OBJECTIVETo review the role of cyclic adenosine monophosphate (cAMP) signal pathway in the pathogenesis of lymphoma and explore a potential lymphoma therapy targeted on this signaling pathway.

DATA SOURCESThe data cited in this review were mainly obtained from the articles listed in Medline and PubMed, published from January 1995 to June 2009. The search terms were "cAMP" and "lymphoma".

STUDY SELECTIONArticles regarding the role of the cAMP pathway in apoptosis of lymphoma and associated cells and its potential role in targeted therapy of lymphoma.

RESULTSIn the transformation of lymphocytic malignancies, several signal pathways are involved. Among of them, the cAMP pathway has attracted increasing attention because of its apoptosis-inducing role in several lymphoma cells. cAMP pathway impairment is found to influence the prognosis of lymphoma. Targeted therapy to the cAMP pathway seems to be a new direction for lymphoma treatment, aiming at restoring the cAMP function.

CONCLUSIONScAMP signal pathway has different effects on various lymphoma cells. cAMP analogues and phosphodiesterase 4B (PDE4B) inhibitors have potential clinical significance. However, many challenges remain in understanding the various roles of such agents.

Animals ; Cyclic AMP ; metabolism ; Humans ; Lymphoma ; metabolism ; Models, Biological ; Signal Transduction ; physiology

Objective To investigate the impact of reduced glutathione(GSH) on the prolifera- tion,oxidative stress and transforming growth factor?1(TGF-?1) expression of human hepatocytes and hepatic stellate cells(HSCs)(LX-2 cell line).Methods Human hepatocytes and HSCs were incubated with various concentrations of GSH(0.5—50 mmol/L or 0.5—10 mmol/L).The effects of GSH on the proliferation of hepatocytes and HSCs were studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphennyhera- zolium bromide colorimetric assay.Human hepatocytes and HSCs were co-cultured with GSH and ferric nitrilotriacetic acid,superoxide dismutase (SOD) activity and malondialdehyde (MDA) contents were detected.HSCs were incubated with high(5.0 mmol/L),media(2.5 mmol/L) and low (0.5 mmol/L) concentrations of GSH,the expressions of TGF-?1 mRNA and protein were detected by ELISA and real- time PCR.Results In concentration ranged from 2.5 to 10 mmol/L,the GSH could promote the pro- liferation of hepatocytes but no HSCs,significantly increased the activity of SOD and decrease the con- tents of MDA in hepatocytes and HSCs,and inhibited the expression of TGF-?1 in HSCs.Conclusions GSH can not only promote the proliferation of hepatocytes,but also protect hepatocytes and HSCs from oxidative stress,and inhibit the secretion of TGF-?1 in HSCs.GSH may play a role in hepatocellular protection,antioxidation and anti-fibrosis.

OBJECTIVETo explore the molecular mechanism of APL cell resistance to ATRA.

METHODSThe ATRA sensitive and resistant APL cell lines, NB4 and NB4-R1, were used as in vitro models. The effects of specific inhibitors and activators of adenylate cyclase (AC) and phosphodiesterase (PDE) on ATRA-induced differentiation was evaluated by cell morphology, cell surface antigen expression and nitroblue-tetrazolium (NBT) reduction assays.

RESULTSSQ22536, a specific antagonist of AC, could dramatically block ATRA-induced NB4 cell differentiation. When ATRA + SQ22536 group compared with ATRA group, the positivity of CD11b decreased from (95.9 +/- 2.5)% to (60.3 +/- 7.1)%, while the A(540) in NBT reduction assay decreased from 0.585 +/- 0.092 to 0.170 +/- 0.028 (P < 0.05). Forskolin, an agonist of AC, could overcome the resistance of NB4-R1 cells to ATRA. When ATRA + forskolin group compared with ATRA group, the positivity of CD11b increased from (34.3 +/- 5.3)% to (94.6 +/- 2.4)%, while the A(540) in NBT reduction assay increased from 0.110 +/- 0.028 to 0.395 +/- 0.049 (P < 0.05). In contrast, the specific antagonist and agonist of PDE, 3-isobutyl-1-methylxanthine (IBMX) and calmodulin, exerted little impact on ATRA treatment.

