Biomedical subjects
Publications and source records attributed to Guang-Sen Zhang.
A rare case of a 46-year-old man who underwent myelodysplastic syndrome, acute monocytic leukemia with FLT3-ITD mutation and splenic disruption following orthotopic liver transplantation is reported. The study of this case may be helpful to understand both the pathogenesis of acute leukemia and new complication of liver transplantation.
Celecoxib, a specific cyclooxygenase-2 (Cox-2) inhibitor, has been shown to possess antitumor activity in a variety of cancer cells. However, the antitumor activity of celecoxib in hematopoietic tumors, especially in chronic myeloid leukemia (CML), has not been well established. This study was designed to investigate the effect of celecoxib on growth and apoptosis in a human CML cell line (K562 cells) or in primary CML cells, and to examine the synergistic actions of celecoxib and hydroxyurea or imatinib on K562 cell proliferation and apoptosis. Celecoxib significantly inhibited the growth of both K562 and primary CML cells and induced apoptosis in a dose-dependent fashion. The IC50 of celecoxib was 46 microM for inhibition of K562 cell proliferation. The effect of celecoxib on growth inhibition was accompanied by the downregulation of cyclin D1 and cyclin E and p-Rb expression, the upregulation of P16(INK4a) and P27KIP expression, and a G1-S phase arrest of the cell cycle. The pro-apoptotic effect of celecoxib was determined to be mediated by caspase-3 activation. When K562 cells were pretreated with DEVD-fmk, a specific inhibitor of caspases, the apoptotic activity of celecoxib was, in part, abrogated. Importantly, we demonstrated for the first time that K562 cells were Cox-2-positive both at the mRNA and protein levels. We noted the following observations: (i) we detected Cox-2 mRNA in K562 cells by reverse transcription-PCR (RT-PCR) and protein expression by western blot analysis; (ii) Cox-2 expression in K562 cells was stimulated by IL-1beta, a specific inducing agent of Cox-2 expression; (iii) primary CML cells from CML patient bone marrow also exhibited Cox-2 protein expression. Furthermore, Cox-2 expression was downregulated at higher doses of celecoxib (80-160 microM), suggesting a Cox-2-dependent mechanism was involved in the drug's effects of growth inhibition and induction of apoptosis. In addition, a synergistic effect was observed when cells were exposed to low-dose celecoxib (40 microM) and hydroxyurea (10 mM) or a combination of celecoxib (40 microM) and imatinib (0.2 microM). These findings provide the basis for uncovering the mechanism of celecoxib's antitumor effects and developing a new therapeutic strategy for treating CML.
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This study was purposed to investigate the change of early hemostatic function in patients with myeloproliferative diseases (MPD) and to explore its significance in combination with clinical data. The platelet aggregative function was measured by using ristomycin, adenosine diphosphate, collagen and adrenine as inductors, the plasma von Willebrand factor-associated antigen (vWF: Ag) level was measured by enzyme-linked immunosorbent assay (ELISA), the plasma von Wellebrand factor-ristomycin cofactor (vWF: Rco) activity was measured in 6 patients with obviously low ristomycin induced platelet aggregation (RIPA). The results showed that the platelet aggregative function obviously decreased in 35 patients, there were distinct differences in maximal platelet aggregative rate between patients and normal controls induced by 4 inductors respectively (P < 0.001, P < 0.001, P = 0.002, P < 0.001). There was no obvious difference between patients with MPD and healthy controls in plasma vWF: Ag level (P > 0.50). Plasma vWF: Rco activity in all 6 patients with MPD chosen was in the normal range, except one patient with essential thrombocytosis (ET) whose plasma vWF: Rco activity was much lower than normal. No correlation was found between platelet count and plasma vWF: Ag level in the patients (r = -0.180). No correlation was found between platelet count and maximal platelet aggregative rate induced by 4 inductors respectively in patients. It is concluded that the occurrence of abnormal platelet aggregative function is high in patients with MPD. The RIPA and vWF: Rco activity decrease in one patient with ET. However, the shortage of vWF polymer existed in his plasma have needs for further research. No correlation was observed between hemostasis and clinical manifestations. However, because of the high occurrence of platelet dysfunction in MPD patients, the clinical application of anti-platelet drugs should be considered carefully.
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OBJECTIVE: To determine whether JAK/STAT pathway is involved in proliferation of hypereosinophilic syndrome (HES) cells, and reveal the pathogenesis of HES; observe the dynamic change of the clinical phenotype and hematological response, the expression of janaus kinase/signal transducer and activator of transcription (JAK/STAT) protein or FIP1L1-PDGFRA mRNA in one HES patient treated with low-dose imatinib. METHODS: The granulocytes of peripheral blood of 4 HES patients, including 3 FIP1L1-PDGFRA positive cases and 1 negative case, were collected. The expression of JAK2, STAT3, and phosphorylated STAT (P-STAT5) proteins were detected by western blotting. One FIP1L1-PDGFRA fusion gene positive patient was administered with low-dose imatinib. Retrospective reverse transcription polymerase chain reaction (RT-PCR) analysis of FIP1L1-PDGFRA was performed and the expressions of JAK2, STAT3 and P-STAT5 were detected by western blotting before treatment and 10, 30, and 60 days after the beginning of treatment. RESULTS: Upregulation of JAK2, STAT3, and P-STAT5 proteins was shown in 3 FIP1L1-PDGFRA fusion gene positive HES patients, while all of these proteins were not expressed in one case of FIP1L1-PDGFRA negative HES. Continuous hematological remission was observed in one FIP1L1-PDGFRA fusion gene positive HES patient after low-dose imatinib treatment. The amount of FIP1L1-PDGFRA transcripts in peripheral blood granulocytes was significantly decreased in 30 days after therapy and turned negative 60 days after therapy. JAK2, STAT3, STAT5, and P-STAT5 expressions were all down-regulated time-dependently and were all negative 60 days after. CONCLUSION: There is excessive activation of JAK/STAT signal pathway in HES patient, which may contribute to the malignant proliferation of eosinophils. Low-dose imatinib, that induces complete hematological and molecular genetic remission, exerts significant effects on FIP1L1-PDGFRA positive HES.
