·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 effec...·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.展开更多
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 clearan...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.展开更多
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 wi...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.展开更多
In acute promyelocytic leukemia, differentiation thera-py based on all-trans-retinoic acid can be complicated by the development of a differentiation syndrome(DS). DS is a life-threatening complication, characterized ...In acute promyelocytic leukemia, differentiation thera-py based on all-trans-retinoic acid can be complicated by the development of a differentiation syndrome(DS). DS is a life-threatening complication, characterized by respiratory distress, unexplained fever, weight gain, interstitial lung infiltrates, pleural or pericardial effusions, hypotension and acute renal failure. The diagnosis of DS is made on clinical grounds and has proven to be difficult, because none of the symptoms is pathognomonic for the syndrome without any definitive diagnostic criteria. As DS can have subtle signs and symptoms at presentation but progress rapidly, end-stage DS clinical picture resembles the acute respiratory distress syndrome with extremely poor prognosis; so it is of absolute importance to be conscious of these complications and initiate therapy as soon as it was suspected. The radiologic appearance resembles the typical features of cardiogenic pulmonary edema. Diagnosis of DS remains a great skill for radiologists and haematologist but it is of an utmost importance the cooperation in suspect DS, detect the early signs of DS, examine the patients' behaviour and rapidly detect the complications.展开更多
AIM To explore the relationship between the configuration changes of the nuclear matrix-intermediate filament system in cancer cell induced by retinoic acid and the malignantphenotypic reversion of cancer cells.METHOD...AIM To explore the relationship between the configuration changes of the nuclear matrix-intermediate filament system in cancer cell induced by retinoic acid and the malignantphenotypic reversion of cancer cells.METHODS The human gastric adenocarcinomacell line MGc80-3 cells were induced with 10-6mol/ L retinoic acid and subouItured at cover slipstrip and gold grids. The cells were treated byselective extraction methOd and prepared for whole mount electron microscopy observation.The samples were examined respectively withscanning and transmission electron microscope.RESULTS The nuclear matrix filaments andintermediate filaments in MGC80-3 cells wererelatively few and scattered, not welldistributed and arranged irregularly. The nuclear lamina was ununiformly thick and compact,connected to the nuclear matrix filaments and intermediate filaments relaxedly. However, thetwo kinds of filaments were abundant and welldistributed, different in slender and thick form and interweaved into a regular network in the cells induced by 10-6 mol/ L RA. The nuclear matrix filaments and intermediate filaments were connected closely by the thin and compact fiber-Iike lamina, and interlaced into a regularnetwork throughout the whole cell region.CONCLUSION The NM-IF system in MGc80-3cells had undergone a restorational changesimilar to those of normaI cells after RAinducement. This alternation is an importantmorpholOgical and functional expression to themalignant phenotypic reversion of cancer cells.展开更多
AIM To study the molecular mechanisms ofretinoic acid(RA)on proliferation andexpression of cyclin-dependent kinase inhibitors(CKI),i.e.p16,p21 and p27 in cultured rathepatic stellate cells(HSC)stimulated withtransform...AIM To study the molecular mechanisms ofretinoic acid(RA)on proliferation andexpression of cyclin-dependent kinase inhibitors(CKI),i.e.p16,p21 and p27 in cultured rathepatic stellate cells(HSC)stimulated withtransforming growth factor beta 1(TGF-β1).METHODS HSC were isolated from healthy ratlivers and cultured.After stimulated with1 mg/L TGF-β1,subcultured HSC were treatedwith or without 1 nmol/L RA.MTT assay,immunocytochemistry(ICC)for p16,p21,p27and α-smooth muscle actin(α-SMA)protein,insitu hybridization(ISH)for retinoic acidreceptor beta 2(RAR-β2)and p16,p21 and p27mRNA and quantitative image analysis(partially)were performed.RESULTS RA inhibited HSC proliferation(41.50%,P【0.05),decreased the protein levelof α-SMA(55.09%,P【0.05),and induced HSCto express RAR-β2 mRNA.In addition,RAincreased the protein level of p16(218.75%,P【0.05)and induced p21 protein expression;meanwhile,p27 was undetectable by ICC in bothcontrol and RA-treated HSC.However,RA hadno influence on the mRNA levels of p16,p21 orp27 as determined by ISH.CONCLISION Up-regulation of p16 and p21 on post-transcriptional level may contribule, in part to RA inhibition of TGF-β1-initiated rat HSC activation in vitro.展开更多
