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PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action. EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, senescence, and lipid metabolism were used to uncover a potential mechanism of action. Standard anti-HER2 therapies were screened in combination with IRX4204 on a panel of breast cancer cell lines to determine drug synergy. RESULTS: IRX4204 significantly inhibits the growth of HER2-positive breast cancer cell lines, including trastuzumab and lapatinib-resistant JIMT-1 and HCC1954. Treatment with IRX4204 reduced tumor growth rate in the MMTV-ErbB2 mouse and HER2-positive PDX model by 49% and 44%, respectively. Mechanistic studies revealed IRX4204 modulates lipid metabolism and induces senescence of HER2-positive cells. In addition, IRX4204 demonstrates additivity and synergy with HER2-targeted mAbs, tyrosine kinase inhibitors, and antibody-drug conjugates. CONCLUSIONS: These findings identify HER2 as a biomarker for IRX4204 treatment response and demonstrate a novel use of RXR agonists to synergize with current anti-HER2 therapies. Furthermore, our results suggest that RXR agonists can be useful for the treatment of anti-HER2 resistant and metastatic HER2-positive breast cancer.

Cellular retinaldehyde-binding protein (CRALBP) supports production of 11-cis-retinaldehyde and its delivery to photoreceptors. It is found in the retinal pigment epithelium (RPE) and Müller glia (MG), but the relative functional importance of these two cellular pools is debated. Here, we report RPE- and MG-specific CRALBP knockout (KO) mice and examine their photoreceptor and visual cycle function. Bulk visual chromophore regeneration in RPE-KO mice is 15-fold slower than in controls, accounting for their delayed rod dark adaptation and protection against retinal phototoxicity, whereas MG-KO mice have normal bulk visual chromophore regeneration and retinal light damage susceptibility. Cone pigment regeneration is significantly impaired in RPE-KO mice but mildly affected in MG-KO mice, disclosing an unexpectedly strong reliance of cone photoreceptors on the RPE-based visual cycle. These data reveal a dominant role for RPE-CRALBP in supporting rod and cone function and highlight the importance of RPE cell targeting for CRALBP gene therapies.

The continuous function of vertebrate photoreceptors requires regeneration of their visual pigment following its destruction upon activation by light (photobleaching). For rods, the chromophore required for the regeneration of rhodopsin is derived from the adjacent retinal pigmented epithelium (RPE) cells through a series of reactions collectively known as the RPE visual cycle. Mounting biochemical and functional evidence demonstrates that, for cones, pigment regeneration is supported by the parallel supply with chromophore by two pathways-the canonical RPE visual cycle and a second, cone-specific retina visual cycle that involves the Müller glial cells in the neural retina. In this article, we review historical information that led to the discovery of the retina visual cycle and discuss what is currently known about the reactions and molecular components of this pathway and its functional role in supporting cone-mediated vision.

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. [ABSTRACT FROM AUTHOR]

Background: Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC. Methods: We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice. Results: Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway. Conclusion: The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis. [ABSTRACT FROM AUTHOR]

Background: Many morphological and histological changes take place in aging skin. Topical tretinoin is the gold standard anti-aging agent used to reduce signs of aging through stimulation of epidermal growth and differentiation and inhibition of collagenase. Objective: The aim of this systematic review is to summarize studies evaluating the efficacy of tretinoin compared with other topical medications and cosmeceuticals in reducing the appearance of skin aging. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. The literature search was conducted using the PubMed and Embase databases from conception to December 2023. Studies were included if they compared anti-aging outcomes of topical medications with those of topical tretinoin (also called all-trans retinoic acid and retinoic acid). Studies were excluded if they compared non-topical anti-aging treatments with tretinoin or were conducted on animal models. Results: The literature search resulted in 25 studies that met all inclusion and exclusion criteria. The most common study comparators to tretinoin included other forms of vitamin A. Outcomes were reported on the basis of visual reduction of aging signs, histological assessment of the epidermis and dermis, and protein expression. Although comparators to tretinoin had variable efficacy (greater in 7 studies, equivalent in 13 studies, and less in 3 studies), most studies found the comparator to be less irritating and better tolerated by patients than tretinoin. Discussion: Tretinoin is currently the gold standard therapy for the treatment of photoaging, but its poor tolerability often limits its use. Unfortunately, given that most studies comparing topical therapies with tretinoin are of poor quality and/or demonstrate bias, there is a lack of substantial evidence to support an alternative first-line therapy. However, given there are some data to support the efficacy of retinoid precursors, namely retinaldehyde, pro-retinal nanoparticles, and conjugated alpha-hydroxy acid and retinoid (AHA-ret), these agents can be considered a second-line option for anti-aging treatment in patients who cannot tolerate tretinoin. [ABSTRACT FROM AUTHOR]

Acne fulminans (AF) is a severe form of inflammatory acne commonly associated with adolescents. It is characterized by an abrupt onset of painful nodules and plaques and can progress to suppurative, ulcerative, and hemorrhagic lesions. AF can be associated with systemic symptoms such as fever, arthralgia, and bone pain. The etiology of AF is unknown but it has been linked to the use of certain medications and has been rarely found in autoinflammatory syndromes. In previous years, there have been reports of <200 cases in the literature; however, AF may be more common in clinical practice than reported. The most common presentation of AF is seen in adolescents starting isotretinoin therapy. Diagnosis of AF is determined based on its clinical findings. The main purpose of this article is to provide clinicians with a practical approach to treating AF. Current evidence for its treatment is limited to case reports and case series. The mainstay treatment of AF is a combination of prednisone and isotretinoin. It is important to taper or discontinue any exacerbating or precipitating medications such as isotretinoin, antibiotics, or androgens when AF is identified. Along with treatment of AF, it is important to treat associated scarring. Early identification and treatment of AF in adolescents is crucial to minimize both acute symptoms and long-term scarring, and further research is needed to determine optimal management. [ABSTRACT FROM AUTHOR]

Retinoic acid is crucial for vertebrate embryogenesis, influencing anterior‐posterior patterning and organogenesis through its interaction with nuclear hormone receptors comprising heterodimers of retinoic acid receptors (RARα, β, or γ) and retinoid X receptors (RXRα, β, or γ). Tissue retinoic acid levels are tightly regulated since both its excess and deficiency are deleterious. Dehydrogenase/reductase 3 (DHRS3) plays a critical role in this regulation by converting retinaldehyde to retinol, preventing excessive retinoic acid formation. Mutations in DHRS3 can result in embryonic lethality and congenital defects. This study shows that mouse Dhrs3 expression is responsive to vitamin A status and is directly regulated by the RAR/RXR complex through cis‐regulatory elements. This highlights a negative feedback mechanism that ensures retinoic acid homeostasis. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusions Many people are interested in addressing visible signs of aging with non‐invasive cosmetic treatments. Development of effective topical products will provide options to delay or support cosmetic procedures.This study assessed and compared the efficacy and tolerance of a topical product used over the course of 16 weeks to a single ablative laser treatment on women with moderate global photodamage on the face.Subjects in Cell 1 (Laser Cell) were treated over the entire face with a fractional CO2 laser system. Subjects in Cell 2 (Topical Serum Cell) were treated with a topical serum containing hydroxypinacolone retinoate and peptides over the entire face, twice per day for 16 weeks. The study was composed of 71 women, with 29 in the Laser Cell (mean age 56.2) and 42 in the Topical Serum Cell (mean age 55.0), between 40 and 65 years old. Expert grading was used to determine efficacy parameters.Participants in the Topical Serum Cell achieved more significant improvement (p < 0.05) in Marionette lines, fine lines (global face), wrinkles (global face), wrinkles (crow's feet), nasolabial folds, texture, smoothness (tactile), global hyperpigmentation, lift, and photodamage compared to participants in the Laser Cell. Participants in the Topical Serum Cell achieved parity in the look of fine lines (crow's feet), forehead lines, glabella, firmness/bounce (tactile), skin tone evenness, radiance.While no statistically significant differences in tolerability were observed, treatment with the topical cosmetic product achieved parity or statistically better improvement in parameters compared to laser treatment at 16 weeks. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The skin structure alters with age, leading to a decrease in collagen and diminished elasticity of the skin. While retinol proves to be an excellent anti-aging solution, its side effects prompt the search for gentler alternatives. This study evaluates bakuchiol's effectiveness and safety compared to traditional retinoids. Material and Methods: A thorough literature review was performed using PubMed and Google Scholar, employing keywords related to the topic. Results: Recent studies highlight bakuchiol's efficacy in reducing wrinkles and hyperpigmentation, with better tolerability than retinol. It is also under investigation for better skin penetration and collagen production. Comparatively, bakuchiol and retinol show significant anti-aging effects, yet bakuchiol's additional antioxidative properties and the lack of side effects present it as a promising skincare ingredient. Conclusions: Bakuchiol offers a natural, effective retinol alternative, matching its rejuvenating effects with enhanced antioxidant benefits. Its superior tolerance makes it suitable for sensitive skin. While promising, further research is needed to fully grasp bakuchiol's long-term benefits and confirm its role in skincare. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Retinoids, defined as synthetic or natural derivatives of vitamin A, have been extensively studied as anti‐aging molecules that are widely applied in cosmetics. However, due to their physicochemical property, retinoids are highly unstable and extremely sensitive to light, oxygen, and temperature. Moreover, topical application of retinoids often leads to cutaneous irritation. These instabilities and irritant properties of retinoids limit their application in cosmetic and pharmaceutical products. Aim: Our study aimed to provide a systematic review to summarize the mechanisms underlying the instability and irritant properties of retinoids, as well as recent developments in addressing these challenges. Methods: A comprehensive PubMed search was conducted using the following keywords: retinoids, chemical instability, skin irritation, retinoid derivatives, nano lipid‐based carriers, liposomes, penetration‐enhancer vesicles, ethosomes, niosomes, nanoemulsions, solid lipid nanoparticles, vitamins, soothing and hydrating agents, antioxidants and metal chelator and retinol combinations. Relevant researches published between 1968 and 2023 and studies related to these reports were reviewed. Results: The development of new retinoid derivatives, the utilization of new delivery systems like nano lipid‐based carriers and the combination with other compounds like vitamins, soothing agents, antioxidants and metal chelator have been explored to improve the stability, bioavailability, and toxicity of the retinoid family. Conclusions: Through advancements in formulation techniques, structure modification of retinoid derivatives and development of novel nano lipid‐based carriers, the chemical instability and skin irritation of retinoids has been mitigated, ensuring their efficacy and potency over extended periods. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusion Methotrexate (MTX) has been a longstanding therapeutic option for mycosis fungoides (MF); however, data on its real‐world effectiveness remain limited.To evaluate treatment‐related outcomes of oral MTX in patients with early‐ and late‐stage MF.This is a retrospective multicentre analysis involving MF subjects from five referral centres for cutaneous lymphomas in Greece. Data regarding the effectiveness and safety were analysed.In total, 211 MF patients were enrolled (males, 68.3%) with a median (IQR) age of diagnosis at 68.3 (56–75) years. Late‐stage (IIB‐IVB) disease was present in 124 patients (59.3%). MTX monotherapy was administered to 112 (53.1%) patients, with 99 receiving combination regimens with phototherapy, interferon and retinoids. MTX was used as first‐line regimen in 103 (48.9%) cases. An overall response rate (ORR) of 55.5% was observed with 29.9% of patients achieving complete responses. MTX demonstrated greater effectiveness as a first‐line treatment compared to subsequent use with no significant differences between monotherapy and combination therapy. The median time to best response was 3.8 months (IQR 2.3–9.9 months). Patients with erythrodermic disease (Stage III) had better ORRs compared to patients with tumour stage disease (Stage II) (61.1% vs. 44.8% respectively). The progression‐free survival (PFS) varied according to stage, with a median PFS of 17.1 months for early‐stage disease, 5.7 months for Stage IIB disease, 46 months for Stage III and 9.6 months for Stage IV disease (0.7‐.). Serious adverse (Grade 3) events leading to treatment discontinuation occurred in 14 (6.7%) cases. All patients received oral MTX once weekly with a median weekly dose of 15 mg/week (7.5–25).Our findings support MTX as a viable treatment option for MF, particularly when used in the first‐line setting, offering a favourable benefit/risk profile. Response rates are stage‐dependent, with erythrodermic patients achieving superior and durable responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma (cSCC) is a common and potentially dangerous skin cancer, especially for people with weakened immune systems, like those who have had organ transplants or certain blood cancers. These individuals are up to 100 times more likely to develop cSCC compared with the general population. This review discusses the current treatments for cSCC in these high-risk patients, emphasizing the importance of prevention and the variety of treatment options available. Using high-SPF sunscreen and certain medications can help reduce the chances of developing cSCC. Adjusting the medications that suppress the immune system can also lower the risk. Surgery remains the main treatment, with radiation therapy recommended for more serious cases. Other treatments such as chemotherapy and newer targeted therapies have been used, with mixed results. Immunotherapy, which helps the body's own immune system fight the cancer, shows promise but needs more research to ensure it is safe for these vulnerable patients. This study highlights the need for future research to explore personalized treatment plans and combination therapies to improve outcomes for people with weakened immune systems. Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and poses a significant risk to immunosuppressed patients, such as solid organ transplant recipients and those with hematopoietic malignancies, who are up to 100 times more likely to develop cSCC compared with the general population. This review summarizes the current state of treatment for cSCC in immunosuppressed patients, focusing on prevention, prophylaxis, surgical and non-surgical treatments, and emerging therapies. Preventative measures, including high-SPF sunscreen and prophylactic retinoids, are crucial for reducing cSCC incidence in these patients. Adjusting immunosuppressive regimens, particularly favoring mTOR inhibitors over calcineurin inhibitors, has been shown to lower cSCC risk. Surgical excision and Mohs micrographic surgery remain the primary treatments, with adjuvant radiation therapy recommended for high-risk cases. Traditional chemotherapy and targeted therapies like EGFR inhibitors have been utilized, though their efficacy varies. Immunotherapy, particularly with agents like cemiplimab and pembrolizumab, has shown promise, but its use in immunosuppressed patients requires further investigation due to potential risks of organ rejection and exacerbation of underlying conditions. Treatment of cSCC in immunosuppressed patients is multifaceted, involving preventive strategies, tailored surgical approaches, and cautious use of systemic therapies. While immunotherapy has emerged as a promising option, its application in immunosuppressed populations necessitates further research to optimize safety and efficacy. Future studies should focus on the integration of personalized medicine and combination therapies to improve outcomes for this vulnerable patient group. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease worldwide and is characterized by progressive muscle atrophy. There are currently two approved treatments, but they only relieve symptoms briefly and do not cure the disease. The main hindrance to research is the complex cause of ALS, with its pathogenesis not yet fully elucidated. Retinoids (vitamin A derivatives) appear to be essential in neuronal cells and have been implicated in ALS pathogenesis. This study explores 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethylnyl]benzoic acid (Ellorarxine, or DC645 or NVG0645), a leading synthetic retinoic acid, discussing its pharmacological mechanisms, neuroprotective properties, and relevance to ALS. The potential therapeutic effect of Ellorarxine was analyzed in vitro using the WT and SOD1G93A NSC-34 cell model of ALS at an administered concentration of 0.3–30 nM. Histological, functional, and biochemical analyses were performed. Elorarxine significantly increased MAP2 expression and neurite length, increased AMPA receptor GluA2 expression and raised intracellular Ca2+ baseline, increased level of excitability, and reduced Ca2+ spike during depolarization in neurites. Ellorarxine also displayed both antioxidant and anti-inflammatory effects. Overall, these results suggest Ellorarxine shows relevance and promise as a novel therapeutic strategy for treatment of ALS. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Rosacea is a chronic, relapsing inflammatory dermatosis predominantly affecting the central face and can result in significant psychosocial impacts. Isotretinoin has been studied for rosacea due to its anti‐inflammatory and sebum reduction properties, but its use remains limited likely due to its off‐label use and potential adverse events.This systematic review and meta‐analysis investigated the efficacy and safety of low‐dose isotretinoin (LDI; ≤0.5 mg/kg/day) for the four main types of rosacea: erythematotelangiectatic, papulopustular, phymatous and ocular rosacea.Randomized and non‐randomized studies evaluating LDI for rosacea were included. Incomplete studies, non‐English studies and case reports were excluded. Study quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation scale.Of 435 studies, and 16 studies involving 1445 patients were included. LDI decreased lesion count (p = 0.03) and erythema (p = 0.01) with large effect [standardized mean difference (SMD) > 0.8]. Compared to topical retinoids and topical antimicrobials, isotretinoin had larger reductions in lesion count (p = 0.03) with moderate effect (SMD > 0.5). Mean lesion count and erythema remained reduced by 70% and 47%, respectively, at 16 weeks after LDI cessation. Relapse rate was 35% at 5.5 months post‐isotretinoin, and three patients (0.4%) experienced worsening of rosacea. Three patients (0.4%) experienced serious adverse events.Study design heterogeneity limited more comprehensive comparisons. Overall, low‐dose isotretinoin may serve as an effective treatment for rosacea with good tolerability and safety. [ABSTRACT FROM AUTHOR]

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives. Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms. Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted. [ABSTRACT FROM AUTHOR]

ABCA4 is an ATP-binding cassette (ABC) transporter that prevents the buildup of toxic retinoid compounds by facilitating the transport of N-retinylidene-phosphatidylethanolamine across membranes of rod and cone photoreceptor cells. Over 1500 missense mutations in ABCA4, many in the nucleotide-binding domains (NBDs), have been genetically linked to Stargardt disease. Here, we show by cryo-EM that ABCA4 is converted from an open outward conformation to a closed conformation upon the binding of adenylylimidodiphosphate. Structural information and biochemical studies were used to further define the role of the NBDs in the functional properties of ABCA4 and the mechanisms by which mutations lead to the loss in activity. We show that ATPase activity in both NBDs is required for the functional activity of ABCA4. Mutations in Walker A asparagine residues cause a severe reduction in substrate-activated ATPase activity due to the loss in polar interactions with residues within the D-loops of the opposing NBD. The structural basis for how disease mutations in other NBD residues, including the R1108C, R2077W, R2107H, and L2027F, affect the structure and function of ABCA4 is described. Collectively, our studies provide insight into the structure and function of ABCA4 and mechanisms underlying Stargardt disease. [ABSTRACT FROM AUTHOR]

Cancer is a major public health problem that ranks as the second leading cause of death. Anti-cancer drug development presents with various hurdles faced throughout the process. Nanoparticle (NP) formulations have emerged as a promising strategy for enhancing drug delivery efficiency, improving stability, and reducing drug toxicity. Previous studies have shown that the adamantyl retinoid ST1926 displays potent anti-tumor activities in several types of tumors, particularly in colorectal cancer (CRC). However, phase I clinical trials in cancer patients using ST1926 are halted due to its low bioavailability. In this manuscript, we developed ST1926-NPs using flash nanoprecipitation with polystyrene-b-poly (ethyleneoxide) as an amphiphilic stabilizer and cholesterol as a co-stabilizer. Dynamic light scattering revealed that the resulting ST1926-NPs Contin diameter was 97 nm, with a polydispersity index of 0.206. Using cell viability, cell cycle analysis, and cell death assays, we showed that ST1926-NP exhibited potent anti-tumor activities in human CRC HCT116 cells. In a CRC xenograft model, mice treated with ST1926-NP exhibited significantly lowered tumor volumes compared to controls at low drug concentrations and enhanced the delivery of ST1926 to the tumors. These findings highlight the potential of ST1926-NPs in attenuating CRC tumor growth, facilitating its further development in clinical settings. [ABSTRACT FROM AUTHOR]

The article examines the relationship between biologic treatments for psoriasis and the risk of developing depression, based on a retrospective analysis of U.S. administrative claims data. Topics include the reduced incidence of depression among patients using biologics compared to conventional treatments, the relative risk reduction associated with different classes of biologics, and the implications of these findings for future treatment strategies.

Melasma is a chronic, acquired disorder of focal hypermelanosis that carries significant psychosocial impact and is challenging for both the patient and the treating practitioner to manage in the medium to long term. Multiple treatments have been explored, often in combination given the many aetiological factors involved in its pathogenesis. Therapeutic discoveries to treat melasma are a focal topic in the literature and include a range of modalities, with recent developments including updates on visible light photoprotection, non-hydroquinone depigmenting agents, oral tranexamic acid, chemical peels, and laser and energy-based device therapy for melasma. It is increasingly important yet challenging to remain up-to-date on the arsenal of treatments available for melasma to find an efficacious and well-tolerated option for our patients. [ABSTRACT FROM AUTHOR]

The article provides a comprehensive overview of acne vulgaris, focusing on its pathophysiology and management strategies. Topics discussed include factors influencing acne such as androgen activity and genetic variants, the impact of lifestyle and dietary behaviors, and current treatment options ranging from topical and oral medications to isotretinoin.

Abstract Background Vitamin A is essential for physiological processes like vision and immunity. Vitamin A’s effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). Methods We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. Results Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p

The inevitable attrition of skin due to ultraviolet radiation, termed photoaging, can be partially restored by treatment with retinoid compounds. Photoaged skin in lightly pigmented individuals, clinically presents with the appearance of wrinkles, increased laxity, and hyper‐ and hypopigmentation. Underlying these visible signs of ageing are histological features such as epidermal thinning, dermal–epidermal junction flattening, solar elastosis and loss of the dermal fibrillin microfibrillar network, fibrillar collagen and glycosaminoglycans. Retinoid compounds are comprised of three main generations with the first generation (all‐trans retinoic acid, retinol, retinaldehyde and retinyl esters) primarily used for the clinical and cosmetic treatment of photoaging, with varying degrees of efficacy, tolerance and stability. All‐trans retinoic acid is considered the ‘gold standard’ for skin rejuvenation; however, it is a prescription‐only product largely confined to clinical use. Therefore, retinoid derivatives are readily incorporated into cosmeceutical formulations. The literature reported in this review suggests that retinol, retinyl esters and retinaldehyde that are used in many cosmeceutical products, are efficacious, safe and well‐tolerated. Once in the skin, retinoids utilize a complex signalling pathway that promotes remodelling of photoaged epidermis and dermis and leads to the improvement of the cutaneous signs of photoaging. [ABSTRACT FROM AUTHOR]

Background: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). Methods: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. Results: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10−6). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity. Conclusions: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern. [ABSTRACT FROM AUTHOR]

Introduction • Palmoplantar keratoderma is an abnormal thickening of the skin on the palms of the hands and soles of the feet. The classification of palmoplantar keratoderma depends on the clinical characteristics and whether it is hereditary or acquired. The traditional approach tries to soften and minimize skin thickness. The usual treatment choices include emollients, keratolytics like salicylic acid or urea, antifungal cream or pills, as well as topical retinoids/calcipotriol and systemic retinoids. However, the persistent use of such medications frequently exhausts the patients because the problem returns as soon as the local applications are discontinued. Methods • The case was recorded in the dermatological department of Dr DY Patil HMC & RC. A 27-year-old female patient prediagnosed with Palmoplantar Keratoderma was treated with individualized homeopathic medicine (iHOM) between 25th February 2021 to 22nd July 2021. During the follow-up visits outcome was assessed. To assess whether the changes were due to homeopathic medicine a modified Naranjo criteria was performed. Based on the totality of symptoms, individualized homeopathic medicine Petroleum 30C was given. Results • The patient was successfully treated for palmoplantar keratoderma with homeopathic Petroleum 30C over five months. Cracks and thickening of skin on the palms and soles resolved completely with no pain and itching. Conclusion • Individualized homeopathic treatment of palmoplantar keratoderma is possible and offers a gentle, non-invasive alternative to pharmaceutical use. [ABSTRACT FROM AUTHOR]

Background/Obectives: Oral retinoids are teratogenic, and pregnancy avoidance is an important part of retinoid prescribing. Australia does not have a standardised pregnancy prevention programme for women using oral retinoids, and the contraception strategies for women who use oral retinoids are not well understood. The objectives were to determine trends in the use of prescription retinoids among Australian reproductive‐aged women and whether women dispensed oral retinoids used contraception concomitantly. Methods: This was a population‐based study using Australian Pharmaceutical Benefits (PBS) dispensing claims for a random 10% sample of 15‐44‐year‐old Australian women, 2013 ‐ 2021. We described rates and annual trends in dispensing claims for PBS‐listed retinoids and contraceptives. We also estimated concomitant oral retinoid and contraceptive use on the day of each retinoid dispensing and determined if there was a period of contraceptive treatment that overlapped. Estimates were then extrapolated to the national level. Results: There were 1,545,800 retinoid dispensings to reproductive‐aged women; 57.1% were oral retinoids. The rate of retinoid dispensing to reproductive‐aged women increased annually, from 28 dispensings per 1000 population in 2013 to 41 per 1000 in 2021. The rate of oral retinoid dispensing doubled over the study period, from 14 dispensings per 1000 population in 2013 to 28 per 1000 in 2021, while topical retinoid dispensing did not change. Only 25% of oral retinoid dispensings had evidence of concomitant contraceptive use in 2021. Conclusions: Rates of oral retinoid dispensing have doubled among reproductive‐aged women over the past decade. A large percentage of oral retinoid use does not appear to have concomitant contraception use, posing a risk of teratogenic effects in pregnancies. [ABSTRACT FROM AUTHOR]

The biosynthesis of 11- cis -retinoids by the isomerohydrolase RPE65 and isomero-oxygenase NinaB has recently been described in molecular detail, revealing an unexpected functional convergence of their isomerase activities. Recent structure–function studies have elucidated the mechanisms of other enzymatically catalyzed reactions that involve isomerization coupled with a second reaction type occurring within a single active site. Through comparative enzymology analysis, we find that enzymes catalyzing these in situ coupled reactions participate in diverse biochemical pathways but are often involved in terpenoid metabolism and frequently catalyze alkene bond transformations such as cis–trans isomerization or allylic rearrangements. Active-site steric factors are often pivotal in driving the isomerization reaction. We draw attention to issues surrounding classification and nomenclature of multi-acting enzymes. Enzymes can usually be unambiguously assigned to one of seven classes specifying the basic chemistry of their catalyzed reactions. Less frequently, two or more reaction classes are catalyzed by a single enzyme within one active site. Two examples are an isomerohydrolase and an isomero-oxygenase that catalyze isomerization-coupled reactions crucial for production of vision-supporting 11- cis -retinoids. In these enzymes, isomerization is obligately paired and mechanistically intertwined with a second reaction class. A handful of other enzymes carrying out similarly coupled isomerization reactions have been described, some of which have been subjected to detailed structure–function analyses. Herein we review these rarefied enzymes, focusing on the mechanistic and structural basis of their reaction coupling with the goal of revealing catalytic commonalities. [ABSTRACT FROM AUTHOR]

Background: 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. Objectives: To determine the potential of retinoids to repair photoaged black skin. Methods: An exploratory intervention study was performed using an in vivo, 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. New treatments are needed for muscle invasive bladder cancers. Here, the authors show that combined Pparg activation and MEK inhibition using FDA approved drugs shrinks tumor volume and induces a Basal/Squamous-to-Luminal shift in the urothelium as well as in invading tumors. [ABSTRACT FROM AUTHOR]

Background: Acne is the most common skin disorder which is known as a chronic inflammatory disease with psychological burden and reduced quality of life. Objective: The objective of this study is to determine, in a real-world effectiveness and clinical experience in treating acne scars which includes evaluating reduction in depth, diameter, erythema and pigmentation, with an acne scar gel, and to evaluate the effect of the product on quality of life. Methods: Overall, 435 patients were assessed for 90 days. The acne scars were counted and classified as mild, moderate or severe and the type of acne scar was registered. The study participants had gone through both oral and topical treatment for a time range of 1 week to over a month depending on the severity of the scars. They had also gone through medical procedures as per the requirement. The results were assessed at an interval of 30 days to 90 days and were graded between 1-5. Results: Overall facial appearance of atrophic acne scars improved after treatment with acne scar gel. Clinical experience with acne scar gel (in terms of reduction of scar depth, diameter, erythema, and pigmentation), and subject satisfaction (happiness and confidence) score along with the sensation and perception of the skin improved in most subjects. Conclusions: Acne scar gel was effective and safe for treatment of moderate-to-severe acne scars. The acne scar gel can be used as topical treatment for acne scars, thereby reducing the need of procedural treatment for acne scars. [ABSTRACT FROM AUTHOR]

The proto‐oncogene MYCN expression marked a cancer stem‐like cell population in hepatocellular carcinoma (HCC) and served as a therapeutic target of acyclic retinoid (ACR), an orally administered vitamin A derivative that has demonstrated promising efficacy and safety in reducing HCC recurrence. This study investigated the role of MYCN as a predictive biomarker for therapeutic response to ACR and prognosis of HCC. MYCN gene expression in HCC was analyzed in the Cancer Genome Atlas and a Taiwanese cohort (N = 118). Serum MYCN protein levels were assessed in healthy controls (N = 15), patients with HCC (N = 116), pre‐ and post‐surgical patients with HCC (N = 20), and a subset of patients from a phase 3 clinical trial of ACR (N = 68, NCT01640808). The results showed increased MYCN gene expression in HCC tumors, which positively correlated with HCC recurrence in non‐cirrhotic or single‐tumor patients. Serum MYCN protein levels were higher in patients with HCC, decreased after surgical resection of HCC, and were associated with liver functional reserve and fibrosis markers, as well as long‐term HCC prognosis (>4 years). Subgroup analysis of a phase 3 clinical trial of ACR identified serum MYCN as the risk factor most strongly associated with HCC recurrence. Patients with HCC with higher serum MYCN levels after a 4‐week treatment of ACR exhibited a significantly higher risk of recurrence (hazard ratio 3.27; p =.022). In conclusion, serum MYCN holds promise for biomarker‐based precision medicine for the prevention of HCC, long‐term prognosis of early‐stage HCC, and identification of high‐response subgroups for ACR‐based treatment. [ABSTRACT FROM AUTHOR]

Human beta-defensins are host defense peptides with broad antimicrobial and inflammatory functions. In the oral cavity, these peptides are produced mainly by the keratinocytes of the epithelium; however, fibroblasts, monocytes, and macrophages also contribute to oral human beta-defensin expressions. The resident and immune cells of the oral cavity come into contact with various microbe-associated molecular patterns continuously and simultaneously. The overall antimicrobial cellular response is highly influenced by local and environmental factors. Recent studies have produced evidence showing that not only systemic chronic diseases but also systemic factors like hyperglycemia, pregnancy, the long-term use of certain vitamins, and aging can modulate oral cellular antimicrobial responses against microbial challenges. Therefore, the aim of this narrative review is to discuss the role of systemic factors on oral human beta-defensin expressions. [ABSTRACT FROM AUTHOR]

Intrinsic fluorescence of drugs brings valuable information on their localization in the organism and their interaction with key biomolecules. In this work, we investigate the absorption and emission properties of the topical retinoid adapalene in different solvents and biological media. While the UVA/UVB absorption band does not exhibit any significant solvent-dependent behavior, a strong positive solvatochromism is observed for the emission. These results are in line with molecular modeling and simulations that show the presence of two quasi-degenerate states, i.e., a local π-π* and an intermolecular charge-transfer (ICT) state. However, molecular modeling also revealed that, whatever the solvent, at the corresponding equilibrium geometry the lowest and emissive excited state is the local π-π*. Finally, the potential of adapalene to act as a biological probe is demonstrated using albumin, DNA and micelles. [ABSTRACT FROM AUTHOR]

Frontal fibrosing alopecia (FFA) is a primary cicatricial alopecia characterized by hairline recession, pruritus, and facial papules (FP). Various therapies are used to stabilize disease activity and induce remission. However, FP of FFA is resistant to treatment in many cases. In this review, we searched the PubMed and Google Scholar databases to screen the published literature on treatment options for FP in the context of FFA. Overall, 12 studies were included in this review. Available literature suggests a noticeable improvement in resistant‐to‐treatment FP in FFA patients with oral isotretinoin. The available evidence is limited and is derived from retrospective studies and case reports/series. Systemic isotretinoin can be considered a promising therapeutic regimen for treating resistant‐to‐treatment FP of FFA patients. However, more extensive, well‐designed studies are necessary for confirmatory evidence. [ABSTRACT FROM AUTHOR]

Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients' quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional treatments, such as retinoids, methotrexate, and even biologics, which although effective in some cases, may be associated with significant side effects, necessitating more effective and safe options. The pathophysiology of Generalized Pustular Psoriasis is complex and not fully understood, but there is some overlap with the pathogenesis of Plaque Psoriasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and imsidolimab, two recently developed therapeutic agents, target the IL-36 inflammatory pathway by binding to the IL-36 receptor (IL-36R). Both biologics have already been evaluated in phase 1 and 2 clinical trials and have shown promising results in terms of safety and efficacy. IL-36 receptor inhibitors demonstrated great efficacy and good safety profile in the management of patients with GPP, demonstrating their potential to emerge as a leading treatment option. This review aims to explore and summarize the current scientific literature on the most recently developed treatments for GPP. [ABSTRACT FROM AUTHOR]

Background: The limited therapies available for treating Merkel cell carcinoma (MCC), a highly aggressive skin neoplasm, still pose clinical challenges, and novel treatments are required. Targeting retinoid signalling with retinoids, such as all‐trans retinoic acid (ATRA), is a promising and clinically useful antitumor approach. ATRA drives tumour cell differentiation by modulating retinoid signalling, leading to anti‐proliferative and pro‐apoptotic effects. Although retinoid signalling is dysregulated in MCC, ATRA activity in this tumour is unknown. This study aimed to evaluate the impact of ATRA on the pathological phenotype of MCC cells. Methods: The effect of ATRA was tested in various Merkel cell polyomavirus‐positive and polyomavirus‐negative MCC cell lines in terms of cell proliferation, viability, migration and clonogenic abilities. In addition, cell cycle, apoptosis/cell death and the retinoid gene signature were evaluated upon ATRA treatments. Results: ATRA efficiently impaired MCC cell proliferation and viability in MCC cells. A strong effect in reducing cell migration and clonogenicity was determined in ATRA‐treated cells. Moreover, ATRA resulted as strongly effective in arresting cell cycle and inducing apoptosis/cell death in all tested MCC cells. Enrichment analyses indicated that ATRA was effective in modulating the retinoid gene signature in MCC cells to promote cell differentiation pathways, which led to anti‐proliferative and pro‐apoptotic/cell death effects. Conclusions: These results underline the potential of retinoid‐based therapy for MCC management and might open the way to novel experimental approaches with other retinoids and/or combinatorial treatments. [ABSTRACT FROM AUTHOR]

Topical retinoids continue to be the treatment of choice for healthcare professionals and patients due to their effectiveness in treating several common skincare concerns. In a comprehensive review, Cigdem Kemal Yilmaz discusses the most used topical retinoids: retinyl palmitate, retinol, retinal (retinaldehyde), tretinoin (retinoic acid) and adapalene, and their potential benefits to the skin. This article also addresses the latest EU regulations impacting their use, and the necessity for healthcare professionals to stay informed about advancements and regulatory changes in topical retinoid therapy in order to provide personalised treatment plans for their patients. [ABSTRACT FROM AUTHOR]

Senile gluteal dermatosis (SGD) is an underdiagnosed skin condition that mostly affects the elderly. It appears as hyperkeratotic or lichenoid papules or plaques over the gluteal area, unilaterally or bilaterally. The etiopathogenesis of this condition is not yet known, but it is considered to be caused by prolonged mechanical stress on the affected area leading to neovascularization and epidermal hyperplasia. SGD poses unique problems in diagnosis and management due to its clinical characteristics and histological findings matching other common conditions. Due to its lesser‐known status, it is frequently misdiagnosed as lichen simplex chronicus, inverse psoriasis, or cutaneous amyloidosis, which results in a variable response to treatment. Lifestyle modifications aiming at reducing pressure at the affected site remain the mainstay of treatment, but some reports have shown better results with topical or systemic retinoids. SGD is underreported in the scientific literature and is still not mentioned significantly in textbooks. This review attempts to give a thorough overview of SGD regarding its clinical presentation, etiology, pathogenesis, dermoscopy, diagnostic standards, differential diagnoses, and accessible treatments. Healthcare practitioners can enhance early recognition and provide the right care for afflicted people by raising knowledge and understanding of this disorder. [ABSTRACT FROM AUTHOR]

All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds. [ABSTRACT FROM AUTHOR]

Objectives To compare the risk of PsA in psoriasis (PsO) patients treated with acitretin vs DMARDs. Methods This retrospective study used Taiwan's National Health Insurance Research Database from 1997 to 2013. Adult PsO patients without PsA prescribed acitretin or DMARDs for ≥30 days within a year were assigned to the acitretin cohort or DMARDs cohort, respectively. Patients in the acitretin cohort prescribed DMARDs for >7 days, or in the DMARDs cohort prescribed acitretin for >7 days, were excluded. Cumulative incidence of PsA were determined within both cohorts using the Kaplan–Meier method. The hazard ratio (HR) comparing acitretin to DMARDs was calculated with Cox regression models, adjusting for demographic and clinical covariates including the use of NSAIDs and comorbidities. Results The study included 1948 patients in each cohort. The 5-year cumulative incidence of PsA in the acitretin cohort was lower than that in the reference cohort (7.52% vs 9.93%; P  = 0.005), with a more pronounced difference in the subpopulation receiving NSAIDs treatment. However, in subpopulations without NSAIDs treatment, the 5-year cumulative incidence of PsA in the acitretin cohort was comparable to the DMARDs cohort (5.26% vs 6.98%; P  = 0.106). Acitretin was not associated with PsA development in PsO (HR 0.83, 95% confidence interval 0.65–1.05). This risk remained consistent regardless of adjustments for NSAID treatment and comorbidities. Other independent risk factors for PsA included female and NSAIDs treatment. Conclusion Compared with DMARDs, acitretin was not associated with increased PsA risk in PsO patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Acne is a chronic inflammatory disease that involves the pilosebaceous follicle. Its pharmacological treatment involves topical and systemic medications, but a heterogeneous group of drugs may exacerbate or induce skin lesions. The aim of this study was to identify the pharmacological management and medications related to the exacerbation of skin lesions in patients diagnosed with acne. METHODS: This was a cross-sectional study that identified the outpatient medication prescription patterns of patients with acne from a dispensing database of 8.5 million members of the Colombian Health System. Sociodemographic and pharmacological variables and the identification of prescriptions that were potentially inappropriate due to the risk of worsening acne were considered. RESULTS: A total of 21,604 patients with acne were identified. Median age was 20.8 years (interquartile range: 17.3-27.3 years), and 60.7 percent were female. Treatment mainly involved antibiotics (79.9% of patients), especially doxycycline (66.0%), and retinoids (55.7%). A total of 17.2 percent of patients had potentially inappropriate prescriptions, predominantly progestogens with androgenic properties (8.9%). Female patients (odds ratio [OR]: 3.55; 95% confidence interval [CI]:3.24-3.90) and patients with pathologies such as systemic lupus erythematosus (OR: 18.61; 95% CI: 7.23-47.93) and rheumatoid arthritis (OR: 10.80; 95% CI: 5.02-23.23) were more likely to receive inappropriate prescriptions, and the risk increased with each year of life (OR: 1.02; 95% CI: 1.02-1.03). LIMITATIONS: Access to medical records was not obtained to verify clinical characteristics of acne. CONCLUSION: Patients with acne are excessively treated with systemic antibiotics, counter to clinical practice guidelines. Approximately one-fifth of these patients received some potentially inappropriate medication that could exacerbate their skin lesions. [ABSTRACT FROM AUTHOR]

