BACKGROUND Portal hypertension(PH),a major complication of cirrhosis,arises from increased intrahepatic resistance and splanchnic vasodilation.Epoxyeicosatrienoic acids(EETs)improve hepatic microcirculation,but their ...BACKGROUND Portal hypertension(PH),a major complication of cirrhosis,arises from increased intrahepatic resistance and splanchnic vasodilation.Epoxyeicosatrienoic acids(EETs)improve hepatic microcirculation,but their effects are rapidly inactivated by soluble epoxide hydrolase(sEH),an enzyme upregulated in the cirrhotic liver.Inhibiting sEH increases EET levels,reducing portal pressure and fibrosis.Dipeptidyl peptidase-4 inhibitors(DPP4-Is)and angiotensin II blockers have been reported to suppress sEH and enhance EET activity.Angiotensin receptorneprilysin inhibitors(ARNIs)also lower portal pressure.However,the combined effect of DPP4-I and ARNI on the sEH-EET axis in PH and liver fibrosis remains uninvestigated.AIM To study the effects of vildagliptin,a DPP4-I and sacubitril/valsartan,an ARNI on PH and liver fibrosis in cirrhotic rats.METHODS Two rodent models of liver cirrhosis:(1)Choline-deficient,L-amino acid-defined,high-fat diet(CDAHFD)diet-fed rats;and(2)Bile duct ligation-induced rats were treated with vildagliptin(10 mg/kg/day),sacubitril/valsartan(30 mg/kg/day),or a combination of both drugs.Hemodynamic parameters,sEH activity,EET levels,vascular remodeling,and fibrosis were assessed using enzyme-linked immunosorbent assay,quantitative real-time polymerase chain reaction,Western blotting,histology,and immunofluorescence.RESULTS In CDAHFD-fed models,both DPP4-I and ARNI significantly reduced portal pressure in cirrhotic rats by decreasing intrahepatic vascular resistance without affecting systemic hemodynamics.These agents downregulated sEH expression and activity,increasing EET levels,and improved endothelial function via nitric oxide signaling enhancement.They also suppressed sinusoidal capillarization,pathological angiogenesis,and Hedgehog signaling,while restoring sinusoidal endothelial markers.Additionally,DPP4-I and ARNI attenuated liver fibrosis and stellate cell activation,reducing profibrotic gene expression.These effects were additive by the combination of both drugs.Similar effects were observed in bile duct ligation-induced PH,confirming their therapeutic potential in managing both PH and liver fibrosis through modulation of the sEH-EET pathway.CONCLUSION Combined DPP4-I with ARNI therapy ameliorates PH and fibrosis via sEH suppression and EET restoration,offering a promising treatment strategy for cirrhosis-related PH.展开更多
To test the hypothesis that mist sauna is a safer way of bathing than dry sauna, we compared changes in circulatory and thermoregulatory functions during 10 min sauna bathing in mist sauna at 40℃ with relative humidi...To test the hypothesis that mist sauna is a safer way of bathing than dry sauna, we compared changes in circulatory and thermoregulatory functions during 10 min sauna bathing in mist sauna at 40℃ with relative humidity of 100%, and in dry sauna by infrared ray at 70℃ with relative humidity of 15%. Subjects were seven healthy young men aged 29 ± 6 yrs (mean ± SD). We measured blood pressure, heart rate, skin temperatures at chest, forearm, thigh, and leg, tympanic temperature (Tty) by thermistors, skin blood flow at forearm by laser Doppler flowmetry, and sweat rate by ventilated capsule method at 1 min intervals throughout the experiment. Total sweating and change of hematocrit were also measured for dehydration analysis. Blood pressure was elevated more and changes in heart rate and total sweating were larger in dry sauna than mist. A significant hematocrit increase was observed in dry sauna bathing only. Mean skin temperature and Tty in dry sauna were elevated higher than those in mist. Heat stress of the dry sauna may be stronger than that of the mist, leading to dehydration and hypovolemia by sweating. Percent plasma volume loss was significantly larger in the dry than mist sauna. Changes in skin blood flow and sweat rate/Tty during mist sauna were significantly larger than those during dry sauna bathing despite heat stress of the mist sauna. The mist sauna bathing may thus be safer physiologically, and provide more effective vascular dilatation and sweating than the dry sauna bathing.展开更多
文摘BACKGROUND Portal hypertension(PH),a major complication of cirrhosis,arises from increased intrahepatic resistance and splanchnic vasodilation.Epoxyeicosatrienoic acids(EETs)improve hepatic microcirculation,but their effects are rapidly inactivated by soluble epoxide hydrolase(sEH),an enzyme upregulated in the cirrhotic liver.Inhibiting sEH increases EET levels,reducing portal pressure and fibrosis.Dipeptidyl peptidase-4 inhibitors(DPP4-Is)and angiotensin II blockers have been reported to suppress sEH and enhance EET activity.Angiotensin receptorneprilysin inhibitors(ARNIs)also lower portal pressure.However,the combined effect of DPP4-I and ARNI on the sEH-EET axis in PH and liver fibrosis remains uninvestigated.AIM To study the effects of vildagliptin,a DPP4-I and sacubitril/valsartan,an ARNI on PH and liver fibrosis in cirrhotic rats.METHODS Two rodent models of liver cirrhosis:(1)Choline-deficient,L-amino acid-defined,high-fat diet(CDAHFD)diet-fed rats;and(2)Bile duct ligation-induced rats were treated with vildagliptin(10 mg/kg/day),sacubitril/valsartan(30 mg/kg/day),or a combination of both drugs.Hemodynamic parameters,sEH activity,EET levels,vascular remodeling,and fibrosis were assessed using enzyme-linked immunosorbent assay,quantitative real-time polymerase chain reaction,Western blotting,histology,and immunofluorescence.RESULTS In CDAHFD-fed models,both DPP4-I and ARNI significantly reduced portal pressure in cirrhotic rats by decreasing intrahepatic vascular resistance without affecting systemic hemodynamics.These agents downregulated sEH expression and activity,increasing EET levels,and improved endothelial function via nitric oxide signaling enhancement.They also suppressed sinusoidal capillarization,pathological angiogenesis,and Hedgehog signaling,while restoring sinusoidal endothelial markers.Additionally,DPP4-I and ARNI attenuated liver fibrosis and stellate cell activation,reducing profibrotic gene expression.These effects were additive by the combination of both drugs.Similar effects were observed in bile duct ligation-induced PH,confirming their therapeutic potential in managing both PH and liver fibrosis through modulation of the sEH-EET pathway.CONCLUSION Combined DPP4-I with ARNI therapy ameliorates PH and fibrosis via sEH suppression and EET restoration,offering a promising treatment strategy for cirrhosis-related PH.
文摘To test the hypothesis that mist sauna is a safer way of bathing than dry sauna, we compared changes in circulatory and thermoregulatory functions during 10 min sauna bathing in mist sauna at 40℃ with relative humidity of 100%, and in dry sauna by infrared ray at 70℃ with relative humidity of 15%. Subjects were seven healthy young men aged 29 ± 6 yrs (mean ± SD). We measured blood pressure, heart rate, skin temperatures at chest, forearm, thigh, and leg, tympanic temperature (Tty) by thermistors, skin blood flow at forearm by laser Doppler flowmetry, and sweat rate by ventilated capsule method at 1 min intervals throughout the experiment. Total sweating and change of hematocrit were also measured for dehydration analysis. Blood pressure was elevated more and changes in heart rate and total sweating were larger in dry sauna than mist. A significant hematocrit increase was observed in dry sauna bathing only. Mean skin temperature and Tty in dry sauna were elevated higher than those in mist. Heat stress of the dry sauna may be stronger than that of the mist, leading to dehydration and hypovolemia by sweating. Percent plasma volume loss was significantly larger in the dry than mist sauna. Changes in skin blood flow and sweat rate/Tty during mist sauna were significantly larger than those during dry sauna bathing despite heat stress of the mist sauna. The mist sauna bathing may thus be safer physiologically, and provide more effective vascular dilatation and sweating than the dry sauna bathing.
