Retinoid Therapy Research Articles

Retinol and Oligopeptide-Loaded Lipid Nanocarriers as Effective Raw Material in Anti-Acne and Anti-Aging Therapies

The use of lipid nanocarriers as components of cosmetic formulations may provide an opportunity to fully exploit the beneficial properties of pentapeptide-18 and retinol while reducing the undesirable effects that occur during retinoid therapy. This study aimed to evaluate the effectiveness of semi-solid formulations enriched with retinol and oligopeptide-loaded lipid nanocarriers. Solid lipid nanoparticles were produced using a high-shear homogenization method. The work included physicochemical characterization of the cosmetic products, and evaluation of their stability as well as their efficacy. The resulting semi-solid preparations were determined to be stable regardless of their storage temperature. No effect of the presence of lipid nanoparticles on the shelf-life stability of the cosmetic products was observed. A temperature of 25 °C was considered the recommended storage temperature for the tested semi-solid formulations. Beneficial effects of the cosmetic products were proven (in vivo study on volunteers), i.e., a significant reduction in the level of sebum secretion (anti-acne therapy) and a decrease in the number of facial wrinkles (anti-aging therapy). In addition, the protective properties of the lipid nanoparticles themselves against the skin were confirmed, reducing the irritating effect of retinol that is usually the case with classic retinoid therapies.

Novel miRNA-inducing drugs enable differentiation of retinoic acid-resistant neuroblastoma cells.

Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest-derived progenitor cells, poses a significant clinical challenge. In particular, unlike adrenergic (ADRN) neuroblastoma cells, mesenchymal (MES) cells are resistant to chemotherapy and retinoid therapy and thereby significantly contribute to relapses and treatment failures. Previous research suggested that overexpression or activation of miR-124, a neurogenic microRNA with tumor suppressor activity, can induce the differentiation of retinoic acid-resistant neuroblastoma cells. Leveraging our established screen for miRNA-modulatory small molecules, we validated PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, as a robust inducer of miR-124. A combination of PP121 and BDNF-activating bufalin synergistically arrests proliferation, induces differentiation, and maintains the differentiated state of MES SK-N-AS cells for 8 weeks. RNA-seq and deconvolution analyses revealed a collapse of the ADRN core regulatory circuitry (CRC) and the emergence of novel CRCs associated with chromaffin cells and Schwann cell precursors. Using a similar protocol, we differentiated and maintained MES neuroblastoma GI-ME-N and SH-EP cell lines, as well as glioblastoma LN-229 and U-251 cell lines, for over 16 weeks. In conclusion, our novel protocol suggests a promising treatment for therapy-resistant cancers of the nervous system. Moreover, these long-lived, differentiated cells provide valuable models for studying mechanisms underlying differentiation, maturation, and senescence.

Rx -to- OTC switch increased access and lowered cost of topical adapalene.

Topical adapalene gel is an effective and well tolerated acne treatment that transitioned from prescription to over-the-counter (OTC) availability in 2016. Historically, prescription to OTC transitions have lowered costs to patients and payers and increased access to medications. This study used sales and prescriber data to assess access to topical retinoid therapies and their costs in the pre- and post- Rx-to-OTC transition. We demonstrate that the prescription to OTC transition of adapalene gel increased access to this medication, while lowering costs to patients and payers, including Medicare patients. These results provide a necessary call to action for future OTC shifts with other high safety profile, well-tolerated medications in ultimate efforts and hopes of cost savings for patients, insurers, and Medicare within our healthcare industry.

Topical and Systemic Retinoids in the Management of Hidradenitis Suppurativa: A Comprehensive Literature Review.

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.

Организация профилактики и терапии угревой болезни у подростков на современном этапе.

The organization of prevention and treatment of acne in adolescents, necessary to improve the quality of medical dermatological care, has not been studied enough. The purpose of the study: аnalysis of current and potential opportunities for organizing the prevention and treatment of acne in adolescents. Results. The pathophysiological mechanisms of acne development are being reviewed, considering the characteristics of the puberty period, however, the trends in introducing new approaches to the organization of prevention and treatment of acne in adolescents are not expressed, with the exception of antiandrogen therapy. The official organization of treatment for adolescents with acne considers that any stage of acne development is multifactorial and is based on an inflammatory process. The officially recommended main method of treating acne in adolescents is the combined use of topical agents, especially the combination of benzoyl peroxide and the retinoid adapalene. In complex cases, topical treatment is supplemented with systemic therapy with retinoids (isotretinoin). Prevention of side effects of topical treatment (dry skin, hyperemia or cheilitis) is achieved through the use of moisturizing cosmetics or cream with dexpanthenol, respectively. Officially, in the field of acne prevention and therapy, such methods of influencing acne vulgaris as dermatocosmetics and corneo-or enzyme therapy are not used. The use of local and systemic pre- and probiotics for the treatment of acne has not been introduced. This reveals a connection between the development of acne and the intestinal microbiome. The use of local antiandrogens and insulin-like growth factor 1 inhibitors to control sebum production, as well as selective retinoic acid receptor agonists with a better safety profile compared to retinoid therapy for acne, may be promising for the prevention and treatment of acne in adolescents. Findings. Organization of effective treatment of acne in adolescents should include their clear instructions and correction of dietary habits. Prevention of acne today is practically not organized in the field of medical services.

Retinoid Treatment for Oral Leukoplakia: Current Evidence and Future Development

Oral leukoplakia (OLK) is one of the most common oral potentially malignant disorders (OPMDs). Preventing malignant transformation is the main purpose of OLK treatment. The treatment approaches of OLK include surgery, chemotherapy, and other therapies, such as photodynamic therapy and CO2 laser. The application of genomic variation-based chemotherapy in OLK deserves further exploration. As chemopreventive drugs, drug resistance and disease recurrence have limited their use in OLK. In this review, we concentrate on the retinoid treatment for OLK, summarizing the current status of retinoids in the treatment of OLK, the mechanism of retinoid action, and the mechanisms of resistance to retinoid therapy, and we highlight the strategies to improve retinoid efficacy in the treatment of OLK, such as the combination of retinoids and epigenetic regulators or metabolism-blocking agents, new synthetic retinoids, and new drug delivery systems of retinoids, providing new methods for the successful clinical application of retinoids in the treatment of OLK.

Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

Genetic variants in the retinoid X receptor gene contribute to osteoarthritis susceptibility

Osteoarthritis (OA) is a progressive disease of the joints that causes a gradual loss of function, resulting in limited mobility. Chronic inflammation is the main molecular process that triggers and propagates this disease. The retinoid X receptor (RXR), a member of the nuclear receptor family, is involved in modulating inflammatory pathways by influencing key procatabolic inflammatory cytokines, chemokines, and enzymes responsible for instigating and sustaining chronic joint inflammation. We evaluated the association between OA risk and genetic variants in the RXR? isoform. Compared to control individuals, a statistically significant difference in genotype distribution was detected for the rs7864987 polymorphism (P=0.008), while a positive inclination toward association was noted for rs3118523 (P=0.077). According to our findings based on the additive model, it appears that RXR? rs7864987 is linked to a higher risk of OA (adjusted odds ratio (OR)=1.846, P=0.012), whereas rs3118523 is associated with decreased risk of OA (adjusted OR=0.569, P=0.030). These results suggest that RXR? could be a significant inflammation-related gene involved in the complex network underlying the immunopathology of osteoarthritis. RXR? polymorphisms could potentially drive individualized retinoid therapy for OA based on genetic profile.

Photoprotection behaviors among patients during retinoid therapy

Aim: The aim of the study was to examine patients on dermatology retinoid treatment attitudes related to skin protection against UV radiation and to check the hypothesis whether patients using retinoids are more aware of the need for photoprotection. Material and methods: Internet-based survey about attitudes associated with sun exposure and photoprotection was carried out between March and May 2023. 176 questionnaires were subject to statistical analysis. Results: The study showed that 73% of the responders used an SPF cream every day. Only 3,8 % didn’t use a UV protection cream. 38% used it on all the exposed body parts. 21% used it only on their face and necks and 10% used it only on their face. As many as 78% of respondents used a cream with protection SPF 50 or more. 40% of patients reapply SPF. Most of the patients use additional tools such as sunglasses, hats and caps. But only 16% use specialized UPF clothing. Conclusion: Patients during their retinoid treatment show increased knowledge and attitude towards photoprotection. They are aware of the risks due to sensitization of their therapy and are trying to mitigate the negative effects of the UV radiation.

The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away.

Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA's success has deepened our understanding of the role of the RARα pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RARα pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.

How to avoid reactions to topical retinoid therapy

Topical retinoids are the first line treatment for mild to moderate acne. Although the drugs of this group are very effective in the treatment of acne, their use often causes irritant dermatitis – xerosis, peeling and other unpleasant symptoms. These adverse events reduce adherence to the therapy and, consequently, the effectiveness of the treatment. However, as shown by foreign clinical experience and our own observations, the use of moisturizers in combination with topical retinoid therapy can reduce the risk of irritant dermatitis. Preference should be given to moisturizers, whose components not only maintain a high level of skin hydration, but also can enhance the effect of the main drug.

Sequential Treatment With Topical Trifarotene and Injectable NASHA Gel in Acne Scars: A Case Series.

Topical retinoids are a mainstay in acne management and have been shown to improve skin texture. Injectable non-animal stabilized hyaluronic acid (NASHATM) gel as skin booster is largely used in aesthetic treatments to improve skin quality including the appearance of atrophic acne scars. To evaluate a new sequential treatment with topical trifarotene and injectable skin booster NASHA gel in acne scars. 10 patients between 19 and 25 years (3 males and 7 females) with previous moderate to severe acne vulgaris on the face with the outcome of atrophic and post-inflammatory slightly hyperpigmented scars were prescribed home short contact therapy (SCT) with topical trifarotene 50 μg/g at the evening for 3 months. A proper skincare routine for sensitive skin was also recommended. The 3-month retinoid therapy was followed by an injectable medical procedure with NASHA gel 20 mg/ml as skin booster. A minimum of 3 sessions to 10 sessions were carried out according to the severity of acne scars and the skin response observed. Adherence to the treatment was complete and the results evaluated by digital photography showed very effective results with high clinical improvement or almost complete resolution of atrophic acne scars. The results observed in this case series show that the sequential treatment with topical trifarotene and injectable NASHA gel as skin booster can be effective in the progressive reduction of acne scarring, potentially related to a synergic effect of skin remodeling and collagen stimulation. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7630.

TRAF4 Silencing Induces Cell Apoptosis and Improves Retinoic Acid Sensitivity in Human Neuroblastoma.

Neuroblastoma (NB) is a pediatric malignancy that arises in the peripheral nervous system, and the prognosis in the high-risk group remains dismal, despite the breakthroughs in multidisciplinary treatments. The oral treatment with 13-cis-retinoic acid (RA) after high-dose chemotherapy and stem cell transplant has been proven to reduce the incidence of tumor relapse in children with high-risk neuroblastoma. However, many patients still have tumors relapsed following retinoid therapy, highlighting the need for the identification of resistant factors and the development of more effective treatments. Herein, we sought to investigate the potential oncogenic roles of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family in neuroblastoma and explore the correlation between TRAFs and retinoic acid sensitivity. We discovered that all TRAFs were efficiently expressed in neuroblastoma, but TRAF4, in particular, was found to be strongly expressed. The high expression of TRAF4 was associated with a poor prognosis in human neuroblastoma. The inhibition of TRAF4, rather than other TRAFs, improved retinoic acid sensitivity in two human neuroblastoma cell lines, SH-SY5Y and SK-N-AS cells. Further in vitro studies indicated that TRAF4 suppression induced retinoic acid-induced cell apoptosis in neuroblastoma cells, probably by upregulating the expression of Caspase 9 and AP1 while downregulating Bcl-2, Survivin, and IRF-1. Notably, the improved anti-tumor effects from the combination of TRAF4 knockdown and retinoic acid were confirmed in vivo using the SK-N-AS human neuroblastoma xenograft model. In conclusion, the highly expressed TRAF4 might be implicated in developing resistance to retinoic acid treatment in neuroblastoma, and the combination therapy with retinoic acid and TRAF4 inhibition may offer significant therapeutic advantages in the treatment of relapsed neuroblastoma.

Retinoid-induced skeletal hyperostosis in disorders of keratinization.

For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.

ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells

Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers.

468 Preferentially Expressed Antigen in Melanoma Modulates Sensitivity to Retinoic Acid and Cell Cycle Control in Immortalized and Malignant Keratinocytes

Retinoids can be used to treat and prevent the formation of basal cell carcinoma (BCC) and squamous cell carcinomas (SCCs; notably cutaneous and oral SCC). Preferentially Expressed Antigen in Melanoma (PRAME), a gamete-specific repressor of retinoid-induced differentiation, is ectopically expressed in BCC and SCC tumors. However, the effects of PRAME on the development of these cancers and their sensitivity to retinoid therapies are unknown. The purpose of this study was to investigate PRAME’s influence on retinoid response and proliferation in benign human keratinocytes, BCC and SCC cells.

