薯蓣皂苷通过调控SIRT1-FoxO1-自噬通路减轻糖尿病大鼠胰岛素抵抗

目的:探究薯蓣皂苷是否通过调控沉默信息调节因子1(sirtuin 1,SIRT1)-叉头框蛋白O1(forkhead box protein O1,FoxO1)-自噬通路减轻糖尿病大鼠胰岛素抵抗。方法:将60只SPF级SD大鼠随机分为对照组、模型组、低剂量(5 mg/kg)薯蓣皂苷组、中剂量(10 mg/kg)薯蓣皂苷组、高剂量(20 mg/kg)薯蓣皂苷组和薯蓣皂苷(20 mg/kg)+EX-527(SIRT1抑制剂)组,每组10只。高脂饲料喂养4周后腹腔注射链脲佐菌素以构建2型糖尿病(type 2 diabetes mellitus,T2DM)大鼠模型,低、中、高剂量薯蓣皂苷组和薯蓣皂苷+EX-527组大鼠分别灌胃相应剂量药物,对照组和模型组大鼠灌胃等量生理盐水,每天1次,为期4周。全自动生化分析仪检测血清中空腹血糖(fasting blood glucose,FBG)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)、甘油三酯(triglyceride,TG)和总胆固醇(total cholesterol,TC)水平,酶联免疫吸附实验检测血清空腹胰岛素(fasting insulin,FINS)水平,计算胰岛素抵抗指数(homeostasis model assessment-insulin resistance,HOMA-IR)和胰岛素敏感指数(insulin sensitivity index,ISI),行口服葡萄糖耐量实验(oral glucose tolerance test,OGTT),计算OGTT曲线下区域面积(area under curve,AUC);HE染色观察大鼠胰腺组织损伤情况;使用Western blot检测胰腺组织中beclin-1、LC3及SIRT1-FoxO1自噬通路相关蛋白的表达。结果:与对照组相比,模型组FBG、AUC、FINS、HOMA-IR、体重、TG、TC和LDL-C水平、胰腺组织损伤程度及FoxO1水平显著增加,ISI、beclin-1、LC3-II/LC3-I和SIRT1水平显著降低(P<0.05);与模型组相比,低、中、高剂量组FBG、AUC、FINS、HOMA-IR、体重、TG、TC和LDL-C水平、胰腺组织损伤程度及FoxO1水平以薯蓣皂苷剂量依赖性的方式显著降低,ISI、beclin-1、LC3-II/LC3-I和SIRT1水平以薯蓣皂苷剂量依赖性的方式显著增加(P<0.05);与高剂量薯蓣皂苷组相比,薯蓣皂苷+EX-527组FBG、AUC、FINS、HOMA-IR、体重、TG、TC和LDL-C水平、胰腺组织损伤程度及FoxO1水平显著增加,ISI、beclin-1、LC3-II/LC3-I和SIRT1水平显著降低(P<0.05)。结论:薯蓣皂苷可能通过激活SIRT1-FoxO1-自噬通路减轻T2DM大鼠胰岛素抵抗。     

