A remarkable role of growth factors in resolving oral and specific periodontal pathologies: a strategic review.

The knowledge and the understanding of the role of growth factors, their mechanisms of action, and molecular signaling pathways, which have been reviewed in this article, suggest the potential for many novel therapeutic targets, not only for applying growth factors but also for the potential use of growth factor inhibitors or agents that target specific parts of the intracellular signaling pathways in controlling oral pathologies. There remains an enormous challenge to convert some of the knowledge from basic studies of bone cell physiology and inflammatory cells to therapeutically useful techniques for the future.

Mollusk-derived growth factor and the new subfamily of adenosine deaminase-related growth factors.

Peptide and protein growth factors play critical roles in the control of proliferation, differentiation and survival of most, if not all, cell types. In this review, we describe a newly isolated growth factor from Aplysia californica, mollusk derived growth factor (MDGF), that is a member of the adenosine deaminase-related growth factor (ADGF) subfamily. Other known subfamily members from a range of invertebrate and vertebrate species include: insect-derived growth factor, Drosophila ADGFs, tsetse salivary growth factors, insect adenosine deaminases (ADAs; Lutzomyia, Culex, Aedes, Anopheles), and cat eye syndrome critical region gene 1 (CECR1) in humans, pigs, and zebrafish. ADGFs from vertebrates and invertebrates contain both an ADA domain and a novel N-terminal region of about 100 amino acids. Catalytic residues involved in ADA activity are conserved in ADGFs, and inhibitors of ADA can block ADGF activity. ADA enzymatic activity has been shown, by inhibitor and site-directed mutagenesis studies, to be related to the ability of ADGFs from many species to stimulate cell proliferation. The available evidence suggests that the conversion of adenosine to inosine (or their analogs) is important for the mitogenic actions of ADGFs. Future investigations of this novel subfamily should lead to the identification of their receptors.

Factores de crecimiento aplicados a la operatoria dental: ¿un nuevo enfoque terapéutico? / Growth factors applied to operatirve dentistry: a new therapeutic approach?

A pesar del progreso logrado en el campo de la biología pulpar, la técnica y la filosofía sobre el recubrimiento pulpar ha generado inmensas controversias. Los clínicos conocen bien los éxitos logrados cuando se trabaja sobre el conducto radicular, pero no están muy convencidos de los éxitos de los recubrimientos pulpares durante actos de operatoria dental. Investigaciones recientes han demostrado que exposiciones pulpares pueden curar mediante la formación de dentina adicional y así separar la pulpa del medio externo. Es sabido, hoy en día, que el pronóstico de un recubrimiento pulpar es un tema a tratar en la operatoria dental. Los elementos que pueden producir un recubrimiento pulpar satisfactorio son discutivos en conjutno con los llamados factores de crecimiento. El propósito de crear nueva dentina es primariamente motivado por la necesidad clínica de restaurar este tejido mineralizado. La dentina rodea y protege el centro vital de la pieza dentaria que reside en la pulpa dental. Este tejido se encuentra mineralizado en un 80 por ciento y provee, en combinación con el esmalte, la mayor estructura del total de la masa dentaria. Al igual que el esmalte, la dentina es un tejido avascular pero, a diferencia de este, las células que sintetiza la dentina (los odontoblastos) pueden permanecer vitales a través de la vida adulta y volver a generar dentina adicional. Recientes investigaciones han sugerido que si los odontoblastos ubicados en la matriz preodontoblástica se pierden, es posible inducir la diferenciación de nuevas células odontoblásticas formadoras del complejo dentinopulpar utilizando las denominadas proteínas morfogenéticas. Desarrollos satisfactorios de procesos de ingeniería molecular que puedan regenerar dentina pueden tener aplicaciones clínicas como un agente para recubrimiento pulpar potenciado como desensibilizante, debido al sellado de los túbulos dentinarios (AU)

Factores de señalización: pilares fundamentales en la regeneración ósea / Signaling factors: fundamental pillars in bone regeneration

El objetivo de este estudio es que el lector se familiarice con la biología ósea y con los aportes que ha realizado la ciencia en cuanto a regeneración ósea a partir de componentes orgánicos del propio paciente como los factores de señalización. Hoy en día, a partir de biología molecular y bioingeniería se obtienen factores de crecimiento a través de recombinaciones del DNA con el fin de generar órdenes de inducción en mecanismos biológicos óseos. La terapéutica con factores de crecimiento es una técnica específica para casos específicos (AU)

Factores de señalización: pilares fundamentales en la regeneración ósea / Signaling factors: fundamental pillars in bone regeneration

El objetivo de este estudio es que el lector se familiarice con la biología ósea y con los aportes que ha realizado la ciencia en cuanto a regeneración ósea a partir de componentes orgánicos del propio paciente como los factores de señalización. Hoy en día, a partir de biología molecular y bioingeniería se obtienen factores de crecimiento a través de recombinaciones del DNA con el fin de generar órdenes de inducción en mecanismos biológicos óseos. La terapéutica con factores de crecimiento es una técnica específica para casos específicos (AU)

The family of hepatoma-derived growth factor proteins: characterization of a new member HRP-4 and classification of its subfamilies.

Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of polypeptides named after HDGF, which was identified by its mitogenic activity towards fibroblasts. In the present study, we describe a hitherto unknown HRP, termed HRP-4. The cDNA of bovine HRP-4 (bHRP-4) predicts a polypeptide of 235 amino acids. Northern- and Western-blot analyses of various bovine tissues demonstrated that HRP-4 is only expressed in the testis. Recombinantly produced bHRP-4 and murine HDGF (mHDGF) histidine-tagged polypeptides display growth-factor activity for cultured primary human fibroblasts at an optimum concentration of 1 ng/ml in serum-free medium. The growth-factor activity declines with increasing concentrations to reach background levels at 1 microg/ml. The expression of the fusion proteins, bHRP-4-green fluorescent protein and mHDGF-green fluorescent protein, in HEK-293 cells demonstrates nuclear localization of the proteins. bHRP-4 and mHDGF bind to the glycosaminoglycans heparin and heparan sulphate, but not to chondroitin sulphate. Affinity constants determined for these interactions are between 6 and 42 nM. Comparison of the bHRP-4 amino acid sequence with HRP-1-3 and p52/75/lens epithelium-derived growth factor (LEDGF) shows that these proteins share a conserved N-terminal part of 91 amino acids but have C-termini of different lengths and charge. This demonstrates the modular structure of these proteins and allows its classification into three groups based on charge, size and sequence comparison. HRP-4, HRP-1 and HDGF are small acidic proteins, HRP-3 is a small basic protein, and HRP-2 and p52/75/LEDGF are larger basic proteins.

Divergence pattern of animal gene families and relationship with the Cambrian explosion.

There are many gene families that are specific to multicellular animals. These have either diverged from ancestral genes that are shared with fungi and/or plants or evolved from an ancestral gene unique to animals. The evolution of gene families involved in cell-cell communication and developmental control has been studied to establish whether the number of member genes increased dramatically immediately prior to or in concert with the Cambrian explosion. A molecular phylogeny-based analysis of several animal-specific gene families has revealed that gene diversification by duplication occurred during two active periods interrupted by a long intervening quiescent period. Intriguingly, the Cambrian explosion is situated in the silent period, indicating that there is no direct link between the first burst of gene diversification and the Cambrian explosion itself. The importance of gene recruitment as a possible molecular mechanism for morphological diversity, and its possible role for the Cambrian explosion, are discussed.

The influence of growth factors on the development of preimplantation mammalian embryos.

The development of the preimplantation mammalian embryo from a fertilized egg to a blastocyst capable of implanting in the uterus is a complex process. Cell division must be carefully programmed. The embryonic genome must be activated at the appropriate stage of development, and the pattern of gene expression must be carefully coordinated for the initiation of the correct program of differentiation. Cell fates must be chosen to establish specific cell types such as the inner cell mass and the trophectoderm, which give rise to the embryo proper and the placenta, respectively. This review summarizes recent findings concerning the influence of growth factors on the development of preimplantation mammalian embryos. Maternal factors secreted into the lumen of the female reproductive tract as well as substances synthesized by the developing embryo itself help to regulate this process. Studies of embryos in culture and investigations using homologous recombination to create embryos and animals null for specific genes have enabled the identification of several growth factors that appear essential for preimplantation mammalian embryo development. Some of the factors are required maternal factors; others are embryo-derived autocrine and paracrine factors. Studies using molecular biology are beginning to identify differences in the patterns of genes expressed by naturally derived embryos and those developing in culture. The knowledge gained from studies on growth factors, media, embryonic development, and gene expression should help improve culture conditions for embryos and will provide for safer outcomes from assisted reproductive procedures in human and animal clinics.

Nonandrogenic mediators of prostatic growth.

Prostate growth and development are primarily under the control of androgens; however, other factors can also influence prostatic growth through alternative pathways. This article discusses some of the major nonandrogenic mediators of prostate growth. Information on the pathways by which these factors exert their effects is also reviewed.

Molecular cloning of delta-4, a new mouse and human Notch ligand.

Complementary DNAs encoding a previously unidentified mouse Notch ligand and its human ortholog were isolated. The new Notch ligand contains a signal sequence, a DSL domain, eight epidermal growth factor-like repeats, a transmembrane domain, and an intracellular region, all of which are characteristics of members of the Delta protein family. The new protein was therefore designated Delta-4. Several previously unidentified sequences in both the extracellular and intracellular regions were shown to be conserved among vertebrate Delta proteins. The tissue distribution of Delta-4 mRNA resembles that previously described for Notch-4 (Int-3) transcripts. However, in situ hybridization with mouse lung revealed that Delta-4 mRNA is abundant in squamous alveolar cells that neighbor endothelial cells; Notch-4 expression is largely restricted to the latter cell type. Soluble forms of the extracellular portion of Delta-4 inhibit the apparent proliferation of human aortic endothelial cells, but not human pulmonary arterial endothelial cells.

