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Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats

Yıl 2018, Cilt: 11 Sayı: 4, 402 - 413, 15.12.2018
https://doi.org/10.30607/kvj.437999

Öz

In recent years,
the usage of exogenous testosterone has tripled in humans. Although, mechanism
has not yet been fully elucidated, there is a correlation between the increased
risk of heart failure and testosterone usage. The aim of this study was to
demonstrate cardiac fibrosis, which a main finding of hearth failure, in
testosterone propionate-applied male rats and to show its regression by
Lonidamine as an anti-hyperplastic agent. A total of 72 adult Wistar albino and
neutralized male rats were divided into 4 groups (n=18 in each groups). Animals
in all groups were received to testosterone propionate until 2nd, 4th, and 12th
weeks (n=6 in each groups). Subsequently, group I and II also received the pure
solution of Lonidamine hydrochloride and its lipid-polymer hybrid
nanoparticulate formulation via intraprostatic injection. Group III, blank
lipid-polymer hybrid nanoparticle formulation were solely administrated via same
way. The control group or group IV were received only testosterone. At the end
of the experiment period, hearts were collected and fibrocytic changes were
confirmed by histochemical and immunohistochemical methods.
Histopathologically, fibrosis were lower in group I and II when comprared to
that of group III and IV. Imunohistochemically, bFGF, cyclin D1 and p16 protein
expressions were evaluated. bFGF and cyclinD1 epxressions correspondingly to
increasing fibrosis were found higher in last two groups during the experiment.
But, p16 expressions were lower in Lonidamine treated-group I and II. In
conclusion, results of this study supported that testosterone propionate may
promote cardiac fibrosis. Lonidamine hydrochloride may be used in its
prevention of fibrosis. 