薯蓣皂苷通过调控SIRT1-FoxO1-自噬通路减轻糖尿病大鼠胰岛素抵抗

目的:探究薯蓣皂苷是否通过调控沉默信息调节因子1(sirtuin 1,SIRT1)-叉头框蛋白O1(forkhead box protein O1,FoxO1)-自噬通路减轻糖尿病大鼠胰岛素抵抗。方法:将60只SPF级SD大鼠随机分为对照组、模型组、低剂量(5 mg/kg)薯蓣皂苷组、中剂量(10 mg/kg)薯蓣皂苷组、高剂量(20 mg/kg)薯蓣皂苷组和薯蓣皂苷(20 mg/kg)+EX-527(SIRT1抑制剂)组,每组10只。高脂饲料喂养4周后腹腔注射链脲佐菌素以构建2型糖尿病(type 2 diabetes mellitus,T2DM)大鼠模型,低、中、高剂量薯蓣皂苷组和薯蓣皂苷+EX-527组大鼠分别灌胃相应剂量药物,对照组和模型组大鼠灌胃等量生理盐水,每天1次,为期4周。全自动生化分析仪检测血清中空腹血糖(fasting blood glucose,FBG)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)、甘油三酯(triglyceride,TG)和总胆固醇(total cholesterol,TC)水平,酶联免疫吸附实验检测血清空腹胰岛素(fasting insulin,FINS)水平,计算胰岛素抵抗指数(homeostasis model assessment-insulin resistance,HOMA-IR)和胰岛素敏感指数(insulin sensitivity index,ISI),行口服葡萄糖耐量实验(oral glucose tolerance test,OGTT),计算OGTT曲线下区域面积(area under curve,AUC);HE染色观察大鼠胰腺组织损伤情况;使用Western blot检测胰腺组织中beclin-1、LC3及SIRT1-FoxO1自噬通路相关蛋白的表达。结果:与对照组相比,模型组FBG、AUC、FINS、HOMA-IR、体重、TG、TC和LDL-C水平、胰腺组织损伤程度及FoxO1水平显著增加,ISI、beclin-1、LC3-II/LC3-I和SIRT1水平显著降低(P<0.05);与模型组相比,低、中、高剂量组FBG、AUC、FINS、HOMA-IR、体重、TG、TC和LDL-C水平、胰腺组织损伤程度及FoxO1水平以薯蓣皂苷剂量依赖性的方式显著降低,ISI、beclin-1、LC3-II/LC3-I和SIRT1水平以薯蓣皂苷剂量依赖性的方式显著增加(P<0.05);与高剂量薯蓣皂苷组相比,薯蓣皂苷+EX-527组FBG、AUC、FINS、HOMA-IR、体重、TG、TC和LDL-C水平、胰腺组织损伤程度及FoxO1水平显著增加,ISI、beclin-1、LC3-II/LC3-I和SIRT1水平显著降低(P<0.05)。结论:薯蓣皂苷可能通过激活SIRT1-FoxO1-自噬通路减轻T2DM大鼠胰岛素抵抗。     

TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice

Nonalcoholic fatty liver is characterized by the fatty deformation and lipid deposition of hepatic parenchymal cells that are associated with cardiometabolic diseases. In this study, we report the effect of capsaicin on its receptor, transient receptor potential vanilloid 1 (TRPV1) cation channel, in preventing fatty liver formation. Functional TRPV1 has been detected in hepatocytes and liver tissues. TRPV1 activation by capsaicin reduced lipid accumulation and triglyceride level in the liver from wild-type (WT) mice. However, these effects were absent in the liver from TRPV1^?/? mice. Chronic dietary capsaicin increased the hepatic uncoupling protein 2 (UCP2) expression in WT but not in TRPV1^?/? mice (P?<?0.01). We conclude that TRPV1 long-time activation might prevent high-fat diet-induced fatty liver in mice through upregulation of hepatic UCP2. Dietary capsaicin may represent a promising intervention in populations at high risk for fatty liver.     

Short-term dietary intervention improves endothelial dysfunction induced by high-fat feeding in mice through upregulation of the AMPK-CREB signaling pathway

Aim

In addition to functioning as an energy sensor switch, AMPK plays a key role in the maintenance of cardiovascular homeostasis. However, obesity disrupts AMPK signaling, contributing to endothelial dysfunction and cardiovascular disease. This study aimed to elucidate if a short-term dietary intervention consisting in replacing the high-fat diet with a standard diet for 2 weeks could reverse obesity-induced endothelial dysfunction via AMPK-CREB activation.

Methods

For this, 5-week-old male C57BL6J mice were fed a standard (Chow) or a high-fat (HF) diet for 8 weeks. The HF diet was replaced by the chow diet for the last 2 weeks in half of HF mice, generating 3 groups: Chow, HF and HF-Chow. Vascular reactivity and western-blot assays were performed in the thoracic aorta.

Results

Returning to a chow diet significantly reduced body weight and glucose intolerance. Relaxant responses to acetylcholine and the AMPK activator (AICAR) were significantly impaired in HF mice but improved in HF-Chow mice. The protein levels of AMPKα, p-CREB and antioxidant systems (heme oxygenase-1 (HO-1) and catalase) were significantly reduced in HF but normalized in HF-Chow mice.

