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1.
Front Immunol ; 10: 2449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824476

RESUMO

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated with an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by in silico analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa (n = 8) showed increased expression of 40 microRNAs and 2,120 mRNAs, while 49 microRNAs and 1,734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and eight members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3'UTR, were decreased (-3.9 to -3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, and miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through qPCR and ELISA, respectively. We determined that aUC (n = 24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC (n = 10) and controls (n = 6). Moreover, both microRNAs were inversely correlated with IL-33 expression, while miR-378c does not show a significant difference. To evaluate the effect of TNFα on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. Based on these findings, we selected miR-378a-3p to exploring the molecular mechanism involved by in vitro assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence ß-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNFα decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis.

2.
Free Radic Biol Med ; 143: 203-208, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408725

RESUMO

The ability to respond to fluctuations of reactive oxygen species (ROS) within the cell is a central aspect of mammalian physiology. This dynamic process depends on the coordinated action of transcriptional factors to promote the expression of genes encoding for antioxidant enzymes. Here, we demonstrate that the transcriptional coregulators, PGC-1α and NCoR1, are essential mediators of mitochondrial redox homeostasis in skeletal muscle cells. Our findings reveal an antagonistic role of these coregulators in modulating mitochondrial antioxidant induction through Sod2 transcriptional control. Importantly, the activation of this mechanism by either PGC-1α overexpression or NCoR1 knockdown attenuates mitochondrial ROS levels and prevents cell death caused by lipid overload in skeletal muscle cells. The opposing actions of coactivators and corepressors, therefore, exert a commanding role over cellular antioxidant capacity.

3.
PLoS Genet ; 15(1): e1007863, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30640919

RESUMO

Many neurons are unable to regenerate after damage. The ability to regenerate after an insult depends on life stage, neuronal subtype, intrinsic and extrinsic factors. C. elegans is a powerful model to test the genetic and environmental factors that affect axonal regeneration after damage, since its axons can regenerate after neuronal insult. Here we demonstrate that diapause promotes the complete morphological regeneration of truncated touch receptor neuron (TRN) axons expressing a neurotoxic MEC-4(d) DEG/ENaC channel. Truncated axons of different lengths were repaired during diapause and we observed potent axonal regrowth from somas alone. Complete morphological regeneration depends on DLK-1 but neuronal sprouting and outgrowth is DLK-1 independent. We show that TRN regeneration is fully functional since animals regain their ability to respond to mechanical stimulation. Thus, diapause induced regeneration provides a simple model of complete axonal regeneration which will greatly facilitate the study of environmental and genetic factors affecting the rate at which neurons die.


Assuntos
Axônios , Proteínas de Caenorhabditis elegans/genética , MAP Quinase Quinase Quinases/genética , Proteínas de Membrana/genética , Regeneração Nervosa/genética , Malformações do Sistema Nervoso/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Diapausa/genética , Diapausa/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Necrose/genética , Necrose/patologia , Malformações do Sistema Nervoso/fisiopatologia , Malformações do Sistema Nervoso/reabilitação , Células Receptoras Sensoriais/metabolismo , Tato/genética
4.
Methods Mol Biol ; 1918: 191-197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30580410

RESUMO

We present a protocol for the study of inter and transgenerational behavioral responses to pathogenesis in C. elegans. Transgenerational and intergenerational effects of microbes are best studied in model organisms with short life cycles, large progenies, and quantifiable cellular and behavioral outcomes. This chapter encompasses basic techniques used to study the consequences of bacterial infection in C. elegans, including worm growth, quantification of dauer larvae, and quantification of bacterial population dynamics within individual animals. Specific methods for studying transgenerational effects and their duration are also described.


Assuntos
Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/fisiologia , Diapausa , Interações Hospedeiro-Patógeno , Animais , Infecções Bacterianas/microbiologia , Modelos Animais de Doenças , Ácido Hipocloroso/farmacologia
5.
Mol Psychiatry ; 23(12): 2363-2374, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30171212

