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1.
Mol Cell ; 76(5): 753-766.e6, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31563432

RESUMO

The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-ß, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator ß-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.


Assuntos
Elementos Facilitadores Genéticos/genética , Complexo Mediador/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica/fisiologia , Humanos , Proteínas Intrinsicamente Desordenadas/metabolismo , Complexo Mediador/fisiologia , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad3/metabolismo , Proteínas da Superfamília de TGF-beta/metabolismo , Transcrição Genética , Via de Sinalização Wnt , beta Catenina/metabolismo
2.
J Aging Phys Act ; 27(3): 384-391, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30299198

RESUMO

To investigate the effects of resistance training and epicatechin supplementation on muscle strength, follistatin, and myostatin in older adults with sarcopenia, a total of 62 males with sarcopenia (68.63 ± 2.86 years) underwent a supervised 8-week randomized controlled trial. Participants were divided into resistance training (RT), epicatechin (EP), resistance training+epicatechin (RT+EP), and placebo (PL) in a double-blind method. A pretest and posttest measurement was conducted. One-way analysis of variance was used to analyze between-group differences. The significantly greatest increase was observed in follistatin, follistatin/myostatin ratio, leg press, and chest press in RT+EP comparing RT, EP, and PL groups, whereas myostatin decreased significantly only in RT+EP and RT groups. However, appendicular muscle mass index and timed up and go test were enhanced significantly in all experimental groups than the PL group (p ≤ .05). Consequently, by comparing the results between three experimental groups, the greatest improvement was detected in the RT+EP group. Therefore, using two interventions simultaneously seems to have a better impact on improving muscle growth factors and preventing the progression of sarcopenia.


Assuntos
Catequina/administração & dosagem , Folistatina/sangue , Músculo Esquelético/efeitos dos fármacos , Miostatina/sangue , Treinamento de Resistência/métodos , Sarcopenia/prevenção & controle , Idoso , Biomarcadores/sangue , Catequina/farmacologia , Suplementos Nutricionais , Feminino , Humanos , Masculino , Força Muscular/fisiologia , Músculo Esquelético/fisiologia , Sarcopenia/sangue , Proteínas da Superfamília de TGF-beta/sangue , Resultado do Tratamento
3.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 3022-3037, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29928977

RESUMO

The pathomechanisms underlying oxidative phosphorylation (OXPHOS) diseases are not well-understood, but they involve maladaptive changes in mitochondria-nucleus communication. Many studies on the mitochondria-nucleus cross-talk triggered by mitochondrial dysfunction have focused on the role played by regulatory proteins, while the participation of miRNAs remains poorly explored. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is mostly caused by mutation m.3243A>G in mitochondrial tRNALeu(UUR) gene. Adverse cardiac and neurological events are the commonest causes of early death in m.3243A>G patients. Notably, the incidence of major clinical features associated with this mutation has been correlated to the level of m.3243A>G mutant mitochondrial DNA (heteroplasmy) in skeletal muscle. In this work, we used a transmitochondrial cybrid model of MELAS (100% m.3243A>G mutant mitochondrial DNA) to investigate the participation of miRNAs in the mitochondria-nucleus cross-talk associated with OXPHOS dysfunction. High-throughput analysis of small-RNA-Seq data indicated that expression of 246 miRNAs was significantly altered in MELAS cybrids. Validation of selected miRNAs, including miR-4775 and miR-218-5p, in patient muscle samples revealed miRNAs whose expression declined with high levels of mutant heteroplasmy. We show that miR-218-5p and miR-4775 are direct regulators of fetal cardiac genes such as NODAL, RHOA, ISL1 and RXRB, which are up-regulated in MELAS cybrids and in patient muscle samples with heteroplasmy above 60%. Our data clearly indicate that TGF-ß superfamily signaling and an epithelial-mesenchymal transition-like program are activated in MELAS cybrids, and suggest that down-regulation of miRNAs regulating fetal cardiac genes is a risk marker of heart failure in patients with OXPHOS diseases.


