目的:观察熊去氧胆酸联合低分子肝素钙注射液与丁二磺酸腺苷蛋氨酸治疗妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)患者的临床疗效,分析患者血清胆汁酸(TBA)、谷丙转氨酶(ALT)和谷草转氨酶(AST)水平的变化及妊娠...目的:观察熊去氧胆酸联合低分子肝素钙注射液与丁二磺酸腺苷蛋氨酸治疗妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)患者的临床疗效,分析患者血清胆汁酸(TBA)、谷丙转氨酶(ALT)和谷草转氨酶(AST)水平的变化及妊娠情况。方法:将收治的135例ICP患者按照治疗方法不同分为A、B、C组,各45例,3组均行常规检查。A组口服熊去氧胆酸片;B组口服熊去氧胆酸片基础上注射丁二磺酸腺苷蛋氨酸治疗;C组在B组治疗基础上联合低分子肝素钙治疗。对比3组临床疗效和妊娠情况,检测所有受试者治疗前后外周血TBA、ALT和AST水平。结果:治疗后,C组临床有效率(93.33%)高于A、B组(P<0.05)。治疗前,3组患者瘙痒评分比较差异无统计学意义(P>0.05);治疗后,3组瘙痒评分较组内治疗前均降低(P<0.05),且治疗后C组低于A和B组(P<0.05),B组低于A组(P<0.05)。治疗前,3组TBA、ALT和AST水平差异无统计学意义(P>0.05);治疗后,3组TBA、ALT和AST水平较组内治疗前均降低(P<0.05),且治疗后C组低于A和B组,B组低于A组(P<0.05)。治疗后,C组患者剖宫产、早产、胎儿窘迫和羊水污染发生率均低于A组和B组,且总不良反应发生率明显低于A组和B组(P<0.05)。结论:熊去氧胆酸联合低分子肝素钙注射液与丁二磺酸腺苷蛋氨酸治疗ICP患者的临床疗效显著,能更有效缓解患者的瘙痒程度,降低血清TBA、ALT和AST水平,保护肝脏,减少胎儿窘迫和羊水污染等情况的发生,具有较高临床价值,可作为ICP的治疗方案进一步推广应用。展开更多
Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)w...Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.展开更多
Polyamines play an important role in plant response to abiotic stress. S-adenosyl-l-methionine decarboxylase （SAMDC） is one of the key regulatory enzymes in the biosynthesis of polyamines. In order to better underst...Polyamines play an important role in plant response to abiotic stress. S-adenosyl-l-methionine decarboxylase （SAMDC） is one of the key regulatory enzymes in the biosynthesis of polyamines. In order to better understand the effect of regulation of polyamine biosynthesis on the tolerance of high-temperature stress in tomato, SAMDC cDNA isolated from Saccharomyces cerevisiae was introduced into tomato genome by means of Agrobacterium tumefaciens through leaf disc transformation. Transgene and expression was confirmed by Southern and Northern blot analyses, respectively. Transgenic plants expressing yeast SAMDC produced 1.7- to 2.4-fold higher levels of spermidine and spermine than wildtype plants under high temperature stress, and enhanced antioxidant enzyme activity and the protection of membrane lipid peroxidation was also observed. This subsequently improved the efficiency of CO2 assimilation and protected the plants from high temperature stress, which indicated that the transgenic tomato presented an enhanced tolerance to high temperature stress （38℃） compared with wild-type plants. Our results demonstrated clearly that increasing polyamine biosynthesis in plants may be a means of creating high temperature-tolerant germplasm.展开更多
Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express...Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express two genes,MAT1A and MAT2A,which encode for MATα1 and MATα2,the catalytic subunits of the MAT isoenzymes,respectively.A third gene MAT2B,encodes a regulatory subunit known as MATβwhich controls the activity of MATα2.MAT1A,which is mainly expressed in hepatocytes,maintains the differentiated state of these cells,whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver(e.g.,hepatic stellate and Kupffer