Objective:To investigate the beneficial effect of bicyclol on rat hearts subjected to ischemia-reperfusion(IR) injuries and its possible mechanism.Methods:Male Sprague-Dawley rats were intragastrically administered wi...Objective:To investigate the beneficial effect of bicyclol on rat hearts subjected to ischemia-reperfusion(IR) injuries and its possible mechanism.Methods:Male Sprague-Dawley rats were intragastrically administered with bicyclol(25,50 or 100 mg/(kg·d)) for 3 d.Myocardial IR was produced by occlusion of the coronary artery for 1 h and reperfusion for 3 h.Left ventricular hemodynamics was continuously monitored.At the end of reperfusion,myocardial infarct was measured by 2,3,5-triphenyltetrazolium chloride(TTC) staining,and serum lactate dehydrogenase(LDH) level and myocardial superoxide dismutase(SOD) activity were determined by spectrophotometry.Isolated ventricular myocytes from adult rats were exposed to 60 min anoxia and 30 min reoxygenation to simulate IR injuries.After reperfusion,cell viability was determined with trypan blue;reactive oxygen species(ROS) and mitochondrial membrane potential of the cardiomyocytes were measured with the fluorescent probe.The mitochondrial permeability transition pore(mPTP) opening induced by Ca2+(200 μmol/L) was measured with the absorbance at 520 nm in the isolated myocardial mitochondria.Results:Low dose of bicyclol(25 mg/(kg·d)) had no significant improving effect on all cardiac parameters,whereas pretreatment with high bicyclol markedly reduced the myocardial infarct and improved the left ventricular contractility in the myocardium exposed to IR(P<0.05).Medium dose of bicyclol(50 mg/(kg·d)) markedly improved the myocardial contractility,left ventricular myocyte viability,and SOD activity,as well decreased infarct size,serum LDH level,ROS production,and mitochondrial membrane potential in rat myocardium exposed to IR.The reduction of ventricular myocyte viability in IR group was inhibited by pretreatment with 50 and 100 mg/(kg·d) bicyclol(P<0.05 vs.IR),but not by 25 mg/(kg·d) bicyclol.The opening of mPTP evoked by Ca2+ was significantly inhibited by medium bicyclol.Conclusions:Bicyclol exerts cardioprotection against IR injury,at least,via reducing oxidative stress and its subsequent mPTP opening.展开更多
AIM: To evaluate the protective effect of bicyclol against bile duct ligation(BDL)-induced hepatic fibrosis in rats.METHODS: Sprague-Dawley male rats underwent BDL and sham-operated animals were used as healthy contro...AIM: To evaluate the protective effect of bicyclol against bile duct ligation(BDL)-induced hepatic fibrosis in rats.METHODS: Sprague-Dawley male rats underwent BDL and sham-operated animals were used as healthy controls. The BDL rats were divided into two groups which received sterilized PBS or bicyclol(100 mg/kg per day) orally for two consecutive weeks. Serum, urine and bile were collected for biochemical determinations. Liver tissues were collected for histological analysis and a whole genome oligonucleotide microarray assay. Reverse transcription-polymerase chain reaction and Western blotting were used to verify the expression of liver fibrosis-related genes.RESULTS: Treatment with bicyclol significantly reduced liver fibrosis and bile duct proliferation after BDL. The levels of alanine aminotransferase(127.7 ± 72.3 vs 230.4 ± 69.6, P < 0.05) and aspartate amino-transferase(696.8 ± 232.6 vs 1032.6 ± 165.8, P < 0.05) were also decreased by treatment with bicyclol in comparison to PBS. The expression changes of 45 fibrogenic genes and several fibrogenesis-related pathways were reversed by bicyclol in the microarray assay. Bicyclol significantly reduced liver m RNA and/or protein expression levels of collagen 1a1, matrix metalloproteinase 2, tumor necrosis factor, tissue inhibitors of metalloproteinases 2, transforming growth factor-b1 and α-smooth muscle actin.CONCLUSION: Bicyclol significantly attenuates BDLinduced liver fibrosis by reversing fibrogenic gene expression. These findings suggest that bicyclol might be an effective anti-fibrotic drug for the treatment of cholestatic liver disease.展开更多
