diseases.


Assuntos
Células Endoteliais/metabolismo , Endotélio/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/genética , Animais , Diferenciação Celular/genética , Linhagem da Célula , Endotélio/citologia , Feminino , Técnicas de Inativação de Genes , Proteínas Hedgehog/metabolismo , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Interferente Pequeno , Receptores Notch/metabolismo , Fatores de Transcrição SOX9/genética , Fator de Crescimento Transformador beta/metabolismo , Cicatrização/genética
16.
Toxicol Lett ; 347: 23-35, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961984

RESUMO

Liver fibrosis is the conjoint consequence of almost all chronic liver diseases. Cholestatic liver injury is a significant stimulus for fibrotic liver. This study was conducted to investigate the hepatoprotective effect of niclosamide as a NOTCH inhibitor and on the Wnt pathway against cholestatic liver fibrosis (CLF) which was experimentally induced by bile duct ligation (BDL). Rats were randomly divided into five main groups (6 per group): sham, BDL, BDL/niclosamide 5, BDL/niclosamide 10 and niclosamide 10 only group. Niclosamide was administered intraperitoneally (i.p.) for 4 weeks starting at the same day of surgery at doses 5 and 10 mg/kg. Liver function, cholestasis, oxidative stress, inflammation, liver fibrosis, NOTCH signaling pathway and Wnt pathway markers were assessed. Niclosamide (5 and 10 mg/kg) significantly reduced liver enzymes levels, oxidative stress, inflammation and phosphorylated signal transducer and activator of transcription3 (p-STAT3). Niclosamide (5 and 10 mg/kg) also significantly reduced NOTCH pathway (Jagged1, NOTCH2, NOTCH3, HES1, SOX9), Wnt pathway (Wnt5B, and Wnt10A), and fibrosis (transforming growth factor-beta1 (TGF-ß1), alpha smooth muscle actin (α-SMA) and collagen deposition with more prominent effect of the higher dose 10 mg/kg. So, this study presents nicloamide as a promising antifibrotic agent in CLF through inhibition of NOTCH and Wnt pathways.


Assuntos
Cirrose Hepática Biliar/prevenção & controle , Fígado/efeitos dos fármacos , Niclosamida/farmacologia , Receptores Notch/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Ductos Biliares/cirurgia , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos Wistar , Fatores de Transcrição SOX9/metabolismo , Fator de Transcrição STAT3/metabolismo
17.
Cell Prolif ; 54(6): e13042, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33955094

RESUMO

OBJECTIVES: The effects of general anaesthetics on fetal brain development remain elusive. Radial glial progenitors (RGPs) generate the majority of neurons in developing brains. Here, we evaluated the acute alterations in RGPs after maternal sevoflurane exposure. METHODS: Pregnant mice were exposed to 2.5% sevoflurane for 6 hours on gestational day 14.5. Interkinetic nuclear migration (INM) of RGPs in the ventricular zone (VZ) of the fetal brain was evaluated by thymidine analogues labelling. Cell fate of RGP progeny was determined by immunostaining using various neural markers. The Morris water maze (MWM) was used to assess the neurocognitive behaviours of the offspring. RNA sequencing (RNA-Seq) was performed for the potential mechanism, and the potential mechanism validated by quantitative real-time PCR (qPCR), Western blot and rescue experiments. Furthermore, INM was examined in human embryonic stem cell (hESC)-derived 3D cerebral organoids. RESULTS: Maternal sevoflurane exposure induced temporary abnormities in INM, and disturbed the cell cycle progression of RGPs in both rodents and cerebral organoids without cell fate alternation. RNA-Seq analysis, qPCR and Western blot showed that the Notch signalling pathway was a potential downstream target. Reactivation of Notch by Jag1 and NICD overexpression rescued the defects in INM. Young adult offspring showed no obvious cognitive impairments in MWM. CONCLUSIONS: Maternal sevoflurane exposure during neurogenic period temporarily induced abnormal INM of RGPs by targeting the Notch signalling pathway without inducing long-term effects on RGP progeny cell fate or offspring cognitive behaviours. More importantly, the defects of INM in hESC-derived cerebral organoids provide a novel insight into the effects of general anaesthesia on human brain development.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Córtex Cerebral/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores Notch/metabolismo , Sevoflurano/efeitos adversos , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Feminino , Feto/efeitos dos fármacos , Feto/metabolismo , Feto/patologia , Humanos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Neurogênese/efeitos dos fármacos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Transdução de Sinais/efeitos dos fármacos
18.
Biomed Pharmacother ; 140: 111693, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029951

