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1.
Int J Mol Sci ; 25(2)2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38256140

RESUMO

Members of the transforming growth factor ß (TGF-ß) family have been implicated in the biology of several cancers. In this review, we focus on the role of TGFß and bone morphogenetic protein (BMP) signaling in glioblastoma. Glioblastoma (GBM) is the most common malignant brain tumor in adults; it presents at a median age of 64 years, but can occur at any age, including childhood. Unfortunately, there is no cure, and even patients undergoing current treatments (surgical resection, radiotherapy, and chemotherapy) have a median survival of 15 months. There is a great need to identify new therapeutic targets to improve the treatment of GBM patients. TGF-ßs signaling promotes tumorigenesis in glioblastoma, while BMPs suppress tumorigenic potential by inducing tumor cell differentiation. In this review, we discuss the actions of TGF-ßs and BMPs on cancer cells as well as in the tumor microenvironment, and their use in potential therapeutic intervention.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Proteínas da Superfamília de TGF-beta , Humanos , Neoplasias Encefálicas/genética , Carcinogênese , Diferenciação Celular , Glioblastoma/genética , Fator de Crescimento Transformador beta , Microambiente Tumoral , Proteínas da Superfamília de TGF-beta/genética
2.
J Orthop Res ; 41(3): 511-523, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35716158

RESUMO

Entheses, which are tendon-to-bone attachment sites in the musculoskeletal system, play important roles in optimizing the mechanical stress and force transmitted from the muscle to the bone. Sports-related enthesopathy shows pathological features, including hyperplasia of the fibrocartilage (FC) region in the enthesis. The amount of exercise and type of muscle contraction during movement is involved in the pathogenesis of sports-related enthesopathy; however, the details of this condition are unclear. Here we examined the molecular pathways involved in the morphological changes of the muscle-tendon-enthesis complex and enthesis FC region in the supraspinatus muscle enthesis of mice under different exercise conditions. Following intervention, morphological changes in the muscle-tendon-enthesis complex were initiated in the eccentric contraction-dominant exercise group at 2 weeks, with activation of the transforming growth factor-ß (TGFß) superfamily pathway predicted by proteome and ingenuity pathway analyses. Histological and molecular biological analyses confirmed the activation of the TGFß/bone morphogenetic protein (BMP)-Smad pathway. The concentric contraction-dominant exercise group showed no change in the morphology of the muscle-tendon-enthesis complex or activation of the TGFß/BMP-Smad pathway, despite overuse exercise. Statement of Clinical Significance: These results suggest that eccentric contraction-dominant exercise induces sports-related enthesopathy-like morphological changes in the early stages as well as molecular biological changes, mainly in the transforming growth factor-ß superfamily pathway in enthesis. Statement of Clinical Significance: These results suggest that eccentric contraction-dominant exercise induces sports-related enthesopathy-like morphological changes in the early stages as well as molecular biological changes, mainly in the transforming growth factor-ß superfamily pathway in enthesis.


Assuntos
Entesopatia , Condicionamento Físico Animal , Proteínas da Superfamília de TGF-beta , Animais , Camundongos , Osso e Ossos/patologia , Tendões/patologia , Proteínas da Superfamília de TGF-beta/metabolismo
3.
Methods Mol Biol ; 2488: 67-80, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35347683

RESUMO

Transforming growth factor-ß (TGF-ß) family members have pivotal functions in controlling breast cancer progression, acting not only on cancer cells but also on other cells within the tumor microenvironment. Here we describe embryonic zebrafish xenograft assays to investigate how TGF-ß family signaling controls breast cancer cell intravasation, extravasation and regulates tumor angiogenesis. Fluorescently mCherry-labeled breast cancer cells are injected in the perivitelline space or Duct of Cuvier of Tg (fli:EGFP) transgenic Casper zebrafish embryos, in which the zebrafish express enhanced green fluorescent protein in the entire vasculature. The dynamic responses of migratory and invasive human cancer cells, and the induction of new blood vessel formation by the cancer cells in zebrafish host, are visualized using a fluorescent microscope. These assays provide efficient, reliable, low-cost models to investigate the effect of (epi)genetic modulators and pharmacological compounds that perturb the activity of TGF-ß family signaling components on breast cancer cell metastasis and angiogenesis.


