高脂饮食对法尼醇受体(FXR)敲除小鼠糖脂代谢及肝脏脂肪变性的影响研究

目的探讨高脂饮食对法尼醇受体（farnesoid X receptor,FXR）敲除小鼠糖脂代谢及肝脏脂肪变性的影响。方法正常饮食（normal diet,ND）组:C57BL/6（wild type,WT）小鼠（n=6）和FXR -/- 小鼠（n=6）给予辐照灭菌维持饲料喂养12周。高脂饮食（high fat diet,HFD）组:C57BL/6小鼠（n=6）和FXR -/- 小鼠（n=6）给予45%高脂饲料喂养12周。小鼠处死后全自动生化分析仪检测血清总胆固醇（total cholesterol,TC）、甘油三酯（triglyceride,TG）、低密度脂蛋白胆固醇（low density lipoprotein cholesterol,LDL-C）、高密度脂蛋白胆固醇（High density lipoprotein cholesterol,HDL-C）、谷丙转氨酶（alanine aminotransferase,ALT）、谷草转氨酶（aspartate aminotransferase,AST）和总胆汁酸（total bile acid,TBA）指标; RT-PCR检测肝脏炎症因子TNF-α、TLR4和FXR下游基因小分子异源二聚体（small heterodimer partner,SHP）、胆固醇7α-羟化酶（cholesterol 7α-hydroxylase,CYP7A1）的相对表达量; HE染色观察肝脏脂肪变性情况。结果高脂饮食喂养条件下,C57BL/6小鼠和FXR -/- 小鼠体质量变化无差异,但相比C57BL/6小鼠,FXR -/- 小鼠表现出更为严重糖耐量受损（P <0. 01）、脂质代谢紊乱（P <0. 01）、血清胆汁酸增高（P <0. 01）、肝脏炎症（P <0. 01）和肝脏脂肪变性。结论 FXR的缺失引起小鼠糖脂代谢紊乱、胆汁酸代谢异常、肝脏脂肪变性,但这种改变需要高脂饮食的诱导。     

NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens

Members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family contribute to immune responses through activation of nuclear factor-κB (NF-κB), type I interferon and inflammasome signalling. Mice lacking the NLR family member NLRP6 were recently shown to be susceptible to colitis and colorectal tumorigenesis, but the role of NLRP6 in microbial infections and the nature of the inflammatory signalling pathways regulated by NLRP6 remain unclear. Here we show that Nlrp6-deficient mice are highly resistant to infection with the bacterial pathogens Listeria monocytogenes, Salmonella typhimurium and Escherichia coli. Infected Nlrp6-deficient mice had increased numbers of monocytes and neutrophils in circulation, and NLRP6 signalling in both haematopoietic and radioresistant cells contributed to increased susceptibility. Nlrp6 deficiency enhanced activation of mitogen-activated protein kinase (MAPK) and the canonical NF-κB pathway after Toll-like receptor ligation, but not cytosolic NOD1/2 ligation, in vitro. Consequently, infected Nlrp6-deficient cells produced increased levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signalling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and -negative bacterial pathogens.     

Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.     

果糖饮水对Ⅱ型糖尿病ICR小鼠体重和血糖的影响

目的观察果糖饮水对高脂饲料-STZ诱导ICR小鼠Ⅱ型糖尿病模型过程中体重及血糖浓度变化的影响。方法选取ICR小鼠(3周龄)雌雄各半,先以高脂饲料及高脂饲料加3%果糖饮水喂养6周,再以链脲佐菌素(STZ)(100 mg/kg体重)腹腔注射,继续喂养6周。每周测定体重,于注射前及注射后4周测定非空腹血糖浓度。结果雄性高脂饲料-果糖饮水组和高脂饲料组体重显著高于对照组(P<0.05),而高脂饲料-果糖饮水组与高脂饲料喂养组间没有显著差异(P>0.05);雌性高脂饲料-果糖饮水组和高脂饲料组体重与对照组均无显著差异(P>0.05),但高脂饲料-果糖饮水组体重显著低于高脂饲料组(P<0.05)。喂养6周后(注射STZ前),高脂饲料-果糖饮水组和高脂饲料组的血糖浓度均显著高于对照组(P<0.05),而实验组间没有显著差异。注射STZ后,雄性高脂饲料-果糖饮水组和高脂饲料组的血糖浓度均显著高于对照组(P<0.01),并且都超过糖尿病小鼠非空腹血糖的成模标准(11 mmol/L),且高脂饲料-果糖饮水组血糖浓度又显著高于高脂饲料喂养组(P<0.05);雌性小鼠高脂饲料-果糖饮水组和高脂饲料组血糖浓度均显著高于对照组(P<0.01),但都没有达到糖尿病小鼠非空腹血糖的成模标准,且高脂饲料-果糖饮水组与高脂饲料组间血糖浓度没有显著差异(P>0.05)。结论在高脂饲料喂养联合腹腔注射STZ制备Ⅱ型糖尿病模型实验中,果糖饮水对高脂饲料致肥胖作用没有显著的改善,而对血糖浓度升高具有明显的促进作用。这种促进作用在雄性小鼠最为明显,而对雌性小鼠没有明显效果。     