Assuntos
Transição Epitelial-Mesenquimal/genética , Insuficiência Cardíaca/genética , Síndrome MELAS/genética , MicroRNAs/genética , Miocárdio/patologia , RNA de Transferência de Leucina/genética , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Conjuntos de Dados como Assunto , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Coração/crescimento & desenvolvimento , Insuficiência Cardíaca/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome MELAS/complicações , Síndrome MELAS/patologia , MicroRNAs/metabolismo , Mitocôndrias/genética , Mitocôndrias/patologia , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Miocárdio/citologia , Miocárdio/metabolismo , Fosforilação Oxidativa , Análise de Sequência de RNA , Transdução de Sinais/genética , Proteínas da Superfamília de TGF-beta/genética , Proteínas da Superfamília de TGF-beta/metabolismo , Regulação para Cima
4.
Biomol Concepts ; 9(1): 43-52, 2018 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29779014

RESUMO

Chronic low back pain is a critical health problem and a leading cause of disability in aging populations. A major cause of low back pain is considered to be the degeneration of the intervertebral disc (IVD). Recent advances in therapeutics, particularly cell and tissue engineering, offer potential methods for inhibiting or reversing IVD degeneration, which have previously been impossible. The use of growth factors is under serious consideration as a potential therapy to enhance IVD tissue regeneration. We reviewed the role of chosen prototypical growth factors and growth factor combinations that have the capacity to improve IVD restoration. A number of growth factors have demonstrated potential to modulate the anabolic and anticatabolic effects in both in vitro and animal studies of IVD tissue engineering. Members of the transforming growth factor-ß superfamily, IGF-1, GDF-5, BMP-2, BMP-7, and platelet-derived growth factor have all been investigated as possible therapeutic options for IVD regeneration. The role of growth factors in IVD tissue engineering appears promising; however, further extensive research is needed at both basic science and clinical levels before its application is appropriate for clinical use.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Degeneração do Disco Intervertebral/tratamento farmacológico , Animais , Fator 2 de Crescimento de Fibroblastos/uso terapêutico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Disco Intervertebral/fisiopatologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/fisiopatologia , Camundongos , Fator de Crescimento Derivado de Plaquetas/uso terapêutico , Coelhos , Ratos , Regeneração , Proteínas da Superfamília de TGF-beta/uso terapêutico
5.
Cell Mol Biol (Noisy-le-grand) ; 64(15): 1-6, 2018 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-30672446

RESUMO

Based on the exciting insights gleaned from decades of ground-breaking research, it has become evident that deregulated signaling pathways play instrumental role in cancer development and progression. Interestingly discovery of non-coding RNAs has revolutionized our understanding related to transcription, post-transcription and translation. Modern era has witnessed landmark discoveries in the field of molecular cancer and non-coding RNA biology has undergone tremendous broadening. There has been an exponential growth in the list of publications related to non-coding RNAs and overwhelmingly increasing classes of non-coding RNAs are adding new layers of complexity to already complicated nature of cancer. Regulation of TGF/SMAD signaling by miRNAs and LncRNAs has opened new horizons for therapeutic targeting of TGF/SMAD pathway. In this review we have set spotlight on central role of LncRNAs in modulation of TGF/SMAD pathway. Major proportion of the available evidence is underlining positive role of LncRNAs in contextual regulation of TGF/SMAD pathway. LncRNAs are vital to these regulatory networks because they provide a background support to make the TGF/SMAD mediated intracellular signaling more smooth or make transduction cascade more flexible in response to cues from extracellular environment. Therefore, in accordance with this notion, MALAT1, OIP5-AS1, MIR100HG, HOTAIR, ANRIL, PVT1, AFAP1-AS1, SPRY4-IT, ZEB2NAT, TUG1 and Lnc-SNHG1 have been reported to positively regulate TGF/SMAD signaling. In this review, we have focused on the regulation of TGF/SMAD signaling by LncRNAs and how these non-coding RNAs can be therapeutically exploited. Short-interfering RNA (siRNA) and natural products are currently being tested for efficacy against different LncRNAs. Nanotechnological strategies to efficiently deliver LncRNA-targeting siRNAs are also currently being investigated in different cancers.


Assuntos
Neoplasias/genética , Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Proteínas da Superfamília de TGF-beta/metabolismo , Animais , Humanos , Modelos Biológicos
6.
Clin Implant Dent Relat Res ; 20(2): 251-260, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29105932

RESUMO

BACKGROUND: The use of bioactive proteins, such as rhBMP-2, may improve bone regeneration in oral and maxillofacial surgery. PURPOSE: Analyze the effect of using bioactive proteins for bone regeneration in implant-based rehabilitation. MATERIALS AND METHODS: Seven databases were screened. Only clinical trials that evaluated the use of heterologous sources of bioactive proteins for bone formation prior to implant-based rehabilitation were included. Statistical analyses were carried out using a random-effects model by comparing the standardized mean difference between groups for bone formation, and risk ratio for implant survival (P ≤ .05). RESULTS: Seventeen studies were included in the qualitative analysis, and 16 in the meta-analysis. For sinus floor augmentation, bone grafts showed higher amounts of residual bone graft particles than bioactive treatments (P ≤ .05). While for alveolar ridge augmentation bioactive treatments showed a higher level of bone formation than control groups (P ≤ .05). At 3 years of follow-up, no statistically significant differences were observed for implant survival (P > .05). CONCLUSIONS: Bioactive proteins may improve bone formation in alveolar ridge augmentation, and reduce residual bone grafts in sinus floor augmentation. Further studies are needed to evaluate the long-term effect of using bioactive treatments for implant-based rehabilitation.