CONCLUSIONSThe defaults in the initiation of AC activation may contribute to the resistance to ATRA in some APL cells.

Adenine ; analogs & derivatives ; pharmacology ; Adenylyl Cyclase Inhibitors ; Adenylyl Cyclases ; metabolism ; Antineoplastic Agents ; pharmacology ; CD11b Antigen ; metabolism ; Cell Differentiation ; drug effects ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; drug effects ; Enzyme Activation ; drug effects ; Enzyme Inhibitors ; pharmacology ; Humans ; Leukemia, Promyelocytic, Acute ; metabolism ; pathology ; Phosphoric Diester Hydrolases ; metabolism ; Tretinoin ; pharmacology

The aim of this study was to find platelet specific autoantibodies against glycoproteins in myelodysplastic syndrome (MDS) and to explore its role in pathogenesis of MDS. The plasma autoantibodies against GP IIb/IIIa and GP Ib/IX were measured by using a modified monoclonal antibody specific immobolization platelet antigens assay (MAIPA). Absorbance greater than mean value plus tripled standard deviation recorded from the normal controls were regarded as positive. The results indicated that the total positive rate in patients with MDS was 16.67% (5/30), the total positive rate in patients with ITP was 46.67% (14/30), the difference between MDS group and ITP group was significant (P < 0.05). It is concluded that partial patients with MDS have plasma specific autoantibodies against platelet GP II b/III a and GP Ib/IX, indicating correlation of thrombocytopenia of patients with immune factors and the autoantibody-mediated platelet destruction may be involved in the pathogenesis of MDS. It provides a new basis for immunosuppression therapy for MDS.
Adolescent ; Adult ; Aged ; Antibodies ; immunology ; Antigens, Human Platelet ; immunology ; Autoantibodies ; biosynthesis ; immunology ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes ; complications ; immunology ; Platelet Glycoprotein GPIIb-IIIa Complex ; immunology ; Platelet Glycoprotein GPIb-IX Complex ; immunology ; Thrombocytopenia ; etiology ; immunology

Cell Line ; Hepatic Stellate Cells ; cytology ; metabolism ; pathology ; Humans ; Oxidative Stress ; Phosphatidylcholines ; pharmacology ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo study CXCR3 and CCR5 chemokine receptor expression in spleens of patients with primary immune thrombocytopenia (ITP) and its clinical significance.

METHODSThe splenectomy specimens from 10 ITP patients (ITP group) and 8 patients with traumatic splenic rupture (normal control group) were studied. Immunohistochemistry (IHC) was used to study the positive rate of CXCR3 and CCR5. Western blot was performed to detect CXCR3 and CCR5 protein expression, while real-time polymerase chain reaction (RT-PCR) was conducted to analyze their mRNA expression.

RESULTSThe positive rate of CXCR3 and CCR5 were both higher in ITP group (90% and 100%, respectively) than those in control group (75% and 87.5%, respectively)(P < 0.05). The differences were statistically significant (P < 0.05). Protein and mRNA level of CXCR3 in ITP group were 3.0 and 3.5 times as high as those in control group, respectively. Those of CCR5 in ITP group were 1.2 and 1.7 times as high as those in control group, respectively.

CONCLUSIONHigh expression of CXCR3 and CCR5 may play a part in the splenic immune disorders in patients with ITP.

