Role Of All-trans Retinoic Acid Research Articles

All-Trans Retinoic Acid-Induced Cell Surface Heat Shock Protein 90 Mediates Tau Protein Internalization and Degradation in Human Microglia.

This study investigates the role of all-trans retinoic acid (ATRA) in modulating the expression of heat shock protein 90 (Hsp90) and its influence on the uptake and degradation of tau proteins in immortalized human microglia cells. We demonstrate that ATRA significantly upregulates Hsp90 expression in a concentration-dependent manner, enhancing both extracellular and intracellular Hsp90 levels. Our results show that ATRA-treated cells exhibit increased tau protein uptake via caveolae/raft-dependent endocytosis pathways. This uptake is mediated by surface Hsp90, as evidenced by the inhibition of tau internalization using an extracellular Hsp90-selective inhibitor. Further, we establish that the exogenously added full-sized monomeric tau proteins bind to Hsp90. The study also reveals that ATRA-enhanced tau uptake is followed by effective degradation through both lysosomal and proteasomal pathways. We observed a significant reduction in intracellular tau levels in ATRA-treated cells, which was reversed by lysosome or proteasome inhibitors, suggesting the involvement of both degradation pathways. Our findings highlight the potential therapeutic role of ATRA in Alzheimer's disease and related tauopathies. By enhancing Hsp90 expression and facilitating tau degradation, ATRA could contribute to the clearance of pathological tau proteins, offering a promising strategy for mitigating neurodegeneration. This research underscores the need for further exploration into the molecular mechanisms of tau protein internalization and degradation, which could provide valuable insights into the treatment of neurodegenerative diseases.

All-trans retinoic acid alleviates collagen-induced arthritis and promotes intestinal homeostasis

All-trans retinoic acid (ATRA) has emerged as a promising adjunctive treatment for rheumatoid arthritis. However, the mechanism by which ATRA mitigates arthritis remains unclear. In this study, we aimed to explore ATRA alleviation of arthritis and the role of ATRA in regulating intestinal homeostasis. Thus, we established a collagen-induced arthritis (CIA) model in Wistar rats. After 6 weeks of ATRA treatment, the arthritis index of CIA rats decreased, synovial inflammation was alleviated, and the disruption of Th17/Treg differentiation in peripheral blood was reversed. Additionally, the Th17/Treg ratio in the mesenteric lymph nodes decreased and the expression of Foxp3 mRNA increased and that of IL-17 mRNA decreased in the colon and ileum. Microscopically, we observed reduced intestinal inflammation. Transmission electron microscopy revealed that ATRA could repair tight junctions, which was accompanied by an increase in the expression of Claudin-1, Occludin and ZO-1. Moreover, ATRA regulated the composition of the gut microbiota, as was characterized based on the reduced abundance of Desulfobacterota and the increased abundance of Lactobacillus. In conclusion, ATRA demonstrates the potential to alleviate arthritis in CIA rats, which might be correlated with modulating the gut microbiota and regulating the intestinal immune response. Our findings provide novel insights into ATRA-mediated alleviation of arthritis.

Regulation of Tyrosinase Gene Expression by Retinoic Acid Pathway in the Pacific Oyster Crassostrea gigas.

Retinoic acid (RA) plays important roles in various biological processes in animals. RA signaling is mediated by two types of nuclear receptors, namely retinoic acid receptor (RAR) and retinoid x receptor (RXR), which regulate gene expression by binding to retinoic acid response elements (RAREs) in the promoters of target genes. Here, we explored the effect of all-trans retinoic acid (ATRA) on the Pacific oyster Crassostera gigas at the transcriptome level. A total of 586 differentially expressed genes (DEGs) were identified in C. gigas upon ATRA treatment, with 309 upregulated and 277 downregulated genes. Bioinformatic analysis revealed that ATRA affects the development, metabolism, reproduction, and immunity of C. gigas. Four tyrosinase genes, including Tyr-6 (LOC105331209), Tyr-9 (LOC105346503), Tyr-20 (LOC105330910), and Tyr-12 (LOC105320007), were upregulated by ATRA according to the transcriptome data and these results were verified by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. In addition, increased expression of Tyr (a melanin-related TYR gene in C. gigas) and Tyr-2 were detected after ATRA treatment. The yeast one-hybrid assay revealed the DNA-binding activity of the RA receptors CgRAR and CgRXR, and the interaction of CgRAR with RARE present in the Tyr-2 promoter. These results provide evidence for the further studies on the role of ATRA and the mechanism of RA receptors in mollusks.

