目的 从“脾主化”角度探讨湿阻中焦证大鼠线粒体能量代谢路径的影响,揭示湿阻中焦致能量代谢失衡的部分分子机制和脾胃调控线粒体能量代谢路径的作用靶点及平胃散对其修复作用机制的科学内涵.方法 模拟“外湿过盛、困阻脾胃、饮食不节,湿从内生、情志不遂,气机受阻、水湿不运”三大致湿病因,建立湿阻中焦证模型.用超微量ATP酶试剂盒检测肝脏组织Na+-K+-ATP酶活性;用酶联免疫法(ELISA)法检测肝脏组织中柠檬酸合酶(CS)及呼吸链复合体Ⅰ(RCCⅠ)、呼吸链复合体Ⅳ(RCCⅣ)活性;微量法检测肝脏组织中α-酮戊二酸脱氢酶(α-KGDHC)、异柠檬酸脱氢酶(IDH)活性;高效液相色谱技术检测组织中ATP、ADP含量;分光光度法检测组织中NAD+含量.结果 与正常组相比,模型组大鼠Na+-K+-ATP酶活性降低,CS,IDH,α-KGDHC活性均升高;ATP、NAD+含量及RCCⅠ、Ⅳ活性均降低.与模型组相比,平胃散组大鼠Na+-K+-ATP酶活性;α-KGDHC活性升高明显,IDH显著降低;RCCⅠ、Ⅳ活性及ADP、NAD+含量均升高,ATP含量有升高趋势.结论 湿阻中焦证模型可以影响线粒体能量代谢路径的相关因子,这可能是湿阻中焦致细胞能量代谢失衡的机制之一;基于“脾主化”理论平胃散能够改善缺损状态,参与能量代谢输布,这可能是脾胃调控能量代谢系统方面的作用靶点及平胃散燥湿健脾的作用机制之一.
目的:以前期研究的水通道蛋白为平台,通过观察并分析水协同转运蛋白KCC1、KCC3、KCC4、NKCC1含量及Na+-K+-ATP酶活性变化,揭示湿阻中焦致水液代谢紊乱及平胃散对其修复作用机制的科学内涵,为中医临床治疗本证型疾病提供实验参考;同时搭建中药复方水通道调节剂的研究平台.方法:模拟“外湿过盛,困阻脾胃、饮食不节,湿从内生、情志不遂,气机受阻、水湿不运三大致湿病因,建立湿阻中焦证模型.用蛋白定量法测定Na+-K+-ATP酶活性,用酶联免疫法(ELISA)测定肾脏组织KCC1,KCC3,KCC4,NKCC1的含量.结果:与空白组比较,模型组肾脏KCC1、KCC4含量升高,KCC3、NKCC1、Na+-K+-ATP酶活力降低,与模型组比较,自然恢复组肾脏KCC1、KCC3、NKCC1含量降低,Na+-K+-ATP酶活力明显升高(P<0.01),KCC4含量有上升趋势,经药物干预后,各给药组KCC1含量均明显降低(P<0.01),平胃散中剂量组KCC3、KCC4含量明显升高(P<0.01),平胃散低剂量组NKCC1含量明显降低(P<0.01);平胃散低剂量组肾脏Na+-K+-ATP酶活力明显升高(P<0.01);呋塞米组和平胃散加泽泻组KCC1、KCC3、KCC4、NKCC1含量及Na+-K+-ATP酶活性均明显降低,差异有统计学意义(P<0.01);与自然恢复组比较,平胃散中剂量组肾脏KCC1、KCC3、KCC4含量及Na+-K+-ATP酶活力有上升趋势,平胃散低剂量组NKCC1含量下降明显(P<0.01),呋塞米组和平胃散加泽泻组KCC1、KCC3、KCC4、NKCC1含量及Na+-K+-ATP酶活性均明显降低,差异有统计学意义(P<0.01).结论:(1)湿阻中焦证模型不仅能够影响体内能量代谢,还能够影响KCC1、KCC3、KCC4、NKCC1含量表达,这可能是湿阻中焦导致水代谢输布障碍的机制之一;(2)平胃散能够调整Na+-K+-ATP酶活性和KCC1、KCC3、KCC4、NKCC1含量分布参与能量代谢和水液代谢调控,这可能是平胃散燥湿运脾、行气导滞、散中焦之湿阻治疗湿阻中焦证的分子机理之一;(3)水协同转运蛋白之间可能存在互补代偿机制.