Simple Summary: Sézary syndrome (SS) is a rare and aggressive form of cutaneous T-cell lymphoma. Despite various treatments, it remains incurable, with a median survival of only 2.1 years. This retrospective study of 17 SS patients in West Sweden from 2012 to 2024 aimed to understand demographic characteristics, treatment effectiveness, and disease progression. Only 35% of patients showed the classic symptoms at diagnosis, indicating the need for personalized diagnostic approaches. Different treatment modalities were used, but combination therapy showed advantages in median survival over monotherapies. Notably, triple therapy involving retinoids, interferon alpha, and extracorporeal photopheresis (ECP) exhibited the longest median time to the next treatment, at 14.1 months. However, early initiation of ECP did not improve outcomes. This study underscores the complexity of SS, emphasizes the urgent need for more effective treatments, and highlights the importance of future prospective research in optimizing treatment strategies. Sézary syndrome (SS) is a rare primary cutaneous T-cell lymphoma variant. Despite various treatment options, it remains incurable, with a poor prognosis. There is an urgent need for additional descriptive research to enhance our understanding and treatment of SS. The aim of this retrospective register-based study was to outline patients' demographic characteristics; investigate the clinical, histopathological, and molecular findings; and assess treatment effectiveness with a focus on time to next treatment (TTNT) and disease progression. Data on 17 patients with SS were obtained from the primary cutaneous lymphoma register in West Sweden between 2012 and 2024. The results revealed that not all patients exhibited the classical triad of symptoms at diagnosis, emphasizing the need for personalized diagnostic approaches. The median survival was only 2.1 years, which reflects the aggressive nature of SS. The longest median TTNT was observed in triple therapy involving retinoids, interferon alpha, and extracorporeal photopheresis (ECP). There was no significant difference in TTNT between various lines of treatment. Early initiation of ECP treatment did not result in improved outcomes. This study highlights the importance of combination therapy for improved outcomes and underscores the need for future studies to identify optimal treatment approaches. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Frontal fibrosing alopecia (FFA) is characterized by scarring alopecia of the frontotemporal scalp and facial papules. Isotretinoin is a vitamin A‐derived retinoid discovered in 1955 and approved for treating nodulocystic acne. This drug can also affect facial papules and frontotemporal hair loss in patients with FFA. In this article, we conducted a review of the available studies investigating the use of oral isotretinoin for FFA treatment. Our study provides insights into the efficacy and safety of isotretinoin as a potential treatment option for FFA and highlights areas for future research. Method: In this study, we aimed to investigate the potential advantages and disadvantages of isotretinoin as a treatment for FFA. To identify all relevant articles, we developed a comprehensive search strategy and conducted a thorough search of three major databases: PubMed, Embase, and Science Direct. We retrieved a total of 82 articles from the search results. Two independent reviewers then screened each of the 82 articles based on our inclusion and exclusion criteria, resulting in the identification of 15 articles that were deemed relevant to our study. Results: Across the 15 articles, 232 patients who suffered from FFA were involved. Nearly 90% of patients experienced a significant reduction of symptoms after receiving oral isotretinoin at 10–40 mg daily. We conclude that isotretinoin can positively affect facial papules and help suppress hair loss. [ABSTRACT FROM AUTHOR]

Background: Historically regarded as a protective barrier organ, the skin is now recognized as an active endocrine organ capable of synthesizing, and secreting diverse hormones and signaling molecules. This review intends to investigate the endocrine function of the epidermis, focusing on its role in hormone synthesis, metabolism, and signaling pathways. Objective: This article aims to provide a comprehensive overview of the endocrine function of the skin, including the identification of key hormones generated in the skin, their regulation, and their physiological significance. In addition, it intends to investigate the relationship between the epidermis and the endocrine system to elucidate the mechanisms underlying hormonal communication within the body. Methodology: Using electronic databases, including PubMed, Scopus, and Web of Science, a comprehensive search of the literature was conducted. Included are relevant studies, evaluations, and articles published between 1990 and 2023. The search strategy centered on the epidermis, endocrine function, hormones, and signaling pathways-related keywords. The retrieved literature was evaluated, and significant findings were analyzed. Results: The epidermis produces and responds to numerous hormones, including corticosteroids, sex hormones, thyroid hormones, Vitamin D, and growth factors, according to the findings. These hormones influence processes, including hair growth, wound healing, immune response, inflammation, and cell proliferation. In addition, the epidermis functions as a target for circulating hormones, participating in feedback loops, and regulating endocrine homeostasis. Conclusion: The skin's endocrine function extends beyond its barrier function to play a significant role in hormonal regulation and communication. Enlightening the precise mechanisms and clinical implications of the endocrine function of the epidermis is necessary for the development of novel therapeutic approaches and interventions. [ABSTRACT FROM AUTHOR]

Introduction: While most patients with iatrogenic tracheal stenosis (ITS) respond to endoscopic ablative procedures, approximately 15% experience a recalcitrant, recurring disease course that is resistant to conventional management. We aimed to explore genetic profiles of patients with recalcitrant ITS to understand underlying pathophysiology and identify novel therapeutic options. Methods: We collected 11 samples of granulation tissue from patients with ITS and performed RNA sequencing. We identified the top 10 most highly up- and down-regulated genes and cellular processes that these genes corresponded to. For the most highly dysregulated genes, we identified potential therapeutic options that favorably regulate their expression. Results: The dysregulations in gene expression corresponded to hyperkeratinization (upregulation of genes involved in keratin production and keratinocyte differentiation) and cellular proliferation (downregulation of cell cycle regulating and pro-apoptotic genes). Genes involved in retinoic acid (RA) metabolism and signaling were dysregulated in a pattern suggesting local cellular RA deficiency. Consequently, RA also emerged as the most promising potential therapeutic option for ITS, as it favorably regulated seven of the ten most highly dysregulated genes. Conclusion: This is the first study to characterize the role of hyperkeratinization and dysregulations in RA metabolism and signaling in the disease pathophysiology. Given the ability of RA to favorably regulate key genes involved in ITS, future studies must explore its efficacy as a potential therapeutic option for patients with recalcitrant ITS. [ABSTRACT FROM AUTHOR]

PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

In the eye, the isomerization of all-trans-retinal to 11-cis-retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential trans-cis isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure-activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were tested in vitro and in vivo for RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties.