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Objective To investigate the effect and mechanism of all-trans retinoic acid (ATRA) on the cyclosporin (CsA)-induced proliferation and apoptosis of glomerular mesangial cells in rat models. Methods The glomerular mesangial cells induced by different doses of CsA were treated with different doses of ATRA. MTT assay was carried out to detect cell proliferation. Hoechst 33258 fluorescent staining was adopted to observe the morphology of the apoptotic cells. Flow cytometry was conducted to detect the cellular apoptosis rate. Immunofluorescent staining was employed to quantitatively measure the expression level of mitochondria-derived pro-apoptotic Smac protein. Results Compared with the control group, administration of CsA at a dose of 0.5 μg/mL and above could suppress cellular proliferation, and use of CsA at a dose of 1.0 μg/mL and above could induce cellular apoptosis. The expression level of Smac protein was significantly up-regulated by CsA administration with a dose and time dependence (all P<0.05).Compared with the CsA group, combined administration of CsA and ATRA exerted a more significant inhibitory effect on cellular proliferation. Supplement of ATRA could significantly inhibit glomerular mesangial cellular apoptosis induced by CsA and down-regulate the expression of Smac protein with a dose dependence (both P<0.05). Conclusions CsA can inhibit cellular proliferation, induce cellular apoptosis and up-regulate the expression of Smac protein of glomerular mesangial cells. ATRA is capable of suppressing glomerular mesangial cellular apoptosis induced by CsA, which is probably mediated by the Smac signaling pathway.
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Objective To investigate the effects of all-trans retinioc acid (ATRA)on proliferation of rat hepatic stellate cells (HSC-T6)and expressions of collagen Ⅰ,matrix metalloproteinase-2 (MMP-2),tissue inhibitor of metalloproteinases-1 (TIMP-1 )and signal protein Smad2/3 in TGF-β1-simulated HSC-T6 so as to explore the impact and molecular mechanisms of ATRA on liver fibrosis in vitro .Methods Cultured HSC-T6s were treated with different concentrations of ATRA (0.1,1,10 μmol/L)for fixed time (12,24,48 hours).After intervention time,cell proliferation was evaluated by MTT.Meanwhile,HSC-T6s stimulated by TGF-β1 (5 ng/mL)were treated with different concentrations of ATRA for 24 h.The mRNA expressions of COL1α2,MMP-2 and TIMP-1 were quantified by RT-PCR;the expression of Smad 2/3 protein was determined by cell immunochemistry.Results The proliferation of hepatic stellate cells was inhibited by ATRA in a dose-dependent manner (P < 0.05 ).After induced by TGF-β1,the mRNA expressions of COL1α2,MMP-2 and TIMP-1 and the expression of Smad 2/3 protein were increased significantly compared with control group (P <0.05).However,ATRA could obviously reduce themRNA expressions of COL1α2,MMP-2 and TIMP-1 and the expression of Smad 2/3 protein in HSC-T6 induced by TGF-β1 (P < 0.05 ).Conclusion ATRA can inhibit the proliferation of HSC-T6s and reduce the mRNA expressions of COL1α2,MMP-2 and TIMP-1 in HSC-T6 which were induced by TGF-β1.The anti-hepatic fibrosis function of ATRA may be related to its inhibition on the expression of Smad 2/3 protein in HSC-T6 to influence TGF-β1/Smad signaling pathway.
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Objective To investigate the effects of all-trans retinioc acid (ATRA)on proliferation of rat hepatic stellate cells (HSC-T6)and expressions of collagen Ⅰ,matrix metalloproteinase-2 (MMP-2),tissue inhibitor of metalloproteinases-1 (TIMP-1 )and signal protein Smad2/3 in TGF-β1-simulated HSC-T6 so as to explore the impact and molecular mechanisms of ATRA on liver fibrosis in vitro .Methods Cultured HSC-T6s were treated with different concentrations of ATRA (0.1,1,10 μmol/L)for fixed time (12,24,48 hours).After intervention time,cell proliferation was evaluated by MTT.Meanwhile,HSC-T6s stimulated by TGF-β1 (5 ng/mL)were treated with different concentrations of ATRA for 24 h.The mRNA expressions of COL1α2,MMP-2 and TIMP-1 were quantified by RT-PCR;the expression of Smad 2/3 protein was determined by cell immunochemistry.Results The proliferation of hepatic stellate cells was inhibited by ATRA in a dose-dependent manner (P < 0.05 ).After induced by TGF-β1,the mRNA expressions of COL1α2,MMP-2 and TIMP-1 and the expression of Smad 2/3 protein were increased significantly compared with control group (P <0.05).However,ATRA could obviously reduce themRNA expressions of COL1α2,MMP-2 and TIMP-1 and the expression of Smad 2/3 protein in HSC-T6 induced by TGF-β1 (P < 0.05 ).Conclusion ATRA can inhibit the proliferation of HSC-T6s and reduce the mRNA expressions of COL1α2,MMP-2 and TIMP-1 in HSC-T6 which were induced by TGF-β1.The anti-hepatic fibrosis function of ATRA may be related to its inhibition on the expression of Smad 2/3 protein in HSC-T6 to influence TGF-β1/Smad signaling pathway.
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Objective:To study the influence of all-trans retinoic acid (atRA)on craniomaxillofacial development of C57 mice. Methods:Pregnant C57BL mice were divided into 4 groups(n =5)at gestation day (GD)1 0.Mice in three atRA-induction groups were given atRA of 60,80 and 1 00 mg/kg,respectively.The mice in control group were given the equivalent volume of corn oil.All pregnant mice were sacrificed at GD1 9 and the embryos were collected.Stereo microscope was used to observe the craniomaxillofacial morphology.Standardized radiographs were taken and cephalometric analysis was performed.Results:The embryonic body length and body mass of control group surpassed those of 80 and 1 00 mg/kg atRA groups(P <0.05,P <0.01 ).atRA induced craniomaxillofacial malformations and maldevelopment.The mice induced by atRA exhibited a shorter mandibular body and more retrusive position of max-illary and mandibular(∠NAK and ∠NBD)when compared with their norm(P <0.01 ).Significant decrease in craniofacial length (Op-Rh)was observed in all atRA-induced groups(P <0.01 ).Decreases in cranial vault height(Fp-Os)and cranial vault length(Pa-Na)dimensions were observed in 80 and 1 00 mg/kg atRA groups(P <0.05,P <0.01 ).Conclusion:Exogenous atRA dose-depend-ently induces retardation of craniomaxillofacial morphology in embryo of C57BL mice by inhibition of the sagital and vertical dimension development of the bone.
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Background: The combination of all trans-retinoic acid (ATRA) and voriconazole may lead to increased ATRA exposure resulting in a higher incidence of differentiation syndrome (DS). Patients and Methods: This single center analysis evaluated the incidence and outcomes of ATRA-induced DS in 46 adult patients with acute promyelocytic leukemia (APL) undergoing induction chemotherapy. Results: Thirty-one patients (69% by day 60) received a chemotherapy regimen including ATRA coinciding with voriconazole administration and 15 patients underwent treatment without voriconazole. The overall incidence of DS was 36% (n=16) by day 60, with patients receiving voriconazole showing a trend towards a higher incidence (HR 2.31, CI 0.78-6.847, p=0.1308). This trend persisted after adjusting for BMI (HR 1.96, CI 0.65-5.94, p=0.23); however, a small number of DS events precluded statistical significance. Conclusion: A trend towards an increased incidence and severity of ATRA-mediated DS was seen in adult APL patients receiving voriconazole prophylaxis during induction chemotherapy. This important finding warrants validation in larger studies.
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BACKGROUND: All-trans-retinoic acid (ATRA) induces complete remission (CR) in the great majority of patients with PML/RAR -positive acute promyelocytic leukemia (APL). However, it is associated with a rapid rise in leukocytes in one third to half the patients, with potentially fatal "ATRA syndrome". Furthermore, most of the patients relapse with maintenance therapy using ATRA alone or low-dose chemotherapy. In this study, we have analyzed the outcome for APL patients who were treated with ATRA alone or combined with low-dose chemotherapy followed by postremission chemotherapy in Chonnam University Hospital from April 1993 to December 1997. METHODS: Sixteen patients with newly diagnosed APL were eligible to analysis. Patients received 45mg/m2 ATRA until CR occurred. If initial WBC were above 5,000/microliter, low-dose chemotherapy was concomitantly given, and if during the ATRA therapy WBC were above 5,000/microliter by day 5 or 10,000/microliter by day 10, or 15,000/microliter by day 15, low-dose chemotherapy was added. Four polychemotherapy cycles or allogeneic bone marrow transplantation were given as postremission therapy. RESULTS: Median age was 34 years (range, 17 to 67). Of 16 APL patients, 15 (93.8%) achieved CR and 1 (6.2%) died of intracerebral hemorrhage. After a median follow-up of 11.5 months (range, 0 to 47), the Kaplan-Meier estimated overall survival (OS) rate was 87.1 +/- 8.6% at 3 year, the event-free survival (EFS) rate was 87.1 +/- 8.6%, 58.0 +/- 24.4% and 29.0 +/- 23.9% at 1 year, 2 year and 3 year, and the disease-free survival (DFS) rate was 92.9 +/- 6.9%, 69.6 +/- 20.7% and 46.4 +/- 23.5% at 1 year, 2 year and 3 year, respectively. CONCLUSION: The present study suggests that ATRA with or without low-dose chemotherapy followed by postremission chemotherapy is a well-tolerated and effective regimen that is shown to improve the CR rate, reduce a early mortality rate and considerably prolong the overall survival in patients with newly diagnosed APL.
Subject(s)
Humans , Bone Marrow Transplantation , Cerebral Hemorrhage , Disease-Free Survival , Drug Therapy , Drug Therapy, Combination , Follow-Up Studies , Leukemia, Promyelocytic, Acute , Leukocytes , Mortality , Recurrence , TretinoinABSTRACT
We repoarted a rare case of AML atypical M2 who developed granulocytic granulocyte sarcoma in the meninges which was induced complete remission with all-trans retinoic acid (ATRA), daunorubicin and cytosine arabinoside (Ara-C). Morphological and immunophenotypic study of leukemic cells in this patient suggested acute promyelocytic leukemia. However, leukemic clees lacked both t (15;17) and PML-RARalpha gene rearragement, rather showed t (8;21). The patient was diagnosed as AML atypical M2.