All-trans retinoic acid alleviates transmissible gastroenteritis virus-induced intestinal inflammation and barrier dysfunction in weaned piglets

Background Transmissible gastroenteritis virus(TGEV)is one of the main pathogens causing severe diarrhea of pig-lets.The pathogenesis of TGEV is closely related to intestinal inflammation.All-trans retinoic acid(ATRA)is the main active metabolite of vitamin A,which has immunomodulatory and anti-inflammatory properties.However,it is unclear whether ATRA can alleviate TGEV-induced intestinal inflammation and barrier dysfunction in piglets.This study aimed to investigate the effects of ATRA on growth performance,diarrhea,intestinal inflammation and intesti-nal barrier integrity of TGEV-challenged piglets.Methods In a 19-d study,32 weaned piglets were randomly divided into 4 treatments:Control group(basal diet),TGEV group(basal diet+TGEV challenge),TGEV+ATRA5 group(basal diet+5 mg/d ATRA+TGEV challenge)and TGEV+ATRA15 group(basal diet+15 mg/d ATRA+TGEV challenge).On d 14,piglets were orally administered TGEV or the sterile medium.Results Feeding piglets with 5 and 15 mg/d ATRA alleviated the growth inhibition and diarrhea induced by TGEV(P<0.05).Feeding piglets with 5 and 15 mg/d ATRA also inhibited the increase of serum diamine oxidase(DAO)activ-ity and the decrease of occludin and claudin-1 protein levels in jejunal mucosa induced by TGEV,and maintained intestinal barrier integrity(P<0.05).Meanwhile,5 mg/d ATRA feeding increased the sucrase activity and the expres-sions of nutrient transporter related genes(GLUT2 and SLC7A1)in jejunal mucosa of TGEV-challenged piglets(P<0.05).Furthermore,5 mg/d ATRA feeding attenuated TGEV-induced intestinal inflammatory response by inhibit-ing the release of interleukin(IL)-1β,IL-8 and tumor necrosis factor-α(TNF-α),and promoting the secretion of IL-10 and secretory immunoglobulin A(sIgA)(P<0.05).Feeding 5 mg/d ATRA also down-regulated the expressions of Toll-like receptors and RIG-I like receptors signaling pathway related genes(TLR3,TLR4,RIG-I,MyD88,TRIF and MAVS)and the phosphorylation level of nuclear factor-κB-p65(NF-κB p65),and up-regulated the inhibitor kappa B alpha(IκBα)protein level in jejunal mucosa of TGEV-challenged piglets(P<0.05).Conclusions ATRA alleviated TGEV-induced intestinal barrier damage by inhibiting inflammatory response,thus improving the growth performance and inhibiting diarrhea of piglets.The mechanism was associated with the inhibi-tion of NF-κB signaling pathway mediated by TLR3,TLR4 and RIG-I.

Effect of palmitoylethanolamide on degeneration of a human-derived retinal pigment epithelial cell induced by all-trans retinal

AIM:To study the effect of palmitoylethanolamide(PEA)on apoptosis of retinal pigment epithelial(RPE)cells induced by all-trans retinal(at RAL)and to explore the possible molecular mechanism.METHODS:Cell Titer 96■Aqueous One Solution Cell Proliferation Assay(MTS)was used to detect the effect of PEA on human-derived retinal epithelial cells(ARPE-19)viability induced by at RAL.A Leica DMi8 inverted microscope was used to observe cell morphology.Reactive oxygen species(ROS)production was evaluated with 2’,7’-dichlorodihydrofluorescein diacetate(H2DCFDA)staining and fluorescence microscopy.Expression of c-Jun N-terminal kinase(JNK),phosphorylated JNK(p-JNK),c-Jun,phosphorylated c-Jun(p-c-Jun),Bak,cleaved caspase-3,C/EBP homologous protein(CHOP),and binding(Bip)protein levels were tested by Western blot.Abca4-/-Rdh8-/-mice,mouse models of at RAL clearance defects which displays some symbolic characteristics of dry age-related macular degeneration(AMD)and Stargardt disease(STGD1).In the animal models,PEA was injected intraperitoneally.The full-field electroretinogram was used to detect visual function under scotopic conditions traced from mice.Optical coherence tomography showed reconstitution or thickening of the retinal pigment epithelium layer.Effect of PEA on fundus injury induced by light in Abca4-/-Rdh8-/-mice was observed by fundus photography.RESULTS:PEA ameliorated ARPE-19 cells apoptosis and inhibited ROS(including mitochondrial ROS)production induced by at RAL.PEA improved the retinal functional,prohibited both RPE and photoreceptor from death,ameliorates light-induced fundus impairment in Abca4-/-Rdh8-/-mice.In vitro and in vivo,PEA inhibited JNK,p-JNK,c-Jun,p-c-Jun,Bak,cleaved caspase-3,CHOP,and Bip protein levels induced by all-trans retinal in ARPE-19 cells.CONCLUSION:PEA has effect on treating RPE cells apoptosis in retinopathy caused by at RAL accumulation.PEA is a potential treatment strategy for dry AMD and STGD1.The molecular mechanism is affecting the ROS-JNKCHOP signaling pathway partly.

