Search Results (40)

Retinol, a bioactive small molecule of the vitamin A family, contributes epidermal and dermal tissue repair through retinoic acid receptor γ (RARγ)/retinoid X receptor (RXR) receptor-mediated transcriptional regulation of keratinocyte differentiation, extracellular matrix (ECM) remodeling, and barrier restoration. However, the relationship between applied concentration, tissue-level regenerative outcomes, and tolerability remains incompletely characterized. This prospective, randomized, single-blind study compared biophysical effects and tolerance of two retinol concentrations in EU-compliant facial creams, high-performance liquid chromatography (HPLC)-verified as 0.104% and 0.247% (w/w). Thirty-eight women aged 40–61 years (Fitzpatrick phototypes II–III) participated across three independent sub-studies: 28 were randomized to either concentration for 12 weeks; 5 underwent split-face ultrasound imaging (0.247% versus retinol-free control) for 8 weeks; and 5 participated in a tape stripping sub-study quantifying stratum corneum interleukin-1 alpha (IL-1α) and interleukin-1 receptor antagonist (IL-1ra) by ELISA before and after 6 weeks of 0.247% retinol treatment. Main cohort assessments included transepidermal water loss (TEWL), hydration, melanin, erythema, pH, sebum, biomechanical parameters, and wrinkle grading. Both concentrations significantly improved barrier parameters—hydration, TEWL, brightness, pH, and sebum—with no inter-group differences. In the ultrasound sub-group, 0.247% retinol increased epidermal thickness (+12.4 μm), epidermal density (+3.84%), and dermal density (+1.81%) versus control, consistent with ECM reorganization and epidermal stratification. Biomechanical parameters showed no significant changes, consistent with retinol’s remodeling timeline. Consumer assessment indicated comparable efficacy; 0.247% demonstrated superior smoothing but higher erythema incidence. In the tape stripping sub-study, IL-1α decreased in all participants (median: 25.1 → 13.2 picograms per tape [pg/Tape]; 5/5 concordant), while IL-1ra increased in 4/5 participants (median: 352.8 → 1403.1 picograms per three sequential tapes [pg/3sT]), indicating a directionally consistent shift in the IL-1α/IL-1ra balance; these results are exploratory and require replication in larger cohorts. These findings collectively support clinically meaningful barrier restoration and structural remodeling within current EU safety limits (Commission Regulation EU 2024/996), with 0.104% offering a favorable efficacy-to-tolerability profile for initial therapy. Full article

Epidermal hyperinnervation is a major cause of intractable itch in barrier dysfunction conditions such as atopic dermatitis. Keratinocyte-derived semaphorin 3A (Sema3A) suppresses epidermal hyperinnervation, but its expression is markedly reduced in barrier-disrupted skin. Although konjac ceramide (kCer) has been reported to act as a Sema3A-like ligand, the mechanisms by which it regulates Sema3A expression in keratinocytes remain unclear. Normal human epidermal keratinocytes (NHEKs) were treated with kCer, konjac glucosylceramide (kGlcCer), or C24 ceramide. Sema3A mRNA and protein levels were assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. The involvement of intracellular signaling was examined using mitogen-activated protein kinase (MAPK) inhibitors, activator protein-1 (AP-1) inhibitors, retinoic acid-related orphan receptor alpha (RORα) inverse agonists, and siRNAs targeting c-Jun, c-Fos, and RORα. kCer induced Sema3A expression in NHEKs more potently than kGlcCer or C24 ceramide and promoted Sema3A protein secretion. Pharmacological inhibition or genetic knockdown of MEK1/2, JNK, AP-1 components, or RORα significantly attenuated kCer-induced Sema3A expression, indicating involvement of the MAPK/AP-1 signaling axis and RORα. kCer upregulates Sema3A expression in human keratinocytes through MAPK/AP-1 signaling and RORα, suggesting it may represent a promising antipruritic agent for epidermal hyperinnervation associated with skin barrier dysfunction. Full article