RESUMO

The typical abnormalities observed in the brain of Alzheimer's disease (AD) patients include synaptic alterations, neuronal death, brain inflammation, and the accumulation of protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Despite the development of many animal and in vitro models for AD, there is a lack of an experimental approach that fully recapitulates essential aspects of the disease in human cells. Here, we report the generation of a new model to study AD, consisting of cerebral organoids (COs) produced from human-induced pluripotent stem cells (iPSCs). Under our experimental conditions, COs grow to form three-dimensional (3D) structures containing neural areas with cortical-like organization. Analysis of COs by histological and biochemical methods revealed that organoids produced from iPSCs derived from patients affected by familial AD or Down syndrome (DS) spontaneously develop over time pathological features of AD, including accumulation of structures highly reminiscent to amyloid plaques and neurofibrillary tangles. These pathological abnormalities were not observed in COs generated from various controls, including human iPSCs from healthy individuals, human iPSCs from patients affected by Creutzfeldt-Jakob disease, mouse embryonic stem cells (ESCs), or mouse iPSCs. These findings enable modeling genetic AD in a human cellular context in a 3D cortical-like tissue developed in vitro from patient-specific stem cells. This system provides a more relevant disease model compared to pre-existing methods and offers a new platform for discovery of novel targets and screening of drugs for therapeutic intervention.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Organoides/metabolismo , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/fisiologia , Encéfalo/metabolismo , Técnicas de Cultura de Células/métodos , Córtex Cerebral , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lactente , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , Neurônios/metabolismo , Fosforilação , Placa Amiloide/metabolismo , Proteínas tau/genética , Proteínas tau/fisiologia
6.
Mol Neurobiol ; 55(11): 8563-8585, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29564811

RESUMO

Astrocytes play metabolic and structural support roles and contribute to the integrity of the blood-brain barrier (BBB), linking communication between neurons and the endothelium. Cyclin-dependent kinase 5 (CDK5) likely exerts a dual effect on the endothelium and astrocytes due to its involvement in migration and angiogenesis; the overactivation of CDK5 is associated with dysfunction in glutamate recapture and hypoxia. Recently, we proposed that CDK5-targeted astrocytes facilitate the recovery of neurological and motor function in transplanted ischemic rats. In the current study, we treated cerebral ischemic rats and endothelial cells exposed to glutamate toxicity with CDK5 knock-down (CDK5-KD) astrocytes to determine the role of CDK5 in neurovascular integrity. We found that the effects of CDK5-KD were sustained for 4 months, preventing neuronal and astrocyte loss, facilitating the recovery of the BBB via the production of BDNF by endogenous astrocytes (GFP-) surrounding vessels in the motor cortex and the corpus callosum of global ischemic rats, and improving neurological performance. These findings were supported by the in vitro findings of increased transendothelial resistance, p120-ctn+ adhesion and reduced intercellular gaps induced by a CDK5 inhibitor (roscovitine) in bEnd.3 cells in a glutamate-toxicity model. Additionally, CDK5-KD astrocytes in co-culture protected the endothelial cell viability, increased BDNF release from astrocytes, increased BDNF immunoreactivity in neighboring astrocytes and endothelial cells and enhanced cell adhesion in a glutamate-toxicity model. Altogether, these findings suggest that a CDK5 reduction in astrocytes protects the endothelium, which promotes BDNF release, endothelial adhesion, and the recovery of neurovascular unit integrity and brain function in ischemic rats.


Assuntos
Astrócitos/transplante , Isquemia Encefálica/enzimologia , Isquemia Encefálica/terapia , Encéfalo/irrigação sanguínea , Quinase 5 Dependente de Ciclina/metabolismo , Técnicas de Silenciamento de Genes , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Adesão Celular , Linhagem Celular , Técnicas de Cocultura , Corpo Caloso/metabolismo , Modelos Animais de Doenças , Impedância Elétrica , Células Endoteliais/metabolismo , Glutamatos/toxicidade , Masculino , Camundongos , Atividade Motora , Córtex Motor/metabolismo , Córtex Motor/patologia , Neurônios/metabolismo , Ratos Wistar , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
7.
mBio ; 8(5)2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-29018118

RESUMO

The dynamic response of organisms exposed to environmental pathogens determines their survival or demise, and the outcome of this interaction depends on the host's susceptibility and pathogen-dependent virulence factors. The transmission of acquired information about the nature of a pathogen to progeny may ensure effective defensive strategies for the progeny's survival in adverse environments. Environmental RNA interference (RNAi) is a systemic and heritable mechanism and has recently been linked to antibacterial and antifungal defenses in both plants and animals. Here, we report that the second generation of Caenorhabditis elegans living on pathogenic bacteria can avoid bacterial infection by entering diapause in an RNAi pathway-dependent mechanism. Furthermore, we demonstrate that the information encoding this survival strategy is transgenerationally transmitted to the progeny via the maternal germ line.IMPORTANCE Bacteria vastly influence physiology and behavior, and yet, the specific mechanisms by which they cause behavioral changes in hosts are not known. We use C. elegans as a host and the bacteria they eat to understand how microbes trigger a behavioral change that helps animals to survive. We found that animals faced with an infection for two generations could enter a hibernationlike state, arresting development by forming dauer larvae. Dauers have closed mouths and effectively avoid infection. Animals accumulate information that is transgenerationally transmitted to the next generations to form dauers. This work gives insight on how bacteria communicate in noncanonical ways with their hosts, resulting in long-lasting effects providing survival strategies to the community.