The immunomodulatory role of all-trans retinoic acid in tumor microenvironment.

Retinoids are essential nutrients for human beings. Among them, all-trans retinoic acid (ATRA), considered one of the most active metabolites, plays important roles in multiple biological processes. ATRA regulates the transcription of target genes by interacting with nuclear receptors bonded to retinoic acid response elements (RAREs). Besides its differentiation-inducing effect in the treatment of acute promyelocytic leukemia and some solid tumor types, its immunoregulatory role in tumor microenvironment (TME) has attracted considerable attention. ATRA not only substantially abrogates the immunosuppressive effect of tumor-infiltrating myeloid-derived suppressor cells but also activates the anti-tumor effect of CD8 + T cells. Notably, the combination of ATRA with other therapeutic approaches, including immune checkpoint inhibitors (ICIs), tumor vaccines, and chemotherapy, has been extensively investigated in a variety of tumor models and clinical trials. In this review, we summarize the current understanding of the role of ATRA in cancer immunology and immunotherapy, dissect the underlying mechanisms of ATRA-mediated activation or differentiation of different types of immune cells, and explore the potential clinical significance of ATRA-based cancer therapy.

The Role of ATRA, Natural Ligand of Retinoic Acid Receptors, on EMT-Related Proteins in Breast Cancer: Minireview.

The knowledge of the structure, function, and abundance of specific proteins related to the EMT process is essential for developing effective diagnostic approaches to cancer with the perspective of diagnosis and therapy of malignancies. The success of all-trans retinoic acid (ATRA) differentiation therapy in acute promyelocytic leukemia has stimulated studies in the treatment of other tumors with ATRA. This review will discuss the impact of ATRA use, emphasizing epithelial-mesenchymal transition (EMT) proteins in breast cancer, of which metastasis and recurrence are major causes of death.

Protective role of All Trans Retinoic Acid on B16F10 melanoma cell line metastasis in C57BL/6 mice by enhancing RAR- β protein and homeostasis maintenance

ABSTRACT Lung cancer is the leading cancer according to the World Health Organization (WHO), resulting in highest death rate worldwide due to the high level of metastasis. Hence, the drugs that protect from metastasis either as an adjuvant or a primary therapeutic agent may help to reduce the death rate. In this study, All Trans Retinoic Acid (ATRA) was tested for its action against metastatic lodging of B16F10 melanoma cells in the lung and liver of the C57BL/6 mouse model. Serum, lung and liver were evaluated biochemically for the cancer associated changes. Metastatic cancer development was confirmed by tumor nodule formation and histopathological analysis. RAR-β protein expression was analyzed by immunohistochemistry and histopathology. ATRA treated mice showed a percentage of inhibition on metastatic tumor growth in lung and liver and a corresponding protection against pathological changes in these organs. Cholesterol and γ-Glutamyl Transferase (GGT) levels found in cancer induced mice were reduced in the ATRA treated group. As compared to the normal group, lung tissue from cell line induced cancer control group had less RAR-β protein expression while the ATRA treated group showed enhanced RAR-β protein expression. This indicates that the anti-metastasis effects of ATRA might have shown the induction of RAR-β expression and subsequent molecular signaling pathways to regulate the homeostasis of biochemical changes. This study demonstrated the capability of ATRA to prevent the establishment of metastasis by the melanoma cell line into the lung and liver of experimental mice.

Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome: Presented in part at the meeting of the American Society of Hematology, San Diego, CA, December 1997.

AbstractWe examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1450/μL at diagnosis and was 31 000/μL (range, 6800-72 000/μL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)

Arsenic induced epigenetic changes and relevance to treatment of acute promyelocytic leukemia and beyond

Epigenetic alterations regulate gene expression without changes in the DNA sequence. It is well-demonstrated that aberrant epigenetic changes contribute to the leukemogenesis of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) is one of the most common drugs used in the frontline treatment of APL that act through targeting and destabilizing the PML/RARα oncofusion protein. ATO together with all-trans retinoic acid (ATRA) lead to durable remission of more than 90% non-high-risk APL patients, turning APL treatment into a paradigm of oncoprotein targeted cure. Although relapse and drug resistance in APL are yet to be resolved in the clinic, epigenetic machineries might hold the key to address this issue. Further, ATO also showed promising anticancer activities against a variety of malignancies, but its application is particularly restricted due to limited understanding of the mechanism. Thus, a thorough understanding of epigenetic mechanism behind anti-leukemic effects of ATO would benefit the development of ATO-based anticancer strategy. Role of ATRA on APL associated epigenetic alterations has been extensively studied and reviewed. Recently, accumulating evidence suggest that ATO also induces some epigenetic changes that might favor APL eradication. In this article, we comprehensively discuss arsenic induced epigenetic changes and its relevance in APL treatment and beyond, so as to provide novel insights into overcoming arsenic resistance in APL and promote application of this drug to other malignancies.