Kaynakça

  • Angell PJ, Chester N, Green DJ. Anabolic steroid use and longitudinal, radial, and circumferential cardiac motion, Med Sci Sports Exerc. 2012; 44: 583–590.
  • Angell PJ, Ismail TF, Jabbour A, Smith G, Dahl A, Wage R, Whyte G, Green DJ, Prasad S, George K. Ventricular structure, function, and focal fibrosis in anabolic steroid users: a CMR study. Eur J Appl Physiol. 2014; 114(5):921-928.
  • Belhani D, Fanton L, Vaillant F, Descotes J, Manati W, Tabib A, bui-xuan B, Timour Q. Cardiac Lesions Induced by Testosterone: Protective Effects of Dexrazoxane and Trimetazidine. Cardiovas Toxicol. 2009; 9: 64-69.
  • Brønnum, H., Kalluri, R. Cardiac fibrosis: Cellular and molecular determinants. In Muscle (Vol. 1). Elsevier Inc, USA, 2012; pp. 389-404.
  • Caputo, A, Silvestrini, B. Lonidamine, a New Approach to Cancer Therapy. Oncology. 1984;41:2–6.
  • Cleland JG, Khand A, Clark A. The heart failure epidemic: exactly how big is it? Eur Heart J. 2001; 22:623-626.
  • Culic V. Androgens in cardiac fibrosis and other cardiovascular mechanisms, Int J Cardiol. 2015; 179: 190–192.
  • D'Andrea A., Caso P., Salerno G., De Corato G, Mita C, Di Salvo G, Severino S, Cuomo S, Liccardo B, Esposito N, Calabrò R. Left ventricular early myocardial dysfunction after chronic misuse of anabolic androgenic steroids: a Doppler myocardial and strain imaging analysis, Br J Sports Med. 2007; 41:149–155.
  • Di Stefano V, Giacca M, Capogrossi MC, Crescenzi M, Martelli F. Knockdown of cyclin-dependent kinase inhibitors induces cardiomyocyte re-entry in the cell cycle. J Biol Chem. 2011; 286: 8644–8654.
  • Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res. 1998; 39(1):89-105.
  • Floridi A, Paggi MG, D'Atri S, De Martino C, Marcante ML, Silvestrini B, Caputo A. Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells. Cancer Res. 1981; 41(11 Pt 1): 4661-4666.
  • Floridi A, Paggi MG, Marcante ML, Silvestrini B, Caputo A, De Martino C. Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells. J Natl Cancer Inst. 1981b; 66(3):497-499.
  • Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev. 2012; 92:635–88.
  • Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview: Cyclin D1: normal and abnormal functions. Endocrinol. 2004, 145(12):5439-47.
  • Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc. 2003, 51: 101–115.
  • Hassan NA, Salem MF, Sayed MA. Doping and effects of anabolic androgenic steroids on the heart: histological, ultrastructural, and echocardiographic assessment in strength athletes. Hum Exp Toxicol. 2009; 28 273–283.
  • Hori Y, Uechi M, Ebisawa T, Yamano S, Yoshioka K, Mutoh KI. The influence of gender on cardiac fibrosis induced by sympathetic stimulation. Chin J Physiol 51(3): 146–151. Erratum in Chin J Physiol. 2008; 31 51(4): 261.
  • Kato A, Bamba H, Shinohara M, Yamauchi A, Ota S, Kawamoto C, Yoshida Y. Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats. J Gastroenterol Hepatol. 2005; 20(8):1198-1205.
  • Marsh JD, Lehmann MH, Ritchie RH, Gwathmey JK, Green GE, Schiebinger RJ. Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation 1998; 98: 256-261.
  • Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A. Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis. J Am Coll Cardiol. 2016; 67: 2018-2028.
  • Nath K, Nelson DS, Heitjan DF, Zhou R, Leeper DB, Glickson JD. Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan. NMR Biomed. 2015; 28(3): 395-403.
  • Nath K, Nelson DS, Heitjan DF, Leeper DB, Zhou R, Glickson JD. Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin NMR Biomed. 2015; 28(3):281-290.
  • Nederlof R, Gürel-Gurevin E, Eerbeek O, Xie C, Deijs GS, Konkel M, Hu J, Weber NC, Schumacher CA, Baartscheer A, Mik EG, Hollmann MW, Akar FG, Zuurbier CJ. Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart. J Physiol Biochem. 2016; 73(3):323-333.
  • Papamitsou T, Barlagiannis D, Papaliagkas V, Kotanidou E, Dermentzopoulou-Theodoridou M. Testosterone-induced hypertrophy, fibrosis and apoptosis of cardiac cells–an ultrastructural and immunohistochemical study. Med Sci Monit. 2011; 17: 266–273.
  • Pasdois P, Parker JE, Halestrap AP. Extent of mitochondrial hexokinase II dissociation during ischemia correlates with mitochondrial cytochrome c release, reactive oxygen species production, and infarct size on reperfusion. J Am Heart Assoc. 2012; 31;2(1):e005645.
  • Pasumarthi KBS, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ Res. 2005; 96: 110–118.
  • Pirompol P, Teekabut V, Weerachatyanukul W, Bupha-Intr T, Wattanapermpool J. Supra-physiological dose of testosterone induces pathological cardiac hypertrophy. J Endocrinol. 2016; 229(1):13-23.
  • Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Therap. 2009; 123 (2):255.
  • Price GS, Page RL, Riviere JE, Cline JM, Thrall DE. Effect of whole-body hyperthermia on the pharmacokinetics and toxicity of lonidamine in dogs. Int. J. Hyperth. 1995; 11(4): 531-544.
  • Price GS, Page RL, Riviere JE, Cline JM, Thrall DE. Pharmacokinetics and toxicity of oral and intravenous lonidamine in dogs. Cancer Chemother Pharmacol.,1996; 38(2):129-135.
  • Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. International Journal of Cancer. 2012; 130 (8): 1715–1725.
  • Sengel-Turk CT, Hascicek C. Design of lipid-poymer hybird nanoparticles for therapy of BPH: Part 1. Formulation optimization using a design of experiment approach. Journal of Drug Delivery Science and Technology. 2017; 39: 16-24.
  • Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993; 366 (6456): 704–707.
  • Tashiro E, Maruki H, Minato Y, Doki Y, Weinstein IB, Imoto M. Overexpression of cyclin D1 contributes to malignancy by up-regulation of fibroblast growth factor receptor 1 via the pRB/E2F pathway. Cancer Res. 2003; 15;63(2):424-31.
  • Thum T, Borlak J. Testosterone, cytochrome P450, and cardiac hypertrophy. FASEB J. 2002;.16: 1537-1549.
  • Toma M, McAlister FA, Coglianese EE. Testosterone supplementation in heart failure: a meta-analysis, Circ Heart Fail. 2012; 5: 315–321.
  • Watts KL, Cottrell E, Hoban PR, Spiteri MA. RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications foridiopathic pulmonary fibrosis. Respir Res. 2006; 7:88. 43.
  • Weidner G. Why do men get more heart disease than women? An international perspective. J Am Coll Health. 2000; 48(6):291-294.
  • Wu R, Smeele KM, Wyatt E, Ichikawa Y, Eerbeek O, Sun L, Chawla K, Hollmann MW, Nagpal V, Heikkinen S, Laakso M, Jujo K, Wasserstrom JA, Zuurbier CJ, Ardehali H. Reduction in hexokinase II levels results in decreased cardiac function and altered remodeling after ischemia/reperfusion injury. Circ Res. 2011;108(1):60-69.
  • Xie J, Chen Y, Hu C, Pan Q, Wang B, Li X, Geng J, Xu B. Premature senescence of cardiac fibroblasts and atrial fibrosis in patients with atrial fibrillation. Oncotarget. 2017; 8(35):57981-57990.
  • Yang X, Wang Y, Yan S, Sun L, Yang G, Li Y, Yu C. Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat. Bioengineered. 2017; 2;8(1):14-20.
  • Zhu F, Li Y, Zhang J, Piao C, Liu T, Li HH, Du J. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One. 2013; 8: e74535.