Assuntos
Neoplasias da Mama , Proteínas da Superfamília de TGF-beta/metabolismo , Peixe-Zebra , Animais , Neoplasias da Mama/patologia , Feminino , Xenoenxertos , Humanos , Transplante de Neoplasias , Transdução de Sinais , Microambiente Tumoral , Peixe-Zebra/metabolismo
4.
J Mol Biol ; 434(5): 167439, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34990654

RESUMO

The 33 members of the transforming growth factor beta (TGF-ß) family are fundamentally important for organismal development and homeostasis. Family members are synthesized and secreted as pro-complexes of non-covalently associated prodomains and growth factors (GF). Pro-complexes from a subset of family members are latent and require activation steps to release the GF for signaling. Why some members are latent while others are non-latent is incompletely understood, particularly because of large family diversity. Here, we have examined representative family members in negative stain electron microscopy (nsEM) and hydrogen deuterium exchange (HDX) to identify features that differentiate latent from non-latent members. nsEM showed three overall pro-complex conformations that differed in prodomain arm domain orientation relative to the bound growth factor. Two cross-armed members, TGF-ß1 and TGF-ß2, were each latent. However, among V-armed members, GDF8 was latent whereas ActA was not. All open-armed members, BMP7, BMP9, and BMP10, were non-latent. Family members exhibited remarkably varying HDX patterns, consistent with large prodomain sequence divergence. A strong correlation emerged between latency and protection of the prodomain α1-helix from exchange. Furthermore, latency and protection from exchange correlated structurally with increased α1-helix buried surface area, hydrogen bonds, and cation-pi bonds. Moreover, a specific pattern of conserved basic and hydrophobic residues in the α1-helix and aromatic residues in the interacting fastener were found only in latent members. Thus, this first comparative survey of TGF-ß family members reveals not only diversity in conformation and dynamics but also unique features that distinguish latent members.


Assuntos
Proteínas da Superfamília de TGF-beta , Ligação de Hidrogênio , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Transdução de Sinais , Proteínas da Superfamília de TGF-beta/química , Proteínas da Superfamília de TGF-beta/metabolismo
5.
Zygote ; 30(1): 65-71, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33966679

RESUMO

Regulation of the transforming growth factor beta (TGFß) superfamily by gonadotrophins in swine follicular cells is not fully understood. This study evaluated the expression of steroidogenic enzymes and members of the TGFß superfamily in prepubertal gilts allocated to three treatments: 1200 IU eCG at D -3 (eCG); 1200 IU eCG at D -6 plus 500 IU hCG at D -3 (eCG + hCG); and the control, composed of untreated gilts. Blood samples and ovaries were collected at slaughter (D0) and follicular cells were recovered thereafter. Relative gene expression was determined by real-time PCR. Serum progesterone levels were greater in the eCG + hCG group compared with the other groups (P < 0.01). No differences were observed in the expression of BMP15, BMPR1A, BMPR2, FSHR, GDF9, LHCGR and TGFBR1 (P > 0.05). Gilts from the eCG group presented numerically greater mean expression of CYP11A1 mRNA than in the control group that approached statistical significance (P = 0.08) and greater expression of CYP19A1 than in both the eCG and the control groups (P < 0.05). Expression of BMPR1B was lower in the eCG + hCG treatment group compared with the control (P < 0.05). In conclusion, eCG treatment increased the relative expression of steroidogenic enzymes, whereas treatment with eCG + hCG increased serum progesterone levels. Although most of the evaluated TGFß members were not regulated after gonadotrophin treatment, the downregulation of BMPR1B observed after treatment with eCG + hCG and suggests a role in luteinization regulation.


Assuntos
Gonadotropina Coriônica , Folículo Ovariano/citologia , Proteínas da Superfamília de TGF-beta/metabolismo , Animais , Gonadotropina Coriônica/farmacologia , Feminino , Progesterona , Suínos
6.
Pediatr Rheumatol Online J ; 19(1): 72, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980237

RESUMO

BACKGROUND: We examined influences of conditioned media from chondrocytes (Ch) on juvenile idiopathic arthritis synovial fibroblasts (JFLS) and potential for JFLS to undergo endochondral bone formation (EBF). METHODS: Primary cells from three control fibroblast-like synoviocytes (CFLS) and three JFLS were cultured in Ch-conditioned media and compared with untreated fibroblast-like synoviocytes (FLS). RNA was analyzed by ClariomS microarray. FLS cells cultured in conditioned media were exposed to either TGFBR1 inhibitor LY3200882 or exogenous BMP4 and compared with FLS cultured in conditioned media from Ch (JFLS-Ch). Media supernatants were analyzed by ELISA. RESULTS: In culture, JFLS downregulate BMP2 and its receptor BMPR1a while upregulating BMP antagonists (NOG and CHRD) and express genes (MMP9, PCNA, MMP12) and proteins (COL2, COLX, COMP) associated with chondrocytes. Important TGFß superfamily member gene expression (TGFBI, MMP9, COL1A1, SOX6, and MMP2) is downregulated when JFLS are cultured in Ch-conditioned media. COL2, COLX and COMP protein expression decreases in JFLS-Ch. BMP antagonist protein (NOG, CHRD, GREM, and FST) secretion is significantly increased in JFLS-Ch. Protein phosphorylation increases in JFLS-Ch exposed to exogenous BMP4, and chondrocyte-like phenotype is restored in BMP4 presence, evidenced by increased secretion of COL2 and COLX. Inhibition of TGFBR1 in JFLS-Ch results in overexpression of COL2. CONCLUSIONS: JFLS are chondrocyte-like, and Ch-conditioned media can abrogate this phenotype. The addition of exogenous BMP4 causes JFLS-Ch to restore this chondrocyte-like phenotype, suggesting that JFLS create a microenvironment favorable for endochondral bone formation, thereby contributing to joint growth disturbances in juvenile idiopathic arthritis.


Assuntos
Proteína Morfogenética Óssea 4 , Transtornos do Crescimento , Osteogênese , Receptor do Fator de Crescimento Transformador beta Tipo I , Sinoviócitos/metabolismo , Proteínas da Superfamília de TGF-beta/metabolismo , Artrite Juvenil/complicações , Artrite Juvenil/metabolismo , Proteína Morfogenética Óssea 4/antagonistas & inibidores , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/fisiologia , Condrócitos/fisiologia , Meios de Cultivo Condicionados/farmacologia , Regulação da Expressão Gênica , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/metabolismo , Humanos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Gene ; 787: 145627, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33831497

RESUMO

The objective of this study was to identify the gonadal somatic cells in the Yesso scallop using a novel molecular marker. This study is the first to identify the bone morphogenetic protein 2a (Bmp2a) gene as a gonadal somatic cell-specific gene in this bivalve. We performed a transcriptomic survey to identify the transforming growth factor-ß (TGFß) superfamily members that act in Yesso scallop gonad development. BLAST survey, phylogenetic tree, and RT-PCR analyses screened BMP molecules (i.e., bmp2a and bmp10a), which are members of the TGFß superfamily that show gonad-specific expression. Among the BMPs from the Yesso scallop, in situ hybridization accompanied by RNAscope assay identified that bmp2a mRNA was specifically expressed in the gonadal somatic cells localized in the interspace between germ cells. Real-time quantitative PCR (qPCR) analysis revealed that bmp2a mRNA expression increased during the reproductive phase. The relative expression of bmp2a mRNA was lowest at the beginning of the growing stage and peaked at the mature stage in both sexes. These observations indicate that bmp2a-positive gonadal somatic cells support germ cell growth and differentiation during the reproductive phase for both sexes. This study provides new insights into gonadal somatic cell biology in marine invertebrates and we propose that TGFß signaling is necessary for gonad development in bivalves.


Assuntos
Gônadas/citologia , Gônadas/metabolismo , Pectinidae/metabolismo , Proteínas da Superfamília de TGF-beta/metabolismo , Animais , Antígenos de Diferenciação , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Simulação por Computador , Feminino , Marcadores Genéticos , Gônadas/crescimento & desenvolvimento , Hibridização In Situ , Masculino , Pectinidae/citologia , Pectinidae/genética , Pectinidae/crescimento & desenvolvimento , Filogenia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodução , Transdução de Sinais , Proteínas da Superfamília de TGF-beta/genética , Distribuição Tecidual , Transcriptoma
8.
Cell Signal ; 77: 109826, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33160018

RESUMO

Most myocardial pathologic conditions are associated with cardiac fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix (ECM) proteins. Although replacement fibrosis plays a reparative role after myocardial infarction, excessive, unrestrained or dysregulated myocardial ECM deposition is associated with ventricular dysfunction, dysrhythmias and adverse prognosis in patients with heart failure. The members of the Transforming Growth Factor (TGF)-ß superfamily are critical regulators of cardiac repair, remodeling and fibrosis. TGF-ßs are released and activated in injured tissues, bind to their receptors and transduce signals in part through activation of cascades involving a family of intracellular effectors the receptor-activated Smads (R-Smads). This review manuscript summarizes our knowledge on the role of Smad signaling cascades in cardiac fibrosis. Smad3, the best-characterized member of the family plays a critical role in activation of a myofibroblast phenotype, stimulation of ECM synthesis, integrin expression and secretion of proteases and anti-proteases. In vivo, fibroblast Smad3 signaling is critically involved in scar organization and exerts matrix-preserving actions. Although Smad2 also regulates fibroblast function in vitro, its in vivo role in rodent models of cardiac fibrosis seems more limited. Very limited information is available on the potential involvement of the Smad1/5/8 cascade in cardiac fibrosis. Dissection of the cellular actions of Smads in cardiac fibrosis, and identification of patient subsets with overactive or dysregulated myocardial Smad-dependent fibrogenic responses are critical for design of successful therapeutic strategies in patients with fibrosis-associated heart failure.


Assuntos
Infarto do Miocárdio/patologia , Proteínas Smad/metabolismo , Animais , Diabetes Mellitus/patologia , Proteínas da Matriz Extracelular/metabolismo , Humanos , Infarto do Miocárdio/metabolismo , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Transdução de Sinais , Proteínas da Superfamília de TGF-beta/metabolismo
9.
Front Immunol ; 11: 2115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117332

RESUMO

The epididymis is an important male accessory sex organ where sperm motility and fertilization ability develop. When spermatozoa carrying foreign antigens enter the epididymis, the epididymis shows "immune privilege" to tolerate them. It is well-known that a tolerogenic environment exists in the caput epididymis, while pro-inflammatory circumstances prefer the cauda epididymis. This meticulously regulated immune environment not only protects spermatozoa from autoimmunity but also defends spermatozoa against pathogenic damage. Epididymitis is one of the common causes of male infertility. Up to 40% of patients suffer from permanent oligospermia or azoospermia. This is related to the immune characteristics of the epididymis itself. Moreover, epididymitis induced by different pathogenic microbial infections has different characteristics. This article elaborates on the distribution and immune response characteristics of epididymis immune cells, the role of epididymis epithelial cells (EECs), and the epididymis defense against different pathogenic infections (such as uropathogenic Escherichia coli, Chlamydia trachomatis, and viruses to provide therapeutic approaches for epididymitis and its subsequent fertility problems.