RESUMO

Nicotinamide phosphoribosyltransferase (NAMPT) maintains mitochondrial function and protects against cerebral ischemic injury by improving energy metabolism. Notoginsenoside R1 (R1), a unique constituent of Panax notoginseng, has been shown to promote the proliferation and tube formation of human umbilical vein endothelial cells. Whether R1 has proangiogenesis on the activation of NAMPT in ischemic stroke remains unclear. The purpose of this study was to investigate the pharmacodynamic effect and mechanism of R1 on angiogenesis after ischemic stroke. We used male Sprague-Dawley (SD) rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). R1 was administered via intraperitoneal (i.p.) injection immediately after ischemia induction. The promotion of R1 on angiogenesis were detected by immunofluorescence staining, 3D stereoscopic imaging and transmission electron microscopy detection. HBMEC cells were pretreated with different concentrations of R1 for 12 h before oxygen-glucose deprivation/reoxygenation (OGD/R) exposure. Afterward, scratch assay, EdU staining and tube formation were determined. Western blot analyses of proteins, including those involved in angiogenesis, NAMPT-SIRT1 cascade, VEGFR-2, and Notch signaling, were conducted. We showed that R1 significantly restored cerebral blood flow, improved mitochondrial energy metabolism and promoted angiogenesis. More importantly, incubation with 12.5-50 µM R1 significantly increased the migration, proliferation and tube formation of HBMECs in vitro. The promotion of R1 on angiogenesis were associated with the NAMPT-NAD+-SIRT1 cascade and Notch/VEGFR-2 signaling pathway, which was partially eliminated by inhibitors of NAMPT and SIRT1. We demonstrated that R1 promotes post-stroke angiogenesis via activating NAMPT-NAD+-SIRT1 cascade. The modulation of Notch signaling and VEGFR-2 contribute to the post-stroke angiogenesis. These findings offer insight for exploring new therapeutic strategies for neurorestoration via R1 treatment after ischemic stroke.


Assuntos
Isquemia Encefálica/metabolismo , Citocinas/metabolismo , Ginsenosídeos/farmacologia , NAD/metabolismo , Neovascularização Patológica/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Receptores Notch/metabolismo , Sirtuína 1/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucose/metabolismo , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Neovascularização Patológica/tratamento farmacológico , Panax notoginseng/química , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Viruses ; 13(4)2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917368

RESUMO

Hearing loss is one of the most prevalent sensory disabilities worldwide with huge social and economic burdens. The leading cause of sensorineural hearing loss (SNHL) in children is congenital cytomegalovirus (CMV) infection. Though the implementation of universal screening and early intervention such as antiviral or anti-inflammatory ameliorate the severity of CMV-associated diseases, direct and targeted therapeutics is still seriously lacking. The major hurdle for it is that the mechanism of CMV induced SNHL has not yet been well understood. In this review, we focus on the impact of CMV infection on the key players in inner ear development including the Wnt and Notch signaling pathways. Investigations on these interactions may gain new insights into viral pathogenesis and reveal novel targets for therapy.


Assuntos
Infecções por Citomegalovirus/complicações , Citomegalovirus/patogenicidade , Regulação da Expressão Gênica , Perda Auditiva Neurossensorial/virologia , Receptores Notch/genética , Transdução de Sinais , Proteínas Wnt/genética , Animais , Citomegalovirus/genética , Humanos , Camundongos , Receptores Notch/metabolismo , Proteínas Wnt/metabolismo
20.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802299

RESUMO

Selenium is an essential micronutrient with a wide range of biological effects in mammals. The inorganic form of selenium, selenite, is supplemented to relieve individuals with selenium deficiency and to alleviate associated symptoms. Additionally, physiological and supranutritional selenite have shown selectively higher affinity and toxicity towards cancer cells, highlighting their potential to serve as chemotherapeutic agents or adjuvants. At varying doses, selenite extensively regulates cellular signaling and modulates many cellular processes. In this study, we report the identification of Delta-Notch signaling as a previously uncharacterized selenite inhibited target. Our transcriptomic results in selenite treated primary mouse hepatocytes revealed that the transcription of Notch1, Notch2, Hes1, Maml1, Furin and c-Myc were all decreased following selenite treatment. We further showed that selenite can inhibit Notch1 expression in cultured MCF7 breast adenocarcinoma cells and HEPG2 liver carcinoma cells. In mice acutely treated with 2.5 mg/kg selenite via intraperitoneal injection, we found that Notch1 expression was drastically lowered in liver and kidney tissues by 90% and 70%, respectively. Combined, these results support selenite as a novel inhibitor of Notch signaling, and a plausible mechanism of inhibition has been proposed. This discovery highlights the potential value of selenite applied in a pathological context where Notch is a key drug target in diseases such as cancer, fibrosis, and neurodegenerative disorders.


Assuntos
Receptores Notch/metabolismo , Ácido Selenioso/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Selênio/metabolismo , Transcriptoma/efeitos dos fármacos
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