他汀类药物的免疫调节及神经保护作用机制

他汀类药物是羟甲基戊二酸单酰辅酶A还原酶的抑制剂,临床上主要用于高胆固醇血症的治疗.近年研究发现,他汀类药物具有抑制促炎性细胞因子(Th1和Th17细胞冈子)的分泌、增加调节性T细胞(Treg)数量和功能、抑制树突状细胞(DC)成熟等作用.通过这些免疫调节和抗炎作用,他汀类药物在神经系统疾病如脑卒中、阿尔茨海默病(AD...     

阿托伐他汀对巨噬细胞肝X受体表达及胆固醇外流的影响

目的:他汀类药物是目前治疗脂代谢的有效药物,通过研究阿托伐他汀对巨噬细胞的肝X受体(LXR)及其下游的一些目的基因的表达和胆固醇外流的影响,探讨他汀类药物对LXR信号系统的作用。方法:分离人外周血的单核细胞,并转化为巨噬细胞。在阿托伐他汀的作用下,观察巨噬细胞的aopA-I介导的胆固醇外流的变化和LXR以及其下游目的基因ABCA1、SREBP2、CETP、PLTP、apoE、MMP-9和MIP-1α的mRNA及蛋白LXRα、ABCA1、MMP-9和MIP-1α的表达。结果:阿托伐他汀上调LXRα、ABCA1、SREBP2、CETP、PLTP基因的表达,而下调MMP-9和MIP-1α基因的表达,同时增强aopA-I介导的胆固醇外流。结论:巨噬细胞在阿托伐他汀的作用下,胆固醇外流增强,这种效应与阿托伐他汀上调LXR及其下游的影响胆固醇代谢的目的基因有关,同时,也抑制一些炎症反应的基因的表达。提示他汀类药物的治疗作用,与其影响巨噬细胞LXR信号途径有关,从而影响泡沫细胞的形成。     

过氧化物酶体增殖物激活受体γ在胰岛素抵抗高脂血症中的作用

目的探讨过氧化物酶体增殖物激活受体γ(peroxide daily proliferator- activated receptor γ,PPARγ)在阿托伐他汀治疗胰岛素抵抗高脂血症中的作用。方法选取2016年10月至2018年5月我院收治的胰岛素抵抗高脂血症患者116例,实时荧光定量PCR检测外周血单个核细胞PPARγ表达。给予阿托伐他汀降脂治疗,检测治疗前后患者血清总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL- C)、高密度脂蛋白胆固醇(HDL- C)、空腹血糖(FBG)、空腹胰岛素(FINS)、白介素6(IL- 6)、C反应蛋白(CRP)和肿瘤坏死因子α(TNF-α)水平并计算胰岛素抵抗指数HOMA- IR。HOMA- IR >2.69的胰岛素抵抗患者纳入研究组,对照组HOMA- IR<2.69。对比两组患者降脂效果和脂肪分泌因子IL- 6、CRP和TNF-α水平变化。结果研究组患者外周血单个核细胞PPARγ表达低于对照组;对照组阿托伐他汀降脂效果优于研究组( P <0.05);治疗后研究组IL- 6、CRP和TNF-α变化明显小于对照组( P <0.05)。结论 PPARγ在胰岛素抵抗高脂血症治疗过程中发挥重要作用,PPARγ可有效增强阿托伐他汀降脂作用并抑制脂肪因子的分泌,其作用机理有待深入研究。     

他汀类药物（Statins）在防治前列腺癌中的应用及存在的问题

前列腺癌(PCa)是男性泌尿生殖系常见恶性肿瘤,其发病机制虽然至今不完全明确,但研究发现高胆固醇血症患者更易患PCa或高级别PCa,PCa向去势难治性前列腺癌(CRPC)转变过程中常伴有癌细胞胆固醇调节机制的改变。他汀类药物(Statins)是3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂,临床用于治疗高脂血症和预防心血管不良事件的发生。最近研究发现,Statins可能抑制PCa的发生发展,降低PCa总发病率。因此,抑制胆固醇介导的细胞生长作用成为预防和治疗PCa和CRPC的新策略。     

依折麦布联合他汀降脂治疗及临床研究进展

低密度脂蛋白胆固醇(LDL-C)水平与动脉粥样硬化有密切关系。虽然临床研究表明强化他汀治疗在降低LDL-C水平和对临床终点事件的影响都优于常规他汀治疗，但由于降脂幅度以及药物的肝毒性和肌毒性的问题，使得强化他汀降脂难以完成。依折麦布是一种新型降LDL-C药物，其作用机制是选择性抑制肠胆固醇吸收。其联合他汀类药物降脂效能已被明确证实，但其对心血管事件的作用尚不明确。现对依折麦布有效性及安全性的临床研究进展做一系统评述。     