Conclusion

Improving dietary intake by replacing a HF diet with a standard diet improves AMPK-mediated responses due to the upregulation of the AMPK/CREB/HO-1 signaling pathway.     

基底外侧杏仁核中SIRT1对小鼠条件奖赏模型中吗啡成瘾记忆的作用

目的:通过建立小鼠吗啡条件奖赏(CR)模型模拟吗啡成瘾记忆的形成、消退和再现,并检测基底外侧杏仁核(BLA)内沉默信息调节因子1(SIRT1)在吗啡成瘾记忆不同阶段的表达。方法:小鼠分为4组:CR-吗啡组; CR-糖水组; na?ve-吗啡组; na?ve-糖水组。进行CR训练时,条件性刺激依次为8 s和4 s。训练结束后进行49 d的遗忘,随后再进行一次条件性刺激为4 s的训练。运用RT-PCR、Western Blot检测不同阶段BLA内SIRT1mRNA及蛋白表达。结果:在CR形成期,吗啡组正确鼻触总时间显著低于糖水组(P 0. 01)。当加大训练难度将条件性刺激缩短为4 s时,吗啡组正确鼻触时间占比发生逆转,呈现高于糖水组的趋势。与na?ve-吗啡组比较,CR-吗啡组小鼠SIRT1 mRNA表达量显著升高(P 0. 001);遗忘后再次测试,CR-吗啡组小鼠前壁红外碰触次数升高(P 0. 001),并更趋向于停留在托盘处等待信号出现,CR-糖水组无效鼻触时间显著升高(P 0. 001)。遗忘后CR-吗啡组正确鼻触时间由24. 8%上升到27. 6%,CR-糖水组由20. 6%下降至16. 7%(P 0. 001)。结论:在条件记忆形成期,吗啡可提高条件记忆的强度,并加强困难条件下的觅药行为。BLA内SIRT1可能对成瘾记忆形成及巩固发挥重要调控作用。     

Glucagon-like peptide 1 receptor signaling influences topography of islet cells in mice

Glucagon-like peptide 1 (GLP-1) amplifies glucose-induced insulin release in vivo and in vitro. Activation of GLP-1 receptor (GLP-1R) signaling leads to differentiation of exocrine cells towards a beta-cell phenotype in vitro and stimulation of islet cell proliferation in vitro and in vivo, suggesting a potential role for GLP-1 in the modulation of islet growth and differentiation. To determine whether basal levels of GLP-1R signaling are essential for islet development, we examined islet cell composition and topography in GLP-1R-/- mice. Total beta-cell volume and number are not altered, but the topography of beta cells is markedly different in GLP-1R-/- mice compared with GLP-1R+/+ controls. The distribution of beta cells is shifted from large to small and medium-sized islets in the absence of GLP-1R signaling (large islets: 50 +/- 3% in GLP-1R+/+ vs 28 +/- 4% in GLP- 1R-/-, P < 0.01 and medium islets: 32 +/- 2% in GLP- 1R+/+ vs 48 +/- 3% in GLP-1R-/-, P < 0.001). Furthermore, GLP-1R-/- islets exhibit abnormalities in cell topography, with two to threefold more centrally located alpha cells detected in GLP-1R-/- islets. These alterations in alpha- and beta-cell topography indicate that basal levels of GLP-1 signaling in the normal rodent are involved in the normal cellular organization of the endocrine pancreas.     

白藜芦醇通过上调SIRT1促进退变髓核细胞胞外基质合成

目的:研究白藜芦醇(RES)对人退变椎间盘髓核细胞(DNPCs)合成细胞外基质(ECM)的影响.方法:对人退变椎间盘髓核组织进行分离、单层培养细胞鉴定、藻酸盐培养.取原代藻酸盐培养细胞分别用0、12.5、25、50、100、200μmol/L的RES分别刺激DNPCs 12、24、48 h,Western blot法检测沉默交配型信息调节因子2同源蛋白1(silent mating type information regulation 2 homolog 1,SIRT1)、Ⅱ型胶原(Colla2α1)、蛋白聚糖聚合物(aggrecan)蛋白表达,real-time 荧光定量PCR检测SIRTl mRNA表达水平.用SIRT1-siRNA 转染后再与100 μmol/L RES共培养24h,观察Colla2α1、aggrecan的蛋白表达.结果:RES上调SIRTl mRNA和蛋白水平的表达,促进DNPCs合成ECM的表达,与对照组相比具有统计意义(P＜0.05).siRNA靶向沉默SIRT1表达后,再加入RES刺激,观察到Colla2α1与aggrecan的蛋白表达与对照组相比显著下降(P＜0.05).结论:RES可刺激DNPCs ECM的合成,且呈现一定的量效关系,这种调节作用与SIRT1的活性有关.     

