BACKGROUND & AIMS: :The extracellular calcium-sensing receptor (CaR) is usually associated with systemic Ca(2+) homeostasis, but the CaR is also expressed in many other tissues, including pancreatic islets of Langerhans. In the present study, we have used human islets and an insulin-secreting cell line (MIN6) to investigate the effects of CaR activation using the calcimimetic R-568, a CaR agonist that activates the CaR at physiological concentrations of extracellular Ca(2+). CaR activation initiated a marked but transient insulin secretory response from both human islets and MIN6 cells at a sub-stimulatory concentration of glucose, and further enhanced glucose-induced insulin secretion. CaR-induced insulin secretion was reduced by inhibitors of phospholipase C or calcium-calmodulin-dependent kinases, but not by a protein kinase C inhibitor. CaR activation was also associated with an activation of p42/44 mitogen-activated protein kinases (MAPK), and CaR-induced insulin secretion was reduced by an inhibitor of p42/44 MAPK activation. We suggest that the beta-cell CaR is activated by divalent cations co-released with insulin, and that this may be an important mechanism of intra-islet communication between beta-cells.

背景与目标： ：细胞外钙敏感受体（CaR）通常与全身性Ca（2）稳态相关，但该CaR在许多其他组织中也表达，包括Langerhans的胰岛。在本研究中，我们已经使用人类胰岛和胰岛素分泌细胞系（MIN6）来研究使用拟钙剂R-568（CaR激动剂在生理浓度的细胞外Ca（2）激活CaR的CaR激活）的CaR激活的影响。 。 CaR激活在葡萄糖的亚刺激浓度下启动了来自人胰岛和MIN6细胞的显着但短暂的胰岛素分泌反应，并进一步增强了葡萄糖诱导的胰岛素分泌。 CaR诱导的胰岛素分泌通过磷脂酶C或钙钙调蛋白依赖性激酶的抑制剂降低，但不通过蛋白激酶C抑制剂降低。 CaR激活还与p42 / 44丝裂原激活的蛋白激酶（MAPK）激活相关，并且CaR诱导的胰岛素分泌被p42 / 44 MAPK激活的抑制剂减少。我们建议β细胞CaR被与胰岛素共释放的二价阳离子激活，这可能是β细胞之间胰岛内通讯的重要机制。

BACKGROUND & AIMS: AIM:To investigate the effects of taurolithocholate (TLC) on the canalicular motility in isolated rat hepatocyte couplets (IRHC). METHODS:TLC was added to IRHC at concentrations of 10 and 50 mumol/L, respectively. In each group, five time-lapse movies containing 3 representative bile canaliculi were taken under phase-contrast microscopy for 12 h. The number of bile canalicular contractions and the intervals between consecutive canalicular contractions were calculated. Furthermore, the effects of TLC on IRHC were examined by transmission electron microscopy. RESULTS:The bile canalicular contractions were spontaneous and forceful in the controls. Active vesicular movement was observed in the pericanalicular region. Immediately after the addition of TLC, the bile canaliculi were deformed, and canalicular bile was incorporated into the vacuoles. The canaliculi were gradually dilated, and canalicular contractions were markedly inhibited by TLC. The vesicular movements became extremely slow in the pericanalicular region. The number of canalicular contractions significantly decreased in the TLC-treated groups, as compared with that in the controls. The time intervals were prolonged, as the TLC dosage increased, indicating that bile secretion into the canaliculi was impaired with TLC. Transmission electron microscopy revealed the lamellar transformation of the canalicular membranes in IRHC treated with TLC. CONCLUSION:TLC impairs both the bile canalicular contractions and the canalicular bile secretion, possibly by acting directly on the canalicular membranes in TLC-induced cholestasis.

