Effects Of Retinoids Research Articles

The effect of topical retinoids in treatment of acne vulgaris in Khartoum Teaching Dermatological Hospital

Background: Acne vulgaris is a chronic inflammatory skin disease affecting approximately 80% of young adults and adolescents. Prolonged therapy is often required for satisfactory results. Topical retinoids play a central role in acne treatment, with evidence supporting their efficacy in achieving significant improvements in acne symptoms. This study aimed to assess the effectiveness of topical retinoids in treating acne vulgaris among patients at Khartoum Dermatology and Venereal Teaching Hospital from August 2019 to August 2020. Methods: A non-randomized interventional study was conducted at Khartoum Dermatology Teaching Hospital, covering patients diagnosed with mild to moderate acne vulgaris. Data were entered, cleaned, and analysed using statistical package for the social sciences (SPSS) version 25.0. Results: The study included 100 patients. Of these, 38% were aged 25-35 years, and 70% were female. 92% had experienced acne symptoms for more than six months. Regarding treatment duration, 87% used topical retinoids for more than three months. Clinical improvement was observed in 83% of patients, while 14% showed no improvement, and 3% experienced worsened symptoms. Conclusions: Topical retinoids are effective in treating mild and moderate acne vulgaris.

6816 The Estrogen Environment Characteristic of Endometriotic Lesion May Attenuate the Receptor γ-Mediated Antiproliferative Activity of Retinoids

Abstract Disclosure: M. Izawa: None. Y. Azuma: None. F. Taniguchi: None. Background: Endometriosis has been accepted as an estrogen-dependent disease, and the estrogen environment in endometriotic lesions has been proposed as a major background of the pathophysiology. Although the hormonal therapy targeting the reduction of estrogen has been employed to reduce endometriosis-associated symptoms, the limitation of therapy has been well recognized. How to overcome the limitation remains an urgent subject to be explored. [Objective:]We focused on retinoids, which have been known to induce an antiproliferative activity in tumors. Based on the retinoic acid receptor (RAR) expression profile in endometriotic lesions, we evaluated the antiproliferative activity of retinoids using endometriotic cells. Finally, we examined the effect of estrogen on antiproliferative activity. Methods: Endometriotic tissue and cells: Institutional Review Boards approved this project. The chocolate cyst lining in the ovaries of patients with endometriosis was the source of endometriotic tissue. Stromal cells collected from endometriotic tissues were used as endometriotic cells. RAR expression: RNAs were prepared from endometriotic tissues and cells, and single-stranded cDNAs were subjected to RT-PCR. Primers were designed using the UCSF genome browser. Protein expression was examined by Western blotting. Cell proliferation assay: Cells were treated with all-trans retinoic acid (ATRA), selective RAR modulators (sRARMs), BMS753, CD2314 and CD437, RARγ antagonist MM11253 and 17β-estradiol (E2). Viable cells were estimated using WST-8 assay. RNA-seq analysis: Cells were treated with retinoids and E2. RNA samples were used for polyA+ selected library and the strand-specific RNA-seq. Differentially expressed genes with p-values < 0.05 and log2 fold changes > 1 were extracted as responsive genes. Results: RAR expression: Transcripts of wild-type RARα, RARβ, and RARγ were demonstrated in arbitrary 10 regions of patient tissue, and in endometriotic cells. The expression of these RARs was almost at a comparable level. Effect of retinoids and/or estrogen on cell proliferation: Cell proliferation rate was significantly decreased in the presence of ATRA. Among sRARMs tested, only CD437 reduced the cell proliferation. The antiproliferative activity of ATRA was attenuated either in the presence of MM11253 or E2, respectively. ATRA- and/or E2-responsive gene expressions To explore gene expressions in response to retinoids and E2, RNA-seq analysis was performed. The results suggest the diversity of ATRA- and E2-responsive genes in endometriotic lesions.[Conclusion:]Endometriotic cell proliferation was significantly suppressed in response to retinoids through RARγ. The observation that the antiproliferative activity was attenuated in the presence of E2 suggests a suppressive environment against the activity of retinois in endometriotic legions. Presentation: 6/2/2024

The Awareness of and Adherence to the Pregnancy Prevention Program for Oral Retinoids: A Questionnaire Survey in Denmark.

