{'fraction_non_alphanumeric': 0.01985843491938655, 'fraction_numerical': 0.0015729453401494297, 'mean_word_length': 5.39070351758794, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The retinoid revolution

The “retinoid revolution” dates back to the beginning of this century with the elaboration of the nutritional role of vitamin A. The reasons for choosing this theme for an issue of The FASEB Journal are the exciting advances that have been achieved with accelerating speed within the last 25 years. The authors of the selected reviews have all contributed with remarkable success to the renaissance of the retinoids. A class of chemical compounds structurally related to vitamin A, the retinoids comprise natural and synthetic analogs. Vitamin A has long been recognized as an indispensable nutritional factor necessary for the promotion of general growth, maintenance of the visual function, regulation of the differentiation of epithelial tissues, and embryonic development. Vitamin A deficiency leads to many diseases, blindness, and even death. The effect of vitamin A on epithelial tissues has attracted much attention for decades because vitamin A deficiency in animals and humans leads to hyperkeratosis of the skin and to hyperplastic and metaplastic changes in the epithelia of mucous membranes. Such alterations are observed in various diseases of the skin and in certain precancerous conditions. This link provoked the interest of dermatologists as well as of oncologists about the role of vitamin A and retinoids in their disciplines. The clinical treatment of dermatological and oncological diseases with vitamin A, however, was disappointing because the doses needed for successful treatment were accompanied by marked signs and symptoms of the hypervitaminosis A syndrome, which was poorly tolerated by patients. Therefore, many retinoids have been tested experimentally and clinically in the hope of discovering retinoids with higher efficacy and fewer side effects. Physiological metabolites of vitamin A, such as all-trans retinoic acid (all-trans RA)’ and 9-cis RA, as well as thousands of new synthetic analogs have been included in experimental investigations. A few selected retinoids have been investigated further in clinical programs. Great progress was achieved with retinoids in treating a series of important dermatological conditions such as acne, psoriasis, and other keratinizing disorders. In oncology, on the other hand, substantial steps forward were made more slowly. This has changed, however, in the last decade with the successful therapy of certain precancerous lesions, the spectacular results in the treatment of acute promyelocytic leukemia with all-trans RA, the prevention of malignancies in high-risk cancer groups, and the therapeutic effect on certain precancerous and cancerous diseases by combination of retinoids, mainly 13-cis RA, with other anticancer agents. Retinoids are compounds with pleiotropic action. They possess a variety of properties that may all contribute to their experimental and clinical effects in dermatology and oncology. The following qualities have been demonstrated in numerous experimental investigations and probably play a major role in the prevention and therapy of tumors: inhibition of cell proliferation, induction of cell differentiation, induction of apoptosis or programmed cell death, immunomodulation, inhibition of angiogenesis, and influence on the expression of oncogenes and tumor suppressor genes. Retinoids have an inhibitory effect on carcinogenesis in animals. They retard or prevent the development of chemically induced tumors of the skin, breast, bladder, lung, and other organs. In addition, they exert a therapeutic effect on already established, chemically induced tumors and on xenografts. Other properties important to dermatology are the antikeratinizing effect, the inhibition of sebum production, and the repair of photodamage. Many retinoids have been found to possess some of the above-mentioned qualities. Each retinoid has its own profile of properties that determines its usefulness in clinical dermatology or oncology. Vitamin A deficiency as well as an excess of retinoids lead to malformations of the embryo. Recent studies have contributed substantially to the elucidation of the role of retinoids in embryonic development. At the level of molecular biology, the discovery of the cytosolic cellular retinoic acid binding proteins I and II (CRABP I and CRABP II), and particularly of the nuclear retinoic acid receptors, has brought more insight into retinoic acid signaling pathways. Two classes of nuclear retinoic acid receptors, termed RAR and RXR, have been identified and cloned. Each receptor class consists of three receptor subtypes, called a, 3, and y, and their isoforms. The RARs bind both all-trans RA and 9-cis RA with high affinity, whereas RXRs bind only9-ci,s RA as their proximal ligand. Increased diversity has also been generated by the heterodimeric interaction of RARs and RXRs. RARs require heterodimerization with RXRs for appreciable binding to the retinoic acid response elements (RARE) of genes. These events result in the synthesis of mRNAs and proteins that may be responsible for the observed biological effects: cell