AIM: To study the toxicity of bicyclol to animals. METHODS: Acute toxicity test was performed in Kunming strain mice that were orally given bicyclol at the doses of 3 and 5 g/kg body weight, respectively. Wistar rats ...AIM: To study the toxicity of bicyclol to animals. METHODS: Acute toxicity test was performed in Kunming strain mice that were orally given bicyclol at the doses of 3 and 5 g/kg body weight, respectively. Wistar rats were orally administered bicyclol at a dose of 5 g/kg body weight. Death and clinical symptoms of animals were recorded within 7 d. Sub-acute toxicity test was carried out in rats that were treated with various doses of bicyclol (150, 300, 600 mg/kg) once daily for 14 d. Animal behaviors, blood biochemical markers, blood and urine pictures were examined. Chronic toxicity test was conducted in 80 Wistar rats of both sexes. The animals were orally administered with various doses of bicyclol [150, 300, 600 mg/kg, 100-400 folds corresponding to the proposed therapeutic dose (1.5 mg/(kg·d)) of bicyclol for patients] once daily for 6 mo except for Sunday. The control group was given the same volume of 0.2% sodium carboxyl methylcellulose (Na-CMC). Twenty-one beagle dogs received bicyclol (25, 75, 225 mg/kg, 16.6, 50, 150 folds corresponding to the proposed therapeutic dose of bicyclol for patients) once a day for 6 mo except for Sunday. The body weight, food intake, urine and feces, blood picture, blood biochemical markers, and pathological examination of main organs were determined. Mutagenicity and teratogenicity were determined. Mutagenicity assay included Ames's test, chromosome aberration test in CHL cells and micronucleus test in mice. For the teratogenicity assay, pregnant Wistar rats weighing 200-250 g were treated with 0.2,1.0 g/kg bicyclol once daily from the 7th d of gestation for 10 d. RESULTS: The oral LD50 of bicyclol was over 5 g/kg in mice and rats. No noticeable alterations in subacute and chronic toxicity of rats and dogs were demonstrated. No mutagenicity and teratogenicity of bicyclol were found. CONCLUSION: Bicyclol has no detectable chronic toxicity as well as mutagenicity and teratogenicity in animals.展开更多
The enantioseparation of anti-hepatitis new drug （±）-bicyclol was performed by optically active alkaloid. The alcoholic acid, the hydrolysate of bicyclol was reacted with optically active alkaloid, such as bruc...The enantioseparation of anti-hepatitis new drug （±）-bicyclol was performed by optically active alkaloid. The alcoholic acid, the hydrolysate of bicyclol was reacted with optically active alkaloid, such as brucine, strychnine, quinidine etc., the diastereoisomeric salts were obtained by fractional recrystallization, then separately decomposed and esterified to obtain the two enantiomers of bicyclol. The pharmacological study showed that the effect of （-）-bicyclol was more potent than racemic bicyclol two times and the potency of （＋）-bicyclol was incative.展开更多
Objective:To investigate the clinical effect of microecological preparation combined with bicyclol on nonalcoholic fatty liver (NAFLD) and its effect on liver fibrosis, serum inflammatory factors and transforming grow...Objective:To investigate the clinical effect of microecological preparation combined with bicyclol on nonalcoholic fatty liver (NAFLD) and its effect on liver fibrosis, serum inflammatory factors and transforming growth factorβ1 (TGF-β1).Methods:106 patients with NAFLD were randomly divided into control group (53 cases) and case group (53 cases). The control group was given routine liver protection and bicyclol, and the case group was given Bifidobacterium triple viable probiotics based on the treatment of the control group. The two groups were treated for 6 weeks. The clinical effect, liver fibrosis, serum inflammatory factors, TGF-β1 and other changes were observed in the two groups after treatment.Results:The total effective rate of the case group was significantly higher than that of the control group (96.22% vs 83.02%), (χ2=4.970,P=0.026). After treatment, the ALB and HDL levels of the