Objective:The neurotoxicity of carbon monoxide(CO)to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning(DEACMP).Our previous study found that retinoic acid...Objective:The neurotoxicity of carbon monoxide(CO)to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning(DEACMP).Our previous study found that retinoic acid(RA)can suppress the neurotoxic effects of CO.This study further explores,in vivo and in vitro,the molecular mechanisms by which RA alleviates CO-induced central nervous system damage.Methods:A cytotoxic model was established using the mouse hippocampal neuronal cell line HT22 and primary oligodendrocytes exposed to CO,and a DEACMP animal model was established in adult Kunming mice.Cell viability and apoptosis of hippocampal neurons and oligodendrocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay and Annexin V/propidium iodide(PI)double staining.The transcriptional and protein expression of each gene was detected using real time fluorescence quantitative PCR(RT-qPCR)and Western blotting.Long noncoding RNA(lncRNA)SNHG15 and LINGO-1 were knocked down or overexpressed to observe changes in neurons and oligodendrocytes.In DEACMP mice,SNHG15 or LINGO-1 were knocked down to assess changes in central nervous tissue and downstream protein expression.Results:RA at 10 and 20μmol/L significantly reversed CO-induced apoptosis of hippocampal neurons and oligodendrocytes,downregulation of SNHG15 and LINGO-1,and upregulation of brain-derived neurotrophic factor(BDNF)and tyrosine kinase receptor B(TrkB)(all P<0.05).Overexpression of SNHG15 or LINGO-1 weakened the protective effect of RA against CO-induced cytotoxicity(all P<0.05).Knockdown of SNHG15 or LINGO-1 alleviated CO-induced apoptosis of hippocampal neurons and oligodendrocytes and upregulated BDNF and TrkB expression levels(all P<0.05).Experiments in DEACMP model mice showed that knockdown of SNHG15 or LINGO-1 mitigated central nervous system injury in DEACMP(all P<0.05).Conclusion:RA alleviates CO-induced apoptosis of hippocampal neurons and oligodendrocytes,thereby reducing central nervous system injury and exerting neuroprotective effects.LncRNA SNHG15 and LINGO-1 are key molecules mediating RA induced inhibition of neuronal apoptosis and are associated with the BDNF/TrkB pathway.These findings provide a theoretical framework for optimizing the clinical treatment of DEACMP and lay an experimental foundation for elucidating its molecular mechanisms.展开更多
Dear Editor,Autism is a neurodevelopmental disorder that poses a significant threat to human health,with its primary manifestations including social disability,impairments in verbal and non-verbal communication,and th...Dear Editor,Autism is a neurodevelopmental disorder that poses a significant threat to human health,with its primary manifestations including social disability,impairments in verbal and non-verbal communication,and the presence of narrow interests along with stereotypical repetitive behaviors.Recent research has shown that the Sox5 transcription factor plays a significant role in the axonal projection,migration,localization,and communication of newly generated neurons[1].Defects in the Sox5 gene are known to increase the risk of autism.A clinical study on 16 patients with Sox5 gene defects found that Sox5 haploinsufficiency is closely linked to key traits like developmental delay,language delay,behavioral problems,and minor deformities such as a protruding forehead and a wide,flat nasal bridge[2].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
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 the...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.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
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, especi...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.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 add (RA) and retinaldehyde dehydrogenase-2 (RALDH(2)) of retina and choroid in the guinea pig lens-induced myopic eyes. METHODS: Totally 45 guinea pigs, at age of three weeks, ...AIM: To investigate the role of retinoic add (RA) and retinaldehyde dehydrogenase-2 (RALDH(2)) 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. RALDH(2) 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, RALDH(2) protein was expressed positively in the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL) and lateral border of outer nuclear layer (ONL). Retinal RALDH(2) protein increased in the lens-induced group, and was also positive in the outer plexiform layer (OPL). In the recovering group, retinal RALDH(2) protein attenuated the expression in the OPL turns to negative. RALDH(2) 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 RALDH(2) protein.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
AIM To evaluate the role of RARα gone in mediating the growth inhibitory effect of all-trans retinoic acid(ATRA) on gastric cancer cells. METHODS The expression levels of retinoic acid receptors(PARs)in gastric cance...AIM To evaluate the role of RARα gone in mediating the growth inhibitory effect of all-trans retinoic acid(ATRA) on gastric cancer cells. METHODS The expression levels of retinoic acid receptors(PARs)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 (βPARE)and AP-1 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,BGC-823 and SGC-7901 cells obviously, resulting in growth inhibition of these cell lines.After sense RARα gone was transfected into MKN-45 cells that expressed rather low level of RARα and could not be induced by ATPA,the cell growth was inhibited by ATPA markedly.In contrast,when antisense RARα gone was transfected into BGC-823 cells,a little inhibitory effect by ATPA was seen,compared with the parallel BGC-823 cells.In transient transfection assay,ATPA effectively induced transcriptional activity of βRARE in MGC80-3, BGC-823,SGC-7902 and MKN/RARα cell lines,but not in MKN-45 and BGC/aRARα cell lines.Similar results were observed in measuring anti-AP-1 activity by ATPA in these cancer cell lines. CONCLUSION ATRA inhibits the growth of gastric cancer cells by up-regulating the level of RARα; RARα is the major mediator of ATRA action in gastric cancer cells;and adequate level of RARα is required for ATRA effect on gastric cancer cells.展开更多
Bone marrow-derived mesenchymal stem cells are multipotent stem cells, an attractive resource for regenerative medicine. Accumulating evidence suggests that all-trans retinoic acid plays a key role in the devel- opmen...Bone marrow-derived mesenchymal stem cells are multipotent stem cells, an attractive resource for regenerative medicine. Accumulating evidence suggests that all-trans retinoic acid plays a key role in the devel- opment and differentiation of smooth muscle cells. In the present study, we demonstrate, for the first time, that rabbit bone marrow-derived mesenchymal stem cells differentiate into smooth muscle cells upon the treatment with all-trans retinoic acid. AII-trans retinoic acid increased the expression of myocardin, caldesmon, 22-kDa smooth muscle cell- specific protein （SM22Q）, and SM-myosin heavy chains in rabbit bone marrow-derived mesenchymal stem cells, as detected by reverse transcription polymerase chain reaction （PCR）. Immunostaining of SM22a and SM-myosin heavy chains using monoclonal antibodies also indicated smooth muscle cell differentiation of rabbit bone marrow- derived mesenchymal stem cells following the treatment with all-trans retinoic acid. In addition, more than 47% of bone marrow-derived mesenchymal stem cells demonstrated the contractile phenotype of smooth muscle cells. Western blot results showed that SM-1 and SM-2 were highly expressed in the differentiated cells. These results suggest that all-trans retinoic acid may serve as a potent agent for functional smooth muscle cell differentiation in tissue engineering.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
Objective To evaluate the effects of retinoic acid （RA） on expression of bone morphogenetic protein 7 （ BMP-7 ） in rat fetus with cleft palate, and the effects of RA on proliferation and apoptosis of osteoblasts. ...Objective To evaluate the effects of retinoic acid （RA） on expression of bone morphogenetic protein 7 （ BMP-7 ） in rat fetus with cleft palate, and the effects of RA on proliferation and apoptosis of osteoblasts. Methods All-trans RA （ATRA） was used to induce congenital cleft palate in Wistar rat. BMP-7 mRNA expression in maxillary bone tissue of fetal rats was measured by Northern blotting analysis. Flow cytometry and MTF assay were used to measure the apoptosis and proliferation of ATRA-treated MC-3T3-E1 cells. BMP-7 mRNA and protein expressions in ATRA-treated MC-3T3-E1 cells were detected by RT-PCR and Western blotting analysis. Remilts ATRA could induce cleft palate of rat fetus. The incidence rate of cleft palate induced by 100 mg/kg AT-RA （45.5%） was significantly higher than 50 mg/kg ATRA （ 12.5%, P 〈 0. 05 ）. BMP-7 mRNA expression decreased in maxillary bone tissue of rat fetus with cleft palate. MC-3T3-E1 cells proliferation treated with 1 × 10^-6 mol/L ATRA decreased by 60%, the cell apoptosis increased by 2 times. BMP-7 mRNA and protein levels in MC-3T3-E1 cells treated with 1 × 10^-6 mol/L ATRA decreased by 60% and 80%, respectively, compared with ATRA-untreated cells （ P 〈 0.05 ）. Conclusions BMP-7 may play an important role in embryonic palate development. RA may possess the ability to down-regulate cell proliferation through regulation of BMP-7 gene expression.展开更多
To illuminate the regulating effect of all trans retinoic acid (ATRA ) on gap junctional intercellular communication (GJIC) and connexin 43 (Cx43) ge ne expression in glioma cells, which is tissue and organ specific. ...To illuminate the regulating effect of all trans retinoic acid (ATRA ) on gap junctional intercellular communication (GJIC) and connexin 43 (Cx43) ge ne expression in glioma cells, which is tissue and organ specific. Method. Rat C6 glioma cells were exposed to ATRA at a concentration of 1, 10, 10 0 μmol/L respectively, and the GJIC function of the cells was examined with scr ape loading dye transfer assay 24 hours, 48 hours and 72 hours after ATRA treat ment. The effect of ATRA on Cx43 gene expression was measured with semiquantitat ive reverse transcription polymerase chain reaction (RT PCR) 24 hours after ATR A exposure. Results. The GJIC function of C6 glioma cells was significantly increased by ATR A at each concentration applied. The dye passed 4 to 5 rows of cells from the sc raping edge in ATRA treated cells, but only 1 or 2 rows in the control. The augm ent effect was observed 24 hours after each concentration ATRA treatment, and la sted till 72 hours after treatment with 1μmol/L and 10μmol/L ATRA. Forty eigh t hours after exposed to 100μmol/L ATRA, the enhancement of GJIC was less obvi ous. There was no significant increase induced by ATRA on the transcription of C x43 gene, as demonstrated by semiquantitative RT PCR. Conclusion. ATRA turned out to be a potent enhancer on GJIC function in C6 gliom a cells, and the enhancement effect was most probable at post transcriptional l evel.展开更多
All-trans retinoid acid （ATRA） is one of the most potent and most thoroughly studied differentiation inducers that induce the differentiation and apoptosis of glioma cells. However, the effect of ATRA on angiogenesi...All-trans retinoid acid （ATRA） is one of the most potent and most thoroughly studied differentiation inducers that induce the differentiation and apoptosis of glioma cells. However, the effect of ATRA on angiogenesis of glioma re- mains poorly understood. We examined the effect of ATRA on the expression of vascular endothelial growth fac- tor （VEGF） in different glioma cell lines and investigated the underlying mechanism, intending to partially reveal the effects of ATRA on angiogenesis of glioma. Glioma cells were treated by ATRA at 5 and 10 μmol/L. The VEGF mRNA transcript levels were determined by real-time RT-PCR and the protein levels of VEGF in glioma cells were evaluated by Western blotting assays. Moreover, hypoxia-inducible factor-1α （HIF-la） mRNA expression was analyzed by using real-time RT-PCR. After treatment with 5 and 10 μmol/L ATRA, the VEGF mRNA tran- script levels in glioma cells increased remarkably, compared with that in the control group, and the relative protein expression of VEGF was also up-regulated. Meanwhile, the HIF-la mRNA expression also increased. ATRA in- creases the expression of VEGF in glioma cells at both transcriptional and translational levels.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
Objective To study the incidence of leukocytosis and retinoic acid （RA） syndrome in newly diagnosed and relapsed acute promyelocytic leukemia （APL） patients treated with arsenic trioxide （ATO）. Methods Thirty pa...Objective To study the incidence of leukocytosis and retinoic acid （RA） syndrome in newly diagnosed and relapsed acute promyelocytic leukemia （APL） patients treated with arsenic trioxide （ATO）. Methods Thirty patients with newly diagnosed or relapsed APL received ATO for remission induction at the dose of 10 mg/d. RA syndrome was defined when patient was with one or more of the following signs or symptoms： fever, dyspnea, serous cavity effusion, muscular pain, pulmonary infiltration, weight gain, or pulmonary infiltration on chest X-ray. Results Twenty-three （77%） patients achieved complete remission, mean time to remission was 37. 1 days. Leukocytosis was observed in 14 （47%） patients, mean time to leukocytosis was 12. 7 days, median baseline leukocyte count for patients with leukocytosis was 3.1 x 109/L, which was higher than that for patients who did not de,.＇elop leukocytosis （2.6 × 10^9/L, z = - 2. 635, P = 0. 008）. No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in 9 （30%） patients, mean time to diagnose of RA syndrome was 13.9 days, median baseline leukocyte count for patients with RA syndrome was 3.6 × 10^9/L, which was higher than that for patients who did not develop RA syndrome （2. 6 × 10^9/L, z = - 1. 909, P =0. 046）. No patient died of RA syndrome. Conclusion Leukocytosis and RA syndrome are associated with ATO and baseline leukocyte count respectively, and there is distinct link between leukocytosis and RA syndrome.展开更多
To investigate the protective effect of retinoic acid （RA） on hyperoxic lung injury and the role of RA as a modulator on mitogen-activated protein kinases （MAPKs）, gastation 21 d Sprague- Dawley （SD） fetuses （t...To investigate the protective effect of retinoic acid （RA） on hyperoxic lung injury and the role of RA as a modulator on mitogen-activated protein kinases （MAPKs）, gastation 21 d Sprague- Dawley （SD） fetuses （term = 22 d） were delivered by hysterotomy. Within 12-24 h of birth, premature rat pups were randomly divided into 4 groups （n= 12 each） ： air-exposed control group （group Ⅰ ） ; hyperoxia-exposed group （ group Ⅱ ）, air-exposed plus RA group （group Ⅲ ）, hyperoxia-exposed plus RA group （group Ⅳ）. Group Ⅰ , Ⅲ were kept in room air, and group Ⅱ , Ⅳ were placed in 85 % oxygen. The pups in groups Ⅲ and Ⅳ were intraperitoneally injected with RA （500 μg/kg every day）. All lung tissues of premature rat pups were collected at the 4th day after birth. Terminal transferase d-UTP nick end labeling （TUNEL） staining was used for the detection of cell apoptosis. The expression of PCNA was immunohistochemically detected. Western blot analysis was employed for the determination of phosphorylated and total nonphosphorylated ERKs, JNKs or p38. Our results showed that lungs from the pups exposed to hyperoxia for 4 d exhibited TUNEL-positive nuclei increased markedly throughout the parenchyma （P〈0.01）, and decreased significantly after RA treatment （P〈0.01）. The index of PCNA-positive cells was significantly decreased （P〈0.01）, and was significantly increased by RA treatment （P〈0.01）. The air-space size was significantly enlarged, secondary crests were markedly decreased in hyperoxia-exposed animals. RA treatment improved lung air spaces and secondary crests in air-exposed pups, hut had no effect on hyperoxia-exposure pups. Western blotting showed that the amounts of JNK, p38 and ERK proteins in hyperoxia-exposure or RA-treated lung tissues were same as those in untreated lung tissues （P〈0.05）, whereas activation of these MAPKs was markedly altered by hyperoxia and RA. After hyperoxia exposure, p-ERK1/2, p-JNK1/2 and p-p38 were dramatically increased （P〈0.01）, whereas p-JNK1/2 and p-p38 were markedly declined and p-ERK1/2 was further elevated by RA treatment （P〈0.01）. It is concluded that RA could decrease cell apoptosis and stimulate cell proliferation under hyperoxic condition. The protection Of RA on hyperoxia-induced lung injury was related＇to the regulation of MAP kinase activation.展开更多
基金supported by the Natural Science Foundation of Hunan Province(2021JJ31089)the Scientific Research Project of Health Commission of Hunan Province(202203104548),China。
文摘Objective:The neurotoxicity of carbon monoxide(CO)to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning(DEACMP).Our previous study found that retinoic acid(RA)can suppress the neurotoxic effects of CO.This study further explores,in vivo and in vitro,the molecular mechanisms by which RA alleviates CO-induced central nervous system damage.Methods:A cytotoxic model was established using the mouse hippocampal neuronal cell line HT22 and primary oligodendrocytes exposed to CO,and a DEACMP animal model was established in adult Kunming mice.Cell viability and apoptosis of hippocampal neurons and oligodendrocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay and Annexin V/propidium iodide(PI)double staining.The transcriptional and protein expression of each gene was detected using real time fluorescence quantitative PCR(RT-qPCR)and Western blotting.Long noncoding RNA(lncRNA)SNHG15 and LINGO-1 were knocked down or overexpressed to observe changes in neurons and oligodendrocytes.In DEACMP mice,SNHG15 or LINGO-1 were knocked down to assess changes in central nervous tissue and downstream protein expression.Results:RA at 10 and 20μmol/L significantly reversed CO-induced apoptosis of hippocampal neurons and oligodendrocytes,downregulation of SNHG15 and LINGO-1,and upregulation of brain-derived neurotrophic factor(BDNF)and tyrosine kinase receptor B(TrkB)(all P<0.05).Overexpression of SNHG15 or LINGO-1 weakened the protective effect of RA against CO-induced cytotoxicity(all P<0.05).Knockdown of SNHG15 or LINGO-1 alleviated CO-induced apoptosis of hippocampal neurons and oligodendrocytes and upregulated BDNF and TrkB expression levels(all P<0.05).Experiments in DEACMP model mice showed that knockdown of SNHG15 or LINGO-1 mitigated central nervous system injury in DEACMP(all P<0.05).Conclusion:RA alleviates CO-induced apoptosis of hippocampal neurons and oligodendrocytes,thereby reducing central nervous system injury and exerting neuroprotective effects.LncRNA SNHG15 and LINGO-1 are key molecules mediating RA induced inhibition of neuronal apoptosis and are associated with the BDNF/TrkB pathway.These findings provide a theoretical framework for optimizing the clinical treatment of DEACMP and lay an experimental foundation for elucidating its molecular mechanisms.
基金supported by the Fujian Provincial Science and Technology Youth Project(2021111)the Technology Innovation Joint Funding Project(2023Y9289)the National Natural Science Foundation of China(82401643).
文摘Dear Editor,Autism is a neurodevelopmental disorder that poses a significant threat to human health,with its primary manifestations including social disability,impairments in verbal and non-verbal communication,and the presence of narrow interests along with stereotypical repetitive behaviors.Recent research has shown that the Sox5 transcription factor plays a significant role in the axonal projection,migration,localization,and communication of newly generated neurons[1].Defects in the Sox5 gene are known to increase the risk of autism.A clinical study on 16 patients with Sox5 gene defects found that Sox5 haploinsufficiency is closely linked to key traits like developmental delay,language delay,behavioral problems,and minor deformities such as a protruding forehead and a wide,flat nasal bridge[2].
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.
基金a grant from the Bureau of Health, Sichuan Province, China (No. 050209).
文摘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.
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.
文摘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.
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 add (RA) and retinaldehyde dehydrogenase-2 (RALDH(2)) 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. RALDH(2) 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, RALDH(2) protein was expressed positively in the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL) and lateral border of outer nuclear layer (ONL). Retinal RALDH(2) protein increased in the lens-induced group, and was also positive in the outer plexiform layer (OPL). In the recovering group, retinal RALDH(2) protein attenuated the expression in the OPL turns to negative. RALDH(2) 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 RALDH(2) protein.
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 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 RARα gone in mediating the growth inhibitory effect of all-trans retinoic acid(ATRA) on gastric cancer cells. METHODS The expression levels of retinoic acid receptors(PARs)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 (βPARE)and AP-1 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,BGC-823 and SGC-7901 cells obviously, resulting in growth inhibition of these cell lines.After sense RARα gone was transfected into MKN-45 cells that expressed rather low level of RARα and could not be induced by ATPA,the cell growth was inhibited by ATPA markedly.In contrast,when antisense RARα gone was transfected into BGC-823 cells,a little inhibitory effect by ATPA was seen,compared with the parallel BGC-823 cells.In transient transfection assay,ATPA effectively induced transcriptional activity of βRARE in MGC80-3, BGC-823,SGC-7902 and MKN/RARα cell lines,but not in MKN-45 and BGC/aRARα cell lines.Similar results were observed in measuring anti-AP-1 activity by ATPA in these cancer cell lines. CONCLUSION ATRA inhibits the growth of gastric cancer cells by up-regulating the level of RARα; RARα is the major mediator of ATRA action in gastric cancer cells;and adequate level of RARα is required for ATRA effect on gastric cancer cells.
基金Project supported by the Science and Technology Department of Zhejiang Province (No. J20020579-30116)the Central Hospital of Huzhou City (No. H20010984-32536),Zhejiang Province,China
文摘Bone marrow-derived mesenchymal stem cells are multipotent stem cells, an attractive resource for regenerative medicine. Accumulating evidence suggests that all-trans retinoic acid plays a key role in the devel- opment and differentiation of smooth muscle cells. In the present study, we demonstrate, for the first time, that rabbit bone marrow-derived mesenchymal stem cells differentiate into smooth muscle cells upon the treatment with all-trans retinoic acid. AII-trans retinoic acid increased the expression of myocardin, caldesmon, 22-kDa smooth muscle cell- specific protein （SM22Q）, and SM-myosin heavy chains in rabbit bone marrow-derived mesenchymal stem cells, as detected by reverse transcription polymerase chain reaction （PCR）. Immunostaining of SM22a and SM-myosin heavy chains using monoclonal antibodies also indicated smooth muscle cell differentiation of rabbit bone marrow- derived mesenchymal stem cells following the treatment with all-trans retinoic acid. In addition, more than 47% of bone marrow-derived mesenchymal stem cells demonstrated the contractile phenotype of smooth muscle cells. Western blot results showed that SM-1 and SM-2 were highly expressed in the differentiated cells. These results suggest that all-trans retinoic acid may serve as a potent agent for functional smooth muscle cell differentiation in tissue engineering.
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.
基金Supported by National Natural Science Foundation of China(30500414)Scientific Research Project in Department of Education of Liaoning Province(05L508,20061010)
文摘Objective To evaluate the effects of retinoic acid （RA） on expression of bone morphogenetic protein 7 （ BMP-7 ） in rat fetus with cleft palate, and the effects of RA on proliferation and apoptosis of osteoblasts. Methods All-trans RA （ATRA） was used to induce congenital cleft palate in Wistar rat. BMP-7 mRNA expression in maxillary bone tissue of fetal rats was measured by Northern blotting analysis. Flow cytometry and MTF assay were used to measure the apoptosis and proliferation of ATRA-treated MC-3T3-E1 cells. BMP-7 mRNA and protein expressions in ATRA-treated MC-3T3-E1 cells were detected by RT-PCR and Western blotting analysis. Remilts ATRA could induce cleft palate of rat fetus. The incidence rate of cleft palate induced by 100 mg/kg AT-RA （45.5%） was significantly higher than 50 mg/kg ATRA （ 12.5%, P 〈 0. 05 ）. BMP-7 mRNA expression decreased in maxillary bone tissue of rat fetus with cleft palate. MC-3T3-E1 cells proliferation treated with 1 × 10^-6 mol/L ATRA decreased by 60%, the cell apoptosis increased by 2 times. BMP-7 mRNA and protein levels in MC-3T3-E1 cells treated with 1 × 10^-6 mol/L ATRA decreased by 60% and 80%, respectively, compared with ATRA-untreated cells （ P 〈 0.05 ）. Conclusions BMP-7 may play an important role in embryonic palate development. RA may possess the ability to down-regulate cell proliferation through regulation of BMP-7 gene expression.
文摘To illuminate the regulating effect of all trans retinoic acid (ATRA ) on gap junctional intercellular communication (GJIC) and connexin 43 (Cx43) ge ne expression in glioma cells, which is tissue and organ specific. Method. Rat C6 glioma cells were exposed to ATRA at a concentration of 1, 10, 10 0 μmol/L respectively, and the GJIC function of the cells was examined with scr ape loading dye transfer assay 24 hours, 48 hours and 72 hours after ATRA treat ment. The effect of ATRA on Cx43 gene expression was measured with semiquantitat ive reverse transcription polymerase chain reaction (RT PCR) 24 hours after ATR A exposure. Results. The GJIC function of C6 glioma cells was significantly increased by ATR A at each concentration applied. The dye passed 4 to 5 rows of cells from the sc raping edge in ATRA treated cells, but only 1 or 2 rows in the control. The augm ent effect was observed 24 hours after each concentration ATRA treatment, and la sted till 72 hours after treatment with 1μmol/L and 10μmol/L ATRA. Forty eigh t hours after exposed to 100μmol/L ATRA, the enhancement of GJIC was less obvi ous. There was no significant increase induced by ATRA on the transcription of C x43 gene, as demonstrated by semiquantitative RT PCR. Conclusion. ATRA turned out to be a potent enhancer on GJIC function in C6 gliom a cells, and the enhancement effect was most probable at post transcriptional l evel.
文摘All-trans retinoid acid （ATRA） is one of the most potent and most thoroughly studied differentiation inducers that induce the differentiation and apoptosis of glioma cells. However, the effect of ATRA on angiogenesis of glioma re- mains poorly understood. We examined the effect of ATRA on the expression of vascular endothelial growth fac- tor （VEGF） in different glioma cell lines and investigated the underlying mechanism, intending to partially reveal the effects of ATRA on angiogenesis of glioma. Glioma cells were treated by ATRA at 5 and 10 μmol/L. The VEGF mRNA transcript levels were determined by real-time RT-PCR and the protein levels of VEGF in glioma cells were evaluated by Western blotting assays. Moreover, hypoxia-inducible factor-1α （HIF-la） mRNA expression was analyzed by using real-time RT-PCR. After treatment with 5 and 10 μmol/L ATRA, the VEGF mRNA tran- script levels in glioma cells increased remarkably, compared with that in the control group, and the relative protein expression of VEGF was also up-regulated. Meanwhile, the HIF-la mRNA expression also increased. ATRA in- creases the expression of VEGF in glioma cells at both transcriptional and translational levels.
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.
文摘Objective To study the incidence of leukocytosis and retinoic acid （RA） syndrome in newly diagnosed and relapsed acute promyelocytic leukemia （APL） patients treated with arsenic trioxide （ATO）. Methods Thirty patients with newly diagnosed or relapsed APL received ATO for remission induction at the dose of 10 mg/d. RA syndrome was defined when patient was with one or more of the following signs or symptoms： fever, dyspnea, serous cavity effusion, muscular pain, pulmonary infiltration, weight gain, or pulmonary infiltration on chest X-ray. Results Twenty-three （77%） patients achieved complete remission, mean time to remission was 37. 1 days. Leukocytosis was observed in 14 （47%） patients, mean time to leukocytosis was 12. 7 days, median baseline leukocyte count for patients with leukocytosis was 3.1 x 109/L, which was higher than that for patients who did not de,.＇elop leukocytosis （2.6 × 10^9/L, z = - 2. 635, P = 0. 008）. No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in 9 （30%） patients, mean time to diagnose of RA syndrome was 13.9 days, median baseline leukocyte count for patients with RA syndrome was 3.6 × 10^9/L, which was higher than that for patients who did not develop RA syndrome （2. 6 × 10^9/L, z = - 1. 909, P =0. 046）. No patient died of RA syndrome. Conclusion Leukocytosis and RA syndrome are associated with ATO and baseline leukocyte count respectively, and there is distinct link between leukocytosis and RA syndrome.
基金This project was supported by a grant from the NationalKey Science and Technology Program of the Tenth Five-years-Plan (No .2004BA720A11) ,and a grant from Nation-al Natural Sciences Foundation of China (No .30471824)
文摘To investigate the protective effect of retinoic acid （RA） on hyperoxic lung injury and the role of RA as a modulator on mitogen-activated protein kinases （MAPKs）, gastation 21 d Sprague- Dawley （SD） fetuses （term = 22 d） were delivered by hysterotomy. Within 12-24 h of birth, premature rat pups were randomly divided into 4 groups （n= 12 each） ： air-exposed control group （group Ⅰ ） ; hyperoxia-exposed group （ group Ⅱ ）, air-exposed plus RA group （group Ⅲ ）, hyperoxia-exposed plus RA group （group Ⅳ）. Group Ⅰ , Ⅲ were kept in room air, and group Ⅱ , Ⅳ were placed in 85 % oxygen. The pups in groups Ⅲ and Ⅳ were intraperitoneally injected with RA （500 μg/kg every day）. All lung tissues of premature rat pups were collected at the 4th day after birth. Terminal transferase d-UTP nick end labeling （TUNEL） staining was used for the detection of cell apoptosis. The expression of PCNA was immunohistochemically detected. Western blot analysis was employed for the determination of phosphorylated and total nonphosphorylated ERKs, JNKs or p38. Our results showed that lungs from the pups exposed to hyperoxia for 4 d exhibited TUNEL-positive nuclei increased markedly throughout the parenchyma （P〈0.01）, and decreased significantly after RA treatment （P〈0.01）. The index of PCNA-positive cells was significantly decreased （P〈0.01）, and was significantly increased by RA treatment （P〈0.01）. The air-space size was significantly enlarged, secondary crests were markedly decreased in hyperoxia-exposed animals. RA treatment improved lung air spaces and secondary crests in air-exposed pups, hut had no effect on hyperoxia-exposure pups. Western blotting showed that the amounts of JNK, p38 and ERK proteins in hyperoxia-exposure or RA-treated lung tissues were same as those in untreated lung tissues （P〈0.05）, whereas activation of these MAPKs was markedly altered by hyperoxia and RA. After hyperoxia exposure, p-ERK1/2, p-JNK1/2 and p-p38 were dramatically increased （P〈0.01）, whereas p-JNK1/2 and p-p38 were markedly declined and p-ERK1/2 was further elevated by RA treatment （P〈0.01）. It is concluded that RA could decrease cell apoptosis and stimulate cell proliferation under hyperoxic condition. The protection Of RA on hyperoxia-induced lung injury was related＇to the regulation of MAP kinase activation.
