Role of NF-κB and cytokine in experimental cancer cachexia

AIM: To assess the putative involvement of NF-κB and proinflammatory cytokines in the pathogenesis of cancer cachexia and the therapeutic efficacy of indomethacin (IND)on cachexia.METHODS: Thirty young male BABL/c mice were divided randomly into five groups: (a) control, (b) tumor-bearing murine were inoculated subcutaneously to induce cachexia.Saline and IND were given intraperitoneally daily for 7 days from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum levels of TNFα and IL-6 and activity of NF-κB in the spleen were investigated in all animals.RESULTS: Weight loss was observed in all tumor-bearing mice. By day 16, body weights of non-tumor mice were about 72 % of healthy controls (P＜0.01), and the weight of gastrocnemius was decreased by 28.7 % (P＜0.01). No difference was found between groups in food intake (P＞0.05).Gastrocnemius weight was increased markedly (P＜0.01)body weights were not significantly elevated. Tumor-bearing caused a 2-3 fold increase in serum levels of both TNF-αand IL-6 (P＜0.01). The concentration of TNF-α (P＜0.05)and IL-6 (P＜0.01) in tumor-bearing mice was reduced after of IL-6 was slightly elevated following treatment of IND 2.0tumor-bearing mice in comparison with controls in electrophoretic mobility shift assay (ENSA). NF-κB activity a higher NF-κB activity was observed in mice treated with CONCLUSION: Colon 26 adenocarcinoma cells can induce severe cancer cachexia experimentally, and the mechanism may be partially due to the enhanced TNF-αand IL-6 in tumor-bearing animals, which is controlled by NF-κB. Low dose of indomethacin alleviates the cachexia,decreases the activation of NF-κB and the serum levels of TNF-α and IL-6, and prevents body weight loss and muscle atrophy, while no further effect is gained by a higher dosage.     

The modulation of B16BL6 melanoma metastasis is not directly mediated by cytolytic activity of natural killer cells in alcohol-consuming mice

BACKGROUND: Previous studies in our laboratory indicate that alcohol consumption suppresses the metastasis of B16BL6 melanoma, whereas the cytolytic activity of natural killer (NK) cells is decreased in female C57BL/6 mice given 20% w/v alcohol in their drinking water. In the present study, we further evaluated the involvement of NK cells and alcohol consumption in the cytolytic activity of NK cells, the surface expression of NK phenotypic markers, and metastasis of B16BL6 melanoma in C57BL/6 beige (bgJ/bgJ) mutant mice, which possess inherently low NK-cell cytolytic activity. METHODS: Beige and control (bgJ/+) mice were given either water or 20% w/v of alcohol in drinking water for 6 1/2 to 7 weeks before assay for cytolytic activity, surface marker expression, and inoculation with B16BL6 melanoma intravenously or into the pinna of the ear. RESULTS: NK cytolytic activity was suppressed in beige mice, and alcohol consumption did not modulate further the cytolytic activity. Beige mice had a lower percentage of NK cells in the peripheral blood and spleen than control mice. Peripheral blood lymphocytes from beige mice also exhibited a reduced percentage of CD4+ T lymphocytes. Alcohol consumption similarly reduced the percentages of NK1.1- and LGL-1-expressing lymphocytes in the peripheral blood and spleen and reduced the percentage of CD8+ T lymphocytes in the peripheral blood in both control and beige mice. Tumor lung colonization was increased in beige mice relative to control mice after intravenous inoculation of B16BL6 melanoma. The increase was more pronounced in water-drinking beige mice than in control mice irrespective of alcohol consumption. Tumor lung colonization was significantly decreased (p < 0.05) by alcohol consumption in one experiment and partially decreased (p = 0.07) in the other. Mice that were inoculated into the pinna of the ear also exhibited a blunted antimetastatic response to alcohol consumption. CONCLUSIONS: These data suggest that the presence of the beige mutation diminishes the antimetastatic effect of alcohol consumption and that there is no interaction between alcohol consumption and NK-cell activity in the modulation of lung metastasis of B16BL6 melanoma cells.     

Role of NF-κB and cytokine in experimental cancer cachexia

AIM: To assess the putative involvement of NF-κB and pronflammatory cytokines in the pathogenesis of cancer cachexia and the therapeutic efficacy of indomethadn (IND)on cachexia. METHODS: Thirty young male BABL/c mice were divided randomly into five groups: (a) control, (b) tumor-bearingplus saline, (c) tumor-bearing plus IND (0.25 mg.kg-1), (d)tumor-bearing plus IND (0.5 mg.kg-1), and (e) tumor-bearingplus IND (2 mg.kg-1). Colon 26 adenocarcinoma cells of murine were inoculated subcutaneously to induce cachexia. Saline and IND were given intraperitoneally daily for 7 days from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum levels of TNF-α and IL-6 and activity of NF-κB in the spleen wereinvestigated in all animals .RESULTS: Weight loss was observed in all tumor-bearingmice. By day 16, body weights of non-tumor mice were about 72 % of healthy controls (P&lt;0.01), and the weight of gastrocnemius was decreased by 28.7 % (P&lt;0.01). No difference was found between groups in food intake (P&gt;0.05). Gastrocnemius weight was increased markedly (P&lt;0.01) after treatment of IND (0.5 mg.kg-1), while the non-tumor body weights were not significantly elevated. Tumor-bearing caused a 2-3 fold increase in serum levels of both TNF-α and IL-6 (P&lt;0.01). The concentration of TNF-α (P&lt;0.05)and IL-6 (P&lt;0.01) in tumor-bearing mice was reduced after administration of 0.5 mg.kg-1 IND for 7 days. But the level of IL-6 was slightly elevated following treatment of IND 2.0mg-kg-1. NF-κB activation in the spleen was increased in tumor-bearing mice in comparison with controls in electrophoretic mobility shift assay (EMSA). NF-κB activity was reduced in mice treated with 0.5 mg.kg-2 of IND, whereas a hiaher NF-κB activity was observed in mice treated with 2.0 mg,kg-1 of IND . CONCLUSION: Colon 26 adenocarcinoma cells can induce severe cancer cachexia experimentally, and the mechanism may be partially due to the enhanced TNF-α and IL-6 in tumor-bearing animals, which is controlled by NF-κB, Low dose of indomethacin alleviates the cachexia,decreases the activation of NF-κB and the serum levelsof TNF-α and IL-6, and prevents body weight loss andmuscle atrophy, while no further effect is gained by ahigher dosage,     

Ethanol Modulates Metastatic Potential of B16BL6 Melanoma and Host Responses

The experimental metastatic potential (lung-colonizing ability) of B16BL6 melanoma cells was examined in C57BL/6 mice after exposure to ethanol in vitro and in vivo. In vitro, tumor cells were cultured with ethanol (0.3% v/v), or medium alone, for three passages at 5-day intervals. In vivo, B16BL6 melanoma was exposed to ethanol by administering ethanol (10% or 20% w/v) to mice following subcutaneous inoculation of tumor cells into the dorsal hip. All tumor cells were subsequently inoculated intravenously into the lateral tail vein of water-drinking mice to assess changes in metastatic phenotype. Tumor cells cocultured in vivo with ethanol produced significantly higher numbers of superficial lung colonies, compared with tumor cells cultured in control medium. Experimental metastasis of tumor cells obtained from 20% w/v ethanol-consuming mice was also significantly increased, compared with cells obtained from water-drinking mice. Metastasis of B16BL6 melanoma cells previously obtained from mice consuming 10% w/v ethanol did not differ from controls. In other experiments, water-drinking and ethanol-consuming (2.5%, 10%, and 20% w/v) mice were inoculated subcutaneously into the dorsal hip with B16BL6 melanoma cells, and monitored for tumor growth rate and survival time. In these experiments, survival times were significantly shorter in mice consuming 20% ethanol, compared with all other groups. Subcutaneous tumor growth rate was unaffected by ethanol consumption. Lung metastasis resulting from subcutaneous tumor implantation of B16BL6 melanoma was respectively inhibited, or absent, in 10% and 20% ethanol-consuming groups. Thus, tumor growth rate and incidence of lung metastases were not apparent determinants of decreased survival in 20% ethanol-consuming mice. The results of this study indicate that the experimental metastatic potential of B16BL6 melanoma is increased during exposure to ethanol; however, metastasis from subcutaneous tumor-bearing mice is suppressed. This latter finding is consistent with previous results in which spontaneous metastasis was also suppressed after inoculation of the tumor into the pinna of the ear. Although ethanol increases the ability of B16BL6 melanoma to colonize the lung after intravenous inoculation, this effect is abated in the presence of host factors in ethanol-consuming mice.     

Free-choice alcohol consumption in mice after application of the appetite regulating peptide leptin

BACKGROUND: Leptin has been shown to regulate food intake and energy expenditure. Very recently, associations of elevated leptin plasma levels during alcohol withdrawal with alcohol craving have been observed in humans. Therefore, we tested the hypothesis that the application of exogenous leptin modulates voluntary alcohol consumption in mice. METHODS: Sixteen mice (129/Sv x C57BL/6J) were habituated to ethanol consumption over a time period of 3 months. After a basal 2-week free-choice drinking phase, mice were separated into two groups (n = 8) according to weight and alcohol consumption. They received recombinant leptin (1 mg/kg) versus saline intraperitoneally daily for 10 days. After 4 days of free-choice consumption of ethanol (16% v/v) versus water, ethanol was withdrawn at day 4 and replaced at day 6 to test the occurrence of an alcohol deprivation effects. Fluid intake was evaluated by controlling the weight of the drinking tubes daily. RESULTS: Free-choice ethanol consumption after withdrawal was significantly elevated in mice after intraperitoneal injection of 1 mg/kg leptin (alcohol deprivation effect), but not during basal drinking. CONCLUSION: We suggest that leptin may enhance motivation for alcohol consumption in habituated mice after alcohol withdrawal.     

Effects of cationic hydroxyethyl cellulose on glucose metabolism and obesity in a diet-induced obesity mouse model

Background: To investigate the effect of a new soluble fiber, namely cationic hydroxyethyl cellulose (cHEC), on weight loss and metabolic disorders associated with obesity using a high‐fat diet‐induced obese mouse model. Methods: Obese male C57BL/6J (B6) mice were fed high‐fat (60% kcal) diets supplemented with cHEC for 5 weeks. Body weight, energy intake, mesenteric adipose and liver weights, plasma cholesterol, plasma insulin, glucose, adiponectin, and leptin were assessed to determine the effects of cHEC. Hepatic and fecal lipids were also analyzed to investigate the effect of cHEC on lipid absorption and metabolism. Results: Supplementation of the high‐fat diet with cHEC resulted in significant weight loss in obese mice. In addition, significant decreases were seen in mesenteric adipose and liver weights, as well as concentrations of plasma cholesterol and hepatic lipids. A significant improvement in glucose homeostasis, insulin sensitivity, and leptin concentrations were observed at 4% cHEC. Moreover, increases in fecal excretion of total bile acids, sterols, and fats indicated altered fat absorption when cHEC was supplemented in the diet. Conclusions: We have shown in the present study that cHEC reduces body weight, improves insulin sensitivity, and prevents the development of metabolic syndrome. Furthermore, the effects of cHEC on glucose and lipid homeostasis in B6 mice are mediated by improvements in leptin sensitivity resulting from reduced fat absorption.     

Effect of high fat diet on body weight and mammary tumor latency in MMTV-TGF-alpha mice

OBJECTIVE: The role of high fat diets in breast cancer/mammary tumor (MT) development is controversial. This may be partially attributable to variable effects of high fat diets on body weight. Here, we used a moderately high fat diet (32.5% fat calories) expected to cause obesity in most mice, but predicted to result in some mice remaining in the weight range of mice fed the low fat diet (11% fat calories). This provided the opportunity to compare mice fed the high fat diet exhibiting different body weights and mice of similar weight consuming high vs low fat diets. EXPERIMENTAL METHODS: Transgenic MMTV-TGF-alpha mice, a model of postmenopausal breast cancer, consumed a low fat diet, that is, chow-fed (n=25) or a moderately high fat diet from 10 weeks of age (n=51). Body weight at 34 weeks of age was used to assign high fat diet mice to obesity-prone>overweight>obesity-resistant groups (n=17) (P<0.0001). Mice were euthanized when MTs developed or at 85 weeks of age. RESULTS: Final body weights were highest in obesity-prone>overweight >obesity-resistant=chow-fed mice. Fat pads and fat pad:carcass were heaviest in obesity-prone followed by overweight mice. However, obesity-resistant mice had fat pad weights and fat pad:carcass three-fold greater than chow-fed mice. All groups had MT incidences between 72 and 82%. Obesity-prone mice exhibited the shortest MT latency (P<0.0001), but obesity-resistant mice had significantly shorter latency than chow-fed mice. CONCLUSIONS: Consumption of a high fat diet increased adiposity and shortened MT latency in relation to its effect on body weight. These results indicate a complex role of dietary fat level on mammary tumorigenesis.     

Effect of hydroxypropyl methylcellulose on obesity and glucose metabolism in a diet-induced obesity mouse model

Background: To investigate the effect of hydroxypropyl methylcellulose (HPMC) on weight loss and metabolic disorders associated with obesity using a high‐fat diet‐induced obese mouse model under a high‐fat diet regimen. Methods: Obese male C57BL/6J (B6) mice were fed either a high‐fat (60% kcal), low‐fat (10% kcal), or high‐fat diet plus HPMC (4% and 8%) for 5 weeks. Body, mesenteric adipose, and liver weights were determined at the end of the study. In addition, plasma cholesterol, insulin, glucose, adiponectin, and leptin were analyzed to determine the effects of HPMC. Hepatic and fecal lipids were measured to determine the effect of HPMC on lipid absorption and metabolism. Results: Supplementation of the high‐fat diet with 4% and 8% HPMC resulted in significant weight loss in obese B6 mice. Furthermore, significant decreases were seen in adipose (30%–40%), liver weights (15%–26%), and concentrations of plasma cholesterol (13%–20%) and hepatic lipids (13%–36%). Supplementation with 8% HPMC led to significant improvements in glucose homeostasis and leptin concentrations. Reductions in plasma cholesterol, glucose, and insulin levels were strongly correlated with reduced leptin concentrations. Moreover, increases in fecal secretion of total bile acids, sterols, and fats indicated altered fat absorption when HPMC was incorporated in the diet. Conclusion: The data indicate that HPMC not only reduces body weight, but also normalizes the metabolic abnormalities associated with obesity and suggest that the effects of HPMC on glucose and lipid homeostasis in B6 mice are mediated by improvements in leptin sensitivity resulting from reduced fat absorption.     

Tofogliflozin,a sodium/glucose cotransporter 2 inhibitor,attenuates body weight gain and fat accumulation in diabetic and obese animal models

Objective:

Tofogliflozin, a highly selective inhibitor of sodium/glucose cotransporter 2 (SGLT2), induces urinary glucose excretion (UGE), improves hyperglycemia and reduces body weight in patients with Type 2 diabetes (T2D). The mechanisms of tofogliflozin on body weight reduction were investigated in detail with obese and diabetic animal models.

Methods:

Diet-induced obese (DIO) rats and KKAy mice (a mouse model of diabetes with obesity) were fed diets containing tofogliflozin. Body weight, body composition, biochemical parameters and metabolic parameters were evaluated.

Results:

In DIO rats tofogliflozin was administered for 9 weeks, UGE was induced and body weight gain was attenuated. Body fat mass decreased without significant change in bone mass or lean body mass. Food consumption (FC) increased without change in energy expenditure, and deduced total calorie balance (deduced total calorie balance=FC−UGE−energy expenditure) decreased. Respiratory quotient (RQ) and plasma triglyceride (TG) level decreased, and plasma total ketone body (TKB) level increased. Moreover, plasma leptin level, adipocyte cell size and proportion of CD68-positive cells in mesenteric adipose tissue decreased. In KKAy mice, tofogliflozin was administered for 3 or 5 weeks, plasma glucose level and body weight gain decreased together with a reduction in liver weight and TG content without a reduction in body water content. Combination therapy with tofogliflozin and pioglitazone suppressed pioglitazone-induced body weight gain and reduced glycated hemoglobin level more effectively than monotherapy with either pioglitazone or tofogliflozin alone.

Conclusion:

Body weight reduction with tofogliflozin is mainly due to calorie loss with increased UGE. In addition, tofogliflozin also induces a metabolic shift from carbohydrate oxidation to fatty acid oxidation, which may lead to prevention of fat accumulation and inflammation in adipose tissue and liver. Tofogliflozin may have the potential to prevent obesity, hepatic steatosis and improve insulin resistance as well as hyperglycemia.     

Knee strength maintained despite loss of lean body mass during weight loss in older obese adults with knee osteoarthritis

BACKGROUND: The effects of weight loss on muscle function in older adults have not been well studied. This study determined the effects of a 6-month weight-loss intervention on muscle strength and quality in older obese adults with knee osteoarthritis. METHODS: Participants were randomized to a weight loss (WL) (n = 44, 70 +/- 6 years) or weight stable (WS) (n = 43, 69 +/- 6 years) group. The WL intervention consisted of weekly educational meetings, a meal replacement diet, and a three-session-per-week structured exercise program to achieve 10%-12% weight loss. The WS intervention included bimonthly group meetings and newsletters. Body composition and knee extensor strength were measured at baseline and after intervention. RESULTS: The WL group decreased body weight, lean body mass, fat mass, and percent body fat (p <.001 for all). Concentric extension strength increased 25% in WL (p >.05), whereas eccentric extension decreased 6% in WS (p =.028). Concentric muscle quality (strength per kg body weight or lean body mass) increased in WL (p <.05), whereas eccentric muscle quality decreased in WS (p <.05). Changes in lean body mass and fat mass were inversely associated with changes in most muscle strength and quality measures (p <.05). Men and women did not differ in response to the intervention in knee strength outcomes. CONCLUSIONS: Hypocaloric dieting in combination with exercise training had beneficial effects on muscle strength/quality, despite loss of lean body mass in this sample of older men and women. Greater fat loss was associated with greater gains in muscle strength and quality. More studies are needed regarding the mechanisms by which loss of fat mass increases muscle strength and quality.     

Loss of total body potassium during rapid weight loss does not depend on the decrease of potassium concentration in muscles. Different methods to evaluate body composition during a low energy diet

OBJECTIVE: The aim of the study was to elucidate whether combustion of skeletal muscle glycogen during a very low calorie diet (VLCD) was associated with decreased muscle potassium content. A comparison between different methods was also performed to evaluate body composition during a VLCD and a low calorie diet (LCD). DESIGN: Dietary treatment of obese women by VLCD and LCD. Measurements after 1 and 2 weeks of VLCD and 6 months of LCD. SUBJECTS: Fifteen perimenopausal obese women aged 46.5+/-1.3 y and 15 of 48.0+/-0.7 y of age. MEASUREMENTS: Skeletal muscle biopsies under local anaesthesia. Body composition measurements by means of deal-energy X-ray absorptiometry (DEXA), and measurements of total body potassium (40K) and total body nitrogen (TBN). Measurements of electrolytes and glycogen concentration in muscle samples. RESULTS: In the first study (1 week of VLCD) skeletal muscle glycogen decreased (P<0.01), but muscle potassium increased (P<0.01). Muscle sodium decreased (P<0.01), while muscle magnesium was unaltered. Body weight decreased by 2.9+/-0.5 kg and 40K decreased. Fat-free mass (FFM) calculated from 40K and DEXA decreased by 2.7 vs 1.9 kg (P<0.001). Body fat measured with DEXA decreased by 1.1 kg (P<0.01), but not body fat calculated from 40K. TBN decreased by 0.03+/-0.01 kg (P<0.05) and FFM calculated from TBN by 2.9+/-0.5 kg (P<0.002). In the second study, 6 months on the LCD resulted in 17.0+/-2.0 kg weight reduction and this was mainly due to reduced body fat, 14. 0+/-2.0 kg measured with DEXA and from 40K (P<0.001). The decrease in FFM was slight. CONCLUSION: One week of VLCD resulted in muscle glycogen depletion but increased muscle potassium content in spite of decreased total body potassium. FFM contributed to the main part of body weight loss during short periods of severe energy restriction, but remained unchanged during long-term dietary treatment. Body fat became mostly responsible for the body weight loss during long-term LCD. Calculations of changes of FFM from 40K and TBN seem to overestimate the FFM decrease associated with short-term VLCD. International Journal of Obesity (2000)24, 101-107     

Inhibition of hepatic gluconeogenesis and enhanced glucose uptake contribute to the development of hypoglycemia in mice bearing interleukin-1beta- secreting tumor

Mice bearing IL-1beta-secreting tumor were used to study the chronic effect of IL-1beta on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1beta gene. Serum IL-1beta levels increased exponentially with time. Secretion of IL-1beta from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1beta caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1beta. Glut-1 and Glut-4 mRNA levels in IL-1beta mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1beta. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1beta-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.     

Effects of topiramate on ethanol and saccharin consumption and preferences in C57BL/6J mice

BACKGROUND: Topiramate has recently been found to be more effective than placebo as an adjunct treatment for alcohol dependence, but it has not yet been investigated in animal models of ethanol consumption. The current experiment examined the effects of topiramate on ethanol drinking in mice using a continuous access, two-bottle choice procedure. METHOD: C57BL/6J male mice were offered a 10% v/v ethanol solution versus tap water over 4 consecutive days per week. Mice were assigned to topiramate (1-50 mg/kg) or saline groups and received injections before the beginning of the dark phase of the light cycle. Topiramate dose increased over 5 successive weeks (1, 5, 10, 25, and 50 mg/kg). Fluid intake was measured 2, 4, and 23 hr after injection. Body weight and food intake were measured at the time of injection. In a second phase, mice were offered saccharin solutions (0.2 and 2.5% w/v) versus tap water after topiramate (50 mg/kg) or saline injections. RESULTS: Results revealed that high topiramate doses (25 and 50 mg/kg) increased water intake and decreased ethanol preference. Compared with saline controls, topiramate produced dose-dependent, bidirectional effects on ethanol dose, with 25 mg/kg of topiramate increasing ethanol dose at 4 and 23 hr after injection but 50 mg/kg topiramate decreasing ethanol dose at 2 hr after injection. During saccharin exposure, topiramate decreased saccharin preference (for 2.5% w/v saccharin solution) and marginally increased water intake but did not directly alter intake of the saccharin solutions. Topiramate had no effects on body weight or daily food intakes. CONCLUSIONS: Topiramate reduced ethanol preference in C57BL/6J mice, but this effect was primarily attributable to elevated water intake. Topiramate also reduced saccharin preference, likely through marginally significant increases in water intake. Increases in water intake and bidirectional effects of topiramate on ethanol dose complicate conclusions with regard to the effects of topiramate on ethanol reward.     

抗抑郁药对胰腺癌移植瘤模型的进食及肿瘤生长的影响

目的 探讨米氮平和氟西汀对胰腺癌皮下移植瘤裸鼠进食量、体重和肿瘤生长的影响.方法 建立21只人胰腺癌细胞SW1990的裸鼠皮下移植瘤动物模型,按完全随机法分为对照组、米氮平组和氟西汀组,各7只.建模后1 d开始分别给各组生理盐水、米氮平10mg·kg-1·d-1和氟西汀1Omg·kg-1·d-1灌胃,每天1次,持续42 d.比较3组裸鼠进食量、体重和肿瘤体积的变化.结果 3组胰腺癌移植瘤体积无明显差异.第2周米氮平组进食量为(5.03±0.16)g,显著较其他2组多,第4周体重为(16.00±1.41)g,较其他2组下降少(P<0.05);氟西汀组从第3周起进食量较对照组显著减少,第6周的体重也较对照组显著下降(P<0.05).在第6周,对照组、米氮平组和氟西汀组的日进食量分别为(3.54±0.13)g、(4.19±0.16)g和(3.34±0.13)g,体重分别为(13.71±1.11)g、(14.86±1.68)g和(12.57±1.51)g.结论 米氮平在改善荷瘤裸鼠进食量和减缓体重下降方面优于氟西汀,但两者对肿瘤生长均无明显影响.     

Blockade of the leptin-sensitive pathway markedly reduces alcohol consumption in mice

BACKGROUND: The neuropeptide leptin links adipose stores with hypothalamic centers and serves as an endocrine signal involved in the regulation of appetite (and possibly in the endorphinergic modulation of the drug reward system). Increased plasma leptin has been observed at the onset of alcohol withdrawal in humans, and ethanol consumption after withdrawal was increased by injection of leptin in mice. We addressed the role of leptin in alcohol-related behaviors by studying ethanol consumption in two strains of spontaneously mutant mice that lack leptin (ob/ob) or the leptin receptor (db/db). METHODS: Two strains of mutant leptin-deficient (ob/ob) or leptin-resistant (db/db) mice were tested in a two-bottle-choice paradigm and were compared with wild-type (C57BL/6 inbred strain) mice. The effects of leptin injection on voluntary ethanol intake have been investigated in ob/ob and C57BL/6 mice. RESULTS: Males and females of both mutant strains showed a significantly lower preference for alcohol in a two-bottle-choice paradigm compared with wild-type mice. Male ob/ob mice demonstrated slightly higher avoidance of bitter taste, and females of the both mutant strains showed a reduced preference for saccharin solutions. Administration of leptin (1 mg/kg intraperitoneally, daily for 8 days) altered body weight but failed to increase the preference for ethanol in ob/ob mice; i.e., we could not correct the effects of leptin deficiency on alcohol consumption by the injection of leptin. Also, there were no differences between the effects of leptin (1 mg/kg intraperitoneally, daily for 8 days) and saline injections on alcohol consumption in C57BL/6 mice. CONCLUSIONS: These data show that blockade of the leptin pathway markedly decreases the preference for alcohol intake, but this decrease may be the result of compensatory or developmental changes in other systems rather than a more direct effect of leptin on alcohol consumption.     

Green coffee bean extract improves obesity by decreasing body fat in high-fat diet-induced obese mice

Objective:To evaluate possible lipid catabolism and body fat regulation effects of 3-caffeoylquinic acid in Green coffee bean extract(GCBE) in high-fat diet(HFD)-induced obese mice.Methods:Obesity was induced in mice using a HFD for four weeks.Then,mice were fed only HFD or HFD with GCBE at 50,100,and 200 mg/kg.Fatty acid synthesis mechanism regulation of body fat was investigated through real-time PCR and Western blot assay.Body fat reduction was measured through dual-energy X-ray absorptiometry.Results:In HFD-induced obese mice,GCBE treatment significantly decreased body weight gain,liver weight and white adipose tissue weights with regulation of adipose tissue lipolysis hormones,like adiponectin and leptin.GCBE treatment decreased mR NA expression levels of adipogenesis and adipocyte metabolism related genes in adipose tissues and the liver,and decreased the corresponding protein expression.Dual energy X-ray absorptiometry measurements were used to compare body fat between mice on high-fat and those treated with GCBE.GCBE treated mice had a lower fat mass compared to HFD alone fed mice and relative body weight and fat mass were markedly decreased.Conclusions:GCBE has a potential anti-obesity effect with lowering body fat accumulation by regulating adipogenesis and lipid metabolism-related genes and proteins in WAT and liver.     

Growth of FasL-bearing tumor cells in syngeneic murine host induces apoptosis and toxicity in Fas(+) organs

In the current study, we investigated whether the growth of FasL-bearing tumor cells would induce apoptosis and toxicity in organs that express high level of Fas. Sera from C57BL/6 +/+ (wild-type) mice injected with syngeneic FasL(+) tumors, LSA, or EL-4, showed significantly higher levels of soluble FasL than that from the nontumor-bearing mice. Furthermore, the soluble FasL was functional inasmuch as the sera from tumor-bearing mice were able to induce apoptosis in Fas(+) but not Fas(-) targets. Histopathologic studies and in situ TUNEL assay to detect apoptosis were carried out in C57BL/6 +/+ (Fas(+)) or C57BL/6 lpr/lpr (Fas(-)) mice injected with syngeneic LSA and EL-4 tumor cells. The morphology of the liver and thymus from tumor bearing C57BL/6 +/+ mice showed marked damage and tissue destruction. In contrast, the liver and thymus from tumor-bearing C57BL/6 lpr/lpr mice showed minimal damage. Furthermore, the tumor-bearing C57BL/6 +/+, but not the C57BL/6 lpr/lpr, mice exhibited significant apoptosis in the liver and thymus. The FasL responsible for toxicity was tumor derived rather than host derived; tumor-bearing C57BL/6 gld/gld (FasL-defective) mice also exhibited significant apoptosis in the liver and thymus. Together, these data suggested that the in vivo growth of FasL-bearing tumor cells can induce significant apoptosis and toxicity in Fas(+) tissues of the host. Such toxicity may be mediated by the soluble FasL produced by tumor cells. (Blood. 2000;95:2111-2117)     

Blunted metabolic response to fasting in obese mice

The aim of the study was to evaluate metabolic changes in response to fasting in normal and obese mice. C57BL6 and obese (diet-induced obesity (DIO) and ob/ob) mice were used in this study. They were fasted for 24 h and re-fed for 24 h. Body weight was monitored before, after fasting and during re-feeding (2 and 24 h after re-feeding). Food intake was measured 2 and 24 h after re-feeding began. Blood samples were taken before and after 24 h fasting. As metabolic parameters, blood glucose, plasma insulin, ghrelin levels and oxygen consumption were measured. Blood glucose and plasma insulin levels in DIO and ob/ob mice were higher than normal mice, and plasma ghrelin levels were lower in DIO and ob/ob mice. There was reduced body weight loss in DIO mice than in normal mice for 24 h fasting. When they were re-fed, DIO and ob/ob mice consumed less food intake than normal mice. Twenty-four hours food deprivation induced significantly smaller plasma ghrelin elevation in these obese mice. Fasting-induced decrease in oxygen consumption was significantly smaller in DIO and ob/ob mice than normal mice. This data show that obese mice may have decreased sensitivity to fasting-induced increase in circulating ghrelin and their oxygen consumption exhibited a blunted response to fasting.     

PPARα、PPARy在左卡尼汀改善结肠癌小鼠恶病质中的作用

左卡尼汀（Lc）改善恶病质的作用已日渐受到关注。目的：探讨PPARα、PPARy在Lc改善结肠癌小鼠恶病质中的作用。方法：建立结肠癌小鼠恶病质模型，并分为Lc组、左卡尼汀棕榈酸酰基转移酶（CPT）抑制剂（ILC）组、阴性对照组（NST），另设立正常对照组（NTB）。实验第19d处死所有小鼠。测定小鼠体质量、去瘤体质量、摄食量，以全自动生化仪检测血清白蛋白、血糖、胆固醇含量，ELISA法检测血清TNF-α、IL-6含量，实时定量PCR和蛋白质印迹法分别检测肝组织PPARa、PPARy,／mRNA和蛋白表达。结果：与NST组、ILC组相比，LC组小鼠体质量、去瘤体质量、摄食量、血清白蛋白、血糖均显著升高（P〈0．05），血清胆固醇、TNF-α、IL-6含量均显著降低（P〈0．05），PPARα、PPAR7mRNA和蛋白表达均显著升高（P〈0．05）。结论：PPARα、PPARy可能参与结肠癌小鼠恶病质的发生；LC可能通过PPARα、PPARy相关肝脏脂质代谢信号通路来改善肿瘤恶病质。