13 - cis - Retinoic acid induces apoptosis and cell cycle arrest in human SEB - 1 sebocytes
ABSTRACT Isotretinoin (13-cis retinoic acid (13-cis RA)) is the most potent inhibitor of sebum production, a key component in the pathophysiology of acne, yet its mechanism of action remains largely unknown. The effects of 13-cis RA, 9-cis retinoic acid (9-cis RA), and all-trans retinoic acid (ATRA) on cell proliferation, apoptosis, and cell cycle proteins were examined in SEB-1 sebocytes and keratinocytes. 13-cis RA causes significant dose-dependent and time-dependent decreases in viable SEB-1 sebocytes. A portion of this decrease can be attributed to cell cycle arrest as evidenced by decreased DNA synthesis, increased p21 protein expression, and decreased cyclin D1. Although not previously demonstrated in sebocytes, we report that 13-cis RA induces apoptosis in SEB-1 sebocytes as shown by increased Annexin V-FITC staining, increased TUNEL staining, and increased cleaved caspase 3 protein. Furthermore, the ability of 13-cis RA to induce apoptosis cannot be recapitulated by 9-cis RA or ATRA, and it is not inhibited by the presence of a retinoid acid receptor (RAR) pan-antagonist AGN 193109. Taken together these data indicate that 13-cis RA causes cell cycle arrest and induces apoptosis in SEB-1 sebocytes by a RAR-independent mechanism, which contributes to its sebosuppressive effect and the resolution of acne.
- SourceAvailable from: Bodo Melnik
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- "Isotretinoin induces cell cycle arrest in SEB-1 sebocytes with increased expression of the cell cycle inhibitor p21 37. Upregulation of the FoxO1 target gene p21 could thus explain isotretinoin-induced sebocyte apoptosis 38. "
ABSTRACT: Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. This hypothesis postulates that antiacne agents either enhance nuclear FoxO activity or inhibit mTORC1. Benzoyl peroxide (BPO), by activation of oxidative stress-inducible kinases, increases nuclear FoxO levels promoting Sestrin3-mediated AMPK activation. Furthermore, BPO-derived ROS may activate AMPK via ataxia-telangiectasia mutated. Isotretinoin and all-trans retinoic acid may stimulate FoxO gene expression. Doxycycline may enhance FoxOs nuclear retention by inhibiting the expression of exportin 1. Suppression of TNFα signalling by tetracyclines, erythromycin and other macrolides may attenuate IKKβ-TSC1-mediated mTORC1 activation. Erythromycin attenuates ERK1/2 activity and thereby increases TSC2. Azelaic acid may decrease mTORC1 by inhibiting mitochondrial respiration, increasing cellular ROS and nuclear FoxO levels. Antiandrogens may attenuate mTORC1 by suppressing mTORC2-mediated Akt/TSC2 signalling. This hypothesis unmasks a common mode of action of antiacne agents as either FoxO enhancers or mTORC1 inhibitors and thus provides a rational approach for the development of new antiacne agents.Experimental Dermatology 07/2013; 22(7):502-504. DOI:10.1111/exd.12172 · 4.12 Impact Factor
- "In the sebaceous gland, RA decreases basal sebocyte proliferation, prohibits sebocyte terminal differentiation, induces sebocyte apoptosis , and suppresses sebum production up to 90% (Nelson et al., 2006). These effects appear to be mediated through receptor-dependent and ‐independent actions (Nelson et al., 2006; Tsukada et al., 2000) and alterations in gene expression (Nelson et al., 2008). In addition, RA may suppress androgen receptors (Ubels et al., 2002, 2003) and inhibit retinol dehydrogenase-4 in sebaceous glands (Karlsson et al., 2003), which would diminish the local, intracrine production of dihydrotestosterone (DHT). "
Article: Aging and dry eye disease[Show abstract] [Hide abstract]
ABSTRACT: Dry eye disease is a prevalent eye disorder that in particular affects the elderly population. One of the major causes of dry eye, meibomian gland dysfunction (MGD), shows increased prevalence with aging. MGD is caused by hyperkeratinization of the ductal epithelium of meibomian gland and reduced quantity and/or quality of meibum, the holocrine product that stabilizes and prevents the evaporation of the tear film. Of note, retinoids which are used in current anti-aging cosmetics may promote the development of MGD and dry eye disease. In this review, we will discuss the possible mechanisms of age-related MGD.Experimental gerontology 04/2012; 47(7):483-90. DOI:10.1016/j.exger.2012.03.020 · 3.53 Impact Factor
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- "This drug acts to suppress acne in multiple ways, reducing sebaceous gland secretion and size, possibly by inhibiting proliferation and inducing apoptosis of sebocytes (Nelson et al. 2006) and also acting as an anti-inflammatory agent blocking the migration of polymorphonuclear leukocytes into the skin (Wozel et al. 1991). It is believed to act by isomerisation to all-trans-RA in tissues (Shih et al. 1986; Tsukada et al. 2000), which then activates specific receptors for retinoic acid (Nelson et al. 2009; Rochette-Egly and Germain 2009). "
ABSTRACT: The acne drug isotretinoin has 13-cis retinoic acid as its active agent. Adverse effects that have been described include severe depression. Animal studies indicate that the hippocampus is particularly sensitive to retinoic acid. Changes induced by isotretinoin to hippocampal function could contribute to depression but may be more evident in altered visuospatial learning and memory, the primary function of the hippocampus. We aimed to test the hypothesis that a course of oral isotretinoin therapy would result in declining visuospatial learning and memory. CANTAB tasks designed to assess visuospatial memory were performed repeatedly on 14 males and 3 females in an open prospective observational study of patients with severe acne undergoing isotretinoin therapy. Beck's Depression Inventory and Global Acne Grade were also administered. Performance stayed unchanged for DMS, SRM and PRM tasks, while surprisingly participants improved their speed on the PRM task. Performance improved across sessions on the PAL task, and moreover the dose of isotretinoin correlated with improvement in the total trial score, reduction in total error rate and stage completed at the first trial. Isotretinoin does not reduce learning and memory and our study suggests that it may instead lead to a dose-related improvement in specific aspects of hippocampal learning and memory. Retinoic acid functions in the hippocampus as the active metabolite of vitamin A, suggesting that this may be a limiting factor in the human hippocampus and addition of exogenous retinoic acid brings levels closer to an optimal state.Psychopharmacology 12/2011; 221(4):667-74. DOI:10.1007/s00213-011-2611-y · 3.99 Impact Factor