Carotenoids and Retinoids: Nomenclature, Chemistry, and Analysis.

Carotenoids are polyenes synthesized in plants and certain microorganisms and are pigments used by plants and animals in various physiological processes. Some of the over 600 known carotenoids are capable of metabolic conversion to the essential nutrient vitamin A (retinol) in higher animals. Vitamin A also gives rise to a number of other metabolites which, along with their analogs, are known as retinoids. To facilitate discussion about these important molecules, a nomenclature is required to identify specific substances. The generally accepted rules for naming these important molecules have been agreed to by various Commissions of the International Union of Pure and Applied Chemistry and International Union of Biochemistry. These naming conventions are explained along with comparisons to more systematic naming rules that apply for these organic chemicals. Identification of the carotenoids and retinoids has been advanced by their chemical syntheses, and here, both classical and modern methods for synthesis of these molecules, as well as their analogs, are described. Because of their importance in biological systems, sensitive methods for the detection and quantification of these compounds from various sources have been essential. Early analyses that relied on liquid adsorption and partition chromatography have given way to high-performance liquid chromatography (HPLC) coupled with various detection methods. The development of HPLC coupled to mass spectrometry, particularly LC/MS-MS with Multiple Reaction Monitoring, has resulted in the greatest sensitivity and specificity in these analyses.

Reversal of skin aging with topical retinoids.

Topical skin care and its place in plastic surgery today are often overlooked by clinicians formulating a plan for facial rejuvenation. Not only is it important to consider topical skin care as part of comprehensive care, but clinicians should also be educated with the data available in today's literature. This review aims to familiarize the reader with the biological processes of skin aging and evidence-based clinical outcomes afforded by various topical therapies. Furthermore, this review will focus on solar damage, the value of retinoids, and how they can be used in conjunction with forms of treatment such as chemical peel, dermabrasion, and lasers. Finally, guidelines will be provided to help the physician administer appropriate skin care based on the data presented.

Respuesta inadecuada a los patógenos y otros agresores: ¿Deficiencia de Vitamina A? / Is inadequate response to pathogens and other aggressors due to vitamin A deficiency?

La vitamina A desempeña un papel fundamental en el desarrollo de los tejidos y órganos gracias a su capacidad de promover la diferenciación celular y regular la apoptosis. Específicamente en el sistema inmune, esta vitamina tiene efectos muy importantes sobre componentes específicos tanto de la respuesta inmune innata como de la adaptativa. En la inmunidad innata, el ácido retinoico (AR) participa en la regeneración de las mucosas y epitelios, promueve la diferenciación de células como los neutrófilos y eosinófilos y potencia la fagocitosis. Además, ayuda a la migración de las diferentes células inmunes promoviendo la producción de metaloproteinasas de matriz extracelular. Aunque sus efectos en las células NK son más controversiales, se ha encontrado que el número y la función lítica de estas células disminuyen cuando hay deficiencia de vitamina A (DVA). Por otra parte, el AR influencia el desarrollo de la inmunidad adaptativa alterando el perfil de producción de citoquinas por parte de las células presentadoras de antígeno, lo que influye en la diferenciación de los linfocitos T ayudadores. En general, se ha observado que el AR amplifica la proliferación de las células T y potencia el desarrollo de células plasmáticas a partir de los linfocitos B maduros. Todos estos efectos tienen repercusiones importantes en la adecuada defensa contra las infecciones, especialmente en la infancia en la cual la DVA es un problema importante de salud pública, no solo en Colombia sino también en aproximadamente otros 60 países.

Vitamin A plays a pivotal role in tissue and organ development due to its ability to regulate cellular differentiation and apoptosis. Moreover, this vitamin produces very important effects on specific components of innate and adaptative immune responses. Concerning the innate immune system, retinoic acid (RA) participates in the regeneration of mucosal surfaces and epithelia, also promoting neutrophil and eosinophil differentiation and enhancing phagocytosis. Additionally, vitamin A supports the production of extracellular matrix metalloproteinases enhancing the migration of different immune cells to effector sites. On the other hand, although the effects of vitamina A in the function of NK cells are more controversial, it is known that blood NK cell numbers and function are diminished during vitamin A deficiency (VAD). In adaptive immunity, RA influences the production of cytokines by antigen presenting cells, in turn, affecting the differentiation of naïve T lymphocytes into different T helper cell subpopulations. Overall, it has been established that RA increases T cell proliferation and enhances the development of plasma cell from mature B lymphocytes. Therefore, vitamin A is essential to promote suitable immune responses against pathogens, especially in children who are commonly affected by VAD not only in Colombia, but also in approximately 60 countries worldwide.

