-
[show abstract]
[hide abstract]
ABSTRACT: Human T-cell leukemia is an aggressive malignancy of T lymphocytes. T-cell leukemia has a very poor prognosis, even with intensive chemotherapy, indicating the need for development of new drugs to treat the disease. Triterpenoid cucurbitacins have been shown to have antitumor activity, but the mechanism of this activity is not fully understood.
The effects of cucurbitacin D on the proliferation and apoptotic induction of T-cell leukemia cells using the Cell viability assay and Annexin V staining were evaluated. To investigate the mechanisms of apoptosis, antiapoptotic protein, NF-κB, and the proteasome activity of leukemia cells treated with cucurbitacin D were evaluated by Western blotting both in vitro and in vivo.
In this study, cucurbitacin D was found to inhibit proliferation and to induce apoptosis of T-cell leukemia cells. Constitutively activated NF-κB was inhibited by cucurbitacin D in the nucleus, which resulted in accumulation of NF-κB in the cytoplasm, leading to down-regulation of the expression of antiapoptotic proteins Bcl-xL and Bcl-2. Furthermore, cucurbitacin D induced the accumulation of inhibitor of NF-κB (IκB)α by inhibition of proteasome activity. Low doses of cucurbitacin D synergistically potentiated the antiproliferative effects of the histone deacetylase inhibitor VPA. Finally, the proapoptotic and proteasome inhibitory activities of cucurbitacin D also were demonstrated using SCID mice in an in vivo study.
Cucurbitacin D induced apoptosis through suppression of proteasome activity both in vitro and in vivo, making cucurbitacin D a promising candidate for clinical applications in the treatment of T-cell leukemia.
Cancer 06/2011; 117(12):2735-46. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Toluene has been extensively examined for effects on the central nervous system. To investigate the influence of low-level inhalation of toluene on the naive immune cells, male C3H/HeN mice were exposed to filtered air (control) and 50 ppm of toluene for 3 weeks. Low-level exposure resulted in (1) increased proliferation of thymocytes, (2) IL-2 production induced in thymocytes and (3) activation of the transcription factors NF-κB, STAT5 and NF-AT in thymocytes. These results suggest that thymocytes are sensitive cells and T cell activators are candidates for biomarkers for low-level exposure to toluene on naive immune cells.
Journal of Applied Toxicology 10/2010; 30(7):656-60. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously reported that peritoneal and splenic macrophages from Th2-dominant BALB/c mice produced higher amounts of prostaglandin (PG) E2 than cells from C57BL/6 mice. In this study, we investigated how macrophages from BALB/c mice acquire the ability of enhanced PGE2 production, using bone marrow-derived macrophages differentiated by M-CSF, GM-CSF or IL-3. There is no strain difference in PGE2 production by GM-CSF- and M-CSF-differentiated macrophages; however, IL-3-differentiated macrophages from BALB/c mice produced higher amounts of PGE2 and lower amounts of type I cytokines than cells from C57BL/6 mice. IL-3-differentiated macrophages from BALB/c mice expressed larger amounts of mRNA of membrane-bound (microsomal) PGE synthase-1 (mPGES-1). The amounts of PGE2 produced by macrophages were significantly reduced in mPGES-1-deficient mice, and these mice displayed enhanced Th1 responses after Propionibacterium acnes treatment compared with wild-type mice. Microarray analysis revealed 63 genes that are differentially expressed more than fivefold in macrophages between C57BL/6 and BALB/c mice. These results indicate that mPGES-1-mediated PGE2 produced by macrophages regulates immune responses, and IL-3 is an important factor for the differentiation of macrophages that produce higher amounts of PGE2 through mPGES-1 activity in BALB/c mice.
European Journal of Immunology 09/2007; 37(8):2185-95. · 5.10 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mast cells play an important role for the induction and the expression of allergic responses. In this report, we studied the strain difference of bone marrow-derived murine mast cell (BMMC) functions in vitro. BMMC were induced by in vitro culture of bone marrow cells from BALB/c and C57BL/6 mice with interleukin (IL)-3 for 4 weeks, stimulated with immunoglobulin E antibody and antigen, and mediators and cytokines released in the culture supernatant were assayed. BMMC from C57BL/6 mice released a higher amount of granule-associated mediators, beta-hexosaminidase, and histamine than that from BALB/c mice. The expression of mRNA of histidine decarboxylase was higher in C57BL/6 mice. Conversely, the productions of newly synthesized mediators, prostaglandin D2 (PGD2), IL-6, and monocyte chemoattractant protein-1, and the mRNA expression of IL-5 were higher in BALB/c BMMC than C57BL/6 BMMC. Although mRNA and protein expression levels of cyclooxygenase-2 were equal in two strains, both expression levels of hematopoietic PGD synthase (hPGDS) were higher in BALB/c BMMC. Mast cells, freshly obtained from mice, also showed the same strain difference concerning the mediator release. These results indicate that the strain difference exists in mast cell functions in mice, and this difference can be considered to induce the susceptibility difference to allergic reactions in mouse strains.
Journal of Leukocyte Biology 10/2005; 78(3):605-11. · 4.99 Impact Factor