two groups of patients were higher than before. ALT, AST, and TBIL, LN, HA, PCIII, CIV, TC, TG, LDL, IL-6, TNF-a, hs-CRP, TGF-β1 were lower, compared with before and after treatment;and the improvement of liver function, liver fibrosis, blood lipid levels, serum inflammatory factors, and TGF-β1 in the case group was better than that in the control group, and the differences were statistically significant (P <0.05). The incidence of adverse reactions in the case group was lower than that in the control group (5.66% vs 11.32%). The difference was not statistically significant (χ2=1.093,P=0.296).Conclusion: Microecological preparations combined with bicyclol in the treatment of NAFLD have exact clinical effects, can significantly improve liver function, regulate blood lipid levels, reduce inflammation and liver fibrosis, and have good safety, which deserves further clinical research and promotion.展开更多
The authors regret that a correction was made in the Materials and Methods section concerning the incomplete supplier information.The antibody for HCV NS5A(pab24633)was from Abnova(Taipei,Taiwan,China).This correction...The authors regret that a correction was made in the Materials and Methods section concerning the incomplete supplier information.The antibody for HCV NS5A(pab24633)was from Abnova(Taipei,Taiwan,China).This correction has no influence on the readers'understanding of the article.展开更多
Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus(HCV) with unknown mechanism. Here, we showed th...Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus(HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein(GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A(VAP-A) in competition with the HCV NS5 A, causing an interruption of the complex formation between VAP-A and HCV NS5 A. As the formation of VAP-A/NS5 A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5 A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents(DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.展开更多
Objective: To assess the genotoxicity and embryotoxicity of bicyclol methyl ether(BME), the main impurity in bicyclol. Methods: Five concentrations of BME(0.5, 5, 50, 500 and 5000 μg/plate) were used in the Ames test...Objective: To assess the genotoxicity and embryotoxicity of bicyclol methyl ether(BME), the main impurity in bicyclol. Methods: Five concentrations of BME(0.5, 5, 50, 500 and 5000 μg/plate) were used in the Ames test to detect gene mutation. In the chromosome aberration test, Chinese hamster lung cells were used to detect chromosomal aberration of BME(15, 30, 60, 120 μg/m L) with or without S9 mixture. Embryotoxicity test was also conducted to determine any embryotoxicity of BME(7.5, 22.5, 67.5 μg/L) using zebrafish embryos. Results: No significant differences were observed in the Ames test and the chromosome aberration test in the BME groups compared with the vehicle control group. The zebrafish embryos toxicity test also showed no embryo development toxicity of BME, including hatching rate, body length, pericardial area and yolk sac area. Conclusions: Bicyclol methyl ether has no genotoxicity in vitro and embryotoxicity in zebrafish embryos, and the impurity in bicyclol is qualified.展开更多
目的探讨双环醇对心肌纤维化模型大鼠的治疗作用及其可能的作用机制。方法选择无特定病原体级雄性SD大鼠24只,随机分为假手术组、模型组、低剂量组及高剂量组,每组6只。除假手术组外,其他各组尾静脉注射异丙肾上腺素5 mg/(kg·d)建...目的探讨双环醇对心肌纤维化模型大鼠的治疗作用及其可能的作用机制。方法选择无特定病原体级雄性SD大鼠24只,随机分为假手术组、模型组、低剂量组及高剂量组,每组6只。除假手术组外,其他各组尾静脉注射异丙肾上腺素5 mg/(kg·d)建立大鼠心肌纤维化模型,低剂量组、高剂量组分别按照100、200 mg/(kg·d)双环醇进行灌胃治疗,连续给药14 d。采用苏木精-伊红染色分析心肌损伤程度,Masson染色检测心肌纤维化程度,Western blot法检测心肌胶原蛋白Ⅰ、胶原蛋白Ⅲ、α平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)、甲基转移酶样蛋白3(methyltransferase-like protein 3(METTL3))、α-酮戊二酸依赖性双加氧酶ALKB同源物5(α-ketoglutarate-dependent dioxygenase alkB homolog5,ALKBH5)及YTH家族蛋白1(YTH domain family protein 1,YTHDF1)表达。结果与假手术组比较,模型组心肌细胞坏死程度明显升高,心肌纤维化程度增高;与模型组比较,低剂量组、高剂量组心肌细胞破裂和坏死程度明显降低,心肌纤维化程度明显改善。与假手术组比较,模型组心肌组织胶原蛋白Ⅰ、胶原蛋白Ⅲ、α-SMA、METTL3及YTHDF1表达明显升高(P<0.05),模型组ALKBH5表达明显降低(0.58±0.02 vs 0.88±0.07,P<0.05)。与模型组比较,低剂量组、高剂量组心肌组织胶原蛋白Ⅰ、胶原蛋白Ⅲ、α-SMA、METTL3及YTHDF1表达明显降低,ALKBH5表达明显升高,差异有统计学意义(P<0.05)。结论双环醇可有效缓解异丙肾上腺素诱导的心肌纤维化大鼠心肌结构损伤和间质胶原纤维化沉积,其机制可能与m^(6)A甲基化修饰相关。展开更多