·AIM:All-trans retinoic acid (RA) is the only extrinsic biochemical candidate known to date that could act as a growth controller,the aim of this study was to investigate the expression cellular retinoic acid bin...·AIM:All-trans retinoic acid (RA) is the only extrinsic biochemical candidate known to date that could act as a growth controller,the aim of this study was to investigate the expression cellular retinoic acid binding proteins I (CRABP-I) and retinoic acid receptor-β (RAR-β) in retina of the guinea pig eyes with experimental myopia.·METHODS:Ninety guinea pigs aged 14 days were equally and randomly divided into three groups:form deprivation (FD),-5D lens,and control.The diffusers for FD were white translucent hemispheres,and-5D lenses were used to introduce hyperopic defocus.Refraction was measured with streak retinoscopy after cycloplegia,and axial length was calculated with Cinescan A/B ultrasonography.Retina harvested at different time points were used to measure RA level with HPLC and expressions of cellular retinoic acid binding proteins I (CRABP-I) and RA receptor-β (RAR-β) were assayed with Western blot and Real-time PCR.SPSS13.0 software was used for statistical analysis.·RESULTS:Up-regulations of CRABP-I and RAR-β in ocular tissues correlated with changes in the refractive status and growth rate of the guinea pig eye (P <0.05).14 days of monocular form-deprivation led to-5.14D myopia and a 0.281mm axial elongation;14 days of monocular defocus produced-3.64D myopia and a 0.163 mm axial elongation.The level of retinal RA started to elevate in 7 days (P <0.05) after visual manipulation in both FD and-5D lens groups and became more prominent by 14 days (P <0.01).The expressions of CRABP-I and RAR-β increased by 14 days after visual manipulation (P <0.05),the mRNA level of RAR-β,however,increased by 7 days after visual manipulation (P <0.05),which suggested that changes of expressions of CRABP-I and RAR-β might lag behind the change of RA.·CONCLUSION:The levels of CRABP-I and RAR-β were elevated in retina of the guinea pig eye with experimental myopia.During the progression of experimental myopia,the retinal RA level increased rapidly,and there might be a positive feedback between the increase of RA and up-regulation of RAR-β.·展开更多
AIM: To investigate the role of retinoic acid (RA) and retinaldehyde dehydrogenase-2 (RALDH2) of retina and choroid in the guinea pig lens-induced myopic eyes. METHODS: Totally 45 guinea pigs, at age of three weeks, w...AIM: To investigate the role of retinoic acid (RA) and retinaldehyde dehydrogenase-2 (RALDH2) of retina and choroid in the guinea pig lens-induced myopic eyes. METHODS: Totally 45 guinea pigs, at age of three weeks, were randomly assigned into three groups: the normal control, the lens-induced group and the recovering group. Out of focus was induced by the -6.00D concave lens on the left eye, and lasted for 15 days. All animals underwent biometric measurement (corneal radius of curvature, refraction and axial length). Subsequently, RA content in the retina and RPE/choriod complex was detected by reversed- phase high-performance liquid chromatography. RALDH2 protein in the retina and RPE/choriod complex was evaluated by the immunohistochemical staining and Western blotting. RESULTS: After wearing -6.00D lens for 15 days, axial length of the lens-induced eye extends and myopia was formed, with RA contents increasing in both the neural retina and RPE/choroid complex. Comparing with the lens-induced group, myopic degree significantly relieved, and its RA contents in both the neural retina and RPE/choroid complex decreased in the recovering group. In the normal control, RALDH2 protein was expressed positively in the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL) and lateral border of outer nuclear layer (ONL). Retinal RALDH2 protein increased in the lens-induced group, and was also positive in the outer plexiform layer (OPL). In the recovering group, retinal RALDH2 protein attenuated the expression in the OPL turns to negative. RALDH2 protein was not expressed in the choroid of any group. CONCLUSION: RA of retina and chorid participates in the regulation of the lens-induced myopia in guinea pigs, which may be related with retinal RALDH2 protein.展开更多
AIM To evaluate the role of RARa gene in mediating the growth inhibitory effect of ail-trans retinoic acid (ATRA)on gastric cancer cells.``METHODS The expression levels of retinoic acid receptors (RARs) in gastric can...AIM To evaluate the role of RARa gene in mediating the growth inhibitory effect of ail-trans retinoic acid (ATRA)on gastric cancer cells.``METHODS The expression levels of retinoic acid receptors (RARs) in gastric cancer cells were detected by Northern blot. Transient transfection and chlorophenicol acetyl transferase (CAT) assay were used to show the transcriptional activity of β retinoic acid response element (βRARE) and AP-l activity. Cell growth inhibition was determined by MTT assay and anchorage-independent growth assay, respectively. Stable transfection was performed by the method of Lipofectamine, and the cells were screened by G418.``RESULTS ATRA could induce expression level of RARα in MGC80-3, BGCC8823 and SGC-7901 cells obviously,resulting in growth inhibition of these cell lines. After sense RARa gene was transfected into MKN-45 cells that expressed rather Iow level of RARα and could not be induced by ATRA, the cell growth was inhibited by ATRA markedly. In contrast, when antisense RARα gene was transfected into BGC-825 cells, a little inhibitory effect by ATRA was seen, compared with the parallel BGC-823cells. In transient transfection assay, ATRA effectively induced transcriptional activity of βRARE in MGC80-3,BGC.823, SGC-7902 and MKN/RARa cell lines, but not in MKN-45 and BGC/aRARa cell lines. Similar results were observed in measuring anti-AP-l activity by ATRA in these cancer cell lines.``CONCLUSION ATRA inhibits the growth of gastric cancer cells by up-regulating the level of RARa; RARa is the major mediator of ATRA action in gastric cancer cells; and adequate level of RAPa is required for ATRA effect on gastric cancer cells.展开更多
