OBJECTIVETo observe the effects of bacterial lysates (OM-85BV) and all trans-retinoic acid (ATRA) on airway inflammation in asthmatic mice, and to investigate the immunoregulatory mechanism of OM-85BV and ATRA for airway inflammation in asthmatic mice.

METHODSForty female BALB/c mice were randomly divided into five groups: normal control, model, OM-85BV, ATRA, and OM-85BV+ATRA. A bronchial asthma model was established by intraperitoneal injection of ovalbumin (OVA) for sensitization and aerosol challenge in all mice except those in the normal control group. On days 25-34, before aerosol challenge, the model, OM-85BV, ATRA, and OM-85BV+ATRA groups were given normal saline, OM-85BV, ATRA, and OM-85BV+ATRA respectively by gavage. Normal saline was used instead for sensitization, challenge, and pretreatment before challenge in the normal control group. These mice were anesthetized and dissected at 24-48 hours after the final challenge. Bronchoalveolar lavage fluid (BALF) was collected from the right lung to measure the levels of interleukin-10 (IL-10) and interleukin-17 (IL-17) by ELISA. The left lung was collected to observe histopathological changes by hematoxylin-eosin staining. The relative expression of ROR-γT mRNA was measured by quantitative real-time PCR.

RESULTSCompared with the normal control group, the model group showed contraction of the bronchial cavity, increased bronchial secretions, and a large number of infiltrating inflammatory cells around the bronchi and alveolar walls, as well as a significantly reduced level of IL-10 (P<0.05) and significantly increased levels of IL-17 and ROR-γT mRNA (P<0.05). Compared with the model group, the OM-85BV, ATRA, and OM-85BV+ATRA groups showed a significant reduction in infiltrating inflammatory cells around the bronchi and alveolar walls; the OM-85BV group showed a significant increase in the level of IL-10 in BALF (P<0.05) and significant reductions in the levels of IL-17 and ROR-γT mRNA (P<0.05); the ATRA group showed significant reductions in the levels of IL-17 and ROR-γT mRNA (P<0.05). Compared with the OM-85BV group, the OM-85BV+ATRA group had significantly increased relative expression of ROR-γT mRNA (P<0.05). Compared with the ATRA group, the OM-85BV+ATRA group had significantly increased levels of IL-10 and IL-17 in BALF (P<0.05).

CONCLUSIONSBoth OM-85BV and ATRA can reduce respiratory inflammation in asthmatic mice. However, a combination of the two drugs does not have a better effect than them used alone.

Animals ; Asthma ; drug therapy ; genetics ; immunology ; Cell Extracts ; administration & dosage ; Female ; Humans ; Interleukin-10 ; genetics ; immunology ; Interleukin-17 ; genetics ; immunology ; Lung ; drug effects ; immunology ; Mice ; Mice, Inbred BALB C ; Tretinoin ; administration & dosage

All-trans retinoic acid (ATRA) inhibits matrix metalloproteinase (MMP)-2 and MMP-9 in synovial fibroblasts, skin fibroblasts, bronchoalveolar lavage cells and cancer cells, but activates MMP-9 in neuroblast and leukemia cells. Very little is known regarding whether ATRA can activate or inhibit MMPs in human dental pulp cells (HDPCs). The purpose of this study was to determine the effects of ATRA on the production and secretion of MMP-2 and -9 in HDPCs. The productions and messenger RNA (mRNA) expressions of MMP-2 and -9 were accessed by gelatin zymography and real-time polymerase chain reaction (PCR), respectively. ATRA was found to decrease MMP-2 level in a dose-dependent manner. Significant reduction in MMP-2 mRNA expression was also observed in HDPCs treated with 25 µmol⋅L(-1) ATRA. However, HDPCs treated with ATRA had no effect on the pattern of MMP-9 produced or secreted in either cell extracts or conditioned medium fractions. Taken together, ATRA had an inhibitory effect on MMP-2 expression in HDPCs, which suggests that ATRA could be a candidate as a medicament which could control the inflammation of pulp tissue in vital pulp therapy and regenerative endodontics.
Cell Culture Techniques ; Cell Survival ; drug effects ; Cells, Cultured ; Culture Media, Conditioned ; Dental Pulp ; cytology ; drug effects ; enzymology ; Dose-Response Relationship, Drug ; Humans ; Matrix Metalloproteinase 2 ; drug effects ; genetics ; Matrix Metalloproteinase 9 ; drug effects ; genetics ; RNA, Messenger ; drug effects ; Real-Time Polymerase Chain Reaction ; Transcription, Genetic ; drug effects ; Tretinoin ; administration & dosage ; pharmacology