We aimed to investigate the awareness of oral retinoid teratogenicity and the adherence to the pregnancy prevention program (PPP) related to oral retinoid use by physicians, pharmacists, and patients in Denmark. As part of the multi-country survey, web-based questionnaires were distributed among Danish dermatologists, general practitioners, community pharmacists, and women of childbearing age, who were using or had used oral retinoids within the past 5 years. A total of 62 physicians, 96 pharmacists, and 50 oral retinoid using women responded; 95%, 100%, and 98%, respectively, were aware of the teratogenic risks of oral retinoids. For physicians, the most applied PPP measures were the usage of the patient (44%) and the healthcare professional (19%) guides, while the least applied measure was signing medication risk awareness form (3%). Among the pharmacists, the warning sign on the outer medication package was the most used measure (45%). Among the women, a majority (90%) had read the patient information leaflet included in the medication package and 72% discussed the use of contraception with their healthcare provider, while risk awareness forms and patient cards were seen by only few. In Denmark, physicians, pharmacists, and medicine users were aware about the teratogenic effects of oral retinoids. Adherence to pregnancy preventionmeasures varied, suggesting unwillingness to use the measures that require patients' signatures among physicians and a lack of awareness of pharmacy targeting measures. Accessibility of the latter measures need to be optimized to improve the safety of oral retinoid use.

The Effect of Retinoids in Vascular Smooth Muscle Cells: From Phenotyping Switching to Proliferation and Migration.

Atherosclerosis, a term derived from the Greek "athero" (atheroma) and "sclerosis" (hardening), is a long-standing process that leads to the formation of atheromatous plaques in the arterial wall, contributing to the development of atherosclerotic cardiovascular disease. The proliferation and migration of vascular smooth muscle cells (VSMCs) and the switching of their phenotype play a crucial role in the whole process. Retinoic acid (RA), a natural derivative of vitamin A, has been used in the treatment of various inflammatory diseases and cell proliferation disorders. Numerous studies have demonstrated that RA has an important inhibitory effect on the proliferation, migration, and dedifferentiation of vascular smooth muscle cells, leading to a significant reduction in atherosclerotic lesions. In this review article, we explore the effects of RA on the pathogenesis of atherosclerosis, focusing on its regulatory action in VSMCs and its role in the phenotypic switching, proliferation, and migration of VSMCs. Despite the potential impact that RA may have on the process of atherosclerosis, further studies are required to examine its safety and efficacy in clinical practice.

Drug-Induced Intracranial Hypertension: The Adverse Effects of Acne Medications and Topical Retinoids.

Tetracyclines and vitamin A derivatives, major components in acne care and antiaging products, have been associated with the development of drug-induced intracranial hypertension (DIIH). Treatment practices and longitudinal visual outcomes have been highly understudied in DIIH. The purpose of this study was to provide management guidelines for DIIH and report visual outcomes of patients with DIIH. This was a single institute ophthalmology center case-control study where patients were seen between June 1, 2012, and September 1, 2023, in the United States. Patients with an International Classification of Disease (ICD) code for IIH and meeting the IIH diagnostic criteria who were taking a tetracycline or a vitamin A derivative during their diagnosis were included in this study. Patients were stratified into the following 3 categories: tetracyclines only, vitamin A derivatives only, or both, and compared with Kruskal-Wallis rank-sum tests. Poor visual outcomes were evaluated for and defined as a visual field mean deviation (peripheral visual measure) of -7 dB or greater. Individuals were followed for up to 1.5 years after diagnosis. Among patients with IIH (n = 839), DIIH occurred in 8.10% of them (n = 68) with 83% taking the medication for acne. 88% of cases were female, and patients had a mean age of 24.96 years. DIIH medications were taken for an average length of 25.79 weeks before diagnosis of IIH. 20.5% of patients with DIIH were not treated with any IIH medication and were discontinued from the inducing drug. 3 patients had a poor visual outcome on follow-up with all of them taking a vitamin A derivative (P < 0.05). Patients identified as having a poor visual outcome did not report discontinuing the DIIH drug (P < 0.05). We propose treatment guidelines highlighting that patients taking a DIIH medication who develop headaches or visual changes should be immediately referred to ophthalmology, removal of the offending agent, and close monitoring by ophthalmology for vision loss. Importantly, vitamin A DIIH may have more severe visual outcomes, but further research is needed to corroborate this finding.

