Role Of Retinoids Research Articles

Regulation of SREBP1c Gene Expression in Skeletal Muscle: Role of Retinoid X Receptor/Liver X Receptor and Forkhead-O1 Transcription Factor

Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene expression in liver and adipose tissue, where its expression is regulated by a heterodimer of nuclear receptor-type transcription factors retinoid X receptor-alpha (RXRalpha) and liver X receptor-alpha (LXRalpha). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene expression of RXRgamma is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene expression of SREBP1c. RXRgamma or RXRalpha, together with LXRalpha, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overexpressing RXRgamma specifically in skeletal muscle showed increased gene expression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overexpressing the dominant-negative form of RXRgamma showed decreased SREBP1c gene expression. The expression of Forkhead-O1 transcription factor (FOXO1), which can suppress the function of multiple nuclear receptors, is negatively correlated to that of SREBP1c in skeletal muscle during nutritional change. Moreover, transgenic mice overexpressing FOXO1 specifically in skeletal muscle exhibited decreased gene expression of both RXRgamma and SREBP1c. In addition, FOXO1 suppressed RXRalpha/LXRalpha-mediated SREBP1c promoter activity in vitro. These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene expression and that FOXO1 antagonizes this effect of RXR/LXR in skeletal muscle.

Chemotherapeutic/chemopreventive role of retinoids in chemically induced skin carcinogenesis in albino mice

To determine the chemotherapeutic effect of retinoids on albino mouse skin. Eighty albino mice were selected for this study and were divided into four groups (A-D, 20 mice in each group). 7,12-Dimethylbenz(a)anthracene (DMBA) and tetradecanoylphorbal-13-acetate (TPA) were given for 15 weeks to produce tumors. Retinoids were given topically and orally after the development of tumors for the following 15 weeks. Of the 80 mice, 69 (86.25%) developed different types of lesion and 11 (13.75%) remained lesion free. Of the 69 mice that developed lesions, 50 (62.50%) developed benign lesions and 19 (23.75%) developed malignant lesions. In all groups of mice, treatment with retinoids was effective against all benign lesions and the early stages of carcinogenesis of the skin. The chemotherapeutic effect against malignant tumors was not satisfactory. This study demonstrates that retinoids are effective as chemopreventive agents in premalignant lesions of the skin, but have a very weak chemotherapeutic role in malignant neoplasms. If retinoids are given at an early stage, they can cause regression of premalignant lesions of the skin. They are best administered both orally and parenterally. These agents should be recommended as they reduce the potential effects of carcinogenesis.

Rat hepatic stellate cells acquire retinoid responsiveness after activation in vitro by post-transcriptional regulation of retinoic acid receptor alpha gene expression

Activation of hepatic stellate cells (HSCs) is a key process in liver fibrogenesis and retinoid loss is a remarkable feature of activated HSCs. However, roles of retinoids in liver fibrogenesis are obscure. We show that mRNA levels of RARα, β and γ were decreased during rat HSC activation in vitro. However, protein levels of RARα and β were increased during HSC activation. A retinoic acid response element-containing luciferase assay indicated that HSCs became responsive to retinoids only after activation in vitro and that this response was mediated by, at least in part, RARα subtype. Immunocytochemical analysis showed that RARα proteins were mainly distributed in cytosol as many spots. All- trans retinoic acid treatment strongly lowered the cytosolic RARα protein levels. These results indicate that rat HSCs become retinoid responsive after activation in vitro, through post-transcriptional up-regulation of RARα gene expression.

Role of Retinoids and their Cognate Nuclear Receptors in Breast Cancer Chemoprevention

Retinoids are natural and synthetic compounds related to retinoic acid that act through interaction with two basic types of nuclear receptors: retinoic acid receptors (RARalpha, RARbeta and RARgamma) and retinoid X receptors (RXRalpha, RXRbeta and RXRgamma) as ligand-activated, DNA-binding, transacting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. Function of retinoids in organisms affecting broad spectrum of various biochemical and molecular biology reactions is unimaginable without fully functional nuclear receptors--retinoid inducible transcription factors. Retinoic acids exert tumour-suppressive activity due to their antiproliferative and apoptosis-inducing effects. A number of novel retinoids and rexinoids acting through cognate nuclear receptors have been tested both in vitro and in vivo, using cell culture or animal models for breast cancer. This article briefly summarizes the role and properties of nuclear retinoid/rexinoid receptors as well as selected effects of retinoic acids or selected synthetic retinoids and rexinoids with respect to their potential use in chemoprevention of breast cancer.

