胰岛素受体底物在乳腺发育和恶性转化中的作用

胰岛素受体底物 (insulin receptor substrates，IRSs)家族是胰岛素受体（insulin receptor，IR）、胰岛素样生长因子-1受体（insulin like growth-1 receptor，IGF-1R）酪氨酸蛋白激酶的主要细胞内底物，主要介导细胞对胰岛素、胰岛素样生长因子-1、白介素、干扰素、肿瘤坏死因子等多种细胞因子的反应。作为结合蛋白，它们通过连接并传递从上游的激活子到下游的效应器之间的信号，从而调节细胞正常的生长、代谢、生存与分化。在胰岛素受体底物家族接受并应答的众多细胞外信号中，大部分是与乳腺发育相关的关键信号，该蛋白在乳腺细胞中的表达是否正常决定乳腺细胞是正常发育还是恶性转化。     

KIT(CD117)在多种正常或肿瘤组织中的表达以及突变与临床病理特征间的相互关系

CD117（KIT）是一种Ⅲ型受体酪氨酸激酶，在多种类型细胞的信号传导通路中发挥作用。正常情况下，KIT结合其受体——干细胞因子后被激活（磷酸化），导致磷酸化级联反应，最终在不同类型的细胞中激活各种相应转录因子。这种激活作用能够调节凋亡、细胞分化、增殖、趋化以及细胞黏附。     

白介素-2及其受体在自身免疫病发病中作用的研究进展

目前已证明IL-2及其受体异常与多种自身免疫病有关。IL-2主要由T细胞产生，是一种促进T细胞发育、分化的细胞因子。IL-2与受体结合具有浓度依赖特点，低剂量IL-2能在不激活效应T细胞的同时激活Treg细胞从而抑制免疫反应。明确IL-2及其受体的免疫调节功能对研究免疫疾病的发病机制及治疗具有重要意义。本文将结合IL-2及其受体的结构和功能特点，探讨其在自身免疫病中如何参与发病和发挥免疫调节作用，为低剂量IL-2靶向性临床应用的理论依据作一简要论述。     

脂联素调控SDF-1α/CXCR4信号轴在炎症微环境下牙周膜干细胞成骨分化中的作用

目的 研究脂联素通过调控基质细胞衍生因子-1α(SDF-1α)/CXC趋化因子受体4(CXCR4信号轴对炎症微环境下牙周膜干细胞（PDLSCs）成骨分化中的影响。方法 原代培养PDLSCs后取第三代细胞进行分组处理，进行成骨分化诱导并用10 ng/mL肿瘤坏死因子-α(TNF-α)模拟微炎症环境、用10μg/mL脂联素处理、转染阴性对照（NC）或SDF-1α的siRNA。成骨诱导第3、5、7 d时，检测碱性磷酸酶（ALP）活性，骨钙素（OCN）、骨保护素（OPN）、SDF-1α、CXCR4的m RNA表达，SDF-1α的含量；成骨诱导第21 d时，进行茜素红染色、观察钙盐沉积情况。结果 炎症微环境下PDSCSs的成骨分化及SDF-1α/CXCR4信号轴的激活均受到抑制；脂联素在炎症微环境下促进PDSCSs的成骨分化及SDF-1α/CXCR4信号轴的激活；转染SDF-1α的siRNA后，SDF-1α/CXCR4信号轴的激活受到抑制，脂联素在炎症微环境下促进PDSCSs成骨分化的作用也被抑制。结论 脂联素通过激活SDF-1α/CXCR4信号轴促进炎症微环境下PDSCSs的成骨分化。     

代谢性核受体及其与代谢综合征的关系

代谢性核受体是一组与代谢调节相关的配体激活核受体转录因子,主要包括脂质过氧化物体增殖物激活受体(PPARs)、肝X受体(LXRs)和法尼酯衍生物X受体(FXRs)3种。它们在胰岛素敏感性、脂肪生成、脂质代谢、能量代谢、血压调节、炎症、细胞生长和分化等过程中起着关键的调节作用,因而近年来倍受关注。越来越多的研究表明这3种核受体不仅与代谢综合征,包括胰岛素抵抗、糖耐量受损2、型糖尿病、肥胖、高脂血症、高血压和微白蛋白尿之间存在密切的关系,也在动脉粥样硬化的发生及发展中有重要的作用。本文就代谢性核受体的生物学活性和生理功能作一简述,并对其在代谢综合征发病机制中的作用进行重点讨论。     

