丹皮酚抗肿瘤作用及其机制研究

丹皮酚主要通过杀伤肿瘤细胞、诱导凋亡,影响肿瘤血管生成,促进IL-2及TNF-α生成,下调COX-2表达发挥抗肿瘤作用;但我们研究证实丹皮酚对体外神经胶质瘤U251细胞及肝癌HepG2细胞无明显抑制作用。丹皮酚作为抗肿瘤有效中药分子开发新药尚需深入的体内外实验研究与探讨。     

蛇毒细胞毒素抗肿瘤作用的研究进展

蛇毒细胞毒素是蛇毒的主要毒性组分之一,约占蛇毒总蛋白含量的25%～60%,具有广泛的生物学活性,能引起可兴奋性细胞如骨骼肌、心肌和神经组织去极化,可促进细胞膜通透性,轴突传导阻滞,以及溶解肿瘤细胞等。自从1936年Sarker从眼镜蛇(Najanajaatra)蛇毒中分离出一个能使离体猫心停搏的毒素以来,多种类似的毒素如心脏毒素、细胞毒素、骨骼肌去极化因子、眼镜蛇碱、直接溶血因子等相继被分离出来,基于这些碱性多肽都作用于细胞膜的共性,又被称为膜毒素(Membranetoxin)或膜活性多肽(Membraneactivepolypeptide),有足够的证据表明,这些物质或是…     

白花丹素抗肿瘤作用机制的研究进展

恶性肿瘤一直是生物医学中的难题,利用放射疗法或化学疗法治疗肿瘤常会引发如呕吐、恶心等不良反应。因此,寻找安全有效治疗肿瘤的替代药物源非常重要。白花丹素(plumbagin, PLB)是从中草药白花丹根部提取出来的一种生物活性化合物,在肿瘤治疗中具有重要作用,并且有较好的抗癌活性。因此,本文将从肿瘤细胞的增殖、凋亡、转移和侵袭、血管生成、铁死亡过程以及化疗敏感性等六个方面对白花丹素的抗肿瘤作用及相关分子机制的研究进行综述,以期为基于白花丹素的抗肿瘤药物研发和临床应用提供科学参考。     

CD3AK细胞抗肿瘤作用的研究进展

抗ＣＤ３单克隆抗体激活的杀伤细胞ＣＤ３ＡＫ是一种新型抗肿瘤免疫活性细胞,具有体外扩增能力强,细胞毒活性高,体内抗肿瘤效果好,低依赖ＩＬ－２等特点。本文综述了ＣＤ３ＡＫ细胞的诱导和扩增、形态学和免疫学特性、体内外抗肿瘤作用和ＣＤ３ＡＫ细胞的活性增强物质,并讨论了ＣＤ３ＡＫ细胞的作用机制     

益生菌增强机体免疫和抗肿瘤作用的分子机制

益生菌(probiotics)是指对人和动植物机体有益的菌。很早以前人类就已经发现,益生菌对人体有重要的有益的影响。1905年,俄国微生物学家发现,高加索地区居民长寿者较多的原因,是由于食用了含有大量乳酸菌的酸奶。20世纪20年代后期,逐渐能用在肠道内生存的嗜酸乳杆菌生产酸奶。20世纪60年代,由于厌氧微生物的分离和培养技术的改进,人们逐渐对益生菌有了更深入的研究,并且随着研究的进行,     

NKT细胞亚群

经典的NKT细胞是一类表面既具有T细胞又具有NK细胞标志的T细胞亚群。与普通T细胞相比,1.NKT细胞不受经典MHC I类分子限制,而受非经典MHC I类分子、CD1d分子限制,不识别蛋白质抗原,而是识别脂类抗原;2.NKT细胞的TCR     

细胞相容性物质的生理功能及其作用机制

以生物界广泛存在的细胞相容性物质甜菜碱为代表,介绍了其生理功能的研究进展,同时对植物中其它细胞相容性物质的一些生理功能,以及这些相容性物质在保护生物大分子结构与功能中的可能作用机制也作了评述。     