Retinoids induce MMP-9 expression through RARα during mammary gland remodeling

Retinoic acid (RA) is a signaling molecule in the morphogenesis of the mammary gland, modulating the expression of matrix metalloproteinases (MMPs). The aim of this paper was to study the role of RA during weaning, which consists of three events: apoptosis of the secretory cells, degradation of the extracellular matrix, and adipogenesis. CRABP II and CRBP-1 carrier proteins increased significantly during weaning compared with lactating glands but reverted to control values after the litter resuckled. The effects of RA are mediated by the nuclear receptors RARalpha, RARbeta, RARgamma, and RXRalpha, which underwent an increase in protein levels during weaning. In an attempt to elucidate the RARalpha-dependent signaling pathway, ChIP assays were performed. The results showed the binding of RARalpha to the MMP-9 promoter after 24- and 72-h weaning together with its coactivator p300; this fact could be responsible for the increase found in MMP-9 mRNA and protein levels in these conditions. Expression of related MMPs (MMP-2 and MMP-3) was also increased during weaning. Using gelatine zymography, we observed a time-dependent increase in active forms of MMP-9 and MMP-2. On the other hand, the inhibitor of MMPs, TIMP-1, was almost undetectable at 24- and 72-h weaning by Western blot. The role of retinoids in matrix remodeling is reinforced by the fact that administration of an acute dose of retinol palmitate to control lactating rats also induces MMP-9 expression. This emphasizes the importance of retinoids in vivo to regulate mammary gland involution.

Bovine Early Embryonic Development and Vitamin A

Vitamin A and its derivatives, collectively termed as retinoids, have been paid attention in recent years because of their effects in bovine reproduction. However, the role of retinoids in the pre-implantation period continues to be largely unexplored, in contrast to later stages of development. Retinoids control cell growth, differentiation and death through binding to specific nuclear receptors by retinoic acid and other active metabolites. This paper reviews how retinoids can influence early embryonic development in cattle through their influence on the follicle, the extrafollicular oocyte and the pre-implantation embryo itself.

The Role of Retinoid X Receptor α in Regulating Alcohol Metabolism

There is substantial overlap in retinol and alcohol metabolism. Mice that lack retinoic acid (RA) receptor retinoid X receptor alpha (RXRalpha) expression in the liver are more susceptible to alcoholic liver disease. To investigate the interaction between RXRalpha and alcoholic liver disease, ethanol metabolism was studied in hepatocyte RXRalpha-deficient [RXRalpha knockout (KO)] mice. Hepatocyte RXRalpha deficiency resulted in a significant increase in hepatic alcohol dehydrogenase (ADH) activity, ADH1 protein, but not Adh1 mRNA. Polysomal distribution analysis indicated that more polysome-associated Adh1 mRNA was present in the mutant mouse livers, suggesting increased ADH1 protein synthesis in RXRalpha KO mice compared with wild-type mice. However, ADH2 and ADH3 enzyme activities were not affected by RXRalpha deficiency. Although ethanol clearance was increased, acetaldehyde elimination was reduced when RXRalpha was not expressed in the liver. Both mitochondrial aldehyde dehydrogenase (ALDH) 2 and cytosolic ALDH activities were reduced in the mutant mice compared with the wild type. Western blot analysis revealed that the levels of ALDH1A1 and ALDH1A2 were decreased in the mutant mice. Semiquantitative reverse transcriptase-polymerase chain reaction indicated that liver Aldh1a1 mRNA level was also reduced due to the lack of RXRalpha expression. Thus, RXRalpha differentially affects ADH and ALDH activity, leading to an increase in alcohol clearance, but a reduction in acetaldehyde elimination. In addition, CYP2E1 as well as mitochondrial and cytosolic glutathione S-transferase activities were significantly lower in RXRalpha KO mice than in wild-type mice. Our results reveal the central role of RXRalpha in ethanol metabolism.

