世界生命科学前沿动态周报（六十二）

（10.17-10.23/2011）
美宝国际集团:陶国新 

　　主要内容：大脑和其他组织的炎症机制不同；肠道细菌促进肠病毒复制和全身感染；SIRT2通过调节APC/C活性维持基因组完整性抑制肿瘤形成；ω-3脂肪酸能够预防或减缓骨关节炎；发现结肠癌可能和细菌存在联系；特异性双价半抗原有效抑制过敏反应。

　　焦点动态：大脑和其他组织的炎症机制不同。

1. 大脑和其他组织的炎症机制不同
【动态】
磷脂酶A2（PLA-2）被认为是环氧合酶（COX）介导的前列腺素的生物合成所需花生四烯酸的主要代谢酶。美国科学家的最新研究发现在大脑中存在不同的代谢途径，单酰甘油酯酶（MAGL）水解内源性大麻素2-花生四烯酸甘油产生引起神经炎症的前列腺素的主要前体花生四烯酸。在帕金森老鼠模型中破坏了MAGL的老鼠表现出神经保护作用。这类老鼠不会发生由细胞质内PLA-2调节前列腺素的内脏中COX抑制剂引起的出血。这些发现确认MAGL是不同的代谢节点在神经系统中连接内源性大麻素和前列腺素信号网络，提示抑制该酶可能是一种新的安全的压制造成神经变性疾病的促炎级联反应的方法。

【点评】
该发现有利于加深对神经变性疾病的理解以及特异性的针对神经病变的更安全的治疗手段。但是由于信号系统的网络调节是多通路多节点并受身体统一调制的，针对单一节点的干预策略总是失之为权宜之计。

【参考论文】
Science, 20 October 2011 DOI: 10.1126/science.1209200
Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation
Daniel K. Nomura, Bradley E. Morrison, Jacqueline L. Blankman, et al.
Phospholipase A2(PLA2) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)–mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA2. These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.

2. 肠道细菌促进肠病毒复制和全身感染
【动态】
肠道菌群帮助促进宿主健康并限制病原菌繁殖，但对肠道病毒的影响还知之甚少。美国科学家最近的研究通过用抗生素清除老鼠肠道菌群，而后接种脊髓灰质炎病毒（一种肠道病毒），这种老鼠比较不容易得脊髓灰质炎，肠道内病毒复制也最低。而暴露于细菌或其含有N-乙酰氨基葡萄糖的表面多糖，包括脂多糖和肽聚糖，会增强脊髓灰质炎病毒的感染性。他们发现脊髓灰质炎病毒与脂多糖结合，而该病毒暴露于细菌增强了宿主细胞的连接和感染。一种不相干的肠道病毒呼肠孤病毒的发病也在有肠道细菌时更严重。这些结果显示抗生素清除肠道细菌后减少了肠道病毒感染以及肠道病毒利用肠道细菌进行复制和传播。

【点评】
该研究的结果说明肠道生态系统也是个动态的环境，寄宿在此的各种微生物和病毒也会有互动。而这个系统的状态直接关系到宿主的健康状况。

【参考论文】
Science, 2011; 334 (6053): 249 DOI: 10.1126/science.1211057 
Intestinal Microbiota Promote Enteric Virus Replication and Systemic Pathogenesis
S. K. Kuss, G. T. Best, C. A. Etheredge, et al.
Intestinal bacteria aid host health and limit bacterial pathogen colonization. However, the influence of bacteria on enteric viruses is largely unknown. We depleted the intestinal microbiota of mice with antibiotics before inoculation with poliovirus, an enteric virus. Antibiotic-treated mice were less susceptible to poliovirus disease and supported minimal viral replication in the intestine. Exposure to bacteria or their N-acetylglucosamine–containing surface polysaccharides, including lipopolysaccharide and peptidoglycan, enhanced poliovirus infectivity. We found that poliovirus binds lipopolysaccharide, and exposure of poliovirus to bacteria enhanced host cell association and infection. The pathogenesis of reovirus, an unrelated enteric virus, also was more severe in the presence of intestinal microbes. These results suggest that antibiotic-mediated microbiota depletion diminishes enteric virus infection and that enteric viruses exploit intestinal microbes for replication and transmission.

3. SIRT2通过调节APC/C活性维持基因组完整性抑制肿瘤形成
【动态】
脱乙酰基酶家族的成员调节多种关键的生物过程，但它们在癌症形成中的作用还存在争议。美国科学家最近通过破坏老鼠的Sirt2基因研究了脱乙酰基酶SIRT2在发育和肿瘤形成中的生理功能。他们的研究表明SIRT2通过去乙酰化辅助激活子APCCDH1 和 CDC20而调节APC/C的活性，SIRT2 缺失导致包括指导中心粒扩增、异倍体性和有丝分裂细胞死亡的Aurora-A 和 B在内的有丝分裂调节子增多。Sirt2缺失的老鼠会发生性别特异性发肿瘤形成，母老鼠主要得乳腺癌，公老鼠更多得肝癌。同正常组织比较，人乳腺癌和肝癌样本SIRT2水平降低。这些数据表明SIRT2 通过调节有丝分裂和基因组完整性而具有肿瘤抑制作用。

【点评】
该研究结果进一步丰富了我们对与衰老和癌症有密切关系的脱乙酰基酶家族的认识，了解了SIRT2的肿瘤抑制作用及其初步机制。

【参考论文】
Cancer Cell, 2011; 20(4) pp. 487 - 499, DOI: 10.1016/j.ccr.2011.09.004
SIRT2 Maintains Genome Integrity and Suppresses Tumorigenesis through Regulating APC/C Activity
Hyun-Seok Kim, Athanassios Vassilopoulos, Rui-Hong Wang, et al.  
Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its coactivators, APCCDH1 and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including Aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with normal tissues. These data demonstrate that SIRT2 is a tumor suppressor through its role in regulating mitosis and genome integrity.

4. ω-3脂肪酸能够预防或减缓骨关节炎
【动态】
英国科学家的最新研究首次发现鱼油中的ω-3不饱和脂肪酸能够明显降低骨关节炎的症状。他们在天然的豚鼠模型中观察了富含ω-3多不饱和脂肪酸的饮食对骨关节炎的作用。天生易患骨关节炎的DH豚鼠和不易患骨关节炎的BS2豚鼠从10周大到30周用标准饮食和ω-3不饱和脂肪酸饮食喂养。通过组织学手段检查软骨和软骨下骨组织病理学，也检查其生化指标包括胶原交联、基质金属蛋白酶（MMPs）、碱性金属蛋白酶、粘多糖和变性的II型胶原。结果显示ω-3不饱和脂肪酸饮食喂养的DH豚鼠的绝大部分指标都向BS2豚鼠靠拢，表明ω-3多不饱和脂肪酸饮食减少了易患骨关节炎的豚鼠种系的症状，大多数疾病指标向正常豚鼠种系的方向改善。

【点评】
该研究发现了ω-3不饱和脂肪酸对健康的又一好处:预防和减缓骨关节炎的发病和进展。对于改善我们的饮食结构有参考价值。

【参考论文】
Osteoarthritis and Cartilage, 2011; 19 (9): 1150 DOI: 10.1016/j.joca.2011.06.005
Regulation of osteoarthritis by omega-3 (n-3) polyunsaturated fatty acids in a naturally occurring model of disease
L. Knott, N.C. Avery, A.P. Hollander, J.F. Tarlton.
Summary
Objective
To examine effects of high omega-3 (n-3) polyunsaturated fatty acid (PUFA) diets on development of osteoarthritis (OA) in a spontaneous guinea pig model, and to further characterise pathogenesis in this model. Modern diets low in n-3 PUFAs have been linked with increases in inflammatory disorders, possibly including OA. However, n-3 is also thought to increases bone density, which is a possible contributing factor in OA. Therefore we aim to determine the net influence of n-3 in disease development.
Method
OA-prone Dunkin-Hartley (DH) Guinea pigs were compared with OA-resistant Bristol Strain-2s (BS2) each fed a standard or an n-3 diet from 10 to 30weeks (10/group). We examined cartilage and subchondral bone pathology by histology, and biochemistry, including collagen cross-links, matrix metalloproteinases (MMPs), alkaline phosphatase, glycosaminoglycan (GAG), and denatured type II collagen.
Results
Dietary n-3 reduced disease in OA-prone animals. Most cartilage parameters were modified by n-3 diet towards those seen in the non-pathological BS2 strain – significantly active MMP-2, lysyl-pyridinoline and total collagen cross-links – the only exception being pro MMP-9 which was lower in the BS2, yet increased with n-3. GAG content was higher and denatured type II lower in the n-3 group. Subchondral bone parameters in the DH n-3 group also changed towards those seen in the non-pathological strain, significantly calcium:phosphate ratios and epiphyseal bone density.
Conclusion
Dietary n-3 PUFA reduced OA in the prone strain, and most disease markers were modified towards those of the non-OA strain, though not all significantly so. Omega-3 did not increase markers of pathology in either strain.