All-Trans Retinoic Acid (atRA) effectively improves liver steatosis in a rabbit model of high fat induced liver steatosis

The aim of this study is to evaluate the role of All-Trans Retinoic Acid, the biologically active metabolite of retinoids, on liver steatosis in a rabbit model of high fat induced lever steatosis. 30 male rabbits were evaluated in 5 groups: group 1 treated with normal diet, group 2–5 included rabbit’s groups 2 to 5 were fed on high cholesterol diet, group 2 received no drugs, group 3 received atorvastatin, group 4 received atRA, and group 5 received both the drugs. the liver was obtained for histopathological evaluation. oral administration of atRA, atorvastatin or their combination significantly decreased serum levels of total cholesterol, LDL, AST and ALT. atorvastatin slightly but atRA remarkably decreased liver steatosis where the difference was significant. atRA group showed the highest TAC and the lowest PCO concentrations. atRA can be effective in reducing liver steatosis and its antioxidant effect plays a crucial role in the process.HighlightsNon-alcoholic fatty liver disease (NAFLD) is the most common disorder of the liver in general population and is strongly associated with metabolic risk factors including hyperlipidaemia, obesity and diabetes.atRA is very effective in reducing liver steatosis and its antioxidant effect plays a crucial role in the process.we suggest focussing on other aspects of liver steatosis such as carbohydrate metabolism and insulin resistance in order to find better ways of controlling and treating liver steatosis.

Effects of ATRA on diabetic rats with renal ischemia-reperfusion injury.

Purpose To explore the role of all-trans retinoic acid (ATRA) in renal ischemia/reperfusion injury of diabetic rats.Methods Sixty adult male rats were randomly divided into 6 groups, including sham group (S group), ischemia-reperfusion group (I/R group), ischemia-reperfusion+ATRA group (A group), diabetic group (D group), diabetic ischemia-reperfusion group (DI/R group), diabetic ischemia-reperfusion +ATRA group (DA group). The levels of creatinine (Cr), cystatin C (Cys-C) and β2-microglobulin (β2-MG) were measured. Morphology of renal tissue was observed under light microscope.Results DJ-1, Nrf2, HO-1 and caspase-3 were detected by western blot. DJ-1, Nrf2, HO-1 and caspase-3 in I/R group, D group and DI/R group was higher than that in S group. Compared with I/R group, Nrf2 and HO-1 in A group was decreased, but caspase-3 was increased. However, Nrf2 in DA group was higher than that in DI/R group, HO-1 and caspase-3 in DA group were lower than that in DI/R group. Compared with group S, Cr, Cys-C and β2-MG in I/R group, A group, D group, and DI/R group were higher. Whereas the levels of Cr, Cys-C, β2-MG and renal injury score in DA group were lower than those in DI/R group.Conclusion ATRA has a protective effect on renal ischemia-reperfusion injury in diabetic rats, maybe relating to DJ/Nrf2 pathway.

Protective role of all-trans retinoic acid (ATRA) against hypoxia-induced malignant potential of non-invasive breast tumor derived cells

BackgroundThe presence of hypoxic areas is common in all breast lesions but no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, particularly by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women.MethodsBy using a DCIS-derived cell line, we evaluated the effects of low oxygen availability on malignant features of non-invasive breast tumor cells and the possible role of all-trans retinoic acid (ATRA), a well-known anti-leukemic drug, in counteracting the effects of hypoxia. The involvement of the β2 isoform of PI-PLC (PLC-β2), an ATRA target in myeloid leukemia cells, was also investigated by specific modulation of the protein expression.ResultsWe demonstrated that moderate hypoxia is sufficient to induce, in DCIS-derived cells, motility, epithelial-to-mesenchymal transition (EMT) and expression of the stem cell marker CD133, indicative of their increased malignant potential.Administration of ATRA supports the epithelial-like phenotype of DCIS-derived cells cultured under hypoxia and keeps down the number of CD133 positive cells, abrogating almost completely the effects of poor oxygenation. We also found that the mechanisms triggered by ATRA in non-invasive breast tumor cells cultured under hypoxia is in part mediated by PLC-β2, responsible to counteract the effects of low oxygen availability on CD133 levels.ConclusionsOverall, we assigned to hypoxia a role in increasing the malignant potential of DCIS-derived cells and we identified in ATRA, currently used in treatment of acute promyelocytic leukemia (APL), an agonist potentially useful in preventing malignant progression of non-invasive breast lesions showing hypoxic areas.

