Background:Busulfan(BU)is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell(HSC)transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells.The suscep...Background:Busulfan(BU)is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell(HSC)transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells.The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU.Different susceptibilities were demonstrated in genetically diverse(GD)mice in our preliminary research.Methods:Three strains of GD mice with different susceptibilities to BU-i nduced HSC injury were used for screening biological markers of HSC injury susceptibility in urine.The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins.Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme-l inked immunoassay(ELISA).Results:Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence,apoptosis,and angiogenesis;whereas the differential proteins of the high-susceptible strain were enriched for the regulation of bone marrow microenvironment pathways,those of low-susceptible strain were enriched for the proapoptotic effect of GTPase pathways.Based on protein abundance differences,several urinary proteins that may be indicative of susceptibility were screened,and ELISA validation results showed that angiotensin-converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning.Conclusions:This study indicates that urinary protein levels can reflect differences in susceptibility to BU-i nduced HSC injury.Using GD mice to construct genetic difference models will provide preclinical data for screening BU-related biological markers.展开更多
Successful spermatogonial transplantation requires depletion of the host germ cells to allow efficient colonization of the donor spermatogonial stem cells. Although a sterilizing drug,busulfan （Myleran）,is commonly ...Successful spermatogonial transplantation requires depletion of the host germ cells to allow efficient colonization of the donor spermatogonial stem cells. Although a sterilizing drug,busulfan （Myleran）,is commonly used for preparing a recipient mouse before transplantation,the optimal dose of this drug has not yet been defined.The present study investigated the effects of different doses of busulfan （10-50 mg per kg body weight） on survival rate,testicular mass and histomorphology,and on the haploid spermatids and spermatozoa of male BALB/c mice.The results suggest that a dosage of 30 mg kg^-1 is optimal for the ablative treatment withbusulfan used to prepare the recipient mice. This dose results in an adequate depletion of the host germ cells for colonization of donorderived spermatogonial stem cells and causes the lowest death rate of the animals.展开更多
Aim: This study was designed to investigate the effect of busulfan treatment on the proliferation of chicken primordialgerm cells (PGCs) in vivo, focusing on the preferential settlement of PGCs onto the germinal ridge...Aim: This study was designed to investigate the effect of busulfan treatment on the proliferation of chicken primordialgerm cells (PGCs) in vivo, focusing on the preferential settlement of PGCs onto the germinal ridges of chicken em-bryos. Methods: Busulfan (250 ng/egg) was injected into the egg white of freshly oviposited fertilized eggs, whichwere then incubated. Embryonic development and viability were examined, and exogenous PGCs collected from embry-onic blood vessels were injected into the germinal crescent region of recipient embryos. The number of PGCs residedonto germinal ridges of the right and left sides were compared. Results: Busulfan had a slight harmful effect on theembryo viability and the PGCs proliferation. The number of PGCs resided onto the left side of germinal ridges wasslightly higher as compared with the right side. Conclusion: Busulfan suppressed the viability of embryos and the pro-liferation of endogenous PGCs in the recipient embryos. However, the number of exogenous PGCs proliferated washigher in embryos treated with busulfan than those without busulfan. Data also suggest the possibility of a preferentialresidence of PGCs toward the left side of the germinal crescent region as compared with the fight, which may be due toa more advanced functional development of the left gonad than the right. (Asian J Androl 1999 Dec; 1: 187-190)展开更多
Testicular damage is one of the most hazardous effects as it’s associated with azoospermia.Busulfan(Bu)is a highly toxic chemotherapeutic drug that affects testis.Thirty male Swiss albino mice divided into six groups...Testicular damage is one of the most hazardous effects as it’s associated with azoospermia.Busulfan(Bu)is a highly toxic chemotherapeutic drug that affects testis.Thirty male Swiss albino mice divided into six groups of 5 animals each.Control(oral 0.9%saline daily for 75 days);Mel(20 mg/kg/day orally for 30 days);ZnO NPs(5 mg/kg/day i.p.for 30 days);BU(single i.p.injection of 40 mg/kg and then left for 45 days);BU+Mel(single 40 mg/kg dose of BU and left for 45 days followed by 20 mg/kg/day Mel for 30 days);BU+ZnO NPs(single dose of 40 mg/kg of BU and left for 45 days,then 5 mg/kg/day ZnO NPs for 30 days).Preparation and Characterization of ZnO NPs.Specimens from testis prepared for ultrastructural investigations using TEM after Masson’s trichrome and toluidine blue staining.BU induced histological and ultrastructural damage of the testis.Moreover,the present results could be concluded that Mel or ZnO NPs can protect the testicular tissue against ultrastructural alterations induced by BU by its antioxidant and anti-apoptotic effects.展开更多
Objective:To evaluate the protective effects of honey compound syrup on sperm count and testis tissue in rats.Methods:Thirty rats were randomly assigned to five groups.The control group received 1 mL normal saline wit...Objective:To evaluate the protective effects of honey compound syrup on sperm count and testis tissue in rats.Methods:Thirty rats were randomly assigned to five groups.The control group received 1 mL normal saline with dimethyl sulfoxide intraperitoneally;the busulfan group received busulfan 10 mg/kg body weight at the first and twenty-first days of the experiment via intraperitoneal injection;the last three groups received busulfan 10 mg/kg body weight to induce azoospermia,and then received 1.0,1.5,or 2.0 mg/kg honey compound syrup,respectively,after induction of azoospermia.After administration,the testis and epididymis of all rats were removed.Then,reproductive organ weight and sperm parameters(sperm concentration,epididymal sperm reserve and daily sperm production)were measured.After hematoxylin-eosin staining,seminiferous tubule cells and diameters were assessed.Results:Busulfan damaged the testis tissue and impaired spermatogenesis.Administration of honey compound syrup in three doses improved testis tissue and spermatogenesis.The protective effects of honey compound syrup may relate to the antioxidant properties of honey and other compounds in this syrup.Conclusions:Administration of honey compound syrup could be an ameliorative agent for the side effects of chemotherapy drugs such as busulfan on the male reproductive system.展开更多
The optimal stem cell transplantation (SCT) conditioning therapy for relapsed/refractory non-Hodgkin lymphoma (NHL) is not clearly defined. In a retrospective analysis, we examined 25 patients with “high risk” relap...The optimal stem cell transplantation (SCT) conditioning therapy for relapsed/refractory non-Hodgkin lymphoma (NHL) is not clearly defined. In a retrospective analysis, we examined 25 patients with “high risk” relapsed/refractory NHL who received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP16) conditioning with autologous or allogeneic SCT. The majority of patients had aggressive histology and 52% had primary refractory NHL. Furthermore, 48% of patients had chemotherapy-resistant disease at the time of SCT. Fifty-six percent of patients underwent allogeneic SCT, while 44% had autologous SCT. The median engraftment time for neutrophils and platelets was 13.5 and 14 days, respectively. The 100-day treatment-related mortality (TRM) was 16%, while the 2-year non-relapse mortality (NRM) rate was also 16%. At a median follow-up of 15 months, the estimated 2-year disease-free survival (DFS) rate was 64% (95% confidence interval (CI): 36%-82%) and the estimated 2-year overall survival (OS) was 69% (95% CI: 40%-86%). Furthermore, the 2-year disease-specific survival (DSS) rate was 73% (95% CI: 40%-90%). Using Cox proportional hazard modeling, the International Prognostic Index at time of relapse predicted DFS and OS. Altogether, Bu/Cy/VP16 was associated with early TRM;however, late toxicities (including NRM) were uncommon resulting in relatively good survival rates in a high-risk relapsed/refractory NHL population.展开更多
An ideal animal model of azoospermia would be a powerful tool for the evaluation of spermatogonial stem cell(SSC)transplantation.Busulfan has been commonly used to develop such a model,but 30%–87%of mice die when adm...An ideal animal model of azoospermia would be a powerful tool for the evaluation of spermatogonial stem cell(SSC)transplantation.Busulfan has been commonly used to develop such a model,but 30%–87%of mice die when administered an intraperitoneal injection of 40 mg kg^?1.In the present study,hematoxylin and eosin staining,Western blot,immunofluorescence,and quantitative real-time polymerase chain reaction were used to test the effects of busulfan exposure in a mouse model that received two intraperitoneal injections of busulfan at a 3-h interval at different doses(20,30,and 40 mg kg^?1)on day 36 or a dose of 40 mg kg^?1 at different time points(0,9,18,27,36,and 63 days).The survival rate of the mice was 100%.When the mice were treated with 40 mg kg^?1 busulfan,dramatic SSC depletion occurred 18 days later and all of the germ cells were cleared by day 36.In addition,the gene expressions of glial cell line-derived neurotrophic factor(GDNF),fibroblast growth factor 2(FGF2),chemokine(C-X-C Motif)ligand 12(CXCL12),and colony-stimulating factor 1(CSF1)were moderately increased by day 36.A 63-day,long-term observation showed the rare restoration of endogenous germ cells in the testes,suggesting that the potential period for SSC transplantation was between day 36 and day 63.Our results demonstrate that the administration of two intraperitoneal injections of busulfan(40 mg kg^?1 in total)at a 3-h interval to mice provided a nonlethal and efficient method for recipient preparation in SSC transplantation and could improve treatments for infertility and the understanding of chemotherapy-induced gonadotoxicity.展开更多
Busulfan/cyclophosphamide(Bu/Cy) conditioning regimen has been widely used to treat cancer patients,while their effects on major internal organs in females are not fully understood.We treated female mice with Bu/Cy,an...Busulfan/cyclophosphamide(Bu/Cy) conditioning regimen has been widely used to treat cancer patients,while their effects on major internal organs in females are not fully understood.We treated female mice with Bu/Cy,and examined the histopathology of major internal organs on Day 30 after the treatment.The results show that Bu/Cy treatment affected the ovaries most extensively,while it had less effect on the spleen,lungs,and kidneys,and no effect on the heart,liver,stomach,and pancreas.To better understand the effect of Bu/Cy on the ovaries,we counted follicles,and determined the levels of ovarian steroids.The Bu/Cy-treated mice showed a reduction of primordial and primary follicles(P<0.01) on Day 30 and a marked loss of follicles at all developmental stages(P<0.01) on Day 60.Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%,respectively.Thus,there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice;this is a profile similar to what is found in women with premature ovarian failure(POF).The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.展开更多
Objective To compare the efficacy,response and survival between high-dose melphalan(HDM)and cyclophosphamide+etoposide+busulfan(CVB)as the conditioning regimen in autologous stem cell transplantation(ASCT)for newly di...Objective To compare the efficacy,response and survival between high-dose melphalan(HDM)and cyclophosphamide+etoposide+busulfan(CVB)as the conditioning regimen in autologous stem cell transplantation(ASCT)for newly diagnosed multiple myeloma(NDMM).Methods 123 consecutive NDMM patients who had received PAD induction with subsequent ASCT from Jan 2011 to Aug 2017 were retrospectively studied.The CVB group and HDM group had 82 and 41 patients respectively.Results①No differences existed between these 2 groups in non-hematological side effects.展开更多
基金National Natural Scientific Foundation of ChinaGrant/Award Number:81972975+2 种基金National Human Diseases Animal Model Resource CenterNational Science Foundation for Young Scientists of ChinaGrant/Award Number:81703170。
文摘Background:Busulfan(BU)is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell(HSC)transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells.The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU.Different susceptibilities were demonstrated in genetically diverse(GD)mice in our preliminary research.Methods:Three strains of GD mice with different susceptibilities to BU-i nduced HSC injury were used for screening biological markers of HSC injury susceptibility in urine.The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins.Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme-l inked immunoassay(ELISA).Results:Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence,apoptosis,and angiogenesis;whereas the differential proteins of the high-susceptible strain were enriched for the regulation of bone marrow microenvironment pathways,those of low-susceptible strain were enriched for the proapoptotic effect of GTPase pathways.Based on protein abundance differences,several urinary proteins that may be indicative of susceptibility were screened,and ELISA validation results showed that angiotensin-converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning.Conclusions:This study indicates that urinary protein levels can reflect differences in susceptibility to BU-i nduced HSC injury.Using GD mice to construct genetic difference models will provide preclinical data for screening BU-related biological markers.
文摘Successful spermatogonial transplantation requires depletion of the host germ cells to allow efficient colonization of the donor spermatogonial stem cells. Although a sterilizing drug,busulfan （Myleran）,is commonly used for preparing a recipient mouse before transplantation,the optimal dose of this drug has not yet been defined.The present study investigated the effects of different doses of busulfan （10-50 mg per kg body weight） on survival rate,testicular mass and histomorphology,and on the haploid spermatids and spermatozoa of male BALB/c mice.The results suggest that a dosage of 30 mg kg^-1 is optimal for the ablative treatment withbusulfan used to prepare the recipient mice. This dose results in an adequate depletion of the host germ cells for colonization of donorderived spermatogonial stem cells and causes the lowest death rate of the animals.
文摘Aim: This study was designed to investigate the effect of busulfan treatment on the proliferation of chicken primordialgerm cells (PGCs) in vivo, focusing on the preferential settlement of PGCs onto the germinal ridges of chicken em-bryos. Methods: Busulfan (250 ng/egg) was injected into the egg white of freshly oviposited fertilized eggs, whichwere then incubated. Embryonic development and viability were examined, and exogenous PGCs collected from embry-onic blood vessels were injected into the germinal crescent region of recipient embryos. The number of PGCs residedonto germinal ridges of the right and left sides were compared. Results: Busulfan had a slight harmful effect on theembryo viability and the PGCs proliferation. The number of PGCs resided onto the left side of germinal ridges wasslightly higher as compared with the right side. Conclusion: Busulfan suppressed the viability of embryos and the pro-liferation of endogenous PGCs in the recipient embryos. However, the number of exogenous PGCs proliferated washigher in embryos treated with busulfan than those without busulfan. Data also suggest the possibility of a preferentialresidence of PGCs toward the left side of the germinal crescent region as compared with the fight, which may be due toa more advanced functional development of the left gonad than the right. (Asian J Androl 1999 Dec; 1: 187-190)
基金This study was funded by Taif University Researchers Supporting Project No.TURSP-2020/222,Taif University,Taif,Saudi Arabia.
文摘Testicular damage is one of the most hazardous effects as it’s associated with azoospermia.Busulfan(Bu)is a highly toxic chemotherapeutic drug that affects testis.Thirty male Swiss albino mice divided into six groups of 5 animals each.Control(oral 0.9%saline daily for 75 days);Mel(20 mg/kg/day orally for 30 days);ZnO NPs(5 mg/kg/day i.p.for 30 days);BU(single i.p.injection of 40 mg/kg and then left for 45 days);BU+Mel(single 40 mg/kg dose of BU and left for 45 days followed by 20 mg/kg/day Mel for 30 days);BU+ZnO NPs(single dose of 40 mg/kg of BU and left for 45 days,then 5 mg/kg/day ZnO NPs for 30 days).Preparation and Characterization of ZnO NPs.Specimens from testis prepared for ultrastructural investigations using TEM after Masson’s trichrome and toluidine blue staining.BU induced histological and ultrastructural damage of the testis.Moreover,the present results could be concluded that Mel or ZnO NPs can protect the testicular tissue against ultrastructural alterations induced by BU by its antioxidant and anti-apoptotic effects.