多糖修饰物及其抗肿瘤作用机制研究

多糖是指一类由十个以上单糖分子通过糖苷键连接而成的糖类物质,因其具有许多重要的生物学活性而备受关注,这其中最为突出的是其在抗肿瘤方面所表现出的效用。目前多糖抗肿瘤方面的主要研究课题集中在如何进一步提高多糖的抗肿瘤活性上。对多糖分子进行结构上的修饰能够使其抗肿瘤的活性得到一定程度地提高。本文对常见的多糖修饰方法,如硫酸化、羧甲基化、磷酸化、硒化、乙酰化等进行了总结,对经修饰后所得产物的抗肿瘤作用的不同机制进行了阐述,并对多糖化学修饰物的应用前景进行了展望,为未来多糖的开发与利用提供一定的理论依据。     

NKT细胞在动脉粥样硬化中的作用

然杀伤T细胞（natural killer T cell,NKT细胞）是一种特殊的淋巴细胞亚群,具有部分T细胞和NK细胞的特征。与这些细胞不同的是,NKT细胞不仅能够识别醣脂类抗原,还在激活后产生促炎症因子和抗炎症因子。由于这些特性,NKT细胞在炎症和免疫方面的研究越来越热。动脉粥样硬化是一种受免疫调节的炎性疾病,因此对NKT细胞在该疾病中作用的研究也逐渐开展起来。     

青蒿素及其衍生物的抗肿瘤机制

恶性肿瘤是严重威胁人类健康的重大疾病。尽管治疗手段不断发展,但推广度及疗效仍极为有限。新近研究发现,经典抗疟一线药青蒿素及其衍生物具有广泛抗肿瘤活性。大量研究提示,青蒿素及其衍生物通过细胞毒性效应直接杀死肿瘤细胞,也可诱导细胞周期阻滞从而抑制细胞增殖。另一方面,可通过凋亡、自噬、铁死亡途径导致细胞死亡。还可调控肿瘤微环境,从而抑制肿瘤细胞侵袭与转移。然而,尽管青蒿素及其衍生物展现出强大的抗肿瘤潜能,但其作用机制仍十分复杂。本文就青蒿素及其衍生物的抗肿瘤机制及其研究进展作一综述。     

Synthesis and evaluation of immunostimulant plasmalogen lysophosphatidylethanolamine and analogues for natural killer T cells

Plasmalogen lysophosphatidylethanolamine (pLPE) had been identified as a self antigen for natural killer T cells (NKT cells). It is very important in the development, maturation and activation of NKT cells in thymus. Besides, pLPE is a novel type of antigen for NKT cells. To evaluate the structure–activity relationship (SAR) of this new antigen, pLPE and its analogues referred to different aliphatic chains and linkages at the sn-1 position of the glycerol backbone were synthesized, and the biological activities of these analogues was characterized. It is discovered that the linkages between phosphate and lipid moiety are not important for the antigens’ activities. The pLPE analogues 1, 3, 4, 7 and 9, which have additional double bonds on lipid parts, were identified as new NKT agonists. Moreover, the analogues 4, 7 and 9 were discovered as potent Th2 activators for NKT cells.     

In vivo priming of natural killer T cells by dendritic cells pulsed with hepatoma-derived acid-eluted substances

Many murine tumor cells express not only individual haplotype-matched class I MHC molecules, but also species-specific CD1d molecules. The former class I MHC molecules generally present internally synthesized tumor-derived peptide antigens to highly specific CD8⁺ cytotoxic T lymphocytes (CTLs) in acquired immunity. In contrast, the latter CD1d molecules may present tumor-associated glycolipid antigens to broadly crossreactive natural killer T (NKT) cells, which might correlate with controlling tumor metastasis. Here, we showed that murine hepatoma cell line Hepa1-6-derived acid-eluted substances might contain both D^b class I MHC-restricted antigens and CD1d-restriced substances, which could sensitize not only syngeneic bone marrow-derived DCs (BM-DCs), but also allogeneic BM-DCs expressing haplotype-mismatched class I MHC and species-specific CD1d molecules. To our surprise, intravenous (i.v.) immunization of C57BL/6 mice with the former syngeneic BM-DCs carrying acid-eluted materials primed both CD4^–CD8^– and CD8⁺ NKT cells in the spleen, whereas immunization with the latter allogeneic BM-DCs loaded the tumor-derived substances primed CD4^–CD8^–, but not CD8⁺ NKT cells. The findings shown in the present study will open a new area for cancer immunotherapy using allogeneic DCs and tumor-derived acid-eluted substances.Abbreviations CTLs cytotoxic T lymphocytes - NKT natural killer T - BM-DCs bone marrow-derived dendritic cells - CTM complete T-cell medium - FCS fetal calf serum - MMC mitomycin C - TCRs T cell receptors     

