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世界性命科学前沿动态周报（二十二）
（08.30 --09.05/ 2010）
俄罗斯贵宾会集团国际集团:陶国新
本周动态蕴含以下内容： 脂肪可用作细胞内涵 pH 感触器； 鱼油抗炎抗糖尿病的机理；发现上皮组织中神秘免疫细胞的职能和机理； 蛋白质 TIMP3 推进造血干细胞割裂； 中草药提取物 大黄素 改善糖尿病和胰岛素抵抗的机理； 共生菌群失调或导致代谢性疾病。
• 脂肪可用作细胞内涵 pH 感触器
【提要】 起源：《科学》 颁布功夫： 2010-8-30 16:44:36
英国哥伦比亚大学（ UBC ）的一个钻研幼组发现细胞膜上存在的一种特异的脂肪可作为一种细胞 pH 感触器。该钻研成就被颁发在《科学》（ Science ）杂志上。 pH 值是对酸度或碱度的一种丈量值。细胞必要维持 pH 不变以保障身段正常的细胞职能。然而细胞 pH 监督器的机造却不明显。“科学家们发现一些特异的蛋白能够检测某些环境下 pH 值的扭转，”英国哥伦比亚大学医学院细胞及生理学科系的副教授、性命科学钻研所的成员 Chris Loewen 说：“我们发现一种存在于所有细胞中称为磷脂酸的特异性磷脂，可能检测细胞中 pH 值的变动。”“使用酿酒酵母作为模型，我们发现当被褫夺营养素时，细胞的 pH 值降落可影响磷脂酸的化学状态，从而扭转基因表白和细胞新陈代谢。”英国哥伦比亚大学和温哥华沿岸卫生钻研所的成员 Loewen 说。
新的发现拥有极度沉要的意思，它有助于钻研者相识人类新陈代谢和疾病，由于所有生物体的脂类结构和职能都是极度类似的�？山涫褂玫狡渌煊蚪懈畹奶剿�，例如肿瘤产生——由于磷脂酸和 pH 值在这一过程中阐扬了极度沉要的作用。亦可利用到大脑钻研，脑细胞 pH 值的动态扭转批注他们也使用了 pH 感触器。
【点评】
发现磷脂酸能够检测细胞内 pH 值的变动并调节与效应蛋白的结合，从而调节机体生理活动。鉴于 pH 值的不变对生物体生计的沉要意思，作为细胞内 pH 值感触器的职能会极大地提高磷脂酸这类脂质在生物体中的沉要性。
【原文摘录】 Science Vol. 329. no. 5995, pp. 1085 – 1088, DOI: 10.1126/science.1191026
Phosphatidic Acid Is a pH Biosensor That Links Membrane Biogenesis to Metabolism
Barry P. Young, John J. H. Shin, Rick Orij, et al.
Recognition of lipids by proteins is important for their targeting and activation in many signaling pathways, but the mechanisms that regulate such interactions are largely unknown. Here, we found that binding of proteins to the ubiquitous signaling lipid phosphatidic acid (PA) depended on intracellular pH and the protonation state of its phosphate head group. In yeast, a rapid decrease in intracellular pH in response to glucose starvation regulated binding of PA to a transcription factor, Opi1, that coordinately repressed phospholipid metabolic genes. This enabled coupling of membrane biogenesis to nutrient availability.