背景与目标： 目的：研究牛磺石胆酸盐（TLC）对离体大鼠肝细胞联（IRHC）中小管运动的影响。
方法：将TLC分别以10和50μmol/ L的浓度添加到IRHC中。在每组中，在相差显微镜下拍摄五张延时电影，其中包含3个代表性的胆小管，时间为12小时。计算胆管小管收缩的次数和连续小管收缩的间隔。此外，通过透射电子显微镜检查了TLC对IRHC的作用。
结果：对照组胆总管收缩自发且有力。在小管周围区域观察到活跃的囊泡运动。加入TLC后，胆小管立即变形，并将胆小管合并入液泡中。 TLC逐渐扩大小管，并显着抑制小管收缩。小管周围区域的水泡运动变得极其缓慢。与对照组相比，TLC治疗组的小管收缩次数明显减少。随着TLC剂量的增加，时间间隔延长，这表明TLC会损害胆汁分泌到小管中。透射电子显微镜显示经薄层色谱处理的IRHC中，小管膜的层状转变。
结论：TLC可能通过直接作用于TLC诱发的胆汁淤积的小管膜上而损害了胆管的收缩和小管的胆汁分泌。

BACKGROUND & AIMS: :Different attempts were made to identify the variables that may be involved in the clinical course of cerebrovascular ischemia. In the case of stroke with mild severity (SMS), the clinical significance of neuroendocrine changes as well as of post-stroke depression (PSD) remains unknown. We therefore evaluated the presence of neuroendocrine changes in the acute and post-acute phase of SMS, and their potential role during convalescence. Serum cortisol, T4, T3, FT4, FT3, TSH and PRL levels were measured in 17 euthyroid patients with stroke on admission (day 1), following morning (day 2), 7 days and 3 months later. TSH and PRL secretion after TRH test were measured. Stroke severity on admission was determined by Scandinavian Stroke Scale (SSS). Montgomery-Asberg Depression Rating Scale (Madrs) was used for assessment of post-stroke depression. On admission, TSH and T3, were within normal limits and were greater compared to values on day 2. Lower basal TSH and decreased TSH response to TRH on day 2, were associated with stroke of greater severity. Delta-PRL after TRH on day 2 was higher in patients who develop PSD. Changes in serum thyroid hormones in SMS, reflects those of non-thyroidal illness. A mild stimulation of hypothalamic-pituitary-adrenal axis was detected. We provide evidence that PRL response to TRH, in the acute phase of stroke may be used as an index for early detection of PSD.

背景与目标： ：进行了不同的尝试来确定可能与脑血管缺血的临床过程有关的变量。在轻度中风（SMS）的情况下，神经内分泌变化以及中风后抑郁症（PSD）的临床意义仍然未知。因此，我们评估了SMS急性期和急性期后神经内分泌变化的存在以及它们在恢复期中的潜在作用。在入院时（第1天），早晨（第2天），第7天和3个月后的17例中风的甲状腺功能正常的甲状腺疾病患者中测量了血清皮质醇，T4，T3，FT4，FT3，TSH和PRL的水平。测量TRH试验后的TSH和PRL分泌。入院时卒中严重程度由斯堪的纳维亚卒中量表（SSS）确定。使用蒙哥马利-阿斯伯格抑郁量表（Madrs）评估中风后抑郁。入院时，TSH和T3在正常范围之内，并且比第2天的值高。在第2天，较低的基础TSH和对TRH的TSH反应降低与卒中严重程度有关。发生PSD的患者在TRH后第2天的Delta-PRL较高。 SMS中血清甲状腺激素的变化反映了非甲状腺疾病的变化。下丘脑-垂体-肾上腺轴受到轻度刺激。我们提供的证据表明，在卒中的急性期PRL对TRH的反应可用作早期检测PSD的指标。

BACKGROUND & AIMS: :In this issue of Immunity, Bezbradica et al., (2006) uncover an unsuspected role for the cytokine GM-CSF in the thymic development of invariant NKT cells, a role that licenses these cells to secrete effector cytokines upon activation in the periphery.

背景与目标： Bezbradica等人（2006）在《免疫》杂志上揭示了细胞因子GM-CSF在恒定NKT细胞的胸腺发育中的作用，这一作用并未受到人们的怀疑，该作用使这些细胞在外围激活后可以分泌效应细胞因子。

