Search Results (361)

Skin aging is characterized by various changes, including epidermal thinning, barrier dysfunction, dermis alteration, and dermal–epidermal junction flattening. These changes lead to wrinkles and loss of skin radiance. This study investigates the potential of a supercritical CO₂ extract derived from Helichrysum italicum distillation co-products (CO₂SC extract) to serve as a botanical anti-aging product, targeting epidermal renewal, barrier reinforcement, dermal–epidermal junction organization, and engagement of retinoid-related gene networks. CO₂SC extract’s effects were examined at 0.005% in aged-human-skin equivalents via histology, immunohistology, and transcriptomics. Furthermore, CO₂SC extract was investigated at 0.1% in human skin explants using label-free proteomics in comparison with retinol (ROL) at 0.1% and 0.3%. The clinical effectiveness and tolerability of 0.1% CO₂SC extract were determined by conducting a randomized, intra-individual comparison with a 0.1% ROL formulation. In aged-human-skin equivalents, CO₂SC extract at 0.005% increased epidermal thickness, enhanced expression of differentiation- and barrier-related genes, and stimulated dermal remodeling by increasing type I and III collagens while promoting type VII collagen at the dermal–epidermal junction. Transcriptomic analysis revealed upregulation of genes involved in ROL metabolism and retinoic-acid-responsive signaling. Proteomic profiling further highlighted treatment-associated molecular signatures in comparison with ROL. Clinically, 0.1% CO₂SC extract significantly improved wrinkles by day 28, with improvements of comparable magnitude to those observed with the 0.1% ROL arm under the tested conditions and good tolerability, with no signs of irritation reported, including in sensitive-skin participants. CO₂SC extract displays anti-aging activity at the molecular, histological, and clinical levels under the tested conditions, modulating gene networks related to ROL metabolism and retinoid signaling while reinforcing barrier integrity and dermal regeneration. Together with its favorable tolerability profile, these findings suggest that this CO₂SC extract triggers retinoid-associated programs while maintaining a molecular profile distinct from that of ROL, supporting further evaluation as a botanical anti-aging ingredient agent. Full article

RARγ is expressed during embryogenesis by stem/primitive progenitor cells, indicating a role in controlling their development. Supporting this view is that a physiological level of 10 nM of the RARγ agonist AGN205327 blocked stem/progenitor cell differentiation during zebrafish embryogenesis, mouse gastruloid development, and adult chondro- and osteogenesis. Similarly, transgene expression of RARγ or the use of the RARγ agonist CD437 enhanced the generation of induced pluripotent stem cells (iPSCs) from human and mouse somatic cells. RARγ regulates many events that control the behavior of stem/progenitor cells regarding whether they develop to give rise to mature cells. RARγ positively regulates the expressions of NOTCH ligands and their receptors, transforming growth factors (TGFs), and molecules pertaining to cell identity, extracellular matrix communication, and all-trans retinoic acid synthesis and catabolism. The genes that are repressed by RARγ include RARγ, PPARγ, and RXRα. RARγ integrates into Wnt/β-catenin and TGFβ signaling by acting as a co-factor to the gene co-activator β-catenin and transcription factor Smad3, respectively. Within the cytoplasm, RARγ regulates Akt/NF-κB signaling. As a model, we propose that ATRA ligand-activated RARγ acts as a gatekeeper to stem cell developmental progression during embryogenesis and that this role extends to stem/progenitor cell homeostasis within adult tissues. Full article