基金This study was supported by Shahid Beheshti University of Medical Sciences(grant number:184)。
文摘Objective:To evaluate the protective effects of honey compound syrup on sperm count and testis tissue in rats.Methods:Thirty rats were randomly assigned to five groups.The control group received 1 mL normal saline with dimethyl sulfoxide intraperitoneally;the busulfan group received busulfan 10 mg/kg body weight at the first and twenty-first days of the experiment via intraperitoneal injection;the last three groups received busulfan 10 mg/kg body weight to induce azoospermia,and then received 1.0,1.5,or 2.0 mg/kg honey compound syrup,respectively,after induction of azoospermia.After administration,the testis and epididymis of all rats were removed.Then,reproductive organ weight and sperm parameters(sperm concentration,epididymal sperm reserve and daily sperm production)were measured.After hematoxylin-eosin staining,seminiferous tubule cells and diameters were assessed.Results:Busulfan damaged the testis tissue and impaired spermatogenesis.Administration of honey compound syrup in three doses improved testis tissue and spermatogenesis.The protective effects of honey compound syrup may relate to the antioxidant properties of honey and other compounds in this syrup.Conclusions:Administration of honey compound syrup could be an ameliorative agent for the side effects of chemotherapy drugs such as busulfan on the male reproductive system.
文摘The optimal stem cell transplantation (SCT) conditioning therapy for relapsed/refractory non-Hodgkin lymphoma (NHL) is not clearly defined. In a retrospective analysis, we examined 25 patients with “high risk” relapsed/refractory NHL who received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP16) conditioning with autologous or allogeneic SCT. The majority of patients had aggressive histology and 52% had primary refractory NHL. Furthermore, 48% of patients had chemotherapy-resistant disease at the time of SCT. Fifty-six percent of patients underwent allogeneic SCT, while 44% had autologous SCT. The median engraftment time for neutrophils and platelets was 13.5 and 14 days, respectively. The 100-day treatment-related mortality (TRM) was 16%, while the 2-year non-relapse mortality (NRM) rate was also 16%. At a median follow-up of 15 months, the estimated 2-year disease-free survival (DFS) rate was 64% (95% confidence interval (CI): 36%-82%) and the estimated 2-year overall survival (OS) was 69% (95% CI: 40%-86%). Furthermore, the 2-year disease-specific survival (DSS) rate was 73% (95% CI: 40%-90%). Using Cox proportional hazard modeling, the International Prognostic Index at time of relapse predicted DFS and OS. Altogether, Bu/Cy/VP16 was associated with early TRM;however, late toxicities (including NRM) were uncommon resulting in relatively good survival rates in a high-risk relapsed/refractory NHL population.
基金This study was supported by the National Natural Science Foundation of China(No.81571489,No.81671834,No.81671449 and No.81871110)the Frontier and Key Technology Innovation Special Foundation of Guangdong Province,China(No.2016B030230001)+3 种基金the Natural Science Foundation of Guangdong Province,China(No.2014A030310359,No.2016A030313229 and No.2015A030313013)the Science and Technology Planning Project of Guangdong Province,China(No.2016A020214004)the Health Care Collaborative Innovation Foundation Major Projects of Guangzhou City,Guangdong Province,China(No.201604020189)the Youth Teacher Training Project of Sun Yat-sen University(No.17ykpy68 and No.18ykpy09).