• 鱼油抗炎抗糖尿病的机理
【提要】
ω-3 脂肪酸拥有抗炎作用，但机理一向不明显。美国加州大学的钻研人员最近发现 G 蛋白偶联受体 GPR120 是 ω-3 脂肪酸的受体 / 感触器，体表细胞试验显示 GPR120 受到 ω-3 脂肪酸或化学激昂剂的刺激会产生宽泛的抗炎作用，而敲除 GPR120 会使所有这些作用隐没。肥胖症胰岛素抗性的一个关键机理是巨噬细胞介导的慢性组织发炎。通过喂食野生型和敲除 GPR120 的肥胖幼鼠增长或不增长 ω-3 脂肪酸的高脂肪饮食，发现给野生型幼鼠增长 ω-3 脂肪酸能够抑造发炎并加强全身胰岛素敏感性，而在敲除 GPR120 的幼鼠则无此成效。因而， ω-3 脂肪酸通过激活 GPR120 受体及其介导的抑造巨噬细胞介导的慢性组织发炎的作用而阐扬体内加强胰岛素敏感性抗糖尿病的作用。
【点评】
鱼油，尤其是其富含的 ω-3 脂肪酸的保健作用的机理一致不太明显，本文的钻研了局在细胞和动物尝试层面上诠氏缢 ω-3 脂肪酸的抗炎和抗糖尿病作用机理，若是同样的成效能够在临床试验中沉现，那对于糖尿病和有关炎症可能会提供一种单一的食疗规划。
【原文摘录】 Cell , 2010; 142 (5): 687-698 DOI: 10.1016/j.cell.2010.07.041
GPR120 Is an Omega-3 Fatty Acid Receptor Mediating Potent Anti-inflammatory and Insulin-Sensitizing Effects .
Da Young Oh, Saswata Talukdar, Eun Ju Bae, et al.
Omega-3 fatty acids (ω-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an ω-3 FA receptor/sensor. Stimulation of GPR120 with ω-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without ω-3 FA supplementation. The ω-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional ω-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
• 发现上皮组织中神秘免疫细胞的职能和机理
【提要】 9 月 3 号的 Science 杂志颁发了 Scripps Research Institute 团队的有关钻研，阐了然皮肤和其他上皮组织中的一种免疫细胞 γδ T 细胞的激活机理。这些免疫细胞在鉴别上皮组织的危险和病变中起怪异而关键的作用。自觉现 γδ T 细胞近三十年来，对其激活机理一向知之甚少�？蒲Ъ曳⑾终饫嘞赴鱿钟谂咛シ⒂缙诘男叵僦�，而后迁徙到上皮组织中。与免疫系统的 αβT 细胞分歧，大部门 γδ T 细胞不在血流中循环，而是作为皮肤、肺和肠的一种重要的 T 细胞定居在那里并监督邻近上皮细胞的危险和病变。而 Havran 辅导的钻研发现 γδ T 细胞能加快伤口愈合， 跟进的钻研证实作为上皮中重要细胞类型的角质细胞感知皮肤危险并表白一种抗原， γδ T 细胞可能鉴别这种抗原进而活化变形成为圆形幼工厂，起头大量出产一种成长因子，这些成长因子结合到角质细胞和其他上皮细胞，推进它们增殖以关合伤口。 γδ T 细胞自身也增殖来加强伤口愈合反映。
【点评】
γδ T 细胞推进上皮组织伤口愈合的职能和机理的说明，会推进对于免疫细胞在创伤愈合中的作用的更深刻钻研，对于进一步理解创伤愈归并开发更好的医治伎俩有很大援手。
【原文摘录】 Science , 2010; 329 (5996): 1205-1210 DOI: 10.1126/science.1192698
The Junctional Adhesion Molecule JAML Is a Costimulatory Receptor for Epithelial γδ T Cell Activation .
Deborah A. Witherden, Petra Verdino, Stephanie E, et al.
T cells present in epithelial tissues provide a crucial first line of defense against environmental insults, including infection, trauma, and malignancy, yet the molecular events surrounding their activation remain poorly defined. Here we identify an epithelial T cell–specific costimulatory molecule, junctional adhesion molecule–like protein (JAML). Binding of JAML to its ligand Coxsackie and adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine and growth factor production. Inhibition of JAML costimulation leads to diminished T cell activation and delayed wound closure akin to that seen in the absence of T cells. Our results identify JAML as a crucial component of epithelial T cell biology and have broader implications for CAR and JAML in tissue homeostasis and repair.