脂联素及其受体在酒精性肝病大鼠肝组织中的表达下降

目的探讨脂联素(Adip)及其受体1和2(AdipoR1,AdipoR2)在酒精性肝病(ALD)发病过程中的表达及意义。方法Wistar大鼠分为对照组和模型组,给模型组大鼠逐渐增加酒精浓度和剂量[30%～60%,5～9 g/(kg.d)]灌胃,分别于4、8、12和16周末随机分批处死,制备10%的肝匀浆,用比色法检测肝组织三酰甘油(TG);酶联免疫吸附法(ELISA)测定血清中TNFα和Adip含量;用RT-PCR和Western blot法观察肝组织Adip、AdipoR1和AdipoR2mRNA及蛋白表达。结果成功制造酒精性肝病大鼠模型,随着时间的延长血清TNFα和肝匀浆TG含量增高,血清Adip含量逐渐减少;肝组织Adip和AdipoR2mRNA和蛋白表达量逐渐减弱而AdipoR1无明显变化,血清Adip和肝组织AdipoR2蛋白表达量与血清TNF-α和肝匀浆TG呈负相关(P<0.01),血清Adipo检测水平与其肝组织蛋白表达量间呈正相关(P<0.01)。结论Adip及其AdipoR2在ALD模型大鼠肝组织表达减弱与肝细胞脂肪变和肝脏炎症反应密切相关。     

SIRT1/eNOS/NO通路在人参皂苷Rb1抗内皮细胞复制性衰老中的作用

目的:观察人参皂苷Rb1延缓人脐静脉内皮细胞(HUVECs)复制性衰老的作用,并探讨SIRT1/e NOS/NO通路在其中的作用机制。方法:建立原代HUVECs复制性衰老模型,根据细胞形态的变化、衰老相关β-半乳糖苷酶(SA-β-Gal)染色阳性率和纤溶酶原激活物抑制剂1(PAI-1)的表达水平评估HUVECs衰老情况;采用real-time PCR方法和Western blot法检测沉默SIRT1前后衰老细胞中e NOS和PAI-1的mRNA和蛋白表达,并检测细胞上清NO的含量。结果:累积细胞群体倍增水平(CPDL)为16的HUVECs可作为复制性衰老模型; 80μmol/L人参皂苷Rb1处理后衰老细胞内SIRT1和eNOS的mRNA及蛋白表达水平增加,NO含量增加(P 0. 05),而PAI-1的mRNA和蛋白表达水平下降(P 0. 05);沉默SIRT1后,衰老细胞内e NOS的mRNA及蛋白表达减少,PAI-1的mRNA及蛋白表达增加,NO含量减少(P 0. 05);与SIRT1沉默组比较,在沉默SIRT1基础上加用人参皂苷Rb1后,e NOS和PAI-1表达水平及NO的含量未见明显变化。结论:人参皂苷Rb1可通过调控SIRT1/e NOS/NO通路延缓HUVECs复制性衰老。     

Renal Angiotensin receptor type 1 and 2 upregulation in intrauterine growth restriction of newborn piglets

