BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented...BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.展开更多
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a global metabolism-associated liver disease.Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered secreted protein that is involved in...BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a global metabolism-associated liver disease.Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered secreted protein that is involved in metabolic homeostasis.However,much remains to be discovered about its function in hepatic lipid metabolism;thus,we assessed whether MANF could regulate hepatic metabolism.AIM To establish in vivo and in vitro NAFLD models to explore the role of MANF in hepatic lipid metabolism.METHODS HepG2 cells treated with free fatty acids (FFAs) and ob/ob mice were used as NAFLD models.Liver tissues collected from wild type and ob/ob mice were used to detect MANF expression.Cells were treated with FFAs for different durations.Moreover,we used lentiviral constructs to establish overexpression and knockdown cell models in order to interfere with MANF expression levels and observe whether MANF influences hepatic steatosis.Western blot analysis and quantitative real-time PCR were used to detect protein and gene expression,and oil red O staining was used to visualize intracellular lipid droplets.RESULTS Hepatic MANF protein and mRNA expression in wild type mice were 10-fold and 2-fold higher,respectively,than those in ob/ob mice.The MANF protein was temporarily increased by 1.3-fold after stimulation with FFAs for 24 h and gradually decreased to 0.66-fold that of the control at the 72 h time point in HepG2 cells.MANF deficiency upregulated the expression of genes involved infatty acid synthesis,cholesterol synthesis,and fatty acid uptake and aggravated HepG2 cell steatosis,while MANF overexpression inhibited fatty acid synthesis and uptake and cholesterol synthesis,and rescued HepG2 cells from FFAsinduced steatosis.Furthermore,a significant decrease in triglyceride levels was observed in the MANF overexpression group compared with the control group(0.4288±0.0081 mmol/g vs 0.3746±0.0121 mmol/g,P <0.05) upon FF As treatment.There was also a 17%decrease in intracellular total cholesterol levels between the MANF overexpression group and the control group (0.1301±0.0059mmol/g vs 0.1088±0.0009 mmol/g,P <0.05) upon FF As treatment.Moreover,MANF suppressed lipid deposition in HepG2 cells.CONCLUSION Our findings indicate that MANF improves the phenotype of liver cell steatosis and may be a potential therapeutic target in hepatic steatosis processes.展开更多
Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all the activities that render us vibrant, unique and indepen...Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all the activities that render us vibrant, unique and independent beings such as working, playing, and dancing. Because people of the same weight have markedly variable activity levels, it is not surprising that NEAT varies substantially between people by 2000 kcal/day. Evidence suggests that low NEAT may occur in obesity but in a very specific fashion. Obese individuals appear to exhibit an innate tendency to be seated for 2.5 hours per day more than sedentary lean counterparts. If obese individuals were to adopt the lean ‘NEAT-o-type’, they could potentially expend an additional 350 kcal/day. Obesity was rare a century ago and the human genotype has not changed over that time. Thus, the obesity epidemic may reflect the emergence of a chair-enticing environment to which those with an innate tendency to sit, did so and became obese. To reverse obesity therefore, we need to develop individual strategies to promote standing & ambulating time by 2.5 hours per day but also re-engineer our work, school and home environments to render active living the option of choice.展开更多
BACKGROUND The estimation of left ventricular ejection fraction(LVEF)by 2D echocardiography(2D-ECHO)is the most used tool to assess LV systolic function(LVSF).Global longitudinal strain(GLS)has recently been suggested...BACKGROUND The estimation of left ventricular ejection fraction(LVEF)by 2D echocardiography(2D-ECHO)is the most used tool to assess LV systolic function(LVSF).Global longitudinal strain(GLS)has recently been suggested as a superior method for several evaluations.This study explored the association and prevalence of LV systolic dysfunction(LVSD)by using these methods in patients with end-stage renal disease(ESRD)and severe hyperparathyroidism(SHPTH);both associated with cardiovascular events(CEs).AIM To evaluate the myocardial function in patients with ESRD and SHPTH by using the GLS and LVEF measured through conventional 2D-ECHO.METHODS In 62 patients with ESRD and SHPTH,asymptomatic,and without a history of CEs,LVSF was evaluated by 2D-ECHO,obtaining the EF,by the Simpson biplane method,and GLS by speckle tracking.RESULTS The total patients with ESRD had a preserved LVEF(>50%)but abnormal GLS(<13.55%).Additionally,multivariate analysis showed an independent association of GLS and serum parathyroid hormone(PTH),LV mass index,and hemoglobin.Also,PTH was independently associated with lateral e'wave and tricuspid regurgitation velocity.CONCLUSION In patients with SHPTH linked to ESRD,the use of GLS by 2D-ECHO is a more sensitive tool than LVEF for detecting LVSD.展开更多
Background Dipeptidyl peptidase-lV （DPP-4） inhibitors are now used to improve postprandial glycemic control in type 2 diabetes. However, their effects on hepatic glucose production （HGP） in obesity are not clear. ...Background Dipeptidyl peptidase-lV （DPP-4） inhibitors are now used to improve postprandial glycemic control in type 2 diabetes. However, their effects on hepatic glucose production （HGP） in obesity are not clear. This study was designed to test the hypothesis that gluconeogenesis and HGP can be modulated by DPP-4 inhibitors in obesity. Methods Sprague Dawley male rats were divided into four groups, each on a different diet： general rat chow, n=10 （G）; G＋sitagliptin, n=10; high fat chow （obesity）, n=10 （55% fat calories, HFO）; HFO＋sitagliptin, n=10. After 10 weeks, the rats were fasted overnight and glucose metabolism was determined using 3-3H-glucose and 14C-glycerol as tracers. Results Glycerol rate of appearance （P 〈0.00001）, plasma glycerol （P 〈0.05） and free fatty acid （FFA） （P 〈0.05） concentrations, and HGP （P 〈0.05） were decreased in HFO＋sitagliptin group compared with HFO group, but there was no significant difference between G and G＋sitagliptin groups （P 〉0.05）. Gluconeogenesis in HFO group was five times of that in G rats （P 〈0.01）, but was significantly declined in HFO＋sitagliptin group （P 〈0.0001）. Conclusions Gluconeogenesis and HGP were inhibited by sitagliptin in high fat-induced obese rats due to decreased glycerol availability, which was a result of reduced glycerol release from adipose tissues. The finding suggests that sitagliptin is potentially useful for controlling fasting glucose in obesity, thereby delaying or preventing the development of diabetes.展开更多
In the world between 1 and 2 billion people have obesity, In the United States, which has the highest obesity rate in the world, one in three people have obesity. Obesity rates are increasing in every country in whic...In the world between 1 and 2 billion people have obesity, In the United States, which has the highest obesity rate in the world, one in three people have obesity. Obesity rates are increasing in every country in which it has taken hold.^1 Obesity rates also affect all ages from the growing elderly-obese population to the dramatic increase in pediatric obesity, for example in the United States it is predicted that by the end of the decade one in two US children will have obesity. Obesity similarly affects all races and both sexes. As a consequence of the co-morbidities of obesity and of the associated costs such as days off work, obesity costs the US economy about 100-200 billion dollars per year.展开更多
基金Supported by Eunice Kennedy Shriver National Institute of Child Health&Human Development of the National Institutes of Health,No.1K08HD079674-01 and 1R41HD092133-01National Institute of Allergy and Infectious Diseases,No.1A21AI169282and VA Research Career Scientist Award,No.1IK6BX004835.
文摘BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system.Calcium-sensing receptor(CaSR)inhibits both actions.The latter has been well documented in vitro but not in vivo.The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo.AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin(CTX)in mice.METHODS CTX was given orally to C57BL/6 mice to induce diarrhea.Calcium and calci-mimetic R568 were used to activate CaSR.To maximize their local intestinal actions,calcium was administered luminally via oral rehydration solution(ORS),whereas R568 was applied serosally using an intraperitoneal route.To verify that their actions resulted from the intestine,effects were also examined on Cre-lox intestine-specific CaSR knockouts.Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl-or clinically by assessing stool consistency and weight loss.RESULTS CTX induced secretory diarrhea,as evidenced by increases in fecal Cl-,stool consistency,and weight loss following CTX exposure,but did not alter CaSR,neither in content nor in function.Accordingly,calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines.Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts(villinCre/Casrflox/flox)and neuronal CaSR knockouts(nestinCre/Casrflox/flox).CONCLUSION Treatment of acute secretory diarrheas remains a global challenge.Despite advances in diarrhea research,few have been made in the realm of diarrhea therapeutics.ORS therapy has remained the standard of care,although it does not halt the losses of intestinal fluid and ions caused by pathogens.There is no cost-effective therapeutic for diarrhea.This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.
基金Supported by National Natural Science Foundation of China,No.81300702 and No.81501199Natural Science Foundation Project of Chongqing CSTC,No.cstc2018jcyj AX0210 and No.cstc2017jcyj AX0016the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University
文摘BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a global metabolism-associated liver disease.Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered secreted protein that is involved in metabolic homeostasis.However,much remains to be discovered about its function in hepatic lipid metabolism;thus,we assessed whether MANF could regulate hepatic metabolism.AIM To establish in vivo and in vitro NAFLD models to explore the role of MANF in hepatic lipid metabolism.METHODS HepG2 cells treated with free fatty acids (FFAs) and ob/ob mice were used as NAFLD models.Liver tissues collected from wild type and ob/ob mice were used to detect MANF expression.Cells were treated with FFAs for different durations.Moreover,we used lentiviral constructs to establish overexpression and knockdown cell models in order to interfere with MANF expression levels and observe whether MANF influences hepatic steatosis.Western blot analysis and quantitative real-time PCR were used to detect protein and gene expression,and oil red O staining was used to visualize intracellular lipid droplets.RESULTS Hepatic MANF protein and mRNA expression in wild type mice were 10-fold and 2-fold higher,respectively,than those in ob/ob mice.The MANF protein was temporarily increased by 1.3-fold after stimulation with FFAs for 24 h and gradually decreased to 0.66-fold that of the control at the 72 h time point in HepG2 cells.MANF deficiency upregulated the expression of genes involved infatty acid synthesis,cholesterol synthesis,and fatty acid uptake and aggravated HepG2 cell steatosis,while MANF overexpression inhibited fatty acid synthesis and uptake and cholesterol synthesis,and rescued HepG2 cells from FFAsinduced steatosis.Furthermore,a significant decrease in triglyceride levels was observed in the MANF overexpression group compared with the control group(0.4288±0.0081 mmol/g vs 0.3746±0.0121 mmol/g,P <0.05) upon FF As treatment.There was also a 17%decrease in intracellular total cholesterol levels between the MANF overexpression group and the control group (0.1301±0.0059mmol/g vs 0.1088±0.0009 mmol/g,P <0.05) upon FF As treatment.Moreover,MANF suppressed lipid deposition in HepG2 cells.CONCLUSION Our findings indicate that MANF improves the phenotype of liver cell steatosis and may be a potential therapeutic target in hepatic steatosis processes.
文摘Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all the activities that render us vibrant, unique and independent beings such as working, playing, and dancing. Because people of the same weight have markedly variable activity levels, it is not surprising that NEAT varies substantially between people by 2000 kcal/day. Evidence suggests that low NEAT may occur in obesity but in a very specific fashion. Obese individuals appear to exhibit an innate tendency to be seated for 2.5 hours per day more than sedentary lean counterparts. If obese individuals were to adopt the lean ‘NEAT-o-type’, they could potentially expend an additional 350 kcal/day. Obesity was rare a century ago and the human genotype has not changed over that time. Thus, the obesity epidemic may reflect the emergence of a chair-enticing environment to which those with an innate tendency to sit, did so and became obese. To reverse obesity therefore, we need to develop individual strategies to promote standing & ambulating time by 2.5 hours per day but also re-engineer our work, school and home environments to render active living the option of choice.
基金Supported by the Secretaría de Investigación y Posgrado of the Instituto Politécnico Nacionalthe Comisión de Operación y Fomento de Actividades Académicas of the Instituto Politécnico Nacionalthe Consejo Nacional de Ciencia y Tecnología
文摘BACKGROUND The estimation of left ventricular ejection fraction(LVEF)by 2D echocardiography(2D-ECHO)is the most used tool to assess LV systolic function(LVSF).Global longitudinal strain(GLS)has recently been suggested as a superior method for several evaluations.This study explored the association and prevalence of LV systolic dysfunction(LVSD)by using these methods in patients with end-stage renal disease(ESRD)and severe hyperparathyroidism(SHPTH);both associated with cardiovascular events(CEs).AIM To evaluate the myocardial function in patients with ESRD and SHPTH by using the GLS and LVEF measured through conventional 2D-ECHO.METHODS In 62 patients with ESRD and SHPTH,asymptomatic,and without a history of CEs,LVSF was evaluated by 2D-ECHO,obtaining the EF,by the Simpson biplane method,and GLS by speckle tracking.RESULTS The total patients with ESRD had a preserved LVEF(>50%)but abnormal GLS(<13.55%).Additionally,multivariate analysis showed an independent association of GLS and serum parathyroid hormone(PTH),LV mass index,and hemoglobin.Also,PTH was independently associated with lateral e'wave and tricuspid regurgitation velocity.CONCLUSION In patients with SHPTH linked to ESRD,the use of GLS by 2D-ECHO is a more sensitive tool than LVEF for detecting LVSD.
文摘Background Dipeptidyl peptidase-lV （DPP-4） inhibitors are now used to improve postprandial glycemic control in type 2 diabetes. However, their effects on hepatic glucose production （HGP） in obesity are not clear. This study was designed to test the hypothesis that gluconeogenesis and HGP can be modulated by DPP-4 inhibitors in obesity. Methods Sprague Dawley male rats were divided into four groups, each on a different diet： general rat chow, n=10 （G）; G＋sitagliptin, n=10; high fat chow （obesity）, n=10 （55% fat calories, HFO）; HFO＋sitagliptin, n=10. After 10 weeks, the rats were fasted overnight and glucose metabolism was determined using 3-3H-glucose and 14C-glycerol as tracers. Results Glycerol rate of appearance （P 〈0.00001）, plasma glycerol （P 〈0.05） and free fatty acid （FFA） （P 〈0.05） concentrations, and HGP （P 〈0.05） were decreased in HFO＋sitagliptin group compared with HFO group, but there was no significant difference between G and G＋sitagliptin groups （P 〉0.05）. Gluconeogenesis in HFO group was five times of that in G rats （P 〈0.01）, but was significantly declined in HFO＋sitagliptin group （P 〈0.0001）. Conclusions Gluconeogenesis and HGP were inhibited by sitagliptin in high fat-induced obese rats due to decreased glycerol availability, which was a result of reduced glycerol release from adipose tissues. The finding suggests that sitagliptin is potentially useful for controlling fasting glucose in obesity, thereby delaying or preventing the development of diabetes.
文摘In the world between 1 and 2 billion people have obesity, In the United States, which has the highest obesity rate in the world, one in three people have obesity. Obesity rates are increasing in every country in which it has taken hold.^1 Obesity rates also affect all ages from the growing elderly-obese population to the dramatic increase in pediatric obesity, for example in the United States it is predicted that by the end of the decade one in two US children will have obesity. Obesity similarly affects all races and both sexes. As a consequence of the co-morbidities of obesity and of the associated costs such as days off work, obesity costs the US economy about 100-200 billion dollars per year.
