• 【骨髓嵌合体小鼠肿瘤浸润基质细胞的制备及功能分析。】 复制标题 收藏 收藏
    DOI:10.1111/j.1348-0421.2006.tb03830.x 复制DOI
    作者列表:Ishigaki H,Yamamoto Y,Ishida H,Kajino K,Itoh Y,Fujiyama Y,Ogasawara K
    BACKGROUND & AIMS: :Tumor-infiltrating stroma cells (TISC) as well as tumors themselves are thought to be involved in tumor-related immunosuppression, which is one of the critical mechanisms of tumor escape from immune surveillance. However, preparation of TISC is difficult because of the small proportion of TISC in established tumors. Thus, the cells thought to be involved in tumor-related immunosuppression are generally prepared from spleens or draining lymph nodes in tumor-bearing mice. In this study, we developed a method for directly preparing TISC from established tumors in order to analyze their function. Using green fluorescent protein (GFP) transgenic (Tg) mice and C57BL/6 mice transplanted with bone marrow (BM) cells of GFPTg mice, we detected three subpopulations of TISC: one is compatible with immature myeloid cells (ImC) derived from BM and the two other subpopulations, CD11b(+) cells and CD11b(-) cells, do not originate from BM. The TISC including these subpopulations but not each subpopulation independently after culturing with tumors in the presence of GM-CSF could suppress T cell proliferation induced by anti-CD3. In our system, tumors did not inhibit T cell responses directly, but unknown factors from tumors affected immunosuppression by TISC.
    背景与目标: : 肿瘤浸润的基质细胞 (TISC) 以及肿瘤本身被认为与肿瘤相关的免疫抑制有关,这是肿瘤逃避免疫监视的关键机制之一。然而,由于TISC在已建立的肿瘤中的比例较小,因此很难制备TISC。因此,被认为与肿瘤相关的免疫抑制有关的细胞通常是从荷瘤小鼠的脾脏或引流淋巴结中制备的。在这项研究中,我们开发了一种从已建立的肿瘤中直接制备TISC的方法,以分析其功能。使用绿色荧光蛋白 (GFP) 转基因 (Tg) 小鼠和C57BL/6小鼠移植了GFPTg小鼠的骨髓 (BM) 细胞,我们检测到了TISC的三个亚群: 一个与BM衍生的未成熟髓样细胞 (ImC) 相容,另外两个亚群,CD11b(+) 细胞和CD11b(-) 细胞不起源于BM。在gm-csf存在下用肿瘤培养后,包括这些亚群但不是每个亚群的TISC可以抑制anti-CD3诱导的T细胞增殖。在我们的系统中,肿瘤没有直接抑制T细胞反应,但是肿瘤的未知因素会影响TISC的免疫抑制。
  • 【P物质氨基末端代谢物在p物质诱导的小鼠脱敏中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/0306-4522(90)90003-3 复制DOI
    作者列表:Igwe OJ,Sun X,Larson AA
    BACKGROUND & AIMS: :Intrathecal injection of mice with substance P or its C-terminal fragments evokes a well documented behavioral syndrome characterized by caudally-directed biting and scratching. We have previously shown that repeated injections of substance P result in naloxone-sensitive desensitization to this substance P-induced behavior, possibly through interactions of N-terminal fragments of substance P with mu opiate binding sites. The present investigation tests the hypothesis that substance P metabolites play a role in the development of desensitization to substance P by using the biting and scratching behavioral paradigm. While substance P-induced behaviors are produced by as little as 1 pmol of substance P, repeated injections of 7.5 pmol at 60-s intervals was found to be the minimum dose capable of causing desensitization. The C-terminal peptides, substance P3-11 and substance P5-11, elicited substance P-like behaviors, but repeated injection of these compounds did not result in desensitization to this behavior. In contrast to C-terminal fragments, intrathecal injection of N-terminal fragments, (substance P1-4, substance P1-7 and substance P1-9), did not elicit any overt substance P-like behaviors when administered alone, but when co-administered with substance P, decreased the magnitude of substance P-induced behaviors in a dose-related fashion. Various peptidase inhibitors significantly inhibited the catabolism of co-administered substance P. Co-administration of substance P with peptidase inhibitors enhanced and prolonged the substance P-induced behavioral episode, but also prevented the development of substance P-induced desensitization. Together these results support the hypothesis that the accumulation of endogenously generated N-terminal metabolites of substance P mediate desensitization to substance P-induced behaviors in the spinal cord. Substance P metabolism may therefore decrease ongoing substance P activity both by the hydrolysis of the C-terminal portion of substance P as well as by the production of N-terminal metabolites that are capable of inhibiting the effects of substance P.