OBJECTIVEThe incidence of food allergy has increased in recent years and there is no effective way to treat it except strict dietary avoidance and rapid medical treatment in case of accidental exposure. Oral tolerance, as a new method, has shown great promise as an alternative approach to prevention and treatment for allergic disease. It was reported that all-trans retinoic acid (atRA) plays an important role in inducing oral tolerance in vitro. Our study aimed to investigate the immunological effect of different doses of atRA on ovalbumin (OVA) allergic BALB/c mice.

METHODBALB/c mice were sensitized by intraperitoneal injection with OVA to establish allergic animal model. According to the dose of atRA given, 40 OVA allergic BALB/c mice were divided into 4 groups: the mice in high dose group were treated with 100 mg/kg atRA (atRA-H), those in median dose group were treated with 50 mg/kg atRA (atRA-M), those in low dose group were treated with 20 mg/kg atRA (atRA-L) and the mice in control group were given vehicle-soy oil only (CTR). After 12 days of atRA intervention, weight was measured, the mice were checked for diarrhea , and intestinal histology was observed after hematoxylin and eosin staining. The level of OVA-IgE in serum, total IgA and OVA-IgA in feces were measured by ELISA. The percentage of CD4⁺ CD25⁺ FoxP3⁺ T cells in CD4⁺ T cells in mesenteric lymph node was detected by flow cytometry.

RESULTCompared with that of CTR group, the level of OVA-IgE in serum (1.221 ± 0.367 vs. 0.793 ± 0.616) and OVA-IgA (1.573 ± 0.656 vs. 0.905 ± 0.279) in feces decreased significantly (P = 0.006 and 0.012, respectively) without weight and intestinal histology changes after low dose of atRA administration. However, there was no significant difference in the percentage of CD4⁺ CD25⁺ FoxP3⁺ T cells in CD4⁺ T cells in mesenteric lymph node (10.641 ± 1.218 vs. 10.936 ± 0.954) between atRA-L and CTR group (P > 0.05). While in animals with high and median dose of atRA administration, no immunologic improvement was found, instead, there was weight loss and intestinal mucosal damage.

CONCLUSIONLow dose of atRA intervention seems to induce immune suppression in vivo resulting in positive effects on OVA allergic mice. However, median and high dose atRA had no therapeutic effect on OVA allergic mice.

Animals ; CD4-Positive T-Lymphocytes ; Food Hypersensitivity ; drug therapy ; immunology ; Immune Tolerance ; drug effects ; Lymph Nodes ; Mice ; Mice, Inbred BALB C ; Ovalbumin ; immunology ; T-Lymphocytes, Regulatory ; Tretinoin ; administration & dosage ; pharmacology

OBJECTIVETo explore the characteristics and risk of etoposide-related leukemia in the treatment of hemophagocytic lymphohistiocytosis (HLH).

METHODClinical characteristics of a case with secondary acute promyelocytic leukemia (APL) were summarized and 10 cases of secondary leukemia after treatment for HLH from literature were analyzed.

RESULTThe child was diagnosed with Epstein-Barr virus associated HLH and received HLH-2004 protocol. The cumulative dose of etoposide (VP16) was 3520 mg/m(2). The patient was diagnosed with APL after 28 months of HLH.He achieved complete remission after induction chemotherapy of all-trans-retinoic acid and darubicin. Consolidated chemotherapy was continued. There were 10 reports of etoposide-related leukemia after treatment for HLH in the literature.Review of 11 cases treated with VP16, of which cumulative doses were 900-20 500 mg/m(2). The interval period between HLH and secondary leukemia was 24 months. The types of secondary leukemia included 1 case with acute lymphoblastic leukemia, 1 case with myelodysplastic syndrome and 9 cases of acute myeloid leukemia. The abnormalities of chromosome included 3 patients with 11q23, 3 APL patients with t (15, 17).Seven patients survived and 4 died.

CONCLUSIONThe latency period of etoposide-related leukemia is short. Acute myeloid leukemia and balanced chromosomal abnormality are common in etoposide-related leukemia. The risk factors for development of secondary leukemia are related to cumulative drug doses of etoposide, treatment schedules and co-administration of other antineoplastic agents.It is appropriate to keep suitable range of the cumulative dose of etoposide in HLH therapy in order to reduce the risk of therapy related leukemia.

