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，被认为负责产生与菠萝蛋白酶处理的自体红细胞（Br-RBC）的天然自身抗体。在此表明，大量常规的CD5阴性脾脏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细胞产生的人口。但是，在体内用细菌脂多糖刺激可优先激活CD5 B细胞基团以分泌抗Br-RBC抗体。

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1型甾体5α-还原酶的雌性小鼠的窝产仔数减少。纯合缺陷型雌性的平均产仔数为2.7头，而野生型对照为8.0头。在突变动物中，卵子发生，受精，着床和胎盘形态正常。胎儿丢失发生在妊娠10.75至11.0天之间，与胎盘雄激素产生的中期妊娠激增和野生型小鼠蜕膜中5α-还原酶1型表达的诱导相称。在淘汰的第9天，雄烯二酮和睾丸激素的血浆水平升高了2至3倍，而在早期和中期妊娠期，雌二醇水平长期升高了2至3倍。在突变小鼠中，雌激素受体拮抗剂或芳香化酶抑制剂的使用可以逆转高死亡率的胎儿死亡，而雌二醇治疗野生型妊娠小鼠会造成胎儿的浪费。结果表明，在缺陷小鼠中，未能通过5α-还原雄激素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，雌性动物体内雄激素的5α-还原在预防妊娠期雌激素毒性中起着至关重要的作用。

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，尽管偶尔出现激素抵抗性克隆，但利用他莫昔芬等拮抗剂开发了乳腺肿瘤的激素依赖性疗法。另一种化学治疗策略是使用微管抑制剂，例如紫杉烷类。不幸的是，这些药物引起毒性，例如白细胞减少，腹泻，脱发和周围神经病，并且还与耐药性的出现有关。先前我们已经描述了微管蛋白结合的天然化合物Noscapine，尽管在10μmol/ L或更高的浓度（取决于细胞类型）下，但在许多类型的癌症中均无毒并引发细胞凋亡。我们现在显示，Noscapine的合成类似物9-bromonoscapine在抑制细胞增殖方面比Noscapine的效力高约10倍至15倍，并在激素不敏感的人类乳腺癌（MDA-MB -231）。此外，线粒体膜电位的明显损失，细胞色素c的释放，末端caspase-3的活化以及其底物（如聚（ADP-核糖）聚合酶）的裂解表明了内在的凋亡机制。综上所述，这些数据表明了激素不敏感的乳腺癌细胞由线粒体介导的凋亡。裸鼠中的人类肿瘤异种移植物显示出明显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，表明9-溴莫可可碱可用于治疗激素难治性乳腺癌。

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尚不清楚。肥胖（ob）和糖尿病（db）突变在同一小鼠品系中均会产生相似的多成分肥胖-高胰岛素血症综合征。为了发现影响兰格罕氏岛或垂体胰岛的神经内分泌功能的这些突变之间的差异，在肥胖和肥胖（ob / ob）和糖尿病患者中，对四种已知能够影响胰岛素分泌速率的神经肽的组织含量进行了检查。 （db / db）小鼠。在第一个研究中，研究了C57BL / 6Job / ob和对照男性在3、4和11周的年龄。在第二项研究中，在发育前的3周龄研究了性别和两种自交系（C57BL / 6J和C57BL / KsJ）的db / db小鼠，它们在糖尿病表型的表达严重程度上有显着差异。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株的雄性ob / ob和db / db小鼠之间未发现差异。在瘦瘦对照小鼠中，在三周龄的胰腺Met-脑啡肽-LI和甘丙肽-LI中发现明显的性别差异（雄性含量高2至3倍）。在3周龄的雄性B6 ob / ob和db / db小鼠中，甘丙肽-LI，Met-脑啡肽-LI和亮-脑啡肽-LI的胰腺含量低（比对照小鼠低50％至70％）与高胰岛素血症相关。年龄，但不是在B6 db / db雌性中，也不是在BK s db / db两种性别的小鼠中。（摘要以250字截断）

