Hypertrichosis is one of the most common side effects of systemic cyclosporine A therapy.It has been previously shown that cyclosporine A induces anagen and inhibits catagen development in mice.In the present study,to...Hypertrichosis is one of the most common side effects of systemic cyclosporine A therapy.It has been previously shown that cyclosporine A induces anagen and inhibits catagen development in mice.In the present study,to explore the mechanisms of cyclosporine A,we investigated the effects of cyclosporine A on hair shaft elongation,hair follicle cell proliferation,apoptosis,and mRNA expression of selected growth factors using an organ culture model of mouse vibrissae.In this model,cyclosporine A stimulated hair growth of normal mouse vibrissae follicles by inhibiting catagen-like development and promoting matrix cell proliferation.In addition,cyclosporine A caused an increase in the expression of vascular endothelial growth factor（VEGF）,hepatocyte growth factor（HGF）,and nerve growth factor（NGF）,and inhibited follistatin expression.Our findings provide an explanation for the clinically observed effects of cyclosporine A on hair growth.The mouse vibrissae organ culture offers an attractive model for identifying factors involved in the modulation of hair growth.展开更多
环孢素A(cyclosporine A,CsA)是由11个氨基酸组成的中性环状多肽,是临床拮抗器官和组织移植后排异反应的首选药物。高效液相色谱法广泛应用于CsA的分离分析,开展CsA色谱行为的研究是使用制备高效液相色谱纯化CsA的关键。该文首先在C18...环孢素A(cyclosporine A,CsA)是由11个氨基酸组成的中性环状多肽,是临床拮抗器官和组织移植后排异反应的首选药物。高效液相色谱法广泛应用于CsA的分离分析,开展CsA色谱行为的研究是使用制备高效液相色谱纯化CsA的关键。该文首先在C18固定相上比较了CsA在甲醇-水和乙腈-水两种流动相体系中的保留行为,结果表明其保留时间对有机相比例变化比较敏感。控制甲醇比例在84%~88%,或者乙腈比例在75%~85%,CsA的保留因子(k)在3~7范围内。考察了上样量对CsA峰形的影响。随着上样量增加,在两种流动相体系中,CsA的峰形都由对称开始变得拖尾,保留时间前移。因此在进行CsA纯化时,需要特别注意前杂的去除情况。然后采用吸附等温线描述CsA的保留行为,当流动相中CsA的质量浓度较低时,有机相比例对溶质在固定相上的吸附量影响并不明显。随着溶质的质量浓度增加至0.5 g/L以上,有机相比例降低有助于提高CsA在固定相上的吸附量。和甲醇-水体系相比,在乙腈-水体系中固定相对溶质有更大的吸附容量。用模型对CsA的等温吸附曲线拟合,在甲醇-水体系中符合Langmuir模型,在乙腈-水体系中为Moreau模型。由模型参数可知在两种体系下,CsA在C18固定相上均为单层吸附,区别在于乙腈-水体系中CsA会产生较大的分子间作用力。最后,实验采用0~60 min 65%~75%乙腈、60~80 min 75%乙腈的条件开展了环孢素A纯化的探索实验,可将CsA的杂质控制在0.2%以下。本研究结果对采用制备高效液相色谱纯化CsA具有指导意义。展开更多
Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of is...Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of ischemia.The hallmark of IRI comprises mitochondrial dysfunction,which generates reactive oxygen species,and cell death through necrosis or apoptosis.Cyclosporine(CsA),which is a well-known immunosuppressive agent that inhibits calcineurin,has the additional effect of inhibiting the mito-chondrial permeability transition pore(mPTP),thereby,preventing mitochondrial swelling and injury.NIM-811,which is the nonimmunosuppressive analog of CsA,has a similar effect on the mPTP.In this study,we tested the effect of both agents on mitigating warm hepatic IRI in a murine model.Materials and methods:Before ischemic insult,the mice were administered with intraperitoneal normal saline(control);CsA at 2.5,10,or 25 mg/kg;or NIM-811 at 10 mg/kg.Thereafter,the mice were subjected to partial warm hepatic ischemia by selective pedicle clamping for 60 min,followed by 6 h of recovery after reperfusion.Serum alanine transaminase(ALT)was measured,and the liver tissue was examined histologically for the presence of apoptosis and the levels of inflammatory cytokines.Results:Compared with the control mice,the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower ALT levels(P<0.001,0.007,and 0.031,respectively).Moreover,the liver tissue showed reduced histological injury scores after treatment with CsA at 2.5,10,and 25 mg/kg and NIM-811(P=0.041,<0.001,0.003,and 0.043,respectively)and significant decrease in apoptosis after treatment with CsA at all doses(P=0.012,0.007,and<0.001,respectively).Levels of the pro-inflammatory cyto-kines,particularly interleukin(IL)-1β,IL-2,IL-4,IL-10,and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA(25 mg/kg)than those in the control mice.Conclusions:Premedication with CsA or NIM-811 miti展开更多
基金supported by grants from the National Natural Science Foundation of China(No.30571678 and No.30771947)the Natural Science Foundation of Jiangsu Province(No.BK2007248)
文摘Hypertrichosis is one of the most common side effects of systemic cyclosporine A therapy.It has been previously shown that cyclosporine A induces anagen and inhibits catagen development in mice.In the present study,to explore the mechanisms of cyclosporine A,we investigated the effects of cyclosporine A on hair shaft elongation,hair follicle cell proliferation,apoptosis,and mRNA expression of selected growth factors using an organ culture model of mouse vibrissae.In this model,cyclosporine A stimulated hair growth of normal mouse vibrissae follicles by inhibiting catagen-like development and promoting matrix cell proliferation.In addition,cyclosporine A caused an increase in the expression of vascular endothelial growth factor（VEGF）,hepatocyte growth factor（HGF）,and nerve growth factor（NGF）,and inhibited follistatin expression.Our findings provide an explanation for the clinically observed effects of cyclosporine A on hair growth.The mouse vibrissae organ culture offers an attractive model for identifying factors involved in the modulation of hair growth.
文摘环孢素A(cyclosporine A,CsA)是由11个氨基酸组成的中性环状多肽,是临床拮抗器官和组织移植后排异反应的首选药物。高效液相色谱法广泛应用于CsA的分离分析,开展CsA色谱行为的研究是使用制备高效液相色谱纯化CsA的关键。该文首先在C18固定相上比较了CsA在甲醇-水和乙腈-水两种流动相体系中的保留行为,结果表明其保留时间对有机相比例变化比较敏感。控制甲醇比例在84%~88%,或者乙腈比例在75%~85%,CsA的保留因子(k)在3~7范围内。考察了上样量对CsA峰形的影响。随着上样量增加,在两种流动相体系中,CsA的峰形都由对称开始变得拖尾,保留时间前移。因此在进行CsA纯化时,需要特别注意前杂的去除情况。然后采用吸附等温线描述CsA的保留行为,当流动相中CsA的质量浓度较低时,有机相比例对溶质在固定相上的吸附量影响并不明显。随着溶质的质量浓度增加至0.5 g/L以上,有机相比例降低有助于提高CsA在固定相上的吸附量。和甲醇-水体系相比,在乙腈-水体系中固定相对溶质有更大的吸附容量。用模型对CsA的等温吸附曲线拟合,在甲醇-水体系中符合Langmuir模型,在乙腈-水体系中为Moreau模型。由模型参数可知在两种体系下,CsA在C18固定相上均为单层吸附,区别在于乙腈-水体系中CsA会产生较大的分子间作用力。最后,实验采用0~60 min 65%~75%乙腈、60~80 min 75%乙腈的条件开展了环孢素A纯化的探索实验,可将CsA的杂质控制在0.2%以下。本研究结果对采用制备高效液相色谱纯化CsA具有指导意义。
文摘Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of ischemia.The hallmark of IRI comprises mitochondrial dysfunction,which generates reactive oxygen species,and cell death through necrosis or apoptosis.Cyclosporine(CsA),which is a well-known immunosuppressive agent that inhibits calcineurin,has the additional effect of inhibiting the mito-chondrial permeability transition pore(mPTP),thereby,preventing mitochondrial swelling and injury.NIM-811,which is the nonimmunosuppressive analog of CsA,has a similar effect on the mPTP.In this study,we tested the effect of both agents on mitigating warm hepatic IRI in a murine model.Materials and methods:Before ischemic insult,the mice were administered with intraperitoneal normal saline(control);CsA at 2.5,10,or 25 mg/kg;or NIM-811 at 10 mg/kg.Thereafter,the mice were subjected to partial warm hepatic ischemia by selective pedicle clamping for 60 min,followed by 6 h of recovery after reperfusion.Serum alanine transaminase(ALT)was measured,and the liver tissue was examined histologically for the presence of apoptosis and the levels of inflammatory cytokines.Results:Compared with the control mice,the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower ALT levels(P<0.001,0.007,and 0.031,respectively).Moreover,the liver tissue showed reduced histological injury scores after treatment with CsA at 2.5,10,and 25 mg/kg and NIM-811(P=0.041,<0.001,0.003,and 0.043,respectively)and significant decrease in apoptosis after treatment with CsA at all doses(P=0.012,0.007,and<0.001,respectively).Levels of the pro-inflammatory cyto-kines,particularly interleukin(IL)-1β,IL-2,IL-4,IL-10,and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA(25 mg/kg)than those in the control mice.Conclusions:Premedication with CsA or NIM-811 miti
