更新于：2024-11-01

GAGs

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 GAGs 相关的药物

Vartumab

靶点

GAGs

作用机制

GAGs 抑制剂

在研机构

Var2 Pharmaceutical

原研机构

Var2 Pharmaceutical

在研适应症

膀胱癌 [+11]

非在研适应症-

最高研发阶段早期临床1期

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GAGs 相关的临床结果

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100 项与 GAGs 相关的转化医学

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0 项与 GAGs 相关的专利（医药）

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项与 GAGs 相关的文献（医药）

2024-09-01·Leukemia

Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis

Article

作者: Abbonante, Vittorio ; Iurlo, Alessandra ; Cattaneo, Daniele ; Malara, Alessandro ; Tosi, Delfina ; Balduini, Alessandra ; Moriggi, Manuela ; Vannucchi, Alessandro Maria ; Gelfi, Cecilia ; Calledda, Francesca R ; Bucelli, Cristina ; Capitanio, Daniele ; Gianelli, Umberto ; Niccolò, Bartalucci

Despite increased understanding of the genomic landscape of Myeloproliferative Neoplasms (MPNs), the pathological mechanisms underlying abnormal megakaryocyte (Mk)-stromal crosstalk and fibrotic progression in MPNs remain unclear. We conducted mass spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis to reveal alterations in signaling pathways and protein changes in Mks, platelets, and bone marrow (BM) cells. The chemokine Platelet Factor 4 (PF4)/Cxcl4 was up-regulated in all proteomes and increased in plasma and BM fluids of fibrotic mice. High TPO concentrations sustained in vitro PF4 synthesis and secretion in cultured Mks, while Ruxolitinib restrains the abnormal PF4 expression in vivo. We discovered that PF4 is rapidly internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. Cxcl4 gene silencing in Mks mitigated the profibrotic phenotype of stromal cells in TPO-saturated co-culture conditions. Consistently, extensive stromal PF4 uptake and altered GAGs deposition were detected in Romiplostim-treated, JAK2^V617F mice and BM biopsies of MPN patients. BM PF4 levels and Mk/platelet CXCL4 expression were elevated in patients, exclusively in overt fibrosis. Finally, pharmacological inhibition of GAGs ameliorated in vivo fibrosis in Romiplostim-treated mice. Thus, our findings highlight the critical role of PF4 in the fibrosis progression of MPNs and substantiate the potential therapeutic strategy of neutralizing PF4-GAGs interaction.

2014-09-01·The Journal of Steroid Biochemistry and Molecular Biology2区 · 生物学

Differential effects of estrogen exposure on arylsulfatase B, galactose-6-sulfatase, and steroid sulfatase in rat prostate development

2区 · 生物学

Article

作者: Sumit Bhattacharyya ; Leo Feferman ; Lynn Birch ; Joanne K. Tobacman ; Gail S. Prins

Sulfatase enzymes remove sulfate groups from sulfated steroid hormones, including estrone-sulfate and dehydroepiandrosterone-sulfate, and from sulfated glycosaminoglycans (GAGs), including chondroitin sulfates and heparan sulfate. The enzymes N-acetylgalactosamine-4-sulfatase (arylsulfatase B; ARSB) and N-acetylgalactosamine-6-sulfatase (GALNS), which remove sulfate groups from the sulfated GAGs chondroitin 4-sulfate (C4S) and chondroitin 6-sulfate, respectively, have not been studied in prostate development previously. In this report, the endogenous variation and the impact of exogenous estradiol benzoate on the immunohistochemistry and activity of ARSB and GALNS in post-natal (days 1-30) ventral rat prostate are presented, as well as measurements of steroid sulfatase activity (STS), C4S, total sulfated GAGs, and versican, an extracellular matrix proteoglycan with chondroitin sulfate attachments on days 5 and 30. Findings demonstrate distinct and reciprocal localization of ARSB and GALNS, with ARSB predominant in the stroma and GALNS predominant in the epithelium. Control ARSB activity increased significantly between days 5 and 30, but following estrogen exposure (estradiol benzoate 25 μg in 25 μl sesame oil subcutaneously on days 1, 3, and 5), activity was reduced and the observed increase on day 30 was inhibited. However, estrogen treatment did not inhibit the increase in GALNS activity between days 5 and 30, and reduced STS activity by 50% on both days 5 and 30 compared to vehicle control. Sulfated GAGs, C4S, and the extracellular matrix proteoglycan versican declined between days 5 and 30 in the control, but these declines were inhibited following estrogen. Study findings indicate distinct variation in expression and activity of sulfatases, sulfated GAGs, C4S, and versican in the process of normal prostate development, and disruption of these events by exogenous estrogen.