High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase\xa0(ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of cancer stem cell (CSC) markers, and high ALDH1 expression has been related to drug resistance and facilitated tumor growth. In this study, we investigated the potential involvement of nuclear factor erythroid 2-like 2 (NFE2L2/NRF2) in CSC-like properties of ALDH-high ovarian CSCs. Our experimental system, ALDH1A1-high (ALDH-H) subpopulation, was isolated and stabilized using doxorubicin-resistant ovarian cancer A2780 cells. ALDH-H exerted CSC-like properties such as drug resistance, colony/sphere formation, and enhanced tumor growth along with high levels of CSCs markers compared to ALDH1A1-low (ALDH-L). Levels of NRF2 and subsequent target genes substantially increased in ALDH-H cells, and the increase in ALDH1A1 and p62 was associated with NRF2 upregulation. ALDH1A1-silencing blocked increases in NRF2, drug efflux transporters, and p62, along with CSC markers in ALDH-H cells. The inhibition of p62, which was elevated in ALDH-H, suppressed NRF2 activation. High NRF2 level was confirmed in the ALDH1-high subpopulation from colon cancer HCT116 cells. The functional implication of NRF2 activation in ovarian CSCs was verified by two experimental approaches. First, CSC-like properties such as high CSC markers, chemoresistance, colony/sphere formation, and tumor growth were significantly inhibited by NRF2-silencing in ALDH-H cells. Second, all-trans retinoic acid (ATRA) suppressed ALDH1 expression, inhibiting NRF2 activation, which led to the attenuation of CSC-like properties in ALDH-H cells but not in ALDH-L cells. These results provide insight into the molecular basis of the ALDH1A1-mediated development of CSC-like properties such as stress/treatment resistance, and further suggest the therapeutic potential of ATRA in ALDH-high ovarian CSCs.

Fabrication of all-trans-retinoic acid-loaded biocompatible precirol: A strategy for escaping dose-dependent side effects of doxorubicin

BackgroundDrug delivery-based nanoparticles have been emerged to be an alternative and efficient approach to cancer therapy compared to conventional systems. Here, we investigated the role of all-trans retinoic acid (ATRA) formulated with precirol in increasing doxorubicin (Dox) induced apoptosis and cell cycle arrest in MDA-MB-231 breast cancer cells. MethodsATRA-loaded Nano structured lipid carriers (NLCs) were evaluated in terms of particle size, zeta potential, Fourier transforms infrared spectroscopy (FTIR), cell internalization, and scanning electron microscope (SEM). To understand molecular mechanism of apoptosis and cell cycle progression flow cytometric assay, MTT and DAPI staining was applied. Real time (RT)-PCR analysis was employed to investigate the expression of apoptosis related genes, including Survivin, Bcl-2 and Bax. ResultsThe optimized ATRA formulation exhibited average particle size of 95±5nm with nearly narrow size distribution. The IC50 values for ATRA and doxorubicin were 48±0.4μM and 0.81±0.02μM, respectively. ATRA-loaded NLCs decreased percentage of cell proliferation from 51±7.2% to 36±4.1% (p <0.05). Co-treatment of the MDA-MB-231 cells with ATRA formulation and doxorubicin caused two-fold increase in the percentage of apoptosis (p<0.05). The results from gene expression exhibited a significant decrease in survivin along with increase at Bax mRNA levels accompanied by a slight increase in Bax/Bcl-2 ratio. ConclusionOur results propose that ATRA encapsulated in precirol as a biocompatible compound augments the efficacy of Dox in cancer therapy.