Assuntos
Bactérias/patogenicidade , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/fisiologia , Diapausa , Interferência de RNA , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Larva/fisiologia , RNA Interferente Pequeno/genética , Transdução de Sinais
8.
Front Mol Neurosci ; 10: 88, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28420961

RESUMO

Astrocytes are commonly involved in negative responses through their hyperreactivity and glial scar formation in excitotoxic and/or mechanical injuries. But, astrocytes are also specialized glial cells of the nervous system that perform multiple homeostatic functions for the survival and maintenance of the neurovascular unit. Astrocytes have neuroprotective, angiogenic, immunomodulatory, neurogenic, and antioxidant properties and modulate synaptic function. This makes them excellent candidates as a source of neuroprotection and neurorestoration in tissues affected by ischemia/reperfusion, when some of their deregulated genes can be controlled. Therefore, this review analyzes pro-survival responses of astrocytes that would allow their use in cell therapy strategies.

9.
Mol Neurobiol ; 54(9): 6681-6696, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-27744570

RESUMO

Cerebral ischemia is a cerebrovascular episode that generates a high incidence of death and physical and mental disabilities worldwide. Excitotoxicity, release of free radicals, and exacerbated immune response cause serious complications in motor and cognitive areas during both short and long time frames post-ischemia. CDK5 is a kinase that is widely involved in the functions of neurons and astrocytes, and its over-activation is implicated in neurodegenerative processes. In this study, we evaluated the brain parenchymal response to the transplantation of CDK5-knockdown astrocytes into the somatosensory cortex after ischemia in rats. Male Wistar rats were subjected to the two-vessel occlusion (2VO) model of global cerebral ischemia and immediately transplanted with shCDK5miR- or shSCRmiR-transduced astrocytes or with untransduced astrocytes (Control). Our findings showed that animals transplanted with shCDK5miR astrocytes recovered motor and neurological performance better than with those transplanted with WT or shSCRmiR astrocytes. Cell transplantation produced an overall prevention of neuronal loss, and CDK5-knockdown astrocytes significantly increased the immunoreactivity (IR) of endogenous GFAP in branches surrounding blood vessels, accompanied by the upregulation of PECAM-1 IR in the walls of vessels in the motor and somatosensory regions and by an increase in Ki67 IR in the subventricular zone (SVZ), partially associated with the production of BDNF. Together, our data suggest that transplantation of shCDK5miR astrocytes protects the neurovascular unit in ischemic rats, allowing the motor and neurological function recovery.


Assuntos
Astrócitos/metabolismo , Astrócitos/transplante , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Quinase 5 Dependente de Ciclina/deficiência , Neuroproteção/fisiologia , Animais , Células Cultivadas , Técnicas de Silenciamento de Genes/métodos , Masculino , Ratos , Ratos Wistar
10.
Adv Genet ; 92: 53-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26639915

RESUMO

Food availability determines developmental rate, behavior, and survival of animals. Animals that enter diapause or hibernate in response to lack of food have a double advantage: they are able to adapt to environmental and cellular challenges and survive to these challenges for a prolonged time. The metabolic and physiological adaptations that make possible diapause and hibernation also provide a favorable cellular environment for tissue protection. This review highlights the benefits of dormancy on neuronal protection in the model organism Caenorhabditis elegans and small mammals such as squirrels. Additionally, I discuss the link between metabolic restructuring occurring in diapause and changes in gene expression with the increased capacity of diapausing animals to protect neurons from degeneration and potentially foster their regeneration.


Assuntos
Caenorhabditis elegans/fisiologia , Neurônios/citologia , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Diapausa de Inseto , Hibernação , Mamíferos/fisiologia , Neurônios/fisiologia , Neuroproteção , Inanição
11.
Elife ; 42015 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-25798732