Assuntos
Epididimo/imunologia , Epididimite/imunologia , Espermatozoides/imunologia , Ativinas/fisiologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Barreira Hematotesticular , Infecções por Chlamydia/imunologia , Chlamydia trachomatis/imunologia , Defensinas/fisiologia , Epididimite/complicações , Epididimite/epidemiologia , Epididimite/microbiologia , Infecções por Escherichia coli/imunologia , Humanos , Sistema Imunitário/citologia , Indolamina-Pirrol 2,3,-Dioxigenase/fisiologia , Infertilidade Masculina/etiologia , Infertilidade Masculina/imunologia , Infertilidade Masculina/microbiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas da Superfamília de TGF-beta/fisiologia , Escherichia coli Uropatogênica/imunologia , Viroses/imunologia , Adulto Jovem
10.
Games Health J ; 9(6): 446-452, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32498637

RESUMO

Objective: To evaluate the effect of exergaming in the plasma levels of adipokines (interleukin [IL]-1ß, IL-6, IL-8, and tumor necrosis factor-alpha [TNF-α]), Th1 (IL-2, IL-12, and interferon gamma [IFN-γ]), Th2 (IL-4 and IL-33), Th17 (IL-17 and IL-23), and regulatory T (Treg) (IL-10 and transforming growth factor-beta [TGF-ß]) in cancer patients undergoing treatment. Materials and Methods: We conducted a quasi-experimental control clinical trial using exergaming in all groups through the Xbox 360 Kinect™. The game used in this study was called Your Shape Fitness Evolved 2012. The volunteer participants played the game two to three times per week, for a total of 20 sessions. Forty-five volunteer participants were divided into 3 groups: cancer patients undergoing chemotherapy and/or radiotherapy treatment (chemotherapy and/or radiotherapy group CRG; n = 15); cancer patients who finished chemotherapy and/or radiotherapy treatment (cancer accompaniment group CAG; n = 15); and the control group (volunteers without a cancer diagnosis CG; n = 15). In the pre- and post-training period, all volunteers submitted to blood collection procedures using the enzyme-linked immunosorbent assay (ELISA). This test was used to obtain the levels of adipokines expression (IL-1ß, IL-6, IL-8, and TNF-α) and the cytokine profiles Th1 (IL-2, IL-12, and IFN-γ), Th2 (IL-4 and IL-33), Th17 (IL-17 and IL-23), and Treg (IL-10 and TGF-ß). Results: After exergaming, the CRG showed significant reductions in proinflammatory cytokines (IL-6: P < 0.05; IL-10: P = 0.038; TGF-ß: P = 0.049) and for CAG (IL-10: P = 0.034), as well as a reduction in the expression of cytokines related to the action of T lymphocytes. Conclusion: Exergaming promoted changes in the expression of cytokine profiles IL-6, IL-10, and TGF-ß, which correlated with the action profiles of CD4+ T lymphocytes.


Assuntos
Exercício Físico/psicologia , Interleucina-10/análise , Neoplasias/genética , Proteínas da Superfamília de TGF-beta/análise , Jogos de Vídeo/normas , Adulto , Idoso , Feminino , Expressão Gênica/fisiologia , Humanos , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Proteínas da Superfamília de TGF-beta/sangue , Jogos de Vídeo/psicologia
11.
Bone ; 137: 115456, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32473314

RESUMO

Teeth consist of two major tissues, enamel and dentin, which are formed during development by epithelial and mesenchymal cells, respectively. Rodent incisors are useful experimental models for studying the molecular mechanisms of tooth formation because they are simultaneously growing in not only embryos but also adults. Members of the transforming growth factor-ß (TGF-ß) family regulate epithelial-mesenchymal interactions through an essential coactivator, Smad4. In the present study, we established Smad4 conditional knockout (cKO) mice and examined phenotypes in adult incisors. Smad4 cKO mice died with severe anemia within one month. Phosphorylated Smad1/5/9 and Smad2/3 were detected in epithelial cells in both control and Smad4 cKO mice. Disorganized and hypoplastic epithelial cells, such as ameloblasts, were observed in Smad4 cKO mice. Moreover, alkaline phosphatase expression and iron accumulation were reduced in dental epithelial cells in Smad4 cKO mice. These findings suggest that TGF-ß family signaling through Smad4 is required for the differentiation and functions of dental epithelial cells in adult mouse incisors.