Minimal contribution of Valpha14 natural killer T cells to Th1 response and host resistance against mycobacterial infection in mice

We elucidated the contribution of Valpha14 NKT cells to Th1 response and host resistance against mycobacterial infection. In Valpha14 NKT cell-deficient mice, host defense and DTH response to Mycobacterium bovis BCG were not different from wild-type mice after pulmonary infection. There was no significant difference in the lung concentrations of IFN-gamma between the two strains of mice. In addition, host defense to systemic infection with M. tuberculosis was similar to that of M. bovis. Our results indicate that Valpha14 NKT cells play only a marginal role, if any, in the Th1 response and host resistance to mycobacterial infection.     

Immunomagnetic selection or irradiation eliminates alloreactive cells but also reduces anti-tumor potential of cytokine-induced killer cells: implications for unmanipulated cytokine-induced killer cell infusion

Background aimsCytokine-induced killer (CIK) cells may offer a novel therapeutic approach for patients with malignancies relapsing after allogeneic stem cell transplantation. Although CIK cells display negligible alloreactivity and cause minimal graft versus-host-disease (GVHD), high CIK cell doses required during relapse may pose a risk for severe GVHD, specifically in the mismatched or haploidentical transplantation setting. Manipulation of CIK cells may reduce risk for GVHD without affecting the anti-tumor potential.MethodsIn this pre-clinical study, we provide a detailed functional comparison of conventional and irradiated, CD56-enriched or T-cell receptor α/β-depleted CIK cells.ResultsIn vitro analysis showed retained anti-leukemic and anti-tumor potential after CIK cell manipulation. Even being sequentially infused into immunodeficient mice grafted with malignant cells, cytotoxic effects were fewest after irradiation but were improved by CD56 enrichment and were best with conventional CIK cells. Hence, considering the proliferative capacity of inoculated malignancies and effector cells, a single dose of conventional CIK cells resulted in prolonged disease-free survival and elimination of rhabdomyosarcoma cells, whereas sequential infusions were needed to achieve comparable results in leukemia-bearing mice. However, this mouse model has limitations: highly effective conventional CIK cells demonstrated both limited xenogenic GVHD and low alloreactive potential in vitro.ConclusionsOur study revealed that conventional CIK cells demonstrate no significant alloreactive potential but provide the strongest anti-tumor efficacy compared with manipulated CIK cells. Conventional CIK cells may therefore be tested in high numbers and short-term intervals in patients with impending relapse even after mismatched transplantation.     

A role for natural killer T cells in asthma

In several mouse models, natural killer T cells have recently been found to be required for the development of airway hyper-reactivity, a cardinal feature of asthma. Moreover, in patients with chronic asthma, natural killer T cells with a T-helper-2-like phenotype (that is, that express CD4 and produce T helper 2 cytokines) are present in the lungs in large numbers. In this Opinion article, we suggest that natural killer T cells, which express a restricted T-cell receptor and respond to glycolipids rather than protein antigens, have a previously unsuspected but crucial role, distinct from that of T helper 2 cells, in the pathogenesis of asthma.     

Invariant natural killer T cells: bridging innate and adaptive immunity

Cells of the innate immune system interact with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptive immune system recognize pathogens through diverse, antigen-specific receptors that are generated by somatic DNA rearrangement. Invariant natural killer T (iNKT) cells are a subset of lymphocytes that bridge the innate and adaptive immune systems. Although iNKT cells express T cell receptors that are generated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limited set of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innate immune system. Functionally, iNKT cells most closely resemble cells of the innate immune system, as they rapidly elicit their effector functions following activation, and fail to develop immunological memory. iNKT cells can become activated in response to a variety of stimuli and participate in the regulation of various immune responses. Activated iNKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response. A variety of glycolipid antigens that can differentially elicit distinct effector functions in iNKT cells have been identified. These reagents have been employed to test the hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases. Here, we review the innate-like properties and functions of iNKT cells and discuss their interactions with other cell types of the immune system.     