RESUMO

During development, biomechanical forces contour the body and provide shape to internal organs. Using genetic and molecular approaches in combination with a FRET-based tension sensor, we characterized a pulling force exerted by the elongating pharynx (foregut) on the anterior epidermis during C. elegans embryogenesis. Resistance of the epidermis to this force and to actomyosin-based circumferential constricting forces is mediated by FBN-1, a ZP domain protein related to vertebrate fibrillins. fbn-1 was required specifically within the epidermis and FBN-1 was expressed in epidermal cells and secreted to the apical surface as a putative component of the embryonic sheath. Tiling array studies indicated that fbn-1 mRNA processing requires the conserved alternative splicing factor MEC-8/RBPMS. The conserved SYM-3/FAM102A and SYM-4/WDR44 proteins, which are linked to protein trafficking, function as additional components of this network. Our studies demonstrate the importance of the apical extracellular matrix in preventing mechanical deformation of the epidermis during development.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/fisiologia , Desenvolvimento Embrionário , Epiderme/patologia , Proteínas dos Microfilamentos/metabolismo , Estresse Mecânico , Animais , Fenômenos Biomecânicos , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/química , Epiderme/embriologia , Epiderme/metabolismo , Éxons/genética , Fibrilinas , Transferência Ressonante de Energia de Fluorescência , Genes de Helmintos , Morfogênese , Mutação/genética , Faringe/fisiologia , Fenótipo , Estrutura Terciária de Proteína , Processamento de RNA/genética , Vertebrados/metabolismo
12.
PLoS Genet ; 8(12): e1003141, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23300463

RESUMO

Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO-dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment.


Assuntos
Axônios , Proteínas de Caenorhabditis elegans/metabolismo , Fator de Crescimento Insulin-Like I , Insulina , Degeneração Neural , Fatores de Transcrição/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Cálcio/metabolismo , Catalase , Fatores de Transcrição Forkhead , Regulação da Expressão Gênica , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas de Membrana , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Degeneração Neural/genética , Degeneração Neural/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase
13.
Nat Methods ; 7(7): 554-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20512143

RESUMO

We expressed SID-1, a transmembrane protein from Caenorhabditis elegans that is required for systemic RNA interference (RNAi), in C. elegans neurons. This expression increased the response of neurons to double-stranded (ds)RNA delivered by feeding. Mutations in the lin-15b and lin-35 genes enhanced this effect. Worms expressing neuronal SID-1 showed RNAi phenotypes when fed with bacteria expressing dsRNA for known neuronal genes and for uncharacterized genes with no previously known neuronal phenotypes. Neuronal expression of sid-1 decreased nonneuronal RNAi, suggesting that neurons expressing transgenic sid-1(+) served as a sink for dsRNA. This effect, or a sid-1(-) background, can be used to uncover neuronal defects for lethal genes. Expression of sid-1(+) from cell-specific promoters in sid-1 mutants results in cell-specific feeding RNAi. We used these strains to identify a role for integrin signaling genes in mechanosensation.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Interferência de RNA/fisiologia , Animais , Proteínas de Caenorhabditis elegans/genética , Regulação da Expressão Gênica/fisiologia , Genes Letais , Proteínas de Membrana/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Nat Methods ; 7(5): 407-11, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20364149

RESUMO

We describe a method for conditional regulation of gene expression based on the processing of an intron cassette. The RNA processing factor MEC-8 is necessary for the function of the Caenorhabditis elegans touch receptor neurons; mec-8 mutants are touch insensitive. We show here that this insensitivity involves the loss of MEC-8-dependent splicing of mec-2, which encodes a component of the mechanosensory transduction complex. MEC-8 is needed to remove the ninth intron in mec-2 pre-mRNA to form the longest of three mRNAs, mec-2a. Without MEC-8, splicing causes the termination of the transcript. Inclusion of mec-2 intron 9 is sufficient to convey mec-8-dependent regulation on other genes and, in mec-8(u218ts) mutants, resulted in their temperature-dependent expression. Because mec-8 is expressed ubiquitously in embryos and extensively in larvae, this system should produce temperature-sensitive expression for most genes. As an example, we report a strain that exhibits temperature-dependent RNA interference.


Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Interferência de RNA/fisiologia , Processamento de RNA/fisiologia , Proteínas de Ligação a RNA/fisiologia , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Genes de Helmintos , Íntrons/fisiologia , Proteínas de Membrana/genética , Temperatura Ambiente
15.
Acta odontol. venez ; 46(3): 361-369, dic. 2008. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-630092

RESUMO

The medicine and dentistry entering a new era in which the news therapy approaches like genetic therapy, cellular therapy, engineering tissue and medicine regenerative they extended the arsenal of possibilities for our patients. The Stem cells in the field of the regenerative medicine, by its characteristics of self renewal, expansion and differentiation, have shown to be an important alternative for the treatment of pathologies and to alterations in the teeth and periodontal structures. The tissue regeneration it implies the replacement of weaves affected with identical cells that can be generated from the stimulation of Mesenchymal Stem Cells (MSCs) by different involved molecular and cellular mechanisms in the dental morphogenetic; for that reason different options look for to facilitate the use of MSCs like clinical treatment of periodontal diseases and functional oral injury