    背景与目标: : 鞘内注射p物质或其C末端碎片的小鼠会引起一种有据可查的行为综合症,其特征是尾侧指向的咬伤和抓挠。我们先前已经表明,重复注射p物质会导致纳洛酮对该p物质诱导的行为敏感的脱敏,这可能是通过p物质的N末端片段与mu阿片结合位点的相互作用。本研究通过使用咬和刮擦行为范式来检验p物质代谢物在对p物质脱敏过程中起作用的假设。虽然只有1 pmol的p物质产生p物质诱导的行为,但发现以60s间隔重复注射7.5 pmol是能够引起脱敏的最小剂量。C端肽,物质P3-11和物质P5-11引起了物质P样行为,但是反复注射这些化合物并未导致对该行为的脱敏。与C末端片段相反,鞘内注射N末端片段 (物质P1-4,物质P1-7和物质P1-9) 在单独给药时不会引起任何明显的p物质样行为,但与p物质共同给药时,以剂量相关的方式降低p物质诱导的行为的程度。各种肽酶抑制剂可显着抑制共同施用的p物质的分解代谢。P物质与肽酶抑制剂的共同给药可增强和延长p物质诱导的行为发作,但也阻止了p物质诱导的脱敏反应的发展。这些结果共同支持以下假设: p物质的内源性N末端代谢物的积累介导了对p物质诱导的脊髓行为的脱敏。因此,p物质的代谢可能会通过水解p物质的C末端部分以及产生能够抑制p物质作用的N末端代谢物来降低正在进行的p物质活性。
  • 【CD5 (Ly-1) 阴性的常规脾b细胞对CBA和BW小鼠的菠萝蛋白酶斑块形成细胞反应做出了重大贡献。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Andrew EM,Annis W,Kahan M,Maini RN
    BACKGROUND & AIMS: :CD5 (Ly-1) B cells are a minor subpopulation in mouse spleen and are thought to be responsible for the production of natural autoantibodies to bromelain-treated autologous erythrocytes (Br-RBC). Here it is shown that substantial numbers of conventional, CD5-negative, splenic B cells also secrete these antibodies in CBA and (NZB x NZW)F1 mice, whereas in NZB and BALB/c mice they are all produced by the CD5 B-cell population. However, stimulation with bacterial lipopolysaccharide in vivo preferentially activates the CD5 B-cell group to anti-Br-RBC antibody secretion.
    背景与目标: : CD5 (Ly-1) b细胞是小鼠脾脏中的次要亚群,被认为负责产生针对菠萝蛋白酶处理的自体红细胞 (br-rbc) 的天然自身抗体。这里显示大量的常规CD5-negative脾b细胞也在CBA和 (NZB x NZW)F1小鼠中分泌这些抗体,而在NZB和BALB/c小鼠中,它们都是由CD5 b细胞群体产生的。然而,体内用细菌脂多糖刺激优先激活CD5 b细胞组,使其分泌抗br-rbc抗体。
  • 【雌激素过量引起的缺乏1型5α-还原酶的小鼠的胎儿死亡。】 复制标题 收藏 收藏
    DOI:10.1210/mend.11.7.9933 复制DOI
    作者列表:Mahendroo MS,Cala KM,Landrum DP,Russell DW
    BACKGROUND & AIMS: :Female mice deficient in steroid 5alpha-reductase type 1 have a decreased litter size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0 pups in wild type controls. Oogenesis, fertilization, implantation, and placental morphology appear normal in the mutant animals. Fetal loss occurs between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in placental androgen production and an induction of 5alpha-reductase type 1 expression in the decidua of wild type mice. Plasma levels of androstenedione and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol levels are chronically elevated by 2- to 3-fold throughout early and midgestation in the knockout mice. Administration of an estrogen receptor antagonist or inhibitors of aromatase reverse the high rate of fetal death in the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal wastage. The results suggest that in the deficient mice, a failure to 5alpha-reduce androgens leads to their conversion to estrogens, which in turn causes fetal death in midgestation. These findings indicate that the 5alpha-reduction of androgens in female animals plays a crucial role in guarding against estrogen toxicity during pregnancy.