cells).The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1.A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation,but this change in the expression pattern of MATs results in reduced hepatic SAMe level.Decades of study have utilized the Mat1a-knockout(KO)mouse that spontaneously develops non-alcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC)to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis.An increasing volume of work indicates that MATs have SAMe-independent functions,distinct interactomes and multiple subcellular localizations.Here we aim to provide an overview of MAT biology including genes,isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation.We will highlight recent breakthroughs in the field and underscore the importance of MAT’s in liver tumorigenesis as well as their potential as targets for cancer therapy.展开更多
BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has...BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies r展开更多
目的:探讨S-腺苷甲硫氨酸(S-adenosylmethionine,SAM)联合还原型谷胱甘肽治疗妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)的临床效果。方法:选取本院2012年1月-2015年6月收治的117例ICP患者采用SPSS 16.0软件生...目的:探讨S-腺苷甲硫氨酸(S-adenosylmethionine,SAM)联合还原型谷胱甘肽治疗妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)的临床效果。方法:选取本院2012年1月-2015年6月收治的117例ICP患者采用SPSS 16.0软件生成随机数字表后分为联合组58例和对照组59例,2组患者均采用SAM+常规治疗,联合组加用还原型谷胱甘肽治疗,2组患者的疗程均为4周,对比2组的治疗效果。结果:治疗前联合组和对照组的血总胆汁酸(TBA)、谷丙转氨酶(ALT)、谷草转氨酶(AST)水平及瘙痒程度评分差异无统计学意义(P>0.05);治疗后2组患者的血TBA、ALT、AST水平及瘙痒程度评分均较本组治疗前显著降低(P<0.05);治疗后,联合组患者的血TBA、ALT、AST水平及瘙痒程度评分低于对照组患者,差异有统计学意义(P<0.05);2组分娩孕周、胎儿窘迫、Apgar评分及新生儿体质量比较,差异无统计学意义(均P>0.05);联合组剖宫产率显著低于对照组,差异有统计学意义(P<0.05)。结论:还原型谷胱甘肽联合SAM治疗ICP较单用SAM具有更加显著的临床效果。展开更多
Background and Objective: S-adenosylmethionine (SAM), the most important methyl donor in human body, is generally used to treat cholestasis in clinic. In recent years, SAM has been found to have inhibitory effects on ...Background and Objective: S-adenosylmethionine (SAM), the most important methyl donor in human body, is generally used to treat cholestasis in clinic. In recent years, SAM has been found to have inhibitory effects on breast cancer, liver cancer and colon carcinoma. This study was to investigate the inhibitory effects of SAM on human gastric cancer cells in vivo and in vitro, and the antitumor mechanisms. Methods: The effects of SAM on the proliferation of gastric cancer SGC-7901 and MKN-45 cells were determined by MTT assay. After SGC-7901 and MKN-45 cells were treated with 0, 2, and 4 mmol/L SAM for 72 h, the expression and methylation of c-myc and urokinase type plasminogen activator (uPA) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP). Tumor xenografts were established by injecting SGC-7901 cells subcutaneously in BALB/c nude mice. The mice were randomized into low concentration group [192 μmol/(kg·day)], high concentration group [768 μmol/(kg·day)], and control group [normal saline (NS)], and received peritoneal injection of relative reagents for 15 days. The tumor size was measured, the protein and mRNA expression of c-myc and uPA were detected by immunohistochemistry