Acute Disease ; Antineoplastic Agents ; administration & dosage ; adverse effects ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Child, Preschool ; Daunorubicin ; administration & dosage ; Epstein-Barr Virus Infections ; complications ; drug therapy ; virology ; Etoposide ; administration & dosage ; adverse effects ; Humans ; Leukemia, Promyelocytic, Acute ; chemically induced ; drug therapy ; Lymphohistiocytosis, Hemophagocytic ; complications ; drug therapy ; virology ; Male ; Neoplasms, Second Primary ; chemically induced ; Risk Assessment ; Treatment Outcome ; Tretinoin ; administration & dosage

The early molecular kinetics during all-trans retinoic acid (ATRA) plus arsenic-based induction therapy and its prognostic value for acute promyelocytic leukemia (APL) remain unclear. This study was purposed to investigate the molecular and cytogenetic kinetics and its clinical significance in treatment of APL with ATRA plus arsenic-based induction. The molecular and cytogenetic kinetics was assessed by real-time quantitative RT-PCR and interphase fluorescence in situ hybridization (FISH) in 32 newly diagnosed APL patients. The results showed that the median PML-RARα transcript levels (PML-RARα/ABL) were very significantly up-regulated at 14 days of induction therapy compared with that of pre-treatment (40.10% vs 57.74%, P < 0.01), and then decreased at 28 days of induction therapy and at the end of consolidation therapy (6.97% and 0%), respectively. The total of 65.62% and 31.25% patients showed up-regulation of PML-RARα transcript at 14 and 28 days after induction, as compared with pretreatment. The PML-RARα copies per APL cell before treatment, and at 14 and 28 days after induction were calculated as 0.9, 2.2, 1.4 by the formula of PML-RARA/ABL(%)×2/APL cells (%). With the median follow-up time of 22 months, 32 patients were still in continuous clinical remission and no molecular relapse occurred. Up-regulation of PML-RARa expression during the induction had no effect on outcomes of APL patients. It is concluded that up-regulation of PML-RARa expression is a common event during induction therapy with ATRA plus arsenics. Up-regulation of PML-RARa expression during induction therapy hasn't influenced the long-term prognosis of APL.
Adolescent ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Arsenicals ; administration & dosage ; Female ; Humans ; Leukemia, Promyelocytic, Acute ; diagnosis ; drug therapy ; metabolism ; Male ; Middle Aged ; Oncogene Proteins, Fusion ; metabolism ; Prognosis ; Tretinoin ; administration & dosage ; Up-Regulation ; drug effects ; Young Adult

OBJECTIVETo observe the effect of rosiglitazone (RGZ) and all-trans-retinoic acid (ATRA) on the growth of myeloma xenograft in nude mice and to explore the influence of RGZ and ATRA on VEGF expression and angiogenesis in the tumor.

METHODSVEGF gene expression in myeloma cell line U266 cells was analyzed by semi-quantitative RT-PCR after incubation with RGZ, ATRA, or RGZ + ATRA for 24 h. Myeloma xenograft was established by subcutaneous injection of 10(7) U266 cells in the scapula area of 4-week old nude mice. 7 days later, the nude mice were administered with RGZ, ATRA or RGZ + ATRA, respectively, by intraperitoneal injection once every day for 21 days. The control mice were given equal volume of normal saline instead of the drug. On the 21(st) day of treatment, the mice were sacrificed and the tumors were taken off, and the tumor volume and weight were measured. The tumors were examined by histopathology with HE staining, and microvessel density (MVD), CD34 and VEGF expression in the tumors were analyzed by immunohistochemical staining.

