A distinct human cell type expressing MHCII and RORγt with dual characteristics of dendritic cells and type 3 innate lymphoid cells.

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt+ MHCII+ type 3 innate lymphoid cells (ILC3) have also been implicated in the instruction of microbiota-specific Tregs. While RORγt+ APCs have been actively investigated in mice, the identity and function of these cell subsets in humans remain elusive. Herein, we identify a rare subset of RORγt+ cells with dendritic cell (DC) features through integrated single-cell RNA sequencing and single-cell ATAC sequencing. These cells, which we term RORγt+ DC-like cells (R-DC-like), exhibit DC morphology, express the MHC class II machinery, and are distinct from all previously reported DC and ILC3 subsets, but share transcriptional and epigenetic similarities with DC2 and ILC3. We have developed procedures to isolate and expand them in vitro, enabling their functional characterization. R-DC-like cells proliferate in vitro, continue to express RORγt, and differentiate into CD1c+ DC2-like cells. They stimulate the proliferation of allogeneic T cells. The identification of human R-DC-like cells with proliferative potential and plasticity toward CD1c+ DC2-like cells will prompt further investigation into their impact on immune homeostasis, inflammation, and autoimmunity.

RXR nuclear receptor signaling modulates lipid metabolism and triggers lysosomal clearance of alpha-synuclein in neuronal models of synucleinopathy.

Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of the neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. Here, we elucidate how retinoid-X-receptor (RXR) nuclear receptor signaling impacts these two aspects of PD pathogenesis. We find that activated RXR differentially regulates fatty acid desaturases, significantly reducing the transcript levels of the largely brain-specific desaturase SCD5 in human cultured neural cells and PD patient-derived neurons. This was associated with reduced perilipin-2 protein levels in patient neurons, reversal of αS-induced increases in lipid droplet (LD) size, and a reduction of triglyceride levels in human cultured cells. With regard to αS proteostasis, our study reveals that RXR agonism stimulates lysosomal clearance of αS. Our data support the involvement of Polo-like kinase 2 activity and αS S129 phosphorylation in mediating this benefit. The lowering of cellular αS levels was associated with reduced cytotoxicity. Compared to RXR activation, the RXR antagonist HX531 had the opposite effects on LD size, SCD, αS turnover, and cytotoxicity, all supporting pathway specificity. Together, our findings show that RXR-activating ligands can modulate fatty acid metabolism and αS turnover to confer benefit in cellular models of PD, including patient neurons. We offer a new paradigm to investigate nuclear receptor ligands as a promising strategy for PD and related synucleinopathies.

Analysis of alcohol-metabolizing enzymes genetic variants and RAR/RXR expression in patients diagnosed with fetal alcohol syndrome: a case-control study.

Understanding the mechanisms underlying alcohol metabolism and its regulation, including the effect of polymorphisms in alcohol-metabolizing enzymes, is crucial for research on Fetal Alcohol Spectrum Disorders. The aim of this study was to identify specific single nucleotide polymorphisms in key alcohol-metabolizing enzymes in a cohort of 71 children, including children with fetal alcohol syndrome, children prenatally exposed to ethanol but without fetal alcohol spectrum disorder, and controls. We hypothesized that certain genetic variants related to alcohol metabolism may be fixed in these populations, giving them a particular alcohol metabolism profile. In addition, the difference in certain isoforms of these enzymes determines their affinity for alcohol, which also affects the metabolism of retinoic acid, which is key to the proper development of the central nervous system. Our results showed that children prenatally exposed to ethanol without fetal alcohol spectrum disorder traits had a higher frequency of the ADH1B*3 and ADH1C*1 alleles, which are associated with increased alcohol metabolism and therefore a protective factor against circulating alcohol in the fetus after maternal drinking, compared to FAS children who had an allele with a lower affinity for alcohol. This study also revealed the presence of an ADH4 variant in the FAS population that binds weakly to the teratogen, allowing increased circulation of the toxic agent and direct induction of developmental abnormalities in the fetus. However, both groups showed dysregulation in the expression of genes related to the retinoic acid pathway, such as retinoic acid receptor and retinoid X receptor, which are involved in the development, regeneration, and maintenance of the nervous system. These findings highlight the importance of understanding the interplay between alcohol metabolism, the retinoic acid pathway and genetic factors in the development of fetal alcohol syndrome.

