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Limb buds develop as bilateral outgrowths of the lateral plate mesoderm and are patterned along three axes. Current models of proximal to distal patterning of early amniote limb buds suggest that two signals, a distal organizing signal from the apical epithelial ridge (AER, Fgfs) and an opposing proximal (retinoic acid [RA]) act early on pattern this axis.Transcriptional analysis of stage 51 Xenopus laevis hindlimb buds sectioned along the proximal-distal axis showed that the distal region is distinct from the rest of the limb. Expression of capn8.3, a novel calpain, was located in cells immediately flanking the AER. The Wnt antagonist Dkk1 was AER-specific in Xenopus limbs. Two transcription factors, sall1 and zic5, were expressed in distal mesenchyme. Zic5 has no described association with limb development. We also describe expression of two proximal genes, gata5 and tnn, not previously associated with limb development. Differentially expressed genes were associated with Fgf, Wnt, and RA signaling as well as differential cell adhesion and proliferation.We identify new candidate genes for early proximodistal limb patterning. Our analysis of RA-regulated genes supports a role for transient RA gradients in early limb bud in proximal-to-distal patterning in this anamniote model organism.

Melasma is a chronic and acquired pigmentary condition that primarily affects women and undermines patient satisfaction and confidence. Melasma mostly affects females, accounting for 90% of all cases. It affects people of all races, particularly those with skin types IV and V who live in areas with lots of UV radiation. According to the studies, Melasma lesions are seen throughout the face in centrofacial, malar, and mandibular patterns. Melasma lesions on the forehead, cheeks, nose, upper lip, and/or chin are the most prevalent centrofacial pattern. Melasma lesions can also be detected along the periorbital area, especially in Asian people. Melasma is notably resistant to treatment, with many patients experiencing only temporary relief and relapses. Combining therapies that target numerous pathologic components, including photodamage, inflammation, aberrant vascularity, and abnormal pigmentation, generally results in the most dramatic therapeutic improvements. Treatments for dark circles include topical depigmenting medicines like hydroquinone, kojic acid, azelaic acid, and topical retinoic acid, and physical treatments such as chemical peels, surgical adjustments, and laser therapy. The objective of therapy should be to figure out what is causing the hyperpigmentation and what is contributing to it. This article provides an overview of melasma therapies and the efficacy of methimazole and cysteamine for melasma therapy.

The vitamin A derivative all-trans retinoic acid (RA) regulates early stages of inner ear development. As the early disruption of the RA pathway results in profound mispatterning of the developing inner ear, this confounds analyses of specific roles in later stages. Therefore, we used the temporal-specific exposure of all-trans RA or diethylaminobenzaldehyde to evaluate RA functions in late otic development.Perturbing late RA signaling causes behavioral defects analogous to those expected in larvae suffering from vestibular dysfunction. These larvae also demonstrate malformations of the semi-circular canals, as visualized through (a) use of the transgenic strain nkhspdmc12a, a fluorescent reporter expressed in otic epithelium; and (b) injection of the fluorescent lipophilic dye DiI. We also noted the altered expression of genes encoding ECM proteins or modifying enzymes. Other malformations of the inner ear observed in our work include the loss or reduced size of the utricular and saccular otoliths, suggesting a role for RA in otolith maintenance.Our work has identified a previously undescribed late phase of RA activity in otic development, demonstrating that vestibular defects observed in human patients in relation to perturbed RA signaling are not solely due to its early disruption in otic development.

Using H9C2 cardiomyoblasts, we have shown that all-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A, affects mitochondrial dynamics and functions. The low dose (10 nM) ATRA stimulates the expression of nuclear retinoid receptors and induces mechanisms that are protective against severe local damage caused by laser irradiation at the mitochondrial level. These changes include increased density of the mitochondrial network, higher number of mitochondrial junctions, and enhanced mitochondrial velocity. Moreover, the treated cells had lower basal level of reactive oxygen species (ROS) and could maintain mitochondrial potential (ΔΨ

The pathogenesis of inflammatory skin diseases is associated with the abnormal activity of keratinocytes and immune cells infiltrate. Vitamin D(3) deficiency can correlate with the increased incidence, severity, and duration of inflammatory skin disorders. The exact mechanism on how vitamin D(3) influences inflammatory skin diseases still requires clarification. However, it can be associated with the disturbances in transmembrane glycoprotein - LRP2/megalin, which is implicated in vitamin D(3) transport to the cell, and defects in vitamin D-signaling through the nuclear receptors. Therefore, by using immunohistochemistry, we analyzed the expression of LRP2/megalin, VDR, RORα and RORγ in allergic contact dermatitis, lichen simplex chronicus, sarcoidosis and psoriasis in comparison to the normal skin. We observed decreased expression of LRP2/megalin in all inflammatory lesions in comparison to the normal skin. Significant differences were also noticed in VDR, RORα and RORγ levels between inflammatory lesions and normal skin. Our research indicates disturbed expression of LRP2/megalin, VDR, RORα and RORγ in inflammatory skin lesions in comparison to normal skin. Therefore, we suggest that changes in the activity of these proteins may play role in pathogenesis of inflammatory skin disorders. Furthermore, we suggest that LRP2/megalin, VDR, RORα and RORy may serve as targets in therapy of these diseases.

Acute myeloid leukaemia (AML) is a biologically heterogeneous disease with an overall poor prognosis; thus, novel therapeutic approaches are needed. Our previous studies showed that 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a new derivative of all-trans retinoic acid (ATRA), could induce AML cell differentiation and cycle arrest. The current study aimed to determine the potential pharmacological mechanisms of ATPR therapies against AML. Our findings showed that E2A was overexpressed in AML specimens and cell lines, and mediate AML development by inactivating the P53 pathway. The findings indicated that E2A expression and activity decreased with ATPR treatment. Furthermore, we determined that E2A inhibition could enhance the effect of ATPR-induced AML cell differentiation and cycle arrest, whereas E2A overexpression could reverse this effect, suggesting that the E2A gene plays a crucial role in AML. We identified P53 and c-Myc were downstream pathways and targets for silencing E2A cells using RNA sequencing, which are involved in the progression of AML. Taken together, these results confirmed that ATPR inhibited the expression of E2A/c-Myc, which led to the activation of the P53 pathway, and induced cell differentiation and cycle arrest in AML.

