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61.
Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-γ, transforming growth factor-β1, interleukin-1β, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis. 相似文献
62.
Griseofulvin (GF), an oral antifungal agent, has been shown to exert antitumorigenesis effect through G2/M cell cycle arrest in colon cancer cells. But the underlying mechanisms remained obscure. The purpose of this study is to test the cytotoxic effect of GF on HL-60 and HT-29 cells and elucidate its underlying molecular pathways. Dose-dependent and time-course studies by flow cytometry demonstrated that 30 to 60 microM GF significantly induced G2/M arrest and to a less extend, apoptosis, in HL-60 cells. In contrast, only G2/M arrest was observed in HT-29 cells under similar condition. Pretreatment of 30 microM TPCK, a serine protease inhibitor, completely reversed GF-induced G2/M cell cycle arrest and apoptosis in HL-60 cells but not in HT-29 cells. The GF-induced G2/M arrest in HL-60 cells is reversible. Using EMSA and super-shift analysis, we demonstrated that GF stimulated NF-kappaB binding activity in HL-60 cells, which was completely inhibited by pretreatment of TPCK. Treatment of HL-60 with 30 microM GF activated JNK but not ERK or p38 MAPK and subsequently resulted in phosphorylation of Bcl-2. Pretreatment of TPCK to HL-60 cells blocked the GF-induced Bcl-2 phosphorylation but not JNK activation. Time course study demonstrated that activation of cdc-2 kinase activity by GF correlated with Bcl-2 phosphorylation. Taken together, our results suggest that activation of NF-kappaB pathway with cdc-2 activation and phosphorylation of Bcl-2 might be involved in G2/M cell cycle arrest in HL-60 cells. 相似文献
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Jun Yao Huasha Zeng Min Zhanga Qinjun Wei Ying Wang Haiyuan Yang Yajie Lu Rongfeng Li Qiang Xiong Lining Zhang Zhibin Chen Guangqian Xing Xin Cao Yifan Dai 《遗传学报》2019,46(8):379-387
Oxysterol binding protein like 2(OSBPL2), an important regulator in cellular lipid metabolism and transport, was identified as a novel deafness-causal gene in our previous work. To resemble the phenotypic features of OSBPL2 mutation in animal models and elucidate the potential genotypephenotype associations, the OSBPL2-disrupted Bama miniature(BM) pig model was constructed using CRISPR/Cas9-mediated gene editing, somatic cell nuclear transfer(SCNT) and embryo transplantation approaches, and then subjected to phenotypic characterization of auditory function and serum lipid profiles. The OSBPL2-disrupted pigs displayed progressive hearing loss(HL) with degeneration/apoptosis of cochlea hair cells(HCs) and morphological abnormalities in HC stereocilia, as well as hypercholesterolaemia. High-fat diet(HFD) feeding aggravated the development of HL and led to more severe hypercholesterolaemia. The dual phenotypes of progressive HL and hypercholesterolaemia resembled in OSBPL2-disrupted pigs confirmed the implication of OSBPL2 mutation in nonsydromic hearing loss(NSHL) and contributed to the potential linkage between auditory dysfunction and dyslipidaemia/hypercholesterolaemia. 相似文献
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Ascorbic Acid Synergistically Potentiates Phloxine B‐induced Photocytotoxicity in Human Acute Promyelocytic Leukemia Cells
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Hang Qi Qian Wu Naomi Abe Shunya Saiki Beiwei Zhu Yoshiyuki Murata Yoshimasa Nakamura 《Journal of biochemical and molecular toxicology》2014,28(4):167-173
Ascorbic acid (AsA) is known as an antioxidant but concomitantly possesses a pro‐oxidant property. Because the impact of AsA on photodynamic therapy response is unclear, we investigated the effect of AsA on photocytotoxicity induced by phloxine B in human acute promyelocytic leukemia HL‐60 cells. AsA synergistically enhanced phloxine B‐induced photocytotoxic effects, including inhibition of cell proliferation, DNA ladder formation, and caspase‐3 activation, whereas AsA itself showed no photocytotoxicity. AsA also enhanced the consumption of the reduced glutathione level compared with the cells treated with phloxine B alone under the light condition. Combination of AsA with phloxine B under the light condition enhanced the phosphorylation of c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase (MAPK). These effects were completely cancelled by catalase. These results suggest that AsA synergistically enhances phloxine B‐induced photocytotoxicity, possibly through the extracellular oxidative stress‐dependent MAPK pathway activation. 相似文献
67.
The clinical efficacy and safety of realgar (arsenic sulfide, As(4)S(4)) in the treatment of acute promyelocytic leukemia in China have given rise to an upsurge in research on the underlying mechanism. We prepared realgar nanoparticles (RNPs) to examine their effect on the differentiation of HL-60 cells. Treatment with RNPs at 6 microM for 72 h induced cell differentiation that was assessed by morphological change, NBT reductive ability, and elevation of CD11b expression at both mRNA and protein levels. The RNP-induced differentiation was synergized, enhanced and suppressed by the inhibition of p38 MAPK, JNK and ERK pathways, respectively. Our findings demonstrate that MAPK signaling pathways are closely related to the RNP-induced differentiation in HL-60 cells. 相似文献
68.
Shared histological characteristics have been observed in the bone matrix and vascularity between Ophiacodontidae and the later therapsids (Synapsida). Historically, this coincidence has been explained as simply a reflection of the presumed aquatic lifestyle of Ophiacodon or even a sign of immaturity. Here we show, by histologically sampling an ontogenetic series of Ophiacodon humeri, as well as additional material, the existence of fibrolamellar bone (FLB) in the postcranial bones of a pelycosaur. Our findings have reaffirmed what previous studies first described as fast growing tissue, and by proxy, have disproven that the highly vascularized cortex is simply a reflection of young age. This tissue demonstrates the classic histological characteristics of true FLB. The cortex consists of primary osteons in a woven bone matrix and remains highly vascularized throughout ontogeny, providing evidence for fast skeletal growth. Overall, the FLB tissue we have described in Ophiacodon is more advanced or “mammal-like” in terms of the osteonal development, bone matrix, and skeletal growth than what has been described thus far for any other pelycosaur taxon. With regards to the histological record, our results remain inconclusive as to the preferred ecology of Ophiacodon due to a similar cortical vascularity pattern exhibited by other carnivorous pelycosaurs. Our findings have set the evolutionary origins of FLB and high skeletal growth rates back approximately 20 million years to the Early Permian, and by phylogenetic extension perhaps the Late Carboniferous. 相似文献
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崔玉东 《中国生物化学与分子生物学报》2002,18(1):1-4
为了解p38促分裂原活化蛋白激酶 (MAPK)参与NADPH氧化酶激活的机理 ,利用p38MAPK抑制剂SB2 0 35 80 ,在甲酰甲硫氨酰 亮氨酰 苯丙氨酸 (FMLP)刺激的分化为中性粒细胞样的HL 6 0细胞中研究p38MAPK对O·2 产生和NADPH氧化酶胞浆成分p4 7phox 的磷酸化作用 .实验发现 ,p38MAPK的激活过程与NADPH氧化酶的激活过程一致 .5 0 μmol LSB2 0 35 80抑制 5 0 % O·2 产生 ,完全抑制p38MAPK激活和部分抑制p4 7phox 体外磷酸化 .结果表明 ,在FMLP刺激的HL 6 0细胞中 ,p38MAPK可以通过磷酸化p4 7phox而参与NADPH氧化酶激活 . 相似文献