AIM: To study the role of autophagy and the relationship between retinoic acid receptor α(RARα) and autophagy in liver ischemia and reperfusion(IR) injury.METHODS: All-trans retinoic acid(ATRA) was administered to m...AIM: To study the role of autophagy and the relationship between retinoic acid receptor α(RARα) and autophagy in liver ischemia and reperfusion(IR) injury.METHODS: All-trans retinoic acid(ATRA) was administered to mice for two weeks before operation. Reverse transcription-polymerase chain reaction and Western blot were used to detect the expression levels of related factors. To demonstrate the role of RARα,LE540,a RARα inhibitor,was used to treat hepatocytes injured by H2O2 in vitro.RESULTS: ATRA pretreatment noticeably diminished levels of serum alanine aminotransferase and as-partate aminotransferase as well as the degree of histopathological changes. Apoptosis was also inhibited,whereas autophagy was promoted. In vitro,RARα was inhibited by LE540,which resulted in decreased autophagy and increased apoptosis. Similarly,the expression of Foxo3 a and p-Akt was downregulated,but Foxo1 expression was upregulated.CONCLUSION: This research provides evidence that ATRA can protect the liver from IR injury by promoting autophagy,which is dependent on Foxo3/p-Akt/Foxo1 signaling.展开更多
Retinoic acid can cause many types of cells,including mouse neuroblastoma Neuro-2 A cells,to differentiate into neurons.However,it is still unknown whether microRNAs(miRNAs)play a role in this neuronal differentiation...Retinoic acid can cause many types of cells,including mouse neuroblastoma Neuro-2 A cells,to differentiate into neurons.However,it is still unknown whether microRNAs(miRNAs)play a role in this neuronal differentiation.To address this issue,real-time polymerase chain reaction assays were used to detect the expression of several differentiation-related miRNAs during the differentiation of retinoic acid-treated Neuro-2 A cells.The results revealed that miR-124 and miR-9 were upregulated,while miR-125 b was downregulated in retinoic acid-treated Neuro-2 A cells.To identify the miRNA that may play a key role,miR-124 expression was regulated by transfection of miRNA mimics or inhibitors.Morphological analysis results showed that inhibition of miR-124 expression reversed the effects of retinoic acid on neurite outgrowth.Moreover,miR-124 overexpression alone caused Neuro-2 A cells to differentiate into neurons,and its inhibitor could block this effect.These results suggest that miR-124 plays an important role in retinoic acid-induced differentiation of Neuro-2 A cells.展开更多
Inclusion compound of retinoic acid with (-cyclodextrin was prepared by coprecipitating method, the structure of resulting product was studied by elemental analysis, differential scanning caloriemetry(DSC) analysis, F...Inclusion compound of retinoic acid with (-cyclodextrin was prepared by coprecipitating method, the structure of resulting product was studied by elemental analysis, differential scanning caloriemetry(DSC) analysis, FT-IR spectroscopy and X-ray diffractometry, and the formed supramolecule self-assembles in aqueous solution according to molar ratio 2:1 of host-guest.展开更多
·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 ...·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.展开更多
O6-methylguanine DNA methyltransferase(MGMT), a DNA repair enzyme, has been reported in some congenital malformations, but it is less frequently reported in neural tube defects. This study investigated MGMT mRNA expre...O6-methylguanine DNA methyltransferase(MGMT), a DNA repair enzyme, has been reported in some congenital malformations, but it is less frequently reported in neural tube defects. This study investigated MGMT mRNA expression and methylation levels in the early embryo and in different embryonic stages, as well as the relationship between MGMT and neural tube defects. Spina bifida aperta was induced in rats by a single intragastric administration of all-trans retinoic acid on embryonic day(E) 10, whereas normal control rats received the same amount of olive oil on the same embryonic day. DNA damage was assessed by detecting γ-H2 A.X in spina bifida aperta rats. Real time-polymerase chain reaction was used to examine mRNA expression of MGMT in normal control and spina bifida aperta rats. In normal controls, the MGMT mRNA expression decreased with increasing embryonic days, and was remarkably reduced from E11 to E14, reaching a minimum at E18. In the spina bifida aperta model, γ-H2 A.X protein expression was increased, and mRNA expression of MGMT was markedly decreased on E14, E16, and E18. Bisulfite sequencing polymerase chain reaction for MGMT promoter methylation demonstrated that almost all CpG sites in the MGMT promoter remained unmethylated in both spina bifida aperta rats and normal controls, and there was no significant difference in methylation level between the two groups on either E14 or E18. Our results show that DNA damage occurs in spina bifida aperta rats. The mRNA expression of MGMT is downregulated, and this downregulation is independent of promoter DNA methylation.展开更多