All-trans retinoic acid regulates the expression of MMP-2 and TGF-β2 via RDH5 in retinal pigment epithelium cells

·AIM: To investigate the effect of all-trans retinoic acid(ATRA) on retinol dehydrogenase 5(RDH5), matrix metalloproteinase-2(MMP-2) and transforming growth factor-β2(TGF-β2) transcription levels, and the effect of RDH5 on MMP-2 and TGF-β2 in retinal pigment epithelium(RPE) cells.·METHODS: After adult RPE cell line-19(ARPE-19 cells) intervened with gradient concentrations of ATRA(0-20 μmol/L) for 24h, flow cytometry was used to detect the proliferation and apoptosis of cells in each group, and quantitative realtime polymerase chain reaction(q RT-PCR) was used to detect RDH5, MMP-2 and TGF-β2 m RNA expression. Then, after ARPE-19 cells transfected with three different si RNA targets for 48h, the RDH5 knockdown efficiency of each group and expression of MMP-2 and TGF-β2 m RNA within them was detected by q RT-PCR. ·RESULTS: Flow cytometry results showed that ATRA could inhibit the proliferation of RPE cells and promote the apoptosis of RPE cells, and the difference of apoptosis was statistically significant when the ATRA concentration exceeded 5 μmol/L and compared with the normal control group(P=0.027 and P=0.031, respectively). q RT-PCR results showed that ATRA could significantly inhibit the expression level of RDH5 m RNA(P<0.001) and promote the expression of MMP-2 and TGF-β2 m RNA(P=0.03 and P<0.001, respectively) in a dose-dependent manner, especially when treated with 5 μmol/L ATRA. The knockdown efficiency of RDH5 si RNA varies with different targets, among which RDH5 si RNA-435 had the highest knockdown efficiency, i.e., more than 50% lower than that of the negative control group(P=0.02). When RDH5 was knocked down for 48h, the results of q RT-PCR showed that the expressions of MMP-2 and TGF-β2 m RNA were significantly up-regulated(P<0.001).·CONCLUSION: ATRA inhibits the expression of RDH5 and promotes MMP-2 and TGF-β2, and further RDH5 knockdown significantly upregulates MMP-2 and TGF-β2. These findings suggest that RDH5 may be involved in an epithelial-mesenchymal transition of RPE cells mediated by ATRA.

CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline drug.However,the administration regimen of AsⅢwas limited due to its fast clearance,short therapeutic window and toxicity as well.Based on CD71 overexpressed on APL cells,in present study,a transferrin(Tf)-modified liposome(LP)was established firstly to encapsulate AsⅢin arsenic-nickel complex by nickel acetate gradient method.The AsⅢ-loaded liposomes(AsLP)exhibited the feature of acid-sensitive release in vitro.Tf-modified AsLP(Tf-AsLP)were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢwhich stimulated reactive oxygen species level and caspase-3 activity.Tf-AsLP prolonged half-life of AsⅢin blood circulation,lowered systemic toxicity,and promoted apoptosis and induced cell differentiation at lesion site in vivo.Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect,accordingly,a Tf-modified RA liposome(Tf-RALP)was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy.As expected,the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model.Furthermore,APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection.The effect of co-administration(Tf-AsLP+Tf-RALP)was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’apoptosis and differentiation in peripheral blood and bone marrow.Collectively,Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug.Moreover,Tf-AsLP combined with Tf-RALP could achieve better efficacy.Thus,transferrinmodified AsⅢliposome would be a novel clinical strategy to improve patient compliance,with promising translation prospects.

