BACKGROUND: Testis is an immune privileged organ, which prevents the immune response against sperm antigens and inflammation. Testicular cells responsible for immune tolerance are mainly Sertoli cells, which form the blood-testis barrier and produce immunosuppressive factors. Sertoli cells prevent inflammation in the testis and maintain immune tolerance by inhibiting proliferation and inducing lymphocyte apoptosis. It has been shown that 9-cis-retinoic acid (9cRA) blocks ex vivo apoptosis of peripheral blood lymphocytes and promotes the differentiation of Treg cells in the gut. However, the role of retinoid signaling in regulating the immune privilege of the testes remains unknown.
OBJECTIVE: The aim of this study was to determine whether 9cRA, acting via the retinoic acid receptors (RAR) and the retinoic X receptors (RXR), controls the immunomodulatory functions of Sertoli cells by influencing the secretion of anti-inflammatory/pro-inflammatory factors, lymphocyte physiology and Treg cell differentiation.
METHODS: Experiments were performed using in vitro model of co-cultures of murine Sertoli cells and T lymphocytes. Agonists and antagonists of retinoic acid receptors were used to inhibit/stimulate retinoid signaling in Sertoli cells.
RESULTS: Our results have demonstrated that 9cRA inhibits the expression of immunosuppressive genes and enhances the expression of pro-inflammatory factors in Sertoli cells and lymphocytes, increases lymphocyte viability and decreases apoptosis rate. Moreover, we have found that 9cRA blocks lymphocyte apoptosis acting through both RAR and RXR and inhibiting FasL/Fas/Caspase 8 and Bax/Bcl-2/Caspase 9 pathways. Finally, we have shown that 9cRA signaling in Sertoli cells inhibits Treg differentiation.
CONCLUSIONS: Collectively, our results indicate that retinoid signaling negatively regulates immunologically privileged functions of Sertoli cells, crucial for ensuring male fertility. 9cRA inhibits lymphocyte apoptosis, which can be related to the development of autoimmunity, inflammation, and, in consequence, infertility.

Hidradenitis suppurativa (HS) is a debilitating chronic skin disorder characterized by painful inflammatory nodules, abscesses and sinus tracts involving intertriginous areas and has an adverse impact on patient quality of life. Over the past decade, the therapeutic options of HS have increased significantly to comprise multiple modalities, including topical medication, systemic therapies (mainly antibiotics, retinoids, and biologics), surgical approaches, and lifestyle modifications. Biologics alone or in combination with surgery remain the treatment of choice for moderate to severe disease. However, non-biologic therapies (including retinoids) may be used as monotherapy for mild disease and in combination with biologics and surgical treatment in moderate to severe disease. Retinoids, specifically isotretinoin, acitretin, and alitretinoin, are historically used in the management of HS, supported by anecdotal evidence and with variable treatment response. Although the current American and European guidelines offer different recommendations on the use of retinoids in HS, retinoids remain a valuable ally in HS management. This review provides a comprehensive analysis of the current scientific literature on retinoid therapy (topical and systemic) in HS, highlighting disparities in mechanisms of action, efficacy, and safety to clarify their role in HS treatment.

Communication between cells in the nervous system is dependent on both chemical and electrical synapses. Factors that can affect chemical synapses have been well studied, but less is known about factors that influence electrical synapses. Retinoic acid, the vitamin A metabolite, is a known regulator of chemical synapses, but few studies have examined its capacity to regulate electrical synapses. In this study, we determine that retinoic acid is capable of rapidly altering the strength of electrical synapses in an isomer- and cell-dependent manner. Furthermore, we provide evidence that this acute effect might be independent of either the retinoid receptors or the activation of a protein kinase. In addition to the rapid modulatory effects of retinoic acid, we provide data to suggest that retinoic acid is also capable of regulating the formation of electrical synapses. Long-term exposure to both all-trans-retinoic acid or 9-cis-retinoic acid reduced the proportion of cell pairs forming electrical synapses, as well as reduced the strength of electrical synapses that did form. In summary, this study provides insights into the role that retinoids might play in both the formation and modulation of electrical synapses in the central nervous system.NEW & NOTEWORTHY Retinoids are known modulators of chemical synapses and mediate synaptic plasticity in the nervous system, but little is known of their effects on electrical synapses. Here, we show that retinoids selectively reduce electrical synapses in a cell- and isomer-dependent manner. This modulatory action on existing electrical synapses was rapid and nongenomic in nature. We also showed for the first time that longer retinoid exposures inhibit the formation of electrical synapses.

