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白藜芦醇调节c57bl/ksj-db/db糖尿病小鼠糖脂代谢的作用与机制  [PDF]
吕秀萍
南方医科大学学报 , 2014,
Abstract: 目的研究白藜芦醇对c57bl/ksj-db/db(db/db)糖尿病小鼠糖脂代谢的作用与机制。方法随机将db/db糖尿病小鼠分为模型组、白藜芦醇组(200mg/kg)和吡格列酮组(5mg/kg),每组8只,给予相应的药物治疗8周。实验结束后比较各组空腹血糖、糖化血清蛋白、糖化血红蛋白、血清总胆固醇、甘油三脂等糖脂代谢指标,比较各组血清胰岛素浓度及胰岛素抵抗指数、胰岛素敏感指数、超氧化物歧化酶活性、丙二醛含量等指标的变化。采用real-timepcr技术和westernblot检查肝脏组织中低密度脂蛋白受体基因和蛋白的表达。结果与模型组比较,白藜芦醇组能显著降低小鼠空腹血糖、糖化血清蛋白、糖化血红蛋白、血清总胆固醇、甘油三脂等指标的升高(p<0.05),明显改善血清胰岛素水平及胰岛素抵抗指数、胰岛素敏感指数,超氧化物歧化酶活性、丙二醛等指标的异常(p<0.05);显著提高肝脏中肝糖原含量和低密度脂蛋白受体的表达(p<0.05)。结论白藜芦醇具有明显改善糖脂代谢紊乱的作用,其作用机制与其改善胰岛素抵抗、提高抗氧化应激能力以及增加低密度脂蛋白受体的表达等密切相关。
Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice
Masahito Shimizu, Yoichi Yasuda, Hiroyasu Sakai, Masaya Kubota, Daishi Terakura, Atsushi Baba, Tomohiko Ohno, Takahiro Kochi, Hisashi Tsurumi, Takuji Tanaka, Hisataka Moriwaki
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-281
Abstract: Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.Hepatocellular carcinoma (HCC) is a serious healthcare problem worldwide because of its increasing morbidity and high mortality. Chronic inflammation of the liver and subsequent cirrhosis, which are highly correlated with hepatitis B and hepatitis C viruses infection and alcoholic liver disease, are the strongest risk factors for HCC development. Recent evidence also indicates that obesity and related metabolic abnormalities, especially diabetes mellitus and insulin resistance, raise the risk of HCC [1-4]. In obese individuals, high levels of free fatty acid (FFA) flux into the liver from excess adipose tissue. This in turn promotes hepatic steatosis and inflammation through the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, and is closely associated with liver carcinogenesis [5-7]. Aberrant lipogenesis in the liver, which is closely linked to obesity and metabolic syndrome, is also a domina
HPN, a Synthetic Analogue of Bromophenol from Red Alga Rhodomela confervoides: Synthesis and Anti-Diabetic Effects in C57BL/KsJ-db/db Mice  [PDF]
Dayong Shi,Shuju Guo,Bo Jiang,Chao Guo,Tao Wang,Luyong Zhang,Jingya Li
Marine Drugs , 2013, DOI: 10.3390/md11020350
Abstract: 3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC 50 = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC 50 0.63 μmol/L and high selectivity against other PTPs (T cell protein tyrosine phosphatase (TCPTP), leucocyte antigen-related tyrosine phosphatase (LAR), Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2). The results of antihyperglycemic activity using db/ db mouse model demonstrated that HPN significantly decreased plasma glucose ( P < 0.01) after eight weeks treatment period. HPN lowered serum triglycerides and total cholesterol concentration in a dose-dependent manner. Besides, both of the high and medium dose groups of HPN remarkably decreased HbA1c levels ( P < 0.05). HPN in the high dose group markedly lowered the insulin level compared to the model group ( P < 0.05), whereas the effects were less potent than the positive drug rosiglitazone. Western blotting results showed that HPN decreased PTP1B levels in pancreatic tissue. Last but not least, the results of an intraperitoneal glucose tolerance test in Sprague–Dawley rats indicate that HPN have a similar antihyperglycemic activity as rosiglitazone. HPN therefore have potential for development as treatments for Type 2 diabetes.
Effects of Gametophytes of Ecklonia Kurome on the Levels of Glucose and Triacylglycerol in db/db, Prediabetic C57BL/6J and IFN-γ KO Mice  [cached]
Febriza Dwiranti,Takahiro Taguchi,Akira Tominaga,Masanori Hiraoka
International Journal of Biomedical Science , 2012,
Abstract: We have studied edible algae that have the potential to down-regulate blood glucose. In Japan, Ecklonia species have been believed to improve the circulation of blood. In this study, we used leptin receptor deficient type 2 diabetes model mice (db/db) and prediabetic C57BL/6J mice. We also focused on the role of IFN-γ in the control of blood levels of triacylglycerol and glucose, because it is reportedly engaged in the regulation of energy consumption together with leptin. We report that gametophytes of Ecklonia kurome down-regulate the blood level of glucose and serum level of triacylglycerol in db/db. We also report that gametophytes of Ecklonia kurome down-regulate the level of glucose but not the level of triacylglycerol in prediabetic C57BL/6J mice induced by a high fat diet. They increased the level of triacylglycerol compared to that of control group in C57BL/6J, but not in IFN-γ KO mice. Gametophytes of Ecklonia kurome were administered orally to prediabetic C57BL/6J and IFN-γ KO mice and oral glucose tolerance tests were performed to evaluate the effects of algae. During the administration of the normal diet, we found a higher level of blood glucose in a glucose tolerance test of IFN-γ KO mice compared with that of C57BL/6J. Although a high fat diet induced a higher level of blood glucose compared with a normal diet group in a glucose tolerance test of C57BL/6J mice, this effect of high fat diet was not observed clearly at first but appeared three hours after glucose administration in IFN-γ KO mice. Gametophytes of Ecklonia kurome down-regulated the level of blood glucose in both C57BL/6J and IFN-γ KO mice, when administered a normal diet after making them prediabetic. These results suggest that Ecklonia kurome are effective to down-regulate the blood glucose and IFN-γ is involved in the regulation of blood glucose and triacylglycerol.
Influences of obese (ob/ob) and diabetes (db/db) genotype mutations on lumber vertebral radiological and morphometric indices: Skeletal deformation associated with dysregulated systemic glucometabolism
Katherine M Burkemper, David R Garris
BMC Musculoskeletal Disorders , 2006, DOI: 10.1186/1471-2474-7-10
Abstract: The influences of single-gene missense mutations, expressing either diabetes (db/db) or obese (ob/ob) metabolic syndromes on vertebral maturation and development in C57BL/KsJ mice were evaluated by radiological and macro-morphometric analysis of the resulting variances in osteodevelopment indices relative to control parameters between 8 and 16 weeks of age (syndrome onset @ 4 weeks), and the influences of low-dose 17-B-estradiol therapy on vertebral growth expression evaluated.Associated with the indicative genotypic obesity and hyper-glycemic/-insulinemic states, both db/db and ob/ob mutants demonstrated a significant (P ≤ 0.05) elongation of total lumbar vertebrae column (VC) regional length, and individual lumbar vertebrae (LV1-5) lengths, relative to control VC and LV parameters. In contrast, LV1-5 width indices were suppressed in db/db and ob/ob mutants relative to control LV growth rates. Between 8 and 16 weeks of age, the suppressed LV1-5 width indices were sustained in both genotype mutant groups relative to control osteomaturation rates. The severity of LV1-5 width osteosuppression correlated with the severe systemic hyperglycemic and hypertriglyceridemic conditions sustained in ob/ob and db/db mutants. Low-dose 17-B-estradiol therapy (E2-HRx: 1.0 ug/ 0.1 ml oil s.c/3.5 days), initiated at 4 weeks of age (i.e., initial onset phase of db/db and ob/ob expressions) re-established control LV 1–5 width indices without influencing VC or LV lengths in db/db groups.These data demonstrate that the abnormal systemic endometabolic states associated with the expression of db/db and ob/ob genomutation syndromes suppress LV 1–5 width osteomaturation rates, but enhanced development related VC and LV length expression, relative to control indices in a progressive manner similar to recognized human metabolic syndrome conditions. Therapeutic E2 modulation of the hyperglycemic component of diabetes-obesity syndrome protected the regional LV from the mutation-induced osteopeni
Rhein Reduces Fat Weight in db/db Mouse and Prevents Diet-Induced Obesity in C57Bl/6 Mouse through the Inhibition of PPARγ Signaling  [PDF]
Yu Zhang,Shengjie Fan,Na Hu,Ming Gu,Chunxiao Chu,Yiming Li,Xiong Lu,Cheng Huang
PPAR Research , 2012, DOI: 10.1155/2012/374936
Abstract: Rheum palmatum has been used most frequently in the weight-reducing formulae in traditional Chinese medicine. However, the components of Rheum palmatum that play the antiobesity role are still uncertain. Here, we tested the weight-reducing effect of two major Rheum palmatum compounds on mouse. We found that rhein (100?mg kg?1?day?1), but not emodin, reduced the fat weight in mouse. Using diet-induced obese (DIO) C57BL/6 mice, we identified that rhein blocked high-fat diet-induced obesity, decreased fat mass and the size of white and brown adipocytes, and lowered serum cholesterol, LDL cholesterol, and fasting blood glucose levels in the mice. To elucidate the underlying mechanisms, we used reporter assay and gene expression analysis and found that rhein inhibited peroxisome proliferator-activated receptor γ (PPARγ) transactivity and the expression of its target genes, suggesting that rhein may act as a PPARγ antagonist. Our data indicate that rhein may be a promising choice for antiobesity therapy. 1. Introduction Obesity is one of the most serious public health problems of the 21st century [1, 2]. It increases the risk of various fetal diseases, particularly coronary artery disease, type II diabetes, hypertension, dyslipidemia, and certain types of cancer [3–5]. At present, there is only one drug, orlistat, approved by the Food and Drug Administration (FDA) for long-term use in the treatment of obesity. Thus, it is urgent to develop a new therapy for the prevention and treatment of obesity [5]. The development of novel antiobesity drugs has been proven difficult because of side-effects and lower efficiency [6–9]. Traditional medicine has various herbs for weight-reducing practice and may be a potential source for novel antiobesity drugs. Rheum palmatum is used most frequently in the weight-reducing formulae of traditional Chinese medicine. Recently, rhein, one of the major components of Rheum palmatum, has been shown to be an inhibitor of 3T3-L1 adipocyte differentiation [10]. Moreover, rhein has been reported to have pharmacological and biochemical effects on the inhibition of liver fibrosis and insulin sensitizing [11–13] and prevent hepatic steatosis through LXR inhibition in a high-fat diet-induced obese mouse model [14]. However, whether rhein plays the antiobesity role in vivo is still uncertain and the underlying mechanisms also need to be elucidated. In the present study, we compared the weight-reducing effect of two major compounds from Rheum palmatum. We found that rhein reduced fat weight in mouse. We also showed that rhein blocked weight
Neoplasms of the limbus  [cached]
Sunderraj P,Viswanathan Ravi,Balachander R
Indian Journal of Ophthalmology , 1991,
Abstract: One hundred consecutively excised and histologically diagnosed limbal neoplasms were analyzed. Majority (56%) of the affected patients were less than 30 years old. Benign tumours (77%) outnumbered the malignancies. Dermoids (29%) and hyperplastic squamous epithelium or ′epidermalization′ (26%) were the commonest benign neoplasms. Squamous cell carcinoma, including frank and non-invasive carcinoma (23%) was the most frequent malignant tumour. These observations were compared with previous Indian and Western studies and the implications discussed.
Krüppel-like factor 5 is a crucial mediator of intestinal tumorigenesis in mice harboring combined ApcMin and KRASV12 mutations
Mandayam O Nandan, Amr M Ghaleb, Beth B McConnell, Nilesh V Patel, Sylvie Robine, Vincent W Yang
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-63
Abstract: At 12 weeks of age, ApcMin/KRASV12 mice had three times as many intestinal tumors as ApcMin mice. This increase in tumor number was reduced by 92% in triple transgenic ApcMin/KRASV12/Klf5+/- mice. The reduction in tumor number in ApcMin/KRASV12/Klf5+/- mice was also statistically significant compared to ApcMin mice alone, with a 75% decrease. Compared with ApcMin/KRASV12, tumors from both ApcMin/KRASV12/Klf5+/- and ApcMin mice were smaller. In addition, tumors from ApcMin mice were more distally distributed in the intestine as contrasted by the more proximal distribution in ApcMin/KRASV12 and ApcMin/KRASV12/Klf5+/- mice. Klf5 levels in the normal-appearing intestinal mucosa were higher in both ApcMin and ApcMin/KRASV12 mice but were attenuated in ApcMin/KRASV12/Klf5+/- mice. The levels of β-catenin, cyclin D1 and Ki-67 were also reduced in the normal-appearing intestinal mucosa of ApcMin/KRASV12/Klf5+/- mice when compared to ApcMin/KRASV12 mice. Levels of pMek and pErk1/2 were elevated in the normal-appearing mucosa of ApcMin/KRASV12 mice and modestly reduced in ApcMin/KRASV12/Klf5+/- mice. Tumor tissues displayed higher levels of both Klf5 and β-catenin, irrespective of the mouse genotype from which tumors were derived.Results of the current study confirm the cumulative effect of Apc loss and oncogenic KRAS activation on intestinal tumorigenesis. The drastic reduction in tumor number and size due to Klf5 heterozygosity in ApcMin/KRASV12 mice indicate a critical function of KLF5 in modulating intestinal tumor initiation and progression.Cancer is the result of deregulated cellular homeostasis and is typically characterized by increased proliferation and/or decreased apoptosis [1]. The mammalian intestinal epithelium is a continuously renewing system that is carefully orchestrated throughout life [2]. Several important signaling pathways are involved in maintaining intestinal epithelial homeostasis and include the Wnt, Notch, Eph/Ephrin, Hedgehog and bone morphogeneti
No Association between Glycemia and Wound Healing in an Experimental db/db Mouse Model  [PDF]
Margrete Berdal,Trond Jenssen
ISRN Endocrinology , 2013, DOI: 10.1155/2013/307925
Abstract: Impaired wound healing is a frequent problem in diabetes. Hyperglycemia may be an operative mechanism, but a link between glycemic control and wound healing has never been established. Wounds in db/db mice have been extensively studied. This study was undertaken to see if plasma glucose was a predictor of wound healing. An excisional wound was made (149 db/db mice). Wound closure was studied versus metabolic variables. The animals were weeks (mean ± standard error of the mean), obese ( ?g), and hyperglycemic (fasting plasma glucose ?mmol/L). Wound closure at day 13 was . In linear mixed model analyses neither fasting plasma glucose nor its change from start to end of experiment was a significant predictor of wound closure ( , , 95% CI: ?0.01 to 0.31 and , , 95% CI: ?0.11 to 0.23, resp.). However, increase in body weight significantly and independently predicted wound closure (for weight change, , , 95% CI: 0.06 to 0.38). This study strongly suggests that wound healing in db/db mice is independent of prevailing glycemia but dependent on anabolic changes such as weight gain over time. 1. Introduction Impaired wound healing—a well-known problem in diabetes—has been extensively studied in animals [1, 2]. One model, which has been explored for this purpose, is the genetically leptin receptor deficient, diabetic db/db mouse with characteristics such as obesity, transient hyperinsulinemia, insulin resistance, severe hyperglycemia, and impaired wound healing [2–8]. Hyperglycemia is one factor that may be implicated in impaired wound repair. Clinical guidelines advocate optimization of metabolic control to facilitate wound healing [9]. A retrospective study in humans suggested that glycated hemoglobin (A1C) predicted healing rates in diabetic wounds [10]. However, as far as we know, direct evidence of a link between glycemic control and healing is lacking [11]. In the db/db mouse model, a few studies have addressed the possible impact of hyperglycemia on wound healing [6, 12, 13]. They included up to 31?db/db mice from one or two age groups, and baseline body weight but not weight change was assessed. No significant associations between metabolic parameters and wound healing were observed [6]. In the present study we included 149?db/db mice, aged 6–16 weeks, with the aim of testing whether fasting plasma glucose at baseline, the change in fasting plasma glucose, or other metabolic parameters, including weight change, were associated with wound closure. 2. Materials and Methods 2.1. Animals Diabetic C57BL/KsBom-db/db mice were studied. All animals were purchased
Effect of Recql5 deficiency on the intestinal tumor susceptibility of Apcmin mice  [cached]
Yiduo Hu, Xincheng Lu, Guangbin Luo
World Journal of Gastroenterology , 2010,
Abstract: AIM: To investigate whether Recql5, a DNA helicase that plays an important role in the maintenance of genome integrity, is a tumor suppressor in the gastrointestinal tract in mice.METHODS: We generated cohorts of both Recql5-proficient and Recql5-deficient Apcmin/+ mice and compared the tumor susceptibility in their gastrointestinal tracts.RESULTS: Recql5 deficiency in Apcmin/+ mice resulted in a significant increase in the tumor incidence in both the colon (P = 0.0162) and the small intestine (P < 0.01). These findings have provided the first genetic evidence for a tumor suppression role of Recql5 in the gastrointestinal tract of mice. Importantly, since mouse Recql5 and human RECQL5 are highly conserved, these findings also suggest that RECQL5 may be a tumor suppressor for human colon cancer.CONCLUSION: Recql5 has a tumor suppression role in the mouse gastrointestinal tract.
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