Nano transdermal system combining mitochondria-targeting cerium oxide nanoparticles with all-trans retinoic acid for psoriasis

Psoriasis is an inflammatory skin disease that is intricately linked to oxidative stress.Antioxidation and inhibition of abnormal proliferation of keratinocytes are pivotal strategies for psoriasis.Delivering drugs with these effects to the site of skin lesions is a challenge that needs to be solved.Herein,we reported a nanotransdermal delivery system composed of all-trans retinoic acid(TRA),triphenylphosphine(TPP)-modified cerium oxide(CeO2)nanoparticles,flexible nanoliposomes and gels(TCeO_(2)-TRA-FNL-Gel).The results revealed that TCeO_(2)synthesized by the anti-micelle method,with a size of approximately 5 nm,possessed excellent mitochondrial targeting ability and valence conversion capability related to scavenging reactive oxygen species(ROS).TCeO_(2)-TRA-FNL prepared by the film dispersion method,with a size of approximately 70 nm,showed high drug encapsulation efficiency(>96%).TCeO_(2)-TRA-FNL-Gel further showed sustained drug release behaviors,great transdermal permeation ability,and greater skin retention than the free TRA.The results of in vitro EGF-induced and H2O2-induced models suggested that TCeO_(2)-TRA-FNL effectively reduced the level of inflammation and alleviated oxidative stress in HaCat cells.The results of in vivo imiquimod(IMQ)-induced model indicated that TCeO_(2)-TRA-FNL-Gel could greatly alleviate the psoriasis symptoms.In summary,the transdermal drug delivery system designed in this study has shown excellent therapeutic effects on psoriasis and is prospective for the safe and accurate therapy of psoriasis.

Redox-sensitive micelles for targeted intracellular delivery and combination chemotherapy of paclitaxel and all-trans-retinoid acid

The application of paclitaxel(PTX) in clinic has been restricted due to its poor solubility.Several traditional nano-medicines have been developed to improve this defect,while they are still lack of tumor targeting ability and rapid drug release. In this work,an amphiphilic polymeric micelle of hyaluronic acid(HA) – all-trans-retinoid acid(ATRA) with a disulfide bond,was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with selfassembling to micelles in water,the delivery system displayed satisfying drug loading capacities for both PTX(32.62% ± 1.39%) and ATRA,due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles(HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides,HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16 F10 cells. Due to these properties,cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly,HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore,redox-sensitive HASS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.

全反式维甲酸对酒精性肝损伤大鼠肝脏retinoids含量和CYP2E1表达的影响

目的:研究补充小剂量全反式维甲酸(ATRA)对酒精喂养大鼠肝脏维生素A类物质(reti- noids,主要是维生素A和RA)含量、维生素A类物质极性代谢产物(PRMs)形成,细胞色素P4502E1(CYP2E1)表达和肝细胞损伤的影响。方法:将30只SD大鼠随机分为A组(正常对照组),B组(单纯乙醇组)、C组(无水乙醇8 g/kg ig8wk+150μg/kg ATRA)、D组(无水乙醇8 g/kg ig 8 wk+1.5 mg/kg ATRA ig 4 wk)四组.光镜下观察肝组织病理变化,高效液相色谱(HPLC)技术测定肝组织中Vitamin A类物质(retinoids)的含量,Western blotting检测肝脏CYP2E1的表达.结果:B组大鼠肝脏RA、维生素A(Retinol)和维生素A棕榈酸酯(retinyl palmitate)与A组相比含量显著降低(0.077±0.029 nmol/g vs 0.183±0.037 nmol/g,8.13±1.379 nmol/g vs 21.43±2.944 nmol/g,132.6±6.472 nmol/g vs 221.1±10.35 nmol/g,P<0.01),且肝脏中出现明显的PRMs.C组RA和Retinol含量恢复至A组水平,retinyl palmitate含量也部分恢复.D组RA和retinyl Dalmilate完全恢复至正常水平,而Retinol水平较A组升高(27.26±3.149 nmol/g vs 21.43±2.944 nmol/g,P<0.05).两种剂量的ATRA均可完全阻止PRMs形成.病理组织学检查显示补充ATRA可明显减轻肝细胞肿胀、脂肪变性,但对CYP2E1的表达没有明显影响。结论:小剂量ATRA能恢复酒精性肝病(ALD)大鼠肝脏retinoids含量,阻止PRMs产生,从而减轻肝细胞损伤.

Study on 3D-QSAR of Retinoids 3D-Interaction between Retinoids and their Receptor **

Fast and precise prediction of the receptor-ligand binding constant is an important aspect of structure-based drug design. Almost all de novo design methods or 3D database search methods tend to structure generation instead of structure evaluation. In this article, epididymal retinoic acid binding protein (ERABP) was used as a template to simulate the interaction between retinoids and their receptor. We deduced an equation predicting the drug-receptor binding constant. Furthermore, the conformers after docking were used in CoMFA analysis to get a pharmacophore model of this series of compounds.