Yetişkin ve Kastre Edilmiş Erkek Ratlarda Yüksek Doz Testosteron Propiyonatın İndüklediği Kardiyak Fibrozis Üzerine Lonidamin Yüklü Lipit-Polimer Hibrit Nanopartiküllerin Etkisi

Yıl 2018, Cilt: 11 Sayı: 4, 402 - 413, 15.12.2018
https://doi.org/10.30607/kvj.437999

Öz

Son yıllarda,
insanlarda ekzojen testosteron kullanımı üç katına çıkmıştır. Mekanizma henüz
tam olarak aydınlatılmamış olmasına rağmen kalp yetmezliği riskini arttırdığına
dair bir korelasyon vardır. Bu çalışmanın amacı, erkek sıçanlarda testosteron
propiyonat kullanımının kalp yetmezliğinin temel bulgusu olan fibrozise yol
açtığını ve bir anti-hiperplastik ajan olan Lonidaminin bunu geriletici
etkisini göstermekti. Çalışmada, toplam 72 adet kastre edilmiş, yetişkin Wistar
albino erkek sıçan kullanıldı ve hayvanlar 4 ana gruba ayrıldı (her bir grupta
için n= 18).  Bu ana gruplar 3 alt gruba
ayrılarak (n=6 her bir grup için) hayvanlara, 2., 4. ve 12. haftalara kadar
testosteron propiyonat uygulandı. Group I ve II için, Lonidamin hidroklorür,
saf çözelti içinde ve bunun lipit-polimer hibrit nanopartikül formülasyonu
halinde prostatlara enjekte edildi. Grup III için sadece lipit-polimer hibrit
nanopartikül formülasyonu uygulandı. Kontrol grubu olarak grup IV’de sadece
testesteron uygulandı. Çalışmanın sonunda kalpler toplandı. Histopatolojik
olarak fibrosis grup I ve II’de grup III ve IV’dekiyle karşılaştırıldığında
daha düşüktü. İmmünohistokimyasal olarak bFGF, siklin D1 ve p16 protein
ekspresyonları değerlendirildi. Son iki grupta, artan fibrozise karşılık gelen
bFGF ve siklinD1 ifadeleri, deney sırasında daha yüksek bulundu. Ancak, p16
ifadeleri Lonidamin uygulanan grup I ve grup II’de daha düşüktü. Sonuç olarak,
bu sonuçlar testosteron propiyonatın kardiyak fibrozisi etkileyebileceğini
desteklemektedir ve fibrozisin önlenmesinde Lonidamin hidroklorür
kullanılabilir.