    背景与目标: : 缺乏类固醇5α-还原酶1型的雌性小鼠的产仔数减少。纯合缺陷雌性的平均产仔为2.7幼仔,而野生型对照为8.0幼仔。在突变动物中,卵子发生,受精,植入和胎盘形态似乎正常。胎儿损失发生在妊娠10.75和11.0之间,与妊娠中期胎盘雄激素产生激增和野生型小鼠蜕膜中5α-还原酶1型表达的诱导相称。在妊娠第9天,雄烯二酮和睾丸激素的血浆水平高2至3倍,在整个妊娠早期和中期,敲除小鼠的雌二醇水平长期升高2至3倍。施用雌激素受体拮抗剂或芳香化酶抑制剂可逆转突变小鼠的高胎儿死亡率,而雌二醇处理野生型妊娠小鼠会导致胎儿浪费。结果表明,在缺陷小鼠中,未能减少5α-雄激素会导致其转化为雌激素,进而导致妊娠中期胎儿死亡。这些发现表明,雌性动物中雄激素的5α 减少在预防怀孕期间的雌激素毒性中起着至关重要的作用。
  • 【激素难治性乳腺癌的治疗: 植入小鼠的人类肿瘤的凋亡和消退。】 复制标题 收藏 收藏
    DOI:10.1158/1535-7163.MCT-06-0205 复制DOI
    作者列表:Aneja R,Zhou J,Zhou B,Chandra R,Joshi HC
    BACKGROUND & AIMS: :Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.
    背景与目标: : 手术后,尽管偶尔会出现激素抗性克隆,但使用他莫昔芬等拮抗剂来治疗乳腺肿瘤的激素依赖性。另一种化疗策略使用微管抑制剂,如紫杉烷。不幸的是,这些药物会引起毒性,例如白细胞减少,腹泻,脱发和周围神经病变,并且还与耐药性的出现有关。我们先前已经描述了一种微管蛋白结合的天然化合物noscapine,它是无毒的,并在许多癌症类型中触发了凋亡,尽管浓度为10 mumol/L或更高,具体取决于细胞类型。我们现在显示,在激素不敏感的人类乳腺癌 (MDA-MB-231) 中,诺司卡平的合成类似物9-溴单司卡平在抑制细胞增殖和诱导G2-M停滞后的凋亡方面比诺司卡平有效约10倍至15倍。此外,线粒体膜电位的明显丧失,细胞色素c的释放,末端caspase-3的激活以及其底物 (例如聚 (ADP-核糖) 聚合酶) 的裂解提示了内在的凋亡机制。综合起来,这些数据指出了激素不敏感的乳腺癌细胞的线粒体介导的凋亡。裸鼠的人类肿瘤异种移植物显示出显着的肿瘤体积减少和寿命的惊人增加,而没有明显的毒性迹象。因此,我们的数据提供了令人信服的证据,证明9-溴单可用于激素难治性乳腺癌的治疗。
  • 【肥胖和糖尿病突变小鼠胰腺和垂体中的神经肽含量: 品系和性别差异。】 复制标题 收藏 收藏
    DOI:10.1016/0026-0495(90)90252-8 复制DOI
    作者列表:Timmers K,Coleman DL,Voyles NR,Powell AM,Rökaeus A,Recant L
    BACKGROUND & AIMS: :The nature of the primary genetic defects in ob/ob and db/db mice are unknown. Both the obese (ob) and diabetes (db) mutations produce similar, multicomponent obese-hyperinsulinemic syndromes when maintained in the same strain of mouse. In an attempt to find differences between these mutations in neuroendocrine function affecting the islets of Langerhans or the pituitary, tissue content of four neuropeptides that are known to be capable of influencing the rate of insulin secretion was examined in obese (ob/ob) and diabetes (db/db) mice. In the first study, C57BL/6Job/ob and control males were studied at 3, 4, and 11 weeks of age. In the second study, db/db mice of both sexes and two inbred strains (C57BL/6J and C57BL/KsJ), which differ markedly in the severity of expression of the diabetes phenotype, were studied at 3 weeks of age, before the development of hyperglycemia and secondary consequences thereof. Immunoreactive peptides were measured in acetic acid extracts of pancreas and pituitary. No differences between male ob/ob and db/db mice of the C57BL/6J strain were found. Marked sex differences in lean control mice were found at 3 weeks of age in pancreatic Met-enkephalin-LI and galanin-LI (with two- to threefold higher content in males). Low pancreatic content (50% to 70% lower than in control mice) of galanin-LI, Met-enkephalin-LI and Leu-enkephalin-LI was associated with hyperinsulinemia in male B6 ob/ob and db/db mice at 3 weeks of age, though not in B6 db/db females and not in BKs db/db mice of either sex.(ABSTRACT TRUNCATED AT 250 WORDS)
    背景与目标: : ob/ob和db/db小鼠的主要遗传缺陷的性质未知。当维持在相同的小鼠品系中时,肥胖 (ob) 和糖尿病 (db) 突变都会产生相似的多成分肥胖-高胰岛素血症综合征。为了寻找影响朗格汉斯或垂体胰岛的神经内分泌功能的这些突变之间的差异,在肥胖 (ob/ob) 和糖尿病 (db/db) 小鼠中检查了四种已知能够影响胰岛素分泌速率的神经肽的组织含量。在第一项研究中,在3、4和11周龄对C57BL/6Job/ob和对照男性进行了研究。在第二项研究中,研究了两种性别和两种近交系 (C57BL/6J和C57BL/KsJ) 的db/db小鼠,它们在糖尿病表型表达的严重程度上明显不同,在3周龄之前发生高血糖及其继发后果。在胰腺和垂体的乙酸提取物中测量了免疫反应性肽。在C57BL/6J品系的雄性ob/ob和db/db小鼠之间没有发现差异。在3周龄时,在胰腺Met-脑啡肽-LI和galanin-LI中发现瘦对照小鼠的明显性别差异 (男性含量高2至3倍)。galanin-LI,Met-脑啡肽-LI和Leu-脑啡肽-LI的低胰腺含量 (50% 70% 低于对照小鼠) 与3周龄雄性B6 ob/ob和db/db小鼠的高胰岛素血症有关,虽然不是在B6 db/db雌性中,也不是在BKs db/db小鼠中。(摘要截断在250个单词)