RESULTSVEGF mRNA was highly expressed in U266 cells and was decreased in a dose-dependent manner after incubation with RGZ. The VEGF mRNA level was further more decreased after RGZ + ATRA treatment. Xenografts of U266 cells were developed in all nude mice. The volume and weight of xenografts in the RGZ group were (785 ± 262) mm(3) and (1748 ± 365) mg, respectively, significantly lower than those of the control group (both P < 0.01). More significant inhibition was in the RGZ + ATRA group, (154 ± 89) mm(3) and (626 ± 102) mg, respectively, both were P < 0.05 vs. the RGZ group. RGZ inhibited the angiogenesis in U266 xenografts and immunohistochemical staining showed that the tumor MVD and VEGF expression were significantly decreased by RGZ treatment, and further more inhibited in the RGZ + ATRA group. VEGF protein was expressed in all xenografts in the nude mice. Its immunohistochemical staining intensity was 2.20 ± 0.40 in the control group, significantly higher than that of 1.48 ± 0.37 in the RGZ group (P < 0.01), and that of RGZ + ATRA group was 0.58 ± 0.26, further significantly lower than that of the RGZ group (P < 0.01). CD34 was expressed in all xenografts, most highly in the control group and lowest in the RGZ + ATRA group. The microvessel density (MVD) was highest in the control group (56.4 ± 15.2), significantly lower in the RGZ group (44.6 ± 11.2) (P < 0.05), and lowest in the RGZ + ATRA group (21.5 ± 8.6, P < 0.01).

CONCLUSIONSThe growth of myeloma cells can also be inhibited by RGZ and ATRA in nude mice in vivo. In addition to differentiation and apoptosis induction, RGZ can inhibit the formation of myeloma xenograft probably also through the downregulation of VEGF expression and subsequent angiogenesis.

Animals ; Antigens, CD34 ; metabolism ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microvessels ; pathology ; Multiple Myeloma ; metabolism ; pathology ; Neoplasm Transplantation ; Neovascularization, Pathologic ; RNA, Messenger ; metabolism ; Thiazolidinediones ; administration & dosage ; pharmacology ; Tretinoin ; pharmacology ; Tumor Burden ; drug effects ; Vascular Endothelial Growth Factor A ; genetics ; metabolism ; Xenograft Model Antitumor Assays

OBJECTIVETo compare the difference in the long-term efficacy between all-trans retinoic acid (ATRA) combined Compound Huangdai Tablet and ATRA combined methotrexate (MTX) and 6-mercaptopurine (6MP) as the sequential maintenance treatment of acute promyelocytic leukemia (APL) patients.

METHODSTotally 83 APL patients in the molecular remission (PML/RARalpha negative) were randomly assigned to two groups, the treatment group (45 cases) and the control group (38 cases) after they were induced to the complete remission (CR) by ATRA combined chemotherapy, and treated by sequential chemotherapy as the consolidated treatment for 3 therapeutic courses. Those in the treatment group were sequentially treated with ATRA and Compound Huangdai Tablet as maintenance therapy, while those in the control group were treated with ATRA and MTX + 6MP as maintenance therapy. After a long-term follow-up (2003 -2011), the long-term therapeutic efficacy and adverse reactions were compared between the two therapeutic regimens.

RESULTSThe 5-year relapse-free survival (RFS) rate was 84.4% +/- 5.4% in the treatment group and 63.2% +/- 7.8% in the control group, showing statistical difference between the two groups (P < 0.05). The 5-year overall survival rate (OSR) was 86.7% +/- 5. 1% in the treatment group and 78.7% +/- 6.7% in the control group, showing no statistical difference between the two groups (P > 0.05). There was no statistical difference in the adverse reaction between the two groups (P > 0.05).

CONCLUSIONThe application of ATRA and Compound Huangdai Tablet as maintenance therapy could elevate the long-term RFS rate of APL patients.

Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; therapeutic use ; Drugs, Chinese Herbal ; administration & dosage ; therapeutic use ; Female ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; Male ; Mercaptopurine ; administration & dosage ; therapeutic use ; Methotrexate ; administration & dosage ; therapeutic use ; Middle Aged ; Phytotherapy ; Treatment Outcome ; Tretinoin ; administration & dosage ; therapeutic use ; Young Adult

OBJECTIVETo study the clinical features of childhood acute promyelocytic leukemia (APL) and to analyze the survival and prognostic factors and efficacy and safety of combined treatment with all-trans retinoic acid (ATRA) and anthracycline.

METHODThe clinical features of 37 children with newly diagnosed APL hospitalized in our center during January 2005 to February 2009 were retrospectively analyzed.

