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Objective To investigate the role of endoplasmic reticulum stress (ERS) in rats with acute respiratory distress syndrome (ARDS) related right ventricular dysfunction and the protective effect of sodium 4-phenylbutyrate (4-PBA) on right ventricle. Methods Sixty male Spragne-Dawley (SD) rats were randomly divided into control group (CON group), lipopolysaccharide (LPS) model group, 4-PBA prevention group and 4-PBA treatment group, with 15 rats in each group. ARDS rat model was established by intratracheal instillation of LPS 10 mg/kg after tracheotomy; CON group was given the same amount of saline. 4-PBA prevention group and 4-PBA treatment group were given 4-PBA 500 mg/kg intragastric administration 2 hours before and after LPS respectively. Echocardiography was performed 12 hours after treatment to evaluate the right ventricular function. Then, the rats were sacrificed by bloodletting, and the serum and right ventricular tissue were harvested. The histopathological changes of myocardial were observed by hematoxylin-eosin (HE) staining, the levels of tumor necrosis factor-α (TNF-α), interleukins (IL-1β and IL-6) in serum and myocardial were detected by enzyme linked immunosorbent assay (ELISA), and Western Blot was used to detect the expression of the marker proteins of ERS in myocardial, including glucose regulatory protein 78 (GRP78), C/EBP cyclic adenosine phosphate reaction primitive binding transcription factor homologous protein (CHOP), caspase-12 and caspase-3. Results Compared with the CON group, the echocardiography showed pulmonary artery maximum pressure gradient (PAmaxPG), pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE) in LPS model group were significantly decreased, and right ventricular end-diastolic excursion (RVDd) was significantly increased, and the levels of TNF-α, IL-1β and IL-6 in serum and myocardial, as well as the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly increased. Compared with LPS model group, TAPSE of 4-PBA preventive and treatment groups were significantly increased (mm: 3.08±0.65, 2.96±0.61 vs. 2.48±0.45), RVDd were significantly decreased (mm: 3.67±0.58, 3.60±0.61 vs. 4.18±0.71), the levels of TNF-α, IL-1β and IL-6 in serum and myocardial were significantly decreased [TNF-α (ng/L): 187.98±18.98, 176.08±17.98 vs. 332.00±19.90 in serum, 135.06±19.00, 132.78±17.00 vs. 155.00±20.00 in myocardial; IL-1β(ng/L): 12.07±2.98, 11.05±2.41 vs. 24.06±4.01 in serum, 19.89±2.80, 21.06±2.80 vs. 26.00±2.60 in myocardial; IL-6 (ng/L): 42.98±7.90, 34.05±6.09 vs. 89.80±10.07 in serum, 129.45±25.00, 127.08±26.06 vs. 145.77±23.00 in myocardial]; the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly decreased (GRP78/GAPDH: 0.090±0.070, 0.103±0.060 vs. 0.167±0.090, CHOP/GAPDH: 0.109±0.090, 0.090±0.080 vs. 0.186±0.090, caspase-12/GAPDH: 0.769±0.230, 0.799±0.210 vs. 1.040±0.350, caspase-3/GAPDH: 0.391±0.060, 0.401±0.054 vs. 0.603±0.340), with statistically significant differences (all P < 0.05). There were no significant differences in each indexes between 4-PBA prevention group and 4-PBA treatment group (all P > 0.05). Conclusions ERS is involved in ARDS-related right ventricular dysfunction. 4-PBA can protect the right ventricular function of ARDS rats by inhibiting ERS and alleviating inflammation, and the preventive and therapeutic effects of 4-PBA are similar.