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： ：已经对小鼠视网膜中的循环GMP代谢进行了研究，这些小鼠对于“感光器营养不良”基因是杂合的，并且其感光细胞中cGMP的浓度降低。视紫红质的浓度，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的亲和力较低。与以前的观察结果一致，外源钙的螯合对光适应性视网膜中cGMP的含量没有影响，但在黑暗适应性组织中却增加了。然后消除了黑暗中杂合子和正常视网膜中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性视网膜中cGMP的稳态水平降低，并且不涉及钙。

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关键作用，促进血液从浅静脉和深静脉向心脏的单向运动。通过防止逆行流动，静脉瓣膜避免了毛细管和小静脉受到破坏性的压力升高，尤其是在骨骼肌收缩期间。病理上，瓣膜功能不全或瓣膜缺失是静脉疾病（例如慢性静脉功能不全和静脉曲张）的常见特征。这些情况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作用。尽管在心脏和淋巴瓣形态发生的研究方面取得了进展，但控制静脉瓣的发育和维持的分子机制仍知之甚少。在这里，我们显示在小鼠的带瓣静脉中，三种间隙连接蛋白（Connexins，Cxs），Cx37，Cx43和Cx47仅以高度极化的方式在瓣膜中表达，而Cx43在瓣膜的上游侧小叶和Cx37在下游侧。出人意料的是，在上层皮肤受伤之后，在浅静脉中的非瓣膜静脉内皮中强烈诱导了Cx43表达。此外，我们显示在Cx37缺陷小鼠中，完全没有静脉瓣膜。因此，Cx37是一种参与细胞-细胞通讯的蛋白质，是目前鉴定出的对静脉瓣膜的形成或维持至关重要的少数几种蛋白质之一。由于Cx也是淋巴管内瓣膜发育所必需的，因此我们的研究结果支持了控制静脉和淋巴管内瓣膜发育的常见分子途径的概念。

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。通过自身反应性B细胞和CD4 T细胞之间的相互作用来产生和维持针对双链DNA（ds DNA）（狼疮的标志）的自身抗体（autoAbs）。这种相互作用是由CD28 / CD80-86 / CTLA-4轴控制的。在这里，我们研究了CD28-CD80 / 86共刺激相互作用的选择性阻断是否消除了狼疮性肾炎在SLE鼠模型中的发展。为了这个目的，将NZB / NZW F1小鼠用抗CD28 Fab'片段或对照Fab'-IgG治疗3个月。评估了CD28阻断对狼疮肾炎发作，生存，抗ds DNA抗体产生和共刺激分子的影响。 CD28阻断可防止狼疮性肾炎的发生，并在3个月的治疗期间和12周后延长生存期。此外，抗ds DNA autoAb的产生减少。最后，CD28阻断的保护作用与免疫调节分子吲哚胺2、3-二加氧酶，共抑制受体编程的细胞死亡-1（PD-1）及其配体编程的死亡配体的肾内表达增加有关。 -1（PDL-1）。总之，CD28阻断可预防NZB / NZW F1小鼠的狼疮性肾炎。这种免疫调节策略是人类SLE治疗的有希望的候选者。

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： 背景：肥胖症与肠道菌群失调，肠壁屏障破坏和慢性炎症有关。鉴于世界范围内肥胖症的发病率不断上升，安全，有效和广泛使用的抗肥胖症治疗方法将是有益的。我们检查了药用蘑菇牛樟芝是否可以减少高脂饮食（HFD）喂养的小鼠的肥胖。
方法：雄性C57BL / 6J小鼠被喂食HFD 8周，以诱导肥胖和慢性炎症。用肉桂曲霉（WEAC）的水提取物治疗小鼠，并监测体重，脂肪堆积，炎症标志物，胰岛素敏感性和肠道菌群。
结果：8周后，喂食HFD的小鼠的平均体重为39.8±1.2 g，而喂食1％WEAC的HFD组的平均体重为35.8±1.3 g，相当于减少了4 g或体重的10％（P < 0.0001）。在HFD喂养的小鼠中，WEAC补充剂以统计学上显着的方式减少了脂肪积累和血清甘油三酯。 WEAC还逆转了HFD对炎症标志物（白介素-1β，白介素-6，肿瘤坏死因子-α），胰岛素抵抗和脂肪因子产生（瘦素和脂联素）的影响。值得注意的是，WEAC增加了小肠中肠紧密连接（小肠闭合带1和闭合蛋白）和抗菌蛋白（Reg3g和溶菌酶C）的表达，从而降低了血液内毒素血症。最后，WEAC调节了肠道菌群的组成，降低了Firmicutes / Bacteroidetes的比例，并增加了Akkermansia muciniphila和其他与抗炎特性相关的细菌的水平。
结论：补充肉桂曲霉可通过维持肠道完整性和调节肠道菌群，在喂食HFD的小鼠中产生抗肥胖，抗炎和抗糖尿病作用。

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： 细菌败血症是一种严重的威胁生命的疾病，由对感染的过度免疫反应引起。 B-1细胞与常规B-2细胞的不同表型和功能不同。表达CD5的B-1细胞子集（称为B-1a细胞）表现出先天免疫活性。在这里，我们报告B-1a细胞通过新型机制缓解过度的炎症反应，在败血症中发挥有益作用。使用细菌性脓毒症的小鼠模型，我们发现各个解剖位置的B-1a细胞数量均明显减少。 B-1a细胞过继转移到败血性小鼠中可显着减轻全身性炎症并提高生存率，而B-1a细胞缺陷型CD19-/-小鼠更易感染传染性炎症和死亡。我们还证明了B-1a细胞产生了大量的IL-10，可控制过度的炎症，并且用IL-10-10缺乏的B-1a细胞治疗的小鼠没有败血症的保护。此外，我们鉴定了一种新型的细胞内信号分子cAMP反应元件结合蛋白（CREB），它是关键的转录因子，可通过其核易位并与假定的反应元件结合来上调脓毒症中B-1a细胞的IL-10产生。在IL-10启动子上。因此，B-1a细胞在细菌性败血症中的益处是由CREB介导的，B-1a细胞中CREB的鉴定揭示了在细菌性败血症中治疗的潜在途径。

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）是由细菌性猪肺炎支原体（Mycoplasma hyopneumoniae）引起的，是全球养猪业中最重要的经济疾病之一。商业细菌仅提供部分保护；因此，有必要开发出更有效的抗PEP疫苗。在这项研究中，肌肉注射BALB / c小鼠后，评估了基于猪肺炎支原体的P37，P42，P46和P95抗原的DNA和重组亚基疫苗引发的细胞和体液免疫反应。通过实时RT-PCR评估来自接种小鼠的脾细胞中细胞因子INFγ，TNFα和IL1的表达。所有作为亚单位疫苗提供的抗原，特别是P42和P95，以及pcDNA3 / P46 DNA疫苗都能够引起强烈的免疫反应。这些疫苗诱导细胞免疫反应，并产生能够与天然猪肺炎支原体蛋白反应的抗体。因为诱导了细胞和体液免疫应答，所以P42和P95是重组亚单位疫苗的有前途的候选者，而P46是抗PEP的DNA疫苗的有前途的候选者。