In order to discuss the TCM literature of water metabolism and dampness obstructed the middle-jiao, discusses the combination of clinical cases on pathological mechanism of spleen dampness obstructing spleen and kidney, and in the prophase of mature dampness obstructing spleen stomach syndrome animal model as the research platform, combined with modern research progress on pathological mechanism of spleen and kidney in traditional Chinese medicine.Regulation of hormone content through experimental detection of rat kidney typical water channel protein content and the production of urine, kidney related mechanisms of regulation of dampness obstructing spleen stomach syndrome of water metabolism, explore the dampness spleen and stomach injury will affect kidney function, is conducive to fully understand and grasp the original thinking in medicine, so as to promote the innovation and development of Chinese medicine the theory and clinical practice.
目的:以前期较成熟的湿阻中焦证大鼠模型为研究平台,研究湿阻中焦证对肺脾肾三脏AQP1含量的影响和不同剂量平胃散对湿阻中焦证大鼠模型肺肝肾水通道蛋白AQP1含量的影响,从AQP1含量变化的角度揭示肺肝肾三脏与水液代谢的关系.方法:选取SPF大鼠雌雄各半,按体重随机分为空白组,模型组,自然恢复组,平胃散高、中、低剂量组.采用综合造模法建立湿阻中焦证大鼠模型,采用酶联免疫法(ELISA)检测各组大鼠肺肝肾AQP1含量,采用免疫组化法检测各组大鼠AQP1平均光密度值.结果:肾脏中AQP1的含量明显高于其他两脏,差异具有统计学意义(P<0.01),平均光密度值显著低于其他两脏,差异具有统计学意义(P<0.05);模型组大鼠AQP1含量有下降趋势,平均光密度值呈上升趋势.服用平胃散后AQP1含量明显上升,平均光密度值明显下降.结论:水液代谢与人体肺肝肾三脏有关,与肾脏关系尤为密切.湿阻中焦证可能影响机体水液的代谢,平胃散能明显改善湿阻中焦证导致机体的水液代谢失常状况.
Obhective:There are many factors of the source of syndrome of dampness in middle Jiao,the spleen deficiency is the main cause.The lung and spleen indistribution and excretion of body fluid is coordinated in the lung is based on lung as the source of waterunder the guidance of the theory,experimental study on the effect of the expression of syndrome of dampness in middleJiaoof Aquaporins in the lung,to reveal the lung and spleen in water metabolism and pathological correlation.Methods:Build a model of the syndrome of dampness in middle Jiao,simulating the three big etiological factors of retention of water and dampness:i.e.the functioning declination of spleen and stomach by exterior dampness luxus,interior dampness caused by intemperant diet,or stagnation of Qi caused by emotional depression.Measure the levels of AQP1,AQP4and AQP8in lung tissue and the changes of Chinese medicine after intervention by enzyme-linkedimmunosorbent assay (Elisa).Results:The expression of AQP1and AQP4was decreased in the model before and after modeling,but this difference is no significant.The expression of AQP8was significantly decreased in the model before and after modeling.The expression of AQP1 in all groups showed an upward trend.The expression of AQP8decreased obviously in the high dose and low dose groups of BuhuanjinzhengqiSan.The syndrome of dampness in middle Jiao,expression of Aquaporin in the lung is changed,and the prescription of Traditional Chinese Medicine forsyndrome of dampness in middle Jiaohas significant curative effect,have certain effect on the changes.Conclusion:There is a certain correlation between lung and spleen in water metabolism.Expression of Aquaporins in the lung,the change of the expression in syndrome of dampness in middle Jiao and the change of the expression in the intervention of Traditional Chinese Medicine,may be spleen governing transportation and transformation of water,"speen-qi on dispersing jing and the essence belongs to the lung" and one of the embodiment and the molecular basis of normal distribution function of liquid water.It suggests that the lung and spleen have some correlation in the metabolism of water.