BACKGROUND & AIMS: :Transcriptome analysis was used to investigate the global stress response of the gram-positive bacterium Bacillus subtilis caused by overproduction of the well-secreted AmyQ alpha-amylase from Bacillus amyloliquefaciens. Analyses of the control and overproducing strains were carried out at the end of exponential growth and in stationary phase, when protein secretion from B. subtilis is optimal. Among the genes that showed increased expression were htrA and htrB, which are part of the CssRS regulon, which responds to high-level protein secretion and heat stress. The analysis of the transcriptome profiles of a cssS mutant compared to the wild type, under identical secretion stress conditions, revealed several genes with altered transcription in a CssRS-dependent manner, for example, citM, ylxF, yloA, ykoJ, and several genes of the flgB operon. However, high-affinity CssR binding was observed only for htrA, htrB, and, possibly, citM. In addition, the DNA macroarray approach revealed that several genes of the sporulation pathway are downregulated by AmyQ overexpression and that a group of motility-specific (sigmaD-dependent) transcripts were clearly upregulated. Subsequent flow-cytometric analyses demonstrate that, upon overproduction of AmyQ as well as of a nonsecretable variant of the alpha-amylase, the process of sporulation is severely inhibited. Similar experiments were performed to investigate the expression levels of the hag promoter, a well-established reporter for sigmaD-dependent gene expression. This approach confirmed the observations based on our DNA macroarray analyses and led us to conclude that expression levels of several genes involved in motility are maintained at high levels under all conditions of alpha-amylase overproduction.

背景与目标： ：转录组分析用于研究革兰氏阳性枯草芽孢杆菌的总体应激反应，该酶是由解淀粉芽孢杆菌分泌的大量分泌良好的AmyQα-淀粉酶引起的。当枯草芽孢杆菌的蛋白质分泌最适时，在指数生长结束时和在稳定期进行对照和高产菌株的分析。在显示增加表达的基因中有htrA和htrB，它们是CssRS regulon的一部分，对高水平的蛋白质分泌和热应激作出反应。在相同的分泌压力条件下，与野生型相比，cssS突变体的转录组图谱分析显示，一些基因以依赖于CssRS的方式改变了转录，例如citM，ylxF，yloA，ykoJ和flgB操纵子。但是，仅对htrA，htrB和citM观察到高亲和力的CssR结合。另外，DNA宏阵列方法揭示了孢子形成途径的几个基因被AmyQ过表达下调，并且一组运动特异性（依赖sigmaD的）转录物明显上调。随后的流式细胞仪分析表明，当AmyQ以及α-淀粉酶的不可分泌变体过量生产时，孢子形成过程将受到严重抑制。进行了类似的实验，以研究hag启动子的表达水平，hag启动子是sigmaD依赖性基因表达的公认报告子。这种方法证实了基于我们的DNA宏阵列分析的观察结果，并导致我们得出结论，在所有α-淀粉酶过量生产的条件下，与运动相关的几个基因的表达水平均维持在较高水平。

BACKGROUND & AIMS: It has been established that oxidized LDL (ox-LDL) modifies cytokine secretion by macrophages, for example, by reducing tumor necrosis factor alpha (TNF-(alpha) m-RNA. However, little is known about the effects of oxidized high density lipoprotein (ox-HDL). This study reports the effects of ox-HDL subfractions 2 and 3 (ox-HDL2, ox-HDL3) compared with that of ox-LDL and some products of oxidation (hydroperoxides and aldehydes) on the secretion of TNF-alpha from THP-1 human monocytes derived macrophages in vitro. HDL2, HDL3 and LDL were oxidized with 10 microM Cu++ for 12 h and/or 24 h. Native and oxidized HDL and LDL were incubated for 24 h with macrophages with or without LPS (10 ng/ml) after which TNF-alpha secretion was measured in the culture medium. Lipid hydroperoxides and apolar aldehydes were also incubated with the cells for 2 h following which the medium was replaced and TNF-alpha secretion measured after a further 22 h of incubation. An inhibition of TNF-alpha by ox-HDL2 (p < .05), ox-HDL3 (p < .05) and ox-LDL (p < .05) from THP-1 macrophages was observed in the presence and absence of LPS. This inhibition remained the same after incubation with ox-HDL 12 h and 24 h. Hydroperoxides of linoleic acid did not modify TNF-alpha secretion by cells while five out of eight aldehydes analyzed (2,4-heptadienal, hexanal, 2-nonenal, 2-octenal, 2,4-decadienal) inhibited TNF-alpha secretion (p < .05). These findings demonstrate that ox-HDL, and some of its lipid peroxidation products, plays a role in the modulation of the inflammatory response by macrophages as previously observed for ox-LDL.

