紫花茉莉抗小鼠前列腺增生的实验研究及其对Ki67、CD34表达的影响
摘要
良性前列腺增生症(Benign Prostatic Hyperplasia,BPH)是一种以排尿困难为主要临床特征的常见的男性老年性疾病。随着前列腺移行区细胞的增生,前列腺体积不断增大,从而压迫前列腺部尿道,引起膀胱出口梗阻,导致患者出现不同程度的排尿困难等症状,严重者可出现双侧上尿路积水并导致肾功能不全。因此,作为男性老年人常见病,前列腺增生症已严重影响老年男性的生命和生活质量。随着人民生活水平的提高和卫生保健工作的进步,老年人口日趋增多,BPH的病例数亦相应增加,BPH已是老年医学中的重要课题。紫花茉莉是广东省农科院土壤肥料研究所开发栽培的一种药用植物,民间运用紫花茉莉治疗老年性良性前列腺增生症,临床应用有一定的效果。我们本着开发紫花茉莉药物功能,验证紫花茉莉的药效,探索紫花茉莉作用机理的宗旨,我们开展了本项研究工作。
一、文献研究
文章复习了近十年现代中医文献对本病的论述,认为前列腺增生症有别于中医癃闭,本病肾虚气弱是基础,瘀滞痰凝为病机,气虚血瘀、肺失宣肃亦为病,本虚标实,虚中夹实之证。虚是肺脾肾等脏腑亏虚,实则为气血痰浊瘀结,水道不通。治宜虚实兼顾,标本同治。在临床治疗上,以辨证分型论治、专方随证诊治、拟方随证诊治、中成药治疗和其他疗法如灌肠、针刺等疗法治疗。临床应用总有效率在59.4%—94%之间。在实验研究上,药理方面主要集中在中药调节体内性激素水平、抗炎消肿、改善膀胱颈痉挛、增加逼尿肌力、抑制纤维增生等方面;临床研究报道,中药可改善IPSS评分和尿动力学指标,主要从中药影响泌尿系平滑肌张力、影响性激素水平、缩小前列腺体积、抑制前列腺细胞增殖、诱导前列腺细胞凋亡等几个方面来论述中医药治疗前列腺增生的可能机制。但缺乏多中心随机双盲的大样本临床实验证明。实践证明,中医中药治疗前列腺增生症可以取得一定的疗效,其作用机制可能是多方面和多因素的。但目前尚缺乏有效的单味中药制剂或从中药中提取的单体;中药复方在临床中应用较多,其临床和实验研究在规范化、标准化、系统化方面有所欠缺。同时需要加以整理提高,在中药作用机理不能完全被阐明的情况下,应该更加重视严谨的临床证据。针对BPH的复杂机制,采取多途径多手段的治疗方法,以期达到症状改善、病因治疗等尽可能全面的作用,同时反过来积极寻求对这个疾病更深刻全面的理解,也许是中药在该领域的发展方向。中医药治疗BPH有一定的疗效,可明显改善症状,为该病的非手术治疗开辟了新的途径,值得进一步研究探索。
目前现代医学对BPH的发病原因已做了许多研究,BPH的致病因子可以归纳为两个部分:内源性(前列腺内部)和外源性(前列腺以外)致病因子,后者
Benign Prostatic Hyperplasia (BPH) is a kind of frequent male old-age disease which clinical feature is urine difficulty. Along with the Cellular proliferation in prostate gland transitional zones, the physical volume of prostate gland enlarges continuously, thus oppresses the urethra part of prostate gland, leads to bladder outlet obstruction (BOO), the patients appear to be different degree urine difficulty symptom, the serious ones will suffer accumulated water in both sides of upper urinary tract and cause renal inadequacy. Therefore, as a frequent disease of male old people, BPH has already affected the life and the quality of life(QOL) of the old age male seriously. Along with progress of the people' s living standard and health care services, the aging population in our country increases gradually, the cases of BPH also increases correspondingly , BPH has already been a important topic in Chinese old-age medical science. The folks use ZiHuaMoLi to cure old age BPH, and get a certain curative effect in clinical application, Based in the medicine function of the ZiHuaMoLi, we launch this research to verify the medicine efficacy of ZiHuaMoLi, and explore the function mechanism of ZiHuaMoLi.1. Documents researchThe article reviews near 10-year modern Chinese medicine documents about this disease, and regards the foundation of this disease as
deficiency of kidney' Qi, the pathogenesis is blood—stasis and coagulated phlegm, blood stasis due to qi deficiency , lung qi loses dispersing also pathogenesis for this disease, so the therapeutical principle shall give consideration to deficiency and excess, treating both manifestation and root cause simultaneously. During the clinical treatment, curing it with differentiation of symptoms and signs for classification of syndrome, draw up particular prescription follow the variation of diagnosis, Chinese patent medicines and others therapy. In empirical study, we discuss the possible mechanism of curing BPH with traditional Chinese medicine mainly from affecting uropoiesis system smooth muscle tension , influencing the sex hormone' s level, contracting the prostate gland' s physical volume > repressing the prostatic cell' s reduplication and inducing prostatic cell' s Apoptosis. Practice certifies that a certain curative effect can be obtained in curing BPH with traditional Chinese medicine, but it also need to take into arrangement and exaltation at the same time, under the condition that the traditional mechanism of Chinese medicine can't be clarified completely, we ought to think more highly of rigorous clinical proof.Currently the modern medical science thinks that this disease' s outbreak reason involves the link such as sex hormone, growth factor and food, the medicine treatment is a developing tendency, clinical medicine curing BPH mainly includs 5 a -reducing enzyme inhibitor, a ,- adrenergic receptor antagonist, androgenic hormone inhibitor, galenical preparations ( include the plant Preparations and the pollen Preparations) etc. 5 a-reducing enzyme inhibitor is slow-moving since the effect, the side reaction is also obvious, the therapy