No abstract available.
Thrombopoietin*

The main physiological function of megakaryocytes is the production of platelets, whose development, maturation and platelet production are a complex regulatory process, and are involved in many factors. In recent years it was found that the lung is also the main site of megakaryocyte-producing platelets in addition to bone marrow. Based on the findings of recent years, this review summarizes the process of megakaryocyte development, maturation and platelet production, with emphasis on the analyzing the regulatory effects of apoptotic factors, miRNA, thrombopoietin and its receptors, interleukins, transcription factors and their corresponding signal pathways on platelet production. To understand the regulatory mechanism of platelet production can help to understand the pathological mechanism of platelet-related diseases and provide new ideas for the diagnosis and treatment of platelet-related diseases.
Blood Platelets ; Bone Marrow Cells ; Megakaryocytes ; Thrombopoiesis ; Thrombopoietin

OBJECTIVE: To investigate the curative effect of simply hormone and combined gamma globulin and thrombopoietin(TPO) on primary immune thrombocytopenia(PITP). METHODS: 100 patients with PITP were divided into simply drug groups, and combined drug group each for 50 cases. The patients in single drug group were given simply hormone therapy, the patients in combined drug group were given gamma globulin and thrombopoietin. The levels of TPO, platelet activating factor (PAF) were detected by DAS-ELISA. The differences of clinical curative effect, clinical indicators, biochemical indexes and adverse reactions between the two groups were compared. RESULTS: The total effective rate of combined drug group (90.00%) was obviously higher than that in single drug group (66.00%)(P<0.05). Amount of platelet infusion in combined drug group was obviously less than that in single drug group, platelet recovery time and effect onset time in combined drug group were significantly shorter than those in single drug group, and the maintaining time in combined drug group was obviously longer than that in single drug group. At the same time, the platelet peak in combined drug group was higher than that in single drug group (P<0.05). The levels of TPO, PAF between the two groups did not show statisticall significant differences before treatment (P>0.05), however, the above-mentioned indexes of two groups after treatment were lower than those before treatment (P<0.05), among them, the indexes in combined drug group were obviously lower ttan those in sigle drug group (P<0.05). The adverse reaction and mortality rate between the two groups did not show statistically significant differences(P>0.05), the recurrence rate in combined drug group(2%) was obviously lower than that in single group(14.00%) (P<0.05). CONCLUSION The curative effect of hormone, as well as gamma globulin combined with TPO to treat PITP are satisfying, can obviously improve the levels of TPO, PAF, and the drug safety is higher. but the efficacy of combined drug is surperior to single drug.
Humans ; Immunoglobulins, Intravenous ; Purpura, Thrombocytopenic, Idiopathic ; Thrombopoietin ; gamma-Globulins

Thrombopoietin (TPO) can activate hematopoietic cell proliferation by its receptor c-MPL mediated downstream pathways and induce the generation of megakaryocyte. In recent years, domestic and foreign researches have confirmed that TPO/ c-MPL pathway also plays an important role in the self-renewal and quiescence of leukemia stem cell, and its expression in acute myeloid leukemia (AML) also indicates the chemotherapy resistance and poor prognosis. In this article, the research progress of the roles of TPO/c-MPL pathway in chemotherapy resistance, prognosis of AML patients, and the application of TPO/ c-MPL receptor agonists in AML were summarized briefly.
Humans ; Leukemia, Myeloid, Acute ; Neoplasm Proteins ; Proto-Oncogene Proteins/metabolism* ; Receptors, Cytokine ; Receptors, Thrombopoietin ; Signal Transduction ; Thrombopoietin