Retinoid chromophores as probes of membrane lipid order.

There is a great need for development of independent methods to study the structure and function of membrane-associated proteins and peptides. Polarized light spectroscopy (linear dichroism, LD) using shear-aligned lipid vesicles as model membranes has emerged as a promising tool for the characterization of the binding geometry of membrane-bound biomolecules. Here we explore the potential of retinoic acid, retinol, and retinal to function as probes of the macroscopic alignment of shear-deformed 100 nm liposomes. The retinoids display negative LD, proving their preferred alignment perpendicular to the membrane surface. The magnitude of the LD indicates the order retinoic acid > retinol > retinal regarding the degree of orientation in all tested lipid vesicle types. It is concluded that mainly nonspecific electrostatic interactions govern the apparent orientation of the retinoids within the bilayer. We propose a simple model for how the effective orientation may be related to the polarity of the end groups of the retinoid probes, their insertion depths, and their angular distribution of configurations around the membrane normal. Further, we provide evidence that the retinoids can sense subtle structural differences due to variations in membrane composition and we explore the pH sensitivity of retinoic acid, which manifests in variations in absorption maximum wavelength in membranes of varying surface charge. Based on LD measurements on cholesterol-containing liposomes, the influence of membrane constituents on bending rigidity and vesicle deformation is considered in relation to the macroscopic alignment, as well as to lipid chain order on the microscopic scale.

The role of topical retinoids in the treatment of photoaging.

Aging of the skin is a complex biological process which is influenced by the interaction of several intrinsic and extrinsic factors. Intrinsic or chronological aging is an inevitable, genetically programmed process, of unclear underlying mechanism, for which no prevention or effective treatment is currently available. Photoaging refers to the gross and microscopic cutaneous changes that are induced by cumulative exposure to UV radiation and are superimposed on the background of chronological aging. Although primarily an aesthetic problem with significant psychological effects, photoaging constitutes the background for the development of precancerous and cancerous skin lesions.Overwhelming clinical and histological evidence indicate that certain structural changes induced by excessive sun exposure can be reversed, to some extent, by the use of topical retinoids. A number of retinoid compounds, for example tretinoin, isotretinoin, retinaldehyde and tazarotene, have been employed for the treatment of photoaged skin, and demonstrate beneficial clinical and histological effects. Adverse effects have been limited to an irritant reaction of variable intensity presenting with dryness, scaling and erythema. Ongoing research will enhance our understanding of the molecular mechanisms that determine the effects of retinoids on photodamaged skin and contribute to the employment of new, more effective and less irritating retinoid compounds.

Effects of methoprene, its metabolites, and breakdown products on retinoid-activated pathways in transfected cell lines.

Methoprene (isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate) is an insect juvenile hormone agonist that blocks metamorphosis in some insects. Recent evidence suggests that a metabolite, methoprene acid, activates vertebrate retinoid X receptors (RXRs), and may interfere with retinoic acid-regulated developmental processes. Methoprene, methoxy-methoprene acid, and two major breakdown products were tested for their ability to interfere with retinoid-regulated pathways when using transfected cells. The CV-1 cells were transiently transfected with genes encoding RXRs and response elements attached to luciferase reporters, and retinoic acid-sensitive F9 cells were stably transfected with retinoic acid receptor (RAR)/RXR response elements attached a lacZ reporter (Sil-REM/beta-gal-NEO). Experiments confirmed that methoxy-methoprene acid acted as a ligand for RXRs and was capable of activating transcription through RAR/RXR response elements. However, neither methoprene nor the breakdown products, 7-methoxycitronellal and 7-methoxycitronellic acid, activated transcription in transfected CV-1 or F9 cells. Methoprene and methoxy-methoprene acid may interfere with the conversion of all-trans-retinol and all-trans-retinaldehyde to all-trans-retinoic acid in the F9-derived cell line. Methoprene was as effective as the retinol dehydrogenase inhibitor citral in blocking the retinol-induced transcription of RAR/RXR-regulated reporter genes, whereas methoxy-methoprene acid blocked transcription stimulated by retinaldehyde.

Retinoides en dermatología / Retinoids in Dermatology

Desde su introducción en la Dermatología hace 60 años, los retinoides han adquirido la condición de fármaco indispensable en nuestra especialidad. Este hecho se debe tanto a la observación de resultados efectivos en un alto número de procesos cutáneos como por las innovaciones que se han realizado tanto en su estructura como en su formulación. En la actualidad su efectividad y seguridad está bien establecida, tanto en formulaciones tópicas como sistémicas, en acné, psoriasis y fotoenvejecimiento. En los últimos años se han descrito nuevas indicaciones de los retinoides en dermatología entre las que caben destacar su uso en el tratamiento del cáncer cutáneo, o con fines cosméticos con buenos resultados en cicatrización de las heridas, estrías cutáneas en fases iniciales o alopecia androgenética. Los avances farmacológicos han permitido derivados de la vitamina A más efectivos y con menos efectos adversos. Tretinoina, aún con una mayor actividad irritante, sigue siendo el fármaco más efectivo por vía tópica en fotoenvejecimiento y cáncer cutáneo. Isotretinoina por vía oral es el fármaco de elección en el acné crónico y severo, adapaleno es la formulación tópica mejor tolerada en el acné, tazaroteno es el primer retinoide tópico con efectividad en psoriasis, etretinato y acitretino se consideran de elección en el tratamiento sistémico del psoriasis. Por último, se han descrito de forma reciente nuevas moléculas que han ampliado las indicaciones de los retinoides en dermatología, son alitretinoina para el sarcoma de Kaposi asociado a SIDA y bexaroteno para el linfoma cutáneo de células T (AU)

Retinoids: fascinating up-and-coming scenario.

Retinoids have been in sharp focus ever since their introduction 30 years ago. They include any drug (s) that bind to retinoid receptors and elicit a biological response. Enormous information on the subject seems to embroil the recent literature. Practically it is impossible to clearly comprehend the undercurrents. The meticulously dispensing text envisages surmounting the perspective reader's predicaments. Accordingly, retinoids and their related facets namely retinoid receptors, classification, mode of action, and the pharmacological diversity have been precisely defined. Commonly used systemic retinoids too have been given a substantial fresh look along with their monitoring. Overall, adverse effects and relative and absolute contraindications have been scrupulously incorporated. Human immuno deficiency virus (HIV) and isoretinoid for acne, in particular, have been highlighted. Micronized isotretinoin formulations have also been taken care so also commonly used topical retinoids. Tretinoin and their newer formulation have also been accounted for along with tretinoin polymer cream. Adapalene, a new chemical entity possessing a unique physico-chemical activity similar to that of tretinoin has also been dealt with. Newer retinoids are likely to be a subject of intrigue. A focus on future potentials of retinoids is its special ingredient. The inclusion of details of rexinoid the most recent introduction in their purview is likely to invoke interest to further consolidate its reckoning in future. All in all the text of the paper should provide an insight into the current rumbling around retinoids.

Clinically potential subclasses of retinoid synergists revealed by gene expression profiling.