La medicina y odontología clínica están entrando en una nueva era en la cual los nuevos enfoques terapéuticos como la terapia génica, la terapia celular, la ingeniería tisular y la medicina regenerativa ampliaran el arsenal de posibilidades para nuestros pacientes. Las células Madres en el campo de la medicina regenerativa, por sus características de autorrenovación, proliferación y diferenciación, han mostrado ser una importante alternativa para el tratamiento de patologías y alteraciones en los dientes y estructuras periodontales. La regeneración tisular implica el reemplazo de tejidos afectados con células idénticas que pueden ser generadas a partir de la estimulación de células Madres mesenquimatosas (MSCs) por diferentes mecanismos moleculares y celulares involucrados en la morfogénesis dental; por ello se buscan diferentes opciones para facilitar la utilización de MSCs como tratamiento clínico de enfermedades periodontales y traumas bucales funcionales. La estandarización de protocolos para la obtención de ASCs autólogas de diferentes tejidos, eliminará problemas de rechazo inmunológico, permitiendo una completa regeneración funcional de los tejidos de la cavidad bucal


Assuntos
Humanos , Células-Tronco , Células-Tronco/microbiologia , Engenharia Tecidual/métodos , Regeneração Tecidual Guiada Periodontal/métodos , Odontologia Geral
16.
Proc Natl Acad Sci U S A ; 103(46): 17079-86, 2006 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17079490

RESUMO

The prohibitin (PHB)-domain proteins are membrane proteins that regulate a variety of biological activities, including mechanosensation, osmotic homeostasis, and cell signaling, although the mechanism of this regulation is unknown. We have studied two members of this large protein family, MEC-2, which is needed for touch sensitivity in Caenorhabditis elegans, and Podocin, a protein involved in the function of the filtration barrier in the mammalian kidney, and find that both proteins bind cholesterol. This binding requires the PHB domain (including palmitoylation sites within it) and part of the N-terminally adjacent hydrophobic domain that attaches the proteins to the inner leaflet of the plasma membrane. By binding to MEC-2 and Podocin, cholesterol associates with ion-channel complexes to which these proteins bind: DEG/ENaC channels for MEC-2 and TRPC channels for Podocin. Both the MEC-2-dependent activation of mechanosensation and the Podocin-dependent activation of TRPC channels require cholesterol. Thus, MEC-2, Podocin, and probably many other PHB-domain proteins by binding to themselves, cholesterol, and target proteins regulate the formation and function of large protein-cholesterol supercomplexes in the plasma membrane.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Colesterol/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Canais Iônicos/metabolismo , Proteínas de Membrana/metabolismo , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Sensibilidade e Especificidade , Alinhamento de Sequência
17.
Genome Biol ; 7(1): R4, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16507136

RESUMO

BACKGROUND: Genome-wide RNA interference (RNAi) screening is a very powerful tool for analyzing gene function in vivo in Caenorhabditis elegans. The effectiveness of RNAi varies from gene to gene, however, and neuronally expressed genes are largely refractive to RNAi in wild-type worms. RESULTS: We found that C. elegans strains carrying mutations in lin-35, the worm ortholog of the tumor suppressor gene p105Rb, or a subset of the genetically related synMuv B family of chromatin-modifying genes, show increased strength and penetrance for many germline, embryonic, and post-embryonic RNAi phenotypes, including neuronal RNAi phenotypes. Mutations in these same genes also enhance somatic transgene silencing via an RNAi-dependent mechanism. Two genes, mes-4 and zfp-1, are required both for the vulval lineage defects resulting from mutations in synMuv B genes and for RNAi, suggesting a common mechanism for the function of synMuv B genes in vulval development and in regulating RNAi. Enhanced RNAi in the germline of lin-35 worms suggests that misexpression of germline genes in somatic cells cannot alone account for the enhanced RNAi observed in this strain. CONCLUSION: A worm strain with a null mutation in lin-35 is more sensitive to RNAi than any other previously described single mutant strain, and so will prove very useful for future genome-wide RNAi screens, particularly for identifying genes with neuronal functions. As lin-35 is the worm ortholog of the mammalian tumor suppressor gene p105Rb, misregulation of RNAi may be important during human oncogenesis.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Interferência de RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína do Retinoblastoma/química , Animais , Caenorhabditis elegans/anatomia & histologia , Proteínas de Caenorhabditis elegans/química , Linhagem da Célula , Inativação Gênica , Genes de Helmintos , Modelos Genéticos , Mutação/genética , Sistema Nervoso/metabolismo , Fenótipo , Proteínas Repressoras/química , Supressão Genética
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