Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows...Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.展开更多
BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against o...BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against oxidative stress and inflammation.AIM To investigate the hepatoprotective effects of ABX against CP-induced liver injury,focusing on oxidative stress,inflammation,and the possible role of cytoglobin,thioredoxin reductase 1(TXNRD1)and high-mobility group box 1(HMGB1).METHODS ABX(20 mg/kg)was orally administered for 7 days,and the rats received a single injection of CP(100 mg/kg)on day 5.Blood and liver samples were collected for analyses,and the affinity of ABX towards cytoglobin,TXNRD1,and HMGB1 was evaluated using molecular docking.RESULTS CP administration significantly elevated alanine aminotransferase,aspartate aminotransferase,and alkaline phosphatase,reduced albumin,and caused multiple histopathological alterations in the liver.ABX effectively restored liver function biomarkers and attenuated histopathological alterations.CP-induced oxidative stress was evidenced by increased malondialdehyde and decreased glutathione and antioxidant enzyme activities,all of which were ameliorated by ABX.CP upregulated toll-like receptor 4(TLR-4),nuclear factor-kappaB(NF-κB)p65 and pro-inflammatory cytokines,while downregulating cytoglobin,TXNRD1 and HMGB1.ABX suppressed TLR-4/NF-κB signaling and pro-inflammatory cytokines,and upregulated cytoglobin,TXNRD1 and HMGB1.In silico molecular docking revealed the affinity of ABX to bind with cytoglobin,TXNRD1,and HMGB1.CONCLUSION ABX protects against CP hepatotoxicity by mitigating oxidative stress,suppressing TLR-4/NF-κB signaling,and upregulating cytoglobin,TXNRD1 and HMGB1.ABX showed binding affinity towards cytoglobin,TXNRD1 and HMGB1.These findings suggest that ABX has therapeutic potential in alleviating hepatotoxicity associated with CP treatment.展开更多
OBJECTIVES:To investigate the therapeutic effect of Huluan decotion(护卵汤,HLD)on cyclophosphamideinduced premature ovarian failure(POF)in mice and its regulatory mechanisms.METHODS:Female BALB/c mice were administere...OBJECTIVES:To investigate the therapeutic effect of Huluan decotion(护卵汤,HLD)on cyclophosphamideinduced premature ovarian failure(POF)in mice and its regulatory mechanisms.METHODS:Female BALB/c mice were administered cyclophosphamide and administered received different doses of HLD for 28 d.Levels of sex hormone,such as estradiol(E2),follicle stimulating hormone(FSH)and luteinizing hormone(LH)in the sera,were assessed using enzyme-linked immunosorbent assay(ELISA).Follicular structure variances were observed through hematoxylin and eosin(HE)staining,while Forkhead box L2(FOXL2)expression were analyzed via immuneohistochemical staining.The primary mechanism of POF were investigated through Western blot analysis.RESULTS:E2 levels decreased,and FSH and LH levels increased in POF model mice,but these trends were reversed with HLD or premarin administration,the expressions of WNT family member 4(Wnt4),β-Catenin and FOXL2 were downregulated in POF model mice,whereas high expression levels were observed in control mice and other groups.CONCLUSION:HLD effectively treats POF induced with cyclophosphamide in mice by enhancing expressions of Wnt4,β-Catenin and FOXL2.展开更多
Objective Overactive bladder,a storage syndrome characterized by urinary urgency,frequency,and nocturia with or without urgency urinary incontinence,severely affects the quality of life of patients.The aim of this stu...Objective Overactive bladder,a storage syndrome characterized by urinary urgency,frequency,and nocturia with or without urgency urinary incontinence,severely affects the quality of life of patients.The aim of this study was to investigate the role and mechanism of the C/EBP homologous protein in the overactive bladder.Methods An overactive bladder mouse model was established via the intraperitoneal injection of cyclophosphamide in wild-type and Chop-deficient mice.An in vitro model was established using interleukin(IL)-6-induced mouse bladder epithelial cells.Hematoxylin–eosin(HE)staining was used to assess bladder tissue damage,and ELISA was used to measure inflammatory cytokine levels.Western blot analysis was used to examine p-PERK,ATF-6,p-eIF2α,BiP,ATF-4,Bax,Bcl-2,and cleaved caspase-3 protein expression levels.TUNEL staining and flow cytometry were conducted to measure the degree of apoptosis in bladder epithelial cells and macrophages.Results C/EBP homologous protein levels were decreased in overactive bladder tissues;nevertheless,macrophage infiltration was found to be increased.Knockout of Chop exacerbated bladder dysfunction,tissue injury,macrophage infiltration,and bladder epithelial apoptosis and alleviated endoplasmic reticulum stress.Conclusions Chop deficiency exacerbates inflammation,injury,and bladder epithelial apoptosis in overactive bladder model mice by inhibiting endoplasmic reticulum stress.展开更多
Objective:To study the antioxidant protective effect and mechanism of melatonin on cyclophosphamide-induced premature ovarian failure model mice.Methods:Six-month sexually mature female Kunming mice were taken for one...Objective:To study the antioxidant protective effect and mechanism of melatonin on cyclophosphamide-induced premature ovarian failure model mice.Methods:Six-month sexually mature female Kunming mice were taken for one week of acclimatization and then randomly divided into a normal group,blank control group,drug control group,ovarian premature aging model group,and melatonin intervention low,medium,and high dose group,with 20 mice in each group.We observed the status and body mass of the mice in each group;observed and monitored the estrous cycle by HE staining;measured the diameter and size of the ovaries and weighed the wet weight of the ovaries;observed the morphological changes of the ovaries by HE staining and counted the developing follicles at all levels;detected the levels of serum estradiol(E2),follicle-stimulating hormone(FSH),and luteinizing hormone(LH)by ELISA;measured the levels of serum MDA,SOD,and GSH-PX by antioxidant kit;detected the levels of protein immunoblotting by ELISA;protein immunoblotting(Western blot)to examine the expression of DNA damage-related proteinsγH2AX,p53,and p21 in ovarian tissues.Results:Compared with the control group,mice in the premature ovarian failure model group showed reduced mobility,rough hair,decreased body weight,disorganized estrous cycle,decreased ovarian weight(P<0.05),decreased number of follicles at all levels of development(P<0.05),increased number of atretic follicles(P<0.05),significantly elevated levels of serum FSH and LH,significantly decreased levels of E2(P<0.05),significantly increased levels of serum MDA,significantly lower SOD and GSH-PX levels(P<0.05),and the expression of p53,p21,andγH2AX in ovarian tissues was increased(P<0.05).Compared with the model group of premature ovarian failure,melatonin improved the changes of the above indexes induced by cyclophosphamide-induced premature ovarian failure in mice.Conclusion:Melatonin can improve the changes of motility cycle disorders,abnormal follicular development,and abnormal serum hormone levels induced by cyclophosphamide-induced oxidative stress in mice with premature ovarian failure.At the same time,melatonin can improve the oxidative stress induced by cyclophosphamide and alleviate the role of oxidative stress-induced DNA damage in mouse ovaries by exerting its antioxidant effect.展开更多
Background:Allogeneic peripheral-blood stem-cell transplantation(SCT)from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers.The comb...Background:Allogeneic peripheral-blood stem-cell transplantation(SCT)from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers.The combination of a calcineurin inhibitor and an antimetabolite remains standard care for graft-versus-host disease(GVHD)prophylaxis in these patients.Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite.展开更多
An experiment was conducted to compare the effects of two mouse thrombocytopenia models induced by cyclophosphamide at two different administration routes to determine a proper cyclophosphamide administration route th...An experiment was conducted to compare the effects of two mouse thrombocytopenia models induced by cyclophosphamide at two different administration routes to determine a proper cyclophosphamide administration route that could cause stable thrombocytopenia. A suitable drug dosage that could induce thrombocytopenia in mouse efficiently with the definite administration route was then investigated. BALB/c mice were randomly divided into Normal, Model A and Model B groups. To Model A, 200 mg/kg of cyclophosphamide was given by vena caudalis injection as first dose and 30 mg/kg as maintenance dose by intraperitoneal injection at the following 6 days. To Model B, 150 mg/kg of cyclophosphamide was given by subcutaneous injection once a day for consecutive 3 days. All groups were under investigation for 15 days. The result suggested that a decrease in the number of blood platelets of Model B at the 7th day were significantly than that of Normal. Other platelet related indices like platelet distribution width, mean platelet volume and platelet-large cell ratio of Model B increased significantly in comparison with those of Normal group. The platelets count was reduced but fluctuated greatly, and more than half of the mice died in Model A. Therefore, subcutaneous injection of cyclophosphamide for 3 days was used for the cyclophosphamide dosage test. BALB/c mice were randomly divided into Normal, cyclophosphamide low dose （100 mg/kg）, medium dose （120 mg/kg） and high dose （140 mg/kg） groups. All groups were under investigation for 11 days. Though all 3 dosages successfully initiated thrombocytopenia as the platelets number dropped at the 7th day, the low dose was considered to be a suitable one that was of high efficacy and low toxicity. Thus, BALB/c mice challenged by subcutaneous injection of cyclophosphamide 100 mg/kg per day for 3 consecutive day is one simple, feasible and stable mouse thrombocytopenia model that could be used for pharmacodynamic test of the drugs which are supposed to have platelets increasing effect.展开更多