BACKGROUND: The megakaryopoiesis and platelet production is regulated by several hematopoietc factors such as thrombopoietin (TPO), interleukin-11 (IL-11) and interleukin-3 (IL-3). IL-11 is a potent stimulator of megakaryopoiesis in vivo, and acts primarily as a megakaryocyte maturation factor in vitro and it can act synergistically with IL-3 and TPO. We performed this study to investigate the effects of recombinant human IL-11 (rhIL-11) with other hematopoietic factors on megakaryocyte colony formation in vitro. METHODS: CD34+ cells were separated from umbilical cord blood and megakaryocyte colonies using MegaCult Assay Kit were cultured with rhIL-11, recombinant human IL-3 (rhIL-3), and recombinant human TPO (rhTPO) for 7 and 14 days. The number and percentage of CD34+ and CD41a+ cells were determined by flowcytometry. RESULTS: The number of CD41a+ cells were 0.54+/-0.05x10(4) (rhIL-11 100 ng/ml), 5.32+.-0.23x10(4) (rhIL-3 100 ng/ml), and 8.76+/-0.15x10(4) (rhTPO 50 ng/ml) of total expanded cells during the culture of the purified CD34+ cells in liquid phase for 7 days. The number of CD41a+ cells were increased to 7.47+/-0.69x10(4) (rhIL-3 rhIL-11), 11.92+/-0.19x10(4) (rhTPO rhIL-11) of total expanded cells, respectively, during the culture of the purified CD34+ cells in liquid phase for 7 days in the presence of rhIL-11 (100 ng/ml). When the purified CD34+ cells were cultured in semisolid media including various concentration of rhIL-11, the megakaryocyte colonies were not formed. When the purified CD34+ cells were cultured with rhIL-11 and rhTPO or with rhIL-11 and rhIL-3, the number of megakaryocyte colonies were increased compared with rhTPO or rhIL-3 alone. CONCLUSION: These results indicate that IL-11 exerts a potent proliferative activity to colony forming unit-megakaryocyte from human umbilical cord blood, and it acts with other hematopoietic factors synergistically
Blood Platelets ; Fetal Blood* ; Humans ; Interleukin-11* ; Interleukin-3 ; Megakaryocytes ; Thrombopoietin ; Umbilical Cord*

OBJECTIVE: To investigate the decisive role of preoperative serum thrombopoietin levels in the discrimination of benign and malignant ovarian pathologies and its value in the evaluation of treatment response. METHODS: Fifty patients with diagnoses of adnexal masses (25 benign, 25 malignant) were included in the study. Blood samples were collected from all cases preoperatively. Age, menopausal status, adnexal mass size, preoperative CA-125 level, platelet count, the stage of the disease (FIGO stage), tumor grade, histologic subgroup, the residual tumor mass, ascites cytology, surgical procedures, and postoperative treatments were recorded for the malignant group. Response to treatment was evaluated based on the revised RECIST guideline. RESULTS: The preoperative serum thrombopoietin levels of the malignant cases (median, 98; range, 7 to 768) were significantly higher when compared with those of benign cases (median, 27; range, 13 to 131; p=0.004). The positive predictive value of CA-125 was found to be 79%, when it was used as a single marker; however it had risen to 85% when both CA-125 and thrombopoietin levels were used. There was no significant relationship between preoperative serum thrombopoietin levels and tumor grade, ascites cytology, presence of residual mass, and response to treatment. The preoperative serum thrombopoietin levels were significantly higher in stage III-IV cases and cases with serous histology. The post-treatment serum thrombopoietin levels in the malignant group were significantly lower as compared with the preoperative thrombopoietin levels. CONCLUSION: Thrombopoietin can play an additive role for prediction of ovarian cancer.
Ascites ; Discrimination (Psychology) ; Humans ; Neoplasm, Residual ; Ovarian Neoplasms ; Platelet Count ; Thrombopoietin ; Biomarkers, Tumor