Alcohol abuse reduces hepatic vitamin A (retinoids), reductions that are associated with progression of alcohol liver disease (ALD). Restoring hepatic retinoids through diet is contraindicated in ALD due to the negative effects of alcohol on retinoid metabolism. There are currently no drugs that can both mitigate alcohol-driven hepatic retinoid losses and progression of ALD. Using a mouse model of alcohol intake, we examined if an agonist for the retinoic acid (RA) receptor β2 (RARβ2), AC261066 (AC261) could prevent alcohol-driven hepatic retinoid losses and protect against ALD. Our results show that mice co-treated with AC261 and alcohol displayed mitigation of ALD, including reduced macro, and microvesicular steatosis, and liver damage. Alcohol intake led to increases in hepatic centrilobular levels of ALDH1A1, a rate-limiting enzyme in RA synthesis, and co-localization of ALDH1A1 with the alcohol-metabolizing enzyme CYP2E1, and 4-HNE, a marker of oxidative stress; expression of these targets was abrogated in mice co-treated with AC261 and alcohol. By RNA sequencing technology, we found that AC261 treatments opposed alcohol modulation of 68 transcripts involved in canonical retinoid metabolism. Alcohol modulation of these transcripts, including CES1D, CES1G, RBP1, RDH10, and CYP26A1, collectively favor hepatic retinoid hydrolysis and catabolism. However, despite this, co-administration of AC261 with alcohol did not mitigate alcohol-mediated depletions of hepatic retinoids, but did reduce alcohol-driven increases in serum retinol. Our data show that AC261 protected mice against ALD, even though AC261 did not prevent alcohol-mediated reductions in hepatic retinoids. These data warrant further studies of the anti-ALD properties of AC261.

Degeneration and apoptotic death of the photoreceptor cell-layer of retina are a major cause of irreversible blindness in the development era. The stem cell replacement therapy is one of the strategies for the retinal repairing. In addition, exogenous signals critically contribute to the direction of lineage decisions that causes the fate-restricted photoreceptor progenitors from stem cell progeny in culture. It has been found that epidermal growth factor (EGF), taurine, and retinoic acid (RA) initially act in the instructive as well as lineage-restricted way in the progenitor lineage for producing neuroretinal cells or photoreceptor like cells from stem cell. The study aims to investigate the effect of RA and taurine in differentiation of the human bone marrow stem cell into cone photoreceptors cells and retinal ganglion cells. Mesenchymal stem cell was derived from human bone marrow of the term delivery. Therefore, the cultured cells have been treated with Dulbecco's modified Eagle's medium (DMEM)/high glucose (H+ ). After the four-cell passage, basal medium was replaced with DMEM/F12 complemented with 50 μmol/L taurine, RA (1 µM) and EGF (1 µg/ml). Subsequently cellular change morphology was detected following 7 and 14 days. Then, gene expression of neuroretinal and photoreceptor cell biomarkers (CRX, OTX2, PKC-α, recoverin, and Rho) were examined by quantitative polymerase chain reaction (Q-PCR). Also, cells were cultured, fixed, and then immunocytochemical analyzed. Primary antibodies included CRX and Rho. Cellular morphology demonstrated spindle elongated morphology. Taurine alone and combination of RA upregulate neuroretinal and photoreceptor cell biomarkers in messenger RNA and protein levels but along with EGF have not significant effect. Our data showed that taurine combination with RA can differentiate bone marrow mesenchymal stem cells into neuroretinal or photoreceptor like cells in vitro that can offer an attractive treatment ground for transplantation in the cell-replacement therapy for some forms of the retinal degeneration.

BACKGROUND The survival of patients with acute promyelocytic leukemia (APL) has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, because of the complexity of the initial management, early mortality (EM) remains a major contributor to treatment failure. It is less known whether advances in treatment, urgent access to specialized care, and broad availability of ATRA/ATO have reduced EM in the last 2 decades. Furthermore, the influence of sociodemographic factors on the risk of EM also remains unclear. METHODS This study used the Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on the rates of EM and overall survival (OS) in patients with APL diagnosed between 1992 and 2015. RESULTS In all, 2224 cases were identified (895 who were younger than 40 years and 1329 who were 40 years old or older); 47.9% had a county-level median household income of $59,630 or higher, 49.0% belonged to counties where more than 31% of adults held at least a bachelor's degree, and 86.0% resided in urban areas. The rate of EM declined from 31.5% in 1992-1995 to 15.9% in 2012-2015 for all patients. It improved for patients younger than 40 years (27.4% in 1992-1995 vs 5.4% in 2012-2015; P < .001) and for patients 40 years old or older but not to the same extent (35.2% in 1992-1995 vs 22.2% in 2012-2015; P = .02). Importantly, improvements in EM were not seen among patients residing in rural areas, with the rate remaining higher than 20% in 2012-2015. The 3-year OS rate was 49.2% for patients with APL diagnosed in 1992-1995 and 76.4% for patients diagnosed in 2012-2015. CONCLUSIONS These findings confirm consistent improvements in EM and OS for patients with APL and point to the challenge of further extending these improvements in EM rates to older patients and to those living in rural areas.

Background Alteration of commensal microbiota is highly correlated with the prevalence of allergic reactions to food in the gastrointestinal tract. The mechanisms by which microbiota modulate food allergen sensitization in the mucosal site are not fully understood. Methods We generate DCs specific knockout of retinoic acid receptor α (Rara) gene mice (DC KO Rara) to evaluate food sensitization. The bile acid-activated retinoic acid response was evaluated by flow cytometry, real-time RT-PCR and Illumina transcriptome sequencing. The global effect of Abx treatment on BA profiles in the mucosal lymph tissue mLN in mice was examined by UPLC-MS analysis. Results In this study, we demonstrate that depletion of commensal gut bacteria leads to enhanced retinoic acid (RA) signaling in mucosal dendritic cells (DCs). RA signaling in DCs is required for the production of food allergen-specific IgE and IgG1. Antibiotics induced an enlarged bile acid (BA) pool, and dysregulated BA profiles contributed to enhanced RA signaling in mucosal DCs. BA-activated RA signaling promoted DC upregulation of interferon I signature, RA signature, OX40L, and PDL2, which may lead to T helper 2 differentiation of CD4+ T cells. BA-activated RA signaling involved the farnesoid X receptor and RA receptor α (RARa) interaction. Depletion of bile acid reduces food allergen specific IgE and IgG1 levels in mice. Conclusion Our research unveils a mechanism of food sensitization modulated by BA-RA signaling in DCs, which suggests a potential new approach for the intervention of food allergic reactions.

HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all‐trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA‐induced differentiation in APL. We observed higher (5‐ to 40‐fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short‐hairpin RNA led to cell death in ATRA‐sensitive NB4 and resistant NB4‐R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4‐R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis‐specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4‐R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4‐R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance., ERK inhibition or heterogeneous nuclear ribonucleoprotein K knockdown decreases cell viability, increases all‐trans retinoic acid (ATRA)‐induced differentiation in acute promyelocytic leukemia (APL) ATRA‐resistant cells, and promotes SET cleavage. Furthermore, findings obtained using a xenograft NB4‐R2 tumor model suggest the use of U0126, a meiosis‐specific serine/threonine protein kinase/ERK inhibitor, combined with arsenic trioxide as a potential therapeutic strategy to be explored for APL. Our study highlights crosstalk between ERK/hnRNPK/SET in APL and ATRA‐induced differentiation.

