世界生命科學(xué)前沿動(dòng)態(tài)周報(bào)（六十二）

（10.17-10.23/2011）
美寶國(guó)際集團(tuán):陶國(guó)新 

　　主要內(nèi)容：大腦和其他組織的炎癥機(jī)制不同；腸道細(xì)菌促進(jìn)腸病毒復(fù)制和全身感染；SIRT2通過調(diào)節(jié)APC/C活性維持基因組完整性抑制腫瘤形成；ω-3脂肪酸能夠預(yù)防或減緩骨關(guān)節(jié)炎；發(fā)現(xiàn)結(jié)腸癌可能和細(xì)菌存在聯(lián)系；特異性雙價(jià)半抗原有效抑制過敏反應(yīng)。

　　焦點(diǎn)動(dòng)態(tài)：大腦和其他組織的炎癥機(jī)制不同。

1. 大腦和其他組織的炎癥機(jī)制不同
【動(dòng)態(tài)】
磷脂酶A2（PLA-2）被認(rèn)為是環(huán)氧合酶（COX）介導(dǎo)的前列腺素的生物合成所需花生四烯酸的主要代謝酶。美國(guó)科學(xué)家的最新研究發(fā)現(xiàn)在大腦中存在不同的代謝途徑，單酰甘油酯酶（MAGL）水解內(nèi)源性大麻素2-花生四烯酸甘油產(chǎn)生引起神經(jīng)炎癥的前列腺素的主要前體花生四烯酸。在帕金森老鼠模型中破壞了MAGL的老鼠表現(xiàn)出神經(jīng)保護(hù)作用。這類老鼠不會(huì)發(fā)生由細(xì)胞質(zhì)內(nèi)PLA-2調(diào)節(jié)前列腺素的內(nèi)臟中COX抑制劑引起的出血。這些發(fā)現(xiàn)確認(rèn)MAGL是不同的代謝節(jié)點(diǎn)在神經(jīng)系統(tǒng)中連接內(nèi)源性大麻素和前列腺素信號(hào)網(wǎng)絡(luò)，提示抑制該酶可能是一種新的安全的壓制造成神經(jīng)變性疾病的促炎級(jí)聯(lián)反應(yīng)的方法。

【點(diǎn)評(píng)】
該發(fā)現(xiàn)有利于加深對(duì)神經(jīng)變性疾病的理解以及特異性的針對(duì)神經(jīng)病變的更安全的治療手段。但是由于信號(hào)系統(tǒng)的網(wǎng)絡(luò)調(diào)節(jié)是多通路多節(jié)點(diǎn)并受身體統(tǒng)一調(diào)制的，針對(duì)單一節(jié)點(diǎn)的干預(yù)策略總是失之為權(quán)宜之計(jì)。

【參考論文】
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. 腸道細(xì)菌促進(jìn)腸病毒復(fù)制和全身感染
【動(dòng)態(tài)】
腸道菌群幫助促進(jìn)宿主健康并限制病原菌繁殖，但對(duì)腸道病毒的影響還知之甚少。美國(guó)科學(xué)家最近的研究通過用抗生素清除老鼠腸道菌群，而后接種脊髓灰質(zhì)炎病毒（一種腸道病毒），這種老鼠比較不容易得脊髓灰質(zhì)炎，腸道內(nèi)病毒復(fù)制也最低。而暴露于細(xì)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，會(huì)增強(qiáng)脊髓灰質(zhì)炎病毒的感染性。他們發(fā)現(xiàn)脊髓灰質(zhì)炎病毒與脂多糖結(jié)合，而該病毒暴露于細(xì)菌增強(qiáng)了宿主細(xì)胞的連接和感染。一種不相干的腸道病毒呼腸孤病毒的發(fā)病也在有腸道細(xì)菌時(shí)更嚴(yán)重。這些結(jié)果顯示抗生素清除腸道細(xì)菌后減少了腸道病毒感染以及腸道病毒利用腸道細(xì)菌進(jìn)行復(fù)制和傳播。

【點(diǎn)評(píng)】
該研究的結(jié)果說明腸道生態(tài)系統(tǒng)也是個(gè)動(dòng)態(tài)的環(huán)境，寄宿在此的各種微生物和病毒也會(huì)有互動(dòng)。而這個(gè)系統(tǒng)的狀態(tài)直接關(guān)系到宿主的健康狀況。

【參考論文】
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通過調(diào)節(jié)APC/C活性維持基因組完整性抑制腫瘤形成
【動(dòng)態(tài)】
脫乙酰基酶家族的成員調(diào)節(jié)多種關(guān)鍵的生物過程，但它們?cè)诎┌Y形成中的作用還存在爭(zhēng)議。美國(guó)科學(xué)家最近通過破壞老鼠的Sirt2基因研究了脫乙?；窼IRT2在發(fā)育和腫瘤形成中的生理功能。他們的研究表明SIRT2通過去乙酰化輔助激活子APCCDH1 和 CDC20而調(diào)節(jié)APC/C的活性，SIRT2 缺失導(dǎo)致包括指導(dǎo)中心粒擴(kuò)增、異倍體性和有絲分裂細(xì)胞死亡的Aurora-A 和 B在內(nèi)的有絲分裂調(diào)節(jié)子增多。Sirt2缺失的老鼠會(huì)發(fā)生性別特異性發(fā)腫瘤形成，母老鼠主要得乳腺癌，公老鼠更多得肝癌。同正常組織比較，人乳腺癌和肝癌樣本SIRT2水平降低。這些數(shù)據(jù)表明SIRT2 通過調(diào)節(jié)有絲分裂和基因組完整性而具有腫瘤抑制作用。