Inhibition of all-trans retinoic acid on MDM2 gene expression in astrocytoma cell line SHG-44

Objective To investigate the impact of all-trans retinoic acid （ATRA） on MDM2 gene expression in astrocytoma cell line SHG-44, and to provide basic data for further research on the progression mechanism and gene therapy of human astrocytoma. Methods The differential expressions of MDM2 gene and protein in SHG-44 cells were detected by cDNA microarray and Western blot, respectively, before and after treatment of ATRA. The expressions of MDM2 protein in WHO grade Ⅱ and grade Ⅳ astrocytomas were determined by immunohistochemical streptavidin-peroxidase method. Some differentially expressed genes were selected randomly for Northern blot analysis. Results The intensity ratio of ATRA-treated to untreated SHG-44 cell was 0.37 in the cDNA microarray, suggesting that the expression of MDM2 gene was down-regulated in SHG-44 cells after treatment with ATRA. Some genes differentially expressed in the microarray were confirmed by Northern blot. Western blot demonstrated that the optical density ratios of MDM2 to β-actin in ATRA-treated and untreated SHG-44 were 14.02±0.35 and 21.40±0.58 （t = 24.728, P = 0.000）, respectively, suggesting that the expression of MDM2 protein was inhibited in ATRA-treated SHG-44 cells. Moreover, the percentages of MDM2-positive protein were 24.00% （6/25） and 56.52% （13/23） （x^2 = 5.298, P = 0.021） in WHO grade Ⅱ and grade Ⅳ astrocytomas, respectively, suggesting that the expression of MDM2 protein may increase along with the elevation of astrocytoma malignancy. Conclusion ATRA can inhibit MDM2 gene expression in SHG-44 cells, and MDM2 is related to astrocytoma progression.

视黄素受体介导的视黄素(retinoids)抗癌作用

对近年来视黄素受体介导视黄素抗癌作用机理的研究进展作一综述 ,主要有 :1)视黄素受体 ;2 )视黄素受体与细胞生长 ;3)视黄素受体与孤生受体的相关性 ;4 )视黄素受体对 AP- 1活性的抑制作用 ;5)视黄素受体介导的信号转导途径 .通过研究 ,对于探讨视黄素受体的功能、阐明视黄素的抗癌机理、合成更多的受体选择性视黄素具有重要的现实意义 .

Study on the Equivalent Conformation of Retinoids

N-(4-Carboxy-phenyl)-3,5-di-t-butyl-4-hydroxy-benzamide (2) possesses structural prerequisite for cell differentiation inducing activity, which constitutes the therapeutic basis of all trans retinoic acid (ATRA) and analogues for the treatment of cancer and dermatosis. In addition to the similarity of the disposition of functional groups with ATRA, 2 shows a conformational equivalence to ATRA in terms of molecular shape, size, as well as the spatial arrangement of functional groups. However, the N methylated compound (3) is devoid of the activity. It owes the biological behavior to the conformational difference, because of the steric interference between N methyl group and the hydrogen atom of a phenyl ring. X ray crystallography, UV, and NMR were performed to investigate the difference.

Potential therapeutic roles of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease

All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid signaling is extremely important in the central nervous system. Impairment of retinoic acid signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired retinoic acid signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease, which is pathologically characterized by extra-neuronal accumulation of amyloid plaques(aggregated amyloid-beta) and intra-neurofibrillary tangles(hyperphosphorylated tau protein) in the temporal lobe of the brain. Alzheimer’s disease is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in Alzheimer’s disease patients. Deficiency or deprivation of retinoic acid in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer’s disease. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of Alzheimer’s disease in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease.