胰岛素样生长因子结合蛋白与胰岛素抵抗的关系

胰岛素样生长因子（Insulin-like growth factor,IGF）系统是一个由配体、受体、结合蛋白及蛋白酶构成的复杂网络,会受到诸多因子的调节。该系统中的胰岛素样生长因子结合蛋白(insulin like growth factor binding protein)在不同细胞的增殖和分化中起着重要的作用。临床及体内外研究表明胰岛素抵抗形成过程中,IGFBP出现异常表达。IGFBP通过不同机制抑制或促进胰岛素抵抗的形成。     

GITR/GITRL系统在免疫调节中的作用

糖皮质激素诱导的肿瘤坏死因子受体（glucocorticoid-induced tumor necrosis factor receptor，GITR）是肿瘤坏死因子受体超家族（TNFRSF）中的第18个成员，是胸腺来源的CD4^＋CD25^＋调节性T细胞（regulatory T cell，Treg）上的一个表面分子，其配体为GITRL。自发现GITR／GITRL以来，大量研究表明，GITR／GITRL具有许多重要的生物学活性，包括细胞的增殖、分化和存活等。     

脑缺血后TLR4作用与小胶质细胞的激活

脑缺血性损伤早期小胶质细胞即被激活。激活的小胶质细胞既有细胞毒性又有神经营养作用。小胶质细胞行使免疫功能的信号转导受体之一是TLR4（toll-like receptor 4）。TLR4在脑内主要表达在小胶质细胞，是一种模式识别受体（pattern recognition receptor，PRR）, 识别一些外源性和内源性的配体。最近的研究表明，TLR4信号通路在脑缺血再灌注损伤中起重要作用。TLR4通过激活小胶质细胞，大量表达炎症因子，加重脑缺血性损伤。     

可溶性TNF受体在大肠杆菌中表达

ＴＮＦ受体（ＴＮＦＲ）通过介导ＴＮＦ的信息而在炎症、肿瘤坏死、细胞增殖、分化及凋亡中发挥着重要作用。ＴＮＦＲ信号传导机理及其在诱导细胞凋亡和激活核因子ＮＦ－ＫａｐｐａＢ之间的平衡是目前研究的热点。为了探索ＴＮＦＲ在炎症及肿瘤细胞中的作用，我们克隆并表...     

人胎盘间充质干细胞诱导分化为胰岛素分泌细胞的研究

目的：探索人胎盘间充质干细胞（MSCs）分化为胰岛素分泌细胞的诱导条件。方法从胎盘组织中获取MSCs,采用激活素A、表皮生长因子（EGF）、碱性成纤维细胞生长因子（bFGF）等多种细胞因子诱导胎盘MSCs向胰岛素分泌细胞分化。利用免疫细胞化学染色、Western Blot及动物实验,对诱导后的细胞进行鉴定。结果经诱导后的细胞具备胰岛β细胞的部分特征,能表达胰十二指肠同源盒-1（PDX-1）、胰岛素和C肽,对糖尿病小鼠具有降糖作用。结论人胎盘MSCs经多种细胞因子诱导后可分化为胰岛素分泌细胞。     

Circulating and local visfatin/Nampt/PBEF levels in spontaneously hypertensive rats,stroke-prone spontaneously hypertensive rats and Wistar-Kyoto rats

Visfatin (also known as nicotinamide phosphoribosyltransferase and pre-B cell colony-enhancing factor) is a multifunctional protein. Visfatin has been reported to be involved in several biological processes in the cardiovascular system, . However, the role of visfatin in hypertension is still unclear. In this study, we examined the circulating and local adipose visfatin levels in spontaneously hypertensive rats (SHR), stroke-prone spontaneously hypertensive rats (SHR-SP), and in their normotensive control Wistar-Kyoto (WKY). SHR and SHR-SP rats exhibited lower body weight, lower fat tissue and hypolipidemia. No differences of serum visfatin levels were observed in SHR/SHR-SP and WKY. Serum visfatin levels did not correlate to serum glucose, lipids, insulin, and fat pad weights, but significantly correlated to weights of skeletal muscle. Visfatin expression in visceral fat tissue was slightly lower in SHR-SP compared with that in WKY. Moreover, there were no significant differences of visfatin expression in skeletal muscles among WKY, SHR and SHR-SP. Finally, visfatin protein was detected in L6 rat skeletal muscle cell culture medium, indicating that visfatin was secreted from skeletal muscle cells. Thus, our results may provide useful information for understanding the characteristic of visfatin in hypertensive models, and support the view that visfatin may be a myokine.     