Darier disease is a rare autosomal dominant genodermatosis that initially first presents in adolescence with scaly reddish brown keratotic papules and plaques with a seborrheic and intertriginous distribution. The absence of specific targeted medications complicates the treatment process, and managing resistant cases can prove challenging due to recurrent exacerbations that may result in serious complications such as secondary bacterial and viral infections. Treatments of choice include antiseptics, topical corticosteroids, and systemic retinoids, mainly acitretin and isotretinoin. We report the case of a female patient with Darier disease that was unsuccessfully treated with acitretin and isotretinoin but showed significant improvement with alitretinoin. Previous reports on the efficacy of alitretinoin in Darier disease are reviewed.

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Background: Systemic remedies such as cyclosporine, methotrexate, and retinoids are off-license treatment options that are considered for severe chronic hand eczema (CHE) that is resistant to first-line treatment. Objectives: The objective of this study was to determine the optimal treatment of CHE patients, including those with atopic Dermatitis®, and to compare the efficacy between cyclosporine and alitretinoin. Methods: This study was retrospective and included CHE patients who visited the Department of Dermatology at Hanyang University Seoul Hospital in Korea between March 2013 and February 2020. Results: A total of 95 CHE patients was included in this study. In the cyclosporine treatment group, there were more patients with severe baseline Investigator Global Assessment (IGA) (P = 0.033) and higher immunoglobulin E (IgE) level (P = 0.019). The mean recurrence duration was 15.9 weeks in the alitretinoin group and 22.9 weeks in the cyclosporine group, the difference between which was not statistically significant. In a subgroup analysis according to treatment drug, only the low IgE group showed a better recurrence profile for alitretinoin treatment compared to cyclosporine treatment (P = 0.039). When comparing the cumulative recurrence rate during the treatment period and subsequent follow-up periods, the cyclosporine group showed a greater incidence of recurrence than the alitretinoin group in all follow-up periods. The results of our study are consistent with the previously reported efficacy of alitretinoin. Despite the rapid response in the cyclosporine group, 12 weeks of CHE treatment with alitretinoin showed superior efficacy compared to cyclosporine treatment. Conclusions: Both alitretinoin and cyclosporine groups showed efficacy in patients with CHE. Cyclosporine is an alternative treatment of CHE that is refractory to alitretinoin or relapses after its use, especially in the presence of atopic Dermatitis®.

9-cis-retinoic acid (9cRA) binds retinoic acid receptors (RAR) and retinoid X receptors (RXR) with nanomolar affinities, in contrast to all-trans-retinoic acid (atRA), which binds only RAR with nanomolar affinities. RXR heterodimerize with type II nuclear receptors, including RAR, to regulate a vast gene array. Despite much effort, 9cRA has not been identified as an endogenous retinoid, other than in pancreas. By revising tissue analysis methods, 9cRA quantification by liquid chromatography-tandem mass spectrometry becomes possible in all mouse tissues analyzed. 9cRA occurs in concentrations similar to or greater than atRA. Fasting increases 9cRA in white and brown adipose, brain and pancreas, while increasing atRA in white adipose, liver and pancreas. 9cRA supports FoxO1 actions in pancreas β-cells and counteracts glucose actions that lead to glucotoxicity; in part by inducing Atg7 mRNA, which encodes the key enzyme essential for autophagy. Glucose suppresses 9cRA biosynthesis in the β-cell lines 832/13 and MIN6. Glucose reduces 9cRA biosynthesis in 832/13 cells by inhibiting Rdh5 transcription, unconnected to insulin, through cAMP and Akt, and inhibiting FoxO1. Through adapting tissue specifically to fasting, 9cRA would act independent of atRA. Widespread occurrence of 9cRA in vivo, and its self-sufficient adaptation to energy status, provides new perspectives into regulation of energy balance, attenuation of insulin and glucose actions, regulation of type II nuclear receptors, and retinoid biology.