The molecular targeted drug ATRA demands a suitable carrier that delivers to the cancer site due to its poor bioavailability and drug resistance. ATRA, being a lipid with carboxylic acid, has been nano‐formulated as a cationic lipo‐ATRA with DOTAP:cholesterol:ATRA (5:4:1) and its pH‐responsive release, intracellular drug accumulation, and anticancer effect on human lung cancer (A549) cell line analysed. The analysis of the physicochemical characteristics of the developed lipo‐ATRA (0.8 µmol) revealed that the size of 231 ± 2.35 d.nm had a zeta potential of 6.4 ± 1.19 and an encapsulation efficiency of 93.7 ± 3.6%. The ATRA release from lipo‐ATRA in vitro was significantly (p ≤ 0.05) higher at acidic pH 6 compared to pH 7.5. The intracellular uptake of ATRA into lipo‐ATRA‐treated A549 cells was seven‐fold higher (0.007 ± 0.001 mg/ml) while only three‐fold uptake was observed in free ATRA treatment (0.003 ± 0.002 mg/ml). The lipo‐ATRA treatment caused a highly significant (p ≤ 0.001) decrease in percent cell viability at 48 h when compared with the free ATRA treatment. Overall, the results proved that the developed lipo‐ATRA has suitable physicochemical properties with enhanced ATRA release at acidic pH, while maintaining stability at physiologic pH and temperature. This resulted in an increased ATRA uptake by lung cancer cells with enhanced treatment efficiency. Hence, it is concluded that DOTAP lipo‐ATRA is a suitable carrier for ATRA delivery to solid cancer cells.

Background The ZBTB16‐RARA fusion gene, resulting from the reciprocal translocation between ZBTB16 on chromosome 11 and RARA genes on chromosome 17 [t(11;17)(q23;q21)], is rarely observed in acute myeloid leukemia (AML), and accounts for about 1% of retinoic acid receptor‐α (RARA) rearrangements. AML with this rare translocation shows unusual bone marrow (BM) morphology, with intermediate aspects between acute promyelocytic leukemia (APL) and AML with maturation. Patients may have a high incidence of disseminated intravascular coagulation at diagnosis, are poorly responsive to all‐trans retinoic acid (ATRA) and arsenic tryoxyde, and are reported to have an overall poor prognosis. Aims The mutational profile of ZBTB16‐RARA rearranged AML has not been described so far. Materials and methods We performed targeted next‐generation sequencing of 24 myeloid genes in BM diagnostic samples from seven ZBTB16‐RARA+AML, 103 non‐RARA rearranged AML, and 46 APL. The seven ZBTB16‐RARA‐positive patients were then screened for additional mutations using whole exome sequencing (n = 3) or an extended cancer panel including 409 genes (n = 4). Results ZBTB16‐RARA+AML showed an intermediate number of mutations per patient and involvement of different genes, as compared to APL and other AMLs. In particular, we found a high incidence of ARID1A mutations in ZBTB16‐RARA+AML (five of seven cases, 71%). Mutations in ARID2 and SMARCA4, other tumor suppressor genes also belonging to SWI/SNF chromatin remodeling complexes, were also identified in one case (14%). Discussion and conclusion Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16‐RARA+AMLs, where they may support the peculiar disease phenotype., This is the first report showing the mutational landscape of the rare ZBTB16‐RARA rearranged acute myeloid leukemia (AML). We identified a high frequency of ARID1A mutations, suggesting the involvement of the SWI/SNF chromatin remodeling complexes in the clinical presentation, acute promyelocytic leukemia‐like morphology and all‐trans retinoic acid/arsenic trioxide treatment resistance of ZBTB16‐RARA rearranged AMLs.

All‐trans‐retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell‐specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations. atRA is synthesized through two enzymatic steps from retinol, but it is unknown if the loss of retinoid stores is associated with changes in atRA formation and which cell types contribute to the metabolic changes. The aim of this study was to determine if the vitamin A metabolic flux is perturbed in acute liver injury, and if changes in atRA concentrations are associated with HSC activation and collagen expression. At basal levels, HSC and Kupffer cells expressed key genes involved in vitamin A metabolism, whereas after acute liver injury, complex changes to the metabolic flux were observed in liver slices. These changes include a reproducible spike in atRA tissue concentrations, decreased retinyl ester and atRA formation rate, and time‐dependent changes to the expression of metabolizing enzymes. Kinetic simulations suggested that oxidoreductases are important in determining retinoid metabolic flux after liver injury. These early changes precede HSC activation and upregulation of profibrogenic gene expression, which were inversely correlated with atRA tissue concentrations, suggesting that HSC and Kupffer cells are key cells involved in changes to vitamin A metabolic flux and signaling after liver injury. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin A is metabolized in the liver for storage as retinyl esters in hepatic stellate cell (HSCs) or to all‐trans‐retinoic acid (atRA), an active metabolite with antifibrogenic properties. Following chronic liver injury, vitamin A metabolic flux is perturbed, and HSC activation leads to diminished retinoid stores. WHAT QUESTION DID THIS STUDY ADDRESS? Do changes in the expression of vitamin A metabolizing enzymes explain changes in atRA concentrations and the regulation of fibrosis following acute liver injury? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In healthy liver, both HSC and Kupffer cells may mediate vitamin A homeostasis. Following acute liver injury, complex changes in metabolizing enzyme expression/activity alter the metabolic flux of retinoids, resulting in a transient peak in atRA concentrations. The atRA concentrations are inversely correlated with profibrogenic gene expression, HSC activation, and collagen deposition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Improved understanding of altered vitamin A metabolic flux in acute liver injury may provide insight into cell‐specific contributions to vitamin A loss and lead to novel interventions in liver fibrosis.

The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.

Background Retinol binding protein 1 (Rbp1) acts as an intracellular regulator of vitamin A metabolism and retinoid transport. In mice, Rbp1 deficiency decreases the capacity of hepatic stellate cells to take up all-trans retinol and sustain retinyl ester stores. Furthermore, Rbp1 is crucial for visual capacity. Although the function of Rbp1 has been studied in the mature eye, its role during early anterior neural development has not yet been investigated in detail. Results We showed that rbp1 is expressed in the eye, anterior neural crest cells (NCCs) and prosencephalon of the South African clawed frog Xenopus laevis. Rbp1 knockdown led to defects in eye formation, including microphthalmia and disorganized retinal lamination, and to disturbed induction and differentiation of the eye field, as shown by decreased rax and pax6 expression. Furthermore, it resulted in reduced rax expression in the prosencephalon and affected cranial cartilage. Rbp1 inhibition also interfered with neural crest induction and migration, as shown by twist and slug. Moreover, it led to a significant reduction of the all-trans retinoic acid target gene pitx2 in NCC-derived periocular mesenchyme. The Rbp1 knockdown phenotypes were rescued by pitx2 RNA co-injection. Conclusion Rbp1 is crucial for the development of the anterior neural tissue.