Natural killer T cells promote collagen-induced arthritis in DBA/1 mice

The role of NKT cells in the pathogenesis of collagen-induced arthritis (CIA) remains unclear since most studies have used C57BL/6 (B6) mice, which are less susceptible to CIA than mice with a DBA/1 background. To clarify the immunological functions of NKT cells in CIA, it is necessary to analyze in detail the effects of NKT cell deficiency on CIA development in DBA/1 mice. The incidence and severity of CIA were significantly exacerbated in DBA/1CD1d^+/− mice as compared to DBA/1CD1d^−/− mice. In DBA/1CD1d^+/− mice, antigen-specific responses of B and T cells against CII were remarkably increased and inflammatory cytokine levels were also increased in vivo and in vitro. The number of IL-17-producing NKT cells significantly increased in DBA/1CD1d^+/− mice as the disease progressed. Our results clearly show that NKT cells are involved not only in accelerating the severity and incidence of CIA but also in perpetuating the disease progression.     

自然杀伤细胞和自然杀伤T细胞在动脉粥样硬化形成中的作用

动脉粥样硬化发生发展与免疫细胞参与的免疫反应密切相关,其中自然杀伤细胞主要是通过释放IFN-γ、穿孔素和颗粒酶等方式发挥生物学作用,自然杀伤T细胞通过释放多种细胞因子影响动脉粥样硬化形成,但其具体机制未明。本文就自然杀伤细胞和自然杀伤T细胞对动脉粥样硬化的影响做一综述,为动脉粥样硬化及其相关疾病的防治研究提供新的思路。     

The regulatory role of natural killer T cells in the airways

Asthma, an inflammatory disorder of the airways, has been considered a disease mediated by allergen-specific Th2 cells and eosinophils, and controlled by allergen-specific regulatory T cells. This paradigm can explain many but features of asthma, but Th2 targeted therapies in patients with asthma have not been as successful as might be predicted by this paradigm. These observations have suggested that other cell types, such as Natural Killer T cells, may play an important role in asthma. In this review, we discuss the data that support the notion that NKT cells critically regulate the development of asthma.     

Natural killer cells and natural killer T cells in Lyme arthritis

Introduction

Natural killer (NK) and natural killer T (NKT) cells provide a first line of defense against infection. However, these cells have not yet been examined in patients with Lyme arthritis, a late disease manifestation. Lyme arthritis usually resolves with antibiotic treatment. However, some patients have persistent arthritis after spirochetal killing, which may result from excessive inflammation, immune dysregulation and infection-induced autoimmunity.

Methods

We determined the frequencies and phenotypes of NK cells and invariant NKT (iNKT) cells in paired peripheral blood (PB) and synovial fluid (SF) samples from eight patients with antibiotic-responsive arthritis and fifteen patients with antibiotic-refractory arthritis using flow cytometry and cytokine analyses.

Results

In antibiotic-responsive patients, who were seen during active infection, high frequencies of CD56bright NK cells were found in SF, the inflammatory site, compared with PB (P <0.001); at both sites, a high percentage of cells expressed the activation receptor NKG2D and the chaperone CD94, a low percentage expressed inhibitory killer immunoglobulin-like receptors (KIR), and a high percentage produced IFN-γ. In antibiotic-refractory patients, who were usually evaluated near the conclusion of antibiotics when few if any live spirochetes remained, the phenotype of CD56bright cells in SF was similar to that in patients with antibiotic-responsive arthritis, but the frequency of these cells was significantly less (P = 0.05), and the frequencies of CD56dim NK cells tended to be higher. However, unlike typical NKdim cells, these cells produced large amounts of IFN-γ, suggesting that they were not serving a cytotoxic function. Lastly, iNKT cell frequencies in the SF of antibiotic-responsive patients were significantly greater compared with that of antibiotic-refractory patients where these cells were often absent (P = 0.003).

Conclusions

In patients with antibiotic-responsive arthritis, the high percentage of activated, IFN-γ-producing CD56bright NK cells in SF and the presence of iNKT cells suggest that these cells still have a role in spirochetal killing late in the illness. In patients with antibiotic-refractory arthritis, the frequencies of IFN-γ-producing CD56bright and CD56dim NK cells remained high in SF, even after spirochetal killing, suggesting that these cells contribute to excessive inflammation and immune dysregulation in joints, and iNKT cells, which may have immunomodulatory effects, were often absent.