Vitamin A - potential anticancer weapon

Introduction: Vitamin A, one of the most popular vitamins that people usually associate with eye health or beautiful skin, also has many other functions and uses. Recently many scientists conducted studies to determine if vitamin A could be a new weapon against cancers. Aim of the study: The aim of the study was to discuss recent findings regarding the impact of Vitamin A and other retinoids on potential applications in anticancer therapy. Materials and methods: This review of studies is based on scientific articles available in PubMed and Google Scholar databases. The names of the cancers were juxtaposed with term "Vitamin A" and with term "Retinoids" to gather data regarding the effect of retinoids on cancer treatment and prevention. Results: After analyzing the gathered publications, it is possible to conclude that retinoids can have a positive impact on cancer treatment. Some of them can induce apoptosis of cancer cells and others can reduce their proliferation. Moreover, retinoids can also play an important role in preventing cancers, such as ovarian, breast, cervical, or skin cancer. The role of retinoids in the prevention of prostate cancer remains unclear due to conflicting research results. Conclusion: The studies have shown promising results which indicate a need for further research into anticancer mechanisms of retinoids. Specifically, more research is needed to explore the positive impact of retinoid use in treating cancer diseases. The significant potential of retinoids may make it possible to include them in clinical practice and develop an effective therapeutic strategy for cancer treatment based on them.

Spectral and mass characterization of kinetic conversion from retinoids to retinoic acid in an in vitro 3-D human skin equivalent model

To investigate the effect of retinoids, such as retinol (ROL), retinal (RAL), and retinyl palmitate (RP), on epidermal integrity, skin deposition, and bioconversion to retinoic acid (RA). 3-D human skin equivalent model (EpiDermFT™) was used. Epidermal cellular integrity measured by TEER values was significantly higher for a topical treatment of ROL and RAL than RP (p < 0.05). The skin deposition (μM) of ROL and RAL was approximately 269.54 ± 73.94 and 211.35 ± 20.96, respectively, greater than that of RP (63.70 ± 37.97) over 2 h incubation. Spectral changes were revealed that the CO maximum absorbance occurred between 1600∼1800 cm−1 and was greater from ROL than that from RAL and RP, indicating conjugation of R–OH to R-CHO or R-COOH could strongly occur after ROL treatment. Subsequently, a metabolite from the bioconversion of ROL and RAL was identified as RA, which has a product ion of m/z 283.06, by using liquid a chromatography-mass spectrometry (LC-MS) - total ion chromatogram (TIC). The amount of bioconversion from ROL and RAL to RA in artificial skin was 0.68 ± 0.13 and 0.70 ± 0.10 μM at 2 h and 0.60 ± 0.04 and 0.57 ± 0.06 μM at 24 h, respectively. RA was not detected in the skin and the receiver compartment after RP treatment. ROL could be a useful dermatological ingredient to maintain epidermal integrity more effectively, more stably deposit on the skin, and more steadily metabolize to RA than other retinoids such as RAL and RP.

Retinoids in the treatment of photoageing: A histological study of topical retinoid efficacy in black skin.