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 inve...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.展开更多
Cervical cancer is one of the leading causes of death in women worldwide, particularly in developing countries. Human papillomavirus has been reported as one of the key etiologic factors in cervical carcinoma. Likewis...Cervical cancer is one of the leading causes of death in women worldwide, particularly in developing countries. Human papillomavirus has been reported as one of the key etiologic factors in cervical carcinoma. Likewise, epigenetic aberrations have ability to regulate cancer pathogenesis and progression. Recent research suggested that methylation has been detected already at precancerous stages, which methylation markers may have significant value in cervical cancer screening. The retinoic acid receptor beta (RARβ) gene, a potential tumor suppressor gene, is usually expressed in normal epithelial tissue. Methylation of CpG islands in the promoter region of the RARβ gene has been found to be associated with the development of cervical cancer. To investigate whether RARβ methylation is a potential biomarker that predicts the progression of invasive cancer, we reviewed 14 previously published articles related to RARβ methylation. The majority of them demonstrated that the frequency of RARβ promoter methylation was significantly correlated with the severity of cervical epithelium abnormalities. However, methylation of a single gene may not represent the best approach for predicting disease prognosis. Analyzing combinations of aberrant methylation of multiple genes may increase the sensitivity, and thus this approach may serve as a better tool for predicting disease prognosis.展开更多
Objective This study aimed to investigate the expression pattern and function of Nuclear receptor subfamily 2 group E member 1(Nr2e1) in retinoic acid(RA)-induced brain abnormality. Methods The mouse model of brain ab...Objective This study aimed to investigate the expression pattern and function of Nuclear receptor subfamily 2 group E member 1(Nr2e1) in retinoic acid(RA)-induced brain abnormality. Methods The mouse model of brain abnormality was established by administering 28 mg/kg RA, and neural stem cells(NSCs) were isolated from the mouse embryo and cultured in vitro. Nr2e1 expression was detected by whole mount in situ hybridization, RT-PCR, and Western blotting. Nr2e1 function was determined by transducing Nr2e1 shRNA into NSCs, and the effect on the sonic hedgehog(Shh) signaling pathway was assessed in the cells. In addition, the regulation of Nr2e1 expression by RA was also determined in vitro. Results Nr2e1 expression was significantly downregulated in the brain and NSCs of RA-treated mouse embryos, and knockdown of Nr2e1 affected the proliferation of NSCs in vitro. In addition, a similar expression pattern of Nr2e1 and RA receptor(RAR) α was observed after treatment of NSCs with different concentrations of RA. Conclusion Our study demonstrated that Nr2e1 could be regulated by RA, which would aid a better understanding of the mechanism underlying RA-induced brain abnormality.展开更多
All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutatio...All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutations is associated with increased risk of relapse.The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA,idarubicin(IDA)and/or ATO,followed by ATRA plus ATO along with anthracycline,as consolidation therapy.A total of 72 patients newly diagnosed with APL were included in this study.83.3%of the patients achieved complete remission(CR)after induction therapy.FLT3-ITD mutations were detected in 16(22.2%)patients and closely related to bcr-3 PML-RARa transcript(P<0.001).The 5-year overall survival(OS)rate was 100%in both FLT3-ITDposltlve and FLT3-ITD^(negatlve)groups,and there was no significant difference in 5-year event-free survival(EFS)between the two groups(78.3%vs.83.3%,P=0.85).ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.展开更多
Objective: The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB...Objective: The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and p16 among benign prostatic hyperplasia (BPH) and prostate cancer patients. Methods: In this case-control study, 63 patients were included in three groups; 21 with BPH as the control group, 21 with prostate cancer and good prognostic factors (based on prostate-specific antigen, Gleason score and stage) as good prognosis group, and 21 with prostate cancer and poor prognostic features as poor prognosis group. The prostate biopsy specimen of each individual was examined for hypermethylation of RARB and p16 promoters by methylation specific PCR (MSPCR). Results: Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis were positive for RARB methylation, which were significantly higher than controls (P <0.0001). p16 promoter methylation was shown in 19.0% and 47.6% patients with good and poor prognosis, respectively. The RARB and p16 promoter methylation in the poor prognosis group was significantly higher than that in the good prognosis group (P =0.02 for RARB and P<0.0001 for p16). Conclusion: Hypermethylation of RARB and p16 promoters may predict prognosis in prostate cancer.展开更多
基金Supported by Project of Science&Technology Department of Sichuan Province (No.23NSFSC1940)City and College Cooperation (No.22SXFWDF0003)。
文摘·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.