Accumulation of evidence suggests that the gut microbiome, its specific metabolites, and differentially expressed proteins (DEPs) are related to non-small cell lung cancer (NSCLC) pathogenesis. We now report the influences of the gut microbiota, metabolites, and DEPs on the mediation of NSCLC's chronic inflammation and immune dysregulation.We conducted 16S ribosomal RNA sequencing for the gut microbiome in healthy volunteers and NSCLC patients. Liquid chromatography-mass spectrometry (LC-MS) analysis was employed to explore differences between metabolites and DEPs in serum samples. Additionally, LC-MS-based metabolomic analysis was conducted in 40 NSCLC tissues and 40 adjacent tissues. The omics data were separately analysed and integrated by using Spearman's correlation coefficient. Then, faecal microbiota transplantation (FMT) assay was used to assess the effects of the gut microbiome and specific metabolites in mice.Faecal microbiome analysis revealed gut microflora dysbiosis in NSCLC patients with Prevotella, Gemmiger, and Roseburia significantly upregulated at the genus level. Then, we identified that nervonic acid/all-trans-retinoic acid level was negatively related to Prevotella. Additionally, a total of core 8 DEPs were selected in the proteome analysis, which mainly participated in the production of IL-8 and NF-κB pathways. CRP, LBP, and CD14 were identified as potential biomarkers for NSCLC. Transplantation of faecal microbiota from patients with NSCLC or Prevotella copri-colonized recipient in mice resulted in inflammation and immune dysregulation. In turn, nervonic acid/all-trans-retinoic acid treatment improved the phenotype of C57BL/6 mice bearing P. copri-treated Lewis lung cancer (LLC).Overall, these results pointed out that P. copri-nervonic acid/all-trans-retinoic acid axis may contribute to the pathogenesis of NSCLC.

This study aimed to clarify the regulation and mechanism of meiotic initiation in FGSC development.FGSCs were induced to differentiate into meiosis in differentiation medium. RNA sequencing was performed to analysis the difference of transcription level. High-through chromosome conformation capture sequencing (Hi-C) was performed to analysis changes of three-dimensional chromatin structure. Chromosome conformation capture further confirmed a spatial chromatin loop. ChIP-qPCR and dual luciferase reporter were used to test the interaction between Stimulated by retinoic acid gene 8 (STRA8) protein and Trip13 promoter.Compared with FGSCs, the average diameter of STRA8-positive germ cells increased from 13 μm to 16.8 μm. Furthermore, there were 4788 differentially expressed genes between the two cell stages; Meiosis and chromatin structure-associated terms were significantly enriched. Additionally, Hi-C results showed that FGSCs underwent A/B compartment switching (switch rate was 29.81%), the number of topologically associating domains (TADs) increasing, the average size of TADs decreasing, and chromatin loop changes at genome region of Trip13 from undifferentiated stage to meiosis-initiation stage. Furthermore, we validated that Trip13 promoter contacted distal enhancer to form spatial chromatin loop and STRA8 could bind Trip13 promoter to promote gene expression.FGSCs underwent chromatin structure remodelling from undifferentiated stage to meiosis-initiation stage, which facilitated STRA8 binding to Trip13 promoter and promoting its expression.

We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure-activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t-butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription-promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα-selectivity of Am80 (3) and Am555S (4). The SARs presented here should be helpful in the development of subtype-selective retinoids, and in particular 24 c might be a promising lead compound for new RARγ ligands.

A little number of current autophagy inhibitors may have beneficial effects on the acute myeloid leukemia (AML) patients. However, there is a strong need to figure out which settings should be activated or inhibited in autophagy pathway to prevail drug resistance and also to improve current treatment options in leukemia. Therefore, this study aimed to compare the effects of well-known inhibitors of autophagy (as 3-MA, BafA1, and HCQ) in leukemia KG-1 and HL-60 cells exposed to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Cell proliferation and cytotoxicity of cells were examined by MTT assay. Autophagy was studied by evaluating the development of acidic vesicular organelles, and the autophagosomes formation was investigated by acridine orange staining and transmission electron microscopy. Moreover, the gene and protein expressions levels of autophagy markers (ATGs, p62/SQSTM1, and LC-3B) were also performed by qPCR and western blotting, respectively. The rate of apoptosis and cell cycle were evaluated using flow cytometry. We compared the cytotoxic and apoptotic effects of ATO and/or ATRA in both cell lines and demonstrated that some autophagy markers upregulated in this context. Also, it was shown that autophagy blockers HCQ and/or BafA1 could potentiate the cytotoxic effects of ATO/ATRA, which were more pronounced in KG-1 cells compared to HL-60 cell line. This study showed the involvement of autophagy during the treatment of KG-1 and HL-60 cells by ATO/ATRA. This study proposed that therapy of ATO/ATRA in combination with HCQ can be considered as a more effective strategy for targeting leukemic KG-1 cells.

BACKGROUND AND PURPOSE: All‐trans retinoic acid (ATRA) is a vitamin A metabolite, important in the developing and mature brain. Pre‐injury ATRA administration ameliorates ischaemic brain insults in rodents. This study examined the effects of post‐traumatic ATRA treatment in experimental traumatic brain injury (TBI). EXPERIMENTAL APPROACH: Male adult mice were subjected to the controlled cortical impact model of TBI or sham procedure and killed at 7 or 30 days post‐injury (dpi). ATRA (10 mg kg−1, i.p.) was given immediately after the injury and 1, 2 and 3 dpi. Neurological function and sensorimotor coordination were evaluated. Brains were processed for (immuno‐) histological, mRNA and protein analyses (qPCR and western blot). KEY RESULTS: ATRA treatment reduced brain lesion size, reactive astrogliosis and axonal injury at 7 dpi, and hippocampal granule cell layer (GCL) integrity was protected at 7 and 30 dpi, independent of cell proliferation in neurogenic niches and blood–brain barrier damage. Neurological and motor deficits over time and the brain tissue loss at 30 dpi were not affected by ATRA treatment. ATRA decreased gene expression of markers for damage‐associated molecular pattern (HMGB1), apoptosis (caspase‐3 and Bax), activated microglia (TSPO), and reactive astrogliosis (GFAP, SerpinA3N) at 7 dpi and a subset of markers at 30 dpi (TSPO, GFAP). CONCLUSION AND IMPLICATIONS: In experimental TBI, post‐traumatic ATRA administration exerted brain protective effects, including long‐term protection of GCL integrity, but did not affect neurological and motor deficits. Further investigations are required to optimize treatment regimens to enhance ATRA's brain protective effects and improve outcomes.