Assuntos
Regeneração Óssea , Transplante Ósseo , Implantação Dentária Endo-Óssea/métodos , Proteínas da Superfamília de TGF-beta/uso terapêutico , Aumento do Rebordo Alveolar/métodos , Estudos de Avaliação como Assunto , Humanos
7.
Molecules ; 22(5)2017 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-28468283

RESUMO

Of the circa 40 cytokines of the TGF-ß superfamily, around a third are currently known to bind to heparin and heparan sulphate. This includes TGF-ß1, TGF-ß2, certain bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), as well as GDNF and two of its close homologues. Experimental studies of their heparin/HS binding sites reveal a diversity of locations around the shared cystine-knot protein fold. The activities of the TGF-ß cytokines in controlling proliferation, differentiation and survival in a range of cell types are in part regulated by a number of specific, secreted BMP antagonist proteins. These vary in structure but seven belong to the CAN or DAN family, which shares the TGF-ß type cystine-knot domain. Other antagonists are more distant members of the TGF-ß superfamily. It is emerging that the majority, but not all, of the antagonists are also heparin binding proteins. Any future exploitation of the TGF-ß cytokines in the therapy of chronic diseases will need to fully consider their interactions with glycosaminoglycans and the implications of this in terms of their bioavailability and biological activity.


Assuntos
Heparina/fisiologia , Heparitina Sulfato/fisiologia , Proteínas da Superfamília de TGF-beta/fisiologia , Animais , Sítios de Ligação , Heparina/química , Heparina/farmacologia , Heparitina Sulfato/química , Heparitina Sulfato/farmacologia , Humanos , Modelos Moleculares , Ligação Proteica , Proteínas da Superfamília de TGF-beta/química
8.
Biomaterials ; 104: 279-96, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27474964

RESUMO

The momentum to compose this Leading Opinion on the synergistic induction of bone formation suddenly arose when a simple question was formulated during a discussion session on how to boost the often limited induction of bone formation seen in clinical contexts. Re-examination of morphological and molecular data available on the rapid induction of bone formation by the recombinant human transforming growth factor-ß3 (hTGF-ß3) shows that hTGF-ß3 replicates the synergistic induction of bone formation as invocated by binary applications of hOP-1:hTGF-ß1 at 20:1 by weight when implanted in heterotopic sites of the rectus abdominis muscle of the Chacma baboon, Papio ursinus. The rapid induction of bone formation in primates by hTGF-ß3 may stem from bursts of cladistic evolution, now redundant in lower animal species but still activated in primates by relatively high doses of hTGF-ß3. Contrary to rodents, lagomorphs and canines, the three mammalian TGF-ß isoforms induce rapid and substantial bone formation when implanted in heterotopic rectus abdominis muscle sites of P. ursinus, with unprecedented regeneration of full thickness mandibular defects with rapid mineralization and corticalization. Provocatively, thus providing potential molecular and biological rationales for the apparent redundancy of osteogenic molecular signals in primates, binary applications of recombinant human osteogenic protein-1 (hOP-1) with low doses of hTGF-ß1 and -ß3, synergize to induce massive ossicles in heterotopic rectus abdominis, orthotopic calvarial and mandibular sites of P. ursinus. The synergistic binary application of homologous but molecularly different soluble molecular signals has indicated that per force several secreted molecular signals are required singly, synchronously and synergistically to induce optimal osteogenesis. The morphological hallmark of the synergistic induction of bone formation is the rapid differentiation of large osteoid seams enveloping haematopoietic bone marrow that forms by day 15 in heterotopic rectus abdominis sites. Synergistic binary applications also induce the morphogenesis of rudimentary embryonic growth plates indicating that the "memory" of developmental events in embryo can be redeployed postnatally by the application of morphogen combinations. Synergistic binary applications or single relatively high doses of hTGF-ß3 have shown that hTGF-ß3 induces bone by expressing a variety of inductive morphogenetic proteins that result in the rapid induction of bone formation. Tissue induction thus invocated singly by hTGF-ß3 recapitulates the synergistic induction of bone formation by binary applications of hTGF-ß1 and -ß3 isoforms with hOP-1. Both synergistic strategies result in the rapid induction and expansion of the transformed mesenchymal tissue into large corticalized heterotopic ossicles with osteoblast-like cell differentiation at the periphery of the implanted reconstituted specimens with "tissue transfiguration" in vivo. Molecularly, the rapid induction of bone formation by binary applications of hOP-1 and hTGF-ß3 or by hTGF-ß3 applied singly resides in the up-regulation of selected genes involved in tissue induction and morphogenesis, Osteocalcin, RUNX-2, OP-1, TGF-ß1 and -ß3 with however the noted lack of TGF-ß2 up-regulation.