Epidemiological and experimental studies suggest that intrauterine growth restriction (IUGR) is associated with abnormalities in kidney development which is thought to be linked with alterations causing adult cardiovascular diseases. The renin-angiotensin system (RAS) plays an important role in the development of renal vascular and tubular structures, and is known to be altered by experimentally induced IUGR. These experimental models of IGUR have been criticized because they may have a more severe impact on intrauterine development than that which is normally encountered in humans. Therefore, we asked whether naturally occurring small-for-gestational-age newborn piglets exhibit features of altered RAS activity. We investigated the regional renal expression of angiotensin II type 1 (AT1) and AT2 receptors in normal-weight and IUGR piglets. The AT1 receptor mRNA expression was markedly enhanced in IUGR piglets, in the renal cortex by 64% and in the renal medulla by 52% (p < 0.05, compared with normal littermates). In contrast, mRNA expression for the AT2 receptor was similar in both the normal-weight and IUGR piglets. A significantly higher AT1 receptor protein expression was found in the IUGR piglets (p < 0.05) in the glomeruli, in the proximal and distal tubules, as well as in the collecting ducts by immunohistochemistry. Furthermore, AT2 receptor protein expression was significantly higher in the IUGR piglets (p < 0.05) in the subcapsular nephrogenic zone and in the distal tubules and collecting ducts. Thus, IUGR is accompanied by an upregulation of angiotensin II receptor expression in the kidneys of newborn piglets. This may indicate an alteration of the RAS in newborns suffering from naturally occurring IUGR.     

Role of SIRT1 and AMPK in mesenchymal stem cells differentiation

The differentiation capabilities of mesenchymal stem cells (MSCs) compromise with age and with in vitro passages which could impair the efficacy of cell therapy and tissue engineering. However, how to maintain these capabilities is not fully understood. Calorie restriction (CR, decreasing caloric intake by 30–40%) could extend longevity and reduce aging-related diseases. Recent studies revealed that CR could influence the lineage determination of stem cells including MSCs. Two important mediators of CR might be silent mating type information regulation 2 homolog 1 (SIRT1), a NAD⁺-dependent deacetylase, and AMP-activated protein kinase (AMPK), an energy-sensing kinase. Evidences are mounting that both SIRT1 and AMPK play important roles in cell fate determination of MSCs. Herein, we intend to sum up our understanding about the role of SIRT1 and AMPK in osteogenic and adipogenic potential of MSCs. Metabolic process of MSCs differentiation and the putative interplay of SIRT1 and AMPK in this process was also discussed.     

能量限制条件下SIRT1和SIRT2的表达变化

目的研究不同程度的能量限制（CR）下,大鼠脑组织中SIRT1和SIRT2的表达变化。方法 60只大鼠随机分成四组：正常对照组、75%CR组（喂养食物为正常对照组的75%）,55%CR组（喂养食物为正常对照组的55%）和高脂组,喂养8周。免疫组织化学检测大鼠脑组织中SIRT1和SIRT2的表达与定位。RT-PCR及Western-blot检测各实验组中SIRT1、SIRT2的表达。结果在大鼠脑组织中发现SIRT1可于细胞浆和细胞核中表达,且主要于细胞核中表达;SIRT2主要在细胞核中表达。能量限制下,与对照组相比SIRT1表达升高;高脂食物条件下,SIRT1表达相对于对照组增高,但是比CR组减少。75%CR与55%CR相比,后者中的SIRT1的表达增加更多。与对照组相比,55%CR增加SIRT1的表达差异有统计学意义（P〈0.05）,而75%CR和HFa增加SIRT1的表达差异无统计学意义。SIRT2在CR和HFa下表达无明显变化。结论 CR能增加SIRT1而不增加SIRT2的表达,重度CR比中等程度CR对SIRT1表达的影响更大。     

Role of peptide-leukotrienes in liver injury in mice

The role of peptide leukotrienes (p-LTs), especially LTC₄ and LTD₄ in liver disease, was investigated in mice experimental liver injury models. The liver injury was induced by the injection of bacterial lipopolysaccharide (LPS) intoCorynebacterium parvum pretreated mice. Carbon tetrachloride (CCl₄)-induced liver injury in mice was used as a standard model. In both injury models, extensive liver parenchymal cell damage was observed by the elevation of glutamate transaminase (GOT and GPT) activity and confirmed by significant histopathological changes in the liver. Moreover, significant elevation of LTC₄ in the liver was observed in both models 1 and 6 h after the onset of disease. Administration of AA-861, a selective 5-lipoxy-genase inhibitor (0.5, 1, and 2 mg/kg) and LY-171883, a p-LT receptor antagonist (50 and 200 mg/kg) suppressed the elevation of serum GOT and GPT levels and histopathological changes in both experimental liver injury models. In addition, when authentic LTC₄ or LTD₄ was injected into the mouse, clear elevation of serum GOT and GPT and histopathological changes of the liver were observed. These results suggest that p-LTs play a role in the onset of liver diseases in mice.     

Role of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2A receptor signaling in the neostriatum

Adenosine is known to modulate the function of neostriatal neurons. Adenosine acting on A(2A) receptors increases the phosphorylation of dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) at Thr34 (the cAMP-dependent protein kinase [PKA] site) in striatopallidal neurons, and opposes dopamine D2 receptor signaling. In contrast, the role of adenosine A(1) receptors in the regulation of dopamine/DARPP-32 signaling is not clearly understood. Here, we investigated the effect of adenosine A(1) receptors on D(1), D(2) and A(2A) receptor signaling using mouse neostriatal slices. An A(1) receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (100 nM), caused a transient increase, followed by a transient decrease, in DARPP-32 Thr34 phosphorylation. Our data support the following model for the actions of the A(1) receptor agonist. The A(1) receptor-induced early increase in Thr34 phosphorylation was mediated by presynaptic inhibition of dopamine release, and the subsequent removal of tonic inhibition by D(2) receptors of A(2A) receptor/G(olf)/cAMP/PKA signaling. The A(1) receptor-induced late decrease in Thr34 phosphorylation was mediated by a postsynaptic G(i) mechanism, resulting in inhibition of D(1) and A(2A) receptor-coupled G(olf)/cAMP/PKA signaling in direct and indirect pathway neurons, respectively. In conclusion, A(1) receptors play a major modulatory role in dopamine and adenosine receptor signaling.     

脂联素受体在人肾上腺皮髓质及其肿瘤中的不同表达

目的 观察脂联素受体1(AdipoR1)、脂联素受体2(AdipoR2)在正常肾上腺皮、髓质及其肿瘤中的mRNA表达.方法 提取6例正常人肾上腺皮质和髓质、10例皮质醇分泌瘤、14例醛固酮分泌瘤和20例嗜铬细胞瘤组织的总RNA,用RT-PCR方法检测AdipoR1、AdipoR2 mRNA表达;并分析AdipoR2与Adipo1的关系.31例患者曾行3 h葡萄糖耐量试验(OGTF),比较AdipoR1/R2与患者OGTT时血糖和胰岛素曲线下面积(GLU<,AUC>、INS<,AUC>)间的关系.结果 在肾上腺皮、髓质及其肿瘤中存在AdipoR1、AdipoR2的mRNA表达.AdipoR1 mRNA在正常肾上腺皮质内的表达明显低于皮质醇分泌瘤和醛固酮分泌瘤(P<0.01),AdipoR1 mRNA在嗜铬细胞瘤内的表达明显高于正常肾上腺髓质(P<0.01).AdipoR2 mRNA在正常肾上腺皮质内的表达明显低于皮质醇分泌瘤(P<0.05).皮质醇分泌瘤内AdipoR2 mRNA表达明显高于醛固酮分泌瘤(P<0.05).在所有组织中,AdipoR2与AdipoR1 mRNA表达高度相关r=0.335,P<0.01),AdipoR2 mRNA表达与GLU<,AUC>呈正相关(r=0.633,P<0.001).结论 肾上腺皮髓质及其肿瘤广泛表达脂联素受体并存在差异,可能与不同的脂联素水平相关.     

Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.     

Protease-activated receptor 2 signaling in inflammation

Protease-activated receptors (PARs) are G protein-coupled receptors that are activated by proteolytical cleavage of the amino-terminus and thereby act as sensors for extracellular proteases. While coagulation proteases activate PARs to regulate hemostasis, thrombosis, and cardiovascular function, PAR2 is also activated in extravascular locations by a broad array of serine proteases, including trypsin, tissue kallikreins, coagulation factors VIIa and Xa, mast cell tryptase, and transmembrane serine proteases. Administration of PAR2-specific agonistic and antagonistic peptides, as well as studies in PAR2 knockout mice, identified critical functions of PAR2 in development, inflammation, immunity, and angiogenesis. Here, we review these roles of PAR2 with an emphasis on the role of coagulation and other extracellular protease pathways that cleave PAR2 in epithelial, immune, and neuronal cells to regulate physiological and pathophysiological processes.