Kaynakça

  • Angell PJ, Chester N, Green DJ. Anabolic steroid use and longitudinal, radial, and circumferential cardiac motion, Med Sci Sports Exerc. 2012; 44: 583–590.
  • Angell PJ, Ismail TF, Jabbour A, Smith G, Dahl A, Wage R, Whyte G, Green DJ, Prasad S, George K. Ventricular structure, function, and focal fibrosis in anabolic steroid users: a CMR study. Eur J Appl Physiol. 2014; 114(5):921-928.
  • Belhani D, Fanton L, Vaillant F, Descotes J, Manati W, Tabib A, bui-xuan B, Timour Q. Cardiac Lesions Induced by Testosterone: Protective Effects of Dexrazoxane and Trimetazidine. Cardiovas Toxicol. 2009; 9: 64-69.
  • Brønnum, H., Kalluri, R. Cardiac fibrosis: Cellular and molecular determinants. In Muscle (Vol. 1). Elsevier Inc, USA, 2012; pp. 389-404.
  • Caputo, A, Silvestrini, B. Lonidamine, a New Approach to Cancer Therapy. Oncology. 1984;41:2–6.
  • Cleland JG, Khand A, Clark A. The heart failure epidemic: exactly how big is it? Eur Heart J. 2001; 22:623-626.
  • Culic V. Androgens in cardiac fibrosis and other cardiovascular mechanisms, Int J Cardiol. 2015; 179: 190–192.
  • D'Andrea A., Caso P., Salerno G., De Corato G, Mita C, Di Salvo G, Severino S, Cuomo S, Liccardo B, Esposito N, Calabrò R. Left ventricular early myocardial dysfunction after chronic misuse of anabolic androgenic steroids: a Doppler myocardial and strain imaging analysis, Br J Sports Med. 2007; 41:149–155.
  • Di Stefano V, Giacca M, Capogrossi MC, Crescenzi M, Martelli F. Knockdown of cyclin-dependent kinase inhibitors induces cardiomyocyte re-entry in the cell cycle. J Biol Chem. 2011; 286: 8644–8654.
  • Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res. 1998; 39(1):89-105.
  • Floridi A, Paggi MG, D'Atri S, De Martino C, Marcante ML, Silvestrini B, Caputo A. Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells. Cancer Res. 1981; 41(11 Pt 1): 4661-4666.
  • Floridi A, Paggi MG, Marcante ML, Silvestrini B, Caputo A, De Martino C. Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells. J Natl Cancer Inst. 1981b; 66(3):497-499.
  • Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev. 2012; 92:635–88.
  • Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview: Cyclin D1: normal and abnormal functions. Endocrinol. 2004, 145(12):5439-47.
  • Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc. 2003, 51: 101–115.
  • Hassan NA, Salem MF, Sayed MA. Doping and effects of anabolic androgenic steroids on the heart: histological, ultrastructural, and echocardiographic assessment in strength athletes. Hum Exp Toxicol. 2009; 28 273–283.
  • Hori Y, Uechi M, Ebisawa T, Yamano S, Yoshioka K, Mutoh KI. The influence of gender on cardiac fibrosis induced by sympathetic stimulation. Chin J Physiol 51(3): 146–151. Erratum in Chin J Physiol. 2008; 31 51(4): 261.
  • Kato A, Bamba H, Shinohara M, Yamauchi A, Ota S, Kawamoto C, Yoshida Y. Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats. J Gastroenterol Hepatol. 2005; 20(8):1198-1205.
  • Marsh JD, Lehmann MH, Ritchie RH, Gwathmey JK, Green GE, Schiebinger RJ. Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation 1998; 98: 256-261.
  • Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A. Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis. J Am Coll Cardiol. 2016; 67: 2018-2028.
  • Nath K, Nelson DS, Heitjan DF, Zhou R, Leeper DB, Glickson JD. Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan. NMR Biomed. 2015; 28(3): 395-403.
  • Nath K, Nelson DS, Heitjan DF, Leeper DB, Zhou R, Glickson JD. Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin NMR Biomed. 2015; 28(3):281-290.
  • Nederlof R, Gürel-Gurevin E, Eerbeek O, Xie C, Deijs GS, Konkel M, Hu J, Weber NC, Schumacher CA, Baartscheer A, Mik EG, Hollmann MW, Akar FG, Zuurbier CJ. Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart. J Physiol Biochem. 2016; 73(3):323-333.
  • Papamitsou T, Barlagiannis D, Papaliagkas V, Kotanidou E, Dermentzopoulou-Theodoridou M. Testosterone-induced hypertrophy, fibrosis and apoptosis of cardiac cells–an ultrastructural and immunohistochemical study. Med Sci Monit. 2011; 17: 266–273.
  • Pasdois P, Parker JE, Halestrap AP. Extent of mitochondrial hexokinase II dissociation during ischemia correlates with mitochondrial cytochrome c release, reactive oxygen species production, and infarct size on reperfusion. J Am Heart Assoc. 2012; 31;2(1):e005645.
  • Pasumarthi KBS, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ Res. 2005; 96: 110–118.
  • Pirompol P, Teekabut V, Weerachatyanukul W, Bupha-Intr T, Wattanapermpool J. Supra-physiological dose of testosterone induces pathological cardiac hypertrophy. J Endocrinol. 2016; 229(1):13-23.
  • Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Therap. 2009; 123 (2):255.
  • Price GS, Page RL, Riviere JE, Cline JM, Thrall DE. Effect of whole-body hyperthermia on the pharmacokinetics and toxicity of lonidamine in dogs. Int. J. Hyperth. 1995; 11(4): 531-544.
  • Price GS, Page RL, Riviere JE, Cline JM, Thrall DE. Pharmacokinetics and toxicity of oral and intravenous lonidamine in dogs. Cancer Chemother Pharmacol.,1996; 38(2):129-135.
  • Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. International Journal of Cancer. 2012; 130 (8): 1715–1725.
  • Sengel-Turk CT, Hascicek C. Design of lipid-poymer hybird nanoparticles for therapy of BPH: Part 1. Formulation optimization using a design of experiment approach. Journal of Drug Delivery Science and Technology. 2017; 39: 16-24.
  • Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993; 366 (6456): 704–707.
  • Tashiro E, Maruki H, Minato Y, Doki Y, Weinstein IB, Imoto M. Overexpression of cyclin D1 contributes to malignancy by up-regulation of fibroblast growth factor receptor 1 via the pRB/E2F pathway. Cancer Res. 2003; 15;63(2):424-31.
  • Thum T, Borlak J. Testosterone, cytochrome P450, and cardiac hypertrophy. FASEB J. 2002;.16: 1537-1549.
  • Toma M, McAlister FA, Coglianese EE. Testosterone supplementation in heart failure: a meta-analysis, Circ Heart Fail. 2012; 5: 315–321.
  • Watts KL, Cottrell E, Hoban PR, Spiteri MA. RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications foridiopathic pulmonary fibrosis. Respir Res. 2006; 7:88. 43.
  • Weidner G. Why do men get more heart disease than women? An international perspective. J Am Coll Health. 2000; 48(6):291-294.
  • Wu R, Smeele KM, Wyatt E, Ichikawa Y, Eerbeek O, Sun L, Chawla K, Hollmann MW, Nagpal V, Heikkinen S, Laakso M, Jujo K, Wasserstrom JA, Zuurbier CJ, Ardehali H. Reduction in hexokinase II levels results in decreased cardiac function and altered remodeling after ischemia/reperfusion injury. Circ Res. 2011;108(1):60-69.
  • Xie J, Chen Y, Hu C, Pan Q, Wang B, Li X, Geng J, Xu B. Premature senescence of cardiac fibroblasts and atrial fibrosis in patients with atrial fibrillation. Oncotarget. 2017; 8(35):57981-57990.
  • Yang X, Wang Y, Yan S, Sun L, Yang G, Li Y, Yu C. Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat. Bioengineered. 2017; 2;8(1):14-20.
  • Zhu F, Li Y, Zhang J, Piao C, Liu T, Li HH, Du J. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One. 2013; 8: e74535.
Toplam 42 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Bölüm ARAŞTIRMA MAKALESİ
Yazarlar