Assuntos
Desenvolvimento Ósseo/fisiologia , Regeneração Óssea/fisiologia , Osteogênese/fisiologia , Proteínas da Superfamília de TGF-beta/metabolismo , Animais , Cães , Humanos , Família Multigênica/fisiologia , Especificidade da Espécie
9.
Neural Dev ; 11: 9, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-27048518

RESUMO

BACKGROUND: Brain size and patterning are dependent on dosage-sensitive morphogen signaling pathways - yet how these pathways are calibrated remains enigmatic. Recent studies point to a new role for microRNAs in tempering the spatio-temporal range of morphogen functions during development. Here, we investigated the role of miR-135a, derived from the mir-135a-2 locus, in embryonic forebrain development. METHOD: 1. We characterized the expression of miR-135a, and its host gene Rmst, by in situ hybridization (ish). 2. We conditionally ablated, or activated, beta-catenin in the dorsal forebrain to determine if this pathway was necessary and/or sufficient for Rmst/miR-135a expression. 3. We performed bioinformatics analysis to unveil the most predicted pathways targeted by miR-135a. 4. We performed gain and loss of function experiments on mir-135a-2 and analyzed by ish the expression of key markers of cortical hem, choroid plexus, neocortex and hippocampus. RESULTS: 1. miR-135a, embedded in the host long non-coding transcript Rmst, is robustly expressed, and functional, in the medial wall of the embryonic dorsal forebrain, a Wnt and TGFß/BMP-rich domain. 2. Canonical Wnt/beta-catenin signaling is critical for the expression of Rmst and miR-135a, and the cortical hem determinant Lmx1a. 3. Bioinformatics analyses reveal that the Wnt and TGFß/BMP cascades are among the top predicted pathways targeted by miR-135a. 4. Analysis of mir-135a-2 null embryos showed that dorsal forebrain development appeared normal. In contrast, modest mir-135a-2 overexpression, in the early dorsal forebrain, resulted in a phenotype resembling that of mutants with Wnt and TGFß/BMP deficits - a smaller cortical hem and hippocampus primordium associated with a shorter neocortex as well as a less convoluted choroid plexus. Interestingly, late overexpression of mir-135a-2 revealed no change. CONCLUSIONS: All together, our data suggests the existence of a Wnt/miR-135a auto-regulatory loop, which could serve to limit the extent, the duration and/or intensity of the Wnt and, possibly, the TGFß/BMP pathways.


Assuntos
MicroRNAs/metabolismo , Prosencéfalo/embriologia , Prosencéfalo/metabolismo , Via de Sinalização Wnt , Animais , Proteínas com Homeodomínio LIM/metabolismo , Camundongos , Proteínas da Superfamília de TGF-beta/metabolismo , Fatores de Transcrição/metabolismo
10.
J Heart Valve Dis ; 25(6): 708-715, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-28290170

RESUMO

BACKGROUND AND AIM OF THE STUDY: Pulmonary arterial hypertension (PAH) is a common accompaniment of rheumatic mitral stenosis (MS), with 70% of patients showing evidence of different grades of PAH. The latter condition is found to be a prognostic factor influencing disease outcome even after interventional or surgical therapy. The cause of the non-regression of PAH following successful balloon mitral valvotomy (BMV) is not clear. Hence, the study aim was to determine if there is an association of mutations in the genes of the TGF-ß superfamily and non-regression of PAH in patients who undergo a successful BMV. METHODS: Forty-six patients who underwent BMV and fulfilled the recruitment criteria were enrolled prospectively in this case-control study. Among the patients, 27 had non-regression of PAH while 19 had regression of PAH and served as controls. The mean age of the population was 32.63 ± 10.65 years. RESULTS: No statistically significant differences were identified in any of the baseline parameters between the two groups. None of the samples had BMPR2 or ACVRL1 mutations. Ten of the patients and four of the controls were positive for Endoglin mutation, but the inter-group difference was not statistically significant (p = 0.25) CONCLUSIONS: The present study - the first of its kind - showed that deletion-duplication mutations in the BMPR2 or ACVRL1 genes may not be associated with non-regression of PAH, even after successful BMV, or in a wider sense serve as a contributor to PAH in rheumatic MS. The association of Endoglin mutation and non-regression of PAH warrants further investigation in a larger population.