Evaluation of COVID-19 risk in patients on systemic retinoid therapy

Evaluation of COVID-19 risk in patients on systemic retinoid therapy

Retinoid therapy restores eye-specific cortical responses in adult mice with retinal degeneration

Despite the recent emergence of multiple cellular and molecular strategies to restore vision in retinal disorders, it remains unclear to what extent central visual circuits can recover when retinal defects are corrected in adulthood. We addressed this question in an Lrat-/- mouse model of Leber congenital amaurosis (LCA) in which retinal light sensitivity and optomotor responses are partially restored by 9-cis-retinyl acetate administration in adulthood. Following treatment, two-photon calcium imaging revealed increases in the number and response amplitude of visually responsive neurons in the primary visual cortex (V1). In particular, retinoid treatment enhanced responses from the ipsilateral eye, restoring the normal balance of eye-specific responses in V1. Additionally, the treatment rescued the modulation of cortical responses by arousal. These findings illustrate the significant plasticity of the adult central visual system and underscore the therapeutic potential of retinoid administration for adults with retinal diseases.

Analysis of acne relapses in women after systemic retinoid therapy

Objective. To analyze the conditions and factors contributing to the development of acne recurrence after therapy with systemic retinoids. Acne is a chronic inflammatory dermatosis characterized by the formation of open and closed comedones, papules, pustules, nodes on skin areas rich in sebaceous glands, significantly disrupting the quality of life of patients. The most effective drugs for its treatment are systemic retinoids. They allow one to achieve complete cleansing of the skin, but even after their use relapses of the disease are possible.
 Materials and methods. The study involved 65 women 1 year after the end of acne treatment with systemic retinoids, who were divided into two groups: group I was formed by 30 women with the development of acne relapses; group II included 35 women without acne relapses. The exclusion criteria were the following: severe endocrine pathology, the presence of cardiovascular diseases, liver disease, pregnancy and lactation, alcoholism, smoking. The study consisted of general clinical techniques and standard laboratory methods, including biochemical blood analysis with the determination of lipid and carbohydrate metabolism, the level of pituitary hormones and sex hormones. Methods of parametric and nonparametric statistics were used to account for and analyze the results.
 Results. In half of the cases, acne relapses were observed after a new coronavirus infection; much less often, in equal proportions, they developed after stress and menstrual cycle failure, there were patients who could not identify the factors preceding the recurrence of acne. The average age of patients with acne relapses after treatment with systemic retinoids was 24.6 2.4 years, patients without acne relapses after appropriate therapy 17.3 1.8 years (p = 0.028). Burdened heredity for acne, combination of acne with seborrheic dermatitis and/or menstrual dysfunction by the type of menstrual arrhythmia were significantly more often determined in patients with acne relapses after therapy with systemic retinoids. In the same group, lipid metabolism disorders and hormonal changes in the form of increased levels of progesterone and androgens were observed significantly more often.
 Conclusions. Acne, even after the therapy with systemic retinoids, can have a recurrent course. The main external factor, preceding relapse is a new coronavirus infection. Relapses after acne treatment with systemic retinoids are developed against the background of burdened heredity for acne, changes in lipid metabolism, persistent imbalance of sex hormones, as well as when acne is combined with seborrheic dermatitis. For pubertal acne without pronounced metabolic and endocrine changes, relapses after therapy with systemic retinoids are not typical.

Gut commensals expand vitamin A metabolic capacity of the mammalian host

Conversion of dietary vitamin A (VA) into retinoic acid (RA) is essential for many biological processes and thus far studied largely in mammalian cells. Using targeted metabolomics, we found that commensal bacteria in the mouse gut lumen produced a high concentration of the active retinoids, all-trans-retinoic acid (atRA) and 13-cis-retinoic acid (13cisRA), as well as the principal circulating retinoid, retinol. Ablation of anerobic bacteria significantly reduced retinol, atRA, and 13cisRA, whereas introducing these bacteria into germ-free mice significantly enhanced retinoids. Remarkably, cecal bacterial supplemented with VA produced active retinoids invitro, establishing that gut bacteria encode metabolic machinery necessary for multistep conversion of dietary VA into its active forms. Finally, gut bacteria Lactobacillus intestinalis metabolized VA and specifically restored RA levels in the gut of vancomycin-treated mice. Our work establishes vitamin A metabolism as an emergent property of the gut microbiome and lays the groundwork for developing probiotic-based retinoid therapy.