Previous studies have found that alpha‐fetoprotein (AFP) can promote the proliferation of hepatoma cells and accelerate the progression of hepatocellular carcinoma (HCC). However, the exact mechanism of action remains unclear. Recent bioinformatics studies have predicted the possible interaction between AFP and retinoic acid receptors (RARs). Thus, the purpose of this study was to investigate the molecular mechanism through which AFP promotes tumour cell proliferation by interfering with the RA‐RAR signal pathway. Our data indicated that AFP could significantly promote the proliferation and weaken ATRA‐induced apoptosis of hepatoma cells. Besides, cytoplasmic AFP interacts with RAR, disrupting its entrance into the nucleus, which in turn affects the expression of the Bcl‐2 gene. In addition, knockdown of AFP in HepG2 cells was synchronously associated with an incremental increase of RAR binding to DNA, as well as down‐regulation of Bcl‐2; the opposite effect was observed in AFP gene‐transfected HLE cells. Moreover, a similar effect of AFP was detected in tumour tissues with high serum AFP, but not in adjacent non‐cancerous liver tissues, or HCC tissues with low serum AFP levels. These results indicate that AFP acts as signalling molecule and prevents RAR from entering into the nucleus by interacting with RAR, thereby promoting the expression of Bcl‐2. Our data reveal a novel mechanism through which AFP regulates Bcl‐2 expression and further suggest that AFP may be used as a novel target for treating HCC.

BACKGROUND To investigate whether folic acid (FA) can rescue anorectal malformations (ARMs) induced by all-trans retinoic acid (ATRA) in rats. METHODS Pregnant Sprague-Dawley rats were randomly divided into three groups. In the model group, rats were administered ATRA (110 mg/kg) by gavage on the 10th day of gestation (E10.5). Rats in the rescue group were administered FA (40 mg/kg) by gavage 0.5 and 12 hr after treatment with ATRA. All fetuses were harvested on E20.5 using cesarean section and examined for ARMs. We recorded the weight, body length, tail length, and associated malformations of all the embryos. Hematoxylin and eosin staining was used to analyze the histopathology of the fetuses. RESULTS Control rats did not show any abnormalities. ARMs, tail deformities (less than half of normal length), and neural tube defects were found in 97.98% (97/99), 92.93% (92/99), and 32.32% (32/99) of the rats in the model group, respectively. The incidence of ARMs and tail deformities were 48.57% (51/105) and 35.24% (37/105), respectively, in the rescue rats; no neural tube defects were observed in these rats. The weight, body length, and tail length of the fetal rats in the rescue group were more than those in the model group, but less than those in the control group. CONCLUSION Taken together, FA rescued ARMs induced by ATRA in rats. Thus, FA may reduce the incidence of associated malformations and improve the growth and development of fetal rats.

BACKGROUND Chemical peelings are used on a wide scale in cosmetic field including melasma treatment. They often provide clinicians with flexibility in tailoring treatments according to patient needs and satisfaction. OBJECTIVE To evaluate safety and efficacy of chemical peeling as single agents in melasma management in patients with darker skin types. METHODS We included randomized controlled trials (RCTs) and prospective studies that assessed efficacy and safety of chemical peeling as single agents for facial melasma. An online bibliographic search was conducted, and data were extracted from the included studies. RESULTS Ten RCTs and three prospective comparative studies (No. of patients = 478) were included. The overall effect estimate favored Glycolic acid (GA) over trichloroacetic acid peel in terms of melasma activity and severity index (MASI) (mean difference [MD] -1.89, 95% CI [-3.26, -0.52], P = .007). On the other hand, the overall effect estimates did not favor GA over tretinoin (MD 0.53, 95% CI [-0.46, 1.52], P = .3), vitamin C iontophoresis (MD 1.50, 95% CI [-0.50, 3.50], P = .14), and amino fruit acid (MD 0.39, 95% CI [-0.64, 1.42], P = .46) in terms of MASI. The overall effect estimates favored trichloroacetic acid peel (MD -5.30, 95% CI [-6.41, -4.19], P

Background Retinoids are widely used in different cosmetic products because of general improvement of skin appearance. However, retinoid concentration in cosmetics is restricted, and one particular form-retinoic acid, is banned in cosmetics due to safety reasons. Aims Within this study, we aimed to examine the quality of a considerable number of commercial retinoid cosmetic products in terms of their content and labeling, including also screening for the presence of retinoic acid. Methods An appropriate analytical methodology, based on HPLC-UV for the simultaneous determination of common retinoids, along with a screening method for retinoic acid, was developed and validated. Structural identity confirmation of the newer retinoid-hydroxypinacolone retinoate, was performed by LC-MS. Results Retinol and retinyl palmitate were most often found, in concentrations mostly below 0.3%, and up to 1.3% retinol equivalents. Determined contents deviated significantly from the quantitatively declared ones in seven products (0%-130%). In more than half of the tested products, inconsistencies between the contained and labeled retinoid were noticed. These products, as well as 14 additional anti-age cosmetics, were screened for retinoic acid, which was detected in two products. Conclusions The obtained results from retinoids assay in commercial cosmetic products confirmed that the proposed method is appropriate for their routine analysis. The presence of retinoic acid in two products and determined retinoid contents above the Scientific Committee on Consumer Safety recommendations in 20% of the tested cosmetics reveal the need for their more strict regulation and quality control to ensure their efficacy and safety.

Retinoic acid (RA) is an active derivative of vitamin A and a key regulator of immune cell function. In dendritic cells (DCs), RA drives the expression of CD103 (integrin α (E)), a functionally relevant DC subset marker. In this study, we analyzed the cell type specificity and the molecular mechanisms involved in RA‐induced CD103 expression. We show that RA treatment caused a significant up‐regulation of CD103 in differentiated monocyte‐derived DCs and blood DCs, but not in differentiated monocyte‐derived macrophages or T cells. DC treatment with an RA receptor α (RARα) agonist led to an increase in CD103 expression similar to that in RA treatment, whereas RARA gene silencing with small interfering RNA blocked RA‐induced up‐regulation of CD103, pointing to a major role of RARα in the regulation of CD103 expression. To elucidate RA‐induced signaling downstream of RARα, we used Western blot analysis of RA‐treated DCs and showed a significant increase of p38 mitogen‐activated protein kinase (MAPK) phosphorylation. In addition, DCs cultured with RA and a p38 MAPK inhibitor had a significantly reduced expression of CD103 compared with DCs cultured with RA only, indicating that p38 MAPK is involved in CD103 regulation. In summary, these findings suggest that the RA‐induced expression of CD103 is specific to DCs, is mediated primarily through RARα and involves p38 MAPK signaling.