Effect of ATRA on Contents of liver Retinoids, Oxidative Stress and Hepatic Injury in Rat Model of Extrahepatic Cholestasis

The effects of all-trans-retinoic acid （ATRA） administration on the concentration of retinoids （RA and vitamin A） in liver, oxidative stress and the hepatic injury in a rat model of common bile duct ligation （CBDL）-induced liver injury were investigated. Female rats were subjected to a sham （n=5） or CBDL （n=48）. Two weeks after operation, rats undergoing CBDL were randomized to receive treatment with either ATRA at three different doses （0.1, 1.5, 7.5 mg/kg） dissolved in bean oil or only bean oil every day over a 4-week experimental period. Rats were killed and blood samples were collected from the heart for determination of the serum transaminase. The contents of retinoids in rat liver were detected by using HPLC. Malondialdehyde （MDA）, glutathione （GSH） and superoxide dismutase （SOD） levels in liver were determined by a spectrophotometric method according to the instruction of the kits. Liver pathologic changes were observed under the light microscopy and electron microscopy. The results showed that compared with sham-operated group, the levels of retinoids in the liver tissue were significantly decreased in the CBDL group （P〈0.01）. ATRA （0.1 mg/kg） administration in CBDL rats partially restored the contents of retinoids （P〈0.05）. Liver RA and vita- min A contents in CBDL group were significantly increased after ATRA （1.5 and 7.5 mg/kg） supplementation as compared with sham-operated group （P〈0.05）. However, in ATRA-treated CBDL group, hepatic GSH level and SOD activity, depressed by CBDL, and hepatic MDA level, increased by CBDL were returned to those in sham-operated group （P〈0.05）. The histologic observation of liver tissues indicated that ATRA treatment notably alleviated hepatocellular swelling, steatosis, the. swelling of mitochondria and proliferation of smooth endoplasmic reticulum （SER）. Treatment with ATRA could reduce levels of serum transaminase as compared with sham-operated group, more greatly in 1.5 and 7.5 mg/kg ATRA-treated groups than in 0.1 mg/kg ATRA-treated group. It was concluded that ATRA treatment can recover MDA and GSH levels and SOD activity in CBDL rat liver through restoring RA and vitamin A contents, and eventually ameliorate liver injury.

Role of retinoids in the prevention and treatment of colorectal cancer

Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer(CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/β-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over-expression, reduction of peroxisome proliferatoractivated receptor γ activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors(RAR). RAR bind to all-trans-retinoic acid(ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms.

Synthesis and anti-tumor activity of all-trans retinoic acid derivatives

A series of retinoate and retinamide derivatives were designed, synthesized, and their anti-tumor activities were investigated in NB4 by MTT and flow cytometry assays （FCM）. All compounds showed cytotoxicity, especially compounds la and ld exhibited a higher cytotoxicity than other derivatives and all-trans rethaoic acid （ATRA）. Furthermore, compound 1d could induce NB4 cell lines differentiation efficiently. O 2009 Fei Hu Chert. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Combination therapies improve the anticancer activities of retinoids in neuroblastoma

Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index,and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer patients achieve complete remission after chemotherapy,death still occurs due to relapse of persistent minimal residual disease(MRD) which remaining after initial cytotoxic chemotherapy. Advanced neuroblastoma(NB) is a leading cause of cancer deaths in young children. Retinoids are an important component of advanced NB therapy at the stage of MRD,yet half of all patients treated with 13-cis-retinoic acid still relapse and die. More effective combination therapies,with a lower side-effect profile,are required to improve outcomes for NB. Fenretinide or N-4-hydroxyphenyl retinamide is a synthetic derivative of retinoic acid which works on cancer cells through nuclear receptor-dependent and-independent signalling mechanisms. Moreover,several histone deacetylase inhibitors have entered early phase trials,and,suberoylanilide hydroxamic acid has been approved for use in adult cutaneous T cell lymphoma. A number of studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity. A better understanding of their mechanism of actions will lead to more evidence-based retinoid combination therapies.

All-trans retinoic acid(ATRA)inhibits insufficient radiofrequency ablation(IRFA)-induced enrichment of tumor-initiating cells in hepatocellular carcinoma

Objective:Local recurrence of hepatocellular carcinoma(HCC)after radiofrequency ablation(RFA)treatment remains a serious problem.Tumor-initiating cells(TICs)are thought to be responsible for tumor relapse.Here,we investigated the effect of the TIC differentiation inducer,all-trans retinoic acid(ATRA),on RFA and explored the potential molecular mechanisms.Methods:The proportions of CD133+and epithelial cell adhesion molecule(Ep CAM);TICs in recurrent HCC after RFA and primary HCC were first determined in clinic.Then,the effect of heat intervention or insufficient RFA(IRFA)on the malignant potential of HCC cells,including cell migration,sphere formation ability,tumor growth,the proportion of CD133+and Ep CAM+TICs and expression of stem cell-related genes,was evaluated in vitro and in vivo.Finally,the effect of ATRA on the tumor growth and the proportion of TICs was evaluated.Results:In clinical data,a higher proportion of CD133+and Ep CAM+TICs was found in recurrent tumors than in primary tumors.In vitro heat intervention promoted the cell migration and sphere formation ability.Additionally,it increased the proportion of CD133+and Ep CAM+TICs and the expression of stem cell-related genes.In addition,after IRFA the residual tumors in xenografts grew faster and had more TICs than untreated tumors.ATRA remarkably inhibited residual tumor growth after IRFA by elimination of TICs though the PI3 K/AKT pathway.Combination treatment with ATRA resulted in longer survival outcomes in mouse xenografts than RFA alone.Conclusions:ATRA,as a TIC differentiation inducer,could help to improve the effect of RFA treatment,which was partially attributed to its effect against TICs.The data indicated its potential as an alternative drug in the development of better therapeutic strategies for use in combination with RFA.