  • 【正常小鼠和早发性感光营养不良杂合子的视网膜中的循环GMP。】 复制标题 收藏 收藏
    DOI:10.1016/0014-4835(85)90094-6 复制DOI
    作者列表:Doshi M,Voaden MJ,Arden GB
    BACKGROUND & AIMS: :Cyclic GMP metabolism has been investigated in the retinas of mice that are heterozygous for a 'photoreceptor dystrophy' gene and have a lowered concentration of cGMP in their photoreceptor cells. The concentration of rhodopsin, retinal morphology and guanylate cyclase kinetics were normal. Cyclic GMP phosphodiesterase had a lowered affinity for cGMP. In accord with previous observations, chelation of exogenous calcium had no effect on cGMP levels in light-adapted retinas but increased them in dark-adapted tissue. The difference between cGMP concentrations in heterozygous and normal retinas in the dark was then eliminated. It was concluded that a modulator of cGMP phosphodiesterase activity is most likely to be causing the lowered steady-state level of cGMP in heterozygous retinas and that calcium is not involved.
    背景与目标: : 已经在 “感光细胞营养不良” 基因杂合的小鼠视网膜中研究了循环GMP代谢,并且其感光细胞中cGMP的浓度降低。视紫红质浓度、视网膜形态和鸟苷酸环化酶动力学均正常。环状GMP磷酸二酯酶对cGMP的亲和力降低。与先前的观察结果一致,外源钙的螯合对光适应视网膜中的cGMP水平没有影响,但在暗适应组织中却增加了cGMP水平。然后消除了黑暗中杂合视网膜和正常视网膜中cGMP浓度之间的差异。结论是,cGMP磷酸二酯酶活性的调节剂最有可能导致杂合视网膜中cGMP的稳态水平降低,并且不涉及钙。
  • 【缺乏连接蛋白的小鼠没有静脉瓣37。】 复制标题 收藏 收藏
    DOI:10.1016/j.ydbio.2012.10.032 复制DOI
    作者列表:Munger SJ,Kanady JD,Simon AM
    BACKGROUND & AIMS: :Venous valves play a crucial role in blood circulation, promoting the one-way movement of blood from superficial and deep veins towards the heart. By preventing retrograde flow, venous valves spare capillaries and venules from being subjected to damaging elevations in pressure, especially during skeletal muscle contraction. Pathologically, valvular incompetence or absence of valves are common features of venous disorders such as chronic venous insufficiency and varicose veins. The underlying causes of these conditions are not well understood, but congenital venous valve aplasia or agenesis may play a role in some cases. Despite progress in the study of cardiac and lymphatic valve morphogenesis, the molecular mechanisms controlling the development and maintenance of venous valves remain poorly understood. Here, we show that in valved veins of the mouse, three gap junction proteins (Connexins, Cxs), Cx37, Cx43, and Cx47, are expressed exclusively in the valves in a highly polarized fashion, with Cx43 on the upstream side of the valve leaflet and Cx37 on the downstream side. Surprisingly, Cx43 expression is strongly induced in the non-valve venous endothelium in superficial veins following wounding of the overlying skin. Moreover, we show that in Cx37-deficient mice, venous valves are entirely absent. Thus, Cx37, a protein involved in cell-cell communication, is one of only a few proteins identified so far as critical for the development or maintenance of venous valves. Because Cxs are necessary for the development of valves in lymphatic vessels as well, our results support the notion of common molecular pathways controlling valve development in veins and lymphatic vessels.