Assuntos
Valvuloplastia com Balão , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Estenose da Valva Mitral/cirurgia , Cardiopatia Reumática/cirurgia , Proteínas da Superfamília de TGF-beta/genética , Receptores de Activinas Tipo II/genética , Adulto , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Estudos de Casos e Controles , Endoglina/genética , Feminino , Deleção de Genes , Rearranjo Gênico , Humanos , Masculino , Estenose da Valva Mitral/fisiopatologia , Projetos Piloto , Estudos Prospectivos , Cardiopatia Reumática/fisiopatologia , Adulto Jovem
11.
PLoS One ; 10(12): e0145322, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26683658

RESUMO

Genomic technologies including microarrays and next-generation sequencing have enabled the generation of molecular signatures of prostate cancer. Lists of differentially expressed genes between malignant and non-malignant states are thought to be fertile sources of putative prostate cancer biomarkers. However such lists of differentially expressed genes can be highly variable for multiple reasons. As such, looking at differential expression in the context of gene sets and pathways has been more robust. Using next-generation genome sequencing data from The Cancer Genome Atlas, differential gene expression between age- and stage- matched human prostate tumors and non-malignant samples was assessed and used to craft a pathway signature of prostate cancer. Up- and down-regulated genes were assigned to pathways composed of curated groups of related genes from multiple databases. The significance of these pathways was then evaluated according to the number of differentially expressed genes found in the pathway and their position within the pathway using Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. The "transforming growth factor-beta signaling" and "Ran regulation of mitotic spindle formation" pathways were strongly associated with prostate cancer. Several other significant pathways confirm reported findings from microarray data that suggest actin cytoskeleton regulation, cell cycle, mitogen-activated protein kinase signaling, and calcium signaling are also altered in prostate cancer. Thus we have demonstrated feasibility of pathway analysis and identified an underexplored area (Ran) for investigation in prostate cancer pathogenesis.


Assuntos
Neoplasias da Próstata/metabolismo , Idoso , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , Transdução de Sinais , Proteínas da Superfamília de TGF-beta/genética , Proteínas da Superfamília de TGF-beta/metabolismo , Transcriptoma
12.
Sci Transl Med ; 7(299): 299rv4, 2015 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-26246170

RESUMO

Immunological and inflammatory processes downstream of dystrophin deficiency as well as metabolic abnormalities, defective autophagy, and loss of regenerative capacity all contribute to muscle pathology in Duchenne muscular dystrophy (DMD). These downstream cascades offer potential avenues for pharmacological intervention. Modulating the inflammatory response and inducing immunological tolerance to de novo dystrophin expression will be critical to the success of dystrophin-replacement therapies. This Review focuses on the role of the inflammatory response in DMD pathogenesis and opportunities for clinical intervention.


Assuntos
Imunidade Inata , Distrofia Muscular de Duchenne , Citocinas/metabolismo , Distrofina/metabolismo , Fibrose , Humanos , Inflamação , Distrofia Muscular de Duchenne/etiologia , Distrofia Muscular de Duchenne/imunologia , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Transdução de Sinais , Proteínas da Superfamília de TGF-beta/metabolismo
13.
Mol Ecol ; 24(18): 4664-78, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26268413

RESUMO

The Antarctic icefish, a family (Channichthyidae) of teleosts within the perciform suborder Notothenioidei, are the only known vertebrates without oxygen-transporting haemoglobins and that are largely devoid of circulating erythrocytes. To elucidate the evo-devo mechanisms underpinning the suppressed erythropoiesis in the icefish, we conducted comparative studies on the transcriptomes and microRNAomes of the primary haematopoietic tissues between an icefish (Chionodraco hamatus) and two red-blooded notothenioids (Trematomus bernacchii and Gymnodraco acuticeps). We identified substantial remodelling of the haematopoietic programs in the icefish through which erythropoiesis is selectively suppressed. Experimental verification showed that erythropoietic suppression in the icefish may be attributable to the upregulation of TGF-ß signalling, which coincides with reductions in multiple transcription factors essential for erythropoiesis and the upregulation of hundreds of microRNAs, the majority (> 80%) of which potentially target erythropoiesis regulating factors. Of the six microRNAs selected for verification, three miRNAs (miR-152, miR-1388 and miR-16b) demonstrated suppressive functions on GATA1 and ALAS2, which are two factors important for erythroid differentiation, resulting in reduced numbers of erythroids in microinjected zebra fish embryos. Codon substitution analyses of the genes of the TGF-ß superfamily revealed signs of positive selection in TGF-ß1 and endoglin in the lineages leading to Antarctic notothenioids. Both genes are previously known to function in erythropoietic suppression. These findings implied a general trend of erythropoietic suppression in the cold-adapted notothenioid lineages through evolutionary modulation of the multi-functional TGF-ß signalling pathway. This trend is more pronounced in the haemoglobin-less icefish, which may pre-emptively hinder the otherwise defective erythroids from production.