Cartílago articular y factores de crecimiento (segunda parte) / Articular cartilage and growth factors (second part)

La supervivencia de los condrocitos adultos y la síntesis de los componentes de la matriz extracelular del cartílago articular es regulada por una serie de moléculas sistémicas y/o locales denominadas factores de crecimiento. Estas sustancias podrían estar implicadas en la etiopatogenia de algunas enfermedades degenerativas del cartílago y han comenzado a utili- zarse con éxito en el tratamiento experimental de las mismas. En este trabajo se realiza una revisión acerca de las acciones de los factores de crecimiento IGFS, TGFS, FGFS, EGF, PDGF y neurotrofinas sobre el cartílago articular y las complejas relaciones que mantienen con las citoquinas. También se exponen los datos obtenidos a partir de animales tramgénicos deficientes o hiperpreductores de estas moléculas y los resultados de la terapia génica usando condrocitos transfectados con los genes de que codifican para diferentes moléculas que intervienen en la biología del cartílago (AU)

Human colon cancer cell proliferation mediated by the M3 muscarinic cholinergic receptor.

We have demonstrated previously cell surface receptors for gastrointestinal peptides on 10 human colon cancer cell lines. Because most of the cells studied bind muscarinic cholinergic agonists, we undertook the determination of the cholinergic receptor subtype expressed by human colon cancer cells, as well as the biological function of these receptors, and more specifically, the effect on cell proliferation. We used radiolabeled ligand binding, PCR, calcium mobilization, and cellular proliferation studies. The present study demonstrates a muscarinic cholinergic receptor having two classes of binding site for carbamylcholine. Analysis demonstrated 2499+/-153 binding sites/cell, of which 75% had a high affinity for carbamylcholine (Kd 55 microM), and 25% had a low affinity (Kd 0.33 mM). N-Methylscopolamine, a receptor antagonist, recognized only one binding site having high affinity (Kd 0.20 nM). The number of muscarinic cholinergic binding sites/cell found on colon cancer cells is 50% of the number of receptors found on guinea pig chief cells in physiological conditions. Specific cholinergic receptor antagonists inhibit binding in the following order of potency: N-methylscopolamine > 4-DAMP >> pirenzipine > AF-DX116. This order of potency pharmacologically classifies the receptor as an M3 subtype. Receptor expression, studied by reverse transcription-PCR, correlates with the binding data. Specifically, cell lines that exhibit binding, abundantly expressed the M3 receptor subtype, whereas cell lines that do not exhibit binding for muscarinic cholinergic agonists did not abundantly express the M3 receptor. Agonist activation of the M3 receptor on these cells resulted in intracellular calcium mobilization. The dose-response curve of calcium mobilization suggests that there are spare receptors on these cells. Signal transduction can be inhibited by receptor antagonists in the same order of potency in which the binding is inhibited. Exogenous agonist added to the cells in culture induces significant cell proliferation. These results demonstrate a muscarinic cholinergic receptor of the M3 subtype on human colon cancer cells. This receptor induces intracellular calcium mobilization and mediates cell proliferation. The data suggest that there are spare receptors present, and that there may be enhanced intracellular signal activation in response to receptor binding.

The importance of growth factors in wound healing.

For the last decade it has been acknowledged that growth factors are essential for regulating the cellular events involved in the formation of granulation tissue and in wound healing. Growth factors attract cells into the wound, stimulate their proliferation, and have a profound influence on extracellular matrix deposition. Studies have demonstrated that several growth factors are promising for cases of impaired healing. This paper is a review of the literature concerning growth factors and focuses on their role in and effect on soft tissue wound healing.

Fitoestrógenos: una nueva preocupación en la alimentación infantil / Phytoestrogens: a new preoccupation in paediatric nutrition

Los fitoestrógenos son sustancias ambientales naturales, producidas por plantas, que a pesar de su estructura química distinta de los estrógenos, actúan como tales. Estudios en adultos sugieren que tendrían efectos protectores para cánceres hormonodependientes (de próstata y mama), dislipidemias y de la mineralización ósea. Se clasifican en isoflavonas, cumestanos y lignanos, y se encuentran principalmente en legumbres y poroto de soya, brotes de poroto, forraje y granos, y en cereales de grano entero y semillas, respectivamente. Estudios recientes han demostrado que los alimentos infantiles, incluyendo algunas fórmulas lácteas, yogur y alimentos de soya, contienen cantidades considerables de fitoestrógenos. Los efectos de estos sobre la salud infantil no han sido del todo aclarados. Existen evidencias epidemiológicas y clínicas de que al actuar como estrógenos débiles prodrían determinar adelanto de los eventos puberales y telarquia en la niña y ginecomastia en el varón. Se hace una revisión del tema y se plantea la necesidad de realizar estudios destinados a aclarar los efectos de los estrógenos ambientales sobre la salud infantil