RGD肽在肿瘤诊断与治疗中的应用

RGD( Arg - Gly- Asp)肽存在于多种生物细胞外基质中,能特异性识别肿瘤细胞表面的整合素并与之结合,可作为体内RGD肽类物质的竞争性抑制剂,从而能抑制肿瘤细胞与细胞外基质的黏附与迁移、抑制肿瘤血管形成、诱导肿瘤细胞凋亡.RGD肽可以作为载体在肿瘤靶向治疗中发挥重要作用,且在肿瘤显像及肿瘤治疗有潜在应用价值.该文主要介绍RGD肽在肿瘤显像中的应用、在肿瘤治疗中作为载体的应用、对肿瘤的直接抑制作用、在抗栓药物中的应用、对血小板功能的影响、诱导骨组织再生的应用研究与新进展.     

他汀类药物调脂及非调脂作用的临床新进展

目的 介绍他汀类调脂及非调脂作用的临床新进展.方法参阅相关文献,经综合、分析和归纳.结果 他汀类药物具有降低胆固醇、低密度脂蛋白的作用和预防心血管疾病,保护肾脏细胞,抗肿瘤细胞的增殖作用,抗癌中的增敏及减少不良反应,抗骨质疏松,预防痴呆,免疫抑制等非调脂作用.结论他汀类药物在临床上具有广阔的应用前景.     

他汀类药物对内皮祖细胞的相关作用

背景：他汀类药物作为临床上广泛应用的降脂类药物,其不同剂量与疗程对于内皮祖细胞有着不同的近期及远期作用。 目的：综述国内外他汀类药物对内皮祖细胞作用的现状和进展。 方法：应用计算机检索CNKI和Pubmed数据库中1995-01/2009-11关于内皮祖细胞和他汀类药物的文章,在标题中以“内皮祖细胞,他汀类药物”或“endothelial progenitor cells,statins”为检索词进行检索。选择文章内容与内皮祖细胞及他汀类药物有关者,同一领域文献则选择近期发表或发表在权威杂志文章。初检得到843篇文献,根据纳入标准选择关于内皮祖细胞及他汀类药物的19篇文献进行综述。 结果与结论：他汀类药物对于内皮祖细胞有多重的作用。在短期治疗和低剂量的情况下,对心血管疾病有保护作用,增强内皮祖细胞各方面功能;在长期、大剂量应用他汀类药物后,造成其数量减少,抑制了血管生成,这对于抑制肿瘤血管发生有一定的研究价值。     

阿托伐他汀治疗前后脑梗死患者颈动脉斑块的变化

目的:观察阿托伐他汀对脑梗死患者颈动脉斑块的作用。方法:68例脑梗死患者除常规治疗外,加用口服阿托伐他汀胶囊20mg,每晚1次,测定开始治疗及连续服用阿托伐他汀胶囊5个月后颈动脉内膜中层厚度(IMT)和血清C反应蛋白(CRP)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平变化。结果:阿托伐他汀胶囊治疗5个月后,患者颈动脉IMT缩小,与治疗前比较,差异有统计学意义(P<0.05)。TC、TG、LDL-C和CRP显著低于治疗前水平(P<0.05)。结论:阿托伐他汀胶囊除有降脂作用外,还可以稳定并缩小脑梗死患者颈动脉斑块。     

不同剂量阿托伐他汀对高胆固醇血症伴骨质疏松患者骨代谢的影响

目的研究不同剂量阿托伐他汀对高胆固醇血症伴骨质疏松患者骨密度及骨代谢的影响。方法将252例高胆固醇血症伴骨质疏松患者分为3组,分别予小剂量阿托伐他汀(A组,n=84)、小剂量阿托伐他汀加依折麦布(B组,n=84)和中剂量阿托伐他汀(C组,n=84)治疗,并在治疗前及治疗后分别检测血胆固醇、骨合成代谢指标骨钙素(BGP)、骨吸收代谢指标尿脱氧吡啶啉和尿肌酐比值(DPD/Cr)和骨密度(BMD)。结果失访7例,245例患者纳入统计,平均治疗周期(5.38±0.79)个月。C组治疗后总胆固醇(TC)、低密度脂蛋白(LDL-C)明显降低,同时BGP增高、DPD/Cr降低,BMD增高。A组治疗后TC、LDL-C降低,BGP增高,但DPD/Cr和BMD较治疗前无明显改变。B组治疗后TC、LDL-C和BGP水平与中剂量他汀组无统计学差异,但与后者相比,前者DPD/Cr明显增高,而BMD明显降低。结论较大剂量阿托伐他汀具有促进骨合成、抑制骨吸收和增加BMD的作用,原因可能与他汀剂量相关,而与胆固醇降低程度无关。     