Assuntos
Evolução Biológica , Eritropoese , Perciformes/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Animais , Regiões Antárticas , MicroRNAs/genética , Filogenia , Seleção Genética , Análise de Sequência de RNA , Proteínas da Superfamília de TGF-beta/genética , Transcriptoma
14.
Genes Chromosomes Cancer ; 54(7): 453-62, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25931269

RESUMO

As a transforming growth factor-ß (TGF-ß)-inducible gene, the expression of Krüppel-like transcription factor 11 (KLF11) is altered in several types of cancer. In the current study, through using human 9K CpG island array, KLF11 was identified as one of hypermethylated genes in RAS-transformed ovarian T29H cells. Methylation of the KLF11 promoter was also observed in ovarian cancer tissue samples accompanied by significantly reduced KLF11 gene expression. Interestingly, the expression of SMAD2, SMAD3, and SMAD7 genes was reduced in the tumour, whilst no change was found in TGF-ß expression. Our data suggest a relationship between promoter DNA methylation and KLF11 gene expression in ovarian cancer tumorigenesis.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Metilação de DNA , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/metabolismo , Idoso , Carcinoma Epitelial do Ovário , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , China , Ilhas de CpG , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Proteínas Repressoras/genética , Proteínas Smad/metabolismo , Proteínas da Superfamília de TGF-beta/metabolismo
15.
Exp Gerontol ; 64: 35-45, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25681638

RESUMO

There is a high need for blood-based biomarkers detecting age-related changes in muscular performance at an early stage. Therefore, we investigated whether serum levels of growth and differentiation factor-15 (GDF-15), activin A, myostatin, follistatin, and insulin-like growth factor-1 (IGF-1) would reflect age- and physical performance-related differences between young (22-28 years) and elderly (65-92 years) females. Isokinetic peak torque of knee extension (PTE) was measured in young females to obtain reference values for the discrimination of different stages of age-associated muscle weakness. Additionally, elderly women were screened for sarcopenia using the algorithm of the European Working Group on Sarcopenia in Older People (low muscle mass in addition to low PTE and/or low walking speed). IGF-1 levels were higher and GDF-15 levels were lower in young females in comparison to the elderly (p < 0.01), whereas members of the activin A/myostatin/follistatin axis showed similar levels across age groups. In older women, IGF-1 correlated negatively with age (ρ = -0.359, p < 0.01) and positively with muscle mass (ρ = 0.365, p < 0.01). In contrast, GDF-15 correlated positively with age (ρ = 0.388, p < 0.001) and negatively with muscle mass (ρ = -0.320, p < 0.01). However, none of the serum markers differed between women classified as non-, mildly and severely dynapenic/sarcopenic. Multiple linear regression analyses revealed that a combination of all blood-based biomarkers obtained in addition to age and fat mass moderately predicted muscle mass (+2.9%). Neither a single nor a combined set of tested biomarkers reflected the presence of dynapenia or sarcopenia in elderly women. However, due to the associations of IGF-1 and GDF-15 with correlates of muscle mass and function, these parameters remain promising candidates in a potential set of blood-based biomarkers to diagnose sarcopenia and/or dynapenia.


Assuntos
Folistatina/sangue , Fator de Crescimento Insulin-Like I/análise , Atrofia Muscular/diagnóstico , Sarcopenia/diagnóstico , Proteínas da Superfamília de TGF-beta/sangue , Ativinas/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Áustria , Biomarcadores/sangue , Composição Corporal , Comorbidade , Feminino , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Atrofia Muscular/sangue , Miostatina/sangue , Exame Físico , Análise de Regressão , Sarcopenia/sangue , Adulto Jovem
16.
J Mol Med (Berl) ; 93(3): 289-302, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25345602