Retinoid cycles in the cone-dominated chicken retina

In past decades, the role of retinoids in support of rod photopigment regeneration has been extensively characterized. In the rhodopsin cycle, retinal chromophore from bleached rod pigments is reduced to retinol and transferred to the retinal pigment epithelium (RPE) to store as all-trans retinyl ester. This ester pool is subsequently utilized for visual pigment regeneration. However, there is a lack of information on the putative cone visual cycle. In the present study, we provide experimental evidence in support of a novel retinoid cycle for cone photopigment regeneration. In the cone-rich chicken, light exposure resulted in the accumulation of 11-cis retinyl esters to the retina and all-trans retinyl esters to the RPE. Both the rate of increase and the amount of 11-cis retinyl esters in the retina far exceeded those of the all-trans retinyl esters in the RPE. In response to dark adaptation, this 11-cis retinyl ester pool in the retina depletes at a rate several times faster than the all-trans retinyl ester pool in the RPE. In vitro, isolated, dark-adapted retinas devoid of RPE show both an accumulation of 11-cis retinyl ester and a concomitant reduction of 11-cis retinal chromophore in response to light exposure. Finally, we provide experimental results to elucidate a cone visual cycle in chicken by relating the change in retinoids (retinal and retinyl ester) with time during light and dark adaptation. Our results support a new paradigm for cone photopigment regeneration in which the 11-cis retinyl ester pool in the retina serves as the primary source of visual chromophore for cone pigment regeneration.

Laryngites chroniques de l’adulte

Chronic laryngitis is a lingering inflammation of the laryngeal mucosa, usually lasting over two weeks. The specific aetiology of chronic laryngitis can include tuberculosis, herpes or sarcoidosis, etc. , however, its origin is often unknown. Specific forms of chronic laryngitis are not included in the present chapter since they are reviewed in the chapters on tuberculosis and other specific diseases. These non specific lesions have several aetiological and pathogenic factors; they present many different histological aspects, and their progression can take several forms including malignant development. The diversity of these characteristics accounts for the absence of codification of preventive and curative therapies. The role of the ENT specialist is to precisely identify such lesions using laryngeal video and/or laryngeal stroboscopic video. The examining physician should look for the most typical risk factors such as tobacco intoxication, ill-treatment of vocal chords or gastroesophageal reflux, in order to adapt preventive treatment. The endoscopic examination of laryngeal lesions using, whenever possible, autofluorescence, is essential in classifying the disease and in simultaneously defining suitable treatment. Within this context, the availability of laser techniques has enabled considerable improvement in the treatment of such lesions. The role of retinoids is limited and their prescription is often experience based. Finally, regular follow-up is essential since the malignant development of these precancerous lesions can be observed several years after initial diagnosis.

All‐trans retinoic acid enhances differentiation and influences permeability of intestinal Caco‐2 cells under serum‐free conditions

Vitamin A and retinoids are essential nutrients for the differentiation of epithelia. Vitamin A deficiency is accompanied by an impairment in intestinal integrity. We investigated whether retinoids influence the differentiation and permeability of Caco-2 cells under serum-free culture conditions as a model for the intestinal epithelium. Treatment of the Caco-2 cells with retinoic acids (RA) resulted in an increased specific activity, enhanced mRNA expression, and induction of the 5'-flanking promoter activity of the marker enzyme for the differentiation intestinal alkaline phosphatase. Surprisingly, permeability of the Caco-2 monolayer, as measured by transepithelial electric resistance and [3H]-mannitol flux, was found to be enhanced by RA. Treatment with RA had only a slight effect on the mRNA expression of the tight junction-associated proteins occludin, ZO-1, claudin-1, -3, and -4, but enhanced the expression of claudin-2, which was recently suggested to form a paracellular ion channel. The role of retinoids as potent inducers of epithelial differentiation was confirmed for the Caco-2 cells under serum-free culture conditions and it was concluded that IAP is a target gene of RA. The inverse regulation of the permeability by RA under these serum-free conditions showed that other mechanisms, which are essential to regulate intestinal epithelial integrity with respect to decreased permeability, have to be identified.

Role of retinoid X receptor mRNA expression in Barrett's esophagus.

The Barrett's multistage process is characterized histopathologically by progression from Barrett's intestinal metaplasia to Barrett's esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett's esophagus disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett's esophagus without carcinoma (BE group), 20 patients with Barrett's-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux disease (CG). RXR-alpha mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-gamma was significantly increased (P < 0.001) at higher stages in Barrett's esophagus. RXR-beta expression was highest in Barrett's tissues and was significantly increased compared to normal squamous tissues (P=0.01; Wilcoxon test) and adenocarcinoma tissues (P=0.018, Mann-Whitney test). RXR-alpha and RXR-beta mRNA expression was significantly associated in normal squamous esophagus tissues (r(2)=0.49; P < 0.001; Spearman test), Barrett's tissues (r(2)=0.63; P < 0.001), and adenocarcinoma tissues (r(2)=0.68; P=0.001). There were significant differences in RXR-alpha (P=0.011) and RXR-beta (P=0.005) mRNA expression in histopathologically normal squamous esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett's esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this disease, and that a widespread "field-effect" is present in the normal esophagus of patients with esophageal adenocarcinoma.

Novel Roles of Retinoid X Receptor (RXR) and RXR Ligand in Dynamically Modulating the Activity of the Thyroid Hormone Receptor/RXR Heterodimer

Many members of the type II nuclear receptor subfamily function as heterodimers with the retinoid X receptor (RXR). A permissive heterodimer (e.g. peroxisome proliferator-activated receptor/RXR) allows for ligand binding by both partners of the receptor complex. In contrast, RXR has been thought to be incapable of ligand binding in a nonpermissive heterodimer, such as that of thyroid hormone receptor (TR)/RXR, where it has been referred to as a silent partner. However, we recently presented functional evidence suggesting that RXR in the TR/RXR heterodimer can bind its natural ligand 9-cis-RA in cells. Here we extended our study of the interrelationship of TR and RXR. We examined the potential modulatory effect of RXR and its ligand on the activity of TR, primarily using a Gal4-TR chimera. This study led to several novel and unexpected findings: 1) heterodimerization of apo-RXRalpha (in the absence of 9-cis-RA) with Gal4-TR inhibits T3-mediated transactivation; 2) the inhibition of Gal4-TR activity by RXRalpha is further enhanced by 9-cis-RA; 3) two different RXR subtypes (alpha and beta) differentially modulate the activity of Gal4-TR; 4) the N-terminal A/B domains of RXR alpha and beta are largely responsible for their differential modulation of TR activity; and 5) the RXR ligand 9-cis-RA appears to differentially affect T3-mediated transactivation from the Gal4-TR/RXRalpha (which is inhibited by 9-cis-RA) and TRE-bound TR/RXRalpha (which is further activated by 9-cis-RA) heterodimers. Taken together, these results further support our recent proposal that the RXR component in a TR/RXR heterodimer is not silent and, more importantly, reveal novel aspects of regulation of the activity of the TR/RXR heterodimer by RXR and RXR ligand.

244.Interaction between bone morphogenetic protein 4 and retinoid signalling in mouse spermatogenesis

Vitamin A (retinol, or ROL) is also essential for normal spermatogenesis in the rat and mouse. Vitamin A-deficient (VAD) rodents suffer various disorders including blindness and male infertility. The molecular mechanisms leading to infertility in vitamin A deficient rodents have never been fully elucidated. Following prolonged vitamin A withdrawal the only germ cells remaining in the VAD rodent testis are stem cell spermatogonia, type A1 spermatogonia, and a few preleptotene spermatocytes. Supplementing the diet of these animals with retinoic acid (RA) alleviates all symptoms of vitamin A deficiency, with the exception of sight and spermatogenesis. It is not until VAD animals are re-administered ROL through the diet, or RA is injected in repeated high doses directly into the testis, that normal spermatogenic function is restored. Here we report an interaction, in germ cells, between the Bone Morphogenetic Protein (BMP) 4 and retinoid signalling pathways that may help explain the molecular mechanics of vitamin A deficiency. We localised BMP4 gene expression to adult germ cells, in particular spermatogonia, at both the mRNA and protein level. We generated VAD mice and found that in the absence of retinoids in vivo, bmp4 gene expression was significantly upregulated in the testis. We also observed that the expression of bmp4 is downregulated by retinoid treatment in germ cells isolated from vitamin A sufficient mice. Expression of bmp4 mRNA in isolated spermatogonia was more sensitive to ROL rather than RA. Our results may reflect a direct requirement for ROL by germ cells for the resumption of spermatogenesis in VAD animals that involves the regulation of BMP4 expression. Furthermore our observations suggest that retinoid signalling in germ cells is different to that observed in somatic cells, and may provide insights into the role of retinoids in spermatogenesis.

Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver.

Lecithin-retinol acyltransferase (LRAT), an enzyme present mainly in the retinal pigmented epithelial cells and liver, converts all-trans-retinol into all-trans-retinyl esters. In the retinal pigmented epithelium, LRAT plays a key role in the retinoid cycle, a two-cell recycling system that replenishes the 11-cis-retinal chromophore of rhodopsin and cone pigments. We disrupted mouse Lrat gene expression by targeted recombination and generated a homozygous Lrat knock-out (Lrat-/-) mouse. Despite the expression of LRAT in multiple tissues, the Lrat-/- mouse develops normally. The histological analysis and electron microscopy of the retina for 6-8-week-old Lrat-/- mice revealed that the rod outer segments are approximately 35% shorter than those of Lrat+/+ mice, whereas other neuronal layers appear normal. Lrat-/- mice have trace levels of all-trans-retinyl esters in the liver, lung, eye, and blood, whereas the circulating all-trans-retinol is reduced only slightly. Scotopic and photopic electroretinograms as well as pupillary constriction analyses revealed that rod and cone visual functions are severely attenuated at an early age. We conclude that Lrat-/- mice may serve as an animal model with early onset severe retinal dystrophy and severe retinyl ester deprivation.

Basaloid follicular hamartomas associated with autoimmune disease: a possible role for retinoids in therapy

A basaloid follicular hamartoma (BFH) may be localized or diffuse. It may also be congenital or acquired. Development of diffuse BFHs has been associated with autoimmune disease and with the development of diffuse alopecia. Two women with autoimmune diseases had diffuse alopecia develop. We present the histologic features of BFH seen in these 2 women using vertical and transverse sections, and the response of 1 patient to retinoid therapy. Histologic sections showed a hamartomatous proliferation of hair follicles involving the majority of their hairs. The hamartomatous follicles showed variable degrees of hair differentiation. One patient, treated with oral and then topical retinoids, showed a partial regrowth of scalp hair and some regression of the cutaneous nodules. Increased sonic hedgehog signaling pathways with increased Gli-1 transcription has been shown to be present in the spectrum of follicular hamartomatous changes seen in BFHs. This may explain the response of one patient to retinoid therapy, because retinoids decrease Gli-1 transcriptional activity.

The role of retinoid X receptor mRNA expression in Barrett's esophagus and Barrett's associated adenocarcinoma of the esophagus

Objective The Barrett's multistage process is characterized histopathologically by progression from Barrett's intestinal metaplasia to Barrett's esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X Receptors (RXR) play an important role m regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors, however the role in Barrett's esophagus d ~ . s e has yet to be determined. Aim of this study was to assess the prevalence and timing of RXR mRNA expression in Barrett's metaplasia-dysplasiaadenocarcinoma sequence and to determine its role for the development and progression of this disease. Methods We analyzed the mRNA expression of all 3 RXR subtypes (RXRalpha, RXR-beta, RXR-gamma) by using a quantitative real-time RT-PCR method (Taqman) in 108 specimens from 19 patients with Barrett's esophagus without carcinoma (BE-group), 20 patients with Barrett's associated adenocarcinoma (F.A-group), and a control group of 10 patients without evidence of gastro-esophageal reflux disease (CG). Results RXR-alpha mRNA expression was significantly decreased (p<0.001; Kruskal-Walhs test), and RXRgamma (p<0.001) was significantly increased at higher stages in Barrett's esophgns disease. gXR-beta expression was highest in Barrett's tissues and significantly increased compared to normal squamous tissues (p = 0.01, Wilcoxon test) and adenocarinoma tissues (p = 0.018, Mann-Whitney test). RXR-alpha and RXR-beta mRNA expression were significantly associated in normal sqnamons esophagus tissues (r2 = 0.49; p<0.001; Spearman test), Barratt's tissues (r2 ~ 0.63; p<0.001), and adenocarcinoma tissues (r2 = 0.68; p = 0.001). There were significant differences in RXR-alpha (p~0.011) and RXR-beta (p=O.O05) mRNA expression in histopathologically normal squamons esophagus tissues in patients with cancer and the normal control group(CG). Conclusions These findings suggest that alterations in the mRNA expression of all 3 RXR subtypes are frequent events in the development and progression of Barrett's esophagus and associated adenocarcinoma, that qnantitation of RXR mRNA expression may be useful biomarkers for this disease, and that a widespread held-effect is present in the normal esophagus of patients with esophageal adenocarcinoma.