OBJECTIVE: To determine whether FIP1L1-PDGFRA fusion exists in hypereosinophilic syndrome (HES) patients, explore the relationship between FIP1L1-PDGFRA fusion and clinical phenotypes, and observe and reveal the expression of signal transducer and activator of transcription 5 (STAT(5)) in granulocytes of HES and the biological significance thereof. METHODS: Specimens of peripheral blood were collected from 4 HES patients diagnosed based on the criteria of Chusid et al. Total RNA was extracted from granulocytes and cDNA was synthesized by reverse transcription. Nested-PCR was used to amplify the target fusion gene and the positive PCR fragments were sequenced directly. Total protein of the peripheral granulocytes was extracted. Western blotting was used to detect the expression of STAT(5) protein in the granulocyte lysates. RESULTS: FIP1L1-PDGFRA fusion genes were found in 3 of the 4 HES patients. The break points in PDGFRA were all located at exon 12, while in FIP1L1 the break points were highly variable, located at exon 8a, intron 8a, and exon 8 respectively. The patients with FIP1L1-PDGFRA fusion were susceptible to cardiac involvement. The expression of STAT(5) protein was upregulated in FIP1L1-PDGFRA positive HES patients, while STAT(5) protein expression was negative in HES patients without FIP1L1-PDGFRA fusion. CONCLUSION: FIP1L1-PDGFRA fusion has a universal significance for HES. The identification of FIP1L1-PDGFRA rearrangement is a useful molecular mark for HES diagnosis and works as the therapeutic target of imatinib. Furthermore, the activation of STAT(5), a downstream signal of the FIP1L1-PDGFRA fusion, indicates that HES is a malignant clonal disease of the hematopoietic tissue.
AIM: To examine the protein expression alterations in liver injury/repair network regulation as a response to gut-derived lipopolysaccharide (LPS) treatment, in order to anticipate the possible signal molecules or biomarkers in signaling LPS-related liver injury. METHODS: Male BALB/c mice were treated with intra-peritoneal (i.p.) LPS (4 mg/kg) and sacrificed at 0, 6, 24 and 30 h to obtain livers. The livers were stained with hematoxylin and eosin for histopathologic analyses. Total liver protein was separated by two-dimensional gel electrophoresis (2-DE). The peptide mass of liver injury or repair related proteins were drawn up and the protein database was searched to identify the proteins. RESULTS: Observations were as follows: (1) TRAIL-R2 was down regulated in livers of LPS-treated mice. TNFAIP1 was significantly up regulated at 6 h, then down- regulated at 24, 30 h with silent expression during senescent stage. (2) The amount of metaxin 2 and mitochondria import inner membrane translocase subunit TIM8a (TIMM8A) was increased upon treatment with LPS. (3) P34 cdc2 kinase was significantly up-regulated 30 h after LPS administration with silent expression during senescent, 6, 24 h treated stage. (4) The amount of proteasome activator 28 alpha subunit (PA28), magnesium dependent protein phosphatase (MDPP) and lysophospholipase 2 was decreased 6 h after LPS treatment but recovered or up-regulated 24 and 30 h after LPS treatment. CONCLUSION: LPS-treated mouse liver displaying a time-dependent liver injury can result in expression change of some liver injury or repair related proteins.
This study was aimed to observe whether expressions of JAK2, STAT1, STAT5 proteins in indomethacin-treated CML cells involved in the proliferation inhibition of CML cells, and elucidate the pharmacological mechanism of indomethacin anti-leukemia. MTT assay and trypan blue dye exclusion test were used to detect the inhibitory effect of indomethacin on CML cells proliferation. JAK2, STAT1, STAT5 proteins were analyzed by Western blot; the subcellular distribution of STAT1, STAT5 were detected with indirect immunofluorescence technique. The results showed that indomethacin at >or= 400 micromol/L significantly inhibited the proliferation of CML cells and down-regulated the expression of STAT1, STAT5 protein, no JAK2 change was observed. STAT1 and STAT5 were located in cytoplasm. It is concluded that indomethacin inhibits the proliferation of CML cells and the mechanism may be related to down-regulated expression of STAT, or blockage of cells growth signals.
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OBJECTIVE: To determine the active protein-2 (AP-2) expression in non-small cell lung cancer (NSCLC) and the relationship between the expression and tumor biological characteristics. METHODS: Fifty NSCLC tissues and 15 normal lung tissues were used to detect the expression of AP-2 transcription factor with the immunohistochemical method. RESULTS: The positive rate of AP-2 expression was zero in the normal lung tissues, but 32% in the NSCLC tissues. The AP-2 expression in the NSCLC tissues was significantly elevated (P < 0.05). The postive rate of AP-2 expression was significantly higher in the NSCLC tissues of pathological grade III (57.89%) than in those of grade I - II (16.13%) (P < 0.05), and higher in patients of clinical stage III - IV (44. 83%) than in those of stage I - II (14.29%) (P <0.01), and in the NSCLC patients with lymph node metastasis (40.54%) than in those without (7.7%) (P < 0.05). CONCLUSION: The up-regulation of AP-2 expression in the NSCLC tissues suggests that AP-2 may be involved in the NSCLC carcinogenesis. AP-2 may play an important role in the genesis and development of NSCLC.