Photoageing describes complex cutaneous changes that occur due to chronic exposure to solar ultraviolet radiation (UVR). The 'gold standard' for the treatment of photoaged white skin is all-trans retinoic acid (ATRA); however, cosmetic retinol (ROL) has also proven efficacious. Recent work has identified that black skin is susceptible to photoageing, characterized by disintegration of fibrillin-rich microfibrils (FRMs) at the dermal-epidermal junction (DEJ). However, the impact of topical retinoids for repair of black skin has not been well investigated. To determine the potential of retinoids to repair photoaged black skin. An exploratory intervention study was performed using an invivo, short-term patch test protocol. Healthy but photoaged black volunteers (>45 years) were recruited to the study, and participant extensor forearms were occluded with either 0.025% ATRA (n = 6; 4-day application due to irritancy) or ROL (12-day treatment protocol for a cosmetic) at concentrations of 0.3% (n = 6) or 1% (n = 6). Punch biopsies from occluded but untreated control sites and retinoid-treated sites were processed for histological analyses of epidermal characteristics, melanin distribution and dermal remodelling. Treatment with ATRA and ROL induced significant acanthosis (all p < 0.001) accompanied by a significant increase in keratinocyte proliferation (Ki67; all p < 0.01), dispersal of epidermal melanin and restoration of the FRMs at the DEJ (all p < 0.01), compared to untreated control. This study confirms that topical ATRA has utility for the repair of photoaged black skin and that ROL induces comparable effects on epidermal and dermal remodelling, albeit over a longer timeframe. The effects of topical retinoids on black photoaged skin are similar to those reported for white photoaged skin and suggest conserved biology in relation to repair of UVR-induced damage. Further investigation of topical retinoid efficacy in daily use is warranted for black skin.

Problems of quality of dermatological care for acne in adolescents

Relevance. The quality of dermatological care in the treatment of acne in adolescents is under-researched. Therefore, it is relevant to analyze the problems that negatively affect the quality of care for adolescents suffering from acne.Target. To identify problems in the quality of dermatological care in relation to the treatment of acne in adolescents.Materials and methods. 20 literature sources over the past 6 years have been found. Standard methods of literature analysis (induction, synthesis and comparison of the presented information) were used.Results. The following have not been sufficiently studied: the psychological aspect of the influence of acne and its treatment on the condition of a teenager; anti-relapse effect of retinoids depending on their dose and course duration; mechanisms of acne formation in adolescents. Information about the possibility of chronic disease and/or relapse of acne in adolescents is fragmentary. Maintenance therapy in adolescents to minimize the side effects of acne treatment has practically not been developed. Problems with compliance of adolescents undergoing treatment for acne are fragmentarily studied.Conclusions. Problems in the development of individualized acne treatment algorithms for adolescents have been identified. At the same time, adolescents are at risk of developing acne and require a special approach in the treatment of acne due to their unstable psyche and the importance of young citizens as a valuable asset of the state.

Retinoids and EZH2 inhibitors cooperate to orchestrate anti-oncogenic effects on bladder cancer cells.

The highly mutated nature of bladder cancers harboring mutations in chromatin regulatory genes opposing Polycomb-mediated repression highlights the importance of targeting EZH2 in bladder cancer. Furthermore, the critical role of the retinoic acid signaling pathway in the development and homeostasis of the urothelium, and the anti-oncogenic effects of retinoids are well established. Therefore, our aim is to simultaneously target EZH2 and retinoic acid signaling in bladder cancer to potentiate the therapeutic response. Here we report that this coordinated targeting strategy stimulates an anti-oncogenic profile, as reflected by inducing a synergistic reduction in cell viability that was associated with increased apoptosis and cell cycle arrest in a cooperative and orchestrated manner. This study characterized anti-oncogenic transcriptional reprogramming centered on the transcriptional regulator CHOP by stimulating the endoplasmic reticulum stress response. We further portrayed a molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of a subset of genes involved in unfolded protein responses, reflecting the molecular mechanism underlying this co-targeting strategy. These findings highlight the importance of co-targeting the EZH2 and retinoic acid pathway in bladder cancers and encourage the design of novel treatments employing retinoids coupled with EZH2 inhibitors in bladder carcinoma.