    背景与目标: : 静脉瓣膜在血液循环中起着至关重要的作用,促进血液从浅静脉和深静脉向心脏的单向运动。通过防止逆行血流,静脉瓣膜备用毛细血管和小静脉不会受到破坏性的压力升高,尤其是在骨骼肌收缩期间。从病理上讲,瓣膜功能不全或瓣膜缺失是静脉疾病的常见特征,例如慢性静脉功能不全和静脉曲张。这些疾病的根本原因尚不清楚,但在某些情况下,先天性静脉瓣膜发育不全或发育不全可能起一定作用。尽管心脏和淋巴管瓣膜形态发生的研究取得了进展,但控制静脉瓣膜发育和维持的分子机制仍知之甚少。在这里,我们显示在小鼠的瓣膜静脉中,三种间隙连接蛋白 (Connexins,Cxs) Cx37,Cx43和Cx47仅在瓣膜中以高度极化的方式表达,其中Cx43位于瓣膜的上游侧小叶和Cx37位于下游侧。令人惊讶的是,上覆皮肤受伤后,在浅静脉的非瓣膜静脉内皮中强烈诱导Cx43表达。此外,我们显示在Cx37-deficient小鼠中,静脉瓣膜完全不存在。因此,Cx37是一种参与细胞-细胞通讯的蛋白质,是迄今为止确定的对静脉瓣膜的发育或维持至关重要的少数蛋白质之一。由于Cxs对于淋巴管中瓣膜的发育也是必需的,因此我们的结果支持控制静脉和淋巴管中瓣膜发育的常见分子途径的概念。
  • 【通过选择性阻断cd28预防NZB/NZW小鼠狼疮性肾炎的发展。】 复制标题 收藏 收藏
    DOI:10.1002/eji.201746923 复制DOI
    作者列表:Laurent L,Le Fur A,Bloas RL,Néel M,Mary C,Moreau A,Poirier N,Vanhove B,Fakhouri F
    BACKGROUND & AIMS: :Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.
    背景与目标: 系统性红斑狼疮 (SLE) 是一种慢性全身性炎症性疾病。抗狼疮标志双链DNA (ds DNA) 的自身抗体 (autoAbs) 是通过自身反应性b细胞和CD4 T细胞之间的相互作用产生和维持的。该相互作用由CD28/CD80-86/CTLA-4轴控制。在这里,我们研究了在SLE的鼠模型中,选择性阻断CD28-CD80/86共刺激相互作用是否可以缓解狼疮性肾炎的发展。为此,用anti-CD28 Fab' 片段或对照Fab'-IgG处理NZB/nzwf1小鼠3个月。评估了CD28阻断对狼疮性肾炎发作,存活,抗ds DNA抗体和共刺激分子产生的影响。CD28阻断可防止狼疮性肾炎的发展,并在3个月的治疗和12周后延长生存期。此外,抗ds DNA autoAbs的产生减少了。最后,CD28阻断的保护作用与免疫调节分子吲哚胺2,3-双加氧酶,共抑制性受体程序性细胞死亡-1 (PD-1) 及其配体程序性死亡配体-1 (PDL-1) 的肾内表达增加有关。总之,CD28阻断阻止了NZB/NZW F1小鼠狼疮性肾炎的发展。这种免疫调节策略是人类SLE治疗的有希望的候选者。
  • 【牛樟芝可减少高脂饮食喂养小鼠的肥胖并调节肠道菌群。】 复制标题 收藏 收藏
    DOI:10.1038/ijo.2017.149 复制DOI
    作者列表:Chang CJ,Lu CC,Lin CS,Martel J,Ko YF,Ojcius DM,Wu TR,Tsai YH,Yeh TS,Lu JJ,Lai HC,Young JD
    BACKGROUND & AIMS: BACKGROUND:Obesity is associated with gut microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Given the high and increasing prevalence of obesity worldwide, anti-obesity treatments that are safe, effective and widely available would be beneficial. We examined whether the medicinal mushroom Antrodia cinnamomea may reduce obesity in mice fed with a high-fat diet (HFD). METHODS:Male C57BL/6J mice were fed a HFD for 8 weeks to induce obesity and chronic inflammation. The mice were treated with a water extract of A. cinnamomea (WEAC), and body weight, fat accumulation, inflammation markers, insulin sensitivity and the gut microbiota were monitored. RESULTS:After 8 weeks, the mean body weight of HFD-fed mice was 39.8±1.2 g compared with 35.8±1.3 g for the HFD+1% WEAC group, corresponding to a reduction of 4 g or 10% of body weight (P<0.0001). WEAC supplementation reduced fat accumulation and serum triglycerides in a statistically significant manner in HFD-fed mice. WEAC also reversed the effects of HFD on inflammation markers (interleukin-1β, interleukin-6, tumor necrosis factor-α), insulin resistance and adipokine production (leptin and adiponectin). Notably, WEAC increased the expression of intestinal tight junctions (zonula occludens-1 and occludin) and antimicrobial proteins (Reg3g and lysozyme C) in the small intestine, leading to reduced blood endotoxemia. Finally, WEAC modulated the composition of the gut microbiota, reducing the Firmicutes/Bacteroidetes ratio and increasing the level of Akkermansia muciniphila and other bacterial species associated with anti-inflammatory properties. CONCLUSIONS:Supplementation with A. cinnamomea produces anti-obesogenic, anti-inflammatory and antidiabetic effects in HFD-fed mice by maintaining intestinal integrity and modulating the gut microbiota.
    背景与目标:
  • 【B-1a细胞保护小鼠免受脓毒症: CREB的关键作用。】 复制标题 收藏 收藏
    DOI:10.4049/jimmunol.1602056 复制DOI
    作者列表:Aziz M,Holodick NE,Rothstein TL,Wang P
    BACKGROUND & AIMS: :Bacterial sepsis is a serious life-threatening condition caused by an excessive immune response to infection. B-1 cells differ from conventional B-2 cells by their distinct phenotype and function. A subset of B-1 cells expressing CD5, known as B-1a cells, exhibits innate immune activity. Here we report that B-1a cells play a beneficial role in sepsis by mitigating exaggerated inflammation through a novel mechanism. Using a mouse model of bacterial sepsis, we found that the numbers of B-1a cells in various anatomical locations were significantly decreased. Adoptive transfer of B-1a cells into septic mice significantly attenuated systemic inflammation and improved survival, whereas B-1a cell-deficient CD19-/- mice were more susceptible to infectious inflammation and mortality. We also demonstrated B-1a cells produced ample amounts of IL-10 which controlled excessive inflammation and the mice treated with IL-10-deficient B-1a cells were not protected against sepsis. Moreover, we identified a novel intracellular signaling molecule, cAMP-response element binding protein (CREB), which serves as a pivotal transcription factor for upregulating IL-10 production by B-1a cells in sepsis through its nuclear translocation and binding to putative responsive elements on IL-10 promoter. Thus, the benefit of B-1a cells in bacterial sepsis is mediated by CREB and the identification of CREB in B-1a cells reveals a potential avenue for treatment in bacterial sepsis.
    背景与目标: : 细菌性败血症是由于对感染的过度免疫反应而引起的严重威胁生命的疾病。B-1细胞与常规B-2细胞的区别在于其独特的表型和功能。表达CD5的B-1细胞的子集 (称为B-1a细胞) 表现出先天免疫活性。在这里,我们报告B-1a细胞通过一种新的机制减轻过度的炎症在败血症中发挥有益的作用。使用细菌败血症的小鼠模型,我们发现不同解剖位置的B-1a细胞数量显着减少。将B-1a细胞过继转移至脓毒症小鼠可显著减轻全身性炎症并改善存活率,而B-1a细胞缺陷型CD19-/-小鼠更容易感染感染性炎症和死亡率。我们还证明了B-1a细胞产生足够量的控制过度炎症的IL-10,并且用IL-10-deficient B-1a细胞处理的小鼠不能防止败血症。此外,我们鉴定了一种新的细胞内信号分子,cAMP反应元件结合蛋白 (CREB),它是脓毒症中B-1a细胞通过其核易位和与IL-10启动子上推定的反应元件结合而上调IL-10产生的关键转录因子。因此,细菌败血症中B-1a细胞的益处由CREB介导,并且B-1a细胞中CREB的鉴定揭示了治疗细菌败血症的潜在途径。
  • 【用重组亚单位或DNA疫苗递送的猪肺炎支原体抗原P37,P42,P46和P95免疫小鼠。】 复制标题 收藏 收藏
    DOI:10.1016/j.vaccine.2012.10.088 复制DOI
    作者列表:Galli V,Simionatto S,Marchioro SB,Fisch A,Gomes CK,Conceição FR,Dellagostin OA
    BACKGROUND & AIMS: :Porcine enzootic pneumonia (PEP), which is caused by the fastidious bacterium Mycoplasma hyopneumoniae, is one of the most economically important diseases in the pig industry worldwide. Commercial bacterins provide only partial protection; therefore, the development of more efficient vaccines against PEP is necessary. In this study, the cellular and humoral immune responses elicited by DNA and recombinant subunit vaccines based on the P37, P42, P46 and P95 antigens of M. hyopneumoniae were evaluated after the intramuscular inoculation of BALB/c mice. The expression of the cytokines INFγ, TNFα and IL1 was evaluated by real-time RT-PCR in splenocytes from vaccinated mice. All antigens delivered as subunit vaccines, especially P42 and P95, and the pcDNA3/P46 DNA vaccine were able to elicit strong immune responses. These vaccines induced cellular immune responses and the production of antibodies able to react with native M. hyopneumoniae proteins. Because both cellular and humoral immune responses were induced, P42 and P95 are promising candidates for a recombinant subunit vaccine and P46 is a promising candidate for a DNA vaccine against PEP.