All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling

The role of all-trans retinoic acid (ATRA) in pulmonary fibrosis is relatively unknown, although this metabolite modulates cell differentiation, proliferation, and development. We aimed to evaluate the role of ATRA in bleomycin-induced pulmonary fibrosis, and whether the mechanism involves EphA2-EphrinA1 and PI3K-Akt signaling. We evaluated three groups of mice: a control group (intraperitoneal DMSO injection 3 times weekly after PBS instillation), bleomycin group (intraperitoneal DMSO injection 3 times weekly after bleomycin instillation), and bleomycin + ATRA group (intraperitoneal ATRA injection 3 times weekly after bleomycin instillation). The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, Ashcroft score, hydroxyproline assay, expression of several signal pathway proteins including EphA2-EphrinA1, and PI3K-Akt, and cytokine levels were compared among the groups. We found that bleomycin significantly increased the protein concentration in the BALF, Ashcroft score in lung tissue, and hydroxyproline contents in lung lysates. Furthermore, bleomycin upregulated EphA2, EphrinA1, PI3K 110γ, Akt, IL-6 and TNF-α. However, administration of ATRA attenuated the upregulation of EphA2-EphrinA1 and PI3K-Akt after bleomycin instillation, and decreased pulmonary fibrosis. In addition, ATRA suppressed IL-6 and TNF-α production induced by bleomycin-induced injury. Collectively, these data suggest that ATRA attenuates bleomycin-induced pulmonary fibrosis by regulating EphA2-EphrinA1 and PI3K-Akt signaling.

Research advances in the protective effect of all-trans retinoic acid against podocyte injury

All-trans retinoic acid (ATRA) is a vitamin A derivative and plays an important role in the regulation of cell aggregation, differentiation, apoptosis, proliferation, and inflammatory response. In recent years, some progress has been made in the role of ATRA in renal diseases, especially its protective effect on podocytes. This article reviews the research advances in podocyte injury, characteristics of ATRA, podocyte differentiation and regeneration induced by ATRA, and the protective effect of ATRA against proliferation, deposition of fibers, and apoptosis.

Low oxygen availability and malignant evolution of non-invasive breast tumors: potential protective role of all-trans retinoic acid (ATRA)

Reduced oxygen availability plays a crucial role in malignancy of solid tumors, including breast cancer. Even if the presence of hypoxic areas is common in all breast lesions, no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, particularly by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women in industrialized countries [1]. We demonstrated that 96 hours of culture under moderate hypoxia is sufficient to induce in DCIS-derived cells motility and epithelial-to-mesenchymal transition (EMT) and to enlarge the number of cells expressing the stem cell marker CD133, indicative of their increased malignant potential. Administration of all-trans retinoic acid (ATRA), a well-known anti-leukemic drug with an anti-tumor role in invasive breast tumor cells [2], supports the epithelial phenotype of DCIS-derived cells cultured under hypoxia and reduces the number of CD133 positive cells, abrogating almost completely the effects of poor oxygenation. In DCIS-derived cells, as in leukemic cells, ATRA up-regulates the β2 isoform of PI-PLC (PLC-β2), ectopically expressed in invasive breast tumors in which counteracts the effects of hypoxia on both EMT and CD133 levels [3]. This suggests that the mechanisms triggered by ATRA in non-invasive breast tumor cells cultured under hypoxia may, at least in part, depend on PLC-β2 activity. Overall, we assigned to hypoxia a role in increasing the malignant potential of DCIS-derived cells and identified in ATRA, currently used in treating acute promyelocytic leukemia (APL), an agonist potentially useful in preventing malignant progression of non-invasive breast lesions with hypoxic areas.

The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells.

Regulatory T (Treg) cells are necessary for immune system homeostasis and the prevention of autoimmune diseases. Foxp3 is specifically expressed in Treg cells and plays a key role in their differentiation and function. Foxp3(+) Treg cells are consisted of naturally occurring, thymus-derived Treg (nTreg) and peripheral-induced Treg (iTreg) cells that may have different functional characteristics or synergistic roles. All-trans retinoic acid (atRA), a vitamin A metabolite, regulates a wide range of biological processes, including cell differentiation and proliferation. Recent studies demonstrated that atRA also regulates the differentiation of T helper (Th) cells and Treg cells. Moreover, atRA also sustains nTreg stability under inflammatory conditions. In this review, we summarize the significant progress of our understanding of the role(s) and mechanisms of atRA in Treg biology.

Effect of Retinoic Acid in a Mouse Model of Allergic Rhinitis.