基金Project (Nos. 2011C23105 and 2012C33088) supported by the Department of Science and Technology of Zhejiang Province,China
文摘Objective:To investigate the beneficial effect of bicyclol on rat hearts subjected to ischemia-reperfusion(IR) injuries and its possible mechanism.Methods:Male Sprague-Dawley rats were intragastrically administered with bicyclol(25,50 or 100 mg/(kg·d)) for 3 d.Myocardial IR was produced by occlusion of the coronary artery for 1 h and reperfusion for 3 h.Left ventricular hemodynamics was continuously monitored.At the end of reperfusion,myocardial infarct was measured by 2,3,5-triphenyltetrazolium chloride(TTC) staining,and serum lactate dehydrogenase(LDH) level and myocardial superoxide dismutase(SOD) activity were determined by spectrophotometry.Isolated ventricular myocytes from adult rats were exposed to 60 min anoxia and 30 min reoxygenation to simulate IR injuries.After reperfusion,cell viability was determined with trypan blue;reactive oxygen species(ROS) and mitochondrial membrane potential of the cardiomyocytes were measured with the fluorescent probe.The mitochondrial permeability transition pore(mPTP) opening induced by Ca2+(200 μmol/L) was measured with the absorbance at 520 nm in the isolated myocardial mitochondria.Results:Low dose of bicyclol(25 mg/(kg·d)) had no significant improving effect on all cardiac parameters,whereas pretreatment with high bicyclol markedly reduced the myocardial infarct and improved the left ventricular contractility in the myocardium exposed to IR(P<0.05).Medium dose of bicyclol(50 mg/(kg·d)) markedly improved the myocardial contractility,left ventricular myocyte viability,and SOD activity,as well decreased infarct size,serum LDH level,ROS production,and mitochondrial membrane potential in rat myocardium exposed to IR.The reduction of ventricular myocyte viability in IR group was inhibited by pretreatment with 50 and 100 mg/(kg·d) bicyclol(P<0.05 vs.IR),but not by 25 mg/(kg·d) bicyclol.The opening of mPTP evoked by Ca2+ was significantly inhibited by medium bicyclol.Conclusions:Bicyclol exerts cardioprotection against IR injury,at least,via reducing oxidative stress and its subsequent mPTP opening.
基金Supported by the National Natural Science Foundation of China,No.81170409,No.81201281the National S&T Major Special Project on Major New Drug Innovation,No.2012ZX09301002-001the Wang Bao En Liver Fibrosis Foundation,No.20110026
文摘AIM: To evaluate the protective effect of bicyclol against bile duct ligation(BDL)-induced hepatic fibrosis in rats.METHODS: Sprague-Dawley male rats underwent BDL and sham-operated animals were used as healthy controls. The BDL rats were divided into two groups which received sterilized PBS or bicyclol(100 mg/kg per day) orally for two consecutive weeks. Serum, urine and bile were collected for biochemical determinations. Liver tissues were collected for histological analysis and a whole genome oligonucleotide microarray assay. Reverse transcription-polymerase chain reaction and Western blotting were used to verify the expression of liver fibrosis-related genes.RESULTS: Treatment with bicyclol significantly reduced liver fibrosis and bile duct proliferation after BDL. The levels of alanine aminotransferase(127.7 ± 72.3 vs 230.4 ± 69.6, P < 0.05) and aspartate amino-transferase(696.8 ± 232.6 vs 1032.6 ± 165.8, P < 0.05) were also decreased by treatment with bicyclol in comparison to PBS. The expression changes of 45 fibrogenic genes and several fibrogenesis-related pathways were reversed by bicyclol in the microarray assay. Bicyclol significantly reduced liver m RNA and/or protein expression levels of collagen 1a1, matrix metalloproteinase 2, tumor necrosis factor, tissue inhibitors of metalloproteinases 2, transforming growth factor-b1 and α-smooth muscle actin.CONCLUSION: Bicyclol significantly attenuates BDLinduced liver fibrosis by reversing fibrogenic gene expression. These findings suggest that bicyclol might be an effective anti-fibrotic drug for the treatment of cholestatic liver disease.