A rapid and simple liquid chromatography method with on-line solid phase extraction was developed and validated for the quantitative determination of cyclophosphamide in rat plasma.The plasma sample was first extracte...A rapid and simple liquid chromatography method with on-line solid phase extraction was developed and validated for the quantitative determination of cyclophosphamide in rat plasma.The plasma sample was first extracted on an Acclaim？ Polar Advantage II C18 guard column（PA II C18,10 mm×4.6 mm,5 μm）,which was also the on-line Extraction Cartridge SPE column,by washing with 100% H2O for 1 min.The extracted sample was then eluted onto a PA II C18 column（150 mm×4.6 mm,5 μm） and separated by isocratic elution with acetonitrile-water（40：60,v/v）.The mobile phase was run at a flow rate of 1.0 mL/min,and the UV detector was set at 195 nm.Retention time of cyclophosphamide was 4.3 min and the total run-time was 6 min.The linear range of the standard curve was from 1.0 to 200 μg/mL（r2 = 0.9999）,and the limits of quantification and detection were 1.0 μg/mL（RSD10%,n = 5） and 0.3 μg/mL（RSD13%,n = 5）,respectively.Both intra-and inter-day variations were less than 5.6%.The developed method can be used for the therapeutic drug monitoring of cyclophosphamide in the clinic.展开更多
Hematological toxicity （bone marrow suppression） is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 （Nrf2） is a pivotal coordinator of cellular defen...Hematological toxicity （bone marrow suppression） is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 （Nrf2） is a pivotal coordinator of cellular defensive responses against chemical insults in many tissues including bone marrow. In the present study, the effects of tert-butylhydroquinone （tBHQ） on the expression of Nrf2-regulated genes in peripheral blood cells and cyclophosphamide （CTX）-induced hematotoxicity in mice were investigated. CTX induced apoptosis of peripheral blood nucleated cells and leukopenia in mice, accompanied by mobilization of bone marrow hematopoietic cells, tBHQ treatment induced the expression of Nrf2-regulated genes such as heine oxygenase 1 （HO1） and glutamate-cysteine ligase catalytic subtmit （GCLC） in RAW264.7 mouse macrophage cells and peripheral blood cells both in vitro and in vivo. Interestingly, pretreatment with tBHQ alleviated CTX-induced mouse peripheral blood cell apoptosis and leukopenia in vivo, indicating possible involvement of Nrf2 in the protection against CTX-induced hematotoxicity. This study provides new information on the chemotherapy-induced hematotoxicity, and suggests Nrf2 could serve as a target for the development of chemoprotectants against hematotoxicity.展开更多
The protective effect of a kind of purified polysaccharides extracted from Radix of Phytolacca acinosa Roxb,with a molecular weight of 10 KDa,on hematopoiesis was investigated.Average survival time of mice treated wit...The protective effect of a kind of purified polysaccharides extracted from Radix of Phytolacca acinosa Roxb,with a molecular weight of 10 KDa,on hematopoiesis was investigated.Average survival time of mice treated with cyclophosphamide (CY) 300 mg/kg once alone was 13.3 ± 7.2d(n=7) however,average survival time of mice treated with CY 300 mg/kg in com-bination with PAP-1 10 mg/kg,3 times/wk was 36.7± 16.4d(n=7,P<0.01).PAP-1,ip had benefi-cial effect on the recovery of the CY induced decrease of peripheral leukocyte number,and the nu-cleated bone marrow cell(BMC)number and[3￣H]TdR uptaken by BMC induced by rmGM-CSF in S180 bearing mice treated with CY,In mice,after the first ip treatment with CY 100 mg/kg on d7,the peripheral leukocyte number decreased on d9 and recovered to normal level about d13 to d15. Such recovery was accelerated by administrating PAP-1,10mg/kg, 3 times/wk.A significant in-crease of the activity to form colony in spleen(colony-forming unit in spleen, CFU-S_8, CUF-S12) in mice irradiated with 550 rad 6O￣Co γ-rays and an enhancement of proliferative response of BMC to rmGM-CSF treated with PAP-1,10mg/kg,3 times/wk, ip were observed.After PAP-1,10 mg/kg,ip once,a significant increase in the number of peripheral blood leukocytes and a rise in the serum of colony stimulating factor(CSF) were also confirmed.The types of CSF in serum were M-CSF and other hematopoietic growth factors,which were confirmed by using McAb of IL-3, GM-CSF and PcAb of M-CSF. These beneficial effects of PAP-1 on hematopoiesis may be related to its activityinducing CSFs and other hematopoietic growth factors and warrant further evaluation of its use-fulness.展开更多
OBJECTIVE To investigate the damage effect and mechanisms of cyclophosphamide(CTX)and its active metabolite derivative 4-hydroperoxycyclophosphamide(4-HC)to human neuroblas⁃toma SH-SY5Y cells.METHODS SH-SY5Y cells wer...OBJECTIVE To investigate the damage effect and mechanisms of cyclophosphamide(CTX)and its active metabolite derivative 4-hydroperoxycyclophosphamide(4-HC)to human neuroblas⁃toma SH-SY5Y cells.METHODS SH-SY5Y cells were treated with CTX[0(cell control),0.01,0.1,1,5,10,20,40 and 80 mmol·L^(-1)]and 4-HC[0(cell control),0.01,0.1,1,5,10,20,40 and 80μmol·L^(-1)]for 48 h.Cell confluence and morphology were observed by the IncuCyte ZOOM system.Cell viability was assessed by CCK-8 assay.Lactate dehydrogenase(LDH)release was measured by LDH assay kit.SH-SY5Y cells were treated with CTX(0,1,5,10 and 20 mmol·L^(-1))and 4-HC(0,1,5,10 and 20μmol·L^(-1))for 48 h before cell proliferation was analyzed by 5-ethynyl-2′-deoxyuridine(EdU)staining assay.Immunofluorescence was employed to assess the levels of the DNA double-strand break markerγ-H2AX and to evaluate changes in mitochondrial membrane potential.SH-SY5Y cells were treated with CTX(0,1,5 and 10 mmol·L^(-1))and 4-HC(0,1,5 and 10μmol·L^(-1))for 48 h,and the alterations in glycolysis and oxidative phosphorylation levels were analyzed using the Seahorse XFe96 Analyzer.RESULTS Compared with the cell control group,cell confluence and cell viability were significantly reduced in the CTX and 4-HC groups(P<0.01),and the half-maximal inhibitory concentrations(IC50)for CTX and 4-HC were 4.44 mmol·L^(-1) and 4.78μmol·L^(-1),respectively.The release rate of LDH was signif⁃icantly increased while the percentage of EdU+cells was significantly reduced in the CTX and 4-HC groups(P<0.01).The percentage ofγ-H2AX+cells was significantly increased and mitochondrial membrane potential significantly decreased in the CTX and 4-HC group(P<0.05).Treatment with CTX and 4-HC resulted in reduced levels of maximum glycolytic capacity,glycolytic reserve,maximal respi⁃ration,and ATP production(P<0.05).CONCLUSION CTX and 4-HC exert significant cytotoxic effects on SH-SY5Y cells by disrupting cell membrane structure,impeding cell proliferation,and reducing cell viability.The mechanisms underlying these effects may involve intracellular DNA damage,disturbance of energy metabolism and mitochondrial dysfunction.展开更多
Novel prodrugs of cyclophosphamide 1a and 1b, which comprised the galactosyl moiety, the key fraction of cyclophosphamide derivates, and the linker 4-hydroxy benzaldehyde, were synthesized. These compounds were antici...Novel prodrugs of cyclophosphamide 1a and 1b, which comprised the galactosyl moiety, the key fraction of cyclophosphamide derivates, and the linker 4-hydroxy benzaldehyde, were synthesized. These compounds were anticipated to exhibit amplified anti-tumor activity and targeting ability.展开更多
Aim:To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate th...Aim:To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid.Methods:The testicular△^(5),3β-hydroxysteroid dehydrogenase(HSD),17β-HSD,peroxidase and catalase activities along with the levels of malondialdehyde(MDA)and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress.The plasma testosterone(T)level was measured by immunoassay.Various germ cells at stageⅦof spermatogenic cycle were quantified from testicular stained sections.Results:Cyclophosphamide treatment results in a significant inhibition in the testicular△^(5),3β-HSD and 17β-HSD activities,a decrease in plasma T level and a diminution in the counts of various germ cells.Moreover,this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis.All these changes were reversed by ascorbic acid co-administration.Conclusion:Cyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.展开更多
Based on the principle of association, a novel class of cyclophosphamide bis-spiropiperazinium compounds was designed and synthesized. A new method of synthesis, separation and purification for this kind of compounds ...Based on the principle of association, a novel class of cyclophosphamide bis-spiropiperazinium compounds was designed and synthesized. A new method of synthesis, separation and purification for this kind of compounds was also developed.展开更多
Objective: Cyclophosphamide(CP) is commonly used to treat some cancers, but its clinical efficacy is also linked with testicular toxicity. We investigated the effects of aqueous extract(AE) and methanolic extract(ME) ...Objective: Cyclophosphamide(CP) is commonly used to treat some cancers, but its clinical efficacy is also linked with testicular toxicity. We investigated the effects of aqueous extract(AE) and methanolic extract(ME) of Helichrysum odoratissimum for reducing CP-induced reproductive toxicity in male rats.Methods: In addition to a normal control(group 1), drugs or vehicles were administered orally to seven groups(n = 5) of rats that had already received 4-weeks of pre-treatment with CP(5 mg/[kgád], per oral administration);group 2 received CP + distilled water(10 m L/[kgád]);group 3 received CP + 5% tween 80(10 m L/[kgád]);group 4 received CP + clomiphene citrate(0.25 mg/[kgád]);groups 5 and 6 received CP + AE(50 and 100 mg/[kgád]) and groups 7 and 8 received CP + ME(50 and 100 mg/[kgád]). Animals were sacrificed on day 15, and body and sexual organ weights, sperm characteristics, testosterone level and testicular histology were evaluated.Results: The CP-treated group showed a significant reduction(P < 0.001) in the body and seminal vesicle weights, testosterone level, sperm count, sperm motility and sperm viability, but elevated(P < 0.001)sperm morphological abnormalities and testicular structure alterations, compared to the control group.Interestingly, these detrimental effects of CP were reversed by treatment with H. odoratissimum extracts.For instance, both extracts and all doses of H. odoratissimum significantly increased the sperm count(P < 0.001), sperm motility(AE, 50 mg/kg, P < 0.05;ME, 50 and 100 mg/kg, P < 0.05) and sperm viability(AE, 50 mg/kg, P < 0.001;ME, 50 and 100 mg/kg, P < 0.001) compared to the CP group. H. odoratissimum also improved plasmatic and intratesticular testosterone levels and prevented histological alterations of the testes.Conclusion: H. odoratissimum might be considered as an alternative drug to alleviate/prevent reproductive damage in cancer patients receiving CP chemotherapy.展开更多
OBJECTIVE: To investigate the therapeutic effects of Jiazhu decoction (JZD) in combination with cyclophosphamide (CTX) on the growth of breast cancer in mice and to explore the possible molecular mechanisms of action....OBJECTIVE: To investigate the therapeutic effects of Jiazhu decoction (JZD) in combination with cyclophosphamide (CTX) on the growth of breast cancer in mice and to explore the possible molecular mechanisms of action. METHODS: BALB/c mice were randomly divided into four groups of 10 (untreated model group, JZD group, CTX group, and JZD + CTX group) and subcutaneously injected with 4T1 mouse breast cancer cells. Tumors were allowed to establish for ~7 d before initiation of treatment with CTX (100 mg/kg every week by intraperitoneal injection) and/or JZD (0.015 mL of 1.65 g/mL crude drug, administered daily by gavage). The model group received equivalent volumes of vehicle on the same schedules. Tumor volumes were measured every 3 d. Mice were sacrificed after 3 weeks of treatment, and tumors were excised and subjected to RT-qPCR and western blot analysis to evaluate expression of the Wnt/β-catenin signaling pathway components β-catenin, c-Myc, and cyclin D1 at the mRNA and protein levels. RESULTS: The mean tumor volume was smaller and the growth rate was slower in the CTX and JZD + CTX groups compared with the model group (P < 0.05), and in the JZD + CTX group compared with the CTX and JZD groups (P < 0.05). Tumor growth was inhibited by 35.4% and 48.1% by CTX and JZD + CTX treatment, respectively (P < 0.001). The expression of β-catenin, c-Myc, and cyclin D1 mRNA and protein in tumors was significantly lower in mice treated with JZD or JZD + CTX compared with the untreated mice (P < 0.05), and was significantly lower in mice treated with JZD + CTX compared with either JZD or CTX alone (P < 0.05). CONCLUSION: JZD inhibited the growth of mouse breast cancer cells in vivo, possibly by reducing the expression of β-catenin, c-Myc, and cyclin D1. Combination therapy with JZD plus CTX had a more potent inhibitory effect on breast cancer growth compared with either agent alone.展开更多
In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its co...In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its combination with cyclophosphamide （CP） （50 mg/kg） were separately dissolved in tap water at 500, 1000, 2000, and 4000 mg/kg. Onions （A. cepa） were suspended in the solutions and controls for 48 h in the dark. Root tips were prepared for microscopic evaluation. 2,2-Diphenyl-l-picrylhydrazyl （DPPH） free radicals＇ scavenging power of the extract was tested using butylated hydroxyanisole （BHA） and butylated hydroxytoluene （BHT） as standards. Water extract of Myristica fragrans scavenged free radicals better than BHA, but worse than BHT. The extract alone, as well as in combination with CP suppressed cell division, and induced chromosomal aberrations that were insignificantly different from the negative control （P≤0.05）. However, cytotoxic and mutagenic actions of CP were considerably suppressed. The observed effects on cell division and chromosomes of A. cepa may be principally connected to the antioxidant properties of the extract. The obtained results suggest mitodepressive and antimutagenic potentials of water extract of the leaves of M. fragrans as desirable properties of a promising anticancer agent.展开更多
The main purpose of this study was to investigate the improvement effect of Mesona chinensis Benth polysaccharide(MP)on cyclophosphamide(CTX)induced liver injury in mice.To explore metabolic profile of liver tissue an...The main purpose of this study was to investigate the improvement effect of Mesona chinensis Benth polysaccharide(MP)on cyclophosphamide(CTX)induced liver injury in mice.To explore metabolic profile of liver tissue and feces among normal group,CTX-induced group and MP management group based on metabolomics method by using UPLC-Q-TOF/MS.The results showed that MP could alleviate liver injury and promote the production of short chain fatty acids(SCFAs),with the best dose of 200 mg/kg·body weight(bw).The principal component analysis(PCA)and orthogonal partial least squares discriminant analysis(OPLSDA)scores plots of the liver and feces samples showed a clear separation among normal,model and highdose of MP(MPH).There were 18 endogenous metabolites in liver and 29 endogenous metabolites in feces,which were mainly involved in 8 metabolic pathways:taurine and hypotaurine metabolism,phenylalanine metabolism,α-linolenic acid metabolism,tricarboxylic acid(TCA)cycle,phenylalanine,tyrosine and tryptophan biosynthesis,arachidonic acid metabolism,sphingolipid metabolism as well as tryptophan metabolism.Moreover,a common metabolite arachidonic acid was observed in liver and feces samples.These endogenous metabolites may be considered to be MP’s response to liver protection.It will help to further understand the mechanism of MP and provide a basis for further research.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
Spermatogenic dysfunction caused by cyclophosphamide(CP)chemotherapy has seriously influenced the life quality of patients.Unfortunately,treatments for CP-induced testicular spermatogenic dysfunction are limited,and t...Spermatogenic dysfunction caused by cyclophosphamide(CP)chemotherapy has seriously influenced the life quality of patients.Unfortunately,treatments for CP-induced testicular spermatogenic dysfunction are limited,and the molecular mechanisms are not fully understood.For the first time,here,we explored the effects of bone marrow mesenchymal stem cell-derived exosomes(BMSC-exos)on CP-induced testicular spermatogenic dysfunction in vitro and in vivo.BMSC-exos could be taken up by spermatogonia(GC1-spg cells).CP-injured GC1-spg cells and BMSC-exos were cocultured at various doses,and then,cell proliferation was measured using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay.In addition,photophosphorylation of extracellular-regulated kinase(ERK),p38 mitogen-activated protein kinase(p38MAPK),and protein kinase B(AKT)proteins was evaluated by western blotting as well as apoptosis in GC1-spg cells measured using flow cytometry.Treatment with BMSC-exos enhanced cell proliferation and reduced apoptosis of CP-injured GCI-spg cells.Phosphorylated levels of ERK,AKT,and p38MAPK proteins were reduced in CP-injured spermatogonia when co-treated with BMSC-exos,indicating that BMSC-exos acted against the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.In experiments in vivo,CP-treated rats received BMSC-exos by injection into the tail vein,and testis morphology was compared between treated and control groups.Histology showed that transfusion of BMSC-exos inhibited the pathological changes in CP-injured testes.Thus,BMSC-exos could counteract the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.The findings provide a potential treatment for CP-induced male spermatogenic dysfunction using BMSC-exos.展开更多
基金supported by the Basic Research Joint Special General Project of Yunnan Provincial Local Universities(part)(No:202301BA070001-029,202301BA070001-044)Yunnan Province High-level Scientific and Technological Talents and Innovation Team Selection Special Young and Middle-aged Academic and Technical Leaders Reserve Talent Project(No:202405AC350067).
文摘Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.
基金Supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project Number(PNURSP2025R381),Princess Nourah bint Abdulrahman University,Riyadh,Saudi Arabia.
文摘BACKGROUND Cyclophosphamide(CP)is a potent chemotherapeutic and immunosuppressant agent,but its hepatotoxicity remains a significant concern.Ambroxol(ABX)is a mucolytic agent with emerging beneficial effects against oxidative stress and inflammation.AIM To investigate the hepatoprotective effects of ABX against CP-induced liver injury,focusing on oxidative stress,inflammation,and the possible role of cytoglobin,thioredoxin reductase 1(TXNRD1)and high-mobility group box 1(HMGB1).METHODS ABX(20 mg/kg)was orally administered for 7 days,and the rats received a single injection of CP(100 mg/kg)on day 5.Blood and liver samples were collected for analyses,and the affinity of ABX towards cytoglobin,TXNRD1,and HMGB1 was evaluated using molecular docking.RESULTS CP administration significantly elevated alanine aminotransferase,aspartate aminotransferase,and alkaline phosphatase,reduced albumin,and caused multiple histopathological alterations in the liver.ABX effectively restored liver function biomarkers and attenuated histopathological alterations.CP-induced oxidative stress was evidenced by increased malondialdehyde and decreased glutathione and antioxidant enzyme activities,all of which were ameliorated by ABX.CP upregulated toll-like receptor 4(TLR-4),nuclear factor-kappaB(NF-κB)p65 and pro-inflammatory cytokines,while downregulating cytoglobin,TXNRD1 and HMGB1.ABX suppressed TLR-4/NF-κB signaling and pro-inflammatory cytokines,and upregulated cytoglobin,TXNRD1 and HMGB1.In silico molecular docking revealed the affinity of ABX to bind with cytoglobin,TXNRD1,and HMGB1.CONCLUSION ABX protects against CP hepatotoxicity by mitigating oxidative stress,suppressing TLR-4/NF-κB signaling,and upregulating cytoglobin,TXNRD1 and HMGB1.ABX showed binding affinity towards cytoglobin,TXNRD1 and HMGB1.These findings suggest that ABX has therapeutic potential in alleviating hepatotoxicity associated with CP treatment.
基金Fujian Natural Science:Study on Potential Protein Targets of Huluan Decotion in the Intervention of Premature Ovarian Failure(No.2021J011173)Major Project Cultivation Plan Project of Ningde Normal University:the Effect of Huluan Decotion on the Decreased Ovarian Reserve Function Induced by Cyclophosphamide is Studied based on Forkhead box L2(No.2019ZDK06)。
文摘OBJECTIVES:To investigate the therapeutic effect of Huluan decotion(护卵汤,HLD)on cyclophosphamideinduced premature ovarian failure(POF)in mice and its regulatory mechanisms.METHODS:Female BALB/c mice were administered cyclophosphamide and administered received different doses of HLD for 28 d.Levels of sex hormone,such as estradiol(E2),follicle stimulating hormone(FSH)and luteinizing hormone(LH)in the sera,were assessed using enzyme-linked immunosorbent assay(ELISA).Follicular structure variances were observed through hematoxylin and eosin(HE)staining,while Forkhead box L2(FOXL2)expression were analyzed via immuneohistochemical staining.The primary mechanism of POF were investigated through Western blot analysis.RESULTS:E2 levels decreased,and FSH and LH levels increased in POF model mice,but these trends were reversed with HLD or premarin administration,the expressions of WNT family member 4(Wnt4),β-Catenin and FOXL2 were downregulated in POF model mice,whereas high expression levels were observed in control mice and other groups.CONCLUSION:HLD effectively treats POF induced with cyclophosphamide in mice by enhancing expressions of Wnt4,β-Catenin and FOXL2.
基金supported by the National Natural Science Foundation of China(No.81974400 and No.82173068).
文摘Objective Overactive bladder,a storage syndrome characterized by urinary urgency,frequency,and nocturia with or without urgency urinary incontinence,severely affects the quality of life of patients.The aim of this study was to investigate the role and mechanism of the C/EBP homologous protein in the overactive bladder.Methods An overactive bladder mouse model was established via the intraperitoneal injection of cyclophosphamide in wild-type and Chop-deficient mice.An in vitro model was established using interleukin(IL)-6-induced mouse bladder epithelial cells.Hematoxylin–eosin(HE)staining was used to assess bladder tissue damage,and ELISA was used to measure inflammatory cytokine levels.Western blot analysis was used to examine p-PERK,ATF-6,p-eIF2α,BiP,ATF-4,Bax,Bcl-2,and cleaved caspase-3 protein expression levels.TUNEL staining and flow cytometry were conducted to measure the degree of apoptosis in bladder epithelial cells and macrophages.Results C/EBP homologous protein levels were decreased in overactive bladder tissues;nevertheless,macrophage infiltration was found to be increased.Knockout of Chop exacerbated bladder dysfunction,tissue injury,macrophage infiltration,and bladder epithelial apoptosis and alleviated endoplasmic reticulum stress.Conclusions Chop deficiency exacerbates inflammation,injury,and bladder epithelial apoptosis in overactive bladder model mice by inhibiting endoplasmic reticulum stress.