T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine

Tolerance induction in T?cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the?cellular mechanism by which TGF-β induces T?cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T?cells from the tumor-draining lymph nodes. Blockade of TGF-β signaling in T?cells enhanced tumor antigen-specific T?cell responses and inhibited tumor development. Surprisingly, T?cell- but not Treg cell-specific ablation of TGF-β1 was sufficient to augment T?cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T?cell production of TGF-β1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-β produced by tumors.     

Stem Cells and Cancer Stem-Like Cells in Endocrine Tissues

Cancer stem-like cells are a subpopulation of self-renewing cells that are more resistant to chemotherapy and radiation therapy than the other surrounding cancer cells. The cancer stem cell model predicts that only a subset of cancer cells possess the ability to self-renew and produce progenitor cells that can reconstitute and sustain tumor growth. Evidence supporting the existence of cancer stem-like cells in the thyroid, pituitary, and in other endocrine tissues is rapidly accumulating. These cells have been studied using specific biomarkers including: CD133, CD44, Nestin, Nanog, and aldehyde dehydrogenase enzyme. Putative cancer stem-like cells can be studied in vitro using serum-free media supplemented with basic fibroblast growth factor and epidermal growth factor grown in low attachment plates or in extracellular matrix leading to sphere formation in vitro. Cancer stem-like cells can also be separated by fluorescent cell sorting and used for in vitro or in vivo studies. Injection of enriched populations of cancer stem-like cells (also referred to as tumor initiating cells) into immunodeficient mice results in growth of xenografts which express cancer stem-like biomarkers. Human cancer stem-like cells have been identified in thyroid cancer cell lines, in primary thyroid cancers, in normal pituitary, and in pituitary tumors. Other recent studies suggest the existence of stem cells and cancer stem-like cells in endocrine tumors of the gastrointestinal tract, pancreas, lungs, adrenal, parathyroid, and skin. New discoveries in this field may lead to more effective therapies for highly aggressive and lethal endocrine cancers.     

In vitro studies of human prostatic epithelial cells: attempts to identify distinguishing features of malignant cells

Recent advances in culture techniques have enabled routine establishment and propagation of epithelial cells derived from normal and malignant tissues of the human prostate. Comparative studies of the responses of normal and cancer-derived cell populations to various growth and differentiation factors in vitro were undertaken to examine the possibility that cancer cells might respond differentially. Clonal growth assays in serum-free medium demonstrated that optimal proliferation of normal as well as cancer cell strains was generally dependent on the presence of cholera toxin, epidermal growth factor, pituitary extract, hydrocortisone, insulin, and high levels of calcium in the culture medium, and on the use of collagen-coated dishes. Only one cancer strain responded aberrantly to epidermal growth factor and hydrocortisone. Putative differentiation factors (transforming growth factor-beta and vitamin A) inhibited the growth of all normal and cancer strains. The origin of a cancer-derived cell strain that responded similarly to normal strains was verified by positive labeling with a prostate cancer-specific antibody, validating the conclusion from these studies that normal and cancer prostatic epithelial cells are not distinguishable on the basis of responses to the tested factors.     

Role of mast cells in tumor growth

The growth of malignant tumors is determined in large part by the proliferative capacity of the tumor cells. Clinical observations and animal experiments have established that tumor cells elicit immune responses. Histopathologic studies show that many tumors are surrounded by mononuclear cell and mast cell infiltrates. Mast cells are ubiquitous in the body and are critical for allergic reactions. Increasing evidence indicates that mast cells secrete proinflammatory cytokines and are involved in neuro-inflammatory processes and cancer. Mast cells accumulate in the stroma surrounding certain tumors, especially mammary adenocarcinoma, and the molecules they secrete can benefit the tumor. However, mast cells can also increase at the site of tumor growth and participate in tumor rejection. Mast cells may be recruited by tumor-derived chemoattractants and selectively secrete molecules such as growth factors, histamine, heparin, VEGF, and IL-8, as well as proteases that permit the formation of new blood vessels and metastases. Tumor mast cell intersections play regulatory and modulatory roles affecting various aspects of tumor growth. Discovery of these new roles of mast cells further complicates the understanding of tumor growth. This review focuses on the strategic importance of mast cells to the progression of tumors, and proposes a revised immune effector mechanism of mast cell involvement in tumor growth.     

肿瘤生物力学新进展

癌症的发生、发育、诊断和治疗均涉及力学、物理学、化学、生物学等因素之间复杂的相互作用与耦合关联。肿瘤生物力学不仅具有非常重要的科学价值,而且可以为癌症的临床诊断和治疗提供理论基础。从细胞和组织两个侧面简要介绍肿瘤生物力学的一些进展,重点关注国内学者近年来取得的成果,包括癌细胞-胞外基质之间的相互作用、血管生成、肿瘤生长等的实验和理论研究。     

In Vitro Studies of Human Prostatic Epithelial Cells: Attempts to Identify Distinguishing Features of Malignant Cells

Abstract

Recent advances in culture techniques have enabled routine establishment and propagation of epithelial cells derived from normal and malignant tissues of the human prostate. Comparative studies of the responses of normal and cancer-derived cell populations to various growth and differentiation factors in vitro were undertaken to examine the possibility that cancer cells might respond differentially. Clonal growth assays in serum-free medium demonstrated that optimal proliferation of normal as well as cancer cell strains was generally dependent on the presence of cholera toxin, epidermal growth factor, pituitary extract, hydrocortisone, insulin, and high levels of calcium in the culture medium, and on the use of collagen-coated dishes. Only one cancer strain responded aberrantly to epidermal growth factor and hydrocortisone. Putative differentiation factors (transforming growth factor-β and vitamin A) inhibited the growth of all normal and cancer strains. The origin of a cancer-derived cell strain that responded similarly to normal strains was verified by positive labeling with a prostate cancer-specific antibody, validating the conclusion from these studies that normal and cancer prostatic epithelial cells are not distinguishable on the basis of responses to the tested factors.     

Pro-inflammatory type-1 and anti-inflammatory type-2 macrophages differentially modulate cell survival and invasion of human bladder carcinoma T24 cells

Findings from numerous studies suggest that inflammation is likely to have an important role in bladder carcinogenesis and cancer disease progression. While macrophages (M?s) constitute a major inflammatory component of the stroma of human bladder carcinoma, the regulatory role of such inflammatory leukocytes in tumor cell survival and invasion remains elusive. Human urothelial bladder cancer (UBC) T24 cells and monocyte-derived macrophages were used to study the relative contribution of pro-inflammatory type-1 (M?-1) and anti-inflammatory type-2 (M?-2) macrophages in the regulation of UBC cell behaviour. Cell-to-cell studies indicated that the number of viable cells were considerable higher in T24 cell/M?-2 cocultures but lower in T24 cell/M?-1 cocultures when compared to cultures of T24 cells alone. M?-1-derived factors inhibit T24 cell growth but fail to induce caspase-3-mediated apoptosis. M?-2-derived factors have the ability to suppress the inhibitory effect of M?-1-derived factors on T24 cell growth. Exogenous interleukin (IL)-10 reverse M?-1-mediated arrest growth in T24 cell/M?-1 cell cocultures. Further analyses showed that M?-1-derived factors induced tumor necrosis factor (TNF)-α gene expression, promoted cellular invasiveness and increased phosphoinositide 3-kinase (PI 3-K)/Akt signaling pathway activity in T24 cells. Inhibition of PI 3-K activation in T24 cells or blockade of TNFα receptor in T24 cell/M?-1 cell cocultures decreased cellular invasiveness but did not affect T24 cell viability. Based on these observations, we propose that similar functional interactions between UBC cells and infiltrating macrophages can take place in vivo and influence tumor cell survival and invasion during bladder cancer progression.     

Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells

OBJECTIVE: Combination of a statin plus estrogen may reveal benefits on the cardiovascular system in postmenopausal women by additively ameliorating both the lipid profile and vascular function. Long-term therapy with estrogens, however, is associated with an increase of breast cancer risk. In contrast, evidence is accumulating that statins may inhibit carcinogenesis because of their central action on important cellular functions. It is of special clinical interest whether a statin/estrogen combination may reduce the most undesired side effect of estrogen therapy, that is, an increase in breast cancer risk. Therefore, in the present in vitro study, for the first time we have compared the effect of five statins on the proliferation of human breast cancer cells alone and in the presence of stimulatory estradiol (E(2)). DESIGN: As cell models, the receptor-positive cell line MCF-7 and the receptor-negative cell line MDA-MB 231 were used. The statins atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin were tested in the concentration range of 1.6 microm to 50 microm alone and in the range of 0.01 nm to 10 microm in combination with E(2). Cell proliferation was measured after 4 days by the adenosinetriphosphate-chemosensitivity test. RESULTS: All statins except pravastatin were able to significantly inhibit dose dependently the cell proliferation of both cell lines. The inhibitory values were between 10% and 90%, whereby the potency was greater in the case of receptor-negative cancer cells. A significant difference in the efficacy of the statins was observed for MCF-7 cells, in which atorvastatin was less effective than the other statins. In contrast, in the presence of E(2), the statins showed similar antiproliferative actions in MCF-7 cells when tested in the concentration range of 0.01 nm to 10 microm. A reduction of cell proliferation of less than 10% was observed at the lower concentrations and between 15% and 25% at the highest concentration of 10 microm. CONCLUSIONS: The present data indicate that statins can inhibit the proliferation of receptor-positive and -negative human breast cancer cells but failed to completely abrogate the E(2)-induced proliferation of receptor-positive breast cancer cells. Clinical trials, however, are necessary to prove this anticarcinogenic action of statins.     

Selective Targeting of Cancer Stem Cells

Although the concept of 'cancer stem cell' was first proposed more then a century ago, it has attracted a great deal of attention recently due to advances in stem cell biology, leading to the identification of these cells in a wide variety of human cancers. There is accumulating evidence that the resistance of cancer stem cells to many conventional therapies may account for the inability of these therapies to cure most metastatic cancers. The recent identification of stem cell markers and advances in stem cell biology have facilitated research in multiple aspects of cancer stem cell behavior. Stem cell subcomponents have now been identified in a number of human malignancies, including hematologic malignancies and tumors of the breast, prostate, brain, pancreas, head and neck, and colon. Furthermore, pathways that regulate self-renewal and cell fate in these systems are beginning to be elucidated. In addition to pathways such as Wnt, Notch and Hedgehog, known to regulate self-renewal of normal stem cells, tumor suppressor genes such as PTEN (phosphatase and tensin homolog on chromosome 10) and TP53 (tumor protein p53) have also been implicated in the regulation of cancer stem cell self-renewal. In cancer stem cells, these pathways are believed to be deregulated, leading to uncontrolled self-renewal of cancer stem cells which generate tumors that are resistant to conventional therapies. Current cancer therapeutics based on tumor regression may target and kill differentiated tumor cells, which compose the bulk of the tumor, while sparing the rare cancer stem cell population. The cancer stem cell model suggests that the design of new cancer therapeutics may require the targeting and elimination of cancer stem cells. Therefore, it is imperative to design new strategies based upon a better understanding of the signaling pathways that control aspects of self-renewal and survival in cancer stem cells in order to identify novel therapeutic targets in these cells.     

Angiocidin inhibits breast cancer proliferation through activation of epidermal growth factor receptor and nuclear factor kappa (NF-ĸB)

Angiocidin, a tumor-associated peptide, has been previously shown to inhibit tumor progression by blocking angiogenesis. We now show that angiocidin has a direct inhibitory effect on tumor cell proliferation. MDA-MB-231 breast cancer cells were inhibited from proliferating in the presence of epidermal growth factor (EGF) and angiocidin. Angiocidin transfected breast cancer cells also displayed growth inhibition in vitro and failed to develop significant tumors in mice as compared to vector controls. The anti-proliferative effect of angiocidin was reversed by treating the cells with the epidermal growth factor receptor (EGFR) inhibitor 4557W, a potent tyrosine kinase inhibitor. Consistent with these results, we found that treatment of breast cancer cells with angiocidin induced a 2.3 fold increase in EGFR tyrosine 845 phosphorylation while no change in phosphorylation was observed in the remaining 16 phosphorylation sites of EGFR and those of its family members as measured by a human EGFR phosphorylation array. Treatment of breast cancer cells with angiocidin also resulted in the activation of nuclear factor ?B (Nf-?B) and the de novo up-regulation of many down-stream genes transcribed by Nf-?B, including cytokines, inflammatory mediators and the cell cycle inhibitor p21^waf1. Therefore, angiocidin is a peptide that not only inhibits tumor angiogenesis but also directly induces inhibition of tumor growth progression through the activation of EGFR and down-stream genes transcribed by Nf-?B.