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Objective To investigate the role of endoplasmic reticulum stress (ERS) in rats with acute respiratory distress syndrome (ARDS) related right ventricular dysfunction and the protective effect of sodium 4-phenylbutyrate (4-PBA) on right ventricle. Methods Sixty male Spragne-Dawley (SD) rats were randomly divided into control group (CON group), lipopolysaccharide (LPS) model group, 4-PBA prevention group and 4-PBA treatment group, with 15 rats in each group. ARDS rat model was established by intratracheal instillation of LPS 10 mg/kg after tracheotomy; CON group was given the same amount of saline. 4-PBA prevention group and 4-PBA treatment group were given 4-PBA 500 mg/kg intragastric administration 2 hours before and after LPS respectively. Echocardiography was performed 12 hours after treatment to evaluate the right ventricular function. Then, the rats were sacrificed by bloodletting, and the serum and right ventricular tissue were harvested. The histopathological changes of myocardial were observed by hematoxylin-eosin (HE) staining, the levels of tumor necrosis factor-α (TNF-α), interleukins (IL-1β and IL-6) in serum and myocardial were detected by enzyme linked immunosorbent assay (ELISA), and Western Blot was used to detect the expression of the marker proteins of ERS in myocardial, including glucose regulatory protein 78 (GRP78), C/EBP cyclic adenosine phosphate reaction primitive binding transcription factor homologous protein (CHOP), caspase-12 and caspase-3. Results Compared with the CON group, the echocardiography showed pulmonary artery maximum pressure gradient (PAmaxPG), pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE) in LPS model group were significantly decreased, and right ventricular end-diastolic excursion (RVDd) was significantly increased, and the levels of TNF-α, IL-1β and IL-6 in serum and myocardial, as well as the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly increased. Compared with LPS model group, TAPSE of 4-PBA preventive and treatment groups were significantly increased (mm: 3.08±0.65, 2.96±0.61 vs. 2.48±0.45), RVDd were significantly decreased (mm: 3.67±0.58, 3.60±0.61 vs. 4.18±0.71), the levels of TNF-α, IL-1β and IL-6 in serum and myocardial were significantly decreased [TNF-α (ng/L): 187.98±18.98, 176.08±17.98 vs. 332.00±19.90 in serum, 135.06±19.00, 132.78±17.00 vs. 155.00±20.00 in myocardial; IL-1β(ng/L): 12.07±2.98, 11.05±2.41 vs. 24.06±4.01 in serum, 19.89±2.80, 21.06±2.80 vs. 26.00±2.60 in myocardial; IL-6 (ng/L): 42.98±7.90, 34.05±6.09 vs. 89.80±10.07 in serum, 129.45±25.00, 127.08±26.06 vs. 145.77±23.00 in myocardial]; the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly decreased (GRP78/GAPDH: 0.090±0.070, 0.103±0.060 vs. 0.167±0.090, CHOP/GAPDH: 0.109±0.090, 0.090±0.080 vs. 0.186±0.090, caspase-12/GAPDH: 0.769±0.230, 0.799±0.210 vs. 1.040±0.350, caspase-3/GAPDH: 0.391±0.060, 0.401±0.054 vs. 0.603±0.340), with statistically significant differences (all P < 0.05). There were no significant differences in each indexes between 4-PBA prevention group and 4-PBA treatment group (all P > 0.05). Conclusions ERS is involved in ARDS-related right ventricular dysfunction. 4-PBA can protect the right ventricular function of ARDS rats by inhibiting ERS and alleviating inflammation, and the preventive and therapeutic effects of 4-PBA are similar.
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Objective@#To investigate the role of endoplasmic reticulum stress (ERS) in rats with acute respiratory distress syndrome (ARDS) related right ventricular dysfunction and the protective effect of sodium 4-phenylbutyrate (4-PBA) on right ventricle.@*Methods@#Sixty male Spragne-Dawley (SD) rats were randomly divided into control group (CON group), lipopolysaccharide (LPS) model group, 4-PBA prevention group and 4-PBA treatment group, with 15 rats in each group. ARDS rat model was established by intratracheal instillation of LPS 10 mg/kg after tracheotomy; CON group was given the same amount of saline. 4-PBA prevention group and 4-PBA treatment group were given 4-PBA 500 mg/kg intragastric administration 2 hours before and after LPS respectively. Echocardiography was performed 12 hours after treatment to evaluate the right ventricular function. Then, the rats were sacrificed by bloodletting, and the serum and right ventricular tissue were harvested. The histopathological changes of myocardial were observed by hematoxylin-eosin (HE) staining, the levels of tumor necrosis factor-α(TNF-α), interleukins (IL-1β and IL-6) in serum and myocardial were detected by enzyme linked immunosorbent assay (ELISA), and Western Blot was used to detect the expression of the marker proteins of ERS in myocardial, including glucose regulatory protein 78 (GRP78), C/EBP cyclic adenosine phosphate reaction primitive binding transcription factor homologous protein (CHOP), caspase-12 and caspase-3.@*Results@#Compared with the CON group, the echocardiography showed pulmonary artery maximum pressure gradient (PAmaxPG), pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE) in LPS model group were significantly decreased, and right ventricular end-diastolic excursion (RVDd) was significantly increased, and the levels of TNF-α, IL-1β and IL-6 in serum and myocardial, as well as the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly increased. Compared with LPS model group, TAPSE of 4-PBA preventive and treatment groups were significantly increased (mm: 3.08±0.65, 2.96±0.61 vs. 2.48±0.45), RVDd were significantly decreased (mm: 3.67±0.58, 3.60±0.61 vs. 4.18±0.71), the levels of TNF-α, IL-1β and IL-6 in serum and myocardial were significantly decreased [TNF-α (ng/L): 187.98±18.98, 176.08±17.98 vs. 332.00±19.90 in serum, 135.06±19.00, 132.78±17.00 vs. 155.00±20.00 in myocardial; IL-1β(ng/L): 12.07±2.98, 11.05±2.41 vs. 24.06±4.01 in serum, 19.89±2.80, 21.06±2.80 vs. 26.00±2.60 in myocardial; IL-6 (ng/L): 42.98±7.90, 34.05±6.09 vs. 89.80±10.07 in serum, 129.45±25.00, 127.08±26.06 vs. 145.77±23.00 in myocardial]; the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly decreased (GRP78/GAPDH: 0.090±0.070, 0.103±0.060 vs. 0.167±0.090, CHOP/GAPDH: 0.109±0.090, 0.090±0.080 vs. 0.186±0.090, caspase-12/GAPDH: 0.769±0.230, 0.799±0.210 vs. 1.040±0.350, caspase-3/GAPDH: 0.391±0.060, 0.401±0.054 vs. 0.603±0.340), with statistically significant differences (all P < 0.05). There were no significant differences in each indexes between 4-PBA prevention group and 4-PBA treatment group (all P > 0.05).@*Conclusions@#ERS is involved in ARDS-related right ventricular dysfunction. 4-PBA can protect the right ventricular function of ARDS rats by inhibiting ERS and alleviating inflammation, and the preventive and therapeutic effects of 4-PBA are similar.
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OBJECTIVE@#To determine the mitigating effects of sodium 4-phenylbutyrate (4-PBA) on high-fat diet (HFD)-induced spermatogenesis dysfunction.@*METHODS@#Male rats (n = 30) were randomly divided into three groups: control, HFD, and 4-PBA (HFD +4-PBA). After 13 weeks, rats were euthanized. Testes and epididymis were harvested for further analysis. Sex hormones were detected, and hematoxylin and eosin staining was performed to examine the histological changes in the testes. Semen samples were collected to evaluate sperm quality. Spermatogenic cell apoptosis was detected by TUNEL assay.@*RESULTS@#Compared with the control group, the final body weight and body weight gain were significantly higher in HFD-fed rats, while the testicle/body weight ratios were lower (P < 0.05). In HFD-fed rats, obvious pathological changes in the testicular tissue were observed. Treatment with 4-PBA attenuated HFD-induced histological damage, ameliorated the HFD-induced decrease in serum testosterone (T), and reduced the rate of testicular cell apoptosis (P < 0.05) in obese male rats. Finally, 4-PBA significantly improved semen parameters in HFD rats (P < 0.05).@*CONCLUSION@#HFD exposure induced detrimental effects on spermatogenesis, semen quality, serum T level, and testicular cell apoptosis in rats. Treatment with 4-PBA ameliorated HFD？induced impaired spermatogenesis via inhibition of apop-tosis in rats. 4-PBA may have therapeutic value in the treatment of obesity？related impairment of spermatogenesis.
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Animales , Masculino , Dieta Alta en Grasa , Fenilbutiratos , Farmacología , Ratas Sprague-Dawley , Análisis de Semen , Espermatogénesis , Testículo , Patología , Testosterona , SangreRESUMEN
OBJECTIVES: The capacity of a human cell line to secrete recombinant factor VIII with a F309S point mutation was investigated, as was the effect of the addition of chemical chaperones (betaine and sodium-4-phenylbutyrate) on the secretion of factor VIII. METHODS: This work used a vector with a F309S mutation in the A1 domain to investigate FVIII production in the HEK 293 human cell line. Factor VIII activity was measured by chromogenic assay. Furthermore, the effects of chemical drugs on the culture were evaluated. RESULTS: The addition of the F309S mutation to a previously described FVIII variant increased FVIII secretion by 4.5 fold. Moreover, the addition of betaine or sodium-4-phenylbutyrate increased the secretion rate of FVIIIÄB proteins in HEK 293 cells, but the same effect was not seen for FVIIIÄB-F309S indicating that all the recombinant protein produced had been efficiently secreted. CONCLUSION: Bioengineering factor VIII expressed in human cells may lead to an efficient production of recombinant factor VIII and contribute toward low-cost coagulation factor replacement therapy for hemophilia A. FVIII-F309S produced in human cells can be effective in vivo.
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Humanos , ADN Recombinante , FenilbutiratosRESUMEN
Bile Salt Export Pump (BSEP) Deficiency disease, including Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2), is a rare disease, usually leading within the first ten years to portal hypertension, liver failure, hepatocellular carcinoma. Often liver transplantation is needed. Sodium 4-phenylbutyrate (4-PB) seems to be a potential therapeutic compound for PFIC2. Psychiatric side effects in the adolescent population are little known and little studied since the drug used to treat children and infants. So we described a case of Caucasian boy, suffering from a late onset PFIC2, listed for a liver transplant when he was sixteen and treated with 4-FB (200 mg per kilogram of body weight per day). The drug was discontinued for the onset of bipolar and related disorders. This case illustrates possible psychiatric side effects of the drug.
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Adolescente , Niño , Humanos , Lactante , Masculino , Bilis , Trastornos Bipolares y Relacionados , Peso Corporal , Carcinoma Hepatocelular , Colestasis Intrahepática , Enfermedades Carenciales , Hipertensión Portal , Hígado , Fallo Hepático , Trasplante de Hígado , Enfermedades Raras , SodioRESUMEN
PURPOSE: Phenylbutyrate is an effective redifferentiating agent in several human cancers. Recently phenylbutyrate has been reported to inhibit histone deacetylase activity. We investigated the effects of sodium 4-henylbutyrate (Na-4-PB) on cell proliferation in a human pancreatic cancer cell line. METHODS: A human pancreatic cancer cell line, Aspc-1 was purchased from Korean Cell Line Bank. Antiproliferative effects of sodium 4-phenylbutyrate were measured by MTT assay and their mechanisms were evaluated by apoptosis assay and cell cycle analysis. RESULTS: After 3 days of treatment with Na-4-PB at the concentration of 2.5, 5, 7.5, and 10 mM, relative growth inhibition compared to control was 21.3+/-8.3% (mean+/-SD), 37.8+/-2.3%, 46.7+/-0.5%, and 56.7+/-1.7% respectively (p < 0.05). Antiproliferative effect of Na-4-PB was also time-dependent. Combination treatment with Na-4-PB and troglitazone, a PPARg agonist, increased antiproliferative effects but was not synergistic. After 48 hour treatment with Na-4-PB, early apoptotic cell population in control, 2.5, and 5 mM of Na-4-PB was 29.6%, 44.2%, and 65.9%, respectively. After 24 hour treatment with Na-4- PB, G0/G1 phase population in control, 2.5, and 5 mM of Na-4-PB was 55.0%, 67.4%, and 65.8%, respectively. CONCLUSION: Na-4-PB inhibited pancreatic cancer cell proliferation by inducing apoptosis and cell cycle arrest at G0/G1 phase in time- and dose-dependent manner. Combination treatment with Na-4-PB and other chemotherapeutic agents such as troglitazone, a PPARg agonist, can enhance antiproliferative effects. Na-4-PB might be a promising potential therapeutic agent for patients with pancreatic cancer.