Heterotopic ossification (HO), the pathological formation of mature bone in non-skeletal soft tissues (e.g., muscles, tendons), severely impairs patient mobility and quality of life. Despite decades of research, systematic analysis of signaling networks across HO subtypes (acquired traumatic HO, hereditary Fibrodysplasia Ossificans Progressiva (FOP), Progressive Osseous Heteroplasia (POH)) remains insufficient, and clinical therapies suffer from high recurrence and severe side effects. This review synthesizes recent advances in HO pathogenesis: FOP involves gain-of-function activin A receptor type I (ACVR1) mutations (mostly R206H), disrupting bone morphogenetic protein (BMP)/Activin A signaling; POH arises from paternal guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) loss-of-function mutations, derepressing Hedgehog signaling via reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activity; tHO features trauma-induced inflammation/hypoxia activating BMP/transforming growth factor–beta (TGF-β) pathways. Key signaling crosstalk (e.g., BMP-Yes-associated protein (YAP)-Indian hedgehog (IHH)) is integrated, and novel therapies (ACVR1 inhibitors, Activin A antibodies, retinoic acid receptor gamma (RARγ) agonists, adeno-associated virus (AAV)-mediated ACVR1 silencing) are highlighted, with emphasis on subtype-specific efficacy. A stratified, mechanism-based HO management framework is proposed, aiming to accelerate precision therapy development and advance understanding of aberrant tissue regeneration. Full article

Tamibarotene (AM80) is an agonist of retinoic acid receptor alpha. It is licensed in Japan for the treatment of acute promyelocytic leukemia. Results from preclinical models suggest that tamibarotene might also be effective in the treatment of diverse autoimmune diseases. The effect of tamibarotene on autoimmune diseases of the skin, however, has not been explored. We therefore examined the effect of tamibarotene on disease in the antibody-transfer mouse model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a prototypical example for pemphigoid diseases. Pemphigoid diseases are a group of autoimmune blistering skin diseases driven by autoantibodies and the recruitment and activity of granulocytes in the dermis. In sharp contrast to its effect in models of other autoimmune diseases, tamibarotene aggravated EBA pronouncedly. At the peak of disease, skin inflammation in tamibarotene-treated mice involved, on average, 1.6-fold more of the total body surface compared to vehicle-treated mice. Tamibarotene markedly reduced the recruitment of regulatory T cells (T_regs) into the dermis. This blunted the counterregulatory mechanisms that normally curb skin inflammation in this model. The effect aligns with previous reports describing tamibarotene-mediated downregulation of skin-homing receptors on T_regs. In addition, tamibarotene prolonged the responsiveness of aging neutrophils to immune complexes in vitro, providing another mechanism that may exacerbate EBA. Collectively, our results suggest that tamibarotene may elicit detrimental effects in patients with EBA by abolishing the recruitment of T_regs into skin. This warrants great caution when using tamibarotene in patients with EBA and possibly other pemphigoid diseases. Full article

Obesity is characterized by chronic low-grade inflammation, largely driven by macrophage infiltration into adipose tissue, which contributes to the development of insulin resistance. All-trans retinoic acid (ATRA), a biologically active metabolite of vitamin A, has demonstrated anti-inflammatory properties. This study examined the effects of ATRA on inflammation and insulin resistance using a coculture model comprising hypertrophied 3T3-L1 adipocytes and RAW264.7 macrophages. Coculture markedly elevated the production of pro-inflammatory mediators—including nitric oxide, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interleukin-6—and increased free fatty acid release while suppressing the secretion of anti-inflammatory adiponectin. Treatment with ATRA (0.1, 1, and 10 μM) significantly reversed these coculture-induced alterations (p < 0.001). ATRA also inhibited the nuclear translocation of NF-κB and downregulated the expression of retinol-binding protein 4 (RBP4). Moreover, ATRA improved insulin-stimulated glucose uptake in adipocytes rendered insulin-resistant by coculture (p < 0.01), an effect associated with the restoration of glucose transporter 4 (GLUT4) and insulin receptor substrate-2 (IRS-2) expression. These findings suggest that ATRA effectively mitigates inflammation and insulin resistance arising from adipocyte–macrophage interactions, highlighting its potential as a therapeutic agent for obesity-related metabolic disorders. Full article

The development and replacement of hair play a significant role in the life history of animals. In recent years, retinoic-acid-related orphan receptor alpha (Rorα) has been found to participate in the regulation of hair follicle development, yet the underlying mechanisms remain incompletely understood. This study aims to analyze the regulatory role of Rorα on the cytoskeleton of hair follicle stem cells (HFSCs). We treated HFSCs with a RORA agonist and subsequently analyzed differential gene expression using qPCR, Western blotting, and immunofluorescence, finding that agonist-induced activation of RORA suppressed the expression levels of cytoskeleton-related genes. Additionally, F-actin staining with phalloidin, followed by migration assays and wound healing tests for cell migration detection, revealed that this process affected the cytoskeletal state of HFSCs and inhibited their migration and adhesion capabilities. We further conducted interaction analyses using CUT&RUN combined with ddPCR and EMSA, demonstrating that RORA can bind to the promoter regions of the Actg1 gene and regulate their transcription. This study contributes to a comprehensive understanding of the regulatory processes involved in hair follicle development and may provide broader insights into the treatment of diseases such as alopecia. Full article