RESUMO

UNLABELLED: Hypertrophic scar contraction (HSc) is caused by granulation tissue contraction propagated by myofibroblast and fibroblast migration and contractility. Identifying the stimulants that promote migration and contractility is key to mitigating HSc. Angiotensin II (AngII) promotes migration and contractility of heart, liver, and lung fibroblasts; thus, we investigated the mechanisms of AngII in HSc. Human scar and unwounded dermis were immunostained for AngII receptors angiotensin type 1 receptor (AT1 receptor) and angiotensin type 2 receptor (AT2 receptor) and analyzed for AT1 receptor expression using Western blot. In vitro assays of fibroblast contraction and migration under AngII stimulation were conducted with AT1 receptor, AT2 receptor, p38, Jun N-terminal kinase (JNK), MEK, and activin receptor-like kinase 5 (ALK5) antagonism. Excisional wounds were created on AT1 receptor KO and wild-type (WT) mice treated with AngII ± losartan and ALK5 and JNK inhibitors SB-431542 and SP-600125, respectively. Granulation tissue contraction was quantified, and wounds were analyzed by immunohistochemistry. AT1 receptor expression was increased in scar, but not unwounded tissue. AngII induced fibroblast contraction and migration through AT1 receptor. Cell migration was inhibited by ALK5 and JNK, but not p38 or MEK blockade. In vivo experiments determined that absence of AT1 receptor and chemical AT1 receptor antagonism diminished granulation tissue contraction while AngII stimulated wound contraction. AngII granulation tissue contraction was diminished by ALK5 inhibition, but not JNK. AngII promotes granulation tissue contraction through AT1 receptor and downstream canonical transforming growth factor (TGF)-ß signaling pathway, ALK5. Further understanding the pathogenesis of HSc as an integrated signaling mechanism could improve our approach to establishing effective therapeutic interventions. KEY MESSAGE: AT1 receptor expression is increased in scar tissue compared to unwounded tissue. AngII stimulates expression of proteins that confer cell migration and contraction. AngII stimulates fibroblast migration and contraction through AT1 receptor, ALK5, and JNK. AngII-stimulated in vivo granulation tissue contraction is AT1 receptor and ALK5 dependent.


Assuntos
Angiotensina II/fisiologia , Cicatriz Hipertrófica/metabolismo , Receptor Tipo 1 de Angiotensina/fisiologia , Células 3T3 , Adulto , Animais , Movimento Celular , Colágeno/metabolismo , Epiderme/metabolismo , Epiderme/patologia , Epiderme/fisiopatologia , Feminino , Humanos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteínas da Superfamília de TGF-beta/fisiologia , Cicatrização , Adulto Jovem
17.
Horm Mol Biol Clin Investig ; 18(2): 53-61, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25390002

RESUMO

Aldosterone regulates sodium (Na+) and potassium (K+) transports in epithelial cells. Besides, aldosterone participates in cardiac alterations associated with hypertension, heart failure, diabetes, and other pathological alterations. One of the main cardiac alterations induced by aldosterone is cardiac hypertrophy in which different mechanisms are involved such as increased cardiomyocyte, calcium concentration, oxidative stress, and inflammatory and fibrotic mediators stimulation. Many epidemiological studies have demonstrated that left ventricular hypertrophy is associated with significantly increased risk of heart failure and malignant arrhythmias. SGK1 is a member of the serine/threonine kinase gene family that plays an important role in the absorption of Na+ and water through the Na+ channel in the apical membrane of tubular epithelial cells. SGK1 has been related to fibrotic mediator increase such as connective tissue growth factor (CTGF) and transforming growth factor-ß (TGF-ß) as well as inflammatory [tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß] and oxidative (NADPH oxidase) species. It has been shown that aldosterone induces SGK1 gene expression not only in kidneys but also in the heart. Supporting the central role of SGK1 in cardiac alterations induced by aldosterone, treatment with the mineralocorticoid antagonist spironolactone is able to reduce the gene expression of SGK1 in aldosterone-treated rats. Taken together, data suggest the involvement of SGK1 in a complex intracellular signaling, involving fibrotic, inflammatory, and oxidative pathways, which lead to cardiac hypertrophy and fibrosis induced by aldosterone.


Assuntos
Aldosterona/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Miocárdio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Endotélio Vascular/metabolismo , Fibrose , Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Miocárdio/patologia , NADPH Oxidases/metabolismo , Estresse Oxidativo , Transdução de Sinais , Proteínas da Superfamília de TGF-beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Semin Cancer Biol ; 29: 51-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25153355