基金Supported by the Grant From Ministry of Sciences and Technology of China, No.96-901-01 -45
文摘AIM: To study the toxicity of bicyclol to animals. METHODS: Acute toxicity test was performed in Kunming strain mice that were orally given bicyclol at the doses of 3 and 5 g/kg body weight, respectively. Wistar rats were orally administered bicyclol at a dose of 5 g/kg body weight. Death and clinical symptoms of animals were recorded within 7 d. Sub-acute toxicity test was carried out in rats that were treated with various doses of bicyclol (150, 300, 600 mg/kg) once daily for 14 d. Animal behaviors, blood biochemical markers, blood and urine pictures were examined. Chronic toxicity test was conducted in 80 Wistar rats of both sexes. The animals were orally administered with various doses of bicyclol [150, 300, 600 mg/kg, 100-400 folds corresponding to the proposed therapeutic dose (1.5 mg/(kg·d)) of bicyclol for patients] once daily for 6 mo except for Sunday. The control group was given the same volume of 0.2% sodium carboxyl methylcellulose (Na-CMC). Twenty-one beagle dogs received bicyclol (25, 75, 225 mg/kg, 16.6, 50, 150 folds corresponding to the proposed therapeutic dose of bicyclol for patients) once a day for 6 mo except for Sunday. The body weight, food intake, urine and feces, blood picture, blood biochemical markers, and pathological examination of main organs were determined. Mutagenicity and teratogenicity were determined. Mutagenicity assay included Ames's test, chromosome aberration test in CHL cells and micronucleus test in mice. For the teratogenicity assay, pregnant Wistar rats weighing 200-250 g were treated with 0.2,1.0 g/kg bicyclol once daily from the 7th d of gestation for 10 d. RESULTS: The oral LD50 of bicyclol was over 5 g/kg in mice and rats. No noticeable alterations in subacute and chronic toxicity of rats and dogs were demonstrated. No mutagenicity and teratogenicity of bicyclol were found. CONCLUSION: Bicyclol has no detectable chronic toxicity as well as mutagenicity and teratogenicity in animals.
文摘The enantioseparation of anti-hepatitis new drug （±）-bicyclol was performed by optically active alkaloid. The alcoholic acid, the hydrolysate of bicyclol was reacted with optically active alkaloid, such as brucine, strychnine, quinidine etc., the diastereoisomeric salts were obtained by fractional recrystallization, then separately decomposed and esterified to obtain the two enantiomers of bicyclol. The pharmacological study showed that the effect of （-）-bicyclol was more potent than racemic bicyclol two times and the potency of （＋）-bicyclol was incative.
基金China Hepatitis Prevention Fund Project(tqgb20170015)Hebei medical science research key project(20170933)+1 种基金Hebei medical science research key project(20150842)Hebei Science and Technology Department funded project(162777133)
文摘Objective:To investigate the clinical effect of microecological preparation combined with bicyclol on nonalcoholic fatty liver (NAFLD) and its effect on liver fibrosis, serum inflammatory factors and transforming growth factorβ1 (TGF-β1).Methods:106 patients with NAFLD were randomly divided into control group (53 cases) and case group (53 cases). The control group was given routine liver protection and bicyclol, and the case group was given Bifidobacterium triple viable probiotics based on the treatment of the control group. The two groups were treated for 6 weeks. The clinical effect, liver fibrosis, serum inflammatory factors, TGF-β1 and other changes were observed in the two groups after treatment.Results:The total effective rate of the case group was significantly higher than that of the control group (96.22% vs 83.02%), (χ2=4.970,P=0.026). After treatment, the ALB and HDL levels of the two groups of patients were higher than before. ALT, AST, and TBIL, LN, HA, PCIII, CIV, TC, TG, LDL, IL-6, TNF-a, hs-CRP, TGF-β1 were lower, compared with before and after treatment;and the improvement of liver function, liver fibrosis, blood lipid levels, serum inflammatory factors, and TGF-β1 in the case group was better than that in the control group, and the differences were statistically significant (P <0.05). The incidence of adverse reactions in the case group was lower than that in the control group (5.66% vs 11.32%). The difference was not statistically significant (χ2=1.093,P=0.296).Conclusion: Microecological preparations combined with bicyclol in the treatment of NAFLD have exact clinical effects, can significantly improve liver function, regulate blood lipid levels, reduce inflammation and liver fibrosis, and have good safety, which deserves further clinical research and promotion.
文摘The authors regret that a correction was made in the Materials and Methods section concerning the incomplete supplier information.The antibody for HCV NS5A(pab24633)was from Abnova(Taipei,Taiwan,China).This correction has no influence on the readers'understanding of the article.
基金supported by the National Natural Science Foundation of China(81321004,81621064,Jiandong Jiang81322050,Zonggen Peng)+2 种基金National Mega-Project for “R&D for Innovative drugs”,Ministry of Science and Technology,China(2012ZX09301-002-001,Jiandong Jiang,2018ZX09711001-003-010,Zonggen Peng)Ministry of Education,China(NCET-12-0072,Zonggen Peng)CAMS Innovation Fund for Medical Sciences,China(CIFMS)(2017-I2M-3-012,Zonggen Peng)
文摘Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus(HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein(GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A(VAP-A) in competition with the HCV NS5 A, causing an interruption of the complex formation between VAP-A and HCV NS5 A. As the formation of VAP-A/NS5 A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5 A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents(DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.
文摘Objective: To assess the genotoxicity and embryotoxicity of bicyclol methyl ether(BME), the main impurity in bicyclol. Methods: Five concentrations of BME(0.5, 5, 50, 500 and 5000 μg/plate) were used in the Ames test to detect gene mutation. In the chromosome aberration test, Chinese hamster lung cells were used to detect chromosomal aberration of BME(15, 30, 60, 120 μg/m L) with or without S9 mixture. Embryotoxicity test was also conducted to determine any embryotoxicity of BME(7.5, 22.5, 67.5 μg/L) using zebrafish embryos. Results: No significant differences were observed in the Ames test and the chromosome aberration test in the BME groups compared with the vehicle control group. The zebrafish embryos toxicity test also showed no embryo development toxicity of BME, including hatching rate, body length, pericardial area and yolk sac area. Conclusions: Bicyclol methyl ether has no genotoxicity in vitro and embryotoxicity in zebrafish embryos, and the impurity in bicyclol is qualified.
文摘目的探讨双环醇对心肌纤维化模型大鼠的治疗作用及其可能的作用机制。方法选择无特定病原体级雄性SD大鼠24只,随机分为假手术组、模型组、低剂量组及高剂量组,每组6只。除假手术组外,其他各组尾静脉注射异丙肾上腺素5 mg/(kg·d)建立大鼠心肌纤维化模型,低剂量组、高剂量组分别按照100、200 mg/(kg·d)双环醇进行灌胃治疗,连续给药14 d。采用苏木精-伊红染色分析心肌损伤程度,Masson染色检测心肌纤维化程度,Western blot法检测心肌胶原蛋白Ⅰ、胶原蛋白Ⅲ、α平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)、甲基转移酶样蛋白3(methyltransferase-like protein 3(METTL3))、α-酮戊二酸依赖性双加氧酶ALKB同源物5(α-ketoglutarate-dependent dioxygenase alkB homolog5,ALKBH5)及YTH家族蛋白1(YTH domain family protein 1,YTHDF1)表达。结果与假手术组比较,模型组心肌细胞坏死程度明显升高,心肌纤维化程度增高;与模型组比较,低剂量组、高剂量组心肌细胞破裂和坏死程度明显降低,心肌纤维化程度明显改善。与假手术组比较,模型组心肌组织胶原蛋白Ⅰ、胶原蛋白Ⅲ、α-SMA、METTL3及YTHDF1表达明显升高(P<0.05),模型组ALKBH5表达明显降低(0.58±0.02 vs 0.88±0.07,P<0.05)。与模型组比较,低剂量组、高剂量组心肌组织胶原蛋白Ⅰ、胶原蛋白Ⅲ、α-SMA、METTL3及YTHDF1表达明显降低,ALKBH5表达明显升高,差异有统计学意义(P<0.05)。结论双环醇可有效缓解异丙肾上腺素诱导的心肌纤维化大鼠心肌结构损伤和间质胶原纤维化沉积,其机制可能与m^(6)A甲基化修饰相关。