and RT-PCR, and the methylation of c-myc and uPA genes was detected by MSP. Results: SAM inhibited the growth of SGC-7901 and MKN-45 cells obviously and the effects were enhanced with the increase of SAM concentration and treatment time. The mRNA expression of c-myc and uPA in SGC-7901 cells and that of uPA in MKN-45 cells significantly decreased. The c-myc and uPA genes in SGC-7901 cells and uPA gene in MKN-45 cells were partly or completely methylated after SAM treatment. The tumor volume was significantly lower in low concentration group [(618.51± 149.27) mm3] and high concentration group [(444.32 ± 118.51) mm3] than in control group [(1018.22 ± 223.07) mm3] (both P < 0.01). The inhibitory rates of tumor growth were 39.26% in low concentration group and 56.36% in high conce展开更多
文摘目的:观察熊去氧胆酸联合低分子肝素钙注射液与丁二磺酸腺苷蛋氨酸治疗妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)患者的临床疗效,分析患者血清胆汁酸(TBA)、谷丙转氨酶(ALT)和谷草转氨酶(AST)水平的变化及妊娠情况。方法:将收治的135例ICP患者按照治疗方法不同分为A、B、C组,各45例,3组均行常规检查。A组口服熊去氧胆酸片;B组口服熊去氧胆酸片基础上注射丁二磺酸腺苷蛋氨酸治疗;C组在B组治疗基础上联合低分子肝素钙治疗。对比3组临床疗效和妊娠情况,检测所有受试者治疗前后外周血TBA、ALT和AST水平。结果:治疗后,C组临床有效率(93.33%)高于A、B组(P<0.05)。治疗前,3组患者瘙痒评分比较差异无统计学意义(P>0.05);治疗后,3组瘙痒评分较组内治疗前均降低(P<0.05),且治疗后C组低于A和B组(P<0.05),B组低于A组(P<0.05)。治疗前,3组TBA、ALT和AST水平差异无统计学意义(P>0.05);治疗后,3组TBA、ALT和AST水平较组内治疗前均降低(P<0.05),且治疗后C组低于A和B组,B组低于A组(P<0.05)。治疗后,C组患者剖宫产、早产、胎儿窘迫和羊水污染发生率均低于A组和B组,且总不良反应发生率明显低于A组和B组(P<0.05)。结论:熊去氧胆酸联合低分子肝素钙注射液与丁二磺酸腺苷蛋氨酸治疗ICP患者的临床疗效显著,能更有效缓解患者的瘙痒程度,降低血清TBA、ALT和AST水平,保护肝脏,减少胎儿窘迫和羊水污染等情况的发生,具有较高临床价值,可作为ICP的治疗方案进一步推广应用。
文摘Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.
基金Supported by the State Key Basic Research and Development Plan of China (2009CB119000)the National Natural Science Foundation of China(30571268)the Hi-Tech Research and Development Plan of China(G2006AA100108)
文摘Polyamines play an important role in plant response to abiotic stress. S-adenosyl-l-methionine decarboxylase （SAMDC） is one of the key regulatory enzymes in the biosynthesis of polyamines. In order to better understand the effect of regulation of polyamine biosynthesis on the tolerance of high-temperature stress in tomato, SAMDC cDNA isolated from Saccharomyces cerevisiae was introduced into tomato genome by means of Agrobacterium tumefaciens through leaf disc transformation. Transgene and expression was confirmed by Southern and Northern blot analyses, respectively. Transgenic plants expressing yeast SAMDC produced 1.7- to 2.4-fold higher levels of spermidine and spermine than wildtype plants under high temperature stress, and enhanced antioxidant enzyme activity and the protection of membrane lipid peroxidation was also observed. This subsequently improved the efficiency of CO2 assimilation and protected the plants from high temperature stress, which indicated that the transgenic tomato presented an enhanced tolerance to high temperature stress （38℃） compared with wild-type plants. Our results demonstrated clearly that increasing polyamine biosynthesis in plants may be a means of creating high temperature-tolerant germplasm.