Effect of non surgical periodontal therapy on gingival crevicular fluid and serum visfatin concentration in periodontal health and disease

Visfatin is a pleiotropic mediator which acts as growth factor, cytokine, enzyme involved in energy including nicotinamide adenine dinucleotide metabolism and has been recently demonstrated to exert several pro-inflammatory functions. The purpose of this study is to evaluate the Visfatin concentration in gingival crevicular fluid (GCF) and serum in patients with chronic periodontitis, and to evaluate the effect of non-surgical periodontal therapy on the GCF and serum visfatin concentration. 30 subjects (age range: 25 to 52 years) were selected and divided into two groups based on the gingival index, probing depth, periodontal attachment level, and radiologic parameters (bone loss): group 1 (15 subjects with healthy periodontium), group 2 (15 subjects with chronic periodontitis), while, Group 2 patients after 8 weeks of the treatment (scaling and root planning, SRP) constituted group 3. GCF samples (by microcapillary pipettes) and serum samples (by venipuncture) were collected to estimate the levels of Visfatin using enzyme linked immunosorbent assay kit. The mean Visfatin concentration in GCF and serum was observed to be the highest in group 2 and lowest in group 1. While concentration in group 3 was similar to group 1. The concentration of Visfatin in GCF and serum decreased after SRP. The Visfatin concentration in GCF and serum found to be highest in chronic periodontitis group and decreases after treatment. Hence Visfatin values can be considered as an "inflammatory marker" can be explored in future as a potential therapeutic target in the treatment of periodontal disease.     

The circulating PBEF/NAMPT/visfatin level is associated with a beneficial blood lipid profile

Visfatin with the official gene name pre-B cell colony-enhancing factor 1 (PBEF) and the protein name nicotinamide phosphoribosyltransferase (NAMPT) is a recently discovered adipocyte-secreted protein that was shown by some to be associated with visceral fat and insulin resistance. To explore the link between PBEF/NAMPT/visfatin and lipid metabolism, we analyzed the relation of its plasma level with several parameters of adiposity, insulin resistance and the circulating blood lipid profile in a group of general population (n = 40) and a group of subjects who are genetically predisposed to insulin resistance and hyperlipidemia (n = 35). In both groups and pooled cohort, PBEF/NAMPT/visfatin lacked association with whole body adiposity, but correlated positively with HDL-cholesterol and negatively with triglycerides. The data suggested a negative correlation of the PBEF level with visceral fat and insulin resistance. But this negative correlation completely disappeared after adjustment for lipid profile. We concluded that circulating PBEF/NAMPT/visfatin level is an indicator of beneficial lipid profile in non-diabetic Caucasian subjects. The relation to lipid metabolism does not depend on visceral obesity and insulin resistance, but may be linked to its enzymatic function in NAD metabolism.     

Visfatin/PBEF/Nampt induces EMMPRIN and MMP-9 production in macrophages via the NAMPT-MAPK (p38, ERK1/2)-NF-κB signaling pathway

The adipocytokine visfatin is closely associated with metabolic disorders. This study explored the effects of visfatin on macrophage-induced inflammation in atheroma. The ability of visfatin to enhance extracellular matrix metalloproteinase inducer (EMMPRIN) expression, matrix metalloproteinase-9 (MMP-9) production and enzymatic activity in THP-1 derived macrophages as well as the mechanisms involved were investigated. EMMPRIN and MMP-9 mRNA levels were investigated by RT-PCR. EMMPRIN and MMP-9 protein levels, nuclear factor (NF)-κB -p65 protein levels, peroxisome proliferator-activated receptor?γ (PPARγ) protein levels, and mitogen-activated protein kinase (MAPK) phosphorylation were determined by Western blotting. MMP-9 enzymatic activity was assayed by gelatin zymography. Visfatin (50-400?ng/ml) induced EMMPRIN and MMP-9 depending on the dosage used. Visfatin elicited the activation of NF-κB and MAPK (p38,?ERK1/2). Exogenous nicotinamide mononucleotide (NMN), the product of nicotinamide phosphoribosyltransferase (NAMPT) activity, mimicked the effects of visfatin on MAPK (p38,?ERK1/2)-NF-κB activation and EMMPRIN/MMP-9 induction. Using the p38 inhibitor, SB203580, the ERK1/2 inhibitor PD98059, the NF-κB inhibitor, pyrrolidine dithiocarbamate and the NAMPT inhibitor FK866, we demonstrated that the visfatin pro-inflammatory action was through the NAMPT-MAPK (p38,?ERK1/2)-NF-κB pathway. Furthermore, the visfatin pro-inflammatory action was not prevented by insulin receptor blockade or by a PPARγ agonist. Visfatin did not modulate PPARγ expression. Retinoid X receptor (RXR) agonist suppressed the effects of visfatin on EMMPRIN/MMP-9, NF-κB, but not on MAPK activation. In conclusion, we have demonstrated that visfatin enhances atheroma inflammation through the NAMPT-MAPK (p38,?ERK1/2)-NF-κB-EMMPRIN/MMP-9 pathway, a key feature of atherosclerotic diseases linked to metabolic disorders.     

Inhibition of visfatin alleviates sepsis-induced intestinal damage by inhibiting Hippo signaling pathway

Background

The aim of this study is to investigate role of Visfatin, one of the pro-inflammatory adipokines, in sepsis-induced intestinal injury and to clarify the potential mechanism.

Methods

C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to establish sepsis model in vivo. Intestinal epithelial cells were stimulated with LPS to mimic sepsis-induced intestinal injury in vitro. FK866 (the inhibitor of Visfatin) with or without XMU-MP-1 (the inhibitor of Hippo signaling) was applied for treatment. The expression levels of Visfatin, NF-κB and Hippo signaling pathways-related proteins were detected by western blot or immunohistochemistry. The intestinal cell apoptosis and intestinal injury were investigated by TUNEL staining and H&E staining, respectively. ELISA was used to determine the production of inflammatory cytokines.

Results

The expression of Visfatin increased in CLP mice. FK866 reduced intestinal pathological injury, inflammatory cytokines production, and intestinal cell apoptosis in sepsis mice. Meanwhile, FK866 affected NF-κB and Hippo signaling pathways. Additionally, the effects of FK866 on inflammatory response, apoptosis, Hippo signaling and NF-κB signaling were partly abolished by XMU-MP-1, the inhibitor of Hippo signaling. In vitro experiments also revealed that FK866 exhibited a protective role against LPS-induced inflammatory response and apoptosis in intestinal cells, as well as regulating NF-κB and Hippo signaling, whereas addition of XMU-MP-1 weakened the protective effects of FK866.

Conclusion

In short, this study demonstrated that inhibition of Visfatin might alleviate sepsis-induced intestinal injury through Hippo signaling pathway, supporting a further research on Visfatin as a therapeutic target.

     

Visfatin Plays a Significant Role in Alleviating Lipopolysaccharide-Induced Apoptosis and Autophagy Through PI3K/AKT Signaling Pathway During Acute Lung Injury in Mice

Archivum Immunologiae et Therapiae Experimentalis - Visfatin is involved in the body’s inflammation and immune response. Inflammation could promote, while visfatin may directly or indirectly...     

Nicotinamide attenuates aquaporin 3 overexpression induced by retinoic acid through inhibition of EGFR/ERK in cultured human skin keratinocytes

The most common adverse effects that are related to all-trans retinoic acid (atRA) treatment are irritation and dryness of the skin. atRA therapy is reported to impair barrier function as achieved by trans-epidermal water loss (TEWL). Treatment with nicotinamide prior to initiation of atRA therapy provides additional barrier protection and thus reduces susceptibility of retinoic acid. Our previous studies showed that atRA upregulates aquaporin 3 (AQP3) in cultured human skin keratinocytes and fibroblasts. Others have demonstrated that in atopic dermatitis, overexpression of AQP3 is linked to elevated TEWL and that nicotinamide treatment reduces skin TEWL. In this study, we observed that while atRA upregulates AQP3 expression in cultured human skin keratinocytes (HaCaT cells), nicotinamide attenuates the effect of atRA in a concentration-dependent manner. atRA treatment induces EGFR and ERK activation. PD153035, an EGFR inhibitor, and U0126, an ERK inhibitor, inhibit atRA-induced upregulation of AQP3. Nicotinamide also inhibits atRA-induced activation of EGFR/ERK signal transduction and decreases water permeability by downregulating AQP3 expression. Collectively, our results indicate that the effect of atRA on AQP3 expression is at least partly mediated by EGFR/ERK signaling in cultured human skin keratinocytes. Nicotinamide attenuates atRA-induced AQP3 expression through inhibition of EGFR/ERK signal transduction and eventually decreases water permeability and water loss. Our study provides insights into the molecular mechanism through which nicotinamide reverses the side effects of dryness in human skin after treatment with atRA.     

Pyridine nucleotide regulation of the KATP channel Kir6.2/SUR1 expressed in Xenopus oocytes

The pancreatic β-cell type of ATP-sensitive potassium (K_ATP) channel (Kir6.2/SUR1) is inhibited by intracellular ATP and ADP, which bind to the Kir6.2 subunit, and is activated by Mg-nucleotide interaction with the regulatory sulphonylurea receptor subunits (SUR1). The nicotinamide adenine dinucleotides NAD and NADP consist of an ADP molecule with a ribose group and a nicotinamide moiety attached to the terminal phosphate. Both these molecules block native K_ATP channels in pancreatic β-cells at concentrations above 500 μM, and activate them at lower concentrations. We therefore investigated whether NAD and NADP interact with both Kir6.2 and SUR1 subunits of the K_ATP channel by comparing the potency of these agents on recombinant Kir6.2ΔC and Kir6.2/SUR1 channels expressed in Xenopus oocytes. Our results show that, at physiological concentrations, NAD and NADP interact with the nucleotide inhibitory site of Kir6.2 to inhibit Kir6.2/SUR1 currents. They may therefore contribute to the resting level of channel inhibition in the intact cell. Importantly, our data also reveal that this interaction is dependent on the presence of SUR1, which may act by increasing the width of the nucleotide-binding pocket of Kir6.2.     

GABA(B) receptors in the nucleus tractus solitarii modulate the carotid chemoreceptor reflex in rats

Ischemia depletes ATP and initiates cascades leading to irreversible tissue injury. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD+) which increases neuronal ATP concentration and protects against malonate-induced neurotoxicity, trauma and nitric oxide toxicity. We therefore examined whether nicotinamide could protect against stroke, using a model of permanent middle cerebral artery occlusion (MCA) occlusion in Wistar rats. Nicotinamide reduced neuronal infarction in a dose-specific manner. Furthermore, nicotinamide (500 mg/kg) reduced infarcts when administered up to 2 h after the onset of permanent MCA occlusion. The mechanism of action underlying the neuroprotection observed with nicotinamide remains to be clarified. These results are potentially important since nicotinamide is already used clinically, though not in the treatment of stroke.     

Visfatin Levels in Behcet’s Disease

The aim of our study is to determine the serum visfatin levels of patients with Behcet’s disease and to investigate the relationship between visfatin, an adipokine released from adipose tissue, levels and activity of Behcet’s disease. Fifty-eight patients with Behcet’s disease were enrolled to the study. Nineteen of the patients were inactive, and 39 of them were active. We enrolled 30 healthy subjects as being control group. Visfatin and tumor necrosis factor alpha (TNF-α) levels were measured with ELISA method. Visfatin levels were significantly lower in patients with Behcet’s disease whose illnesses were active or inactive than the control group (p < 0.05). There was no significant difference between the active patient and inactive patient group. The reason for the lower levels of serum visfatin in active and inactive patients’ group could be due to pro-inflammatory cytokines such as TNF-α and IL-6 which suppress genetic expression of visfatin in patients with Behcet’s disease, or else.