    背景与目标: : 猪传染性肺炎 (PEP) 是由挑剔的细菌支原体肺炎e引起的,是全球养猪业最重要的经济疾病之一。商业细菌仅提供部分保护; 因此,必须开发针对PEP的更有效疫苗。在这项研究中,在肌内接种BALB/c小鼠后,评估了基于猪肺炎支原体P37,P42,P46和P95抗原的DNA和重组亚基疫苗引起的细胞和体液免疫反应。通过实时rt-pcr评估了免疫小鼠脾细胞中细胞因子inf γ,tnf α 和IL1的表达。作为亚单位疫苗递送的所有抗原,尤其是P42和P95,以及pcDNA3/P46 DNA疫苗能够引发强烈的免疫反应。这些疫苗可诱导细胞免疫反应,并产生能够与天然猪肺炎支原体蛋白反应的抗体。由于诱导了细胞和体液免疫反应,因此P42和P95是重组亚单位疫苗的有希望的候选者,而P46是针对PEP的DNA疫苗的有希望的候选者。
  • 【p21-activated激酶1的耗竭会上调APC∆ 14/小鼠的免疫系统并抑制肠道肿瘤的发生。】 复制标题 收藏 收藏
    DOI:10.1186/s12885-017-3432-0 复制DOI
    作者列表:Huynh N,Wang K,Yim M,Dumesny CJ,Sandrin MS,Baldwin GS,Nikfarjam M,He H
    BACKGROUND & AIMS: BACKGROUND:P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC∆14/+ mice. METHODS:The PAK1 KO APC∆14/+ mice were generated by cross-breeding of PAK1 KO mice with APC∆14/+ mice. Splenic lymphocytes were analysed by flow cytometry, and immunohistochemical staining. The numbers of intestinal tumours were counted. Blood cells were also counted. RESULTS:Compared to APC+/+ mice, the numbers of both T- and B- lymphocytes were reduced in the spleen of APC∆14/+ mice. Depletion of PAK1 in APC∆14/+ mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC∆14/+ mice with PF-3758309, a PAK inhibitor reduced the numbers of intestinal tumours and increased the numbers of blood lymphocytes. CONCLUSION:Depletion of active PAK1 up-regulates the immune system of APC∆14/+ mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.
    背景与目标:
  • 【当归可改善东莨菪碱诱导的小鼠记忆障碍。】 复制标题 收藏 收藏
    DOI:10.1248/bpb.b12-00681 复制DOI
    作者列表:Oh SR,Kim SJ,Kim DH,Ryu JH,Ahn EM,Jung JW
    BACKGROUND & AIMS: :Memory impairment is the most common symptom in patients with Alzheimer's disease (AD). Angelica keiskei (AK) has traditionally been used as a diuretic, laxative, analeptic and galactagogue. However, the anti-amnesic effects of AK and its molecular mechanisms have yet to be clearly elucidated. The aim of the present study is to evaluate the effects of AK on scopolamine-induced memory impairments in mice. The regulatory effect of AK on memory impairment was investigated using passive avoidance, Y-maze and the Morris water maze tasks. Acetylcholinesterase (AChE) activity assay was performed to investigate the cholinergic antagonistic effect of AK in the hippocampus. The effect of AK on phosphorylation of cAMP response element-binding protein (CREB) and expression of brain-derived neurotrophic factor (BDNF) were evaluated by Western blot assays and immunohistochemistry. The findings showed that AK significantly attenuated scopolamine-induced cognitive impairment in mice. Increase of AChE activity caused by scopolamine was significantly attenuated by AK. Additionally, AK significantly recovered the phosphorylation of CREB and expression of BDNF reduced by scopolamine in the hippocampus. Taken together, these results provide experimental evidence that AK might be a useful agent in preventing deficit of learning and memory caused by AD and aging.
