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Objective@#To investigate the development of hepatocyte senescence during liver fibrogenesis and to explore the effect and possible mechanism of insulin-like growth factor 1 (IGF-1) on hepatocyte senescence and liver fibrosis.@*Methods@#A total of 42 male Sprague Dawley (SD) rats were selected. Eighteen rats were induced by carbon tetrachloride (CCl4) to establish the rat model of liver fibrosis. On the day 0, six and 28 after the establishment of the model, six rats were executed respectively to analyze the liver fibrosis and hepatocyte senescence in CCl4-induced liver fibrosis rat models. Twenty-four rats were divided into control group, CCl4 group, CCl4+ lentivirus vector (LV-CTR) group and CCl4+ LV-IGF-1 group, with six rats in each group.The rats were sacrificed on the 28th day after the establishment of the model. The liver tissues were obtained and the inferior vena cava blood was collected to analyze the effect of IGF-1 overexpression on liver fibrosis and hepatocyte senescence. Analysis variance (ANOVA), least significant difference (LSD) and Dunnett T3 test were performed for statistical analysis.@*Results@#Steatohepatitis on the 6th day and early stage of hepatic fibrosis on the 28th day, which indicated the model was successfully established. The results of the effects of IGF-1 overexpression on hepatic fibrosis and hepatocyte senescence showed that on the 28th day, compared with those of control group, both the score of Ishak liver inflammation and necrosis and the score of Ishak liver fibrosis were increased in the CCl4 group, CCl4+ LV-CTR group and CCl4+ LV-IGF-1 group (0, 14.55±1.94, 15.43±2.19 and 10.29±1.47, respectively; 0, 3.51±0.51, 3.21±0.79 and 1.32±0.40, respectively). The area of liver tissues by Masson staining (0.45±0.40, 5.62±1.08, 6.03±0.65 and 2.88±1.54), SA-β-Gal staining (1.75±0.80, 4.28±1.19, 4.92±1.14, 3.11±0.79), p53 (2.02±0.81, 4.36±1.02, 4.72±0.72 and 3.58±0.70) and progerin (0.72±0.40, 4.52±1.01, 4.01±1.25 and 2.66±0.80) all were increased. The levels of serum IGF-1 all were decreased ((632.00±6.04), (503.00±40.42), (508.00±21.94) and (572.40±5.94) ng/L). However the levels of ALT all were increased ((11.20±5.97), (214.00±73.90), (245.00±76.06) and (30.00±5.00) U/L). The relative expression levels of p53 (0.58±0.06, 1.78±0.18, 1.72±0.10 and 1.23±0.22) and progerin (0.12±0.02, 0.78±0.15, 1.32±0.20 and 0.81±0.16) in the primary hepatocytes were increased. The differences were all statistically significant (F=91.674, 90.778, 32.982, 9.726, 10.640, 17.029, 103.910, 30.059, 64.707 and 97.457, all P<0.05). Compared with those of CCl4+ LV-CTR group, the score of Ishak liver inflammation and necrosis and the score of Ishak liver fibrosis were decreased in the rats′ liver tissues of CCl4+ LV-IGF-1 group, the areas of Masson staining, SA-β-Gal staining, p53 and progerin in the liver tissues were decreased, the level of serum IGF-1 was increased, the level of ALT was decreased, and the relative expression levels of p53 and progerin in primary hepatocytes both were decreased. The differences were all statistically significant (all P<0.05, respectively).@*Conclusions@#Hepatocyte senescence increases in the process of liver fibrosis induced by CCl4. Overexpression of IGF-1 may alleviate liver injury, improve hepatocyte senescence and liver fibrogenesis by regulating the nuclear p53/progerin pathway.
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Objective To investigate the development of hepatocyte senescence during liver fibrogenesis and to explore the effect and possible mechanism of insulin-like growth factor 1 (IGF-1) on hepatocyte senescence and liver fibrosis.Methods A total of 42 male Sprague Dawley (SD) rats were selected.Eighteen rats were induced by carbon tetrachloride (CCl4) to establish the rat model of liver fibrosis.On the day 0,six and 28 after the establishment of the model,six rats were executed respectively to analyze the liver fibrosis and hepatocyte senescence in CCl4-induced liver fibrosis rat models.Twenty-four rats were divided into control group,CCl4 group,CCl4 + lentivirus vector (LV-CTR) group and CCl4 + LV-IGF-1 group,with six rats in each group.The rats were sacrificed on the 28th day after the establishment of the model.The liver tissues were obtained and the inferior vena cava blood was collected to analyze the effect of IGF-1 overexpression on liver fibrosis and hepatocyte senescence.Analysis variance (ANOVA),least significant difference (LSD) and Dunnett T3 test were performed for statistical analysis.Results Steatohepatitis on the 6th day and early stage of hepatic fibrosis on the 28th day,which indicated the model was successfully established.The results of the effects of IGF-1 overexpression on hepatic fibrosis and hepatocyte senescence showed that on the 28th day,compared with those of control group,both the score of Ishak liver inflammation and necrosis and the score of Ishak liver fibrosis were increased in the CCl4 group,CCl4 + LV-CTR group and CCl4 + LV-IGF-1 group (0,14.55 ±1.94,15.43 ±2.19 and 10.29 ±1.47,respectively;0,3.51 ±0.51,3.21 ±0.79 and 1.32 ±0.40,respectively).The area of liver tissues by Masson staining (0.45 ±0.40,5.62 ± 1.08,6.03 ± 0.65 and 2.88 ± 1.54),SA-β-Gal staining (1.75 ± 0.80,4.28 ± 1.19,4.92 ± 1.14,3.11 ± 0.79),p53 (2.02 ±0.81,4.36 ±1.02,4.72 ±0.72 and 3.58 ±0.70) and progerin (0.72 ±0.40,4.52±1.01,4.01 ± 1.25 and 2.66 ± 0.80) all were increased.The levels of serum IGF-1 all were decreased ((632.00 ± 6.04),(503.00 ± 40.42),(508.00 ± 21.94) and (572.40 ± 5.94) ng/L).However the levels of ALT all were increased ((11.20 ± 5.97),(214.00 ± 73.90),(245.00 ± 76.06) and (30.00 ± 5.00) U/L).The relative expression levels of p53 (0.58 ± 0.06,1.78 ± 0.18,1.72 ± 0.10 and 1.23 ± 0.22) and progerin (0.12 ± 0.02,0.78 ± 0.15,1.32 ± 0.20 and 0.81 ± 0.16) in the primary hepatocytes were increased.The differences were all statistically significant (F =91.674,90.778,32.982,9.726,10.640,17.029,103.910,30.059,64.707 and 97.457,all P ＜ 0.05).Compared with those of CCl4 + LV-CTR group,the score of Ishak liver inflammation and necrosis and the score of Ishak liver fibrosis were decreased in the rats' liver tissues of CCl4 + LV-IGF-1 group,the areas of Masson staining,SA-β-Gal staining,p53 and progerin in the liver tissues were decreased,the level of serum IGF-1 was increased,the level of ALT was decreased,and the relative expression levels of p53 and progerin in primary hepatocytes both were decreased.The differences were all statistically significant (all P ＜ 0.05,respectively).Conclusions Hepatocyte senescence increases in the process of liver fibrosis induced by CCl4.Overexpression of IGF-1 may alleviate liver injury,improve hepatocyte senescence and liver fibrogenesis by regulating the nuclear p53/progerin pathway.
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<p><b>OBJECTIVE</b>To investigate whether transdermal scopolamine increased cardiac vagal activity in patients during the acute phase of myocardial infarction.</p><p><b>METHODS</b>30 patients with a first acute myocardial infarction and preserved sinus rhythm who were on no drug that could influence the sinus node were randomly assigned to either treatment group or placebo group. Measures of heart rate variability (HRV) in patients given drug or placebo were obtained by digital 24 hour Holter recording before and after treatment. Baroreflex sensitivity was performed using the phenylephrine method.</p><p><b>RESULTS</b>No significant differences was found in the indices of the time domain and the frequency domain in both groups before treatment. Patients with transdermal scopolamine showed a significant increase in the standard deviation of normal RR intervals (SDNN), standard deviation of all five min mean normal RR intervals (SDANN), root mean square of differences of successive normal RR intervals (rMSSD), total power (TP, 0.000. - 0.40 Hz), low frequency peak (LF, 0.040 - 0.15 Hz), high frequency peak (HF, 0.15 - 0.40 Hz), and Baroreflex sensitivity after treatment (P < 0.05 - 0.01). These indices did not change in patients given placebo.</p><p><b>CONCLUSION</b>Low doses of transdermal scopolamine safely increase cardiac parasympathetic activity and improve autonomic indices in patients with acute myocardial infarction.</p>
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Administration, Cutaneous , Baroreflex , Dose-Response Relationship, Drug , Heart , Heart Rate , Myocardial Infarction , Scopolamine , Pharmacology , Vagus NerveABSTRACT
Objective To investigate if there is any effect of interleukin-18 (IL-18) or if IL-18 modulates IL-1β effects on islet fun ction.Methods Insulin release and nitrite production from isolated islets of newborn Wistar rats were measured after incubation with or w ithout cytokines.Reverse transcription polymerase chain reaction (RT-PCR) was u sed to detect mRNA expression of the IL-18 receptor signaling chain (IL-18Rβ) .Results (1) There were no significant effects of 0.625～ 10nmol/L of recombinant murine (rm) IL-18 alone on accumulated or glucose-cha llenged insulin release and nitrite production after 24h.(2) 15pg/ml of recombi nant human (rh) IL-1β significantly increased nitrite production and inhibited insulin release.However,0.625～10nmol/L of rm IL-18 failed to modulate the abo ve effects caused by IL-1β.(3) 24h rm IL-12 preincubation failed to sensitize islets to the effects of 10nmol/L of rm or recombinant rat (rr) IL-18 alone or to pri me islets to IL-1β actions on insulin release and nitrite production.(4) IL-1 8Rβ mRNA was not expressed in isolated islets even after exposure to IL-12 for 48h.Conclusion Unlike IL-1β,IL-18 dose not play a dir ect role in the destruction of islet β-cell function.
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Objective To investigate if there is any effect of interleukin-18 (IL-18) or if IL-18 modulates IL-1? effects on islet function.Methods Insulin release and nitrite production from isolated islets of newborn Wistar rats were measured after incubation with or without cytokines.Reverse transcription polymerase chain reaction (RT-PCR) was used to detect mRNA expression of the IL-18 receptor signaling chain (IL-18R?).Results (1) There were no significant effects of 0.625～10nmol/L of recombinant murine (rm) IL-18 alone on accumulated or glucose-challenged insulin release and nitrite production after 24h.(2) 15pg/ml of recombinant human (rh) IL-1? significantly increased nitrite production and inhibited insulin release.However,0.625～10nmol/L of rm IL-18 failed to modulate the above effects caused by IL-1?.(3) 24h rm IL-12 preincubation failed to sensitize islets to the effects of 10nmol/L of rm or recombinant rat (rr) IL-18 alone or to prime islets to IL-1? actions on insulin release and nitrite production.(4) IL-18R? mRNA was not expressed in isolated islets even after exposure to IL-12 for 48h.Conclusion Unlike IL-1?,IL-18 dose not play a direct role in the destruction of islet ?-cell function.