Search Results (497)

Background and Objectives: Vitamins A and D have been reported to improve cancer outcomes. In this work, we reviewed recent meta-analyses, preclinical, and transcriptomics data for these vitamins and combinations for breast and colon cancers. Methods: Searches for meta-analyses, preclinical, and transcriptomic data for vitamins A and D in breast and colorectal cancers were conducted using electronic databases from June 2012 to May 2025. Studies describing the effects of vitamin A and D levels (through diet, supplementation, and serum concentrations) on the risk, prognosis, metastasis, and survival rates of breast and colon cancer patients, and the doses needed to achieve these endpoints, were included. Preclinical and transcriptomics studies investigating combinations of vitamins A and D were also reviewed. Results: The reviewed studies showed an inverse correlation between vitamin A intake and the risk and survival rates of breast cancers. Sufficient vitamin D3 levels were associated with improved survival outcomes, lower tumor grades, and less ER- or triple-negative breast cancers. For colorectal cancers, meta-analyses showed conflicting results for vitamin A, but clear evidence that vitamin D reduced both risk and mortality. Preclinical and transcriptomics studies provide compelling evidence that vitamins A and D combinations may be more effective for the prevention and treatment of breast and colon cancers, due to their significant synergistic effects and the larger number of cancer-signaling pathways impacted. Conclusions: Vitamins A and D reduce breast and colorectal cancer incidence, risk and mortality through multiple mechanisms of action, and offer significant potential as therapeutic and chemopreventative agents. Full article

Background: Lichen planus (LP) is a chronic immune-mediated inflammatory disorder affecting skin, mucosae, nails, and appendages, often with significant impact on quality of life. While associations between oral LP (OLP) and other localizations have been described, comprehensive analyses of patients presenting with multiple LP localizations remain limited. The aim of the study was describing the association of multisite LP among our patients in order to contribute to knowledge about this rare, but possible, clinical situation and its clinical implications in terms of follow-up. Methods: We conducted a retrospective observational study including 44 adult patients with histologically confirmed OLP and at least two additional LP subtypes. Data were collected at the joint dermatology–oral pathology clinic of Policlinico Sant’Orsola Malpighi, Bologna, between January 2022 and December 2024. Demographic characteristics, clinical manifestations, comorbidities, and therapeutic approaches were analyzed. Results: The cohort comprised 31 women and 13 men (mean age at first LP diagnosis: 56 years). All patients presented OLP, predominantly erosive (73%). During a follow-up, 39 patients developed three LP subtypes, and 5 patients developed four LP subtypes. Cutaneous LP was universal, while mucosal involvement included genital LP (n = 23), esophageal/pharyngeal/laryngeal LP (n = 8), and vulvar lichen sclerosus (n = 6). Nail LP was diagnosed in seven cases and frontal fibrosing alopecia in ten cases. Autoimmune comorbidities were frequent, including thyroiditis, psoriasis, systemic sclerosis, lupus, and Sjögren’s syndrome. First-line therapy consisted of topical and systemic corticosteroids, with adjuvant retinoids, cyclosporine, or immunosuppressants in refractory cases. No malignant transformation or dysplasia was detected during the observation period, and the mean follow-up period was 24 months (range: 12–36 months). Conclusions: Multisite LP is a complex, underrecognized condition requiring multidisciplinary management. OLP frequently represents the initial manifestation, followed by progressive involvement of cutaneous and mucosal sites. Regular full-body, oral, and genital examinations, together with tailored systemic treatments, are essential to prevent scarring sequelae and improve quality of life. Our findings highlight the need for heightened clinical vigilance and integrated care pathways for patients with multi-site LP. Full article

