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
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
·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
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
·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
Human amniotic basement membrane (HABM) model and agarose drop explant method were used to in-vestigate the effects of retinoic acid(RA) on the invasive-ness alld adhesiveness to the basement membrane, and the migrati...Human amniotic basement membrane (HABM) model and agarose drop explant method were used to in-vestigate the effects of retinoic acid(RA) on the invasive-ness alld adhesiveness to the basement membrane, and the migration of a highly invassive human colorectal cancer cell line CCL229. Results showed that 5 ×106 MRA markedly reduced the in vitro invasiveness and adhesiveness to the HABM, and the migration of the CCL229 cells. In addi-tion, to elucidate the relation between expression of epider-mal growth factor receptor (EGFR) and the invasiveness of the colorectal carcinoma cells, two well-differentiated, but with different invasiveness colorectal cancer cell lines were compared at mRNA level for expressioll of EGFR by using EGFR cDNA probe labeled with digoxigenin (DIG). Expression of EGFR was showll to be markedly higher in the highly invassive CCL229 cells than that in the low in- vasive CX-1 cells. Furthermore, expression of EGFR in RA treated CCL229 cells gradually decreased with time,the level being the lowest on day 6 of the RA treatment.展开更多
Objective: To evaluate the expression and its clinical significance of interleukin 6 (IL-6), soluble glycoprotein 130 (sgp130), interleukin 8 (IL-8) and type A interleukin 8 receptor (IL-8RA) in acute promyelocytic le...Objective: To evaluate the expression and its clinical significance of interleukin 6 (IL-6), soluble glycoprotein 130 (sgp130), interleukin 8 (IL-8) and type A interleukin 8 receptor (IL-8RA) in acute promyelocytic leukemia (APL) patients during all-trans retinoic acid (ATRA) induction treatment. Methods: Plasma and bone marrow mononuclear cell (MNC) culture supernatant IL-6, sgp130, IL-8 concentration of 18 cases with APL were kinetically measured in vivo and in vitro (ELISA). Bone marrow MNC IL-8RA was measured by flow cytometry after being cultured with ATRA (10?6mmol/L). Results: Plasma IL-6, sgp130, IL-8 levels were higher than normal (P<0.05), IL-6, spg130 levels correlated with white blood cell (WBC) counts (P<0.05) while IL-8 levels correlated with body temperature (P<0.05) at initial diagnosis. After 72-hour incubation with ATRA, concentration of IL-6 of bone marrow MNC culture supernatant did not change, that of sgp130 mildly decreased, and IL-8 significantly decreased while the positive rate of IL-8RA on bone marrow MNC increased. During ATRA treatment, plasma IL-6 changes were correlated with WBC counts. Peak levels of IL-6 and WBC were lower in patients who received intermittent therapy than those who received continuous therapy. Plasma IL-6 and IL-8 were increased when complicated with infection and IL-8 seemed more sensitive. Conclusion: Plasma IL-6, sgp130, IL-8 levels may reflect patients' responsiveness to ATRA treatment, and could be used to predict hyperleukocytosis and intercurrent infection. ATRA induces APL cell differentiation possibly via sgp130 signal transducer chain. Measurement of sgp130 had certain meaning to prognosis.展开更多
All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodim...All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodimerize with retinoid X receptors (RXRs). RAR/RXR heterodimers function as ATRA-dependent transcriptional regulators by binding to retinoic acid response elements (RAREs). To identify RAR/RXR heterodimer-binding sites in the human genome, we performed a modified yeast one-hybrid assays and identified 193 RAR/RXR heterodimer-binding fragments in the human genome. The putative target genes included genes involved in development process and cell differentiation. Gel mobility shift assays indicated that 160 putative RAREs could directly interact with the RAR/RXR heterodimer. Moreover, 19 functional regulatory single nucleotide polymorphisms (rSNPs) on the RAR/RXR-binding sequences were identified by analyzing the difference in the DNA-binding affinities. These results provide insights into the molecular mechanisms underlying the physiological and pathological actions of RAR/RXR heterodimers.展开更多
The nuclear retinoic acid receptor may play a critical role in the process of lung carcinogenesis. Alteration or loss of nuclear retinoic acid receptors (RARs) has been associated with progression in premalignant and ...The nuclear retinoic acid receptor may play a critical role in the process of lung carcinogenesis. Alteration or loss of nuclear retinoic acid receptors (RARs) has been associated with progression in premalignant and malignant tissues and it is associated with malignant transformation in human cells. Vitamin A derivates, such as retinoic acid, have emerged as adjuvant to therapy in several types of cancer with favorable effects. Retinoic acid regulates the expression of target genes through the binding and activation of RARs, inhibiting growth proliferation. Diverse studies have evaluated different retinoids alone or in combination with chemotherapy in lung cancer, from which results have been controversial with benefits observed only in the subpopulation with high levels of triglycerides. Additionally, several large randomized trials using retinoids to prevent tobacco-related cancer have failed;due to the latter the use of retinoids in clinical trials remains controversial. However they could reduce the risk of cancer development in non-smokers. There is evidence that retinoids have different effects on lung cancer;still the identification of biomarkers could determinate their benefits as preventive or therapy agents. This review describes the RAR alterations during the development of Non-Small Cell Lung Cancer and sets out the importance of several cancer treatments with retinoid compounds.展开更多
To investigate whether treatment with retinoic acid (RA) could improve level of lung alveolarization and influence lung collagen in newborn rats exposed to hyperoxia, newborn Sprague-Dawley rats aged 2 days were ra...To investigate whether treatment with retinoic acid (RA) could improve level of lung alveolarization and influence lung collagen in newborn rats exposed to hyperoxia, newborn Sprague-Dawley rats aged 2 days were randomly assigned to 8 groups:(1) air, (2) O 2, (3) air+NS, (4) O 2+NS, (5) air+dex, (6) O 2+dex, (7) air+RA and (8) O 2+RA. Group 2, 4 6 and 8 were kept in chambers containing 85 % oxygen, the values were checked 3 times a day. The other 4 groups were exposed to room air. Level of alveolarization and lung collagen were analyzed at age of 14 or 21 days through radial alveolar counts, alveolar airspace measurements, type Ⅰ, Ⅲ collagen immunohistochemical methods (SP method) and image processing system. Transforming growth factor-β receptors and procollagen mRNA accumulation were examined at age of 14 days through immunohistochemical methods and in situ hybridization. Our results showed that radial alveolar counts were increased and distal airspace was enlarged in group 8. TypeⅠcollagen was markedly increased, and transforming growth factor-β receptors and procollagen mRNA were decreased by retinoic acid in bronchial epithelial cells, alveolar epithelial cells and alveolar intersitium. It is concluded that retinoic acid can partially reverse lung development arrest during exposure to hyperoxia by increasing lung collagen.展开更多
Breast cancer brain metastasis(BCBrM)is a crucial and hard area of research which guarantees an urgent need to understand the underlying molecular mechanisms.A recent study by Li et al.[1]published in Military Medical...Breast cancer brain metastasis(BCBrM)is a crucial and hard area of research which guarantees an urgent need to understand the underlying molecular mechanisms.A recent study by Li et al.[1]published in Military Medical Research investigated the role of retinoic acid receptor responder 2(RARRES2)in regulating lipid metabolism in BCBrM,highlighting the clinical relevance of alterations in lipid metabolites,such as phosphatidylcholine(PC)and triacylglycerols(TAGs),by RARRES2 through the modulation of phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway.This commentary aims to elaborate on the key findings and their relevance to the field.展开更多
The brain is one of the most common metastatic sites for carcinoma,especially for breast cancer,the second leading cause of brain metastases(BrM)after lung cancer[1].During organ‐tropic metastases,cancer cells have t...The brain is one of the most common metastatic sites for carcinoma,especially for breast cancer,the second leading cause of brain metastases(BrM)after lung cancer[1].During organ‐tropic metastases,cancer cells have to survive and expand in target organs through a process involving a complex interplay between invading cells and the microenvironment.展开更多
OBJECTIVE To observe the effect of all-trans retinoic acid （ATRA） on inducing human glioma MO59K cells differentiation and further explore the underlying molecular mechanisms.METHODS The expression of glial fibrilla...OBJECTIVE To observe the effect of all-trans retinoic acid （ATRA） on inducing human glioma MO59K cells differentiation and further explore the underlying molecular mechanisms.METHODS The expression of glial fibrillary acidic protein （GFAP） was detected by immunocytochemistry staining. The mRNA levels of GFAP, retinoid X receptor α（RXRα）, p21 were examined by semi-quantitative RT-PCR analysis. Luciferase activity assay was performed in the COS-7, MO59K cells to measure p21 promoter transcription activity.RESULTS ATRA could significantly enhance the expression and mRNA level of GFAP by immunostaining and RT-PCR （P〈0.05）. Simultaneously, the mRNA levels of RXRα and p21 were remarkably increased in dose-dependent manner by RT-PCR （P〈0.05）. Furthermore, luciferase assay confirmed that ATRA and RXRα could transactivate p21 promoter in COS-7 and glioma cells （P〈0.05）.CONCLUSION ATRA can induce differentiation of human glioma cells. The RXRα and p21 were activated during ATRAinduced differentiation process. This effect may be caused by directly RXRα-induced p21 gene transactivation. Our findings provide novel evidence for the future studies to explore the molecular mechanism of transcriptional regulation for glioma cell differentiation and cellular therapeutic approaches for glioblastoma.展开更多
Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphol...Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphological and functional regeneration in these species are not well understood.Recent evidence supports a role for retinoid signaling in the intrinsic ability of neurons,in these regeneration-competent species,to regrow after CNS injury.Previously,we demonstrated that a specific retinoic acid receptor（RAR）subtype,RARβ,mediates the effects of endogenous retinoic acid（RA）on neuronal growth and guidance in the adult newt CNS after injury.Here,we now examine the expression of the retinoid X receptor RXRα（a potential heterodimeric transcriptional regulator with RARβ）,in newt tail and spinal cord regeneration.We show that at 21 days post-amputation（dpa）,RXRαis expressed at temporally distinct periods and in non-overlapping spatial domains compared to RARβ.Whereas RARβprotein levels increase,RXRαproteins level decrease by 21 dpa.A selective agonist for RXR,SR11237,prevents both this downregulation of RXRαand upregulation of RARβand inhibits tail and caudal spinal cord regeneration.Moreover,treatment with a selective antagonist for RARβ,LE135,inhibits regeneration with the same morphological consequences as treatment with SR11237.Interestingly,LE135 treatment also inhibits the normal downregulation of RXRαin tail and spinal cord tissues at 21 dpa.These results reveal a previously unidentified,indirect regulatory feedback loop between these two receptor subtypes in regulating the regeneration of tail and spinal cord tissues in this regeneration-competent newt.展开更多
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.
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 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.
文摘Human amniotic basement membrane (HABM) model and agarose drop explant method were used to in-vestigate the effects of retinoic acid(RA) on the invasive-ness alld adhesiveness to the basement membrane, and the migration of a highly invassive human colorectal cancer cell line CCL229. Results showed that 5 ×106 MRA markedly reduced the in vitro invasiveness and adhesiveness to the HABM, and the migration of the CCL229 cells. In addi-tion, to elucidate the relation between expression of epider-mal growth factor receptor (EGFR) and the invasiveness of the colorectal carcinoma cells, two well-differentiated, but with different invasiveness colorectal cancer cell lines were compared at mRNA level for expressioll of EGFR by using EGFR cDNA probe labeled with digoxigenin (DIG). Expression of EGFR was showll to be markedly higher in the highly invassive CCL229 cells than that in the low in- vasive CX-1 cells. Furthermore, expression of EGFR in RA treated CCL229 cells gradually decreased with time,the level being the lowest on day 6 of the RA treatment.
文摘Objective: To evaluate the expression and its clinical significance of interleukin 6 (IL-6), soluble glycoprotein 130 (sgp130), interleukin 8 (IL-8) and type A interleukin 8 receptor (IL-8RA) in acute promyelocytic leukemia (APL) patients during all-trans retinoic acid (ATRA) induction treatment. Methods: Plasma and bone marrow mononuclear cell (MNC) culture supernatant IL-6, sgp130, IL-8 concentration of 18 cases with APL were kinetically measured in vivo and in vitro (ELISA). Bone marrow MNC IL-8RA was measured by flow cytometry after being cultured with ATRA (10?6mmol/L). Results: Plasma IL-6, sgp130, IL-8 levels were higher than normal (P<0.05), IL-6, spg130 levels correlated with white blood cell (WBC) counts (P<0.05) while IL-8 levels correlated with body temperature (P<0.05) at initial diagnosis. After 72-hour incubation with ATRA, concentration of IL-6 of bone marrow MNC culture supernatant did not change, that of sgp130 mildly decreased, and IL-8 significantly decreased while the positive rate of IL-8RA on bone marrow MNC increased. During ATRA treatment, plasma IL-6 changes were correlated with WBC counts. Peak levels of IL-6 and WBC were lower in patients who received intermittent therapy than those who received continuous therapy. Plasma IL-6 and IL-8 were increased when complicated with infection and IL-8 seemed more sensitive. Conclusion: Plasma IL-6, sgp130, IL-8 levels may reflect patients' responsiveness to ATRA treatment, and could be used to predict hyperleukocytosis and intercurrent infection. ATRA induces APL cell differentiation possibly via sgp130 signal transducer chain. Measurement of sgp130 had certain meaning to prognosis.
文摘All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodimerize with retinoid X receptors (RXRs). RAR/RXR heterodimers function as ATRA-dependent transcriptional regulators by binding to retinoic acid response elements (RAREs). To identify RAR/RXR heterodimer-binding sites in the human genome, we performed a modified yeast one-hybrid assays and identified 193 RAR/RXR heterodimer-binding fragments in the human genome. The putative target genes included genes involved in development process and cell differentiation. Gel mobility shift assays indicated that 160 putative RAREs could directly interact with the RAR/RXR heterodimer. Moreover, 19 functional regulatory single nucleotide polymorphisms (rSNPs) on the RAR/RXR-binding sequences were identified by analyzing the difference in the DNA-binding affinities. These results provide insights into the molecular mechanisms underlying the physiological and pathological actions of RAR/RXR heterodimers.
文摘The nuclear retinoic acid receptor may play a critical role in the process of lung carcinogenesis. Alteration or loss of nuclear retinoic acid receptors (RARs) has been associated with progression in premalignant and malignant tissues and it is associated with malignant transformation in human cells. Vitamin A derivates, such as retinoic acid, have emerged as adjuvant to therapy in several types of cancer with favorable effects. Retinoic acid regulates the expression of target genes through the binding and activation of RARs, inhibiting growth proliferation. Diverse studies have evaluated different retinoids alone or in combination with chemotherapy in lung cancer, from which results have been controversial with benefits observed only in the subpopulation with high levels of triglycerides. Additionally, several large randomized trials using retinoids to prevent tobacco-related cancer have failed;due to the latter the use of retinoids in clinical trials remains controversial. However they could reduce the risk of cancer development in non-smokers. There is evidence that retinoids have different effects on lung cancer;still the identification of biomarkers could determinate their benefits as preventive or therapy agents. This review describes the RAR alterations during the development of Non-Small Cell Lung Cancer and sets out the importance of several cancer treatments with retinoid compounds.
文摘To investigate whether treatment with retinoic acid (RA) could improve level of lung alveolarization and influence lung collagen in newborn rats exposed to hyperoxia, newborn Sprague-Dawley rats aged 2 days were randomly assigned to 8 groups:(1) air, (2) O 2, (3) air+NS, (4) O 2+NS, (5) air+dex, (6) O 2+dex, (7) air+RA and (8) O 2+RA. Group 2, 4 6 and 8 were kept in chambers containing 85 % oxygen, the values were checked 3 times a day. The other 4 groups were exposed to room air. Level of alveolarization and lung collagen were analyzed at age of 14 or 21 days through radial alveolar counts, alveolar airspace measurements, type Ⅰ, Ⅲ collagen immunohistochemical methods (SP method) and image processing system. Transforming growth factor-β receptors and procollagen mRNA accumulation were examined at age of 14 days through immunohistochemical methods and in situ hybridization. Our results showed that radial alveolar counts were increased and distal airspace was enlarged in group 8. TypeⅠcollagen was markedly increased, and transforming growth factor-β receptors and procollagen mRNA were decreased by retinoic acid in bronchial epithelial cells, alveolar epithelial cells and alveolar intersitium. It is concluded that retinoic acid can partially reverse lung development arrest during exposure to hyperoxia by increasing lung collagen.
文摘Breast cancer brain metastasis(BCBrM)is a crucial and hard area of research which guarantees an urgent need to understand the underlying molecular mechanisms.A recent study by Li et al.[1]published in Military Medical Research investigated the role of retinoic acid receptor responder 2(RARRES2)in regulating lipid metabolism in BCBrM,highlighting the clinical relevance of alterations in lipid metabolites,such as phosphatidylcholine(PC)and triacylglycerols(TAGs),by RARRES2 through the modulation of phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway.This commentary aims to elaborate on the key findings and their relevance to the field.
文摘The brain is one of the most common metastatic sites for carcinoma,especially for breast cancer,the second leading cause of brain metastases(BrM)after lung cancer[1].During organ‐tropic metastases,cancer cells have to survive and expand in target organs through a process involving a complex interplay between invading cells and the microenvironment.
基金the National Natural Science Foundation of China，Shandong Province Natural Science Foundation，Tianjin Natural Science Foundation
文摘OBJECTIVE To observe the effect of all-trans retinoic acid （ATRA） on inducing human glioma MO59K cells differentiation and further explore the underlying molecular mechanisms.METHODS The expression of glial fibrillary acidic protein （GFAP） was detected by immunocytochemistry staining. The mRNA levels of GFAP, retinoid X receptor α（RXRα）, p21 were examined by semi-quantitative RT-PCR analysis. Luciferase activity assay was performed in the COS-7, MO59K cells to measure p21 promoter transcription activity.RESULTS ATRA could significantly enhance the expression and mRNA level of GFAP by immunostaining and RT-PCR （P〈0.05）. Simultaneously, the mRNA levels of RXRα and p21 were remarkably increased in dose-dependent manner by RT-PCR （P〈0.05）. Furthermore, luciferase assay confirmed that ATRA and RXRα could transactivate p21 promoter in COS-7 and glioma cells （P〈0.05）.CONCLUSION ATRA can induce differentiation of human glioma cells. The RXRα and p21 were activated during ATRAinduced differentiation process. This effect may be caused by directly RXRα-induced p21 gene transactivation. Our findings provide novel evidence for the future studies to explore the molecular mechanism of transcriptional regulation for glioma cell differentiation and cellular therapeutic approaches for glioblastoma.
基金supported by Natural Sciences and Engineering Council of Canada Discovery Grant to RLC and GES
文摘Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphological and functional regeneration in these species are not well understood.Recent evidence supports a role for retinoid signaling in the intrinsic ability of neurons,in these regeneration-competent species,to regrow after CNS injury.Previously,we demonstrated that a specific retinoic acid receptor（RAR）subtype,RARβ,mediates the effects of endogenous retinoic acid（RA）on neuronal growth and guidance in the adult newt CNS after injury.Here,we now examine the expression of the retinoid X receptor RXRα（a potential heterodimeric transcriptional regulator with RARβ）,in newt tail and spinal cord regeneration.We show that at 21 days post-amputation（dpa）,RXRαis expressed at temporally distinct periods and in non-overlapping spatial domains compared to RARβ.Whereas RARβprotein levels increase,RXRαproteins level decrease by 21 dpa.A selective agonist for RXR,SR11237,prevents both this downregulation of RXRαand upregulation of RARβand inhibits tail and caudal spinal cord regeneration.Moreover,treatment with a selective antagonist for RARβ,LE135,inhibits regeneration with the same morphological consequences as treatment with SR11237.Interestingly,LE135 treatment also inhibits the normal downregulation of RXRαin tail and spinal cord tissues at 21 dpa.These results reveal a previously unidentified,indirect regulatory feedback loop between these two receptor subtypes in regulating the regeneration of tail and spinal cord tissues in this regeneration-competent newt.
