Retro-retinoids in regulated cell growth and death.

Vitamin A serves as a prohormone from which three classes of active metabolites are derived: the aldehydes, the carboxylic acids, and the retro-retinoids. Although these three classes are united under the rubric of signal transduction, they act by different molecular mechanisms: the 11-cis-retinaldehydes combine with opsin to form the universal visual pigments and the retinoic acids form ligands for transcription factors, whereas the retro-retinoids, as shown here, intersect with signal transduction at a cytoplasmic or membrane site. The retro-retinoid, anhydroretinol (AR), has long been known to act as a growth inhibitor in lymphocytes, whereas 14-hydroxy-4,14-retro-retinol (14-HRR) is required for normal lymphocyte proliferation. A mutually reversible relationship exists between these two retro-retinoids as one can reverse the effects of the other when given in pharmacological doses. The common explanation for reversible inhibition is competition for a shared receptor. We now provide evidence that when AR is given to T cells unmitigated by 14-HRR, rapid cell death can occur. The circumstances are closely related to nonclassical forms of apoptosis: within 2 h of AR administration the T cells undergo widespread morphological changes, notably surface blebbing and ballooning and, inevitably, bursting. In contrast, nuclear changes are comparatively mild, as indicated by absence of chromatin condensation and overt DNA cleavage to discrete nucleosomal fragments, although DNA nicks are readily discernible by terminal deoxynucleotidyl transferase assay. What further distinguishes the AR-induced form of apoptosis from classical ones is a lack of requirements of messenger RNA and protein synthesis, suggesting that the events leading to cell death are primarily initiated and play themselves out in the cytoplasm. This view is further reinforced by the finding that herbimycin A can prevent the onset of programmed cell death. The importance of our findings is that they strongly suggest a second messenger role for vitamin A metabolites in the cytoplasmic realm that has not been seen previously. These findings are entirely compatible with a general notion that in a cell requiring multiple coordinated signals for survival, the provision of an unbalanced signal can initiate programmed cell death. Collectively, our data also challenge the paradigm that retinoids (outside vision) solely mediate their function via the steroid/ retinoic acid receptor family of nuclear transcription factors. Instead, a mode of action in the cytoplasmic realm akin to one attributed to other small lipophilic second messenger molecules, such as diacyl glycerol or ceramide, may apply to retro-retinoids.

The cysteine-rich regions of the regulatory domains of Raf and protein kinase C as retinoid receptors.

Vitamin A and its biologically active derivatives, the retinoids, are recognized as key regulators of vertebrate development, cell growth, and differentiation. Although nuclear receptors have held the attention since their discovery a decade ago, we report here on serine/threonine kinases as a new class of retinoid receptors. The conserved cysteine-rich domain of the NH(2)-terminal regulatory domains of cRaf-1, as well as several select domains of the mammalian protein kinase C (PKC) isoforms alpha, delta, zeta, and mu, the Drosophila and yeast PKCs, were found to bind retinol with nanomolar affinity. The biological significance was revealed in the alternate redox activation pathway of these kinases. Retinol served as a cofactor to augment the activation of both cRaf and PKC alpha by reactive oxygen, whereas the classical receptor-mediated pathway was unaffected by the presence or absence of retinol. We propose that bound retinol, owing to its electron transfer capacity, functions as a tag to enable the efficient and directed redox activation of the cRaf and PKC families of kinases.

Kappa B-specific DNA binding proteins: role in the regulation of human interleukin-2 gene expression.

Transcriptional activation of the human interleukin-2 (IL-2) gene, like induction of the IL-2 receptor alpha (IL-2R alpha) gene and the type 1 human immunodeficiency virus (HIV-1), is shown to be modulated by a kappa B-like enhancer element. Mutation of a kappa B core sequence identified in the IL-2 promoter (-206 to -195) partially inhibits both mitogen- and HTLV-I Tax-mediated activation of this transcription unit and blocks the specific binding of two inducible cellular factors. These kappa B-specific proteins (80 to 90 and 50 to 55 kilodaltons) similarly interact with the functional kappa B enhancer present in the IL-2R alpha promoter. These data suggest that these kappa B-specific proteins have a role in the coordinate regulation of this growth factor-growth factor receptor gene system that controls T cell proliferation.

The role of differential class II antigen expression in stimulation of allogeneic mixed lymphocyte reactions by human monocyte hybridomas.

The recognition of foreign class II antigens on accessory cells is the crux of an alloreactive immune response. This phenomenon is clearly demonstrated in the primary mixed lymphocyte reaction, which correlates with the type and density of expressed gene products of the HLA-D region. We have generated a series of human monocyte hybridomas by fusing monocytes with the hypoxanthine guanine phosphoribosyl transferase (HGPRT)-deficient, HLA-D antigen-negative U937 histiocytic cell line. Clones bearing combination of HLA-DQ, -DP with or without HLA-DR have been isolated, allowing for the functional assessment of these molecules. In contrast to the U937 cells, the HLA-DR+DQ+DP+ clone 16.1 was capable of stimulating a primary allogeneic MLR. Interestingly, the DR- but DP+DQ+ clones 13 and 15 were also capable of stimulating alloreactive T cells, and the addition of anti-DQ or -DP but not -DR was associated with significant inhibition of the MLR response. Furthermore, gamma-IFN was found to have diverse effects on class II antigen expression in the U937 cells and the hybrids. gamma-IFN down-regulated the expression of HLA-DQ, -DP without altering -DR on clone 16.1, and this was associated with a significant reduction in its MLR stimulatory capacity. The MLR generated by this gamma-IFN-stimulated hybridoma (HLA-DR+DQ-DP-) was now unaffected by the addition of anti-DQ or -DP mAbs. In contrast, up-regulation of DQ and DP antigens on the U937 cells by gamma-IFN now rendered these cells stimulatory in MLR. These data are consistent with the concept that DQ and DP are both important allostimulatory determinants. Our results stress the potential importance of all D-region molecules in acute allograft rejection or successful engraftment.