4. 蛋白质 TIMP3 推进造血干细胞割裂
【提要】 新华网 2010-8-31 9:20:54
一项新钻研发现，一种蛋白质可能推进造血干细胞增殖并形成血液细胞，因而这种蛋白质有可能用来造作药剂，以用于复原因放化疗而削减的白细胞和红细胞。造血干细胞是指骨髓中的干细胞，拥有自我复造能力，且能够割裂形成白细胞、红细胞和血幼板等。但造血干细胞通常只有很少一部门缓慢割裂，大部门险些都处于 “ 蛰伏状态 ” 。人体因化疗和放疗导致血液细胞削减后，造血干细胞会起头割裂，但其机造一向没有弄清。日本庆应义塾大学副教授中岛秀明等人在 27 日的美国《血液》月刊上颁发论文说，他们在动物尝试中发现，老鼠进行化疗和放疗后，骨髓中称为 “TIMP3” 的蛋白质增长。而在造就皿中，向采自老鼠骨髓的造血干细胞增长 “TIMP3” 蛋白质进行造就后，发现造血干细胞增殖活跃，数量相当于未增长时的 1.5 倍至 2 倍，血液细胞也随之增长。钻研人员还发现，若是使老鼠体内无法出产 “TIMP3” 蛋白质，则血液细胞削减难以复原。而一旦 “TIMP3” 过剩，处于 “ 蛰伏 ” 状态的造血干细胞就复苏过来，起头割裂。钻研人员说，在进行化疗和放疗时，人体骨髓中的血液细胞会受到粉碎，从而削减，容易出现习染和 血虚 等问题。如利用 “TIMP3” 蛋白质，就有望加快复原因化疗和放疗而削减的血液细胞，除预防习染表，还能够削减输血量。
【点评】
老鼠细胞造就和动物尝试显示 TIMP3 蛋白质能够推进造血干细胞割裂增殖，但进展这一蛋白能有助于癌症的辅助医治，还需进一步钻研是否在人体中有同样成效以及若何推进在体内产生这类蛋白质。
【原文摘录】 Blood DOI 10.1182/blood-2010-01-266528.
TIMP-3 recruits quiescent hematopoietic stem cells into active cell cycle and expands multipotent progenitor pool
Hideaki Nakajima1, Miyuki Ito, David S. Smookler, et al.
Regulating transition of hematopoietic stem cells (HSCs) between quiescent and cycling states is critical for maintaining homeostasis of blood cell production. The cycling states of HSCs are regulated by the extracellular factors such as cytokines and extracellular matrix, however, the molecular circuitry for such regulation remains elusive. Here we show that tissue inhibitor of metalloproteinase-3 (TIMP-3), an endogenous regulator of metalloproteinases, stimulates HSC proliferation by recruiting quiescent HSCs into the cell cycle. Myelosuppression induced TIMP -3 in the bone marrow prior to hematopoietic recovery. Interestingly, TIMP-3 enhanced proliferation of HSCs and promoted expansion of multipotent progenitors, which was achieved by stimulating cell-cycle entry of quiescent HSCs without compensating their long-term repopulating activity. Surprisingly, this effect did not require metalloproteinase inhibitory activity of TIMP-3, and was possibly mediated through a direct inhibition of angiopoietin-1 signaling, a critical mediator for HSC quiescence. Furthermore, BM recovery from myelosuppression was accelerated by overexpression of TIMP-3, and in turn, impaired in TIMP-3-deficient animals. These results suggest that TIMP-3 may act as a molecular cue in response to myelosuppression for recruiting dormant HSCs into active cell cycle, and may be clinically useful for facilitating hematopoietic recovery after chemotherapy or ex vivo expansion of HSCs.