    背景与目标: : 记忆障碍是阿尔茨海默病 (AD) 患者最常见的症状。传统上,当归 (AK) 被用作利尿剂,泻药,反作用剂和半乳糖剂。然而,AK的抗遗忘作用及其分子机制尚未明确阐明。本研究的目的是评估AK对东pol碱诱导的小鼠记忆障碍的影响。使用被动回避,Y迷宫和莫里斯水迷宫任务研究了AK对记忆障碍的调节作用。进行乙酰胆碱酯酶 (AChE) 活性测定以研究AK在海马中的胆碱能拮抗作用。通过Western blot法和免疫组织化学方法评估了AK对cAMP反应元件结合蛋白 (CREB) 磷酸化和脑源性神经营养因子 (BDNF) 表达的影响。研究结果表明,AK可显着减轻东莨菪碱引起的小鼠认知障碍。东莨菪碱引起的AChE活性增加被AK显著减弱。此外,AK显着恢复了东pol碱在海马中CREB的磷酸化和BDNF的表达。总之,这些结果提供了实验证据,证明AK可能是防止AD和衰老引起的学习和记忆缺陷的有用手段。
  • 【高山姜通过调节脂肪生成和脂肪生成抑制小鼠脂肪细胞分化和高脂饮食诱导的肥胖。】 复制标题 收藏 收藏
    DOI:10.1089/jmf.2012.2286 复制DOI
    作者列表:Jung CH,Jang SJ,Ahn J,Gwon SY,Jeon TI,Kim TW,Ha TY
    BACKGROUND & AIMS: :Although Alpinia officinarum has been used in traditional medicine for the treatment of several conditions, such as abdominal pain, emesis, diarrhea, impaired renal function, and dysentery, little is known about its function in obesity. In this study, we investigated the antiobesity effect of A. officinarum ethanol extract (AOE) on lipid accumulation in 3T3-L1 cells and obesity in mice fed a high-fat diet (HFD). AOE dose-dependently suppressed lipid accumulation during differentiation of 3T3-L1 preadipocytes by downregulating CCAAT enhancer binding protein α (C/EBPα), sterol regulatory element binding protein-1 (SREBP-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) genes. Galangin, a major component of A. officinarum, had antiadipogenic effects in 3T3-L1 cells. AOE supplementation in mice fed a HFD revealed that AOE significantly decreased HFD-induced increases in body, liver, and white adipose tissue weights and decreased serum insulin and leptin levels. To elucidate the inhibitory mechanism of AOE in obesity, lipid metabolism-related genes were identified. AOE efficiently suppressed protein expressions of C/EBPα, fatty acid synthase, SREBP-1, and PPAR-γ in the liver and adipose tissue. The protein expression patterns, observed by immunoblot, were confirmed by quantitative real-time polymerase chain reaction. Collectively, these results suggest that AOE prevents obesity by suppressing adipogenic and lipogenic genes. AOE has potential for use as an antiobesity therapeutic agent that can function by regulating lipid metabolism.
    背景与目标: : 尽管高山姜已在传统医学中用于治疗多种疾病,例如腹痛,呕吐,腹泻,肾功能受损和痢疾,但对其在肥胖症中的功能知之甚少。在这项研究中,我们研究了A. officinarum乙醇提取物 (AOE) 对高脂饮食 (HFD) 小鼠3T3-L1细胞脂质积累和肥胖的抗肥胖作用。AOE通过下调CCAAT增强子结合蛋白 α (C/ebp α),固醇调节元件结合蛋白1 (SREBP-1) 和过氧化物酶体增殖物激活受体-γ (PPAR-γ) 基因,剂量依赖性地抑制3T3-L1前脂肪细胞分化过程中的脂质积累。高良姜是a.officinarum的主要成分,在3T3-L1细胞中具有抗脂肪作用。在喂食HFD的小鼠中补充AOE表明,AOE显着降低了HFD诱导的身体,肝脏和白色脂肪组织重量的增加,并降低了血清胰岛素和瘦素水平。为了阐明AOE对肥胖的抑制机制,确定了脂质代谢相关基因。AOE可有效抑制肝脏和脂肪组织中C/ebp α,脂肪酸合酶,SREBP-1和PPAR-γ 的蛋白表达。通过定量实时聚合酶链反应证实了通过免疫印迹观察到的蛋白质表达模式。总的来说,这些结果表明AOE通过抑制成脂和生脂基因来预防肥胖。AOE具有用作抗肥胖治疗剂的潜力,可以通过调节脂质代谢来发挥作用。

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