基金National Institutes of Health,NIAAA,No.R01AA026759(Lu)National Institutes of Health,NIDDK,No.R01DK107288(Lu)+4 种基金National Institutes of Health,NCCIH,No.R01AT001576National Institutes of Health,NCI,No.R01CA172086(Lu and Mato)Agencia Estatal de Investigación MINECO,No.SAF 2017-88041-RISCiii PIE14/00031,No.CIBERehdISCiiiSevero Ochoa Excellence Accreditation,No.SEV-2016-0644)(Mato)
文摘Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express two genes,MAT1A and MAT2A,which encode for MATα1 and MATα2,the catalytic subunits of the MAT isoenzymes,respectively.A third gene MAT2B,encodes a regulatory subunit known as MATβwhich controls the activity of MATα2.MAT1A,which is mainly expressed in hepatocytes,maintains the differentiated state of these cells,whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver(e.g.,hepatic stellate and Kupffer cells).The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1.A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation,but this change in the expression pattern of MATs results in reduced hepatic SAMe level.Decades of study have utilized the Mat1a-knockout(KO)mouse that spontaneously develops non-alcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC)to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis.An increasing volume of work indicates that MATs have SAMe-independent functions,distinct interactomes and multiple subcellular localizations.Here we aim to provide an overview of MAT biology including genes,isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation.We will highlight recent breakthroughs in the field and underscore the importance of MAT’s in liver tumorigenesis as well as their potential as targets for cancer therapy.
文摘BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies r
文摘目的:探讨S-腺苷甲硫氨酸(S-adenosylmethionine,SAM)联合还原型谷胱甘肽治疗妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)的临床效果。方法:选取本院2012年1月-2015年6月收治的117例ICP患者采用SPSS 16.0软件生成随机数字表后分为联合组58例和对照组59例,2组患者均采用SAM+常规治疗,联合组加用还原型谷胱甘肽治疗,2组患者的疗程均为4周,对比2组的治疗效果。结果:治疗前联合组和对照组的血总胆汁酸(TBA)、谷丙转氨酶(ALT)、谷草转氨酶(AST)水平及瘙痒程度评分差异无统计学意义(P>0.05);治疗后2组患者的血TBA、ALT、AST水平及瘙痒程度评分均较本组治疗前显著降低(P<0.05);治疗后,联合组患者的血TBA、ALT、AST水平及瘙痒程度评分低于对照组患者,差异有统计学意义(P<0.05);2组分娩孕周、胎儿窘迫、Apgar评分及新生儿体质量比较,差异无统计学意义(均P>0.05);联合组剖宫产率显著低于对照组,差异有统计学意义(P<0.05)。结论:还原型谷胱甘肽联合SAM治疗ICP较单用SAM具有更加显著的临床效果。
文摘Background and Objective: S-adenosylmethionine (SAM), the most important methyl donor in human body, is generally used to treat cholestasis in clinic. In recent years, SAM has been found to have inhibitory effects on breast cancer, liver cancer and colon carcinoma. This study was to investigate the inhibitory effects of SAM on human gastric cancer cells in vivo and in vitro, and the antitumor mechanisms. Methods: The effects of SAM on the proliferation of gastric cancer SGC-7901 and MKN-45 cells were determined by MTT assay. After SGC-7901 and MKN-45 cells were treated with 0, 2, and 4 mmol/L SAM for 72 h, the expression and methylation of c-myc and urokinase type plasminogen activator (uPA) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP). Tumor xenografts were established by injecting SGC-7901 cells subcutaneously in BALB/c nude mice. The mice were randomized into low concentration group [192 μmol/(kg·day)], high concentration group [768 μmol/(kg·day)], and control group [normal saline (NS)], and received peritoneal injection of relative reagents for 15 days. The tumor size was measured, the protein and mRNA expression of c-myc and uPA were detected by immunohistochemistry and RT-PCR, and the methylation of c-myc and uPA genes was detected by MSP. Results: SAM inhibited the growth of SGC-7901 and MKN-45 cells obviously and the effects were enhanced with the increase of SAM concentration and treatment time. The mRNA expression of c-myc and uPA in SGC-7901 cells and that of uPA in MKN-45 cells significantly decreased. The c-myc and uPA genes in SGC-7901 cells and uPA gene in MKN-45 cells were partly or completely methylated after SAM treatment. The tumor volume was significantly lower in low concentration group [(618.51± 149.27) mm3] and high concentration group [(444.32 ± 118.51) mm3] than in control group [(1018.22 ± 223.07) mm3] (both P < 0.01). The inhibitory rates of tumor growth were 39.26% in low concentration group and 56.36% in high conce