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： 背景：P21激活激酶1（PAK1）通过多种信号通路的激活刺激结直肠癌（CRC）的生长和转移。 PAK1对CRC干细胞标志物的上调也有助于CRC对5-氟尿嘧啶的抗性。这项研究的目的是研究PAK1的消耗和抑制对APC∆14 /小鼠免疫系统和肠道肿瘤形成的影响。
方法：PAK1 KO APC∆14 /小鼠是通过将PAK1 KO小鼠与APC∆14 /小鼠杂交而产生的。通过流式细胞术和免疫组织化学染色分析脾淋巴细胞。计算肠道肿瘤的数量。还对血细胞计数。
结果：与APC /小鼠相比，APC∆14 /小鼠脾脏中T淋巴细胞和B淋巴细胞的数量均减少。 APC∆14 /小鼠中PAK1的消耗增加了脾脏T-和B-淋巴细胞的数量，并减少了肠肿瘤的数量。用PAK抑制剂PF-3758309治疗APC∆14 /小鼠，可减少肠道肿瘤的数量并增加血液淋巴细胞的数量。
结论：活性PAK1的耗尽可上调APC∆14 /小鼠的免疫系统并抑制肠道肿瘤的发展。这些观察结果表明PAK1在对肿瘤的免疫应答中起重要作用。

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： 记忆力减退是阿尔茨海默氏病（AD）患者最常见的症状。当归（AK）传统上已被用作利尿剂，泻药，镇痛药和催乳剂。但是，AK的抗记忆效应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Morris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对海马的胆碱能拮抗作用。通过蛋白质印迹法和免疫组织化学评估了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可以显着减轻东pol碱引起的小鼠认知障碍。东碱引起的AChE活性增加被AK明显减弱。此外，AK可显着恢复海马中东pol碱所致的CREB磷酸化和BDNF的表达。综上所述，这些结果提供了实验证据，表明AK可能是预防由AD和衰老引起的学习和记忆不足的有用药物。

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： ：Alpinia officinarum虽然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，我们研究了厚朴乙醇提取物（AOE）对高脂饮食（HFD）喂养的3T3-L1细胞脂质堆积和肥胖症的抗肥胖作用。 AOE通过下调CCAAT增强子结合蛋白α（C /EBPα），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）来剂量依赖性地抑制3T3-L1前脂肪细胞分化过程中的脂质蓄积。 -γ）基因。高良姜精是A. officinarum的主要成分，在3T3-L1细胞中具有抗脂肪形成作用。补充了HFD的小鼠中的AOE补充显示，AOE显着降低了HFD诱导的人体，肝脏和白色脂肪组织重量增加，并降低了血清胰岛素和瘦素水平。为了阐明AOE在肥胖中的抑制机制，鉴定了脂质代谢相关基因。 AOE有效抑制肝脏和脂肪组织中C /EBPα，脂肪酸合酶，SREBP-1和PPAR-γ的蛋白质表达。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。总体而言，这些结果表明，AOE通过抑制脂肪形成和脂肪形成基因来预防肥胖。 AOE有潜力用作抗肥胖症治疗剂，可以通过调节脂质代谢发挥作用。

BACKGROUND & AIMS: :Epidemiologic studies have reported the association between fine particles (aerodynamic diameter ≤ 2.5 μm; PM2.5) and health effects, but the immunological mechanisms are not clear. To investigate the dose and time-dependent role of toll-like receptor (TLR) and Th1/Th2 shift in local and systemic inflammation induced by PM2.5, mice were subjected to intratracheal instillation of 2.5, 5, or 10 mg/kg PM2.5 in this study. After 24 h, 72 h, 7 days, and 14 days, mice were sacrificed to measure TLR2 and TLR4 expressions and Th1/Th2 related cytokines in bronchoalveolar lavage fluid (BALF) and peripheral blood. Histopathological changes in lung were also examined. Inflammatory infiltration and macrophages with engulfed particles were found by lung histopathology after PM2.5 exposure. TLR4 positive cells decreased in BALF but increased in blood at 24 h after the exposure. The low percentage of TLR4 positive cells continued to day 14 in BALF, but recovered at day 7 and decreased further to lower than the control value at day 14 in blood. TLR2 positive cell changed similar to TLR4 in BALF on the dose effects. In BALF at 24 h after the exposure, the Th2 related cytokines IL-5 and IL-10 increased dose-dependently; and in blood, the Th2 related cytokines IL-4, IL-5, and IL-10 also increased. These results suggest that acute exposure of PM2.5 leads to acute inflammatory responses locally and systemically in mice. TLR2 and TLR4 are involved in this process and PM2.5 can drive a Th2-biased immune response.