BACKGROUND: Acitretin, a synthetic vitamin A derivative, is the most studied and widely used oral retinoid for ichthyoses. Its major disadvantage is the need for contraceptive measures during 3 years after discontinuation. An alternative is needed for women of childbearing age. With alitretinoin, another retinoid, pregnancy is considered safe 1 month after discontinuation.
OBJECTIVE: The aim of this study was to provide evidence for alitretinoin as an alternative for acitretin for ichthyosis in women of childbearing age. Our experience is shared in a case series combined with an overview of the current literature.
METHODS: Nine women of childbearing age (19-31 years, median 21) with different subtypes of ichthyosis (autosomal recessive congenital ichthyosis, (superficial) epidermolytic ichthyosis, erythrokeratoderma variabilis, and epidermolytic epidermal nevi, a mosaic form of epidermolytic ichthyosis) were included and treated with 30 mg alitretinoin during 2-28 months. Severity was measured by Ichthyosis Area Severity Index (IASI) and Investigator Global Assessment (IGA). A literature search in Pubmed using the Mesh terms \"alitretinoin,\" \"skin diseases, genetic\" and \"ichthyosis\" was performed.
RESULTS: Significant reduction in the mean scores of IGA, IASI-erythema, IASI-scaling, and IASI-total was seen. Seven patients are still being treated, 1 patient stopped to become pregnant, 1 patient discontinued due to financial reasons. Observed side effects were reversible headache (n = 6), asteatotic eczema (n = 1), \"not feeling well\" temporarily (n = 1), and easier blistering of the feet (n = 1). The literature search resulted in six case reports and case series about alitretinoin in ichthyosis and ichthyosis syndromes with in total 29 patients. The vast majority of articles (21/29) reported significant improvement or even complete remission of skin symptoms. However, validated outcome measures to support these results were lacking. Side effects (n = 16) were relatively mild, except for benign intracranial hypertension (n = 1) and autoimmune hypothyroidism (n = 1).
CONCLUSIONS: Our study shows, with validated outcome measures, that alitretinoin is effective to mitigate the symptoms of ichthyosis in women of childbearing age and a suitable alternative to acitretin.

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Kaposi sarcoma (KS) is one of the most common AIDS-related malignant neoplasms, which can leave lesions on the skin among HIV patients. These lesions can be treated with 9-cis-retinoic acid (9-cis-RA), an endogenous ligand of retinoic acid receptors that has been FDA-approved for treatment of KS. However, topical application of 9-cis-RA can induce several unpleasant side effects, like headache, hyperlipidemia, and nausea. Hence, alternative therapeutics with less side effects are desirable. There are case reports associating over-the-counter antihistamine usage with regression of KS. Antihistamines competitively bind to H1 receptor and block the action of histamine, best known for being released in response to allergens. Furthermore, there are already dozens of antihistamines that are FDA-approved with less side effects than 9-cis-RA. This led our team to conduct a series of in-silico assays to determine whether antihistamines can activate retinoic acid receptors. First, we utilized high-throughput virtual screening and molecular dynamics simulations to model high-affinity interactions between antihistamines and retinoic acid receptor beta (RARβ). We then performed systems genetics analysis to identify a genetic association between H1 receptor itself and molecular pathways involved in KS. Together, these findings advocate for exploration of antihistamines against KS, starting with our two promising hit compounds, bepotastine and hydroxyzine, for experimental validation study in the future.