研究平胃散对葡萄糖酵解途径的影响.方法:SPF大鼠雌雄各半,按体质量分层随机分为空白组,模型组,自然恢复组,平胃散20%乙醇提取物高、低剂量组,平胃散50%乙醇提取物高、低剂量组,平胃散95%乙醇提取物高、低剂量组,平胃散正丁醇提取物高、低剂量组,平胃散乙酸乙酯提取物高、低剂量组,平胃散水提取物高、低剂量组,每组10只.建立湿阻中焦证大鼠模型,检测各组大鼠血清中葡萄糖含量、肝脏中丙酮酸(PEP)的含量、丙酮酸激酶(PK)的活性.结果:与空白组比较,模型组大鼠血清中葡萄糖含量较高(P<0.01),肝脏丙酮酸的含量偏高,但差异无统计学意义(P>0.05),肝脏丙酮酸激酶活力升高(P<0.01).经平胃散治疗后相较于空白组和自然恢复组血清中葡萄糖含量均有所下降,肝脏丙酮酸含量及肝脏丙酮酸激酶活力均有上升(P<0.01或P<0.05).结论:平胃散可能影响糖酵解途径中血清葡萄糖含量、肝脏中PEP含量及PK活性,且通过不同方法提取的平胃散进行试验检测,各组的葡萄糖、PEP含量及PK活性也存在差异.
目的 探究湿阻中焦证动物模型对血糖及葡萄糖代谢无氧酵解的影响以及平胃散的干预,揭示湿阻中焦证动物模型对血糖及葡萄糖无氧酵解的影响的相关机制,从代谢组学层面揭示脾胃参与调控能量代谢以及平胃散燥湿和胃的科学内涵.方法 参照前期较成熟的湿阻中焦证动物模型的造模方法,采用自然造模与综合造模相结合的方法,模拟湿病产生的三大主要因素,建立湿阻中焦证动物模型.检测湿阻中焦证模型及平胃散干预后的大鼠血清葡萄糖、胰岛素、胰高血糖素含量及肝脏组织己糖激酶、丙酮酸激酶、磷酸果糖激酶-1、肝糖原、2,6-双磷酸果糖的含量变化.结果 与空白组比较,湿阻中焦证模型肝脏葡萄糖、血清葡萄糖以及肝糖原含量均升高(P<0.01),胰岛素、胰高血糖素、己糖激酶、磷酸果糖激酶-1、丙酮酸激酶含量降低(P<0.01),2,6-双磷酸果糖含量有降低趋势.平胃散干预后,与模型组比较,肝脏葡萄糖、血清葡萄糖、胰岛素、胰高血糖素、肝糖原含量均降低(P<0.01);丙酮酸激酶、己糖激酶、磷酸果糖激酶-1、2,6-双磷酸果糖含量升高(P<0.01).结论 湿阻中焦证可使机体葡萄糖代谢失衡、血清葡萄糖升高,葡萄糖的无氧酵解在一定程度上被抑制;平胃散对湿阻中焦证造成的糖代谢失衡有一定的调节作用,可改善湿阻中焦证机体的供能状态.
回顾近年来的文献资料,对平胃散在内科、外科、妇科、儿科、皮肤科、五官科等方面的临床应用加以总结,认为平胃散的临床应用范围日趋广泛,充分体现了中医学异病同治的原则.
大黄牡丹汤是医圣张仲景在《金匮要略·疮痈肠痈浸淫病脉证并治》篇中所立之方.近年来,本方广泛用治于临床各科疾病,疗效满意.本文就近年来有关本方的临床新用及研究进展综述如下. 1 内科疾病 1.1 消化系统疾病 1.1.1肠炎 徐惠琴[1]用大黄牡丹汤(大黄、牡丹皮、桃仁、红藤、蚂蚁草、川连、木香)治疗1例辨证为湿热蕴结,热毒稽留于肠中,日久成瘀的慢性肠炎急性发作患者,疗效显著.张彩兰等[2]用大黄牡丹汤灌肠治疗溃疡性结肠炎30例,经过1个疗程的治疗后,治愈9例,好转16例,无效5例,有效率为80.3%,无效的5例病程均超过10年.胡宏中[3]用大黄牡丹汤加黄芩、马齿苋、仙鹤草、生黄芪等治疗溃疡性结肠炎34例,显效22例,有效11例,无效1例,总有效率达97.1%.
目的:观察平胃散对湿阻中焦证大鼠肝脏水通道蛋白SLC12家族的影响,探讨平胃散揭示湿阻中焦证可能存在的作用机制.方法:将大鼠分成正常组、模型组、自然恢复组、平胃散6.0、3.0、1.5g/kg剂量组,连续灌胃3天.利用酶联免疫法分别检测各组大鼠肝脏水通道蛋白KCC1、KCC3、KCC4、NKCC1含量.结果:与正常组比较,模型组胃肠动力明显障碍,肠道吸收明显降低,Na+-K+-ATP酶活力显著降低,肝脏组织KCC1、KCC3、NKCC1含量明显上升,KCC4含量明显下降.与模型组比较,平胃散组胃肠动力肠道吸收明显改善,Na+-K+-ATP酶活力显著增强,以平胃散1.5 g,/kg剂量组尤为明显,KCC1含量下降,KCC3和NKCC1含量明显上升.结论:平胃散能够减轻湿阻中焦证大鼠症状,可能与平胃散降低胃残留,促进肠道吸收功能,改善Na+-K+-ATP酶活性,抑制KCC1,激活KCC3和NKCC1的表达有关.
Objective:To study the effects of different extracts from Sichuan Huoxiang non volatile components on the gastrointestinal hormones in rats.Methods:Sichuan Huoxiang crude powder was extracted by steam distillation to get volatile oil and non volatile oil.The components of Sichuan Huoxiang non volatile oil were extracted with equal volume of ethyl acetate,acetic ether,butyl alcohol and distilled water in turn.Non volatile oil was obtained from Sichuan Patchouli ether,ethyl acetate,n-butyl alcohol and distilled water extracts.Non volatile oil was obtained from Sichuan Patchouli ether,ethyl acetate,n-butyl alcohol and distilled water extracts.The establishment of gastrointestinal motility disorder model and Sichuan Huoxiang,Sichuan cablin patchouli oil,non volatile oil of different solvent extracts were as therapeutic drugs counterevidence.Observe cholecystokinin in rats (CCK rats),gastrin (GAS),motilin (MTL) and other indicators.Results:Compared with the normal group,the CCK in model group and spontaneous recovery group was decreased (P < 0.01) and the natural recovery group,Sichuan Agastache rugosa group and ether extracts high dose group's CCK were increased (P < 0.01).Sichuan Agastache rugosa group had no statistical significance.Compared with the normal group,model group and natural recovery group's MTL and GAS were decreased(P < 0.01).Compared with model group,Sichuan Huoxiang group,Sichuan Huoxiang non volatile component group's GAS increased.Sichuan Huoxiang group and water extract (high,low dose) group's MTL increased(P < 0.01).Conclusion:Sichuan Huoxiang non essential oils and different solvent extracts regulate the secretion of hormone of gastrointestinal motility in rats and the effect may better than agastache rugosus.
九味羌活汤首载于元代王好古的《此事难知》中,一般认为该方为解表而设,现代方剂学教材中认为其主治外感风寒湿邪、内有蕴热证,以发汗祛湿、兼清里热为主要功用[1].陈潮祖老先生在《中医治法与方剂》中则提到该方主治外感风寒湿邪、恶寒发热、肌表无汗、头痛项强、肢体酸楚疼痛、口苦微渴[2].本文从王氏原书出发,辨析“解利”之含义,查考张仲景之《伤寒论》,寻找九味羌活汤解利的依据,使其解利之法为大家所知,为临床治疗提供更多的思路,更好地指导临床实践.
吴茱萸汤为中医的一首经典方剂,一般用于温胃止呕、温脾止泻、回阳固脱等,疗效显著.咳嗽为临床常见疾病,持续性咳嗽、咳而欲呕的病人辩证为脾胃阳虚者,应当可用吴茱萸汤加减治疗.黄秀深教授近期遇一例咳而欲呕患者,以吴茱萸汤加减治疗,终得痊愈.
Objective:To establish the dampness obstructing spleen stomach syndrome of interstitial cells of Cajal model and to evaluate it.Methods:70 rats were randomly div ided into blank group,control group,model group,natural recovery group,Pingwei San (high,medium and low dose)group,10 rats in each group.The establishment of dampness obstructing spleen stomach syndrome animal model,and select Pingweisan as disproof of drugs.To observe of the thymus weight of rats,organ coefficient,tumor necrosis factor TNF-α,IL-2,CD4+,CD8+,CD44+/CD88+ ratio and other indicators.Results:Compared with the blank group,the model group,the natural recovery group,the thymus weight and organ coefficient of the Pingwei San (high,medium and low close)group were all decreased,and the thymus weight and organ coefficient of the middle dose group (3 g/kg) was the highest (P<0.05).Compared with the blank group,the model group,the control group TNF-α decreased,compared with the model group,the level of P<0.O1 (high,medium and low dose) group were elevated (TNF-α),the dose gromp of TNF-α (3 g/kg) a close to normal value.The ratio of CD4 and/CD8 in model group was lower than that in the blank group (CD4 was not statistically significant,P<0.05).Model group CD8+ high in blank group (no statistical significance),flat stomach scattered (high,medium and low dose group)CD4,CD4+/CD8+,Pingwei San (high and low dose group CD8 than spontaneous recovery group were decreased (P<0.01).Conclusion:Dampness obstructing spleen stomach syndrome causes abnormal change of rats thymus immune function,Pingwei San have improvement effect on it,maybe related to its bitter and warm dampness use.
目的:观察芎桃二乌止痛酊对皮肤的刺激性及过敏性.方法:以实验豚鼠为模型,分别进行皮肤刺激实验和致敏试验,观察芎桃二乌止痛酊对皮肤的刺激作用和致敏作用.结果:皮肤刺激实验中完整皮肤组及破损皮肤组未见红斑和水肿,平均分值为零;皮肤过敏实验中芎桃二乌止痛酊不引起豚鼠过敏反应,致敏率为零.结论:芎桃二乌止痛酊对豚鼠皮肤无刺激、无致敏作用,外用质量安全可控.
目的 探讨平胃散如何影响湿阻脾胃证模型ICC内、外Ca2+浓度及G蛋白偶联—PLC—IP3信号途径,并揭示平胃散调节胃肠运动的作用机制.方法 用湿阻脾胃证模型动物血清建立“湿阻脾胃证ICC模型”.动物血清的制备:采用本实验室建立的湿阻脾胃证动物模型方法造模,造模20天后,分别取正常组动物血清,湿阻模型组动物血清,给药组动物血清及自然恢复组血清.用Ⅱ胶原酶消化法体外培养小鼠小肠ICC,经形态学观察和免疫荧光学鉴定成功后,通过细胞造模后血清给药,观察细胞内PLC活性,IP3、IP3R含量以及细胞内、外Ca2+浓度变化.结果 与正常组比较,模型组细胞内、外Ca2+浓度水平均降低(P<0.05),PLC活性升高(P<0.05),IP3含量无显著性差异,IP3R含量降低(P<0.05);与正常组比较,自然恢复组细胞内、外Ca2+浓度水平均无显著性差异,PLC活性升高(P<0.05),IP3含量无显著性差异,IP3R含量升高(P<0.05);与模型组比较,自然恢复组细胞内、外Ca2+浓度水平均升高(P<0.05),PLC活性升高(P<0.05),IP3含量无显著性差异,IP3R含量升高;平胃散组细胞内、外Ca2+浓度水平均升高(P<0.05),PLC活性大幅升高(P<0.05),IP3含量升高(P<0.05),IP3R含量升高(P<0.05).结论 平胃散可能是通过影响G蛋白—PLC—IP3信号途径,使ICC细胞内Ca2+浓度周期性震荡恢复,产生起搏电位,而起到调节胃肠运动.
目的:通过芎桃二乌止痛酊对SD大鼠急性毒性实验研究,为其安全性评价提供理论依据.方法:用芎桃二乌止痛酊以最大给药容量的药液进行大鼠膝关节给药2次/d,连续观察2周,记录大鼠毒性反应情况,计算大鼠脏器系数,检测血常规及血液生化指标,并对脏器进行病理学检查.结果:给药组的大鼠外观、行为体征、活动、精神状态均无明显异常;体重正常增加,脏器系数比较差异均无统计学意义(P>0.05);无大鼠死亡情况发生,无中毒反应;主要血液学指标、生化指标、病理学检查与白酒对照组比较差异均无统计学意义(P>0.05).结论:芎桃二乌止痛酊经膝关节给药对实验大鼠无急性毒性反应,可以在临床安全使用.
Objective:Establishement and evaluature of of interstitial cells of Cajal spleen and stromach bloked by dampness syndrone in vitro study.Methods:The dampness obstructing spleen stomach syndrome animal model establishment and animal serum preparation;ICC cultured in vitro by collagenase Ⅱ,The dampness containing animal serum in vitro model of middle energizer dampness obstructing spleen stomach syndrome of interstitial cells of Cajal model,Simulation of rat model in vivo ICC growth,Pingwei power and serum regulating mechanism of ICC cells in the treatment of dampness syndrome.The successful establishment of cell model counterevidence syndrome.Results:After the cell model was made,the Na +-K +-ATP enzyme activity decreased,K + concentration and ATP increased,and the anaerobic metabolism ability of ICC cells was enhanced.Wet resistance of middle energizer cells through a flat stomach scattered serum intervention,and natural recovery group compared,fiat stomach scattered group ICC Na +-K +-ATPase and K activity was significantly increased,the decline in ATP and LDH activity decreased.Conclusion:The dampness obstructing spleen stomach syndrome ICC model cells and normal ICC have differences.The successful cell model was established successfully,the sodium pump activity is the basic pathological change in the change of the dampness obstructing spleen stomach syndrome,and the level of the stomach may be through the recovery of sodium potassium pump activity,Blocking the downward trend of K+ concentration of dampness obstructing spleen stomach syndrome in the Cajal interstitial cell metabolism.
Objective:To observe long term toxicity and recovery of rats which given Xiongtao Erwu Dicentrine for 6 weeks.Metheds:The rats were treated with intact skin and damaged skin once a day for 6 weeks (stop drug on one day every week)with different Xiongtao Erwu Dicentrine dose,according to the calculation of the quantity of drug,separately180,90,45 μ L · cm-2.To observe the general character of rats and record the weight change of rats before and after treatment,at the same time,examine the blood test,liver function,renal function,lucose metabolism and so on.Then killed the rats,taking out the heart,liver,spleen,lung,kidney,brain mass,and calculating organ coefficient comparison and pathological examining the organs.The remaining rats were administered for 3 weeks to observe the recovery of the rats,and the same indexes were detected.Results:After 6 weeks,there was no statistical significance between high,medium and low dose group of intact skin group and damaged skin group on appearance,behavior,physical activity,mental state.There was no death and no toxic reaction.There was no statistical significance on normal weight gain and organ coefficient comparison (P>0.05);the PLT amd LY% were increased,ALB was decreased,compared with the blank control group,there was statistical significance (P<0.05).Pathological examination showed no pathological changes;all the abnormal indexes were normal in recovery period,compared with the blank control group,there was statistical significance (P<0.05).Conclusion:Long time given Xiongtao Erwu Dicentrine can be used security in the clinical,which is ceritified by the experience.
Objective:Research of Huoxiangzhengqi powder intervention on syndrome of dampness in middle Jiao model effects on metabolism glucose and gluconeogenesis mechanism to reveal the effects of syndrome of dampness in middle Jiao model on glucose metabolism in the gluconeogenic pathway,revealed in the regulation of energy metabolism and the spleen and stomach Huoxiangzhengqi powder in the treatment of syndrome of dampness in middle Jiao of the scientific connotation from the level of system biology.Methods:The natural model and comprehensive model combined with the three main factors of establishing simulation of dampness,syndrome of dampness in middle Jiao model.Measure the content of pyruvate pyruvate carboxylase and glucose by biochemical method;measure the content of pyruvic acid and glucose-6-phosphatase by enzyme-linked immunosorbent assay.Results:The content of syndrome of dampness in middle Jiao model of pyruvic acid reduce,pyruvate carboxylase,glucose-6-phosphatase are reduce and glucose content increased;Huoxiangzhengqi powder can enhance the glucose metabolism of gluconeogenesis.Conclusion:Thesyndrome of dampness in middle Jiao will lead to increased energy consumptionrather than the body's absorption and use of glucose lead to inadequate energy supply,which may be one of the pathological basis of syndrome of dampness in middle Jiao of lassitude,anorexia,diet reduction;Huoxiangzhengqi powder could strengthen the effect of syndrome of dampness in middle Jiao energizer gluconeogenesis and glucose some of the decomposition and transformation,which may be Huoxiangzhengqi powder treatment of rheumatism,a mechanism of action to alleviate the lassitude,anorexia and other symptoms of diet reduction.