PurposeAll-trans retinoic acid (ATRA) modulates immune responses by affecting T cells. Several studies have revealed that allergic inflammation of the lower airways is negatively associated with the vitamin A concentration. However, the role of ATRA in allergic inflammation of the upper airways is unclear. We investigated the effects of ATRA in an allergic rhinitis mouse model.MethodsBALB/c mice except control groups (CON group) were sensitized with and challenged intra-nasally with Dermatophagoides farina (AR group). The ATRA groups were administered ATRA intraperitoneally. The steroid groups were administered steroid intranasally (ST group). Allergic symptoms and the average eosinophil number were counted. Cytokines and transcription factors were measured by Real-Time PCR and Western blotting. Der f-specific immunoglobulin E (IgE) was measured. Flow cytometry results of CD4+CD25+Foxp3+ T cells were analyzed.ResultsThe symptom scores were lower in the ATRA group than in the AR group and higher than in the CON group. The levels of IgE were lower in the ATRA group than in the AR group and higher than in the CON and ST groups. The levels of Foxp3, TGF-β, and IL-10 mRNA, as well as the percentage of CD4+CD25+Foxp3+ T cells, were higher in the ATRA group than in theAR group. In the ATRA group the levels of IFN-γ mRNA were higher, and the levels of GATA-3 and IL-4 mRNA, and ROR-γt were lower. In Western blotting analyses, the expression patterns of all factors, except Foxp3, showed similar to those of mRNA expression.ConclusionsATRA has anti-allergic effects in an allergic rhinitis model, and its underlying mechanisms mainly include the induction of regulatory T cells and the inhibition of Th2 responses.

Critical role of all-trans retinoic acid in stabilizing human nTregs under inflammatory conditions (P5133)

Abstract Recent studies have demonstrated that thymus-derived naturally-occurring CD4+Foxp3+ regulatory T cells (nTregs) in both human and mouse are unstable and dysfunctional in the presence of pro-inflammatory cytokines. All-trans Retinoic Acid (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. Herein, we report that atRA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function in vitro or in vivo following encountering with IL-1 and IL-6. Interestingly, adoptive transfer of human nTregs pre-treated with atRA significantly enhanced their suppressive effect on xeno-graft versus host diseases (xGVHD) and only these cells after stimulating with IL-1/IL-6 sustained the functional activity against xGVHD in a humanized animal model. atRA suppresses IL-1R upregulation and accelerates IL-6R downregulation and diminishes their signaling events, as well as increases histone acetylation on FOXP3 gene promoter and CpG demethylation in CNS regions of FOXP3 gene locus. These results strongly implicate that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated inflammatory diseases.

All-trans retinoic acid effectively inhibits breast cancer stem cells growth in vitro

To detect the inhibitory effect of all-trans retinoic acid(ATRA) on breast cancer stem cells (CSCs). The inhibitory effect of ATRA on MCF-7 and SK-BR-3 cell lines was analyzed using a Cell Counting Kit-8 (CCK-8). The proportion of CD44(+)CD24(-) tumor cells of the two cell lines were measured before and after the ATRA treatment, and the role of ATRA in the regulation of CSC self-renewing ability was evaluated with a tumor sphere assay. The tumor spheres were grown in an adherent culture to evaluate the ATRA-induced differentiation of breast cancer stem cells. ATRA effectively inhibited the unsorted cells and stem cells, but the CSCs were more sensitive to ATRA. At a concentration of 10(-6) mol/L, the inhibitory rate of MCF-7 unsorted cells and stem cells were (8.66 ± 1.06)% and (21.09 ± 3.25)%, respectively (P = 0.004). For SK-BR-3 cells, the rates were (39.19 ± 1.47)% and (51.22 ± 2.80)%, respectively (P = 0.005). The self-renewing ability of the CSCs was impaired by ATRA at a concentration of 10(-6) mol/L. The rate of MCF-7 and SK-BR-3 stem cells to form tumor sphere was 5.2% (5/96) and 13.5% (13/96), respectively. For the control group, it was 86.5% (83/96) and 93.8% (90/96), respectively (P < 0.001). ATRA also promoted the CD44(+)CD24(-) subpopulation to differentiate. SK-BR-3 stem cells were grown in an adherent culture. After using ATRA, the proportion of CD44(+)CD24(-) cells was (48.1 ± 2.5)% and that of the control group was (86.6 ± 2.5)% (P < 0.001). ATRA effectively inhibits breast NCSCs and CSCs, but CSCs are more sensitive to ATRA. ATRA impairs the self-renewing ability of CSCs and promotes CSCs to differentiate.