RESULTThirty percent of patients were at low risk, 43% patients were at intermediate risk, 27% patients were at high risk. Sixty percent of patients had DIC. Retinoic acid syndrome (RAS) was present in 2 patients (6%). Death during induction occurred in 3 patients (8%). Complete remission (CR) was achieved in 83.7% of patients. The patients in high risk group had higher risk than those in intermediate and low risk group (P = 0.029). The time to achieve CR was not significantly different (P = 0.612). Idarubicin had no advantage compared with daunorubicin in time to achieve CR (P = 0.628). Survival rates were calculated using Kaplan-Meier statistical method, and 2 years event-free survival (EFS) rate was 81%, the 2-year EFS rate was 100% for low-risk group, 81% for intermediate-risk group, and 60% for high-risk group.

CONCLUSIONUsing combined chemotherapy with ATRA and anthracyclines had the following advantages: high CR rate, high long-time survival rate and low side effect. DIC remained the main complication among patients receiving induction treatment. Initial WBC count and platelet count are important prognostic factors which might be useful in prognostication and treatment planning.

Adolescent ; Anthracyclines ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Child ; Child, Preschool ; Female ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; Male ; Prognosis ; Retrospective Studies ; Treatment Outcome ; Tretinoin ; administration & dosage

OBJECTIVETo study the effect of arsenic trioxide (As2O3) and all-trans retinoic acid (ATRA) on human cervical carcinoma HeLa cell line.

METHODSHeLa cells were treated with As2O3 and ATRA. The cell proliferation was evaluated by MTT assay. The expressions of NDRG-1 protein and mRNA were determined by Western blot and RT-PCR analysis.

RESULTSMTT assay showed that As2O3 and ATRA inhibited the growth of human cervical carcinoma HeLa cells in vitro in a dose- and time-dependent manner. Western blot and RT-PCR techniques showed that As2O3 and ATRA down-regulated the expressions of NDRG-1 protein and mRNA (P < 0.05).

CONCLUSIONAs2O3 and ATRA can significantly inhibit the growth and proliferation of HeLa cells. The reason of these changes may be related with the down-regulation of expression of NDRG-1.

Antineoplastic Agents ; administration & dosage ; pharmacology ; Arsenicals ; administration & dosage ; pharmacology ; Blotting, Western ; Cell Cycle Proteins ; genetics ; metabolism ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; genetics ; metabolism ; Oxides ; administration & dosage ; pharmacology ; RNA, Messenger ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tretinoin ; administration & dosage ; pharmacology

OBJECTIVETo assess complete remission (CR), the overall survival (OS), event-free survival (EFS) and adverse events of newly diagnosed acute promyelocytic leukemia (APL) with homoharringtonine (HHT) plus ATRA, to evaluate the therapeutic effect by comparing HHT plus ATRA with daunorubicin plus ATRA as induction regimen (HA with DA as post-remission regimen).

METHODS115 APL patients (54 in HHT group, 61 in DNR group) after long-term follow-up were enrolled in the analyses of clinical feature, chromosome karyotype, molecular biology, OS and EFS.

RESULTSThe overall CR of 115 patients was 100%, the median interval to achieve hematological CR was 32 (22 - 43) days, the overall median OS was within 0.23 - 77.34 months, median EFS was within 0.23 - 77.34 months. 3-year OS rate was 93%, 5-year OS rate 93%, 3-year EFS rate 85% and 5-year RFS rate 75% respectively. Converting to PML-RARα PCR-negative after the induction therapy in the HHT and DNR group was 31.3% and 15.5% respectively, at the end of 1 consolidation course was 68.6% and 77.6% respectively, while the remaining 4 patients tested PML-RARα PCR-negative at the end of 2 consolidation courses in the DNR group. While both groups obtained the identical molecular biology relapse rate (9.8% and 8.6%, respectively). Survival analysis indicated that no significant difference was found on OS and EFS between the HHT group and the DNR group (P = 0.206 and 0.506). 5-year OS rate was 87% for the HHT group while 98% for the DNR group, 5-years EFS rate was 80% for the HHT group while 71% for the DNR group. And the risk group was not the factor affecting OS and EFS (P = 0.615 and 0.416). Grade 2 fever in the HHT group was less than in the DNR group during induction therapy. And no difference was found in terms of liver dysfunction, renal dysfunction, cardiac dysfunction, and hematologic toxicity between two groups.

CONCLUSIONOur study demonstrated comparable therapeutic effect of HHT or DNR on APL. HHT was also well tolerated and didn't cause serious adverse events.

Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Female ; Harringtonines ; administration & dosage ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; Male ; Middle Aged ; Prognosis ; Treatment Outcome ; Tretinoin ; administration & dosage ; Young Adult