RESUMO

Cripto-1 (CR-1)/Teratocarcinoma-derived growth factor1 (TDGF-1) is a cell surface glycosylphosphatidylinositol (GPI)-linked glycoprotein that can function either in cis (autocrine) or in trans (paracrine). The cell membrane cis form is found in lipid rafts and endosomes while the trans acting form lacking the GPI anchor is soluble. As a member of the epidermal growth factor (EGF)/Cripto-1-FRL-1-Cryptic (CFC) family, CR-1 functions as an obligatory co-receptor for the transforming growth factor-ß (TGF-ß) family members, Nodal and growth and differentiation factors 1 and 3 (GDF1/3) by activating Alk4/Alk7 signaling pathways that involve Smads 2, 3 and 4. In addition, CR-1 can activate non-Smad-dependent signaling elements such as PI3K, Akt and MAPK. Both of these pathways depend upon the 78kDa glucose regulated protein (GRP78). Finally, CR-1 can facilitate signaling through the canonical Wnt/ß-catenin and Notch/Cbf-1 pathways by functioning as a chaperone protein for LRP5/6 and Notch, respectively. CR-1 is essential for early embryonic development and maintains embryonic stem cell pluripotentiality. CR-1 performs an essential role in the etiology and progression of several types of human tumors where it is expressed in a population of cancer stem cells (CSCs) and facilitates epithelial-mesenchymal transition (EMT). In this context, CR-1 can significantly enhance tumor cell migration, invasion and angiogenesis. Collectively, these facts suggest that CR-1 may be an attractive target in the diagnosis, prognosis and therapy of several types of human cancer.


Assuntos
Transição Epitelial-Mesenquimal/genética , Proteínas Ligadas por GPI/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Invasividade Neoplásica/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Neovascularização Patológica/genética , Receptores de Ativinas Tipo I/metabolismo , Membrana Celular/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Proteínas de Membrana/genética , Neoplasias/patologia , Células-Tronco Neoplásicas/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Notch/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad4/metabolismo , Proteínas da Superfamília de TGF-beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/metabolismo
19.
Pancreas ; 43(7): 1083-92, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25003220

RESUMO

OBJECTIVE: Epithelial-mesenchymal transition may interfere with the differentiation of cultured pancreatic acinar cells toward endocrine cells. Therefore, it will be important to investigate into detail the reprogramming of human pancreatic acinar cells toward a mesenchymal phenotype: the association with acinoductal transdifferentiation, the influence of cell adhesion, and the regulation behind this process. METHODS: Human exocrine cells, isolated from donor pancreata, were cultured in suspension or as monolayers. Non-genetic lineage tracing, using labeled ulex europaeus agglutinin 1 lectin, was performed, and the role of the transforming growth factor (TGF-ß) superfamily was investigated. RESULTS: After 7 days in monolayer culture, the human acinar cells coexpressed the mesenchymal marker vimentin and the ductal marker Sox9. However, when the human exocrine cells were cultured in suspension, epithelial-mesenchymal transition was not observed. The spontaneous transition of the human acinar cells toward a ductal and mesenchymal phenotype was decreased by inhibition of the TGF-ß and activin signaling pathways. CONCLUSIONS: The human acinar cells spontaneously undergo TGF-ß- regulated reprogramming in the monolayer culture. These observations are helpful to develop culture methods for the in vitro reprogramming of pancreatic exocrine to endocrine cells. They are also of potential interest for studies on exocrine acinar cells in the development of pancreatic cancer.


Assuntos
Células Acinares/efeitos dos fármacos , Ativinas/fisiologia , Benzamidas/farmacologia , Técnicas de Cultura de Células , Dioxóis/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Pâncreas Exócrino/citologia , Proteínas da Superfamília de TGF-beta/fisiologia , Células Acinares/citologia , Células Acinares/metabolismo , Ativinas/antagonistas & inibidores , Biomarcadores , Proteína Morfogenética Óssea 4/antagonistas & inibidores , Proteína Morfogenética Óssea 4/farmacologia , Linhagem da Célula , Células Cultivadas , Humanos , Lectinas de Plantas , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Fatores de Transcrição SOX9/biossíntese , Fatores de Transcrição SOX9/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail , Suspensões , Proteínas da Superfamília de TGF-beta/antagonistas & inibidores , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Vimentina/biossíntese , Vimentina/genética
20.
Nihon Rinsho ; 72(6): 1163-71, 2014 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-25016821

RESUMO

Marfan syndrome is an autosomal dominant disorder, characterized by tall stature, long arms and legs, ectopia lentis, and aortic aneurysms and dissections. Recent research has revealed that these phenotypes are caused by mutations in fibrillin-1, the major structural component of elastic microfibrils, and the continuing dysregulation of transforming growth factor beta (TGFbeta) signaling is principally considered to be contributing to the pathophysiological background of the disease. Blockade of TGFbeta signaling by angiotensin II receptor antagonism is a novel promising therapeutic option, and thus such large clinical randomized controlled trials are underway. Here, we review the past development, current status and future perspectives in the research field for Marfan syndrome.


Assuntos
Síndrome de Marfan , Fibrina/genética , Humanos , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/terapia , Proteínas da Superfamília de TGF-beta/genética
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