Intracellular retinoid-binding proteins, including cellular retinol-binding proteins (CRBPs) and cellular retinoic acid-binding proteins (CRABPs), belong to the intracellular lipid-binding protein (iLBP) family, whereas cellular retinaldehyde-binding protein (CRALBP) is a structurally distinct retinoid-binding protein belonging to the CRAL-TRIO protein family and functions as an active regulator of retinoid trafficking, metabolism, and signaling. Although these proteins are directly implicated in inherited retinal dystrophies, retinoid-dependent cancers, and neurodegenerative diseases, they have received comparatively little attention as pharmacological targets relative to the extracellular carrier Retinol-Binding Protein 4 (RBP4). High-resolution structural studies, including atomic-resolution X-ray co-crystal structures of protein–ligand complexes, have defined the binding pocket architecture of each protein and established a basis for structure-guided drug discovery. This review critically evaluates the druggability of CRBP, CRALBP, and CRABP by integrating structural, biochemical, and pharmacological evidence. We discuss known small-molecule modulators, including the first-in-class CRBP1 inhibitor abn-CBD and next-generation non-retinoid scaffolds, alongside gene therapy strategies targeting CRALBP deficiency. We further address the selectivity challenges inherent to the conserved iLBP fold and identify future directions for the development of isoform-selective therapeutics for retinal degeneration, oncology, and neurodegeneration. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and is characterized by excessive hepatic lipid accumulation and metabolic dysfunction. Although microRNA-34a (miR-34a) has been implicated in hepatic lipid metabolism, the molecular mechanisms underlying its contribution to MASLD remain incompletely understood. Here, we investigated the role of miR-34a in FFA-induced hepatic steatosis using HepG2 cells and explored RXR-associated signaling as a potential therapeutic strategy. RT-qPCR quantified miR-34a expression; direct target interactions were validated using dual-luciferase reporter assays; proteomic alterations were characterized by iTRAQ-based proteomics followed by Ingenuity Pathway Analysis (IPA); and transcriptomic responses to 9-cis-retinoic acid (9-cis-RA) were analyzed by RNA sequencing. FFA treatment significantly increased miR-34a expression, and dual-luciferase assays confirmed that miR-34a directly targets the 3′-UTRs of RXRα, PPARα, and SIRT1. Integrated proteomic and transcriptomic analyses consistently identified LXR/RXR signaling as one of the principal pathways associated with miR-34a dysregulation and 9-cis-RA treatment. Pharmacological activation of RXR-associated signaling with the pan-RXR agonist 9-cis-RA attenuated intracellular lipid accumulation and reduced the expression of key regulators of lipogenesis and fatty acid uptake, including FASN, SCD1, FABP4, and CD36. Collectively, these findings support the miR-34a–RXRα axis as one regulatory component within a broader nuclear receptor network associated with hepatic lipid homeostasis and support further investigation of RXR-associated signaling as a potential therapeutic strategy for MASLD. Nevertheless, confirmation of receptor-specific mechanisms and validation in more physiologically relevant experimental models will be required. Full article

Posterior axis development during mammalian embryogenesis is driven by transient progenitor states that give rise to neural and mesodermal lineages, including neuromesodermal progenitors (NMPs). In vitro derivation of posterior progenitor populations from human pluripotent stem cells (hPSCs) has relied on modulation of Wnt and FGF signaling; however, these approaches frequently generate heterogeneous and unstable cell populations. Here, we investigated whether sodium butyrate (NaB) supplementation could promote a posteriorly biased intermediate state without extensive extracellular signaling control. We show that NaB, a histone deacetylase inhibitor, promotes the induction of posterior pre-neural progenitors (PNPs) characterized by co-expression of CDX2 and SOX2, together with suppression of SOX1. Transcriptomic analyses revealed that NaB-treated cells exhibit a posteriorly enriched PNPs with restrained anterior neural differentiation, transient early TBXT induction, and progressive activation of posterior HOX genes, consistent with an incompletely caudalized intermediate rather than a fully specified NMP population. Importantly, these PNPs remained responsive to canonical neural tube patterning cues, including retinoic acid and smoothened agonists, enabling further differentiation toward ventral spinal cord lineages. Collectively, our findings demonstrate that NaB supplementation supports posterior PNPs from hPSCs, providing a simple and reproducible platform for modeling early posterior neural development in vitro. Full article

Cancer development arises from dynamic interactions between inherited susceptibility and modifiable environmental exposures, among which diet plays a central role. Carotenoids, lipophilic plant-derived pigments including lycopene, α-carotene, and β-carotene, and retinoids, the vitamin A derivatives that regulate gene transcription via retinoic acid receptors (RARs) and retinoid X receptors (RXRs), have been extensively investigated for their chemopreventive and therapeutic potential. This review aims to provide an integrated, mechanism-based synthesis of the roles of lycopene, α- and β-carotene, and retinoids in cancer chemoprevention and to clarify the conditions under which they are most likely to be effective. Beyond summarizing established antioxidant and nuclear-receptor mechanisms, we highlight as a novel emphasis the epigenetic actions of these compounds, including effects on DNA methylation, histone modification, and microRNA regulation, and we integrate these with the well-recognized divergence between dietary and high-dose supplement outcomes. Experimental evidence demonstrates that carotenoids modulate oxidative stress, inflammation, proliferation, apoptosis, angiogenesis, and metastasis through pathways such as Nrf2/ARE, NF-κB, STAT3, Akt/mTOR, MAPK, and Wnt/β-catenin. Lycopene, in particular, exhibits strong antioxidant capacity and multi-target signaling effects, while provitamin A carotenoids additionally influence retinoid-mediated transcriptional programs. Retinoids exert broader differentiation-inducing and antiproliferative effects through direct nuclear receptor signaling and represent one of the few successful differentiation therapies in oncology, most notably in acute promyelocytic leukemia. Epidemiologic studies generally associate higher dietary carotenoid intake with reduced risk of several malignancies, including prostate, breast, lung, colorectal, and gastric cancers. However, randomized trials of isolated high-dose supplementation, particularly β-carotene in smokers, have demonstrated null or harmful effects, highlighting a critical divergence between whole-food dietary patterns and pharmacologic supplementation. In conclusion, carotenoids and retinoids possess biologically plausible anticancer properties, yet their clinical utility remains context dependent. Future research should prioritize biomarker-guided, precision-based strategies, standardized formulations, and whole-food dietary approaches to clarify their role in cancer prevention and treatment. Full article

