Effect of BCLAF1 on HDAC inhibitor LMK-235-mediated apoptosis of diffuse large B cell lymphoma cells and its mechanism

Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma. It is a group of malignant tumors with a large number of clinical manifestations and prognoses. Therefore, it is necessary to explore its unknown potential therapeutic targets. Histone deacetylase inhibitor (HDACi) is a novel drug for the treatment of DLBCL, however pan-HDACis cannot be ignored because of their clinical efficacy. By contrast, specific HDACi is well-tolerated, and LMK-235 is a novel HDACi that is a specific inhibitor of HDAC4 and HDAC5. In this study, we investigated the up-regulation of BCLAF1 through NF-κB signaling pathways in LMK-235, mediating the apoptosis of two diffuse large B-cell lymphoma cell lines, OCI-LY10 and OCI-LY3. Further studies showed that BCLAF1 expression was increased in DLBCL cells after treatment with the NF-κB inhibitor Bay11-7082. The combination of Bay11-7082 and siRNA si-HDAC4 significantly increased BCLAF1 expression and further increased apoptosis. These results indicate that BCLAF1 plays an important role in LMK-235-mediated apoptosis and may be a potential target for the treatment of diffuse large B-cell lymphoma.     

恶性淋巴瘤NF-kB活化与化疗药物诱导细胞凋亡的关系及地塞米松的影响作用

目的：研究化疗药物诱导Raji恶性淋巴瘤细胞核因子-kB（NF-kB）活化与凋亡关系，并探讨地塞米松（DXH）对其的影响作用。方法：采用电泳迁移率变动分析（EHSA）检测细胞NF-kB活化水平：采用TdT介导的dUPT缺口末端标记技术（Tunel）检测细胞凋亡。结果：化疗药物诱导Raji恶性淋巴瘤NF-kB活化与化疗药物诱导细胞凋亡明显相关，lumol／LDXM能显著抑制阿糖胞苷（Ara-C）1umol／L或鬼臼乙叉甙（VP-16）1umol／L诱导的Raji细胞NF-kB活化，抑制率分别为64.6％和40.4％，并增强他们诱导Raji细胞凋亡的作用，凋亡增加率分别为27.96名和29.95％。Raij细胞在接触化疗药物前，NF-kB亦有一定程度的活化。结论：化疗药物在诱导Raij恶性淋巴瘤细胞凋亡的同时活化NF-kB，DXM可通过抑制NF-kB活化以增强化疗药物诱导恶性淋巴瘤细胞凋亡的作用。     

NF-kB expression in IgA nephropathy outcome

Some studies have demonstrated the involvement of nuclear factor-kappa B (NF-kB) in the pathogenesis of glomerulonephritis. The aim of our study was twofold: (1) to analyze the prognostic value of NF-kB expression in primary IgA nephropathy (IgAN) and (2) to compare the results of NF-kB expression by immunohistochemistry (IHC) and southwestern histochemistry (SWH). We analyzed 62 patients diagnosed with IgAN from 1987 to 2003. We used monoclonal antibodies to CD68 and mast cell tryptase and polyclonal antibodies to TGF-β1, α-SMA and NF-kB p65. We used SWH for the in situ detection of activated NF-kB. The results showed that NF-kB expression (mainly by SWH) correlated with clinical and histological parameters. An unfavorable clinical course of IgAN was significantly related to tubular NF-kB expression by SWH, but not by IHC. The Kaplan-Meier curves demonstrated that increased NF-kB expression, which was measured by IHC and SWH, decreased renal survival. In conclusion, the increased expression of NF-kB in the tubular area may be a predictive factor for the poor prognosis of patients with IgAN. Compared with IHC, NF-kB expression determined by SWH was correlated with a larger number of parameters of poor disease outcome.     

NF-κB在上颌窦鳞状细胞癌中的表达

[目的]探讨核因子-κB（NF-κB）在上颌窦鳞状细胞癌中的表达及其与主要临床指标间的关系.[方法]采用免疫组化SP法检测42例上颌窦鳞状细胞癌和20例正常上颌窦黏膜组织中NF-κB的表达情况.[结果]20例正常上颌窦黏膜组织表达全部为阴性,42例上颌窦鳞状细胞癌中28例NF-κB表达上调（阳性率66.7%）.NF-κB的表达与肿瘤分期、淋巴结转移之间无明显相关性,而与组织分化程度显著相关,低分化上颌窦鳞状细胞癌较中、高度分化上颌窦鳞状细胞癌NF-κB的表达明显增高（P〈0.05）;具有NF-κB阳性表达的上颌窦鳞状细胞癌患者3年生存率明显低于阴性患者（P〈0.05）.[结论]NF-κB的表达在上颌窦鳞状细胞癌的发生、发展中起一定作用,并可作为判断上颌窦鳞状细胞癌生物学行为和预后的一个参考指标.     

Polyclonal hypergammaglobulinemia in a case of B-cell chronic lymphocytic leukaemia: the result of IL-2 production by the proliferating monoclonal B cells?

Summary. CLL is typically characterized by acquired hypogammaglobulinemia. We report the case of a female patient suffering from B-CLL who developed polyclonal hypergammaglobulinaemia: 38-3 g/I polyclonal IgG, 0.97g/1 IgA and 0.33 g/1 IgM. Immunophenotyping showed a monoclonal lymphocytic population CD19⁺ CD5⁺ CD40⁺ CD23+, low slg⁺ (95%), K type in the great majority (96%). RT-PCR of immunoglobulin genes gave evidence of monoclonal rearrangement of the IgM type. Our tests showed that IL-2 was produced when leukaemic B cells were stimulated with phorbol myristate acetate, ionomycin and lipopoly-saccharide. In addition, transfections with the full IL-2 promoter or elements thereof revealed that IL-2 expression is inducible and mediated through the NF-kB-promoter element. Finally, the amount of IL-2 secreted by these cells is about 39ng/ml/10⁶ cells, which is remarkably high for non-T cells. These results suggest that the large amounts of polyclonal IgG seen in this case of B-CLL are secreted by normal B cells which are in turn stimulated by IL-2 produced by proliferating monoclonal (leukaemic) B cells. Under cyclosporin A treatment, immunoglobulin secretion and B cell count remained low.     

抑制NF-κB活性下调高糖培养的大鼠肾小球系膜细胞血管紧张素原表达水平

在体外原代培养的SD大鼠肾小球系膜细胞中,观察高糖培养条件下血管紧张素原(AGT)表达和血管紧张素Ⅱ(AngⅡ)水平变化,以及吡咯烷二硫代氨基甲酸酯(PDTC)的干预作用.结果 显示高糖上调ACT mRNA(0.29±0.07对0.20±0.05,P<0.05)和蛋白(0.66±0.23对0.37±0.15,P<0.05)表达以及AngⅡ分泌[(9.85+2.08对7.50±1.51)ps/ml,P<0.05]水平,PDTC通过抑制NF-κB活性下调其水平.     

Is it safe to use TNF-α blockers for systemic inflammatory disease in patients with heart failure? Importance of dosage and receptor specificity

Tumor necrosis factor-alpha (TNF-α) blockers are widely used in the treatment of chronic inflammatory diseases, especially chronic arthritis. Current guidelines advise against the use of such agents in patients who have a concomitant heart failure. Consequently, a group of patients with a devastating inflammatory disease cannot benefit from an excellent treatment option. After a critical review of the current literature, we conclude that there is not sufficient evidence to warn against such a regimen if recommended standard doses are used. A negative effect on the heart function seems to occur if unconventional high doses of TNF-α blockers are given. The theoretical background for this is discussed.     

Breast adenocarcinoma MCF-7 cell line induces spontaneous osteoclastogenesis via a RANK-ligand-dependent pathway

The metastasis of breast cancer to the skeleton is a serious clinical problem resulting in hypercalcemia, bone fragility and insurmountable pain. The invasion of bony tissue by neoplastic cells usually very rapidly affects the balance between bone apposition and bone resorption. In order to elucidate a mechanism for cancer-induced osteoclastogenesis, cells from a human breast cancer line, MCF-7, were directly co-cultured with murine monocytes RAW 264.7 type CRL 2278. Compared with controls, co-culture of MCF-7 induced differentiation of multinucleated cells by membrane-bound and soluble receptor activator of NF-kB ligand (RANKL) as quantified by ELISA, Western blot analysis, transmission electron microscopy (TEM), and immunocytochemistry. The aim of this study was to determine an in vitro model system of MCF-7 human breast cancer cells grown together with monocytes to show that expression of RANKL promotes osteoclastogenesis, which may indicate a mechanism for the development of osteolytic lesions in breast cancer bone metastasis.