Control of Mitochondrial Electron Transport Chain Flux and Apoptosis by Retinoic Acid: Raman Imaging In Vitro Human Bronchial and Lung Cancerous Cells.

The multiple functions of cytochrome c (cyt c) and their regulation in life and death decisions of the mammalian cell go beyond respiration, apoptosis, ROS scavenging, and oxidation of cardiolipine. It has become increasingly evident that cyt c is involved in the propagation of mitogenic signals. It has been proposed that the mitogenic signals occur via the PKCδ-retinoic acid signal complex comprising the protein kinase Cδ, the adapter protein Src homologous collagen homolog (p66Shc), and cyt c. We showed the importance of retinoic acid in regulating cellular processes monitored by the Raman bands of cyt c. To understand the role of retinoids in regulating redox status of cyt c, we recorded the Raman spectra and images of cells receiving redox stimuli by retinoic acid at in vitro cell cultures. For these purposes, we incubated bronchial normal epithelial lung (BEpC) and lung cancer cells (A549) with retinoic acid at concentrations of 1, 10, and 50 µM for 24 and 48 h of incubations. The new role of retinoic acid in a change of the redox status of iron ion in the heme group of cyt c from oxidized Fe3+ to reduced Fe2+ form may have serious consequences on ATPase effectiveness and aborting the activation of the conventional mitochondrial signaling protein-dependent pathways, lack of triggering programmed cell death through apoptosis, and lack of cytokine induction. To explain the effect of retinoids on the redox status of cyt c in the electron transfer chain, we used the quantum chemistry models of retinoid biology. It has been proposed that retinol catalyzes resonance energy transfer (RET) reactions in cyt c. The paper suggests that RET is pivotally important for mitochondrial energy homeostasis by controlling oxidative phosphorylation by switching between activation and inactivation of glycolysis and regulation of electron flux in the electron transport chain. The key role in this process is played by protein kinase C δ (PKCδ), which triggers a signal to the pyruvate dehydrogenase complex. The PKCδ-retinoic acid complex reversibly (at normal physiological conditions) or irreversibly (cancer) responds to the redox potential of cyt c that changes with the electron transfer chain flux.

Acne vulgaris and treatment with topical retinoids - adapalene and tretinoin

Introduction and purpose: Acne vulgaris is a disease that mainly affects young people and is associated with overactive sebaceous glands. The disease mainly affects the face but can also occur on the back. Depending on the clinical picture, we can distinguish different types of acne and make our treatment dependent on it. The aim of the study will be to compare the effects of topical retinoids on acne vulgaris. State of knowledge: Topical retinoids have a direct anti-inflammatory effect and prevent the formation of blackheads and microcomedones. Five retinoids are currently available for topical treatment of acne vulgaris. We distinguish three generations. The mechanism of action is not fully understood, but it is known that they react with the RAR and RXR receptors. In the review paper, we will compare the effects of adapalene with tretinoin. Conclusion: According to the indicated study results, there is no significant difference in the effect of treatment with adapalene or tretinoin. Adapalene showed less irritation during treatment than tretinoin. The most important thing during acne treatment is choosing the right concentration and formulation by the dermatologist so that the patient does not stop treatment.