5. 中草药提取物 大黄素 改善糖尿病和胰岛素抵抗的机理
【提要】
大黄素是一种可得意黄、虎杖等多种中草药之中提取的天然产品，它在减轻 II 型糖尿病的影响方面显示出了很大的前途�５窃赜诒驹隆队⒐├硌诳罚� British Journal of Pharmacology ）的钻研了局显示，对由饮食导致肥胖的幼鼠赐与大黄素之后，其血糖和血清胰岛素浓度降低，其胰岛素抵抗得到了改善，从而导致更好的血脂健全水平。同时它还减轻了幼鼠的体沉，并削减了其中央体脂。论文重要作者、就职于中国科学院上海药物钻研所（ Shanghai Institute of Materia Medica, Chinese Academy of Sciences ）的 冷颖 博士说路： “ 若是在人类身上沉现这一了局，所有这些变动都将有益于受 II 型糖尿病或者其他与胰岛素抵抗有关联的代谢性疾病影响的病人。 ” 越来越多的钻研显示，一种名为 11β-HSD1 的酶在人体对饮食中所含糖分的反映中表演了沉要角色。当一幼我食用含糖食品时，大量葡萄糖进入血液。作为回应，人体开释出胰岛素，这种激素会触发各类职能，援手从血液中断根过量的葡萄糖。然而，人体内还有另一系列激素，名为糖皮质激素，它们的作用与胰岛素正好相反。而这里正是 11β-HSD1 起作用的关键，由于这种酶使糖皮质激素的作用能力增长。
该项钻研初次批注，大黄素对 11β-HSD1 来说是一种强有力的选择性抑造剂，从而可能有效地限度糖皮质激素的作用成效，并改善糖尿病和胰岛素抵抗。 冷 博士说： “ 俄罗斯贵宾会集团工作显示，这种中草药的天然提取物可能指出了一条援手医治 II 型糖尿病以及其他代谢错乱的新的蹊径。为进一步发展这种蹊径，钻研人员必要开发与大黄素作用类似的化学药品，看看这些药品是否能够作为医治药物使用。 ”
【点评】
中草药天然提取物作用机理的逐步说明，将极大的推动中草药及其天然提取物在现代药物医治中的作用和沉要性，尤其是在西药出格是化学合成药出现后继乏力的近况下。
【原文摘录】 British Journal of Pharmacology DOI: 10.1111/j.1476-5381.2010.00826.x
Emodin, a natural product, selectively inhibits 11β-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice
Ying Feng, Su-ling Huang, Wei Dou, et al.
BACKGROUND AND PURPOSE 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11β-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice.
EXPERIMENTAL APPROACH Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11β-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice.
KEY RESULTS Emodin is a potent and selective 11β-HSD1 inhibitor with the IC 50 of 186 and 86 nM for human and mouse 11β-HSD1, respectively. Single oral administration of emodin inhibited 11β-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11β-HSD 1 in vivo . In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA.
CONCLUSIONS AND IMPLICATIONS This study demonstrated a new role for emodin as a potent and selective inhibitor of 11β-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes.
6. 共生菌群失调或导致代谢性疾病
【提要】 （起源：文汇报 许琦敏）
吃酸奶、补充益生菌，对健全好，吃太多肉会使体内产生不少毒素 —— 这是告白勾画的臆想，还是真有其事？近年来，科学家发现，除了遗传和不健全的生涯方式表， 寄居在人体内的共生菌群失调同样有可能引发慢性代谢性疾病，而炊事是调节菌群的沉要蹊径之一。
有细菌入侵，人体就会发热，这是不言而喻的炎症。不外，人体内还存在另一种 “ 温吞水 ” 般的慢性炎症。这要从菌群说起。人体肠路中存在大量的共生细菌，分为革兰氏阳性菌和革兰氏阴性菌，后者会产生内毒素，并在菌体身后将其开释进血液。 动物钻研发现，高脂肪食品会扭转肠路菌群的组成，使革兰氏阴性菌的比例增高，从而导致血液中的内毒素浓度升高。而内毒素又会通过一系列反映，开启人体中的炎症通路，让人体处于慢性炎症状态中 ，这就好比对免疫系统的游击战，日积月累会令机体疲于应对，无法进行正常的新陈代谢，肥胖、糖尿病、心血管疾病等代谢性疾病就不请自来了。
菌群的变动是否同样影响着中国人的健全呢？中科院上海生科院营养科学钻研所林旭钻研员辅导的钻研团队与上海疾控中心合作，通过在上海社区人群中发展 “ 营养、肠路菌群与肥胖关系的病例 - 对照钻研 ” 项目，发现 内毒素的结合蛋白与慢性代谢性综合征和 2 型糖尿病亲昵有关 。 而内毒素作为一种表源性的诱导物，可能在激活慢性炎症通路和代谢错乱的产生过程中起到沉要作用 。该论文最近颁发于权威杂志《糖尿病护理》（ Diabetes Care ）。