FMS-like tyrosine kinase 3 (FLT3) is a crucial regulator of normal hematopoiesis, with high expression in hematopoietic stem and progenitor cells. Beyond its role in stem cell survival and proliferation, FLT3 signaling is essential for immune regulation, particularly dendritic cell differentiation and NK cell expansion. In acute myeloid leukemia (AML), FLT3 mutations—most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions—are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. The clinical development of FLT3 inhibitors has been a decades-long endeavor. Early multikinase agents established proof-of-concept but were hampered by off-target effects and incomplete efficacy. The subsequent generation of potent and selective inhibitors has transformed outcomes, culminating in FDA approvals of midostaurin, quizartinib, and gilteritinib. Together with allogeneic transplantation, these agents have reshaped the treatment paradigm for FLT3-mutant AML, converting a historically high-risk subset into one with realistic prospects for long-term survival. Despite these advances, challenges remain. Resistance emerges through cell-intrinsic mechanisms such as acquisition of secondary TKD or RAS pathway mutations, metabolic reprogramming, and antiapoptotic shifts, as well as cell-extrinsic mechanisms mediated by the bone marrow microenvironment, including cytokine support, stromal CYP3A4 metabolism, and retinoid inactivation. These pathways sustain measurable residual disease (MRD), the key predictor of relapse. Rational combination strategies and MRD-directed approaches are therefore essential to fully realize the curative potential of FLT3 inhibition. 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

Retinoids are central regulators of skin biology, influencing keratinocyte proliferation, differentiation, immune modulation, and barrier maintenance. Their therapeutic relevance has long been attributed to retinoic acid receptor (RAR)-mediated transcriptional activity; however, recent studies have revealed additional layers of regulation, including epigenetic modifications, kinase signaling networks, and interactions with the skin microbiome. These mechanisms not only refine our understanding of retinoid function but also inform strategies to overcome therapeutic limitations such as resistance, irritation, and systemic toxicity. Advances in medicinal chemistry have yielded synthetic retinoids with enhanced receptor selectivity, particularly for RAR-γ agonists such as trifarotene, as well as inhibitors of cytochrome P450–mediated retinoic acid metabolism, which sustain endogenous activity and mitigate resistance (DX314 and other RAMBAs). In parallel, the development of nanocarriers, stimuli-responsive gels, and other targeted delivery systems has improved drug stability, bioavailability, and tolerability. Together, these innovations underscore the evolving role of retinoid-based interventions in precision dermatology, providing opportunities to optimize treatment outcomes for acne, psoriasis, photoaging, and other dermatological disorders while addressing the shortcomings of earlier generations. Full article

Background: Skin aging is influenced by intrinsic factors such as genetics and cellular decline, and extrinsic factors including UV exposure, pollution, and lifestyle. Cosmetic or over-the-counter retinoids, particularly retinal (retinaldehyde), have shown strong efficacy in reducing photoaging signs—such as fine lines, wrinkles, and pigmentation—while offering improved tolerability compared to prescription-based retinoids like all-trans retinoic acid. However, their instability in formulations and limited bioavailability when applied topically remain major challenges. Objective: This exploratory study aimed to assess the efficacy and safety of a novel mix-activated anhydrous 0.1% retinal concentrate formulated also with hydrophilic active ingredients—N-acetyl glucosamine, niacinamide, ascorbic acid, and alpha-glucan oligosaccharide—in improving signs of skin aging over six weeks. Methods: A prospective, single-center study was conducted with 27 healthy adults (24 female and 3 male, aged 40–69 years, 21 with skin phototype III and 6 with phototype II) exhibiting visible signs of photoaging. Participants applied the retinal concentrate once daily, mixed in a 1:2 ratio with a moisturizer before application. Objective skin parameters, including pigmentation, fine lines, wrinkles, texture, volume, and pore visibility, were assessed using the Antera 3D imaging system at baseline and after six weeks. A self-evaluation questionnaire was completed at week six. Statistical significance was determined using the Wilcoxon signed-rank test (p < 0.05) and was corrected for multiple analyses. Results: Significant improvements were observed across all parameters: pigmentation (−12%, p < 0.0001), fine lines (−14%, p < 0.0001), wrinkle depth (−5%, p = 0.0045), skin texture (+12%, p < 0.0001), volume irregularities (−15%, p < 0.0001), and pore visibility (−24%, p < 0.0001). No significant change in redness was detected (p = 0.6664), indicating a good tolerability to the test product. Self-assessments reflected high user satisfaction: 81% reported improved skin appearance, 43% noted reduced need for makeup use, and 40% observed visible improvements already within two weeks. Conclusions: The anhydrous 0.1% retinal concentrate with hydrophilic actives significantly improved clinical signs of photoaging without causing irritation. The innovative mix-activated formulation stabilizes sensitive ingredients and enhances their efficacy, offering a novel, active, and well-tolerated approach to anti-aging skincare. Full article

Autism spectrum disorder (ASD) is a group of neurodevelopmental dysfunctions characterized by a heterogeneous etiology that involves gene–environment interactions. Early postnatal lead (Pb) exposure has been found to be associated with the etiology of ASD, but the mechanisms remain unclear. The present study aims to investigate the effects of early Pb exposure on the emergence of ASD-like behaviors in offspring and to evaluate its potential relationship with morphological changes and underlying mechanisms in the cerebellum. The study established a mouse model to study early postnatal Pb exposure and examined ASD-like behaviors through the open field test, novel object recognition test, marble burying test, and three-chamber social test. Quantification of Pb levels was performed in cerebellar tissue, examination of Purkinje cell morphology was carried out, and identification of differential protein expression was conducted using TMT-based quantitative proteomics. The study revealed that the offspring of Pb-exposed mice showed significant social deficits, increased repetitive behaviors, and cognitive impairments. The cerebellum showed both elevated Pb levels and a reduction in Purkinje cells. Proteomic analysis identified 45 proteins that were differentially expressed, showing disruption in the retinoid signaling pathway. These findings demonstrate that early postnatal Pb exposure leads to ASD traits and that retinoid signaling may be a key pathway in the cerebellum, at least in part. Full article

Keratoacanthoma (KA) is a rapidly growing epithelial neoplasm characterized by clinical and histopathological features that often overlap with well-differentiated squamous cell carcinoma (SCC), posing diagnostic challenges. This review provides a comprehensive overview of KA, emphasizing advances in non-invasive diagnostic techniques such as dermoscopy, reflectance confocal microscopy (RCM), and line-field confocal optical coherence tomography (LC-OCT), which improve lesion characterization and differentiation from SCC. We discuss the histopathological phases of KA and highlight key features aiding in diagnosis. Furthermore, we explore the emerging role of human papillomavirus (HPV), particularly β-genus types, as a cofactor in KA carcinogenesis through modulation of apoptosis and DNA damage response pathways, especially under ultraviolet (UV) radiation exposure. Therapeutic strategies remain centered on complete surgical excision; however, alternative treatments, including radiotherapy, cryotherapy, topical agents, and systemic retinoids, are discussed with their respective benefits and limitations. Finally, we review current HPV vaccines and novel vaccine candidates targeting a broad spectrum of mucosal and cutaneous HPV types. This review underscores the importance of integrated diagnostic and therapeutic approaches to optimize KA management and highlights future directions in understanding its pathogenesis and treatment. Full article

Chronic dermatological conditions such as acne vulgaris, androgenetic alopecia (AGA), and alopecia areata (AA) affect hundreds of millions worldwide and contribute substantially to quality-of-life impairment. Despite the availability of systemic retinoids, anti-androgens, and JAK inhibitors, therapeutic responses remain heterogeneous and relapse is common, underscoring the need for biologically grounded stratification. Over the past decade, large genome-wide association studies and functional analyses have clarified disease-specific and cross-cutting mechanisms. In AA, multiple independent HLA class II signals and immune-regulatory loci such as BCL2L11 and LRRC32 establish antigen presentation and interferon-γ/JAK–STAT signalling as central drivers, consistent with clinical responses to JAK inhibition. AGA is driven by variation at the androgen receptor and 5-α-reductase genes alongside WNT/TGF-β regulators (WNT10A, LGR4, RSPO2, DKK2), explaining follicular miniaturisation and enabling polygenic risk prediction. Acne genetics highlight an immune–morphogenesis–lipid triad, with loci in TGFB2, WNT10A, LGR6, FASN, and FADS2 linking follicle repair, innate sensing, and sebocyte lipid metabolism. Barrier modulators such as FLG and OVOL1, first described in atopic dermatitis, further shape inflammatory thresholds across acne and related phenotypes. Together, these findings position genetics not as an abstract catalogue of risk alleles but as a map of tractable biological pathways. They provide the substrate for patient-stratified interventions ranging from JAK inhibitors in AA, to endocrine versus morphogenesis-targeted strategies in AGA, to lipid- and barrier-directed therapies in acne, while also informing cosmetic practices focused on barrier repair, sebaceous balance, and follicle health. Full article

Background: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia driven by the PML/RARα fusion protein. Standard treatment with all-trans retinoic acid (ATRA) combined with chemotherapy is effective, but resistance and adverse effects remain significant challenges. Melittin, the primary peptide component of bee venom, has demonstrated potent anticancer activity across multiple leukemia subtypes through mitochondrial-dependent mechanisms. Building upon this established evidence, we investigated melittin’s therapeutic potential in APL to address the specific clinical challenge of ATRA resistance. Methods: The cytotoxic and pro-apoptotic effects of melittin were studied on the human APL cell line HL-60. Cell viability was assessed using MTT and trypan blue assays. Mitochondrial membrane potential (MMP) was measured with JC-1 staining. Apoptosis was quantified using Annexin V/propidium iodide flow cytometry, caspase-3/7 activity assays, and real-time PCR analysis of apoptosis-related genes (BCL-2, BAX, APAF-1, CASP-3, CASP-8, CASP-9). Results: Melittin reduced HL-60 cell viability in a dose- and time-dependent manner, with significant decreases after 24 and 48 h. MMP analysis revealed mitochondrial depolarization, and Annexin V staining confirmed the induction of apoptosis. Caspase-3/7 activity increased markedly, supporting activation of the intrinsic apoptotic pathway. Gene expression profiling revealed downregulation of the anti-apoptotic BCL-2 and upregulation of the pro-apoptotic BAX, APAF1, and CASP3. At the same time, CASP8 and CASP9 showed no significant changes, suggesting a predominant involvement of the intrinsic pathway. Conclusions: These findings confirm and extend established evidence by demonstrating that melittin’s mitochondrial apoptotic mechanism is consistently active in promyelocytic HL-60 model (PML/RARα-negative). This retinoid-independent mechanism suggests potential therapeutic utility for ATRA-resistant cases or as a complementary strategy in APL treatment. However, selectivity validation in non-cancerous hematopoietic cells represents an important future research priority. Full article

Retinoic acid (RA) binds RA (RAR) and Retinoid X (RXR) receptors to elicit biological effects by regulating transcription. RA is also known to have non-canonical activities mediated, primarily, by cellular retinoic acid-binding protein 1 (CRABP1) which forms protein complexes named “CRABP1 signalosomes” to regulate cytosolic signaling independent of RARs/RXRs. This review focuses on therapeutic applications in neurodegeneration by targeting CRABP1 signalosomes including CRABP1–MAPK, CRABP1–CaMKII, CRABP1–eIF2α, and others recently identified from our proteomic studies. The mouse Crabp1 gene is regulated by various epigenetic factors and is important for the health of multiple cell types including motor neurons (MNs). In humans, CRABP1 gene expression is reduced in ALS- and SMA-patient MNs. RA is a therapeutic agent for leukemias and dermatological disorders and is being investigated for managing neurodegenerative diseases, but its therapeutic effects are accompanied by RAR-mediated toxic effects. We have uncovered a novel class of synthetic retinoids that bind CRABP1 without acting on RARs, circumventing RAR-mediated toxic effects. These first-generation CRABP1-selective compounds C3, C4, and C32 target CRABP1–MAPK and/or CRABP1–CaMKII signalosomes. This knowledge, together with emerging structural information, sheds lights on the strategies in designing next-generation CRABP1-signalosome-selective retinoids for the management of neurodegenerative diseases. Full article

Objectives: Retinitis pigmentosa (RP) is commonly initiated by rod photoreceptor degeneration due to genetic mutations, followed by secondary cone loss and progressive blindness. Preserving rod function during the earlier stages of RP is a key therapeutic goal, as rod survival supports cone maintenance and delays vision loss. In this study, we investigated the therapeutic potential of transient knockdown of retinoid-related orphan receptor beta (RORB) using a cell-penetrating asymmetric small interfering RNA (cp-asiRORB) in Rho^P23H mice, a model of autosomal dominant RP. While the role of RORB in the adult retina remains unclear, prior studies of related nuclear receptors suggest potential involvement in proteostasis. Based on this, we hypothesized that persistent RORB expression may influence photoreceptor homeostasis under degenerative stress. Methods: We first optimized the cp-asiRORB design to enhance gene silencing and cellular uptake. In vitro studies were conducted under proteotoxic stress. In vivo studies involved intravitreal administration of cp-asiRORB in Rho^P23H mice. Furthermore, single-cell RNA sequencing of rod photoreceptors was performed. Results: In vitro studies demonstrated that RORB knockdown improved cell viability, reduced apoptosis, and diminished aggresome formation under proteotoxic stress. Intravitreal administration of cp-asiRORB in Rho^P23H mice effectively reduced RORB expression in the retina, leading to improved photoreceptor survival and preserved visual function. Single-cell RNA sequencing revealed upregulation of proteasomal subunit genes in cp-asiRORB-treated eyes, indicating enhanced proteostasis. Conclusions: Together, these results demonstrate that transient suppression of RORB mitigates proteotoxic stress and slows RP progression, highlighting a novel RNAi-based therapeutic strategy for retinal degeneration. Full article

Erythema ab igne (EAI), also known as “hot water bottle rash” or “toasted skin syndrome”, is a benign cutaneous condition caused by chronic exposure to low-level infrared heat. It typically begins as transient erythema and evolves into a reticulated brown pigmentation with telangiectasias. A skin biopsy, ideally taken from the central area of the hyperpigmented lesion, is recommended to exclude differential diagnoses. Although usually benign, EAI has been associated with rare malignant transformations, supported only by low-level evidence. Elimination of the heat source is essential, and topical treatments such as hydroquinone or retinoids may be considered, while agents like 5-fluorouracil or imiquimod are reserved for dysplastic lesions. Women with endometriosis frequently use heating devices to alleviate dysmenorrhea and chronic pelvic pain. However, prolonged or inappropriate heat application can lead to chronic thermal injury, including EAI, and may delay medical consultation. While controlled trials confirm short-term analgesic efficacy of heat therapy, extrapolating these findings to unrestricted home use without standardized safety recommendations can be misleading. EAI illustrates the broader impact of chronic pain in endometriosis, linking cutaneous manifestations with neuroplastic alterations and psychiatric comorbidities. A nuanced approach combining patient education on safe use of heat, close dermatologic monitoring, and multidisciplinary pain management is warranted. Full article

The yak is a large ruminant that lives in the high-altitude and hypoxic environment of the Qinghai–Tibet Plateau in China and typically exhibits limited reproductive capacity, posing a significant challenge to the advancement of animal husbandry in the region. Retinoid X receptors (RXRs), as an important member of the NR superfamily, play a key role in the regulation of reproductive hormone synthesis, follicular development, and embryo implantation. However, there is still a lack of systematic research on the expression characteristics and potential functions of RXRs in the yak’s reproductive system. This study characterized RXR expression in ovarian, uterine, and oviductal tissues from three yaks per reproductive phase (follicular, luteal, and pregnancy). Using Quantitative Real-Time PCR Experiments (RT-qPCR), Western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF), we analyzed RXR mRNA and protein expression and localization. RXR expression varied significantly (p ≤ 0.05), peaking in ovaries during the follicular phase, oviducts during the luteal phase, and uteri during pregnancy. RXRs were localized in ovarian granulosa and theca cells, oviductal epithelium, and uterine endometrial glands, with dynamic nuclear–cytoplasmic shifts. These findings suggest RXRs regulate key reproductive processes in yaks, offering insights on improving fertility in high-altitude environments. Full article

Intracellular lipid-binding proteins (iLBPs) are key mediators of intracellular transport for fatty acids and retinoids, functioning as lipid chaperones. Beyond lipid transport, iLBPs regulate signalling pathways, gene expression, oxidative balance, and inflammation. Furthermore, they are increasingly recognised for their involvement in gastrointestinal (GI) diseases, especially in cancer. iLBPs are classified into four different subfamilies, each displaying distinct tissue distributions and ligand preferences. Functional roles are context-dependent, for instance, CRABP2 may act as either tumour suppressor or promoter, and FABP4 exhibits metabolic state dependent effects. These proteins also influence drug resistance, immune evasion, and lipid-mediated signalling. Overall, iLBPs extend beyond lipid trafficking to intersect with oncogenic pathways, influence cell fate, and affect treatment response, highlighting their potential as biomarkers and therapeutic targets in GI oncology. Full article