Abstract 1502: PRAME modulates the effect of retinoids on keratinocyte differentiation and cell cycle progression in basal cell carcinoma and cutaneous squamous cell carcinoma

Abstract Substantial research supports the use of retinoids as prophylactics and treatments for keratinocyte carcinomas (KC). However, the practical applications of these compounds for KC management are limited by a poor understanding of the molecular basis of retinoid resistance. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer-testis antigen that functions as a retinoic acid receptor repressor and as a substrate recognition subunit for Cullin-2 E3 ubiquitin ligase, targeting degradation of cell cycle regulatory factors. PRAME is ectopically expressed in both types of KC: basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). The functions and clinicopathological relevance of PRAME expression in BCC and SCC are unknown. The purpose of this study is to investigate the effect of PRAME on retinoid sensitivity and the pathogenesis of BCC and SCC. Cell lines representative of human BCC, SCC and immortalized keratinocytes were subjected to shRNA-mediated PRAME knockdown, PRAME knockout using CRISPR-Cas9, and ORF overexpression. Cells were treated with retinoids (all-trans retinoic acid, acitretin or tazarotene), and subjected to assays for cell proliferation (e.g., flow cytometric cell cycle analysis, label-free confluence tracking, Ki-67 immunofluorescence, etc.), cell death/survival (e.g., clonogenic assay, caspase staining, etc.) and for retinoid-induced gene expression changes (RT-qPCR and immunoblotting, etc.). PRAME overexpression attenuated retinoid-induced changes in cytokeratin expression in immortalized keratinocytes and SCC cells. PRAME knockdown in BCC and SCC cells augmented retinoid-induced changes in cytokeratin expression. Importantly, PRAME overexpression attenuated the pro-differentiation synergy between high calcium culture conditions and retinoid treatment in immortalized keratinocytes. PRAME also altered expression of several cell cycle regulatory proteins (p14/ARF, p16/INK4A, p21/Waf, p27/Kip1, etc.), which was in turn reflected accelerated cell proliferation dynamics in some PRAME-overexpressing cell lines. PRAME also conferred increased resistance to retinoid-induced cell cycle arrest in SCC cells, which was restored by PRAME knockdown. Furthermore, PRAME expression was inversely correlated with the pro-apoptotic protein Tazarotene Inducible Gene 3 (TIG3) in SCC cells. Our results implicate PRAME in KC tumorigenesis and differentiation, and suggest that PRAME could serve as a therapeutic target to optimize the use of retinoids to manage these cancers. We propose future studies to determine the clinicopathological relevance of PRAME expression in KC, PRAME-targeting strategies to enhance retinoid sensitivity, and the use skin tissue organoid models to study the effect of PRAME on epidermal differentiation dynamics in premalignant skin and KCs. Citation Format: Brandon Liam Ramchatesingh, Ivan Litvinov. PRAME modulates the effect of retinoids on keratinocyte differentiation and cell cycle progression in basal cell carcinoma and cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1502.

Abstracts 13th PCNE Working Conference “Pharmacies' new roles in pharmaceutical care: bridging research and practice”

Abstracts 13th PCNE Working Conference “Pharmacies' new roles in pharmaceutical care: bridging research and practice”

The role of the retinoids in topical treatment of skin diseases - the review of the literature

INTRODUCTION: Retinoids are a broad group of natural and synthetic compounds derived from vitamin A. Many studies have shown strong anti-aging effects, and they have also been shown to have therapeutic effects on acne vulgaris or psoriasis. Vitamin A and its derivatives make the skin more elastic and smooth, cause a decrease in fine wrinkles and cause an increase in fibroblast activity and collagen fiber production. Retinoid compounds regulate biological processes of the skin such as immune processes, angiogenesis, proliferation and differentiation. THE AIM OF STUDY: The purpose of this paper is to discuss the effects of retinoids and the use of the substances in skin diseases. MATERIALS AND METHOD: Literature review of PubMed, Google Scholar and Science Direct and evaluation of available randomized controlled trials using retinoids in terms of treatment effectiveness in terms of skin quality, anti-aging benefits use in dermatology. CONCLUSIONS: Vitamin A and its derivatives plays an important role in anty-aging prevention and treatment of skin diseases, such as acne vulgaris, psoriasis and photo-aging. There are still many ongoing studies and not known opportunities of its use to treat other skin diseases that we should be aware of and keep track of new papers that indicate such.