Background: Coarctation of the aorta (CoA) is a congenital narrowing of the aortic isthmus near the ductus arteriosus or ligamentum arteriosum. Despite successful anatomical repair, patients remain at risk of recoarctation, arterial hypertension, and diffuse aortopathy, suggesting intrinsic vessel-wall abnormalities beyond localized obstruction. The developmental and molecular basis of these persistent vascular features remains incompletely understood. Methods: Human aortic tissue samples were obtained from 8 male infants with CoA and 6 age- and sex-matched controls aged <1 year. Total RNA was isolated, and gene expression profiling was performed using whole human genome oligo microarrays (Agilent). Differentially expressed transcripts were subjected to pathway, network, and upstream regulator analyses using Ingenuity Pathway Analysis (IPA, Qiagen). Selected candidate genes were evaluated by RT-qPCR in independent verification sets. Results: Transcriptomic profiling identified 402 analysis-ready transcripts distinguishing CoA from control tissue. Exploratory pathway analyses suggested extracellular matrix remodeling characterized by collagen turnover, integrin-mediated cell–matrix interactions, wound-healing signaling, and fibrosis-associated programs. In addition, enrichment analyses identified developmental annotations involving retinoic acid (RA)/RAR/RXR signaling, HOX-associated developmental programs, and a shared HOX/MEIS-associated signature. Network and upstream regulator analyses further suggested associations with cytoskeletal, muscle-associated, and epigenetic regulatory pathways, including KAT6A, KAT6B, retinoic acid/RAR/RXR signaling, DNMT3B, KMT2A, and ARID1A. RT-qPCR independently confirmed increased expression of EDN1, AGTR2, IRS4, and TFAP2B.Conclusions: Infantile CoA tissue exhibited molecular signatures consistent with vessel-wall remodeling accompanied by developmental, vascular signaling, and smooth muscle/cytoskeletal regulatory programs. These findings support the hypothesis that developmental patterning signals and postnatal extracellular matrix remodeling coexist within CoA tissue and may contribute to persistent vascular abnormalities beyond anatomical repair. Given the exploratory nature of the study, these observations should be considered hypothesis-generating and require validation in independent cohorts. Full article

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital craniofacial anomalies worldwide and presents significant functional, esthetic, and psychosocial challenges. Despite advances in multidisciplinary care and surgical reconstruction, complications such as impaired wound healing, scar formation, and growth disturbances warrant the development of novel regenerative and surgical strategies, which heavily rely on animal models at the pre-clinical stage. For the current narrative review, the literature search was performed by combining cleft phenotype terms with modeling-approach terms in six databases and was supplemented by manual review of reference lists from full-text articles. The included articles were summarized based on cleft type and the methods for cleft induction (chemically induced, genetically engineered, and surgically created). Particularly, chemical teratogens such as retinoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), corticosteroids, and 6-aminonicotinamide have been widely used to induce cleft phenotypes and elucidate environmental influences on palatogenesis, whereas genetic models have clarified the roles of key molecules and signaling pathways, including Sonic hedgehog (SHH), bone morphogenetic protein (BMP), and transforming growth factor-β (TGF-β), in the development of lip and palate. Meanwhile, the surgical models have focused on the alveolar cleft in skeletally mature animals for evaluating novel grafting materials. By comparing the strengths and limitations of existing models, this review highlights opportunities for improving experimental design and translational relevance in future cleft research. Overall, despite a wide range of CL/P animal models available, few replicate clinically relevant defect anatomy and the postnatal craniofacial deformation observed in CL/P patients, underscoring the need for the development of new models. Full article

Growth hormone-releasing hormone (GHRH) antagonists have displayed anti-neoplastic activity against a multitude of cancers in vitro, as well as in vivo, via xenografted tumors in nude mice. Following a successful demonstration of GHRH antagonists treating non-Hodgkin’s lymphoma and the discovery of GHRH mRNA and peptide products in immune cells, GHRH antagonism was explored in acute myeloid leukemia (AML), a disease characterized by a malignant expansion of immature myeloid progenitors, and poor 5-year survival. Targeted therapies have yielded breakthroughs in treatment response and overall survival, such as all-trans retinoic acid/arsenic trioxide (ATRA/ATO) for acute promyelocytic leukemia (APL), or FLT3 inhibitors, IDH inhibitors, and menin inhibitors for AML harboring actionable genetic lesions. However, therapeutic resistance remains a major barrier to durable remission. GHRH receptor (GHRH-R) has been reported in several experimental models of AML, including drug-resistant sublines. Significant time- and dose-dependent reduction in leukemic growth was observed in vitro and in vivo following MIA-602 treatment. FLT3 inhibitor resistance has been associated with activation of PI3K/AKT, ERK/MAPK, inflammatory, stromal, and apoptotic escape pathways. The documented effects of GHRH-R antagonism raise the possibility that it could influence signaling networks relevant to therapeutic resistance in AML. This hypothesis remains speculative; to date no studies have stratified AML by FLT3 status in the context of GHRH-R expression or GHRH antagonism, and there is currently no evidence that MIA-602 directly alters FLT3 receptor signaling or inhibitor sensitivity. Full article

Background: Natto, a well-known fermented soybean product beneficial for bone health, remains unclear in its mechanism. Methods: This study investigated its effect on secondary osteoporosis (OP) in mice. Results: Natto significantly inhibited weight loss, bone quality deterioration, and bone morphological damage, and regulated OPG/RANKL pathway protein expression (p < 0.05) in OP mice. Analysis of 16S rRNA revealed that natto increased gut microbiota α-diversity and the abundance of Sutterella, Roseburia, and Coprococcus, while reducing harmful bacteria such as Streptococcus, Shigella, and Helicobacter. These microbial changes positively correlated with body weight, bone size, and serum osteogenic metabolism in OP mice. Serum metabolomics showed differential metabolites of the natto group enriched in PPAR signaling and primary bile acid biosynthesis. Verification by mRNA and ELISA indicated that the upregulated liver and circulating PPARα by natto may regulate downstream bile acid pathways, linking gut microbiota to multi-organ metabolic functions. Conclusions: In summary, natto may act on gut microbiota to alleviate bone loss via the “gut microbiota–bile acid–OPG/RANKL” network, targeting multiple organs including gut, liver, and bone. This provides a theoretical basis for natto dietary intervention in osteoporosis prevention through the gut–bone axis. Full article

Spermatogenesis is a highly coordinated biological process in which diploid spermatogonia undergo mitotic expansion, meiotic division, and terminal differentiation into haploid spermatozoa. This process is tightly regulated by intrinsic germ cell programs and extrinsic signals from Sertoli cells within the seminiferous epithelium. Among the signaling pathways governing male germ cell development, all-trans retinoic acid (RA), a bioactive metabolite of vitamin A, has emerged as a master regulator of meiotic initiation and spermatogonial differentiation in mammals. RA functions through nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which regulate transcriptional networks essential for germ cell progression, including the activation of Stimulated by Retinoic Acid 8 (STRA8), a key determinant of meiotic entry. Intratesticular RA homeostasis is maintained by a balance between synthesis via aldehyde dehydrogenase (ALDH) enzymes and degradation by cytochrome P450 family 26 (CYP26) enzymes, ensuring precise temporal and spatial control of germ cell development. While rodent models have defined core mechanisms of RA signaling, the canine testis provides a valuable comparative and translational system due to its physiological similarity to human spermatogenesis and relevance to reproductive management. Recent studies highlight conserved RA signaling pathways in dogs, including receptor-mediated transcriptional regulation, feedback control of RA metabolism, and post-transcriptional modulation via microRNAs. Importantly, pharmacological manipulation of RA signaling can reversibly disrupt spermatogenesis, supporting its potential applications in non-hormonal male contraception. This review integrates molecular, developmental, pharmacological, and comparative evidence and presents RA signaling as a central regulatory axis of spermatogenesis with important translational applications. Full article

Glioblastoma (GBM) is an extremely invasive and incurable tumor. We previously reported predominant ALDH1A3 expression at the invasive front of GBM tumors, which was associated with shorter patient survival, and further showed that ALDH1A3 promoted tumor angiogenesis involving plasminogen activator inhibitor-1 (PAI-1). Here, we investigated whether ALDH1A3 drives cell invasion through retinoic acid (RA) and PAI-1 signaling. Analysis of the TCGA-GBM dataset revealed a positive association between ALDH1A3 and PAI-1 (SERPINE1) expression. Overexpression of ALDH1A3 in GBM cells markedly increased PAI-1 mRNA and protein levels, with cellular colocalization of both proteins, accompanied by robust migration and invasion. These effects were reversed by treatment with a pan-RA receptor (RAR) antagonist AGN193109 (AGN), with a specific PAI-1 inhibitor tiplaxtinin (Tip) or by CRISPR/Cas9-mediated knockout of PAI-1. In a chick chorioallantoic membrane (CAM) model, ALDH1A3-overexpressing cells showed increased invasion, which was reduced by tiplaxtinin (Tip) treatment or PAI-1 knockout. Mechanistically, ChIP-qPCR demonstrated that RA treatment or ALDH1A3 overexpression increased RARα occupancy at the PAI-1 regulatory region, accompanied by increased PAI-1 expression, both of which were diminished by AGN. Collectively, the present study defines an ALDH1A3-RA-PAI-1 signaling axis that contributes to GBM cell motility and invasion. Full article

6:2 Chlorinated polyfluoroether sulfonate (F-53B), an emerging per- and polyfluoroalkyl substance used as a perfluorooctane sulfonate substitute in electroplating, may co-occur with Cr(VI) in industrially affected aquatic environments. However, their combined developmental toxicity in vertebrates remains poorly understood. This study compared the effects of F-53B and Cr(VI) alone and in combination on zebrafish embryos and larvae exposed from 0 to 120 hpf at environmentally relevant concentrations (10 and 100 μg/L). Developmental toxicity, ocular morphology, retinal histology, locomotor behavior, and ocular-development-related gene expression were assessed. Single Cr(VI) exposure produced prominent effects on hatching, locomotor activity, retinal-layer thickness, and selected transcriptional responses related to retinoic acid signaling and ocular development. F-53B alone caused developmental and ocular alterations but generally produced weaker or more selective responses than Cr(VI). Co-exposure did not uniformly intensify the toxicity of either compound. Instead, the mixture enhanced some endpoints, including malformation, heart rate, and specific ocular or retinal alterations while showing weaker or divergent responses for other endpoints, such as locomotor activity and selected transcriptional markers. These findings indicate that F-53B/Cr(VI) co-exposure produces endpoint-dependent toxicity rather than a consistent synergistic pattern. Overall, the study highlights the importance of comparing single and combined exposures across multiple biological endpoints when assessing the developmental risks of co-occurring contaminants. 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

The innate immune system, particularly the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway, is a major early defense barrier against influenza A virus infection. However, excessive immune responses can trigger lethal cytokine storms and severe immune-mediated pathology. In this study, we performed a genome-wide CRISPR/dCas9 gene activation screen in human lung epithelial (A549) cells by using an A/Puerto Rico/8/1934 (H1N1) reporter virus, and identified the ubiquitin-specific protease USP17L13 as a novel negative regulator of innate immunity that promotes influenza virus replication. Overexpression of USP17L13 significantly enhanced the replication of multiple subtypes of influenza viruses in A549 cells, including a human pandemic H1N1 virus, seasonal H3N2 viruses, as well as a globally circulating clade, 2.3.4.4b, of the highly pathogenic avian H5N1 virus. Transcriptomic analysis demonstrated that USP17L13 suppresses host antiviral defenses by downregulating nuclear factor kappa B (NF-κB) signaling and arachidonic acid metabolism, while upregulating pathways associated with ribosomal translation and oxidative phosphorylation to facilitate viral production. Mechanistically, USP17L13 attenuates the host interferon (IFN) response by promoting the degradation of the key viral RNA sensors, RIG-I, and melanoma differentiation-associated protein 5 (MDA5). Further analysis revealed that USP17L13 is inducible by type I and type II interferons as well as inflammatory cytokines, suggesting that it may act as a negative-feedback regulator to limit excessive inflammation. Collectively, our findings identify USP17L13 as a previously unrecognized proviral host factor and provide new insight into how host deubiquitinases shape influenza virus-host interactions, with potential implications for host-directed approaches to controlling excessive inflammation during viral infection and improving influenza vaccine production. Full article