背景与目标： 已经确定氧化的LDL（ox-LDL）可以通过减少肿瘤坏死因子α（TNF-αm-RNA）来调节巨噬细胞的细胞因子分泌。但是，对氧化的高密度脂蛋白的作用知之甚少（ox-HDL）。这项研究报告了与ox-LDL和某些氧化产物（氢过氧化物和醛类）相比，ox-HDL亚组分2和3（ox-HDL2，ox-HDL3）对TNF分泌的影响THP-1人单核细胞衍生的α-α体外，将HDL2，HDL3和LDL用10 microM Cu氧化12 h和/或24 h，将天然和氧化的HDL和LDL与有或没有LPS的巨噬细胞一起孵育24 h （10 ng / ml），然后在培养基中测量TNF-α的分泌，脂质过氧化氢和非极性醛也与细胞一起孵育2小时，然后更换培养基，再过22 h后测量TNF-α的分泌ox-HDL2对TNF-α的抑制作用（p < .05），在存在和不存在LPS的情况下观察到THP-1巨噬细胞的ox-HDL3（p <.05）和ox-LDL（p <.05）。与ox-HDL孵育12小时和24小时后，这种抑制作用保持不变。亚油酸的氢过氧化物不会改变细胞的TNF-α分泌，而分析的八种醛中的五种（2,4-庚二烯醛，己醛，2-壬烯醛，2-辛烯醛，2,4-癸二烯醛）抑制TNF-α分泌（p <.05）。这些发现表明，ox-HDL及其某些脂质过氧化产物在巨噬细胞对炎症反应的调节中起着作用，正如以前对ox-LDL所观察到的一样。

BACKGROUND & AIMS: :Cystic fibrosis (CF) airway disease arises from defective innate defenses, especially defective mucus clearance of microorganisms. Airway submucosal glands secrete most airway mucus, and CF airway glands do not secrete in response to VIP or forskolin. CFTR, the protein that is defective in CF, is expressed in glands, but immunocytochemistry finds the highest expression of CFTR in either the ciliated ducts or in the acini, depending on the antibodies used. CFTR is absolutely required for forskolin-mediated gland secretion; we used this finding to localize the origin of forskolin-stimulated, CFTR-dependent gland fluid secretion. We tested the hypothesis that secretion to forskolin might originate from the gland duct rather than or in addition to the acini. We ligated gland ducts at various points, stimulated the glands with forskolin, and monitored the regions of the glands that swelled. The results supported an acinar rather than ductal origin of secretion. We tracked particles in the mucus using Nomarski time-lapse imaging; particles originated in the acini and traveled toward the duct orifice. Estimated bulk flow accelerated in the acini and mucus tubules, consistent with fluid secretion in those regions, but was constant in the unbranched duct, consistent with a lack of fluid secretion or absorption by the ductal epithelium. We conclude that CFTR-dependent gland fluid secretion originates in the serous acini. The failure to observe either secretion or absorption from the CFTR and epithelial Na(+) channel (ENaC)-rich ciliated ducts is unexplained, but may indicate that this epithelium alters the composition rather than the volume of gland mucus.

背景与目标： 囊性纤维化（CF）气道疾病源于先天防御能力不足，尤其是微生物清除粘液的能力不足。气道粘膜下腺分泌大多数气道粘液，而CF气道腺不响应VIP或毛喉素而分泌。 CFTR是CF中的缺陷蛋白，在腺体中表达，但免疫细胞化学发现CFTR在纤毛管或腺泡中的表达最高，具体取决于所使用的抗体。 CFTR是forskolin介导的腺体分泌所绝对必需的。我们利用这一发现来定位受福斯高林刺激的，依赖CFTR的腺体分泌液的起源。我们检验了福斯克林分泌可能起源于腺管而不是腺泡或除了腺泡之外的假说。我们结扎腺体的各个部位，用福司可林刺激腺体，并监测肿胀的腺体区域。结果支持腺泡而不是导管的分泌来源。我们使用Nomarski延时成像技术追踪了粘液中的颗粒。颗粒起源于腺泡，并朝着导管孔口行进。估计的腺泡和粘液小管中的总流量加速，与那些区域的液体分泌一致，但在未分支的导管中恒定，这与导管上皮缺乏液体分泌或吸收一致。我们得出结论，CFTR依赖的腺体液分泌起源于浆液性腺泡。无法观察到CFTR和富含上皮Na（）通道（ENaC）的纤毛导管的分泌或吸收均无法解释，但可能表明该上皮改变了组成而不是腺黏液的体积。

BACKGROUND & AIMS: Important advances in our understanding of the regulation of hepatic apolipoprotein B secretion have been made in the past year. A diverse group of studies have provided evidence that the inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors decreases the hepatic assembly and secretion of apolipoprotein B-containing lipoproteins. Apolipoprotein B kinetic studies performed in animals and human individuals indicate that inhibition of VLDL-apolipoprotein B secretion is an important mechanism whereby reductase inhibitors decrease plasma concentrations of these lipoproteins. Studies in cultured hepatocytes and in-vivo animal models have provided insights into how reduction of cholesterol synthesis decreases apolipoprotein B secretion. A decrease in hepatic acyl-coenzyme Acholesterol acyltransferase activity, secondary to reduced microsomal cholesterol concentrations, has been implicated.

背景与目标： 在过去的一年中，我们对调节肝载脂蛋白B分泌的认识取得了重要进展。各种各样的研究已经提供了证据，证明3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂对胆固醇合成的抑制作用会减少肝细胞的聚集和载脂蛋白B脂蛋白的分泌。在动物和人类体内进行的载脂蛋白B动力学研究表明，抑制VLDL-载脂蛋白B分泌是重要的机制，还原酶抑制剂可降低这些脂蛋白的血浆浓度。对培养的肝细胞和体内动物模型的研究提供了有关胆固醇合成减少如何减少载脂蛋白B分泌的见解。提示由于降低的微粒体胆固醇浓度，肝酰基辅酶胆固醇酰基转移酶活性降低。

BACKGROUND & AIMS: :Type III protein secretion systems, which are organelles with the capacity to deliver bacterial proteins into host cells, have been adapted to deliver heterologous antigens for vaccine development. A limitation of these antigen delivery systems is that some proteins are not amenable to secretion through this pathway. We show here that proteins from the simian and human immunodeficiency viruses that are not permissive for secretion through a Salmonella enterica serovar Typhimurium type III secretion system can be modified to travel this secretion pathway by introduction of discrete mutations. Proteins optimized for secretion were presented more efficiently via the major histocompatibility complex class I pathway and were able to induce a better immune response.

背景与目标： ：III型蛋白质分泌系统具有细胞器的能力，能够将细菌蛋白质传递到宿主细胞中，已经适应于传递异源抗原用于疫苗开发。这些抗原递送系统的局限性是某些蛋白质不适合通过该途径分泌。我们在这里表明，猿猴和人类免疫缺陷病毒不允许通过沙门氏菌肠炎血清型鼠伤寒III型分泌系统分泌的蛋白质可以通过引入离散突变而被修饰为通过这种分泌途径。通过主要的组织相容性复合体I类途径可以更有效地表达针对分泌优化的蛋白质，并且能够诱导更好的免疫反应。

BACKGROUND & AIMS: :The present study investigated the effect of resveratrol on the electrophysiology and insulin secretion of pancreatic beta cells, and examined resveratrol-induced alterations in insulin levels and plasma glucose of normal and streptozotocin-induced diabetic rats. Whole-cell voltage clamp study in the MIN6 cell, a mouse beta cell line, revealed that resveratrol significantly inhibited ATP-sensitive K(+) current at 3 micromol/l, and voltage-gated K(+) currents at 30 micromol/l. Ca(2+)-activated K(+) current was activated by resveratrol at 100 micromol/l. In MIN6 cells stained with membrane potential dye DiBAC(4)(5), resveratrol markedly depolarized membrane potential at the concentrations of 3-100 micromol/l. Insulin secretion was increased in the presence of resveratrol in MIN6, Hit-T15, and RIN-m5F cells. Resveratrol (3 mg/kg, i.p.) increased insulin secretion associated with a lowering in plasma glucose in normal rats, but not in streptozotocin-diabetic rats within the initial 60 min. In conclusion, resveratrol can act as an insulin-secretagogue through I(KATP) and I(KV) inhibition which can contribute to plasma glucose lowering effect in normal rats.