Retinoids have chemopreventive and therapeutic potency in oncology and dermatology, although their application is restricted by many undesirable side effects. For the development of more effective and less toxic retinoids, gene expression analyses using DNA microarrays have the potential to supplement conventional screening methods, which are based on the changes in cell morphology and/or function. In this study, we applied the class prediction algorithm, which was used in the molecular phenotyping of tumors, for the classification of synthetic retinoids (Am80 and Tp80) and retinoid synergists (HX630, TZ335, and PA024) as all-trans retinoic acid-like, 9-cis retinoic acid-like, and control-like classes. By analyzing the effects of all-trans retinoic acid and 9-cis retinoic acid on the gene expressions in a human promyelocytic leukemia cell line, HL60, we successfully selected 50 marker genes whose expression pattern could distinguish these classes. Moreover, the classification revealed the existence of two subclasses among the retinoid synergists used with Am80. Close inspection of the DNA microarray analyses indicated that these two subclasses had different effects on the apoptosis of HL60 cells, and this was confirmed by in vivo experiments. These results indicate that the retinoidal activity of Am80, which has already been used in clinical trials, could be modulated differently by the two classes of retinoid synergists. Thus, these two subclasses of retinoid synergists have the potency to widen the usage of Am80. Our analyses demonstrated that the gene expression profiling could provide important information for developing useful retinoid synergists by compensating conventional screening methods.

A new class of RAR subtype selective retinoids: correlation of pharmacological effects with receptor activity.

The synthesis and biological activity of a series of structurally related retinoids with different RAR subtype selectivities are described. These retinoids bind to all three RAR subtypes but in functional transactivation assays, they show RARbeta or RARbeta,gamma selectivity with weak RARalpha activity. The subtype selectivity of these retinoids was found to correlate with their efficacy (ODC inhibition) and toxicity (topical irritation and teratogenicity) profiles. The degree of RARgamma transactivation activity correlates with their topical toxicity and teratogenicity as measured by the inhibition of chondrogenesis. Of the RARbeta selective retinoids reported here, retinoid 12 is the most promising, as it is completely devoid of two common retinoid related toxicities, namely topical irritation and teratogenesis.

Retinoids can be classified according to their effects on vitamin A metabolism in HeLa cells.

Although retinoids may exert their action via binding to nuclear retinoic acid receptors (RARs), other mechanisms of action are not excluded. For example, the anti-acne drug, isotretinoin, lacks affinity for the receptors, but is a very potent inhibitor of endogenous vitamin A metabolism in human epidermal cells. To further extend this observation, we studied the effect of 12 different retinoids on the metabolism of [3H]retinol ([3H]ROH) in HeLa cells, previously shown to produce constant levels of 3,4-didehydroretinol (ddROH). The cells were cultured in the presence of the unlabeled retiniods for 20 h, followed by 4 h incubation with [3H]ROH. The accumulation of [3H]ROH and [3H]ddROH in cellular extracts was analysed by HPLC. Addition of 10(-10) to 10(-5) M of four naturally occurring isomers of retinoic acid caused a 4- to 6-fold increase in [3H]ROH accumulation and an 80% decrease in [3H]ddROH. Addition of synthetic retinoids with a terminal carboxyl (CD270, CD271, CD367 and Ro 13-7410) decreased the [3H]ddROH accumulation with about 70%, but hardly at all affected the accumulation of [3H]ROH. We conclude that cultured HeLa cells appear to be useful for screening retinoids for their effects on vitamin A metabolism showing that a terminal carboxylic acid is a prerequisite for any major effects on metabolism to occur. Whether this effect is due to interaction with RARs or to competitive inhibition of vitamin-A-metabolizing enzymes demands to be studied.

A new class of retinoids with selective inhibition of AP-1 inhibits proliferation.

Retinoids regulate many biological processes, including differentiation, morphogenesis and cell proliferation. They are also important therapeutic agents, but their clinical usefulness is limited because of side effects. Retinoid activities are mediated by specific nuclear receptors, the RARs and RXRs, which can induce transcriptional activation through specific DNA sites or by inhibiting the transcription factor AP-1 (refs 12-15), which usually mediates cell proliferation signals. Because the two types of receptor actions are mechanistically distinct, we investigated whether conformationally restricted retinoids, selective for each type of receptor action, could be identified. Here we describe a new class of retinoids that selectively inhibits AP-1 activity but does not activate transcription. These retinoids do not induce differentiation in F9 cells but inhibit effectively the proliferation of several tumour cell lines, and could thus serve as candidates for new retinoid therapeutic agents with reduced side effects.

Retinoids in cancer treatment.

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis-retinoic acid in patients with acute promyelocytic leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all-trans-retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocytic leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinogenesis.