目的 分析X连锁显性低血磷性佝偻病(X-linked dominant hypophosphatemia,XLH)患者的临床表型、生化特点及X染色体上内肽酶同源磷调节基因(phosphate-regulating gene with homologies to endopeptidase on the X chromosome, PHEX )突...目的 分析X连锁显性低血磷性佝偻病(X-linked dominant hypophosphatemia,XLH)患者的临床表型、生化特点及X染色体上内肽酶同源磷调节基因(phosphate-regulating gene with homologies to endopeptidase on the X chromosome, PHEX )突变特征。方法 收集2016至2018年就诊于上海交通大学附属第六人民医院骨质疏松和骨病专科的19例XLH患者的临床资料,利用sanger测序技术进行 PHEX 基因突变检测,酶联免疫吸附试验检测血清成纤维生长因子23(fibroblast growth factor 23,FGF23)水平。结果 确诊 19例 PHEX 突变导致XLH患者,其中男性7例,女性12例;9例为散发;共鉴定出13个不同 PHEX 突变位点,5个新发突变。未成年患者身高均低于同年龄组,4例低于同年龄组1个标准差,4例低于同年龄组2个标准差。成年男性患者和女性患者身高分别为130 cm ( n =1)和142(134~146)cm( n =6)。不同程度的骨痛 5/11 例,牙齿疾患10/11例,下肢弯曲畸形16/16例。XLH患者血清全段FGF23水平[80.8(45.0~ 141.9)pg/mL ]存在不同程度升高,与正常对照组[40.6(33.9~51.8)pg/mL]比较,差异有统计学意义( P =0.002)。结论本研究丰富了 PHEX 基因致病的表型谱及突变谱;散发病例高发,应避免散发患者的漏诊、误诊;需重视基因鉴定及产前诊断对该病预防及诊治的重要性。展开更多
多巴胺和cAMP调节的磷蛋白(dopam ine and adenosine 3'5'-monophosphate-regulated phos-pho-protein,Mr 32 kD,DARPP-32)是一个具有双重功能的独特蛋白,它既是磷酸酶(如PP-1)的抑制剂,也是蛋白激酶(如PKA)的抑制剂,即DARPP-3...多巴胺和cAMP调节的磷蛋白(dopam ine and adenosine 3'5'-monophosphate-regulated phos-pho-protein,Mr 32 kD,DARPP-32)是一个具有双重功能的独特蛋白,它既是磷酸酶(如PP-1)的抑制剂,也是蛋白激酶(如PKA)的抑制剂,即DARPP-32通过自身不同位点的磷酸化对蛋白质磷酸化和去磷酸化过程发挥着双向调控的作用。DARRP-32在脑内存在于接受多巴胺能投射的神经元中,其磷酸化过程受多种神经递质的调控,在信号转导途径中处于中心位置,整合多种胞内信号转导,调节神经元的电学和化学性质以及动物的生理行为反应,参与多种生理功能和病理过程,包括药物成瘾、抑郁症、精神分裂症等。此外,DARPP-3 2在非神经系统的功能也逐渐被人们所认识。本文就DARPP-32的分布,生物活性的调控、生理功能及在病理过程中的作用作简要综述。展开更多
TRESK is the most recently reported two-pore domain K^＋ channel, and different from other two-pore domain channels in gene, molecular structure, electrophysiological and pharmacological properties. Although the curre...TRESK is the most recently reported two-pore domain K^＋ channel, and different from other two-pore domain channels in gene, molecular structure, electrophysiological and pharmacological properties. Although the current knowledge of this potassium channel is inadequate, researches have demonstrated that TRESK is remarkablely linked to acute and chronic pain by activation of calcineurin. The fact that TRESK is sensitive to volatile anesthetics and localization in central nerve system implies that TRESK may play a very important role in the mechanism mediating general anesthesia. The further research of TRESK may contribute to explore the underlying mechanism of some pathological conditions and yield novel treatments for some diseases.展开更多
Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in t...Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in the low millimolar range, but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here, we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration （between 50 and 100μM） stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intraceHular ATP attenuated the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly upregulate proteasome activity on ATP reduction under stress conditions.展开更多
Objectives Partial hepatectomy induces a rapid transformation within the remnant liver, prompting a wave of hepatocyte mitosis which abates when the lost cell mass has been recovered. The mechanism of co-ordinated con...Objectives Partial hepatectomy induces a rapid transformation within the remnant liver, prompting a wave of hepatocyte mitosis which abates when the lost cell mass has been recovered. The mechanism of co-ordinated control of metabolism and maintenance of function during this period of dynamic change is incompletely understood. Furthermore, the biochemical basis of growth regulation in the regenerating liver has not been well defined. We have studied human liver regeneration using in vivo 31-phosphorus magnetic resonance spectroscopy (31 P MRS). This non-invasive technique allows assay of high-energy phosphate compounds and also of phospholipid metabolites thought to be involved in cellular renewal processes.Methods Five patients undergoing liver resection were studied. Hepatic metabolism was evaluated using 31P MRS before surgery and on postoperative days 2,4,6 and 14. Estimation of liver volume by magnetic resonance imaging and blood sampling for biochemistry were performed at the same time points.Results We found that the regenerative response following loss of liver parenchyma produced a reversible decline in energy state which necessitated compensatory adjustments in liver synthetic and excretory (unctions. Volume regain was associated with alterations in phospholipid metabolism, which normalized when the hepatic growth spurt was completed.Conclusion These observations indicate that modulation of hepatocyte energy economy is necessary for the integrated recovery of liver cell mass and function. We propose that deficient hepatic energy production may explain the mechanism of liver failure after hepatectomy, and suggest that in vivo measurement of liver metabolism may provide a rational basis for the development and evaluation of hepatic support strategies.展开更多
文摘目的 分析X连锁显性低血磷性佝偻病(X-linked dominant hypophosphatemia,XLH)患者的临床表型、生化特点及X染色体上内肽酶同源磷调节基因(phosphate-regulating gene with homologies to endopeptidase on the X chromosome, PHEX )突变特征。方法 收集2016至2018年就诊于上海交通大学附属第六人民医院骨质疏松和骨病专科的19例XLH患者的临床资料,利用sanger测序技术进行 PHEX 基因突变检测,酶联免疫吸附试验检测血清成纤维生长因子23(fibroblast growth factor 23,FGF23)水平。结果 确诊 19例 PHEX 突变导致XLH患者,其中男性7例,女性12例;9例为散发;共鉴定出13个不同 PHEX 突变位点,5个新发突变。未成年患者身高均低于同年龄组,4例低于同年龄组1个标准差,4例低于同年龄组2个标准差。成年男性患者和女性患者身高分别为130 cm ( n =1)和142(134~146)cm( n =6)。不同程度的骨痛 5/11 例,牙齿疾患10/11例,下肢弯曲畸形16/16例。XLH患者血清全段FGF23水平[80.8(45.0~ 141.9)pg/mL ]存在不同程度升高,与正常对照组[40.6(33.9~51.8)pg/mL]比较,差异有统计学意义( P =0.002)。结论本研究丰富了 PHEX 基因致病的表型谱及突变谱;散发病例高发,应避免散发患者的漏诊、误诊;需重视基因鉴定及产前诊断对该病预防及诊治的重要性。
文摘多巴胺和cAMP调节的磷蛋白(dopam ine and adenosine 3'5'-monophosphate-regulated phos-pho-protein,Mr 32 kD,DARPP-32)是一个具有双重功能的独特蛋白,它既是磷酸酶(如PP-1)的抑制剂,也是蛋白激酶(如PKA)的抑制剂,即DARPP-32通过自身不同位点的磷酸化对蛋白质磷酸化和去磷酸化过程发挥着双向调控的作用。DARRP-32在脑内存在于接受多巴胺能投射的神经元中,其磷酸化过程受多种神经递质的调控,在信号转导途径中处于中心位置,整合多种胞内信号转导,调节神经元的电学和化学性质以及动物的生理行为反应,参与多种生理功能和病理过程,包括药物成瘾、抑郁症、精神分裂症等。此外,DARPP-3 2在非神经系统的功能也逐渐被人们所认识。本文就DARPP-32的分布,生物活性的调控、生理功能及在病理过程中的作用作简要综述。
基金This work was supported by the National Natural Science Foundation of China （No. 30672020）；the B. Braun Anesthesia Foundation of B. Braun Medical （Shanghai） International Trading Co., Ltd.
文摘TRESK is the most recently reported two-pore domain K^＋ channel, and different from other two-pore domain channels in gene, molecular structure, electrophysiological and pharmacological properties. Although the current knowledge of this potassium channel is inadequate, researches have demonstrated that TRESK is remarkablely linked to acute and chronic pain by activation of calcineurin. The fact that TRESK is sensitive to volatile anesthetics and localization in central nerve system implies that TRESK may play a very important role in the mechanism mediating general anesthesia. The further research of TRESK may contribute to explore the underlying mechanism of some pathological conditions and yield novel treatments for some diseases.
基金Acknowledgments This work was supported by the National High Technol- ogy Research and Development Program of China （Project 2006AA02Z4B5）, the National Natural Science Foundation of China （Project 2010）, and a Key Project （9251018201002） of Guangdong Province Natural Science Foundation （to JL）. It was also supported in part by Grants HL072166, HL085629, and HL068936 of the NIH and an Established Investigator Award （0740025N） of the American Heart Association （to XW）.
文摘Intracellular protein degradation by the ubiquitin-proteasome system is ATP dependent, and the optimal ATP concentration to activate proteasome function in vitro is -100 μM. IntraceUular ATP levels are generally in the low millimolar range, but ATP at a level within this range was shown to inhibit proteasome peptidase activities in vitro. Here, we report new evidence that supports a hypothesis that intracellular ATP at the physiological levels bidirectionally regulates 26S proteasome proteolytic function in the cell. First, we confirmed that ATP exerted bidirectional regulation on the 26S proteasome in vitro, with the optimal ATP concentration （between 50 and 100μM） stimulating proteasome chymotrypsin-like activities. Second, we found that manipulating intracellular ATP levels also led to bidirectional changes in the levels of proteasome-specific protein substrates in cultured cells. Finally, measures to increase intracellular ATP enhanced, while decreasing intraceHular ATP attenuated the ability of proteasome inhibition to induce cell death. These data strongly suggest that endogenous ATP within the physiological concentration range can exert a negative impact on proteasome activities, allowing the cell to rapidly upregulate proteasome activity on ATP reduction under stress conditions.
文摘Objectives Partial hepatectomy induces a rapid transformation within the remnant liver, prompting a wave of hepatocyte mitosis which abates when the lost cell mass has been recovered. The mechanism of co-ordinated control of metabolism and maintenance of function during this period of dynamic change is incompletely understood. Furthermore, the biochemical basis of growth regulation in the regenerating liver has not been well defined. We have studied human liver regeneration using in vivo 31-phosphorus magnetic resonance spectroscopy (31 P MRS). This non-invasive technique allows assay of high-energy phosphate compounds and also of phospholipid metabolites thought to be involved in cellular renewal processes.Methods Five patients undergoing liver resection were studied. Hepatic metabolism was evaluated using 31P MRS before surgery and on postoperative days 2,4,6 and 14. Estimation of liver volume by magnetic resonance imaging and blood sampling for biochemistry were performed at the same time points.Results We found that the regenerative response following loss of liver parenchyma produced a reversible decline in energy state which necessitated compensatory adjustments in liver synthetic and excretory (unctions. Volume regain was associated with alterations in phospholipid metabolism, which normalized when the hepatic growth spurt was completed.Conclusion These observations indicate that modulation of hepatocyte energy economy is necessary for the integrated recovery of liver cell mass and function. We propose that deficient hepatic energy production may explain the mechanism of liver failure after hepatectomy, and suggest that in vivo measurement of liver metabolism may provide a rational basis for the development and evaluation of hepatic support strategies.