Background Melasma is a chronic recalcitrant pigmentary disorder whose treatment frustrates physician and patient alike. Tranexamic acid, a plasmin inhibitor, has demonstrated hypopigmenting properties. Aim To compare safety and efficacy of combination of oral tranexamic acid (TXA) and topical fluocinolone-based combination cream (FbTC) with that of topical FbTC alone in melasma. Method One hundred and eighty patients patients of facial melasma of either sex attending dermatology OPD were screened. Consenting 130 participants were randomized into two blinded groups with 65 patients in each group. Group A patients received oral tranexamic acid 250 mg and oral ranitidine 150 mg twice daily and applied a triple combination cream containing fluocinolone acetonide 0.01%, tretinoin 0.05% and hydroquinone 2% once daily, and Group B was asked to take placebo tablets (calcium lactate and multivitamin) and apply the cream only for 12 weeks. Response was evaluated using modified melasma area severity index (mMASI) and graded mMASI improvement at 4th, 8th and 12th weeks, and at 24th week for recurrence. Data were analysed using SPSS software. Results Results were analysed in 120 patients who completed the study with 61 and 59 patients in group A and B, respectively. Demographic profile was equally distributed in both the groups. In group A, 13.1% patients showed marked improvement (>75%) in mMASI as compared to group B (1.7%) at 4th week. By 12th week, 65.6% patients had marked improvement in group A in contrast to only 27.1% in group B. At 24th week, group A (65.6%) had sustained improvement as compared to group B (11.9%) despite stopping treatment; all of which were statistically significant. Recurrence observed was 18.03% in group A vs. 64.4% in group B at 24th week. Conclusion Oral tranexamic acid is definitely a boon to the armamentarium of melasma management and should be used as an adjuvant to fluocinolone-based triple combination cream for a faster, sustained improvement and to prevent recurrence.

Background Teratogenic potential has been linked to various industrial compounds. Methoxyacetic acid (MAA) is a primary metabolite of the widely used organic solvent and plasticizer, methoxyethanol and dimethoxyethyl phthalate, respectively. Studies using model animals have shown that MAA acts as the proximate teratogen that causes various malformations in developing embryos. Nonetheless, the molecular mechanisms by which MAA exerts its teratogenic effects are not fully understood. Methods Gastruloids of mouse P19C5 pluripotent stem cells, which recapitulate axial elongation morphogenesis of gastrulation-stage embryos, were explored as an in vitro model to investigate the teratogenic action of MAA. Morphometric parameters of gastruloids were measured to evaluate the morphogenetic effect, and transcript levels of various developmental regulator genes were examined to assess the impact on gene expression patterns. The effects of MAA on the level of retinoic acid (RA) signaling and histone deacetylase activity were also measured. Results MAA reduced axial elongation of gastruloids at concentrations comparable to the teratogenic plasma level (5 mM) in vivo. MAA at 4 mM significantly altered the expression profiles of developmental regulator genes. In particular, it upregulated the RA signaling target genes. The concomitant suppression of RA signaling using a pharmacological agent alleviated the morphogenetic effect of MAA. MAA at 4 mM also significantly reduced the activity of purified histone deacetylase protein. Conclusions MAA impaired axial elongation morphogenesis in a RA signaling-dependent manner in mouse gastruloids, possibly through the inhibition of histone deacetylase.

BACKGROUND The role of arsenic trioxide (As2 O3 ) in the maintenance of first complete remission (CR1) in acute promyelocytic leukemia (APL) is unclear. METHODS A total of 129 consecutive adult patients with APL of all risk categories who achieved CR1 with conventional induction (all-trans retinoic acid [ATRA]/daunorubicin) and consolidation (daunorubicin/cytarabine [induction daunorubicin and consolidation omitted for age ≥70 years]) underwent maintenance comprising ATRA (45 mg/m2 /day), oral As2 O3 (10 mg/day), and ascorbic acid (1 g/day) (AAA) for 2 weeks every 2 months for 2 years. RESULTS Over a 17-year period from August 1, 2002, to July 31, 2019, 63 men and 66 women (median age, 46 years [range, 18-82 years]) received AAA maintenance, which was already completed in 117 patients. At a median follow-up of 100 months (range, 8-215 months), 17 patients (13%) developed first relapse (R1) (hematologic, n = 14; molecular, n = 3) after a median of 19 months (range, 7-96 months) from CR1. Two R1 patients had concomitant central nervous system (CNS) involvement. All patients achieved CR2 with oral As2 O3 -based salvage. Five patients had a subsequent relapse and died. Eight patients died of unrelated causes while still in CR1. The 5-year and 10-year rates of relapse-free survival (RFS) were 89% and 85%, respectively. The 5-year and 10-year rates of overall survival (OS) were 94% and 87%, respectively. Multivariate analysis showed that inferior RFS was associated with FLT3-ITD (P = .005) and CNS involvement on presentation (P = .004), and inferior OS was associated with therapy-related APL (P = .03), FLT3-ITD (P = .03), and relapse (P = .03). The safety profile was favorable, with no grade 3/4 organ toxicities. CONCLUSION CR1 maintenance with AAA is safe and results in favorable long-term survival in patients with APL.

Mesenchymal stem cells (MSCs) have multilineage differentiation potential and can transform into neuron cells under an appropriate environment. Retinoic acid (RA) facilitates the neuronal differentiation of MSCs. We found that RXRα, a RA receptor, was significantly upregulated in RA-induced process. Here, we show that RXRα collaborated with myocardin-related transcription factor-A (MRTF-A) to strongly promote the RA-induced process as evidenced by the increase in NF-H expression and NF-H promoter transcription activity. Our studies reveal that RXRα and MRTF-A exhibit protein interactions and synergistically inhibit the MSCs apoptosis by enhancing the P21 expression. Furthermore, RXRα and MRTF-A can activate P21 transcription by affecting the formation of the MRTF-A/RXRα/RARE complex. These findings reveal the important roles of RXRα and MRTF-A signaling in RA-induced neural-like differentiation of MSCs and describe a new mechanism underlying the synergistic interaction of RXRα and MRTF-A.

AIMS: Retinoic acid‐related orphan receptor γ (RORγ), a master regulator of T‐helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17‐driven diseases. This first‐in‐human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS: We conducted a phase I, randomized, single‐blind, placebo‐controlled, two‐part, first‐in‐human study with healthy subjects receiving single (4–238 mg) or multiple (12–100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high‐calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo‐stimulated interleukin (IL)‐17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS: Eighty‐three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half‐life of 13–16 hours. Both the area under the concentration‐time curve (AUC) and maximum concentration (C (max)) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71–0.84 and 0.72–0.88 for AUC and C (max), respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half‐life. AZD0284 showed dose‐dependent reduction of ex vivo‐stimulated IL‐17A release after both single and multiple doses. No significant safety concerns were identified in the study. CONCLUSIONS: AZD0284 was well tolerated, rapidly and dose‐dependently absorbed, and reduced stimulated IL‐17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.