背景与目标： ：本研究调查了白藜芦醇对胰腺β细胞电生理和胰岛素分泌的影响，并研究了白藜芦醇诱导的正常和链脲佐菌素诱导的糖尿病大鼠胰岛素水平和血浆葡萄糖的变化。在MIN6细胞（一种小鼠​​β细胞系）中进行全细胞电压钳研究，发现白藜芦醇在3微摩尔/升时显着抑制ATP敏感的K（）电流，在30微摩尔/升时抑制电压门控的K（）电流。 Ca（2）激活的K（）电流被白藜芦醇以100 micromol / l激活。在用膜电位染料DiBAC（4）（5）染色的MIN6细胞中，白藜芦醇在3-100 micromol / l的浓度下可显着去极化膜电位。在MIN6，Hit-T15和RIN-m5F细胞中存在白藜芦醇时，胰岛素分泌增加。在正常大鼠中，白藜芦醇（3 mg / kg，i.p.）在最初60分钟内胰岛素分泌增加与血浆葡萄糖降低有关，但在链脲佐菌素-糖尿病大鼠中却没有。总之，白藜芦醇可以通过I（KATP）和I（KV）抑制作用起胰岛素分泌的作用，这可以促进正常大鼠血浆葡萄糖的降低作用。

BACKGROUND & AIMS: :Cortisol is used in research as a biomarker of psychological stress. Logistical considerations argue for collecting as few samples as possible, balanced against diurnal rhythms and intra-individual variations. 100 pregnant women gave five saliva samples a day for 3 days, at waking, 30 min after waking, and 11:00 a.m., 5:00 p.m., and 9:00 p.m. Timing of collection was confirmed by monitors. Another sample was taken during a clinic visit. Using the 15 measures as the gold standard, correlations and mean area under the curve (AUC) were compared with subsets and the single clinic sample to evaluate alternate collection protocols. Five samples in 1 day, or protocols involving morning and night samples, had the highest correlations with mean AUC (correlation coefficient ranging from 0.82 to 0.88). Standardizing the clinic measurement to a single time of day did not substantially improve correlations with mean AUC. Correlations with measures of reported stress were also not strong.

背景与目标： ：Cortisol在研究中用作心理压力的生物标记。物流方面的考虑认为应收集尽可能少的样本，并与昼夜节律和个体内部差异保持平衡。 100名孕妇在清醒，醒后30分钟和上午11:00，下午5:00和下午9:00每天提供五份唾液样本，为期3天。监控人员确认了收集时间。在诊所就诊时采集了另一个样本。使用15个度量作为金标准，将相关性和曲线下的平均面积（AUC）与子集和单个临床样本进行比较，以评估备用收集方案。 1天中的五个样本或涉及早晨和晚上样本的协议与平均AUC的相关性最高（相关系数范围从0.82到0.88）。将临床测量标准化为一天中的某个时间并不能显着改善与平均AUC的相关性。与报告的压力测量值的相关性也不强。

BACKGROUND & AIMS: :Many standard textbooks of physiology have a diagram that shows the transporting elements that lead to the secretion of HCl by the parietal cell. The transporters are neatly aligned, and students see an elegant mechanism that neatly balances the ions to maintain electroneutrality. They little realize the time and effort required to tease out each of those steps bit by bit. This essay uses three papers by Horace Davenport to highlight the experimental evidence for a crucial step in that process: the generation of H(+) and HCO(3)(-) through the agency of carbonic anhydrase. All three papers form part of the classic papers available through the American Physiological Society Legacy Project.

背景与目标： ：许多生理学标准教科书都有一张图表，显示了导致顶细胞分泌HCl的转运元素。转运蛋白排列整齐，学生们看到了一种优雅的机制，它可以平衡离子以保持电子中性。他们几乎没有一点一点地花时间来梳理每个步骤所需要的时间和精力。本文使用Horace Davenport的三篇论文来强调该过程中关键步骤的实验证据：通过碳酸酐酶的作用生成H（）和HCO（3）（-）。所有这三篇论文都是可通过美国生理学会旧版计划获得的经典论文的一部分。