Association of mitochondria DNA with viral DNA in purified preparations of poxviruses.

The presence of cellular material in purified preparations of Shope fibroma virus (SFV) and two orthopoxviruses (vaccinia and Indiana), was investigated. Mitochondria were observed in purified preparations of SFV by electron microscopy and mitochondrial (mt) DNA was identified in restricted viral DNA by Southern blot hybridization with cloned mouse mt DNA. Mitochondrial DNA was also detected in vaccinia and SFV DNAs extracted from purified virions treated with DNase I followed by core isolation. The viral and mt DNAs could be separated on the basis of their size by agarose gel electrophoresis, but not by their buoyant density by centrifugation in cesium chloride gradients. These findings led us to re-examine previously reported results showing some homology between SFV, a leporipoxvirus and Indiana, an Orthopoxvirus (Berkowitz and Pogo, Virology 142, 437-440, 1985) using cloned fragments of SFV DNA instead of the entire viral DNA. The results indicated that cross-hybridization between SFV and Indiana DNAs was due in part to mt DNA but they also revealed an unrecognized region of homology between the two poxvirus genera.

Retinoids as ligands and coactivators of protein kinase C alpha.

Whereas retinoic acids control nuclear events, a second class of retinol metabolites, that is, the hydroxylated forms exemplified by 14-hydroxy-retro-retinol (HRR), operate primarily in the cytoplasm. They function as regulatory cofactors for cell survival/cell death decisions. In accordance with these biological aspects, we demonstrate that these retinoids bound protein kinase C (PKC) alpha with nanomolar affinity and markedly enhance the activation of PKC alpha and the entire downstream MAP kinase pathway by reactive oxygen species. HRR was 10 times more efficient than retinol, and the optimum doses are 10-7 and 10-6 M, respectively. PKC alpha activation was reversed rapidly by imposition of reducing conditions. The retinoid binding site was mapped to the first cysteine-rich region in the regulatory domain, C1A, yet was distinct from the binding sites of diacylglycerol and phorbol esters. The C1B domain bound retinoids poorly. The emerging theme is that retinoids serve as redox regulators of protein kinase C.

Tabaquismo y envejecimiento cutáneo: una revisión de la literatura / Smoking and skin aging: a literature review

Es frecuente encontrarse con personas que lucen mayores respecto de su edad cronológica. Un 40 por ciento de los factores que contribuyen a las variaciones de la edad percibida son exógenos: fotoexposición, tabaquismo y consumo de alcohol se asocian con un aspecto de mayor envejecimiento. La asociación entre tabaco y envejecimiento facial prematuro, evaluada por la aparición de arrugas, se ha demostrado tanto en hombres como en mujeres y tanto en fumadores activos como en ex fumadores, quienes lucen mayores que no fumadores de la misma edad. Muchos fumadores desconocen la asociación entre tabaquismo y envejecimiento y consideran que la mayoría de los fumadores la calificarían como importante al decidir suspender el tabaco, especialmente los fumadores más jóvenes. La relación entre tabaco y envejecimiento cutáneo representa un arma importante para intentar detener el tabaquismo aún sin explorar, por lo que es relevante que la población médica y general se informe al respecto.

It is not rare to find people that look older than their age. Forty percent of the factors involved in premature skin aging are exogenous: sun exposure, smoking and alcohol intake play a role in aging. A relation between smoking and premature aging, represented by the number of facial wrinkles, has been found in men and women, active and former smokers who look older when compared with none smokers of the same age. Many smokers are not aware of this association and consider that most smokers would take this into account when deciding to stop smoking, specially young smokers. The association between smoking and skin aging represents a strong argument to try to stop the smoking habit and has not yet been explored. It is therefore important for both the medical and general community to be informed about this relationship.

Vacunación del niño en viajes internacionales / Vaccine recommendations for infants and children travelers

El número de personas que realizan viajes internacionales es cada vez mayor. Esto conlleva un aumento en el riesgo de contraer enfermedades infecciosas que pueden ser graves y difíciles de diagnosticar. Las medidas de prevención son muy importantes para disminuir este riesgo, especialmente en una población muy susceptible, como son los niños. La vacunación es una de las principales herramientas de prevención. Se debería confirmar antes del viaje que tienen correctamente actualizadas sus vacunaciones rutinarias, incluso completarlas con pautas aceleradas si es necesario y considerar la inmunización frente a otras enfermedades en función del riesgo que su viaje pueda suponer (país, duración, estación, área rural o urbana, etc) La Organización Mundial de la Salud clasifica las vacunas para viajeros en tres grupos: las obligatorias, exigidas por la ley para entrar en ciertos países (fiebre amarilla y enfermedad meningocócica), rutinarias (incluidas en los calendarios vacunales de cada país) y vacunas recomendadas según las circunstancias (cólera, encefalitis japonesa, encefalitis centroeuropea, enfermedad de lyme, fiebre tifoidea, gripe, hepatitis A, rabia, tuberculosis, varicela).Las medidas generales de prevención y protección son también muy importantes en los niños, ya que para algunas patologías no se dispone de vacunas o bien no está demostrada su eficacia en este grupo de edad (AU)