In Vitro and in Vivo Assays for Testing Retinoids Effect on Intestinal Progenitors' Lineage Commitments.

The intestine consists of epithelial cells surrounded by a complex environment as mesenchymal cells and the gut microbiota. With its impressive stem cell regeneration capability, the intestine is able to constantly replenish cells lost through apoptosis or abrasion by food passing through. Over the past decade, researchers have identified signaling pathways involved in stem cell homeostasis such as retinoids pathway. Retinoids are also involved in cell differentiation of healthy and cancer cells. In this study, we describe several approaches in vitro and in vivo to further investigate the effect of retinoids on stem cells, progenitors, and differentiated intestinal cells.

Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3.

Clearance of apoptotic cells by bone marrow-derived macrophages differentiated from monocytes plays a central role in the resolution of inflammation, as the conversion of pro-inflammatory M1 macrophages to M2 macrophages that mediate the resolution process occurs during efferocytosis. Thus, proper efferocytosis is a prerequisite for proper resolution of inflammation, and failure in efferocytosis is associated with the development of chronic inflammatory diseases. Previous studies from our laboratory have shown that (13R)-all-trans-13,14-dihydroretinol (DHR), the product of retinol saturase, acting from day 4 of monocyte differentiation enhances the efferocytosis capacity of the resulted macrophages. Loss of retinol saturase in mice leads to impaired efferocytosis, and to development of autoimmunity. In the present paper, we report that in differentiating monocytes DHR, retinol, and all-trans retinoic acid all act directly on retinoic acid receptors and enhance the clearance of apoptotic cells by upregulating the expression of several efferocytosis-related genes. The effect of retinoids seems to be mediated by bone morphogenetic protein (BMP)-2, and the Smad3 transcription factor. In addition, retinoids also upregulate the expression of the vitamin D receptor and that of vascular endothelial growth factor A, indicating that altogether retinoids promote the generation of a pro-reparative M2 macrophage population during monocyte differentiation.

Molluscan RXR Transcriptional Regulation by Retinoids in a Drosophila CNS Organ Culture System.

Retinoic acid, the active metabolite of Vitamin A, is important for the appropriate development of the nervous system (e.g., neurite outgrowth) as well as for cognition (e.g., memory formation) in the adult brain. We have shown that many of the effects of retinoids are conserved in the CNS of the mollusc, Lymnaea stagnalis. RXRs are predominantly nuclear receptors, but the Lymnaea RXR (LymRXR) exhibits a non-nuclear distribution in the adult CNS, where it is also implicated in non-genomic retinoid functions. As such, we developed a CNS Drosophila organ culture-based system to examine the transcriptional activity and ligand-binding properties of LymRXR, in the context of a live invertebrate nervous system. The novel ligand sensor system was capable of reporting both the expression and transcriptional activity of the sensor. Our results indicate that the LymRXR ligand sensor mediated transcription following activation by both 9-cis RA (the high affinity ligand for vertebrate RXRs) as well as the vertebrate RXR synthetic agonist, SR11237. The LymRXR ligand sensor was also activated by all-trans RA, and to a much lesser extent by the vertebrate RAR synthetic agonist, EC23. This sensor also detected endogenous retinoid-like activity in the CNS of developing Drosophila larvae, primarily during the 3rd instar larval stage. These data indicate that the LymRXR sensor can be utilized not only for characterization of ligand activation for studies related to the Lymnaea CNS, but also for future studies of retinoids and their functions in Drosophila development.

Systemic Medications Associated With Hair Texture Changes.