Mouse models serve as a means of examining immune changes when genes of interest are knocked out (KO). One group of immune gene-producing cells that have been identified is type 2 innate lymphoid cells (Ilc2). These cells are involved in the production of Th2 equivalent immune responses and signal cytokine production during the resolution of Nippostrongylus brasiliensis parasite infection in mice lungs. However, many questions about Ilc2 activity in the gut remain. To study this, retinoic acid receptor (RAR)-related orphan receptor alpha (RORα)-deficient mice were infected with adult N. brasiliensis and arranged into four treatment groups. Ten days post-infection (dpi), mouse ileum tissue was extracted for RNA-Seq. The RORα-deficient mice showed little change in gene expression at 10 dpi (N = 51) when compared to the WT mice at 10 dpi (N = 915), displaying dysregulation within the mouse gut. Based on the results, the gene expression in the gut of Ilc2-deficient mice denoted that the inability to craft Ilc2 cells left the mice unable to mount classical helminth immune responses involving humoral, mast cell, and antibody Th2-driven reactions. Overall, the results showed the importance of Ilc2 in the gut during N. brasiliensis infections and the effect that the lack of these cells had on immunity. Full article

PEG400 is widely used as a pharmaceutical excipient in the biomedical field. Increasing evidence suggests that PEG400 is not an inert drug carrier; it can influence the activity of various drug-metabolizing enzymes and transporters, thereby affecting the in vivo process of drugs. It can also alleviate obesity and adipose tissue inflammation induced by a high-fat diet. In this study, we employed proteomics to investigate the impact of PEG400 on hepatic protein expression in rats. We found that over 40 metabolic enzymes were altered, with UDP-glucuronosyltransferase 1a9 (Ugt1a9) showing the most significant upregulation. This observation is consistent with our previous findings. KEGG pathway enrichment analysis revealed that PEG400 influences retinol metabolism, steroid hormone biosynthesis, drug metabolism, bile secretion, fatty acid degradation, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and pentose and glucuronate interconversions. Western blot and molecular docking were used to quantitatively analyze related proteins. The results demonstrated that PEG400 promotes the metabolism of retinol to produce retinoic acid; enhances bile secretion by upregulating bile acid synthesis and transporter proteins; and activates the PPARα signaling pathway to regulate the expression of fat metabolism-related proteins, thereby reducing lipid accumulation. Furthermore, as natural ligands for nuclear receptors, retinoic acid and bile acids may activate nuclear receptors and initiate the regulation of target gene expression. We found upregulation of the nuclear receptors PPARα, retinoid X receptor alpha (RXRα), and pregnane X receptor (PXR). RXRα can form a dimer with PPARα or PXR to regulate the expression of target genes, which may explain the changes in the expression of numerous metabolic enzymes. This study provides a comprehensive understanding of the effects of PEG400 on liver metabolism in rats, reveals its potential biological functions, and offers new insights into the application and development of PEG400. Full article

The hair coat is an adaptive evolutionary trait unique to mammals, aiding them in adapting to complex environmental challenges. Although some of the factors involved in regulating hair follicle development have been characterized, further in-depth research is still needed. Retinoic acid receptor-related orphan receptor alpha (RORA), as a member of the nuclear receptor family, is highly involved in the regulation of cellular states. Previous studies have shown that autophagy plays a significant role in hair follicle development. This study uses rat hair follicle stem cells (HFSCs) as a model to analyze the impact of RORA on the autophagy levels of HFSCs. Upon activation of RORA, autophagy indicators such as the LC3-II/LC3-I ratio and MDC staining significantly increased, suggesting an elevated level of autophagy in HFSCs. Following treatment with chloroquine, the LC3-II/LC3-I ratio, as well as the expression levels of BECN1 protein and SQSTM1 protein, were markedly elevated in the cells, indicating that the autophagic flux was unobstructed and ruling out the possibility that RORA activation impeded autophagy. Additionally, the level of the Sqstm1 gene increased markedly after RORA activation promoted autophagy in the cells. We found that RORA regulates the transcription level of Sqstm1 by binding to its promoter region. We believe that RORA activation significantly promotes the level of autophagy, particularly selective autophagy, in HFSCs, suggesting that RORA has the potential to become a new target for research on hair follicle development. This research provides a theoretical foundation for studies on hair follicle development and also offers new insights for the treatment of diseases such as alopecia. Full article