Expression and role of retinoic acid receptor alpha in lens regeneration.

The role of retinoids in eye development has been well studied. Retinoids and their receptors regulate gene expression and morphogenesis of the eye. In this study, a highly specific antagonist of retinoic acid receptor (RAR)-alpha was used in an attempt to study its function in lens regeneration. It was found that this antagonist inhibited lens regeneration and lens fiber differentiation. It was also shown that RAR-alpha is expressed in the lens during the process of regeneration. These results indicate that different RAR might have unique as well as redundant effects and patterns of expression in the regenerating lens.

Retinoic acid and limb regeneration--a personal view.

Here I describe the situation which led up to the descriptions of the dramatic effects of retinoids on the regenerating amphibian limb. The original papers from an Indian group were published in relatively obscure journals but thanks to literature searches were made available for reading. Repetition of this work and its publication in widely read journals spawned the new field of research on the role of retinoids in developing and regenerating limbs.

Anticancer activity and mechanism of action of retinoids in oral and pharyngeal cancer

Retinoids are the natural and synthetic derivatives of vitamin A. Epidemiological studies indicate that a low intake of vitamin A is associated with an increased risk of squamous cancer. In vitro studies on cancer cells show that exposure to retinoids results in the inhibition of growth, by blocking the cell cycle or by inducing apoptosis. With respect to the clinical efficacy of retinoids some positive effects have been observed in early stage oral and oropharyngeal cancer. Administration of retinoids has been shown to elicit responses in leukoplakia, a premalignant lesion of the oral mucosa that frequently develops into invasive cancer. Furthermore, it has been possible with a retinoid, 13-cis-retinoic acid, to delay or inhibit the development of second primary tumors in patients who have been curatively treated for a first primary tumor in the oral cavity or oropharynx. Recent trials, however, failed to show protective effects on the development of second primary tumors. Because of the short duration of the response, the intrinsic resistance to retinoids and the toxic side effects, the treatment with this class of compounds has not become a standard therapy. Recent studies have shed light on how preneoplastic and neoplastic cells defend themselves against the growth inhibiting action of retinoids. An increased retinoid breakdown and an inactivation of nuclear retinoid receptor appear to be the cause of acquired or intrinsic resistance. This knowledge can be used to develop novel tumor-selective strategies. This review gives an update on the role of retinoids in oral and oropharyngeal cancer and their precursor lesions. The focus will be on the anticancer activity, the mechanism of action and future directions.

The role of retinoids in the prevention and repair of aged and photoaged skin.

Retinoids, either naturally occurring or synthetic, are defined by their ability to bind nuclear retinoid receptors of the steroid/thyroid superfamily. Their protean but key function in physiology is control of cellular proliferation and differentiation. Topical retinoids, namely tretinoin, have been proven to prevent and repair clinical features of photoageing; these processes are facilitated by an ability to prevent loss of collagen from, and stimulate new collagen formation in, the papillary dermis of sun-exposed skin. Emerging evidence indicates that intrinsic, chronological ageing of the skin shares several mechanistic features with photoageing. Indeed aged skin is characterized by retinoid sensitivity and is probably reparable by application of topical retinoids.