In addition to hair loss, alterations in hair texture can be a worrisome side effect of certain medications yet are seldom reported and poorly characterized. To systematically analyze the scientific literature to characterize medication-associated hair texture changes. Relevant primary literature within PubMed and Cochrane was reviewed from 1985-2021 including 31 articles (1 randomized controlled trial with texture changes incidentally noted, 6 cohort, 1 cross-sectional, 23 case studies), comprising 2594 patients. Texture changes were associated primarily with antineoplastic agents (n = 97), antiepileptics (n = 56), retinoids (n = 15), immunomodulators (n = 3), and antiretroviral therapy (n = 1). Average age was 48.4 years old (41.2% female). De novo or exaggerated curling patterns were most commonly reported. Average time to texture change varied from 4.5 months (immunomodulators) to 17 months (antiretrovirals). Prognosis was seldom discussed with reversibility noted across all medication classes (n = 17/21; 3 weeks to 5 years post therapy). Irreversible changes were linked with antiretrovirals, retinoids, and antineoplastics. Inability to define true incidence rates, ethnicity, and severity of texture changes due to the nature of available literature. Hair texture changes are potential side effects of antineoplastics, antiepileptics, retinoids, immunomodulators, and antiretroviral therapy. As these can have associated psychosocial impact, awareness among prescribing physicians is important.J Drugs Dermatol. 2022;21(9):989-996 doi:10.36849/JDD.6852.

Abstract 6067: Studying the anti-proliferating and differentiating effects of retinoids based on pathway genotype of colorectal cancer cell lines

Abstract Background: Our overarching goal is to therapeutically sensitize human colorectal cancer stem cells to differentiation-inducing effects of retinoid agents. Tumorigenesis in colorectal cancer (CRC) results from the acquisition of mutations in a colonic stem cell which transforms it into a cancer stem cell (CSC). There are no curative treatments for advanced CRC due to the resistance of CSCs to chemotherapy and/or radiation. All-trans retinoic acid (ATRA) is known to be a greatly effective treatment for acute promyelocytic leukemia (APL) which is caused by translocation in the retinoic acid receptor alpha (RARA) gene. We conjecture that the response of retinoic acid (RA) agents may have effects on solid tumors depending on their pathway genotype. Results from our bioinformatics analysis on mutations and overexpression of RA signaling component genes in CRC showed that the majority of RA pathway genes are overexpressed in CRC. Therefore, we hypothesize that the ability of retinoid and retinoid metabolism blocking agents to induce differentiating effects in CSCs depends on the RA pathway genotype expressed in CRC cells. Methods: The ability of RA agents (ATRA, 13-cis retinoic acid, 9-cis retinoic acid) and RA metabolism blocking agents (Liarozole and Talarozole) to inhibit proliferation and induce differentiation on CRC cell lines with different mutations in RA signaling were evaluated. Additionally, Nanostring Profiling was used to measure the effects of the agents on mRNA expression of CSC markers, indicators of cell differentiation, and RA receptors. Results: Our results show that the RA pathway genotype affects the response of RA agents in CRC cell lines. Both HCT116 and SW480 CRC cell lines, which are both mutant in RARA and RARA and RXRG respectively displayed resistance to ATRA. HT29 CRC cells express wild- type RA receptors and are sensitive to ATRA. All three cell lines showed similar dose responses to the CYP26A1 inhibitor Liarozole. This indicates that regardless of RA receptor mutations, inhibition of ATRA metabolism increases intracellular RA levels in a similar manner on all 3 cell lines. Nanostring Profiling shows that ATRA treatment of HT29 cells induces: an increase in the expression of RARA, CYP26A1 (ATRA metabolizing enzyme) and KRT20 (differentiation marker); and a decrease in the expression of CSC markers LGR5 and ALDH1A1. This indicates an active RA signaling pathway, induced differentiation, and a decrease in stem cells. Discussion: Overall, our findings indicate that colon SCs are regulated by RA signaling mechanisms and dysregulation of RA signaling contributes to the SC overpopulation that drives CRC growth. Therefore, further investigation on how to therapeutically sensitize human colonic CSCs to the differentiation-inducing effects of retinoid agents should provide insight into designing new SC-targeted therapies for CRC. Citation Format: Victoria O. Hunsu, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Studying the anti-proliferating and differentiating effects of retinoids based on pathway genotype of colorectal cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6067.