基金supported by the Science and Technology Commission of Shanghai Municipality (20S11902600)the National Natural Science Foundation of China (82172615)the PDH-SPFDU Joint Research Fund (RHJJ2018-05)
文摘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.
基金supported by Zhejiang Provincial Natural Science Foundation of China under Grant No.LYY21H300001Zhejiang Medical and Health Science and Technology project under Grant No.2021KY906Hangzhou Medical Key Discipline Construction Project under Grant No.[2021]21–39
文摘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.
文摘In acute promyelocytic leukemia, differentiation thera-py based on all-trans-retinoic acid can be complicated by the development of a differentiation syndrome(DS). DS is a life-threatening complication, characterized by respiratory distress, unexplained fever, weight gain, interstitial lung infiltrates, pleural or pericardial effusions, hypotension and acute renal failure. The diagnosis of DS is made on clinical grounds and has proven to be difficult, because none of the symptoms is pathognomonic for the syndrome without any definitive diagnostic criteria. As DS can have subtle signs and symptoms at presentation but progress rapidly, end-stage DS clinical picture resembles the acute respiratory distress syndrome with extremely poor prognosis; so it is of absolute importance to be conscious of these complications and initiate therapy as soon as it was suspected. The radiologic appearance resembles the typical features of cardiogenic pulmonary edema. Diagnosis of DS remains a great skill for radiologists and haematologist but it is of an utmost importance the cooperation in suspect DS, detect the early signs of DS, examine the patients' behaviour and rapidly detect the complications.
文摘AIM To explore the relationship between the configuration changes of the nuclear matrix-intermediate filament system in cancer cell induced by retinoic acid and the malignantphenotypic reversion of cancer cells.METHODS The human gastric adenocarcinomacell line MGc80-3 cells were induced with 10-6mol/ L retinoic acid and subouItured at cover slipstrip and gold grids. The cells were treated byselective extraction methOd and prepared for whole mount electron microscopy observation.The samples were examined respectively withscanning and transmission electron microscope.RESULTS The nuclear matrix filaments andintermediate filaments in MGC80-3 cells wererelatively few and scattered, not welldistributed and arranged irregularly. The nuclear lamina was ununiformly thick and compact,connected to the nuclear matrix filaments and intermediate filaments relaxedly. However, thetwo kinds of filaments were abundant and welldistributed, different in slender and thick form and interweaved into a regular network in the cells induced by 10-6 mol/ L RA. The nuclear matrix filaments and intermediate filaments were connected closely by the thin and compact fiber-Iike lamina, and interlaced into a regularnetwork throughout the whole cell region.CONCLUSION The NM-IF system in MGc80-3cells had undergone a restorational changesimilar to those of normaI cells after RAinducement. This alternation is an importantmorpholOgical and functional expression to themalignant phenotypic reversion of cancer cells.
基金the National Natural Science Foundation of China,No.39670287the Scientific Research Foundation for Doctorate Education,State Education Commission.No.96026530
文摘AIM To study the molecular mechanisms ofretinoic acid(RA)on proliferation andexpression of cyclin-dependent kinase inhibitors(CKI),i.e.p16,p21 and p27 in cultured rathepatic stellate cells(HSC)stimulated withtransforming growth factor beta 1(TGF-β1).METHODS HSC were isolated from healthy ratlivers and cultured.After stimulated with1 mg/L TGF-β1,subcultured HSC were treatedwith or without 1 nmol/L RA.MTT assay,immunocytochemistry(ICC)for p16,p21,p27and α-smooth muscle actin(α-SMA)protein,insitu hybridization(ISH)for retinoic acidreceptor beta 2(RAR-β2)and p16,p21 and p27mRNA and quantitative image analysis(partially)were performed.RESULTS RA inhibited HSC proliferation(41.50%,P【0.05),decreased the protein levelof α-SMA(55.09%,P【0.05),and induced HSCto express RAR-β2 mRNA.In addition,RAincreased the protein level of p16(218.75%,P【0.05)and induced p21 protein expression;meanwhile,p27 was undetectable by ICC in bothcontrol and RA-treated HSC.However,RA hadno influence on the mRNA levels of p16,p21 orp27 as determined by ISH.CONCLISION Up-regulation of p16 and p21 on post-transcriptional level may contribule, in part to RA inhibition of TGF-β1-initiated rat HSC activation in vitro.