文摘An ideal animal model of azoospermia would be a powerful tool for the evaluation of spermatogonial stem cell(SSC)transplantation.Busulfan has been commonly used to develop such a model,but 30%–87%of mice die when administered an intraperitoneal injection of 40 mg kg^?1.In the present study,hematoxylin and eosin staining,Western blot,immunofluorescence,and quantitative real-time polymerase chain reaction were used to test the effects of busulfan exposure in a mouse model that received two intraperitoneal injections of busulfan at a 3-h interval at different doses(20,30,and 40 mg kg^?1)on day 36 or a dose of 40 mg kg^?1 at different time points(0,9,18,27,36,and 63 days).The survival rate of the mice was 100%.When the mice were treated with 40 mg kg^?1 busulfan,dramatic SSC depletion occurred 18 days later and all of the germ cells were cleared by day 36.In addition,the gene expressions of glial cell line-derived neurotrophic factor(GDNF),fibroblast growth factor 2(FGF2),chemokine(C-X-C Motif)ligand 12(CXCL12),and colony-stimulating factor 1(CSF1)were moderately increased by day 36.A 63-day,long-term observation showed the rare restoration of endogenous germ cells in the testes,suggesting that the potential period for SSC transplantation was between day 36 and day 63.Our results demonstrate that the administration of two intraperitoneal injections of busulfan(40 mg kg^?1 in total)at a 3-h interval to mice provided a nonlethal and efficient method for recipient preparation in SSC transplantation and could improve treatments for infertility and the understanding of chemotherapy-induced gonadotoxicity.
基金Project(No.2010CB945002) supported by the National Basic Research Program(973) of China
文摘Busulfan/cyclophosphamide(Bu/Cy) conditioning regimen has been widely used to treat cancer patients,while their effects on major internal organs in females are not fully understood.We treated female mice with Bu/Cy,and examined the histopathology of major internal organs on Day 30 after the treatment.The results show that Bu/Cy treatment affected the ovaries most extensively,while it had less effect on the spleen,lungs,and kidneys,and no effect on the heart,liver,stomach,and pancreas.To better understand the effect of Bu/Cy on the ovaries,we counted follicles,and determined the levels of ovarian steroids.The Bu/Cy-treated mice showed a reduction of primordial and primary follicles(P<0.01) on Day 30 and a marked loss of follicles at all developmental stages(P<0.01) on Day 60.Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%,respectively.Thus,there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice;this is a profile similar to what is found in women with premature ovarian failure(POF).The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.
文摘Objective To compare the efficacy,response and survival between high-dose melphalan(HDM)and cyclophosphamide+etoposide+busulfan(CVB)as the conditioning regimen in autologous stem cell transplantation(ASCT)for newly diagnosed multiple myeloma(NDMM).Methods 123 consecutive NDMM patients who had received PAD induction with subsequent ASCT from Jan 2011 to Aug 2017 were retrospectively studied.The CVB group and HDM group had 82 and 41 patients respectively.Results①No differences existed between these 2 groups in non-hematological side effects.
文摘为了获取生殖细胞移植的不育受体,本研究使用白消安(1,4-丁二醇二甲磺酸酯)对二龄半红鳍东方鲀(Takifugu rubripes)进行处理,使用40 mg/kg白消安注射处理两次后,进行了对照组、注射组的性腺取样和转录组测序,分析了白消安的处理效果和白消安对性腺基因表达的影响。研究表明:40 mg/kg白消安其对精巢的处理效果显著,生精小管中的生殖细胞大量减少;对卵巢的处理效果不佳,实验组与对照组的卵巢在组织形态上无显著差异。性腺转录组的分析结果显示,与注射二甲基亚砜(Dimethyl sulfoxide,DMSO)溶剂的对照组相比,经过白消安处理后,精巢组中获得差异表达基因576个,卵巢组中获得差异表达基因74个,白消安处理对精巢基因的转录水平影响更大。差异表达基因的GO(Gene Ontology)富集分析显示,氧化还原酶活性、单加氧酶活性、双加氧酶活性等氧化代谢相关条目被显著富集;KEGG(Kyoto Encyclopedia of Genes and Genomes)富集分析显示,氧化磷酸化、核苷酸切除修复、范可尼贫血、同源重组、DNA复制和错配修复等通路被显著富集。GSEA(Gene set enrichment analysis)结果显示,错配修复、范可尼贫血、同源重组等通路被上调,DNA复制和核苷酸切除修复通路下调。研究结果表明,白消安处理导致了雄性受体的内源生殖细胞数量减少,并使精巢处于DNA损伤和氧化应激的状态。不同性腺组织对白消安的不同反应可能与其细胞类型对氧化应激和DNA损伤的抵抗有关。