Involvement of serum retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers in Hungary

AIM: To analyze the serum levels of retinoids and Leiden mutation in patients with esophageal, gastric, liver,pancreatic, and colorectal cancers.METHODS: The changes in serum levels of retinoids (vitamin A, α- and β-carotene, α- and β-cryptoxanthin,zeaxanthin, lutein) and Leiden mutation were measured by high liquid performance chromatography (HPLC)and polymerase chain reaction (PCR) in 107 patients (70 males/37 females) with esophageal (0/8), gastric (16/5), liver (8/7), pancreatic (6/4), and colorectal (30/21including 9 patients suffering from in situ colon cancer)cancer. Fifty-seven healthy subjects (in matched groups)for controls of serum retinoids and 600 healthy blood donors for Leiden mutation were used.RESULTS: The serum levels of vitamin A and zeaxanthin were decreased significantly in all groups of patients with gastrointestinal (GI) tumors except for vitamin A in patients with pancreatic cancer. No changes were obtained in the serum levels of α- and β-carotene,α- and β-cryptoxanthin, zeaxanthin, lutein in patients with GI cancer. The prevalence of Leiden mutation significantly increased in all groups of patients with GI cancer.CONCLUSION: Retinoids (as environmental factors)are decreased significantly with increased prevalence of Leiden mutation (as a genetic factor) in patients before the clinical manifestation of histologically different (planocellular and hepatocellular carcinoma, and adenocarcinoma) GI cancer.

Inhibition of matrix metalloproteinases expression in human dental pulp cells by all-trans retinoic acid

All-trans retinoic acid（ATRA） inhibits matrix metalloproteinase（MMP）-2 and MMP-9 in synovial fibroblasts, skin fibroblasts,bronchoalveolar lavage cells and cancer cells, but activates MMP-9 in neuroblast and leukemia cells. Very little is known regarding whether ATRA can activate or inhibit MMPs in human dental pulp cells（HDPCs）. The purpose of this study was to determine the effects of ATRA on the production and secretion of MMP-2 and-9 in HDPCs. The productions and messenger RNA（mRNA） expressions of MMP-2 and-9 were accessed by gelatin zymography and real-time polymerase chain reaction（PCR）, respectively. ATRA was found to decrease MMP-2 level in a dose-dependent manner. Significant reduction in MMP-2 mRNA expression was also observed in HDPCs treated with 25 mmol？L21ATRA. However, HDPCs treated with ATRA had no effect on the pattern of MMP-9 produced or secreted in either cell extracts or conditioned medium fractions. Taken together, ATRA had an inhibitory effect on MMP-2 expression in HDPCs,which suggests that ATRA could be a candidate as a medicament which could control the inflammation of pulp tissue in vital pulp therapy and regenerative endodontics.

Potential role of nuclear receptor ligand all-trans retinoic acids in the treatment of fungal keratitis

·Fungal keratitis(FK) is a worldwide visual impairment disease. This infectious fungus initiates the primary innate immune response and, later the adaptive immune response. The inflammatory process is related to a variety of immune cells, including macrophages, helper T cells, neutrophils, dendritic cells, and Treg cells, and is associated with proinflammatory, chemotactic and regulatory cytokines. All-trans retinoic acids(ATRA)have diverse immunomodulatory actions in a number of inflammatory and autoimmune conditions. These retinoids regulate the transcriptional levels of target genes through the activation of nuclear receptors.Retinoic acid receptor α(RAR α), retinoic acid receptor γ(RAR γ), and retinoid X receptor α(RXR α) are expressed in the cornea and immune cells. This paper summarizes new findings regarding ATRA in immune and inflammatory diseases and analyzes the perspective application of ATRA in FK.