Retinol is well-known anti-aging material in the cosmetics industry, owing to its proven superior efficacy both in vitro and in vivo. Despite its high efficacy, retinol is associated with limitations, such as skin irritation and its potential photodegradation. Retinol is converted into retinoid acid within cells, which then exerts a cellular response by activating both the retinoic acid receptor (RAR) and retinoid x receptor (RXR). Noting that RAR activity is associated with skin irritation and RXR activation alone can enhance skin-related indicators without inducing inflammation, we developed an alternative approach for skin anti-aging focusing solely on RXR activation. We found that combined treatment of andrographolide and Bidens pilosa extract successfully activated RXR alpha and enhanced RXRA gene expression. Moreover, we investigated their efficacy using dermal fibroblasts and keratinocytes and found that they enhanced the gene expression of extracellular matrix (ECM) proteins with anti-oxidant and anti-inflammation efficacies. Finally, in a human clinical trial, we confirmed that our materials successfully improved wrinkles in various areas, skin elasticity and hydration without causing irritating side effects. These findings highlight the potential of our RXR alpha-activating materials as an anti-wrinkle solution that avoids the typical side effects associated with retinol. Full article

Background: Within the past few years, many new therapies have emerged for psoriasis and psoriatic arthritis (PsA). Current topical therapies—including corticosteroids, vitamin D analogs, tapinarof, and roflumilast—remain the mainstay for mild disease, while oral systemic and biologic options are for moderate to severe cases. Biologics—such as Tumor necrosis factor-alpha (TNF-alpha), Interleukin 12/23 (IL-12/23), Interleukin-17 (IL-17), and Interleukin-23 (IL-23)—have revolutionized care by providing highly effective and safer alternatives. Oral small molecules, including Janus kinase (JAK) and tyrosine kinase 2 (TYK2) inhibitors, further expand the therapeutic options. Objectives: The goal for this review article was to examine current and latest treatments for psoriasis and PsA and discuss whether these emerging therapeutic options address the unmet needs of current treatments. Methods: The search for this review article included PubMed, Google Scholar, and ClinicalTrials.gov for relevant articles and current clinical trials using keywords. Results: A wide range of novel psoriatic and PsA therapies are currently undergoing clinical trials. These include selective JAK inhibitors, TYK2 inhibitors, retinoic acid-related orphan receptor (RORγT) inhibitors, oral IL-23 receptor inhibitors, oral IL-17A inhibitors, nanobody products, sphingosine-1-phosphate (S1P1R) antagonists, A3 adenosine receptor (A3AR) agonists, heat shock protein (HSP) 90 inhibitors, and rho-associated protein kinases (ROCK-2) inhibitors. Conclusions: These different mechanisms of action not only expand treatment options but may offer potential solutions for patients who do not achieve adequate response with existing therapies. However, the safety and contraindications of these newer agents remain an important consideration to ensure appropriate patient selection and minimize potential risks. Certain mechanisms may pose increased risks for infection, cardiovascular manifestations, malignancy, or other immune-related adverse events, necessitating careful monitoring and individualized treatment decisions. Ongoing clinical research aims to address unmet needs for patients who do not respond to previous agents to achieve sustained remission, monitor long-term safety outcomes, and assess patient preferences for delivery, including a preference for oral delivery. Oral IL-23 inhibitors hold potential due to their robust safety profiles. In contrast, oral IL-17 inhibitors and TYK-2 inhibitors are effective but may present side effects that could impact their acceptability. It is essential to balance efficacy, safety, and patient preferences to guide the selection of appropriate therapies. Full article