BACKGROUND & AIMS: :Particulate matter PM2.5 is a class of airborne particles and droplets with sustained high levels in many developing countries. Epidemiological studies have shown the association between sustained high level of PM2.5 and the risk of many diseases in the respiratory system, including lung cancer. However, the precise mechanisms through which PM2.5 induces respiratory diseases are still unclear. In this study, we demonstrated that CD4+ and CD8+ T cells following PM2.5 treatment demonstrated significantly elevated mRNA and protein levels of interferon (IFN)-γ, interleukin (IL)-10, IL-17, and IL-21 production. This increase in cytokines required the presence of macrophages, such that CD4+ and CD8+ T cells treated with PM2.5 in the absence of macrophages did not present higher IFN-γ, IL-10, or IL-21 expression. In contrast, PM2.5-treated macrophages could significantly upregulate T cell cytokine secretion, even when excess PM2.5 was removed from cell culture. We also observed a macrophage-dependent upregulation of granzyme A and granzyme B expression by CD4+ and CD8+ T cells following PM2.5 treatment. These PM2.5-stimulated CD4+ and CD8+ T cells potently induced the death of human bronchial epithelial (HBE) cells. Interestingly, the CD4+ and CD8+ T cells presented synergistic effects at inducing HBE cytotoxicity, such that CD4+ T cells and CD8+ T cells combined resulted in higher HBE cell death than the sum of the separate effects of CD4+ T cells and CD8+ T cells. While blocking cytotoxic molecule release significantly compromised the T cell-mediated cytotoxicity against HBE cells, blocking IFN-γ, but not IL-10, could also slightly but significantly reduce T cell-mediated cytotoxicity. Together, these data demonstrated that PM2.5 could promote the inflammation of cytotoxicity of T cells in a macrophage-dependent manner. In addition, PM2.5-treated macrophages presented long-lasting proinflammatory effects on T cells.

背景与目标： ：颗粒物PM2.5是一类在许多发展中国家持续高水平飞行的空气颗粒和小滴。流行病学研究表明，持续高水平的PM2.5与呼吸系统多种疾病（包括肺癌）的风险之间存在关联。然而，PM2.5诱发呼吸系统疾病的确切机制仍不清楚。在这项研究中，我们证明了PM2.5处理后的CD4和CD8 T细胞显示出干扰素（IFN）-γ，白介素（IL）-10，IL-17和IL-21产生的mRNA和蛋白质水平显着升高。细胞因子的这种增加需要巨噬细胞的存在，以致在没有巨噬细胞的情况下用PM2.5处理的CD4和CD8 T细胞不会表现出更高的IFN-γ，IL-10或IL-21表达。相反，即使从细胞培养物中去除了过量的PM2.5，经PM2.5处理的巨噬细胞也可以显着上调T细胞细胞因子的分泌。我们还观察到PM2.5处理后CD4和CD8 T细胞巨噬细胞依赖颗粒酶A和颗粒酶B表达的上调。这些PM2.5刺激的CD4和CD8 T细胞有效诱导人支气管上皮（HBE）细胞死亡。有趣的是，CD4和CD8 T细胞在诱导HBE细胞毒性方面表现出协同作用，因此与CD4 T细胞和CD8 T细胞单独作用的总和相比，CD4 T细胞和CD8 T细胞的结合导致更高的HBE细胞死亡。尽管阻断细胞毒性分子的释放显着损害了针对HBE细胞的T细胞介导的细胞毒性，但阻断IFN-γ（而非IL-10）也可以略微但显着降低T细胞介导的细胞毒性。总之，这些数据表明PM2.5可以以巨噬细胞依赖性方式促进T细胞的细胞毒性炎症。此外，经PM2.5处理的巨噬细胞对T细胞具有持久的促炎作用。

BACKGROUND & AIMS: :To gain insight into the mechanism of the altered carbohydrate metabolism in thyrotoxicosis, intravenous glucose tolerance tests (IVGTT) and pancreatic suppression tests (PST) were performed in hyperthyroid rats (0.1 mg/kg T4 X 5 days) to assess insulin secretion and action in vivo. Thyroid hormone injections significantly increased T4 levels (182.8 nM +/- 11.6 (SEM) versus 50.2 +/- 6.4; P less than 0.001) and baseline glucose concentrations (9.3 mM +/- 0.2 versus 7.1 +/- 0.2; P less than 0.001). Body weights, basal insulin concentrations, glucose concentrations during IVGTT, glucose disappearance rates and steady state plasma glucose levels (SSPG) were normal. Insulin concentrations during the glucose tolerance test and during the PST were significantly decreased. The metabolic clearance rate of insulin (ml/min/kg +/- SEM) was significantly (P less than 0.01) increased (54.4 +/- 3.5 versus 41.6 +/- 2.3) in the hyperthyroid rats. If the different baseline glucose values were subtracted from the glucose concentrations achieved during the 2 tests, both the glucose disappearance rate and the fall in SSPG levels were significantly enhanced in the T4-injected animals. Thus, in the hyperthyroid rat, insulin secretion is decreased, the clearance of insulin is increased and insulin sensitivity is either normal or possibly enhanced.

背景与目标： ：为了深入了解甲状腺毒症中碳水化合物代谢改变的机理，对甲亢大鼠（0.1 mg / kg T4 X 5天）进行了静脉葡萄糖耐量试验（IVGTT）和胰腺抑制试验（PST），以评估胰岛素的分泌和作用体内。甲状腺激素注射显着提高了T4水平（182.8 nM /-11.6（SEM）对50.2 /-6.4; P小于0.001）和基线葡萄糖浓度（9.3 mM /-0.2对7.1 /-0.2; P小于0.001）。体重，基础胰岛素浓度，IVGTT期间的葡萄糖浓度，葡萄糖消失率和稳态血浆葡萄糖水平（SSPG）正常。葡萄糖耐量试验期间和PST期间的胰岛素浓度显着降低。在甲状腺功能亢进的大鼠中，胰岛素的代谢清除率（ml / min / kg /-SEM）显着提高（P小于0.01）（54.4 /-3.5对41.6 /-2.3）。如果从两次测试中获得的葡萄糖浓度中减去不同的基线葡萄糖值，则注射T4的动物的葡萄糖消失率和SSPG水平的下降均显着增强。因此，在甲状腺功能亢进的大鼠中，胰岛素分泌减少，胰岛素清除率增加，胰岛素敏感性正常或可能增强。

BACKGROUND & AIMS: :Amphibian skin secretions are known to contain numerous peptides with a large array of biological activities. Bombinins are a group of amphibian-derived peptides with broad spectrum antimicrobial activities that have been only identified from the ancient toad species, Bombina. In this study, we described the identification and characterization of a novel bombinin precursor which encoded a bombinin-like peptide (BLP-7) and a novel bombinin H-type peptide (named as Bombinin H-BO) from the skin secretion of Oriental fire-bellied toad, Bombina orientalis. The primary structures of both mature peptides were determined by combinations of molecular cloning of peptide precursor-encoding cDNAs and mass spectrometry techniques. Secondary structure prediction revealed that both peptides had cationic amphipathic α-helical structural features. The synthetic replicate of BLP-7 displayed more potent antimicrobial activity than Bombinin H-BO against Gram-positive and Gram-negative bacteria and yeast. Also, in vitro antitumour assay showed that both peptides possessed obvious antiproliferative activity on three human hepatoma cells (Hep G2/SK-HEP-1/Huh7) at the non-toxic doses. These results indicate the peptide family of bombinins could be a potential source of drug candidates for anti-infection and anticancer therapy.

背景与目标： 已知两栖动物的皮肤分泌物中含有许多具有多种生物活性的肽。 Bombinins是一组具有广谱抗菌活性的两栖动物衍生肽，仅从古老的蟾蜍物种Bombina中鉴定出来。在这项研究中，我们描述了一种从东方火的皮肤分泌物中鉴定出一种新的蛙新蛋白前体的鉴定和表征，该前体编码了一种蛙新蛋白样肽（BLP-7）和一种新颖的蛙新蛋白H型肽（称为蛙新蛋白H-BO）。腹蟾蜍，Bombina Orientalis。通过结合肽前体编码cDNA的分子克隆和质谱技术确定两种成熟肽的一级结构。二级结构预测表明，两种肽均具有阳离子两亲性α-螺旋结构特征。与Bombinin H-BO相比，BLP-7的合成复制品对革兰氏阳性和革兰氏阴性细菌和酵母菌显示出更强的抗菌活性。同样，体外抗肿瘤试验表明，两种肽均以无毒剂量对三种人肝癌细胞（Hep G2 / SK-HEP-1 / Huh7）具有明显的抗增殖活性。这些结果表明，蛙皮素的肽家族可能是抗感染和抗癌治疗候选药物的潜在来源。