Serum MYCN as a predictive biomarker of prognosis and therapeutic response in the prevention of hepatocellular carcinoma recurrence.

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.

Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer.

Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated with a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.

Expression of proteins supporting visual function in heterobranch gastropods.

To sense light, animals often utilize mechanisms that rely on visual pigments composed of opsin and retinal. The photon-induced isomerization of 11-cis-retinal to the all-trans configuration triggers phototransduction cascades, resulting in a change in the membrane potential of the photoreceptor. In mollusks, the most abundant opsin in the eye is Gq-coupled rhodopsin (Gq-rhodopsin). The Gq-rhodopsin-based visual pigment is bistable, with the regeneration of 11-cis-retinal occurring in a light-dependent manner without leaving the opsin moiety. 11-cis-retinal is also regenerated by the action of retinochrome in the cell bodies. Retinal binding protein (RALBP) mediates retinal transport between Gq-rhodopsin and retinochrome in the cytoplasm. However, recent studies have identified additional bistable opsins in mollusks, including Opn5 and xenopsin. It is unknown whether these bistable opsins require RALBP and retinochrome for the continuous regeneration of 11-cis-retinal. In the present study, we examined the expression of RALBP and retinochrome in the photoreceptors expressing Opn5 or Xenopsin in the heterobranch gastropods Limax and Peronia. Our findings revealed that retinochrome, but not RALBP, was present in some of the Opn5A-positive brain photosensory neurons of Limax. The ciliary cells in the dorsal eye of Peronia, which express Xenopsin2, lacked both retinochrome and RALBP. Therefore, bistable opsins do not necessarily depend on the RALBP-retinochrome system in a cell. We also examined the expression of other proteins that support visual function, such as ß-arrestin, Gq, and Go, in all types of photoreceptors in these animals, and uncovered differences in the molecular composition among the photoreceptors.

Triphenyltin isoselenocyanate: a novel nuclear retinoid X receptor ligand with antiproliferative and cytotoxic properties in cell lines derived from human breast cancer.

Several commercially available triorganotin compounds were previously found to function as agonist ligands for nuclear retinoid X receptor (RXR) molecules. Triphenyltin isoselenocyanate (TPT-NCSe), a novel selenium atom containing a derivative of triorganotin origin, was found to represent a new cognate bioactive ligand for RXRs. TPT-NCSe displayed a concentration- and time-dependent decrease in the cell viability in both human breast carcinoma MCF-7 (estrogen receptor positive) and MDA­MB­231 (triple negative) cell lines. Reactive oxygen species levels generated in response to TPT-NCSe were significantly higher in both carcinoma cell lines treated with TPT-NCSe when compared to mock-treated samples. Treatment with 500 nM TPT-NCSe caused a decrease in SOD1 and increased SOD2 mRNA in MCF-7 cells. The levels of SOD2 mRNA were more increased following the treatment with TPT-NCSe along with 1 µM all-trans retinoic acid (AtRA) in MCF-7 cells. An increased superoxide dismutase SOD1 and SOD2 mRNA levels were also detected in combination treatment of 500 nM TPT-NCSe and 1 µM AtRA in TPT-NCSe-treated MDA-MB-231 cells. The data have also shown that TPT-NCSe induces apoptosis via a caspase cascade triggered by the mitochondrial apoptotic pathway. TPT-NCSe modulates the expression levels of apoptosis­related proteins, Annexin A5, Bcl­2 and BAX family proteins, and finally, it enhances the expression levels of its cognate nuclear receptor subtypes RXRalpha and RXRbeta.

Treatment of Post-Inflammatory Hyperpigmentation in Skin of Colour: A Systematic Review.

Post inflammatory hyperpigmentation (PIH) affects all skin types with a heightened predilection for darker skin tones. Its course is chronic once developed and treatment is often difficult. This systematic review aims to summarize the treatment outcomes for PIH with a focus on skin of colour (SOC) individuals. A literature search was conducted using MEDLINE (from 1946), Embase (from 1974), PubMed, and Cochrane in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline. Results from 48 studies summarized 1356 SOC individuals. The mean age was 29 years (n = 1036) and 78% were female (n = 786). The ethnic prevalence was 70% Black, 27% Asian, and 3% Latin. Overall, 20% were Fitzpatrick skin type (FST) III, 40% FST IV, 34% FST V, and 6% FST VI. Most cases were precipitated by inflammatory conditions (89%) and localized to the face (83%). The most frequently reported interventions were topical retinoids (22%) and laser therapy (17%). Partial improvement was seen in 85% and 66% of participants, respectively. Laser was the only intervention that offered complete resolution in a subgroup of patients (26%); however, there were reported cases of PIH exacerbation following treatment. Chemical peels (9%) and hydroquinone (7%) were among other treatments with less effective outcomes. PIH and its persistence is a prevalent issue, significantly affecting many affected individuals with darker skin tones. Our results show a lack of robust efficacy across all treatment modalities. There is considerable room for improvement in interventions for at-risk populations.

An Overview on the Management of Atrophic Acne Scars: The Role of Trifarotene as an Adjunct.

Acne vulgaris is a common, often chronic inflammatory disease that can affect all ages and skin tones. Beyond acute lesions, the sequelae of acne - specifically scarring and dyspigmentation - can be long-lasting, challenging to treat and have substantial psychosocial impact on affected individuals. For acne scarring, treatment modalities include topical, physical, and laser and light therapies, with combination approaches typically yielding optimal outcomes. Trifarotene is a novel fourth generation retinoid with targeted action towards retinoid acid receptor gamma (RAR-γ), the most common isotype found in the epidermis, that has previously been approved for the management of moderate-to-severe facial and truncal acne in individuals over the age of 12 years. Recently, data on trifarotene supports its application in acne scarring. Herein, we provide a succinct review on various treatments for acne scarring and explore how trifarotene and its mechanism of action present an additional topical approach to target atrophic acne scarring.

Experience With Bexarotene to Treat Cutaneous T-Cell Lymphomas: A Study of the Spanish Working Group of Cutaneous Lymphomas. / [Artículo traducido] Experiencia con bexaroteno en linfoma cutáneo de células T: un estudio del Grupo Español de Linfomas Cutáneos (GELC).

BACKGROUND AND OBJECTIVES: Bexarotene has been approved to treat advanced stage cutaneous T-cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. MATERIAL AND METHOD: This was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or Sézary syndrome (42) on a 10-year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. RESULTS: A total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27-95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1-114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment-related grade 5 adverse events were reported. CONCLUSIONS: Our study confirms bexarotene is a safe and effective therapy for the long-term treatment of CTCL.

Experience With Bexarotene to Treat Cutaneous T-Cell Lymphomas: A Study of the Spanish Working Group of Cutaneous Lymphomas.

BACKGROUND AND OBJECTIVES: Bexarotene has been approved to treat advanced stage cutaneous T-cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. MATERIAL AND METHOD: This was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or Sézary syndrome (42) on a 10-year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. RESULTS: A total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27-95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1-114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment-related grade 5 adverse events were reported. CONCLUSIONS: Our study confirms bexarotene is a safe and effective therapy for the long-term treatment of CTCL.

Cancer drugs with high repositioning potential for Alzheimer's disease.

INTRODUCTION: Despite the recent full FDA approval of lecanemab, there is currently no disease modifying therapy (DMT) that can efficiently slow down the progression of Alzheimer's disease (AD) in the general population. This statement emphasizes the need to identify novel DMTs in the shortest time possible to prevent a global epidemic of AD cases as the world population experiences an increase in lifespan. AREAS COVERED: Here, we review several classes of anti-cancer drugs that have been or are being investigated in Phase II/III clinical trials for AD, including immunomodulatory drugs, RXR agonists, sex hormone therapies, tyrosine kinase inhibitors, and monoclonal antibodies. EXPERT OPINION: Given the overall course of brain pathologies during the progression of AD, we express a great enthusiasm for the repositioning of anti-cancer drugs as possible AD DMTs. We anticipate an increasing number of combinatorial therapy strategies to tackle AD symptoms and their underlying pathologies. However, we strongly encourage improvements in clinical trial study designs to better assess target engagement and possible efficacy over sufficient periods of drug exposure.

Rational design and virtual screening identify mimetics of the RXR agonist valerenic acid.

The ligand-sensing transcription factor retinoid X receptor (RXR) is the universal heterodimer partner of nuclear receptors and involved in multiple physiological processes. Its pharmacological modulation holds therapeutic potential in cancer and neurodegeneration but many available RXR ligands lack specificity. The sesquiterpenoid valerenic acid has been identified as RXR agonist with unprecedented subtype and homodimer preference. Here, we identified simplified mimetics of the complex natural product by rational design and virtual screening that exhibited similar activity profiles on RXR and informed about structural elements contributing to the favorable activity.

WYC-209 inhibited GC malignant progression by down-regulating WNT4 through RARα.

Gastric cancer (GC) has been a major health burden all over the world but there are fewer promising chemotherapeutic drugs due to its multidrug resistance. It has been reported that WYC-209 suppresses the growth and metastasis of tumor-repopulating cells but the effect on GC was not explored. MTT, colony formation, and transwell assays were performed to examine the effects of WYC-209 on the proliferation, colony growth, and mobility of GC cells. Western blotting and qRT-PCR were used to detect the expression of proteins and mRNA. RNA-seq and enrichment analyses were conducted for the differentially expressed genes and enriched biological processes and pathways. The rescue experiments were carried out for further validation. Besides, we constructed xenograft model to confirm the effect of WYC-209 in vivo. The dual-luciferase reporter and Chromatin immunoprecipitation were implemented to confirm the underlying mechanism. WYC-209 exerted excellent anti-cancer effects both in vitro and in vivo. Based on RNA-seq and enrichment analyses, we found that Wnt family member 4 (WNT4) was significantly down-regulated. More importantly, WNT4 overexpression breached the inhibitory effect of WYC-209 on GC progression. Mechanically, WYC-209 significantly promoted the binding between retinoic acid receptor α (RARα) and WNT4 promoter. WYC-209 exerts anti-tumor effects in GC by down-regulating the expression of WNT4 via RARα.

Triple Combination Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% for Acne: Efficacy and Safety from a Pooled Phase 3 Analysis.

INTRODUCTION: A three-pronged approach to acne treatment combining an antibiotic, antimicrobial, and retinoid may be more efficacious than single/double treatments while potentially reducing antibiotic resistance. This study evaluated the efficacy and safety of the first fixed-dose, triple-combination topical acne product, clindamycin 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel (CAB) using pooled phase 3 data. METHODS: In two identical phase 3 (N = 183; N = 180), double-blind, 12-week studies, participants aged ≥ 9 years with moderate-to-severe acne were randomized 2:1 to receive once-daily CAB or vehicle gel. Endpoints included ≥ 2-grade reduction from baseline in Evaluator's Global Severity Score and clear/almost clear skin (treatment success) and least-squares mean percent change from baseline in acne lesion counts. Treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability were evaluated. RESULTS: At week 12, 50.0% of participants achieved treatment success with CAB versus 22.6% with vehicle gel (P < 0.001). CAB resulted in > 70% reductions in inflammatory and noninflammatory lesions at week 12 (77.9% and 73.0%, respectively), which were significantly greater than vehicle (57.9% and 48.2%; P < 0.001, both). Most TEAEs were of mild-moderate severity, and < 3% of CAB-treated participants discontinued study/treatment because of AEs. Transient increases from baseline in scaling, erythema, itching, burning, and stinging were observed with CAB, but resolved back to or near baseline values by week 12. CONCLUSIONS: The innovative fixed-dose, triple-combination clindamycin phosphate 1.2%/adapalene 0.15%/BPO 3.1% gel was efficacious and well tolerated in children, adolescents, and adults with moderate-to-severe acne. Half of participants achieved clear/almost clear skin by 12 weeks, rates not previously seen in clinical studies of other topical acne products. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04214639 and NCT04214652.

Canadian Expert Consensus on the Use of Halobetasol Propionate/Tazarotene Lotion for Plaque Psoriasis.

INTRODUCTION: An expert panel of Canadian dermatologists was assembled to develop consensus statements regarding the current landscape of topical therapies for plaque psoriasis and the place in therapy of the recently approved fixed-dose combination halobetasol propionate (HP)/tazarotene (TAZ) lotion (HP/TAZ) in the treatment algorithm for plaque psoriasis. METHOD: A modified nominal group technique, which combined both independent and group input from the expert panel, was used to develop the consensus statements. The expert panel completed surveys to elicit their independent views on the current landscape of topical therapies for plaque psoriasis in Canada. The first expert panel session was held to discuss the existing body of literature and develop draft consensus statements about topical therapies and the place in therapy of HP/TAZ. Independent feedback on the draft consensus statements was solicited from expert panel members prior to another expert panel session where the amended consensus statements were further discussed, edited and, finally, voted on. RESULTS: The expert panel reached consensus on 20 statements. CONCLUSION: Expert panel members agreed, based on the existing body of literature, that there is a place in therapy for HP/TAZ to address several current unmet treatment needs of patients with plaque psoriasis. Studies have shown that HP/TAZ is an effective and safe first-line treatment for moderate-to-severe plaque psoriasis. Due to its cosmetically pleasing vehicle and once-daily administration, HP/TAZ may improve patient acceptance and treatment adherence.

A dermocosmetic regimen is able to mitigate skin sensitivity induced by a retinoid-based fixed combination treatment for acne: Results of a randomized clinical trial.

INTRODUCTION: Topical retinoids cause retinoid-induced skin discomfort (RISD) mainly during the first weeks of use leading to noncompliance and premature treatment discontinuation. A dermocosmetic (DC) may help to reduce treatment-related signs and symptoms and improve adherence. OBJECTIVES: To assess the benefit of a DC regimen compared to a routine skin care regimen (RC) by reducing RISD signs and symptoms induced by a retinoid/benzoyl peroxide fixed-drug combination in subjects with acne. MATERIALS AND METHODS: Double-blind, randomized, comparative study in subjects ≥16 years with mild to moderate acne candidates to a topical adapalene/BPO fixed drug combination (A/BPO). Evaluations took place at Day 0, 7, 14, 28, and 84 and included erythema, desquamation, burning, itching and stinging and RISD (SD, a composite score of local treatment-related signs and symptoms and acne severity. Subjects used daily the DC or RC together with the fixed combination for 84 days. RESULTS: Eighty-eight subjects were included, the mean age was 21 years; 84% were females. At Day 0 the SD score was 0.8 in both groups. A statistically significant difference in terms of skin sensitivity with DC compared to RC (1.6 points, vs. 2.4 points p < 0.05) was observed at Day 14. Clinical sign and symptom scores were more reduced with DC than with RC at all time points. Acne severity improved in both groups. CONCLUSION: DC significantly reduces A/BPO-related RISD compared to RC, especially during the first 14 days of treatment, without interfering with the clinical efficacy of the treatment, thus helping to maintain treatment adherence.