Background The increase in the pigmentation of skin grafts during the healing process is a cosmetic problem. There are a variety of medical and surgical treatment options for skin graft darkening. Aims The aim of this study was to investigate the effects of topical hydroquinone, tretinoin, and betamethasone application on hyperpigmentation of skin grafts. Methods A skin defect was created on the backs of 17 Long-Evans rats, and a 2 × 2 cm split-thickness skin graft was sutured. After 15 days, eight rats in the treatment group were treated with application of hydroquinone, tretinoin, and betamethasone cream, while nine rats in the control group were not treated. Visual evaluation was performed on days 45 and 75 using the Melasma Severity Scale (MSS), and histological evaluation was performed on day 75 using S100 and Masson Fontana (MF) staining. The Mann-Whitney U test was used for statistical analysis. Results Mean MSS values of the treatment group on days 45 were significantly lower compared to the control group (P = .036). On day 75, the mean MSS score of the treatment group was also lower; however, the difference was not statistically significant (P = .302). Histological evaluation of S100 and MF staining scores of the treatment group showed fewer melanocytes and fewer pigments in epidermis (P = .009 and P = .002, respectively). Conclusions This study showed that topical application of hydroquinone, tretinoin, and betamethasone reduced the hyperpigmentation, number of melanocytes, and melanin pigment intensity that developed on the rat skin graft models. Clinical studies are needed to assess whether a similar effect could be observed with human skin grafts.

This study aimed to investigate the biological impacts and possible mechanisms of a novel lncRNA, LncSIK1, in AML progression and retinoic acid-regulated AML cell development.The expression pattern of LncSIK1 was evaluated by qPCR and fluorescence in situ hybridization. CCK-8 assay, immunofluorescence, Wright-Giemsa staining, flow cytometry and Western blotting were performed to assess cell proliferation and differentiation. Bioluminescence imaging and HE staining were used to detect AML progression in vivo. RNA or chromatin immunoprecipitation assays were conducted to measure the interaction of E2F1 and LncSIK1 or the LC3 and DRAM promoters. Autophagy was measured by transmission electron microscopy and Western blotting.LncSIK1 was silenced in bone marrow mononuclear cells from AML patients compared with those from healthy donors. LncSIK1 strengthened the effect of retinoic acid in inducing cell differentiation and inhibiting cell proliferation in AML cells. Moreover, the silencing of LncSIK1 was critical to maintaining AML leukaemogenesis, as LncSIK1 enhancement retarded AML progression in vivo. Mechanistically, in NB4 cells, LncSIK1 recruited the E2F1 protein to the promoters of LC3 and DRAM and induced autophagy-dependent degradation of the oncoprotein PML-RARa. However, LncSIK1 blocked E2F1 expression and the E2F1-mediated transcription of LC3 and DRAM, thereby relieving aggressive autophagy in Molm13 cells.Taken together, these data indicated that LncSIK1 was an important regulator of AML development through regulating the E2F1/autophagy signalling pathway.

Supporting information is available online at https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.31983#support-information-section . From 2023 Hepatology is published by Wolters Kluwer Health on behalf of the American Association for the Study of Liver Diseases. Background and Aims Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and thus the key downstream effectors of this pathway remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signalling in ICC that could open new therapeutic opportunities. Approach and Results Using loss- and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumours, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 via all-trans retinoic acid (ATRA), an FDA-approved drug, impairs the growth of both cultured and xenografted ICC cells. Conclusions Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation via PIN1 inhibition. AMMF - The Cholangiocarcinoma Charity. Grant Number: 2014; Foundation for Liver Research. Grant Number: Start-up 2010; Guts UK. Grant Number: DGO2019_02; Rosetrees Trust. Grant Number: M894; Brunel University London. Grant Number: BRIEF LBL348; Blood Cancer UK. Grant Number: 17014; Faculty of Medicine and Health, University of Leeds. Grant Number: 250 ; Great Minds University Academic Fellowship 2016.

The pluripotent mouse embryonal carcinoma cell line P19 is widely used as a model for research on all-trans-retinoid acid (RA)-induced neuronal differentiation; however, the signaling pathways involved in this process remain unclear. This study aimed to reveal the molecular mechanism underlying the RA-induced neuronal differentiation of P19 cells. Real-time quantitative polymerase chain reaction and Western blot analysis were used to determine the expression of neuronal-specific markers, whereas flow cytometry was used to analyze cell cycle and cell apoptosis. The expression profiles of messenger RNAs (mRNAs) in RA-induced neuronal differentiation of P19 cells were analyzed using high-throughput sequencing, and the functions of differentially expressed mRNAs (DEMs) were determined by bioinformatics analysis. RA induced an increase in both class III β-tubulin (TUBB3) and neurofilament medium (NEFM) mRNA expression, indicating that RA successfully induces neuronal differentiation of P19 cells. Cell apoptosis was not affected; however, cell proliferation decreased. We found 4117 DEMs, which were enriched in the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, Wnt signaling pathway, and cell cycle. Particularly, a few DEMs could be identified in the PI3K/Akt signaling pathway networks, such as PI3K, Akt, glycogen synthase kinase-3β (GSK3β), cyclin-dependent kinase 4 (CDK4), P21, and Bax. RA significantly increased the protein expression of PI3K, Akt, phosphorylated Akt, GSK3β, phosphorylated GSK3β, CDK4, and P21, but it reduced Bax protein expression. The Akt inhibitor affected the increase of TUBB3 and NEFM mRNA expression in RA-induced P19 cells. The molecular mechanism underlying the RA-induced neuronal differentiation of P19 cells is potentially involved in the PI3K/Akt/GSK3β signaling pathway. The decreased cell proliferation ability of neuronally differentiated P19 cells could be associated with the expression of cell cycle proteins.

BACKGROUND Alitretinoin is a systemic retinoid licensed for use in adult patients suffering from chronic hand eczema recalcitrant to potent topical steroids. Experience with its use in childhood is lacking. OBJECTIVES To report on the efficacy and safety of alitretinoin treatment in a cohort of children and adolescents with chronic hand eczema (CHE) and other inflammatory skin diseases. METHODS We performed a retrospective chart review of all consecutive patients under the age of 18 years treated with alitretinoin at our paediatric skin centre. Physician's Global Assessment (PGA) was used as the primary outcome measure. RESULTS Thirteen children (9 girls and 4 boys) were enrolled in this study. The median age at start of treatment with alitretinoin was 11.5 years (range 5.8-15.8 years). Nine children were diagnosed with CHE, two with severe atopic dermatitis (AD), and two with inherited ichthyosis [netherton syndrome (NS), autosomal recessive congenital ichthyosis (ARCI)]. Moderate to excellent response (PGA decrease of ≥1 point) was observed in 7 (78%) of the nine patients with CHE, one of the two patients with extensive AD and in the one patient with ARCI. In the remaining four subjects, no convincing effect was documented. Tolerability was overall very good. The most common adverse event was headache in 10 patients (77%) during the initiation of treatment, leading to interruption of therapy in one subject. CONCLUSIONS Alitretinoin seems to be highly effective and safe for the treatment of paediatric CHE and should thus be considered in children with refractory disease under topical therapy. Larger studies are required to corroborate these findings.