【點(diǎn)評(píng)】
該研究結(jié)果進(jìn)一步豐富了我們對(duì)與衰老和癌癥有密切關(guān)系的脫乙?；讣易宓恼J(rèn)識(shí)，了解了SIRT2的腫瘤抑制作用及其初步機(jī)制。

【參考論文】
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脂肪酸能夠預(yù)防或減緩骨關(guān)節(jié)炎
【動(dòng)態(tài)】
英國(guó)科學(xué)家的最新研究首次發(fā)現(xiàn)魚油中的ω-3不飽和脂肪酸能夠明顯降低骨關(guān)節(jié)炎的癥狀。他們?cè)谔烊坏碾嗍竽Ｐ椭杏^察了富含ω-3多不飽和脂肪酸的飲食對(duì)骨關(guān)節(jié)炎的作用。天生易患骨關(guān)節(jié)炎的DH豚鼠和不易患骨關(guān)節(jié)炎的BS2豚鼠從10周大到30周用標(biāo)準(zhǔn)飲食和ω-3不飽和脂肪酸飲食喂養(yǎng)。通過組織學(xué)手段檢查軟骨和軟骨下骨組織病理學(xué)，也檢查其生化指標(biāo)包括膠原交聯(lián)、基質(zhì)金屬蛋白酶（MMPs）、堿性金屬蛋白酶、粘多糖和變性的II型膠原。結(jié)果顯示ω-3不飽和脂肪酸飲食喂養(yǎng)的DH豚鼠的絕大部分指標(biāo)都向BS2豚鼠靠攏，表明ω-3多不飽和脂肪酸飲食減少了易患骨關(guān)節(jié)炎的豚鼠種系的癥狀，大多數(shù)疾病指標(biāo)向正常豚鼠種系的方向改善。

【點(diǎn)評(píng)】
該研究發(fā)現(xiàn)了ω-3不飽和脂肪酸對(duì)健康的又一好處:預(yù)防和減緩骨關(guān)節(jié)炎的發(fā)病和進(jìn)展。對(duì)于改善我們的飲食結(jié)構(gòu)有參考價(jià)值。

【參考論文】
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. 發(fā)現(xiàn)結(jié)腸癌可能和細(xì)菌存在聯(lián)系
【動(dòng)態(tài)】
結(jié)直腸癌的腫瘤微環(huán)境是個(gè)復(fù)雜的群落，有基因突變的癌細(xì)胞、非腫瘤細(xì)胞和多種多樣的微生物群。每一部分都可能對(duì)腫瘤形成有影響，而微生物群的作用是所知最少的。美國(guó)科學(xué)家在9對(duì)腫瘤/正常樣本中用全基因組序列分析檢測(cè)了結(jié)直腸癌中的微生物群的組成。通過95組腫瘤/正常DNA的定量PCR和16S rDNA序列分析確證：在腫瘤樣本中發(fā)現(xiàn)異常高水平的梭菌屬的序列，而沒有擬桿菌和厚壁菌群落。通過熒光原位雜交也能夠看到結(jié)直腸癌中的梭桿菌。這些發(fā)現(xiàn)顯示結(jié)直腸癌的微生物群發(fā)生了變化，對(duì)于結(jié)直腸癌病理學(xué)中梭桿菌的確切作用還需進(jìn)一步的研究。

【點(diǎn)評(píng)】
結(jié)直腸癌中異常高水平的梭桿菌意味著這種菌群可能對(duì)結(jié)直腸癌的發(fā)生有作用，有可能會(huì)成為該種癌癥診斷、預(yù)防和治療的關(guān)鍵因素。但其可能的作用機(jī)制尚需深入研究。

【參考論文】
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. 特異性雙價(jià)半抗原有效抑制過敏反應(yīng)
【動(dòng)態(tài)】
美國(guó)科學(xué)家最近報(bào)道了一種雜二價(jià)配體（HBL）系統(tǒng)能夠競(jìng)爭(zhēng)性地抑制過敏原與肥大細(xì)胞上的IgE抗體結(jié)合，從而抑制肥大細(xì)胞脫顆粒作用。HBLs的組成包括一個(gè)半抗原，結(jié)合在核苷酸類似物上使得能夠同時(shí)錨定IgE抗體Fab區(qū)域的抗原結(jié)合部位和非常規(guī)的核苷酸結(jié)合部位。同時(shí)結(jié)合在兩個(gè)不同性質(zhì)的結(jié)合部位使得HBLs 對(duì)IgEDNP的親和力以及對(duì)過敏原與IgEDNP的結(jié)合的抑制作用比只有一個(gè)結(jié)合部位的半抗原提高了100倍以上。在細(xì)胞實(shí)驗(yàn)中，HBLs (IC50 = 15 M)能夠有效抑制肥大細(xì)胞脫顆粒作用，而單價(jià)半抗原則檢測(cè)不到抑制作用。

【點(diǎn)評(píng)】
通過增加一個(gè)結(jié)合部位的設(shè)計(jì)，新的雙價(jià)半抗原HBLs對(duì)抑制過敏原與抗體的結(jié)合獲得了百倍的提高，從而能夠有效的與過敏原競(jìng)爭(zhēng)抗體，抑制食物藥物過敏和哮喘而不會(huì)壓制患者的整個(gè)免疫系統(tǒng)。

【參考論文】
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.