Assuntos
Diferenciação Celular , Células Epiteliais , Incisivo , Proteína Smad4 , Proteínas da Superfamília de TGF-beta , Animais , Camundongos , Camundongos Knockout , Proteína Smad4/fisiologia , Proteínas da Superfamília de TGF-beta/fisiologia
12.
Genes (Basel) ; 11(3)2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32213808

RESUMO

During embryonic development in vertebrates, morphogens play an important role in cell fate determination and morphogenesis. Bone morphogenetic proteins (BMPs) belonging to the transforming growth factor-ß (TGF-ß) family control the dorsal-ventral (DV) patterning of embryos, whereas other morphogens such as fibroblast growth factor (FGF), Wnt family members, and retinoic acid (RA) regulate the formation of the anterior-posterior (AP) axis. Activation of morphogen signaling results in changes in the expression of target genes including transcription factors that direct cell fate along the body axes. To ensure the correct establishment of the body plan, the processes of DV and AP axis formation must be linked and coordinately regulated by a fine-tuning of morphogen signaling. In this review, we focus on the interplay of various intracellular regulatory mechanisms and discuss how communication among morphogen signaling pathways modulates body axis formation in vertebrate embryos.


Assuntos
Padronização Corporal , Comunicação Celular , Proteínas da Superfamília de TGF-beta/metabolismo , Proteínas Wnt/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Proteínas da Superfamília de TGF-beta/genética , Proteínas Wnt/genética
13.
Reprod Fertil Dev ; 32(6): 539-552, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32024582

RESUMO

Survival of the embryo and establishment of a pregnancy is a critical period in the reproductive function of female cattle. This review examines how the transforming growth factor-ß (TGFB) superfamily (i.e. bone morphogenetic protein (BMP) 15, growth differentiation factor (GDF) 9, anti-Müllerian hormone (AMH)) and interferon-τ (IFNT) affect ovarian function and embryo development. The oocyte in a primary follicle secretes BMP15 and GDF9, which, together, organise the surrounding granulosa and theca cells into the oocyte-cumulus-follicle complex. At the same time, the granulosa secretes AMH, which affects the oocyte. This autocrine-paracrine dialogue between the oocyte and somatic cells continues throughout follicle development and is fundamental in establishing the fertilisation potential and embryo developmental competency of oocytes. The early bovine embryo secretes IFNT, which acts at the uterine endometrium, corpus luteum and blood leucocytes. IFNT is involved in the maternal recognition of pregnancy and immunomodulation to prevent rejection of the embryo, and supports progesterone secretion. Manipulation of BMP15, GDF9, AMH and IFNT in both invivo and invitro studies has confirmed their importance in reproductive function in female cattle. This review makes the case that a deeper understanding of the biology of BMP15, GDF9, AMH and IFNT will lead to new strategies to increase embryo survival and improve fertility in cattle. The enhancement of oocyte quality, early embryo development and implantation is considered necessary for the next step change in the efficiency of natural and assisted reproduction in cattle.


Assuntos
Comunicação Celular , Desenvolvimento Embrionário , Fertilidade , Interferon Tipo I/metabolismo , Ovário/metabolismo , Proteínas da Gravidez/metabolismo , Proteínas da Superfamília de TGF-beta/metabolismo , Animais , Hormônio Antimülleriano/metabolismo , Proteína Morfogenética Óssea 15/metabolismo , Bovinos , Feminino , Fator 9 de Diferenciação de Crescimento/metabolismo , Gravidez , Técnicas de Reprodução Assistida/veterinária , Transdução de Sinais
14.
Genomics ; 112(1): 332-345, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30779940

RESUMO

Guard hair and cashmere undercoat are developed from primary and secondary hair follicle, respectively. Little is known about the gene expression differences between primary and secondary hair follicle cycling. In this study, we obtained RNA-seq data from cashmere and milk goats grown at four different seasons. We studied the differentially expressed genes (DEGs) during the yearly hair follicle cycling, and between cashmere and milk goats. WNT, NOTCH, MAPK, BMP, TGFß and Hedgehog signaling pathways were involved in hair follicle cycling in both cashmere and milk goat. However, Milk goat DEGs between different months were significantly more than cashmere goat DEGs, with the largest difference being identified in December. Some expression dynamics were confirmed by quantitative PCR and western blot, and immunohistochemistry. This study offers new information sources related to hair follicle cycling in milk and cashmere goats, which could be applicable to improve the wool production and quality.