All-trans retinoic acid (ATRA) has been extensively studied as an integrating component of endocrine functions in the pancreas. The aim of this study was to evaluate the effects of ATRA on physiopathological biomarkers in an experimental model of rat with type 1 diabetes induced by alloxan (T1D). Twenty Wistar rats were divided equally into five groups, each receiving a different treatment: a control group (CG), a diabetic group without T1D treatment, a diabetic group treated with ATRA, a diabetic group supplemented with vitamin E (VIT E), and a group that was given olive oil (V). The administration of ATRA for 17 days produced a significant reduction in weight and glucose levels, compared to the T1D and VIT E groups. The evaluation of total antioxidant capacity (TAC) and lipoperoxidation showed no relevant difference among the groups. The results of the histological analysis showed similarities both in the size and in the number of islets of Langerhans in the pancreatic tissue obtained from the ATRA group and the CG. ATRA displayed a significant reduction of glycemic values in diabetic rats. Ultrastructurally, ß-cells, acinar, and ductal cells restored their normal appearance. ATRA can contribute to the recovery of pancreatic damage due to alloxan induction. It seems that the antioxidant effect of ATRA is not responsible for the differences observed.

Background The objective of this study was to conduct the first systematic evaluation of the long-term economic impact of arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) for the treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) from the perspective of the Chinese health care system. Methods On the basis of clinical data from a randomized phase 3 trial, a time-dependent Markov model with 4 health states (complete remission, relapse or treatment failure, post-treatment failure, and death) was used to evaluate the incremental costs per quality-adjusted life-year (QALY) gained from the ATO plus ATRA regimen compared with the ATRA plus chemotherapy (CT) regimen over a 30-year period. All costs were adjusted to 2018 levels based on the Chinese Consumer Price Index. Both costs and health outcomes were discounted by 3% annually. One-way sensitivity analysis and probability sensitivity analysis were performed. Results Compared with the ATRA plus CT strategy, the ATO plus ATRA strategy was associated with 1.38 additional QALYs gained and $392.05 (estimated in 2018 US dollars) in incremental costs per patient over 30 years. Consequently, the incremental cost-effectiveness ratio was $284.02 per QALY gained, which was far below the Chinese willingness-to-pay threshold of $29,306 per QALY gained. Sensitivity analyses demonstrated the robustness of these results. Conclusions From the perspective of the Chinese health care system, the ATO plus ATRA strategy is cost-effective for patients with newly diagnosed APL compared with the ATRA plus CT strategy. Therefore, the authors strongly suggest that China's health authorities choose the former strategy for these patients, whether for the elderly or for young people.

Background Retinoic acid (RA) is a synthetic vitamin derivative. It exerts toxic and teratogenic effects on the development of embryonic organs in dose- and time-dependent manners in mice. Curcumin is a compound obtained from rhizomes of turmeric (Curcuma longa) and has protective effects on teratogenic agents. The current study examined the effects of curcumin on embryos treated with RA. Methods A total of 24 female NMRI mice (8-week-old pregnant mice) were investigated in the current study. All of them were treated for 10 days during days 15 to 50 of pregnancy. In the first group, the animals were fed with normal diets (control); in the second group, with 60 mg/kg all- trans RA; in the third group, with 10 mg/kg curcumin; and in the fourth group, with RA and curcumin in their diets. The animals were killed by cervical dislocation at the 18th day of pregnancy and embryos were separated from the uteruses. The embryo weight and crown rump (CR) length were measured, and the SPSS software was used to analyze data. Results There was a significant increase in the lengths of CR and weights of embryos after using curcumin, but RA had no effect on the length of CR and weight of embryos at a dose of 60 mg/kg. Morphometric assay of liver tissue was performed, and data analysis indicated that there were significant differences between groups in terms of morphometric parameters of liver tissue. Therefore, RA increased the cell number and sinusoid diameter and decreased the cell areas in the embryonic liver tissue. However, curcumin decreased these side effects of RA on the embryonic liver tissue. Conclusion The results indicated that curcumin could decrease the toxic and teratogenic effects of RA in mouse embryos.

Background Retinoic acid (RA) plays an important role in organogenesis as a paracrine signal through transcriptional regulation of an increasing number of known downstream target genes, regulating cell proliferation, and differentiation. During the development of the inner ear, RA directly governs the morphogenesis and specification processes mainly by means of RA-synthesizing retinaldehyde dehydrogenase (RALDH) enzymes. Interestingly, CYP1B1, a cytochrome P450 enzyme, is able to mediate the oxidative metabolisms also leading to RA generation, its expression patterns being associated with many known sites of RA activity. Results This study describes for the first time the presence of CYP1B1 in the developing chick inner ear as a RALDH-independent RA-signaling mechanism. In our in situ hybridization analysis, Cyp1B1 expression was first observed in a domain located in the ventromedial wall of the otic anlagen, being included within the rostralmost aspect of an Fgf10-positive pan-sensory domain. As development proceeds, all identified Fgf10-positive areas were Cyp1B1 stained, with all sensory patches being Cyp1B1 positive at stage HH34, except the macula neglecta. Conclusions Cyp1B1 expression suggested a possible contribution of CYP1B1 action in the specification of the lateral-to-medial and dorsal-to-ventral axes of the developing chick inner ear.

The effects of chalcone and butein on the induction of the superoxide anion (O2 - )-generating system were studied in U937 cells by all-trans retinoic acid (RA). The chalcone skeleton, a common structural motif in them, significantly enhanced the transcription of gp91-phox in an epigenetic manner. In contrast, chalcone and butein showed opposite effects on the induction of the O2 - -generating activity by RA and the expression of gp91-phox protein. Chalcone inhibited, whereas butein promoted, the induction of O2 - -generating activity by RA and the expression of gp91-phox protein. These data raise the possibility that modification of the chalcone skeleton could produce more effective differentiation-promoting agents.

BACKGROUND Aquatic species in several clades possess cement glands producing adhesive secretions of various strengths. In vertebrates, transient adhesive organs have been extensively studied in Xenopus laevis, other anurans, and in several fish species. However, the development of these structures is not fully understood. RESULTS Here, we report on the development and functional morphology of the adhesive gland of a giant danio species, Devario malabaricus. We found that the gland is localized on the larval head, is composed of goblet-like secretory cells framed by basal, bordering, and intercalated apical epithelial cells, and is innervated by the trigeminal ganglion. The gland allows nonswimming larvae to adhere to various substrates. Its secretory cells differentiate by 12 hours postfertilization and begin to disappear in the second week of life. Exogenous retinoic acid disrupts the gland's patterning. More importantly, the single mature gland emerges from fusion of two differentiated secretory cells fields; this fusion is dependent on nonmuscle myosin II function. CONCLUSIONS Taken together, our studies provide the first documentation of the embryonic development, structure, and function of the adhesive apparatus of a danioninae. To our knowledge, this is also the first report of a cement gland arising from convergence of two bilateral fields.

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.

Purpose The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin. Methods Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure. Results We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations. Conclusions Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies.