企业邮箱
天下生命科学前沿动态周报（二十二）
（08.30 --09.05/ 2010）
一竞技国际集团:陶国新
本周动态包括以下内容： 脂肪可用作细胞内在 pH 感受器； 鱼油抗炎抗糖尿病的机理；发明上皮组织中神秘免疫细胞的功效和机理； 卵白质 TIMP3 增进造血干细胞破碎； 中草药提取物 大黄素 改善糖尿病和胰岛素对抗的机理； 共生菌群失调或导致代谢性疾病。
• 脂肪可用作细胞内在 pH 感受器
【摘要】 泉源：《科学》 宣布时间： 2010-8-30 16:44:36
英国哥伦比亚大学（ UBC ）的一个研究小组发明细胞膜上保存的一种特异的脂肪可作为一种细胞 pH 感受器。该研究效果被揭晓在《科学》（ Science ）杂志上。 pH 值是对酸度或碱度的一种丈量值。细胞需要维持 pH 稳固以包管身体正常的细胞功效。然而细胞 pH 监视器的机制却不清晰。“科学家们发明一些特异的卵白可以检测某些情形下 pH 值的改变，”英国哥伦比亚大学医学院细胞及心理学科系的副教授、生命科学研究所的成员 Chris Loewen 说：“我们发明一种保存于所有细胞中称为磷脂酸的特异性磷脂，能够检测细胞中 pH 值的转变。”“使用酿酒酵母作为模子，我们发明当被剥夺营养素时，细胞的 pH 值下降可影响磷脂酸的化学状态，从而改变基因表达和细胞新陈代谢。”英国哥伦比亚大学和温哥华沿岸卫生研究所的成员 Loewen 说。
新的发明具有很是主要的意义，它有助于研究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功效都是很是相似的�？山湓擞玫狡渌煊蚓傩懈畹奶教�，例如肿瘤爆发——由于磷脂酸和 pH 值在这一历程中施展了很是主要的作用。亦可应用到大脑研究，脑细胞 pH 值的动态改变批注他们也使用了 pH 感受器。
【点评】
发明磷脂酸可以检测细胞内 pH 值的转变并调理与效应卵白的团结，从而调理机体心理运动。鉴于 pH 值的稳固对生物体生涯的主要意义，作为细胞内 pH 值感受器的功效会极大地提高磷脂酸这类脂质在生物体中的主要性。
【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
【摘要】
ω-3 脂肪酸具有抗炎作用，但机理一直不清晰。美国加州大学的研究职员最近发明 G 卵白偶联受体 GPR120 是 ω-3 脂肪酸的受体 / 感受器，体外细胞试验显示 GPR120 受到 ω-3 脂肪酸或化学激动剂的刺激会爆发普遍的抗炎作用，而敲除 GPR120 会使所有这些作用消逝。肥胖症胰岛素抗性的一个要害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 的肥胖小鼠添加或不添加 ω-3 脂肪酸的高脂肪饮食，发明给野生型小鼠添加 ω-3 脂肪酸可以抑制发炎并增强全身胰岛素敏感性，而在敲除 GPR120 的小鼠则无此效果。因此， ω-3 脂肪酸通过激活 GPR120 受体及其介导的抑制巨噬细胞介导的慢性组织发炎的作用而施展体内增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清晰，本文的研究效果在细胞和动物实验层面上诠释了 ω-3 脂肪酸的抗炎和抗糖尿病作用机理，若是同样的效果可以在临床试验中重现，那关于糖尿病和相关炎症可能会提供一种简朴的食疗计划。
【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.
• 发明上皮组织中神秘免疫细胞的功效和机理
【摘要】 9 月 3 号的 Science 杂志揭晓了 Scripps Research Institute 团队的相关研究，剖析了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。这些免疫细胞在识别上皮组织的损伤和病变中起奇异而要害的作用。自觉现 γδ T 细胞近三十年来，对其激活机理一直知之甚少�？蒲Ъ曳⒚髡饫嘞赴浩鹩谂咛シ⒂缙诘男叵僦�，此后迁徙到上皮组织中。与免疫系统的 αβT 细胞差别，大部分 γδ T 细胞不在血流中循环，而是作为皮肤、肺和肠的一种主要的 T 细胞假寓在那里并监视邻近上皮细胞的损伤和病变。而 Havran 向导的研究发明 γδ T 细胞能加速伤口愈合， 跟进的研究证实作为上皮中主要细胞类型的角质细胞感知皮肤损伤并表达一种抗原， γδ T 细胞能够识别这种抗原进而活化变形成为圆形小工厂，最先大宗生产一种生长因子，这些生长因子团结到角质细胞和其他上皮细胞，增进它们增殖以闭合伤口。 γδ T 细胞自己也增殖来增强伤口愈合反应。
【点评】
γδ T 细胞增进上皮组织伤口愈合的功效和机理的剖析，会增进关于免疫细胞在创伤愈合中的作用的更深入研究，关于进一步明确创伤愈合并开发更好的治疗手段有很大资助。
【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. 卵白质 TIMP3 增进造血干细胞破碎
【摘要】 新华网 2010-8-31 9:20:54
一项新研究发明，一种卵白质能够增进造血干细胞增殖并形成血液细胞，因此这种卵白质有可能用来制作药剂，以用于恢复因放化疗而镌汰的白细胞和红细胞。造血干细胞是指骨髓中的干细胞，具有自我复制能力，且可以破碎形成白细胞、红细胞和血小板等。但造血干细胞通常只有很少一部分缓慢破碎，大部分险些都处于 “ 蛰伏状态 ” 。人体因化疗和放疗导致血液细胞镌汰后，造血干细胞会最先破碎，但其机制一直没有弄清。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》月刊上揭晓论文说，他们在动物实验中发明，老鼠举行化疗和放疗后，骨髓中称为 “TIMP3” 的卵白质增添。而在作育皿中，向采自老鼠骨髓的造血干细胞添加 “TIMP3” 卵白质举行作育后，发明造血干细胞增殖活跃，数目相当于未添加时的 1.5 倍至 2 倍，血液细胞也随之增添。研究职员还发明，若是使老鼠体内无法生产 “TIMP3” 卵白质，则血液细胞镌汰难以恢复。而一旦 “TIMP3” 过剩，处于 “ 蛰伏 ” 状态的造血干细胞就苏醒过来，最先破碎。研究职员说，在举行化疗和放疗时，人体骨髓中的血液细胞会受到破损，从而镌汰，容易泛起熏染和 血虚 等问题。如使用 “TIMP3” 卵白质，就有望加速恢复因化疗和放疗而镌汰的血液细胞，除避免熏染外，还可以镌汰输血量。
【点评】
老鼠细胞作育和动物实验显示 TIMP3 卵白质可以增进造血干细胞破碎增殖，但期望这一卵白能有助于癌症的辅助治疗，还需进一步研究是否在人体中有同样效果以及怎样增进在体内爆发这类卵白质。
【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对抗的机理
【摘要】
大黄素是一种可自尊黄、虎杖等多种中草药之中提取的自然产品，它在减轻 II 型糖尿病的影响方面显示出了很大的前途�？怯诒驹隆队⒐├硌诳罚� British Journal of Pharmacology ）的研究效果显示，对由饮食导致肥胖的小鼠给予大黄素之后，其血糖和血清胰岛素浓度降低，其胰岛素对抗获得了改善，从而导致更好的血脂康健水平。同时它还减轻了小鼠的体重，并镌汰了其中央体脂。论文主要作者、就职于中国科学院上海药物研究所（ Shanghai Institute of Materia Medica, Chinese Academy of Sciences ）的 冷颖 博士说道： “ 若是在人类身上重现这一效果，所有这些转变都将有益于受 II 型糖尿病或者其他与胰岛素对抗相关联的代谢性疾病影响的病人。 ” 越来越多的研究显示，一种名为 11β-HSD1 的酶在人体对饮食中所含糖分的反应中饰演了主要角色。当一小我私家食用含糖食物时，大宗葡萄糖进入血液。作为回应，人体释放出胰岛素，这种激素会触发种种功效，资助从血液中扫除过量的葡萄糖。然而，人体内尚有另一系列激素，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 起作用的要害，由于这种酶使糖皮质激素的作用能力增添。
该项研究首次批注，大黄素对 11β-HSD1 来说是一种强有力的选择性抑制剂，从而能够有用地限制糖皮质激素的作用效果，并改善糖尿病和胰岛素对抗。 冷 博士说： “ 我们的事情显示，这种中草药的自然提取物可能指出了一条资助治疗 II 型糖尿病以及其他代谢杂乱的新的途径。为进一步生长这种途径，研究职员需要开发与大黄素作用类似的化学药品，看看这些药品是否可以作为治疗药物使用。 ”
【点评】
中草药自然提取物作用机理的逐步剖析，将极大的推动中草药及其自然提取物在现代药物治疗中的作用和主要性，尤其是在西药特殊是化学合成药泛起后继乏力的现状下。
【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
【摘要】 （泉源：文汇报 许琦敏）
吃酸奶、增补益生菌，对康健好，吃太多肉会使体内爆发不少毒素 —— 这是广告勾勒的臆想，照旧真有其事？近年来，科学家发明，除了遗传和不康健的生涯方法外， 借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，而膳食是调理菌群的主要途径之一。
有细菌入侵，人体就会发热，这是显而易见的炎症。不过，人体内还保存另一种 “ 温吞水 ” 般的慢性炎症。这要从菌群提及。人体肠道中保存大宗的共生细菌，分为革兰氏阳性菌和革兰氏阴性菌，后者会爆发内毒素，并在菌体死后将其释放进血液。 动物研究发明，高脂肪食物会改变肠道菌群的组成，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应，开启人体中的炎症通道，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，无法举行正常的新陈代谢，肥胖、糖尿病、心血管疾病等代谢性疾病就不请自来了。
菌群的转变是否同样影响着中国人的康健呢？中科院上海生科院营养科学研究所林旭研究员向导的研究团队与上海疾控中心合作，通过在上海社区人群中开展 “ 营养、肠道菌群与肥胖关系的病例 - 比照研究 ” 项目，发明 内毒素的团结卵白与慢性代谢性综合征和 2 型糖尿病亲近相关 。 而内毒素作为一种外源性的诱导物，可能在激活慢性炎症通路和代谢杂乱的爆发历程中起到主要作用 。该论文最近揭晓于权威杂志《糖尿病照顾护士》（ Diabetes Care ）。
在这次大规模人群研究中，科学家发明，肥胖个体中内毒素相关指标比正常体重个体横跨 1.76 倍；并且，血浆中内毒素相关指标高的个体，身体中所有 “ 坏分子 ” 、炎症因子的水平都响应偏高，而对机体有�；ぷ饔玫� “ 好分子 ” 又都偏少。 “ 我们发明血浆中内毒素相关指标的浓度越高，罹患代谢性疾病的危害也越大。 ” 论文主要作者之一、营养所孙亮博士告诉记者，血浆中内毒素相关指标最高组的个体与最低组相比，罹患代谢综合征的危害横跨 2.5 倍、患 2 型糖尿病的危害横跨 4.5 倍！
这项研究首次在国际上通过较大规模的人群研究证实：菌群生物标记物与慢性代谢性疾病保存显著的关联关系。关于通俗人而言，科学家提醒说，平时注重多吃点酸奶、蔬菜，少吃些肉，从菌群调理上说，简直会更有利于康健，在一定水平上镌汰得代谢性疾病的危害。
【点评】
大规模人群研究发明血浆中内毒素相关指标的浓度越高，罹患代谢性疾病的危害也越大，菌群生物标记物与慢性代谢性疾病保存显著的关联关系。调理体内菌群以有利于康健需要改善饮食结构。
【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.