5. 发现结肠癌可能和细菌存在联系
【动态】
结直肠癌的肿瘤微环境是个复杂的群落，有基因突变的癌细胞、非肿瘤细胞和多种多样的微生物群。每一部分都可能对肿瘤形成有影响，而微生物群的作用是所知最少的。美国科学家在9对肿瘤/正常样本中用全基因组序列分析检测了结直肠癌中的微生物群的组成。通过95组肿瘤/正常DNA的定量PCR和16S rDNA序列分析确证：在肿瘤样本中发现异常高水平的梭菌属的序列，而没有拟杆菌和厚壁菌群落。通过荧光原位杂交也能够看到结直肠癌中的梭杆菌。这些发现显示结直肠癌的微生物群发生了变化，对于结直肠癌病理学中梭杆菌的确切作用还需进一步的研究。

【点评】
结直肠癌中异常高水平的梭杆菌意味着这种菌群可能对结直肠癌的发生有作用，有可能会成为该种癌症诊断、预防和治疗的关键因素。但其可能的作用机制尚需深入研究。

【参考论文】
Genome Research, 2011; DOI: 10.1101/gr.126573.111
Genomic analysis identifies association of Fusobacterium with colorectal carcinoma
Kostic AD, Gevers D, Pedamallu CS, et al. 
The tumor microenvironment of colorectal carcinoma is a complex community of genomically altered cancer cells, nonneoplastic cells, and a diverse collection of microorganisms. Each of these components may contribute to carcinogenesis; however, the role of the microbiota is the least well understood. We have characterized the composition of the microbiota in colorectal carcinoma using whole genome sequences from nine tumor/normal pairs. Fusobacterium sequences were enriched in carcinomas, confirmed by quantitative PCR and 16S rDNA sequence analysis of 95 carcinoma/normal DNA pairs, while the Bacteroidetes and Firmicutes phyla were depleted in tumors. Fusobacteria were also visualized within colorectal tumors using FISH. These findings reveal alterations in the colorectal cancer microbiota; however, the precise role of Fusobacteria in colorectal carcinoma pathogenesis requires further investigation.
 

6. 特异性双价半抗原有效抑制过敏反应
【动态】
美国科学家最近报道了一种杂二价配体（HBL）系统能够竞争性地抑制过敏原与肥大细胞上的IgE抗体结合，从而抑制肥大细胞脱颗粒作用。HBLs的组成包括一个半抗原，结合在核苷酸类似物上使得能够同时锚定IgE抗体Fab区域的抗原结合部位和非常规的核苷酸结合部位。同时结合在两个不同性质的结合部位使得HBLs 对IgEDNP的亲和力以及对过敏原与IgEDNP的结合的抑制作用比只有一个结合部位的半抗原提高了100倍以上。在细胞实验中，HBLs (IC50 = 15 M)能够有效抑制肥大细胞脱颗粒作用，而单价半抗原则检测不到抑制作用。

【点评】
通过增加一个结合部位的设计，新的双价半抗原HBLs对抑制过敏原与抗体的结合获得了百倍的提高，从而能够有效的与过敏原竞争抗体，抑制食物药物过敏和哮喘而不会压制患者的整个免疫系统。

【参考论文】
Chemistry & Biology, 2011; 18 (9): 1179 DOI: 10.1016/j.chembiol.2011.06.012 
Design of a Heterobivalent Ligand to Inhibit IgE Clustering on Mast Cells
Michael W. Handlogten, Tanyel Kiziltepe, Demetri T. Moustakas, Başar Bilgiçer.
We describe the design, synthesis, and characterization of a heterobivalent ligand (HBL) system that competitively inhibits allergen binding to mast cell bound IgE antibody, thereby inhibiting mast cell degranulation. HBLs are composed of a hapten conjugated to a nucleotide analog allowing simultaneous targeting of the antigen-binding site as well the unconventional nucleotide binding site on IgE Fab domains. Simultaneous bivalent binding to both sites provides HBLs with over 100-fold enhancement both in avidity for IgEDNP (Kd = 0.33 M) and in inhibition of allergen binding to IgEDNP (IC50 = 0.45 M) than the monovalent hapten (Kdmono = 41 M; IC50mono = 55.4 M, respectively). In cellular assays, HBL2 effectively inhibits mast cell degranulation (IC50 = 15 M), whereas no inhibition is detected by the monovalent hapten. In conclusion, this study establishes the use of multivalency in a novel HBL design to inhibit mast cell degranulation.