背景与目标： ：流行病学研究已经报告了微粒（空气动力学直径≤2.5μm； PM2.5）与健康影响之间的关联，但免疫机制尚不清楚。为了研究Toll样受体（TLR）和Th1 / Th2转移在PM2.5诱导的局部和全身炎症中的剂量和时间依赖性作用，对小鼠进行气管内滴注2.5、5或10μmg/ kg PM2 .5在这项研究中。在24小时，72小时，7天和14天后，处死小鼠以测量支气管肺泡灌洗液（BALF）和外周血中TLR2和TLR4的表达以及Th1 / Th2相关的细胞因子。还检查了肺的组织病理学变化。 PM2.5暴露后通过肺组织病理学发现炎症浸润和吞噬颗粒的巨噬细胞。暴露24h后，BALF中TLR4阳性细胞减少，但血液中TLR4阳性细胞增加。在BALF中，TLR4阳性细胞的低百分比持续至第14天，但在第7天恢复，并且在血液中第14天进一步下降至低于对照值。在剂量效应上，TLR2阳性细胞的变化与BALF中的TLR4相似。暴露后24h，在BALF中，与Th2相关的细胞因子IL-5和IL-10呈剂量依赖性增加。在血液中，与Th2相关的细胞因子IL-4，IL-5和IL-10也增加。这些结果表明，PM2.5的急性暴露导致小鼠局部和全身急性炎症反应。 TLR2和TLR4参与了这一过程，而PM2.5可以驱动偏向Th2的免疫反应。

BACKGROUND & AIMS: :Satellite cells, localized within muscles in vivo, are Pax7+ muscle stem cells supporting skeletal muscle growth and regeneration. Unfortunately, their amplification in vitro, required for their therapeutic use, is associated with reduced regenerative potential. In the present study, we investigated if human myogenic reserve cells (MRC) obtained in vitro, represented a reliable cell source for muscle repair. For this purpose, primary human myoblasts were freshly isolated and expanded. After 2 days of differentiation, 62 ± 2.9% of the nuclei were localized in myotubes and 38 ± 2.9% in the mononucleated non-fusing MRC. Eighty percent of freshly isolated human MRC expressed a phenotype similar to human quiescent satellite cells (CD56+/Pax7+/MyoD-/Ki67- cells). Fourteen days and 21 days after cell transplantation in immunodeficient mice, live human cells were significantly more numerous and the percentage of Pax7+/human lamin A/C+ cells was 2 fold higher in muscles of animals injected with MRC compared to those injected with human myoblasts, despite that percentage of spectrin+ and lamin A/C+ human fibers in both groups MRC were similar. Taken together, these data provide evidence that MRC generated in vitro represent a promising source of cells for improving regeneration of injured skeletal muscles.

背景与目标： ：卫星细胞位于体内肌肉中，是支持骨骼肌生长和再生的Pax7肌肉干细胞。不幸的是，其治疗用途所需的体外扩增与降低的再生潜力有关。在本研究中，我们调查了体外获得的人肌原性储备细胞（MRC）是否代表肌肉修复的可靠细胞来源。为此目的，新鲜分离并扩增了原代人成肌细胞。分化2天后，有62％±2.9％的细胞核位于肌管中，有38％±2.9％的细胞位于单核非融合性MRC中。 80％的新鲜分离出的人类MRC表现出与人类静止卫星细胞（CD56 / Pax7 / MyoD- / Ki67-细胞）相似的表型。在免疫缺陷小鼠中，细胞移植后第14天和第21天，活人细胞明显增多，并且与注射人成肌细胞的动物相比，注射MRC的动物的肌肉中Pax7 /人层粘连A / C细胞的百分比高2倍，尽管两组中的血影蛋白和层状A / C人纤维百分比均相似。综上所述，这些数据提供了证据，证明体外产生的MRC代表了改善受损骨骼肌再生的有希望的细胞来源。