Mehmet Eray Alçığır

Ceyda Tuba Şengel Türk

Okan Ekim Bu kişi benim

Canan Hasçiçek

Yayımlanma Tarihi 15 Aralık 2018
Kabul Tarihi 5 Eylül 2018
Yayımlandığı Sayı Yıl 2018 Cilt: 11 Sayı: 4

Kaynak Göster

APA Alçığır, M. E., Şengel Türk, C. T., Ekim, O., Hasçiçek, C. (2018). Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats. Kocatepe Veterinary Journal, 11(4), 402-413. https://doi.org/10.30607/kvj.437999
AMA Alçığır ME, Şengel Türk CT, Ekim O, Hasçiçek C. Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats. kvj. Aralık 2018;11(4):402-413. doi:10.30607/kvj.437999
Chicago Alçığır, Mehmet Eray, Ceyda Tuba Şengel Türk, Okan Ekim, ve Canan Hasçiçek. “Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats”. Kocatepe Veterinary Journal 11, sy. 4 (Aralık 2018): 402-13. https://doi.org/10.30607/kvj.437999.
EndNote Alçığır ME, Şengel Türk CT, Ekim O, Hasçiçek C (01 Aralık 2018) Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats. Kocatepe Veterinary Journal 11 4 402–413.
IEEE M. E. Alçığır, C. T. Şengel Türk, O. Ekim, ve C. Hasçiçek, “Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats”, kvj, c. 11, sy. 4, ss. 402–413, 2018, doi: 10.30607/kvj.437999.
ISNAD Alçığır, Mehmet Eray vd. “Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats”. Kocatepe Veterinary Journal 11/4 (Aralık 2018), 402-413. https://doi.org/10.30607/kvj.437999.
JAMA Alçığır ME, Şengel Türk CT, Ekim O, Hasçiçek C. Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats. kvj. 2018;11:402–413.
MLA Alçığır, Mehmet Eray vd. “Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats”. Kocatepe Veterinary Journal, c. 11, sy. 4, 2018, ss. 402-13, doi:10.30607/kvj.437999.
Vancouver Alçığır ME, Şengel Türk CT, Ekim O, Hasçiçek C. Effects of Lonidamine-Loaded Lipid-Polymer Hybrid Nanoparticles on Cardiac Fibrosis Induced By High-Dose Testosterone Propionate In Adult and Neutered Male Rats. kvj. 2018;11(4):402-13.

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