Topical retinoids: Novel derivatives, nano lipid-based carriers, and combinations to improve chemical instability and skin irritation.

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.

Molecular and biochemical characterizations of a Fasciola gigantica retinoid X receptor-α isoform A (FgRXRα-A).

Fascioliasis is a parasitic infection in animals and humans caused by the parasitic flatworm genus Fasciola, which has two major species, F. hepatica and F. gigantica. A major concern regarding this disease is drug resistance, which is increasingly reported worldwide. Hence, the discovery of a novel drug as well as drug targets is crucially required. Therefore, this study aims to characterize the novel drug target in the adult F. gigantica. In the beginning, we hypothesized that the parasite might interact with some host molecules when it lives inside the liver parenchyma or bile ducts, specifically hormones and hormone-like molecules, through the specific receptors, primarily nuclear receptors (NRs), which are recognized as a major drug target in various diseases. The retinoid X receptor (RXR) is a member of subfamily 2 NRs that plays multitudinous roles in organisms by forming homodimers or heterodimers with other NRs. We obtained the full-length amino acid sequences of F. gigantica retinoid X receptor-alpha (FgRXRα-A) from the transcriptome of F. gigantica that existed in the NCBI database. The FgRXRα-A were computationally predicted for the basic properties, multiple aligned, phylogeny analyzed, and generated of 2D and 3D models. Moreover, FgRXRα-A was molecular cloned and expressed as a recombinant protein (rFgRXRα-A), then used for immunization for specific polyclonal antibodies. The native FgRXRα-A was detected in the parasite extracts and tissues, and the function was investigated by in vitro binding assay. The results demonstrated the conservation of FgRXRα-A to the other RXRs, especially RXRs from the trematodes. Interestingly, the native FgRXRα-A could be detected in the testes of the parasite, where the sex hormones are accumulated. Moreover, the binding assay revealed the interaction of 9-cis retinoic acid and FgRXRα-A, suggesting the function of FgRXRα-A. Our findings suggested that FgRXRα-A will be involved with the sexual reproduction of the parasite by forming heterodimers with other NRs, and it could be the potential target for further drug development of fascioliasis.

Activation of retinoid X receptors protects retinal neurons and pigment epithelial cells from BMAA-induced death.

Exposure to the non-protein amino acid cyanotoxin ß-N-methylamino-L-alanine (BMAA), released by cyanobacteria found in many water reservoirs has been associated with neurodegenerative diseases. We previously demonstrated that BMAA induced cell death in both retina photoreceptors (PHRs) and amacrine neurons by triggering different molecular pathways, as activation of NMDA receptors and formation of carbamate-adducts was only observed in amacrine cell death. We established that activation of Retinoid X Receptors (RXR) protects retinal cells, including retina pigment epithelial (RPE) cells from oxidative stress-induced apoptosis. We now investigated the mechanisms underlying BMAA toxicity in these cells and those involved in RXR protection. BMAA addition to rat retinal neurons during early development in vitro increased reactive oxygen species (ROS) generation and polyADP ribose polymers (PAR) formation, while pre-treatment with serine (Ser) before BMAA addition decreased PHR death. Notably, RXR activation with the HX630 agonist prevented BMAA-induced death in both neuronal types, reducing ROS generation, preserving mitochondrial potential, and decreasing TUNEL-positive cells and PAR formation. This suggests that BMAA promoted PHR death by substituting Ser in polypeptide chains and by inducing polyADP ribose polymerase activation. BMAA induced cell death in ARPE-19 cells, a human epithelial cell line; RXR activation prevented this death, decreasing ROS generation and caspase 3/7 activity. These findings suggest that RXR activation prevents BMAA harmful effects on retinal neurons and RPE cells, supporting this activation as a broad-spectrum strategy for treating retina degenerations.