Adolescent ; Adult ; Case-Control Studies ; Child ; Female ; Humans ; Male ; Middle Aged ; Receptors, CCR5 ; metabolism ; Receptors, CXCR3 ; metabolism ; Spleen ; metabolism ; Thrombocytopenia ; immunology ; metabolism ; Young Adult

To explore the molecular mechanisms of acute promyelocytic leukemia cell differentiation induced by cAMP combined with low-dose As2O3, the PR9 cell line, which was stably transfected by PML-RARa fusion gene, was used as in vitro model. The effects of PML-RARa on cAMP-induced AML cell differentiation were evaluated according to cell growth, cell morphology, cell surface antigen as well as luciferase reporter gene assay, in the cells before and after the treatment with cAMP and/or As2O3. The results showed that cAMP alone could slightly increase the expression of CD11b in the PR9 cells expressing the PML-RARa fusion protein, but could not induce these cells to differentiate. The cells presented the terminal differentiation morphology and significantly increased CD11b expression only under the treatment of cAMP combined with As2O3. In addition, PML-RARa had strong inhibitory activity on the transcription of the reporter gene containing cAMP response elements. In conclusions, the PML-RARa fusion protein could dramatically block the signaling pathway of cAMP during the AML cell differentiation.
Arsenicals ; pharmacology ; Cell Differentiation ; drug effects ; Cell Line, Tumor ; Cyclic AMP ; metabolism ; pharmacology ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia, Promyelocytic, Acute ; genetics ; metabolism ; Oncogene Proteins, Fusion ; genetics ; Oxides ; pharmacology ; Signal Transduction ; Transfection

OBJECTIVETo investigate the quantitative and qualitative changes of TCRVα24(+)Vβ11(+) natural killer T (NKT) cells from bone marrow (BM) of aplastic anemia (AA) after in vitro stimulation of α-galactosylceramide (α-Galcer).

METHODSNKT cells in the bone marrow mononuclear cells (BMMNCs) from either AA patients or healthy controls were enumerated with flow cytometry. BMMNCs were cultured in RPMI1640 medium supplemented with either α-Galcer and rhIL-2 or α-Galcer, rhIL-2 and rhG-CSF. The proliferative capacity of NKT cells was determined by NKT cell numbers before and after in vitro culture. Expression of intracellular IFNγ and IL-4 in activated NKT cells was analyzed with flow cytometry.

RESULTSIn AA group, the percentage of NKT cells in BMMNCs was (0.19 ± 0.09)%. Addition of rhG-CSF into the α-Galcer/rhIL-2 culture medium resulted in significantly reduced expansion of NKT cells (67.45 ± 29.42-fold vs 79.91 ± 40.56 fold, P < 0.05). Meanwhile, addition of rhG-CSF reduced IFNγ positive NKT cells \[(37.45 ± 7.89)% vs (62.31 ± 14.67)%, P < 0.01\] and increased IL-4 positive NKT cells \[(55.11 ± 12.13)% vs (27.03 ± 9.88)%, P < 0.01\]. In healthy control group, the percentage of NKT cells in BMMNCs was (0.25 ± 0.12)%. Addition of rhG-CSF into the α-Galcer/rhIL-2 culture medium also significantly reduced expansion of NKT cells (97.91 ± 53.22-fold vs 119.58 ± 60.49-fold, P < 0.05), reduced IFNγ positive NKT cells \[(28.65 ± 10.63)% vs (50.87 ± 12.66)%, P < 0.01\], and increased IL-4 positive NKT cells \[(66.53 ± 14.96)% vs (31.11 ± 10.07)%, P < 0.01\].

CONCLUSIONCompared to those from healthy controls, BMMNCs from AA patiants have a reduced fraction of NKT cells, which possesses a decreased potential to expand in vitro in response to α-Galcer stimulation, and produce more IFNγ(+) NKT1 cells. rhG-CSF, in combination with α-Galcer, confers polarization of NKT cells towards IL-4(+) NKT2 subpopulation.

Anemia, Aplastic ; metabolism ; Bone Marrow ; metabolism ; Humans ; Interleukin-4 ; metabolism ; Killer Cells, Natural ; cytology ; Natural Killer T-Cells

Adolescent ; Adult ; Child ; Decision Trees ; Female ; HIV Infections ; economics ; transmission ; Humans ; Infectious Disease Transmission, Vertical ; economics ; prevention & control ; Kenya ; Middle Aged ; Mothers ; South Africa ; Vietnam ; Young Adult