Cytokines such as erythropoietin (EPO) and thrombopoitein (TPO) and so on, which stimulate hematopoiesis, can regulate self-renewal, proliferation, differentiation, maturation and programmed cell death of hematopoietic cells through specifically binding to surface receptors. Recently random phage display peptide libraries and other screening methods have been used to isolate mimetic including small peptides and non-peptides molecules, which can mimic the same effects as cytokines, such as EPO and TPO, and demonstrate the similar potency and activity as EPO and TPO in a panel of in vitro biological assays and in animal experiments. These approaches are critical to further research of interactive mechanisms between cytokine and receptor, receptor activation and rational design of other desired cytokine mimetic. This review concisely introduced recent advances in research on mimetic of EPO, TPO and other cytokines and future directions.
Animals ; Cytokines ; pharmacology ; Erythropoietin ; pharmacology ; Hematopoiesis ; drug effects ; physiology ; Humans ; Peptide Library ; Peptides ; pharmacology ; Thrombopoietin ; pharmacology

AIMDesign, construction, expression in E coli and protein characteristics prediction of bimolecular thrombopoietin (T-T) with more stability, efficiency, and lower toxicity.

METHODSThe expression vectors of TPO and T-T, pET32 a(+)/TPO and pET32 a (+)/T-T, had been constructed by molecular cloning methods. Then, they were expressed in host bacterium. Their products were identified by Western blot. The protein characteristics, such as second structure, antigenicity, hydrophilicity, flexibility and isoelectric point, were predicted by DS Gene and Protscale software.

RESULTSThe expressing vectors pET32a(+)/TPO and T-T were constituted correctly and expressed in origami (DE3), and their expression efficiency were more than 40 percent of total protein. T-T was identified correctly by Western blot. DS Gene and Protscale software predict the protein characteristics of TPO sequences in T-T molecule were no change, there was high flexibility in the linker domain. But two amino acids in T-T molecule have been mutated, and an insert fragment with 34 amino acids following the linker had antigenicity, hydrophilicity, and beta-sheet structure.

CONCLUSIONWe have constructed correctly and expressed T-T with high level in E Coli. Protein characteristics prediction of T-T accords with our design.

In order to find a new TPO-mimic peptide with similar activity to TPO while reducing the side effects, a TPO-mimic peptide (P1) screened from a random peptide library was restructured. The new structure of the TPO mimic peptide (P2) was synthesized. After coupling P2 with Dextran 10 and performing intermolecular oxidation, dextran-coupled and dimerized form of P2 were obtained, naming D-P2 and (P2)(2) respectively. The activities of the peptides in vitro were measured with MTT method. The results showed that the EC50 of P2 was 20 nmol/L, 700 times higher than P1. The EC50 of D-P2 and (P2)(2) were 0.35 nmol/L and 0.14 nmol/L, respectively. After administrating to the mouse, the peptides increased the number of platelets in the blood circulation obviously without influence on other blood cells. In conclusion, the TPO-mimic peptides have prospects in treating diseases related with thrombocytopenia.
Animals ; Female ; Male ; Mice ; Platelet Count ; Thrombopoietin ; analogs & derivatives ; chemical synthesis ; pharmacology

Thrombopoietin (TPO) is a major cytokine for megakaryocytopoiesis and thrombopoiesis, and also plays an important role in the regulation of early hematopoiesis. TPO activates a number of signal pathways to exert its biological function by binding to its receptor (c-mpl). Once these signal pathways (including Jak/STAT, PI3K/Akt, Ras/MAPK) are activated, the expression of the downstream signal molecules can be changed, which then induces biological effects. Recent researches have suggested the novel functions of TPO in many systems. The receptor of TPO (c-mpl) has been shown not only present in hematological cells, but also in many other cells and organs, such as neurons, heart muscle cells, vessel endothelial cells and so on. TPO exerts a protective effect on these cells through the interaction with c-mpl. This review discusses the molecular mechanism of TPO signal and the effect of TPO on multi-nonhematopoietic cells.
Animals ; Humans ; Myocytes, Cardiac ; Neurons ; Signal Transduction ; genetics ; Thrombopoietin ; genetics ; metabolism