南京体育学院教职工2006年血液检测结果分析

目的:分析我院教职工血液检测结果,以便更好地做到疾病的早发现、早治疗;方法:对930名教职工进行抽血并检测其血脂、血糖、血尿酸;结果:930名教职工中血脂增高者占39.5%,血糖增高者占9.78%,血尿酸增高者占12.80%,40岁以上教职工的异常检出率明显高于40岁以下者;结论:饮食搭配不科学,生活无规律,缺乏体育锻炼和嗜烟酒等是导致教职工高血脂、高血糖、高血尿酸等“三高”现象的主要原因。     

A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.     

Smad3基因剔除小鼠的基因型鉴定与繁殖性能研究

以前的研究显示Smad3基因剔除 (Smad3ex8 ex8)导致小鼠发生渐进性的白细胞增多症、牙周炎、胃炎、肠炎以及粘膜表面附近脓肿形成的慢性感染。对有症状的Smad3ex8 ex8小鼠淋巴结的组织学及免疫表型分析显示T细胞有增强的增殖能力及活化的表型。进一步的研究表明Smad3ex8 ex8小鼠胸腺细胞及外周T细胞彻底失去了对TGF β的应答。此外 ,Smad3ex8 ex8突变纯合子小鼠还表现出典型的骨关节炎、骨质疏松和创伤愈合速度加快表型。因此 ,Smad3ex8 ex8突变纯合子小鼠有可能作为研究粘膜免疫缺陷和骨性关节炎等疾病发生的分子机制的模型动物 ,为了…     

脂肪酶催化改性乳脂肪的应用研究

乳脂肪具有令人愉悦的风味但成分复杂，应用于食品领域时存在饱和脂肪酸含量较高，不利于健康，且在低温下涂抹性能较差等问题。利用脂肪酶的专一性和特殊性，可催化乳脂肪生成特殊结构的甘油三酿，得到风味饱满、营养价值高、利于应用的产物。现概述目前国内外脂肪酶酶解乳脂肪的研究进展及改性乳脂肪的应用，并介绍了用脂肪酶催化改性后乳脂肪的优点及应用，主要包括：生成更高含量的短链脂肪酸酯，提高低熔点甘油三酯的含量和降低饱和脂肪酸的含量三个方面。     

FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.     

ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.     

Innate immunity and intestinal microbiota in the development of Type 1 diabetes

Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing beta-cells. Its incidence has increased during the past several decades in developed countries, suggesting that changes in the environment (including the human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products. Here we show that specific pathogen-free NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free MyD88-negative NOD donors attenuates T1D in germ-free NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.     

肝郁脾虚证动物模型的研究进展

对近年来肝郁脾虚证动物模型的研究现状进行了评述 ,对存在的问题进行了分析讨论。肝郁脾虚证动物模型主要有CCl4 ,注射法、高脂饲料饲喂与CCl4 注射联合造模法、夹尾激怒加苦寒泻下法、限食限动加结肠注射醋酸法复制肝郁脾虚证或肝郁脾虚证溃疡性结肠炎病证结合模型 ,为肝郁脾虚证的深入研究开辟了新途径。但还存在一些问题 ,应进一步提高和完善 ,如在造模方法上应尽可能注意与中医传统病因学说的相似性 ,在模型症状指标上应结合动物的生理、病理特征建立起符合动物特性的统一的判断标准 ,并建立起本模型的生物学特征 ,在客观指标的确立上应重视多指标互参 ,在复健方药的选择上应力求标准化     

Cr3＋生理功能的研究进展

Cr3＋作为人体必需微量元素,在体内起到重要的生理作用,但是,最近有研究显示,饮食中缺少Cr3＋,可能对实验动物的身体不会造成任何影响．尽管如此,随着食物精炼和加工,导致食物中Cr3＋的大量流失,Cr3＋仍然可能影响核酸、蛋白质、碳水化合物和脂肪等生物大分子的代谢,饮食中适当地补充Cr3＋变得更加重要．膳食中补充Cr3＋,可能引起机体脂肪的流失增加,同时保持肌肉;克服胰岛素抵抗和改善糖尿病;抑制自由基的形成;降低总胆固醇和低密度脂蛋白（LDL）等各种生理反应．本文对Cr3＋在体内可能的生理功能做一综述．     

An obesity-associated gut microbiome with increased capacity for energy harvest

The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.     

Lifespan: catch-up growth and obesity in male mice

Poor fetal growth is linked with long-term detrimental effects on health in adulthood. Here we investigate whether the lifespan of male mice is affected by their growth rate when they were suckling and find that limiting growth during that period not only increases longevity but also protects against the life-shortening effect of an obesity-inducing diet later on. By contrast, we find that lifespan is considerably shortened if the postnatal period of growth is accelerated to make up for reduced growth in utero, and that, in addition, these mice are susceptible to the adverse effects on longevity of an obesity-inducing diet after weaning.     

Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence

Cell-surface heparan sulphate proteoglycans (HSPGs) are ubiquitous and abundant receptors/co-receptors of extracellular ligands, including many microbes. Their role in microbial infections is poorly defined, however, because no cell-surface HSPG has been clearly connected to the pathogenesis of a particular microbe. We have previously shown that Pseudomonas aeruginosa, through its virulence factor LasA, enhances the in vitro shedding of syndecan-1-the predominant cell-surface HSPG of epithelia. Here we show that shedding of syndecan-1 is also activated by P. aeruginosa in vivo, and that the resulting syndecan-1 ectodomains enhance bacterial virulence in newborn mice. Newborn mice deficient in syndecan-1 resist P. aeruginosa lung infection but become susceptible when given purified syndecan-1 ectodomains or heparin, but not when given ectodomain core protein, indicating that the ectodomain's heparan sulphate chains are the effectors. In wild-type newborn mice, inhibition of syndecan-1 shedding or inactivation of the shed ectodomain's heparan sulphate chains prevents lung infection. Our findings uncover a pathogenetic mechanism in which a host response to tissue injury-syndecan-1 shedding-is exploited to enhance microbial virulence apparently by modulating host defences.     

油脂和肥皂中脂肪酸组份的气相色谱分析

肥皂中脂肪酸组份的配比是制皂工业的基础。动、植物油脂中脂肪酸组份的含量随产地、品种差异很大,研究油脂和肥皂中各种脂肪酸组份的情况至关重要。 用双柱补偿气相色谱法,对厦门国际比学公司使用的椰子油、牛油等10多种原料油,以及对国内外性能优良的10多种肥皂中所含C_8～C~(20)饱和与不饱和的脂肪酸组份进行分离和测定。结果表明各种油脂中主要的脂肪酸成份与有关资料报道的基本相符,方法简便,重现性好,取得了较满意的结果,为制皂生产中油脂配方的数据处理提供依据。     

T-cell-mediated enhancement of host-versus-graft reactivity in mice fed a diet enriched in vitamin A acetate

Retinol (vitamin A) and some of its derivatives have an important role in: (1) regulating growth, proliferation and differentiation of various tissues and (2) maintaining reproduction and visual function in man and higher animals. Vitamin A and retinoids are also known as potent immunoregulatory and antineoplastic agents. Their ability to increase reactivity to histoincompatible tissues is well documented but the mechanism of this action is unclear. Here we report that mice fed on an otherwise conventional diet supplemented with vitamin A acetate (VAA) respond to 10(5) semiallogeneic cells (a suboptimal dose) in a host-versus-graft (HvG) reaction, whereas mice on a conventional diet do not. It is possible to transfer this enhanced immune reactivity by injecting lymphoid cells from VAA-fed animals into those syngeneic mice maintained on the conventional diet. Using a positive selection technique, we demonstrate that the phenotype of the cell probably responsible for this phenomenon is Lyt 1+ 2-.