基金Key Program of National Natural Science Foundation of China (No.30530770)Scientific Research Program of Shanghai Municipal Health Bureau, China (No.054072)
文摘·AIM:All-trans retinoic acid (RA) is the only extrinsic biochemical candidate known to date that could act as a growth controller,the aim of this study was to investigate the expression cellular retinoic acid binding proteins I (CRABP-I) and retinoic acid receptor-β (RAR-β) in retina of the guinea pig eyes with experimental myopia.·METHODS:Ninety guinea pigs aged 14 days were equally and randomly divided into three groups:form deprivation (FD),-5D lens,and control.The diffusers for FD were white translucent hemispheres,and-5D lenses were used to introduce hyperopic defocus.Refraction was measured with streak retinoscopy after cycloplegia,and axial length was calculated with Cinescan A/B ultrasonography.Retina harvested at different time points were used to measure RA level with HPLC and expressions of cellular retinoic acid binding proteins I (CRABP-I) and RA receptor-β (RAR-β) were assayed with Western blot and Real-time PCR.SPSS13.0 software was used for statistical analysis.·RESULTS:Up-regulations of CRABP-I and RAR-β in ocular tissues correlated with changes in the refractive status and growth rate of the guinea pig eye (P <0.05).14 days of monocular form-deprivation led to-5.14D myopia and a 0.281mm axial elongation;14 days of monocular defocus produced-3.64D myopia and a 0.163 mm axial elongation.The level of retinal RA started to elevate in 7 days (P <0.05) after visual manipulation in both FD and-5D lens groups and became more prominent by 14 days (P <0.01).The expressions of CRABP-I and RAR-β increased by 14 days after visual manipulation (P <0.05),the mRNA level of RAR-β,however,increased by 7 days after visual manipulation (P <0.05),which suggested that changes of expressions of CRABP-I and RAR-β might lag behind the change of RA.·CONCLUSION:The levels of CRABP-I and RAR-β were elevated in retina of the guinea pig eye with experimental myopia.During the progression of experimental myopia,the retinal RA level increased rapidly,and there might be a positive feedback between the increase of RA and up-regulation of RAR-β.·
基金National Natural Science Foundation of China (No.81070752)
文摘AIM: To investigate the role of retinoic acid (RA) and retinaldehyde dehydrogenase-2 (RALDH2) of retina and choroid in the guinea pig lens-induced myopic eyes. METHODS: Totally 45 guinea pigs, at age of three weeks, were randomly assigned into three groups: the normal control, the lens-induced group and the recovering group. Out of focus was induced by the -6.00D concave lens on the left eye, and lasted for 15 days. All animals underwent biometric measurement (corneal radius of curvature, refraction and axial length). Subsequently, RA content in the retina and RPE/choriod complex was detected by reversed- phase high-performance liquid chromatography. RALDH2 protein in the retina and RPE/choriod complex was evaluated by the immunohistochemical staining and Western blotting. RESULTS: After wearing -6.00D lens for 15 days, axial length of the lens-induced eye extends and myopia was formed, with RA contents increasing in both the neural retina and RPE/choroid complex. Comparing with the lens-induced group, myopic degree significantly relieved, and its RA contents in both the neural retina and RPE/choroid complex decreased in the recovering group. In the normal control, RALDH2 protein was expressed positively in the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL) and lateral border of outer nuclear layer (ONL). Retinal RALDH2 protein increased in the lens-induced group, and was also positive in the outer plexiform layer (OPL). In the recovering group, retinal RALDH2 protein attenuated the expression in the OPL turns to negative. RALDH2 protein was not expressed in the choroid of any group. CONCLUSION: RA of retina and chorid participates in the regulation of the lens-induced myopia in guinea pigs, which may be related with retinal RALDH2 protein.
基金Supported by the National Outstanding Youth Science Foundation of China(B type),No.39825502 National Natural Science Foundation of China,No.39880015.
文摘AIM To evaluate the role of RARa gene in mediating the growth inhibitory effect of ail-trans retinoic acid (ATRA)on gastric cancer cells.``METHODS The expression levels of retinoic acid receptors (RARs) in gastric cancer cells were detected by Northern blot. Transient transfection and chlorophenicol acetyl transferase (CAT) assay were used to show the transcriptional activity of β retinoic acid response element (βRARE) and AP-l activity. Cell growth inhibition was determined by MTT assay and anchorage-independent growth assay, respectively. Stable transfection was performed by the method of Lipofectamine, and the cells were screened by G418.``RESULTS ATRA could induce expression level of RARα in MGC80-3, BGCC8823 and SGC-7901 cells obviously,resulting in growth inhibition of these cell lines. After sense RARa gene was transfected into MKN-45 cells that expressed rather Iow level of RARα and could not be induced by ATRA, the cell growth was inhibited by ATRA markedly. In contrast, when antisense RARα gene was transfected into BGC-825 cells, a little inhibitory effect by ATRA was seen, compared with the parallel BGC-823cells. In transient transfection assay, ATRA effectively induced transcriptional activity of βRARE in MGC80-3,BGC.823, SGC-7902 and MKN/RARa cell lines, but not in MKN-45 and BGC/aRARa cell lines. Similar results were observed in measuring anti-AP-l activity by ATRA in these cancer cell lines.``CONCLUSION ATRA inhibits the growth of gastric cancer cells by up-regulating the level of RARa; RARa is the major mediator of ATRA action in gastric cancer cells; and adequate level of RAPa is required for ATRA effect on gastric cancer cells.
基金Supported by National Natural Science Foundation of ChinaNo.81273261
文摘AIM: To study the role of autophagy and the relationship between retinoic acid receptor α(RARα) and autophagy in liver ischemia and reperfusion(IR) injury.METHODS: All-trans retinoic acid(ATRA) was administered to mice for two weeks before operation. Reverse transcription-polymerase chain reaction and Western blot were used to detect the expression levels of related factors. To demonstrate the role of RARα,LE540,a RARα inhibitor,was used to treat hepatocytes injured by H2O2 in vitro.RESULTS: ATRA pretreatment noticeably diminished levels of serum alanine aminotransferase and as-partate aminotransferase as well as the degree of histopathological changes. Apoptosis was also inhibited,whereas autophagy was promoted. In vitro,RARα was inhibited by LE540,which resulted in decreased autophagy and increased apoptosis. Similarly,the expression of Foxo3 a and p-Akt was downregulated,but Foxo1 expression was upregulated.CONCLUSION: This research provides evidence that ATRA can protect the liver from IR injury by promoting autophagy,which is dependent on Foxo3/p-Akt/Foxo1 signaling.
基金supported by the Natural Science Foundation of Shanghai of China,No.16ZR1410500(to SZD)
文摘Retinoic acid can cause many types of cells,including mouse neuroblastoma Neuro-2 A cells,to differentiate into neurons.However,it is still unknown whether microRNAs(miRNAs)play a role in this neuronal differentiation.To address this issue,real-time polymerase chain reaction assays were used to detect the expression of several differentiation-related miRNAs during the differentiation of retinoic acid-treated Neuro-2 A cells.The results revealed that miR-124 and miR-9 were upregulated,while miR-125 b was downregulated in retinoic acid-treated Neuro-2 A cells.To identify the miRNA that may play a key role,miR-124 expression was regulated by transfection of miRNA mimics or inhibitors.Morphological analysis results showed that inhibition of miR-124 expression reversed the effects of retinoic acid on neurite outgrowth.Moreover,miR-124 overexpression alone caused Neuro-2 A cells to differentiate into neurons,and its inhibitor could block this effect.These results suggest that miR-124 plays an important role in retinoic acid-induced differentiation of Neuro-2 A cells.
文摘Inclusion compound of retinoic acid with (-cyclodextrin was prepared by coprecipitating method, the structure of resulting product was studied by elemental analysis, differential scanning caloriemetry(DSC) analysis, FT-IR spectroscopy and X-ray diffractometry, and the formed supramolecule self-assembles in aqueous solution according to molar ratio 2:1 of host-guest.
基金Supported by National Natural Science Foundation of China(No.81300727)Jilin University Basic Scientific Research Operating Expenses Fund(Research Fund of the Bethune B Plan of Jilin University,2012No.2012230)
文摘·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.
基金supported by the National Natural Science Foundation of China,No.81671469,81171072(to ZWY)the National Basic Research Program of China(973 Program),No.2013CB945402(to ZWY)the Program for Liaoning Innovative Research Team in University of China,No.LT2013016(to ZWY)
文摘O6-methylguanine DNA methyltransferase(MGMT), a DNA repair enzyme, has been reported in some congenital malformations, but it is less frequently reported in neural tube defects. This study investigated MGMT mRNA expression and methylation levels in the early embryo and in different embryonic stages, as well as the relationship between MGMT and neural tube defects. Spina bifida aperta was induced in rats by a single intragastric administration of all-trans retinoic acid on embryonic day(E) 10, whereas normal control rats received the same amount of olive oil on the same embryonic day. DNA damage was assessed by detecting γ-H2 A.X in spina bifida aperta rats. Real time-polymerase chain reaction was used to examine mRNA expression of MGMT in normal control and spina bifida aperta rats. In normal controls, the MGMT mRNA expression decreased with increasing embryonic days, and was remarkably reduced from E11 to E14, reaching a minimum at E18. In the spina bifida aperta model, γ-H2 A.X protein expression was increased, and mRNA expression of MGMT was markedly decreased on E14, E16, and E18. Bisulfite sequencing polymerase chain reaction for MGMT promoter methylation demonstrated that almost all CpG sites in the MGMT promoter remained unmethylated in both spina bifida aperta rats and normal controls, and there was no significant difference in methylation level between the two groups on either E14 or E18. Our results show that DNA damage occurs in spina bifida aperta rats. The mRNA expression of MGMT is downregulated, and this downregulation is independent of promoter DNA methylation.
基金supported by National Natural Science Foundation of China(No.81773286,81971718,and 81772632)Beijing Baiqianwan Talents Project(No.2020A47)Science Foundation of Peiking University Cancer Hospital(No.2020-9)。
文摘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.
基金Supported by Research Chair Grant from the National Science and Technology Development Agency,No.P-15-50004the Center of Excellence in Clinical Virology,Chulalongkorn Unversity and King Chulalongkourn Memorial Hospital,No.GCE 5900930-005the Rachadapisek Sompote Fund of Chulalongkorn University for postdoctoral fellowships to Chaninya Wongwarangkana
文摘Cervical cancer is one of the leading causes of death in women worldwide, particularly in developing countries. Human papillomavirus has been reported as one of the key etiologic factors in cervical carcinoma. Likewise, epigenetic aberrations have ability to regulate cancer pathogenesis and progression. Recent research suggested that methylation has been detected already at precancerous stages, which methylation markers may have significant value in cervical cancer screening. The retinoic acid receptor beta (RARβ) gene, a potential tumor suppressor gene, is usually expressed in normal epithelial tissue. Methylation of CpG islands in the promoter region of the RARβ gene has been found to be associated with the development of cervical cancer. To investigate whether RARβ methylation is a potential biomarker that predicts the progression of invasive cancer, we reviewed 14 previously published articles related to RARβ methylation. The majority of them demonstrated that the frequency of RARβ promoter methylation was significantly correlated with the severity of cervical epithelium abnormalities. However, methylation of a single gene may not represent the best approach for predicting disease prognosis. Analyzing combinations of aberrant methylation of multiple genes may increase the sensitivity, and thus this approach may serve as a better tool for predicting disease prognosis.
基金supported by National Natural Science Foundation Projects(No.81671462)National Natural Science Foundation for Young Scientists of China(No.81300487)+1 种基金Shanxi Province Science and Technology Creative Team(No.2013131016)Shanxi Province Overseas Returnee Scientific Research Fund(No.2013-key 5)
文摘Objective This study aimed to investigate the expression pattern and function of Nuclear receptor subfamily 2 group E member 1(Nr2e1) in retinoic acid(RA)-induced brain abnormality. Methods The mouse model of brain abnormality was established by administering 28 mg/kg RA, and neural stem cells(NSCs) were isolated from the mouse embryo and cultured in vitro. Nr2e1 expression was detected by whole mount in situ hybridization, RT-PCR, and Western blotting. Nr2e1 function was determined by transducing Nr2e1 shRNA into NSCs, and the effect on the sonic hedgehog(Shh) signaling pathway was assessed in the cells. In addition, the regulation of Nr2e1 expression by RA was also determined in vitro. Results Nr2e1 expression was significantly downregulated in the brain and NSCs of RA-treated mouse embryos, and knockdown of Nr2e1 affected the proliferation of NSCs in vitro. In addition, a similar expression pattern of Nr2e1 and RA receptor(RAR) α was observed after treatment of NSCs with different concentrations of RA. Conclusion Our study demonstrated that Nr2e1 could be regulated by RA, which would aid a better understanding of the mechanism underlying RA-induced brain abnormality.
文摘All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutations is associated with increased risk of relapse.The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA,idarubicin(IDA)and/or ATO,followed by ATRA plus ATO along with anthracycline,as consolidation therapy.A total of 72 patients newly diagnosed with APL were included in this study.83.3%of the patients achieved complete remission(CR)after induction therapy.FLT3-ITD mutations were detected in 16(22.2%)patients and closely related to bcr-3 PML-RARa transcript(P<0.001).The 5-year overall survival(OS)rate was 100%in both FLT3-ITDposltlve and FLT3-ITD^(negatlve)groups,and there was no significant difference in 5-year event-free survival(EFS)between the two groups(78.3%vs.83.3%,P=0.85).ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.
文摘Objective: The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and p16 among benign prostatic hyperplasia (BPH) and prostate cancer patients. Methods: In this case-control study, 63 patients were included in three groups; 21 with BPH as the control group, 21 with prostate cancer and good prognostic factors (based on prostate-specific antigen, Gleason score and stage) as good prognosis group, and 21 with prostate cancer and poor prognostic features as poor prognosis group. The prostate biopsy specimen of each individual was examined for hypermethylation of RARB and p16 promoters by methylation specific PCR (MSPCR). Results: Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis were positive for RARB methylation, which were significantly higher than controls (P <0.0001). p16 promoter methylation was shown in 19.0% and 47.6% patients with good and poor prognosis, respectively. The RARB and p16 promoter methylation in the poor prognosis group was significantly higher than that in the good prognosis group (P =0.02 for RARB and P<0.0001 for p16). Conclusion: Hypermethylation of RARB and p16 promoters may predict prognosis in prostate cancer.