在这次大规模人群钻研中，科学家发现，肥胖个别中内毒素有关指标比正常体沉个别逾越 1.76 倍；并且，血浆中内毒素有关指标高的个别，身段中所有 “ 坏分子 ” 、炎症因子的水平都相应偏高，而对机体有�；ぷ饔玫� “ 好分子 ” 又都偏少。 “ 我们发现血浆中内毒素有关指标的浓度越高，罹患代谢性疾病的风险也越大。 ” 论文重要作者之一、营养所孙亮博士通知记者，血浆中内毒素有关指标最高组的个别与最低组相比，罹患代谢综合征的风险逾越 2.5 倍、患 2 型糖尿病的风险逾越 4.5 倍！
这项钻研初次在国际上通过较大规模的人群钻研证实：菌群生物象征物与慢性代谢性疾病存在显著的关联关系。对于通常人而言，科学家提醒说，平时把稳多吃点酸奶、蔬菜，少吃些肉，从菌群调节上说，简直会更有利于健全，在肯定水平上削减得代谢性疾病的风险。
【点评】
大规模人群钻研发现血浆中内毒素有关指标的浓度越高，罹患代谢性疾病的风险也越大，菌群生物象征物与慢性代谢性疾病存在显著的关联关系。调节体内菌群以有利于健全必要改善饮食结构。
【原文摘录】 Diabetes Care September 2010 vol. 33 no. 9 1925-1932
A Marker of Endotoxemia Is Associated With Obesity and Related Metabolic Disorders in Apparently Healthy Chinese
Liang Sun , Zhijie Yu , Xingwang Ye , et al.
OBJECTIVE Elevated lipopolysaccharide-binding protein (LBP), a marker of subclinical endotoxemia, may be involved in the pathogenesis of obesity and metabolic risk. We aimed to investigate the association between plasma LBP and metabolic disorders in apparently healthy Chinese.
RESEARCH DESIGN AND METHODS A population-based study including 559 overweight/obese (BMI ≥ 24.0 kg /m 2 ) and 500 normal-weight (18.0 ≤ BMI < 24.0 kg /m 2 ) subjects aged 35–54 years was conducted in Shanghai , China . Fasting plasma glucose, lipid profile, LBP, high-sensitivity C-reactive protein, interleukin-6, high-molecular-weight (HMW) adiponectin, leptin, hepatic enzymes, and body composition were measured. Metabolic syndrome was defined by the updated National Cholesterol Education Program Adult Treatment Panel III criterion for Asian Americans.
RESULTS LBP levels were significantly higher in overweight/obese individuals than in normal-weight individuals (geometric mean 27.6 [95% CI 25.2–30.3] vs. 10.0 [9.1–11.1] μg/ml; P < 0.001). After multiple adjustments including BMI, the odds ratios were 3.54 (95% CI 2.05–6.09) and 5.53 (95% CI 2.64–11.59) for metabolic syndrome and type 2 diabetes, respectively, comparing the highest with the lowest LBP quartile. Further adjustments for inflammatory markers almost abolished the significant association of LBP with metabolic syndrome but not that with type 2 diabetes, and controlling for adipokines and hepatic enzymes did not substantially alter the results.
CONCLUSIONS Elevated circulating LBP was associated with obesity, metabolic syndrome, and type 2 diabetes in apparently healthy Chinese. These findings suggested a role of lipopolysaccharide via initiation of innate immune mechanism(s) in metabolic disorders. Prospective studies are needed to confirm these results.