Seasonal molting in mammals is a crucial survival strategy, yet the underlying molecular mechanisms have not been fully characterized. Melatonin, serving as a bridge for the transmission of photoperiod signals, plays a significant regulatory role in animals’ seasonal molting, and the physiological regulatory effects of melatonin signaling are highly dependent on the retinoic-acid-related orphan receptor alpha (Rorα). Hair follicle stem cells (HFSCs) are the most essential cell type in the process of hair follicle regeneration and seasonal replacement. Therefore, this study aims to discuss the regulatory effects of melatonin and its nuclear receptor RORA on HFSCs. This research found that RORA can downregulate cellular proliferation levels by inhibiting the cell cycle of HFSCs, while simultaneously promoting apoptosis in HFSCs and affecting the expression of some genes involved in ferroptosis. RORA can directly bind to the promoter regions of the cyclin genes Ccna2 and Ccne1 to regulate their transcription. Melatonin may enhance the viability of HFSCs by downregulating RORA levels. In this study, the impact of melatonin and its nuclear receptor RORA on the viability of HFSCs, along with some of the underlying molecular mechanisms, is characterized. These findings provide a theoretical foundation for research on the regulation of animal hair follicle development. Full article

The prevalence and deaths from esophageal cancer (EC) have recently increased. Although therapeutic strategies depend on the EC stage and recurrence, such as surgical intervention, chemotherapy, radiation therapy, chemoradiation therapy, targeted therapy, and immunotherapy, a more effective and novel treatment for EC is still required. This review briefly describes and summarizes some insightful oncotargets involved in the metabolic modulation of EC, including (1) cancer stem cells (CSCs) for EC progression, poor prognosis, tumor recurrence, and therapy resistance; (2) retinoic acid receptors (RARs) for esophageal carcinogenesis and regeneration; (3) phosphofructokinase (PFK) for EC-reprogrammed glycolysis; (4) lactate dehydrogenase (LDH) as an EC peripheral blood biomarker; and (5) hypoxia-inducible factor-1 alpha (HIF-1α) for the tumor microenvironment under hypoxic conditions. Moreover, the aforementioned oncotargets can be modulated by mutant TP53 and have their own features in the carcinogenesis, differentiation, proliferation, and metastasis of EC. Thus, the clarification of pharmacological mechanisms regarding the interaction between mutant TP53 and the abovementioned oncotargets could provide precise and perspective opinions for minimizing prediction errors, reducing therapy resistance, and developing novel drugs against EC. Full article

The development and regulation of hair are widely influenced by biological rhythm signals. Melatonin plays a crucial role as a messenger in transmitting biological rhythm signals, and its impact on hair development has been well documented. During the process of hair follicle reconstruction, hair follicle stem cells (HFSCs) are the most important cell type, but the regulatory effect of melatonin on the state of HFSCs is still not fully understood. Therefore, it is necessary to conduct a more comprehensive characterization of the effects of melatonin on the state of hair follicle stem cells. The research results indicate that HFSCs express retinoic acid receptor-related orphan receptor alpha (Rorα), and melatonin inhibits the expression level of RORA. Experimental results from CUT&Tag, CUT&RUN, and dual luciferase reporter assays demonstrate that Foxc1 is a downstream target gene of RORA, with RORA regulating Foxc1 expression by binding to the promoter region of Foxc1. The CCK-8 assay results show that low doses of melatonin upregulate the survival rate of hair follicle stem cells, while high doses have the opposite effect. The knockdown of Foxc1 reverses the inhibitory effect of high-dose melatonin on the survival rate of hair follicle stem cells. Based on these findings, we believe that melatonin-mediated circadian signals exert a bidirectional regulatory effect on the state of HFSCs. Full article

The hair, an exclusive keratinized dermal appendage in mammals, stands as a quintessential outcome of adaptive evolution, conferring resilience against adverse environmental conditions. The ontogenesis of the coat displays a pronounced rhythmic pattern, with hair follicle stem cells (HFSCs) emerging as pivotal facilitators of hair follicle reconstitution. The retinoic acid-related orphan receptor alpha, a nuclear receptor with extensive involvement in the regulation of cellular physiological states, exerts its functions predominantly through the modulation of downstream target gene transcription. The Bnip3 gene exhibits a robust correlation with cellular apoptosis and autophagy, which are indispensable physiological mechanisms underlying the maintenance of HFSC homeostasis. Consequently, the expression level of Bnip3 may be intimately linked to the status of HFSCs. In this investigative endeavor, we employed rat HFSCs as a model system to validate the regulatory impact of RORA on Bnip3 gene expression. Our findings unequivocally demonstrate that Bnip3 serves as a direct downstream target of RORA. Specifically, RORA binds to the motif within the Bnip3 promoter region, thereby upregulating Bnip3 expression levels. In light of our research findings, we propose that RORA holds potential as a target for modulating the status of HFSCs. Full article