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。

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。

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。

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)

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。

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。

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。

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：

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。

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。

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：

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。

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。

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： 流行病学研究报道了细颗粒 (空气动力学直径 ≤ 2.5微米; PM2.5) 与健康影响之间的关联，但免疫学机制尚不清楚。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，本研究对小鼠进行气管内滴注2.5、5或10  mg/kg PM2.5。分别于24  h、72  h、7 d、14 d处死小鼠，检测支气管肺泡灌洗液 (BALF) 和外周血中TLR2、TLR4的表达及Th1/Th2相关细胞因子。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巨噬细胞被吞噬的颗粒。暴露后24小时，BALF中TLR4阳性细胞减少，但血液中TLR4阳性细胞增加。BALF中TLR4阳性细胞的低百分比持续到第14天，但在第7天恢复，并进一步下降至低于血液中第14天的对照值。TLR2阳性细胞改变与TLR4在BALF上的剂量效应相似。在暴露后24小时的BALF中，Th2相关细胞因子的IL-5和IL-10呈剂量依赖性增加; 在血液中，Th2相关细胞因子的IL-4，IL-5和IL-10也增加。这些结果表明，PM2.5的急性暴露会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，PM2.5可以驱动Th2-biased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： : 体内定位在肌肉内的卫星细胞是Pax7 + 肌肉干细胞，支持骨骼肌生长和再生。不幸的是，其治疗用途所需的体外扩增与再生潜力降低有关。在本研究中，我们研究了体外获得的人肌源性储备细胞 (MRC) 是否代表了用于肌肉修复的可靠细胞来源。为此，新鲜分离并扩增了原代人类成肌细胞。分化2天后，62个nuclei ±   2.9% 的细胞核位于肌管中，38个   ±   2.9% 位于单核非融合MRC中。80% 的新鲜分离的人MRC表达的表型类似于人静止卫星细胞 (CD56/Pax7/MyoD-/Ki67-细胞)。免疫缺陷小鼠细胞移植后14天和21天，活人细胞数量明显增加，注射MRC的动物肌肉中Pax7 +/人lamin A/C + 细胞的百分比比注射人成肌细胞高2倍，尽管两组MRC中spectrin和lamin A/C人类纤维的百分比相似。总之，这些数据提供了证据，表明体外产生的MRC代表了改善受损骨骼肌再生的有希望的细胞来源。