expenses is higher too. As to a i~ adrenergic receptor antagonist, seeing from patients individual, not all patients can obtain the obvious curative effect. As far as the plant preparations and the pollen preparations are concerned, their mechanisms are still not quite clear. About the anti- androgenic hormone medicine, it will cause the level of testosterone in blood plasma to descend significantly, the curative effect is not good and side effect is not a few. Although some new medicine have entered the clinical application and the verification stages, but as to cure BPH, these medicine still exist many disadvantages such as inaccurate curative effect, big side effect
and expensive cost.2, Experiment research(1) max administration experiment :In order to prove the clinical application safety of ZiHuaMoLi, we carries out the acute toxicity experiment, infuses The NIH small rat with 35 g(crude drug) / ml /once, the max administration of ZiHuaMoLi water-lifted liquid is the 30 ml/ kg ( the 1050.0 g crude drug / kg), namely the LD50 is more than 1050.0 g crude drug / kg. It is 628. 74 times more than the clinical day dosage( the 1.67 g crude drug / kg). Finally did not find the death of the animal or the abnormality of other internal organs. As a result , the ZiHuaMoLi water-lifted liquid is a kind of Chinese drugs preparation that takes orally safely.(2) observation of ZiHuaMoLi ' s function to anti-experimental BPH: In order to approach to the effect difference between ZiHuaMoLi and Proscar for BPH. We make the small rat BPH model with testosterone propionate hypodermical injection, by using this models we take intragastric administration difference with ZiHuaMoLi high dose , ZiHuaMoLi low dose, and Proscar , after the experiment, separate the small rat' s prostate gland tissue, measure the prostate gland wet weight, examine the small rats' testosterone (T) and serum androstanolone (DHT) content respectively, respectively observe the anti-BPH function and mechanism of ZiHuaMoLi high dose group, ZiHuaMoLi low dose group, and Proscar group .Result: Making the small rat BPH model with testosterone propionate hypodermical injection;Under the condition of owning the sex gland, the ZiHuaMoLi contain the anti- BPH function, at the same time there is no obvious difference of anti-BPH among ZiHuaMoLi high dose group, ZiHuaMoLi low dose group, and Proscar group. The mechanism of ZiHuaMoLi in inhibiting from BPH could be the same as Proscar, that' s inhibiting the transformation from testosterone to be androstanolone. But as for inhibiting the size of the prostate, the effect is less stable than Proscar, maintaining factors of unstable and variation, the anti-BPH function of ZiHuaMoLi is mostly repressing the transform of the testosterone to be androstenalone.(3) Effect of ZiHuaMoLi to prostate gland hyperplastic tissue' s Ki67, CD34 antigen presentation: Through the experiment of HE dyeing for
each prostate gland tissue, carry out the immunohistochemistry examination simultaneously, observe the prostate gland hyperplastic tissue' s Ki67> CD34 antigen presentation , the result shows there is not Ki67 antigen presentation in the normal small rats' prostate gland tissue , but the Ki67 antigen presentation rate in hyperplasy group and negative control group are obviously higher than Proscar group and ZiHuaMoLi high, low dose group , it shows the ZiHuaMoLi can lower Cellular proliferation and lower activity of cell multiplication, the anti-BPH mechanism of Proscar is similar to ZiHuaMoLi.At the same time the Ki67 and the MVD values present direct correlation, it hints that the expression of Ki67 and CD34 is direct correlation, the ZiHuaMoLi and the Proscar both have the function to lower the index of Ki-67 and CD34. MVD values in the the small rat' s prostate Interstitial tissue is higher than control group, hints that the BPH can be regarded as a kind of new-born vessels dependence disease. Supposing that MVD values increment in BPH small rats is relevant to vasiformation, is shows the Proscar can anti-BPH by repressing the generation of prostate gland tissue' s new-born vessels, thus keep prostate gland from hyperplasia, so attain the goal of prevent BPH. In general , the mechanism of the ZiHuaMoLi is similar to The Proscar.
一、文献研究
文章复习了近十年现代中医文献对本病的论述,认为前列腺增生症有别于中医癃闭,本病肾虚气弱是基础,瘀滞痰凝为病机,气虚血瘀、肺失宣肃亦为病,本虚标实,虚中夹实之证。虚是肺脾肾等脏腑亏虚,实则为气血痰浊瘀结,水道不通。治宜虚实兼顾,标本同治。在临床治疗上,以辨证分型论治、专方随证诊治、拟方随证诊治、中成药治疗和其他疗法如灌肠、针刺等疗法治疗。临床应用总有效率在59.4%—94%之间。在实验研究上,药理方面主要集中在中药调节体内性激素水平、抗炎消肿、改善膀胱颈痉挛、增加逼尿肌力、抑制纤维增生等方面;临床研究报道,中药可改善IPSS评分和尿动力学指标,主要从中药影响泌尿系平滑肌张力、影响性激素水平、缩小前列腺体积、抑制前列腺细胞增殖、诱导前列腺细胞凋亡等几个方面来论述中医药治疗前列腺增生的可能机制。但缺乏多中心随机双盲的大样本临床实验证明。实践证明,中医中药治疗前列腺增生症可以取得一定的疗效,其作用机制可能是多方面和多因素的。但目前尚缺乏有效的单味中药制剂或从中药中提取的单体;中药复方在临床中应用较多,其临床和实验研究在规范化、标准化、系统化方面有所欠缺。同时需要加以整理提高,在中药作用机理不能完全被阐明的情况下,应该更加重视严谨的临床证据。针对BPH的复杂机制,采取多途径多手段的治疗方法,以期达到症状改善、病因治疗等尽可能全面的作用,同时反过来积极寻求对这个疾病更深刻全面的理解,也许是中药在该领域的发展方向。中医药治疗BPH有一定的疗效,可明显改善症状,为该病的非手术治疗开辟了新的途径,值得进一步研究探索。
目前现代医学对BPH的发病原因已做了许多研究,BPH的致病因子可以归纳为两个部分:内源性(前列腺内部)和外源性(前列腺以外)致病因子,后者
Benign Prostatic Hyperplasia (BPH) is a kind of frequent male old-age disease which clinical feature is urine difficulty. Along with the Cellular proliferation in prostate gland transitional zones, the physical volume of prostate gland enlarges continuously, thus oppresses the urethra part of prostate gland, leads to bladder outlet obstruction (BOO), the patients appear to be different degree urine difficulty symptom, the serious ones will suffer accumulated water in both sides of upper urinary tract and cause renal inadequacy. Therefore, as a frequent disease of male old people, BPH has already affected the life and the quality of life(QOL) of the old age male seriously. Along with progress of the people' s living standard and health care services, the aging population in our country increases gradually, the cases of BPH also increases correspondingly , BPH has already been a important topic in Chinese old-age medical science. The folks use ZiHuaMoLi to cure old age BPH, and get a certain curative effect in clinical application, Based in the medicine function of the ZiHuaMoLi, we launch this research to verify the medicine efficacy of ZiHuaMoLi, and explore the function mechanism of ZiHuaMoLi.1. Documents researchThe article reviews near 10-year modern Chinese medicine documents about this disease, and regards the foundation of this disease as
deficiency of kidney' Qi, the pathogenesis is blood—stasis and coagulated phlegm, blood stasis due to qi deficiency , lung qi loses dispersing also pathogenesis for this disease, so the therapeutical principle shall give consideration to deficiency and excess, treating both manifestation and root cause simultaneously. During the clinical treatment, curing it with differentiation of symptoms and signs for classification of syndrome, draw up particular prescription follow the variation of diagnosis, Chinese patent medicines and others therapy. In empirical study, we discuss the possible mechanism of curing BPH with traditional Chinese medicine mainly from affecting uropoiesis system smooth muscle tension , influencing the sex hormone' s level, contracting the prostate gland' s physical volume > repressing the prostatic cell' s reduplication and inducing prostatic cell' s Apoptosis. Practice certifies that a certain curative effect can be obtained in curing BPH with traditional Chinese medicine, but it also need to take into arrangement and exaltation at the same time, under the condition that the traditional mechanism of Chinese medicine can't be clarified completely, we ought to think more highly of rigorous clinical proof.Currently the modern medical science thinks that this disease' s outbreak reason involves the link such as sex hormone, growth factor and food, the medicine treatment is a developing tendency, clinical medicine curing BPH mainly includs 5 a -reducing enzyme inhibitor, a ,- adrenergic receptor antagonist, androgenic hormone inhibitor, galenical preparations ( include the plant Preparations and the pollen Preparations) etc. 5 a-reducing enzyme inhibitor is slow-moving since the effect, the side reaction is also obvious, the therapy expenses is higher too. As to a i~ adrenergic receptor antagonist, seeing from patients individual, not all patients can obtain the obvious curative effect. As far as the plant preparations and the pollen preparations are concerned, their mechanisms are still not quite clear. About the anti- androgenic hormone medicine, it will cause the level of testosterone in blood plasma to descend significantly, the curative effect is not good and side effect is not a few. Although some new medicine have entered the clinical application and the verification stages, but as to cure BPH, these medicine still exist many disadvantages such as inaccurate curative effect, big side effect
and expensive cost.2, Experiment research(1) max administration experiment :In order to prove the clinical application safety of ZiHuaMoLi, we carries out the acute toxicity experiment, infuses The NIH small rat with 35 g(crude drug) / ml /once, the max administration of ZiHuaMoLi water-lifted liquid is the 30 ml/ kg ( the 1050.0 g crude drug / kg), namely the LD50 is more than 1050.0 g crude drug / kg. It is 628. 74 times more than the clinical day dosage( the 1.67 g crude drug / kg). Finally did not find the death of the animal or the abnormality of other internal organs. As a result , the ZiHuaMoLi water-lifted liquid is a kind of Chinese drugs preparation that takes orally safely.(2) observation of ZiHuaMoLi ' s function to anti-experimental BPH: In order to approach to the effect difference between ZiHuaMoLi and Proscar for BPH. We make the small rat BPH model with testosterone propionate hypodermical injection, by using this models we take intragastric administration difference with ZiHuaMoLi high dose , ZiHuaMoLi low dose, and Proscar , after the experiment, separate the small rat' s prostate gland tissue, measure the prostate gland wet weight, examine the small rats' testosterone (T) and serum androstanolone (DHT) content respectively, respectively observe the anti-BPH function and mechanism of ZiHuaMoLi high dose group, ZiHuaMoLi low dose group, and Proscar group .Result: Making the small rat BPH model with testosterone propionate hypodermical injection;Under the condition of owning the sex gland, the ZiHuaMoLi contain the anti- BPH function, at the same time there is no obvious difference of anti-BPH among ZiHuaMoLi high dose group, ZiHuaMoLi low dose group, and Proscar group. The mechanism of ZiHuaMoLi in inhibiting from BPH could be the same as Proscar, that' s inhibiting the transformation from testosterone to be androstanolone. But as for inhibiting the size of the prostate, the effect is less stable than Proscar, maintaining factors of unstable and variation, the anti-BPH function of ZiHuaMoLi is mostly repressing the transform of the testosterone to be androstenalone.(3) Effect of ZiHuaMoLi to prostate gland hyperplastic tissue' s Ki67, CD34 antigen presentation: Through the experiment of HE dyeing for
each prostate gland tissue, carry out the immunohistochemistry examination simultaneously, observe the prostate gland hyperplastic tissue' s Ki67> CD34 antigen presentation , the result shows there is not Ki67 antigen presentation in the normal small rats' prostate gland tissue , but the Ki67 antigen presentation rate in hyperplasy group and negative control group are obviously higher than Proscar group and ZiHuaMoLi high, low dose group , it shows the ZiHuaMoLi can lower Cellular proliferation and lower activity of cell multiplication, the anti-BPH mechanism of Proscar is similar to ZiHuaMoLi.At the same time the Ki67 and the MVD values present direct correlation, it hints that the expression of Ki67 and CD34 is direct correlation, the ZiHuaMoLi and the Proscar both have the function to lower the index of Ki-67 and CD34. MVD values in the the small rat' s prostate Interstitial tissue is higher than control group, hints that the BPH can be regarded as a kind of new-born vessels dependence disease. Supposing that MVD values increment in BPH small rats is relevant to vasiformation, is shows the Proscar can anti-BPH by repressing the generation of prostate gland tissue' s new-born vessels, thus keep prostate gland from hyperplasia, so attain the goal of prevent BPH. In general , the mechanism of the ZiHuaMoLi is similar to The Proscar.
引文
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