Xanthohumol ameliorates 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin–induced cellular toxicity in cultured MC3T3‐E1 osteoblastic cells

2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is an environmental contaminant. Xanthohumol is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The aim of the current study was to explore the role of xanthohumol in modulating the toxicity of TCDD in MC3T3‐E1 osteoblastic cells. In cells treated with TCDD alone, intracellular Ca²⁺ concentrations, mitochondrial membrane potential disruption, reactive oxygen species production, cardiolipin peroxidation, nitric oxide release and cytochrome P450 1A1 expression were significantly increased. TCDD treatment increased the mRNA levels of extracellular signal‐regulated kinase 1 and nuclear factor kappa B, and significantly decreased the level of protein kinase B (AKT) in MC3T3‐E1 osteoblastic cells. However, the presence of xanthohumol alleviated the pathological effects of TCDD. In addition, xanthohumol treatment significantly increased the expression of genes associated with osteoblast differentiation (alkaline phosphatase, osteocalcin, osteoprotegerin and osterix). We conclude that xanthohumol has a beneficial influence and may antagonize TCDD toxicity in osteoblastic cells.     

Identification, quantitation and biological activity of phytoestrogens in a dietary supplement for breast enhancement

A hop-based dietary supplement, marketed for natural breast enhancement, was analysed to determine the identity and biological activity of active constituents and potential biological effects in man. Extracts of the dietary supplement were analysed by LC-MS(n) and phytoestrogens identified and quantitated by reference to appropriate standards. Only hop-associated phytoestrogens were found in the dietary supplement at significant concentrations as follows (mean+/-1 S.D.); 8-prenylnaringenin 10.9+/-0.3, 6-prenylnaringenin 27.4+/-1.2, 6,8-diprenylnaringenin 0.9+/-0.1, xanthohumol 321+/-17 and isoxanthohumol 81.1+/-1.6 microg/g of dietary supplement. The oestrogenic activity of extracts in an ERalpha reporter gene assay was equivalent to 48+/-6.3 ng 17beta-oestradiol/g supplement and consistent with the 8-prenylnaringenin content. The dietary supplement extract also inhibited reductive 17beta-hydroxysteroid oxidoreductase activity, but to a greater extent than a concentration matched reference mixture of hop phytoestrogens. However, the supplement was only weakly active in mouse uterotrophic assays following administration in feed or after subcutaneous injection of extract at doses of 8-PN up to 250 times higher than that recommended for women. These preliminary findings suggest that the dietary supplement is unlikely to produce oestrogenic effects in vivo at the level of the uterus; supporting evidence is still required to demonstrate efficacy.     

黄腐酚类似物通过cAMP/Wnt/β-catenin信号通路抑制卵巢癌细胞增殖降低对顺铂的耐药性

目的:探究黄腐酚（xanthohumol,XN）类似物通过cAMP/Wnt/β-catenin信号通路调控卵巢癌细胞增殖的作用及对顺铂耐药性的影响。方法:以人卵巢癌细胞株HO-8910为研究材料,分为不同浓度(0、5、7.5、15、20 μmol/L)黄腐酚类似物组、对照组、顺铂组、黄腐酚类似物+顺铂组。采用四甲基偶氮唑蓝（methyl thiazolyl tetrazolium,MTT）法、实时荧光定量酶链式反应（quantitative real-time polymerase chain reaction,qRT-PCR）、蛋白免疫印迹法（Western blot,WB）检测黄腐酚类似物对HO-8910细胞增殖及对顺铂耐药性的影响。结果:与对照组比,黄腐酚类似物能够明显抑制HO-8910细胞增殖,差异具有统计学意义（P<0.05）;黄腐酚类似物a13+顺铂组HO-8910细胞对顺铂的半数抑制浓度（half maximal inhibitory concentration,IC50）显著低于顺铂组,细胞活性抑制率（inhibition rate,IR）显著高于顺铂组,差异具有统计学意义（P<0.05）;PKIβ（cAMP抑制剂）、IWP-2（Wnt/β-catenin抑制剂）可降低黄腐酚类似物a13对HO-8910细胞增殖的抑制作用,逆转黄腐酚类似物a13抑制HO-8910细胞对顺铂的耐药作用,差异具有统计学意义（P<0.05）。结论:黄腐酚类似物可提高顺铂对卵巢癌细胞增殖的抑制作用,降低细胞对顺铂的耐药性,作用机制与激活cAMP/Wnt/β-catenin信号通路有关。     

黄腐酚对顺铂诱导H1650细胞凋亡的影响

目的 以顺铂为主的非小细胞肺癌化疗方案不断更新,目前研究旨在寻求疗效的放大及毒副作用的缩小.黄腐酚被证明有抗癌及保护正常细胞的作用.本实验主要探讨黄腐酚的不同给药方式对顺铂诱导人非小细胞肺癌细胞株H1650凋亡的影响.方法 采用CCK-8法检测黄腐酚、顺铂单用及先用低浓度黄腐酚干预,后补入顺铂对H1650细胞增殖的影响;使用流式细胞术分别分析先用黄腐酚后用顺铂、先用顺铂再补入黄腐酚2种干预方式对H1650细胞凋亡率或存活率的影响.结果 CCK-8检测结果显示,2μmol/L黄腐酚干预H1650细胞48 h后,继续给予20、40和80μmol/L顺铂干预24 h,抑制细胞增殖率分别为(13.16±1.06)%、(19.14±1.67)%和(28.17±2.79)%,均低于同浓度顺铂单纯干预24 h组的(18.96±3.02)%、(23.28±1.43)%和(39.79±3.44)%,P<0.05.流式细胞术检测结果显示,10、20和40μmol/L顺铂干预细胞24 h后,继续给予7〔(85.66±3.19)%、(74.62±2.98)%和(59.55±2.70)%〕或14μmol/L〔(82.04±2.88)%、(76.50±3.11)%和(61.76±3.01)%〕黄腐酚干预24 h,其细胞存活率明显高于同浓度顺铂单纯干预48 h组的(72.60±2.69)%、(56.98±3.80)%和(44.15±2.01)%,P<0.05.3μmol/L黄腐酚干预细胞24 h,弃培养液,更换10、20和40μmol/L顺铂再干预24 h,其细胞凋亡率分别为(29.79±3.78)%、(30.53±3.89)%和(39.48±4.98)%,明显高于顺铂单纯干预24 h组的(17.21±3.01)%、(14.53±2.99)%和(18.88±4.20)%,P<0.05.结论 黄腐酚直接有效保护顺铂对H1650细胞的杀伤,但低浓度黄腐酚的前期干预间接提高了顺铂对H1650细胞的凋亡率.     

Xanthohumol,a hop-derived prenylflavonoid present in beer,impairs mitochondrial functionality of SW620 colon cancer cells

Xanthohumol (XN) is a hop-derived prenylflavonoid and have been reported to exhibit anticancer properties in several types of cancer. It presents a great interest against colon cancer due to high exposure of this compound in this tissue. Metastatic SW620 cell line was treated with doses ranging from 0.001 to 10?µM of XN to assess their effects on cell viability and mitochondrial function. At low concentrations, XN had no effect on assays carried out, but high concentration of XN led to a decrease in cell viability. In addition, at 10?μM XN, it gave rise to an increase in ROS production accompanied by a decrease in OXPHOS complexes and sirtuin 1 protein expression levels. These results suggest that XN could act as a mitocan and impairs mitochondrial function.     

Xanthohumol Induces Different Cytotoxicity and Apoptotic Pathways in Malignant and Normal Astrocytes

Cytotoxicity and the mechanisms of cell death induced by xanthohumol (XN) were compared in normal and cancerous human cells as the differences may be relevant for the potential use of XN in cancer therapy. The cancer cells seemed to be more susceptible to the cytotoxicity of XN than normal cells, but a significant difference was observed only in astrocytic cells. XN induced a higher rate of apoptosis in glioblastoma cells than in normal astrocytes, which was associated with activation of p53 and an elevated Bax/Bcl‐2 ratio in glioblastoma cells, indicating an intrinsic caspase‐dependent apoptotic pathway. In contrast, a reduced Bax/Bcl‐2 ratio was observed in normal human astrocytes. This was also associated with higher expression of the cell cycle inhibitor, p21, in glioblastoma cells than in normal astrocytes. In addition, at a lower, non‐cytotoxic concentration, XN partially inhibited the invasiveness of glioblastoma cells. Due to the selective sensitivity of astrocytic cells to XN, this compound should be studied further as a candidate for adjuvant therapy in the treatment of glioma. Copyright © 2012 John Wiley & Sons, Ltd.     

Protein kinase A inhibition facilitates the antitumor activity of xanthohumol,a valosin‐containing protein inhibitor

Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin‐containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.     

啤酒花及其活性成分黄腐酚抗糖皮质激素性骨质疏松的作用研究

目的 研究对啤酒花及其活性成分黄腐酚抗糖皮质激素性骨质疏松（GIOP）作用。方法 腹腔注射地塞米松（DEX）造模,并结合Micro-CT及Elisa试剂盒检测等方法,对小鼠股骨的骨微结构、骨密度及血清骨生化指标进行评价。同时,采用DEX损伤成骨细胞,对其增殖、分化水平及骨形成相关蛋白的表达进行评价。结果 啤酒花提取物及黄腐酚可显著改善GIOP小鼠的骨微结构破坏,增强骨密度,改善骨小梁参数。在成骨细胞水平上,啤酒花及黄腐酚既可促进DEX损伤成骨细胞的增殖、分化,又可提高骨钙素（BGP）、骨形成蛋白2（BMP-2）以及成骨特异性转录因子（Runx-2）的表达水平,促进骨形成。结论 该研究首次明确了啤酒花及黄腐酚具有抗GIOP作用,为抗骨质疏松药物的开发提供了新资源。