Assuntos
Cabras/genética , Folículo Piloso/metabolismo , Transcriptoma , Animais , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Genômica , Cabras/metabolismo , Folículo Piloso/crescimento & desenvolvimento , RNA-Seq , Estações do Ano , Proteínas da Superfamília de TGF-beta/genética , Proteínas da Superfamília de TGF-beta/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
15.
Domest Anim Endocrinol ; 70: 106398, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677486

RESUMO

The aim of this study was to investigate some of the growth and transcriptional factors originating from oocytes and granulosa cells in follicular fluid and to identify the relationships between the basic blood metabolite-metabolic hormones and intrafollicular lipopolysaccharide (LPS) concentrations. Thirty cows included in the study were allocated into 2 groups comprising 15 cows with healthy preovulatory follicles (cyclic cows) and 15 cows with confirmed cystic follicles. The ovaries and uteri of all cows were assessed by transrectal ultrasonographic examination. Blood serum samples were collected at 15, 25, 35, 45, and 55 d after calving for analysis of nonesterified fatty acids, ß-hydroxybutyrate, insulin, glucose, IGF-I, ACTH, and cortisol. Ovaries and uteri were examined using transrectal ultrasound. Vaginal discharge was evaluated on the same days. Follicular fluid was also aspirated on days 35-55 from the healthy preovulatory follicles and cystic follicles using a transvaginal ovum pickup method. The densitometric levels of inhibin-α, growth and differentiation factor (GDF-9), bone morphogenetic protein (BMP-6), and GATA-4 and GATA-6 proteins were analyzed by the Western blotting technique; the concentrations of antimullerian hormone (AMH), IGF-I, estradiol-17 beta (E2), and progesterone (P4) were determined by ELISA; and the concentrations of LPS in the follicular fluid were measured by the Limulus amebocyte lysate test. The serum insulin, ACTH, and cortisol concentrations were higher in cystic cows than cyclic cows, but serum IGF-I concentrations were lower in cystic cows. The IGF-I concentrations of cystic follicular fluids were lower, whereas AMH levels were significantly greater than those of healthy preovulatory follicular fluids. The cystic follicles had significantly lower expression levels of GDF-9, BMP-6, GATA-4, and GATA-6; in contrast, inhibin-α expression and LPS concentrations were significantly higher than in healthy preovulatory follicles. The proportion of pathologic vaginal discharge within 25 d postpartum in cystic cows were higher than in the cyclic group. In conclusion, it is suggested that intrafollicular dysregulation of the transforming growth factor-ß superfamily, growth, and transcriptional factors is affected by high intrafollicular LPS concentrations and systemic metabolic changes and these disturbances may be responsible for the generation of ovarian cysts.


Assuntos
Doenças dos Bovinos/metabolismo , Lipopolissacarídeos/metabolismo , Cistos Ovarianos/veterinária , Folículo Ovariano/crescimento & desenvolvimento , Proteínas da Superfamília de TGF-beta/metabolismo , Fatores de Transcrição/metabolismo , Animais , Glicemia , Bovinos , Doenças dos Bovinos/sangue , Feminino , Regulação da Expressão Gênica , Cistos Ovarianos/metabolismo , Proteínas da Superfamília de TGF-beta/genética , Fatores de Transcrição/genética
16.
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 Gênica , Via de Sinalização Wnt , beta Catenina/metabolismo
17.
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 Força/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
18.
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
19.
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
20.
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 Endóssea/métodos , Proteínas da Superfamília de TGF-beta/uso terapêutico , Aumento do Rebordo Alveolar/métodos , Estudos de Avaliação como Assunto , Humanos
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