基金2023 Special Project for Serving the National Development Strategy with Basic Scientific Research Fees from Central Universities(No.31920230188)2023 Northwestern Minzu University College-Level Innovation and Entrepreneurship Training Program(No.X202310742289)2024 National College Students’Innovation and Entrepreneurship Training Program(No.202410742005)。
文摘Objective:To study the antioxidant protective effect and mechanism of melatonin on cyclophosphamide-induced premature ovarian failure model mice.Methods:Six-month sexually mature female Kunming mice were taken for one week of acclimatization and then randomly divided into a normal group,blank control group,drug control group,ovarian premature aging model group,and melatonin intervention low,medium,and high dose group,with 20 mice in each group.We observed the status and body mass of the mice in each group;observed and monitored the estrous cycle by HE staining;measured the diameter and size of the ovaries and weighed the wet weight of the ovaries;observed the morphological changes of the ovaries by HE staining and counted the developing follicles at all levels;detected the levels of serum estradiol(E2),follicle-stimulating hormone(FSH),and luteinizing hormone(LH)by ELISA;measured the levels of serum MDA,SOD,and GSH-PX by antioxidant kit;detected the levels of protein immunoblotting by ELISA;protein immunoblotting(Western blot)to examine the expression of DNA damage-related proteinsγH2AX,p53,and p21 in ovarian tissues.Results:Compared with the control group,mice in the premature ovarian failure model group showed reduced mobility,rough hair,decreased body weight,disorganized estrous cycle,decreased ovarian weight(P<0.05),decreased number of follicles at all levels of development(P<0.05),increased number of atretic follicles(P<0.05),significantly elevated levels of serum FSH and LH,significantly decreased levels of E2(P<0.05),significantly increased levels of serum MDA,significantly lower SOD and GSH-PX levels(P<0.05),and the expression of p53,p21,andγH2AX in ovarian tissues was increased(P<0.05).Compared with the model group of premature ovarian failure,melatonin improved the changes of the above indexes induced by cyclophosphamide-induced premature ovarian failure in mice.Conclusion:Melatonin can improve the changes of motility cycle disorders,abnormal follicular development,and abnormal serum hormone levels induced by cyclophosphamide-induced oxidative stress in mice with premature ovarian failure.At the same time,melatonin can improve the oxidative stress induced by cyclophosphamide and alleviate the role of oxidative stress-induced DNA damage in mouse ovaries by exerting its antioxidant effect.
文摘Background:Allogeneic peripheral-blood stem-cell transplantation(SCT)from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers.The combination of a calcineurin inhibitor and an antimetabolite remains standard care for graft-versus-host disease(GVHD)prophylaxis in these patients.Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite.
基金Supported by the 211 Project of Jinan Universitythe Team Project of Natural Science Foundation of Guangdong Province (8351063201000003)+3 种基金the Popular Science Foundation of Science & Technology Bureau of Guangzhou City (2008KP055)the Natural Science Foundation of Guangdong Province (06025198)the Jinan University Natural Science Foundation (51204017)the Science and Technology Innovation Project for Undergraduates (cx08120)
文摘An experiment was conducted to compare the effects of two mouse thrombocytopenia models induced by cyclophosphamide at two different administration routes to determine a proper cyclophosphamide administration route that could cause stable thrombocytopenia. A suitable drug dosage that could induce thrombocytopenia in mouse efficiently with the definite administration route was then investigated. BALB/c mice were randomly divided into Normal, Model A and Model B groups. To Model A, 200 mg/kg of cyclophosphamide was given by vena caudalis injection as first dose and 30 mg/kg as maintenance dose by intraperitoneal injection at the following 6 days. To Model B, 150 mg/kg of cyclophosphamide was given by subcutaneous injection once a day for consecutive 3 days. All groups were under investigation for 15 days. The result suggested that a decrease in the number of blood platelets of Model B at the 7th day were significantly than that of Normal. Other platelet related indices like platelet distribution width, mean platelet volume and platelet-large cell ratio of Model B increased significantly in comparison with those of Normal group. The platelets count was reduced but fluctuated greatly, and more than half of the mice died in Model A. Therefore, subcutaneous injection of cyclophosphamide for 3 days was used for the cyclophosphamide dosage test. BALB/c mice were randomly divided into Normal, cyclophosphamide low dose （100 mg/kg）, medium dose （120 mg/kg） and high dose （140 mg/kg） groups. All groups were under investigation for 11 days. Though all 3 dosages successfully initiated thrombocytopenia as the platelets number dropped at the 7th day, the low dose was considered to be a suitable one that was of high efficacy and low toxicity. Thus, BALB/c mice challenged by subcutaneous injection of cyclophosphamide 100 mg/kg per day for 3 consecutive day is one simple, feasible and stable mouse thrombocytopenia model that could be used for pharmacodynamic test of the drugs which are supposed to have platelets increasing effect.
基金National Natural Science Foundation of China(Grant No.81072612)the Natural Science Foundation of Beijing(Grant No.7102107)+1 种基金the Open Foundation of State Key Laboratory of Natural and Biomimetic Drugs(Grant No.K20110109)Specialized Research Fund for the Doctoral Program of Higher Education(Grant No.20110001110021)
文摘A rapid and simple liquid chromatography method with on-line solid phase extraction was developed and validated for the quantitative determination of cyclophosphamide in rat plasma.The plasma sample was first extracted on an Acclaim？ Polar Advantage II C18 guard column（PA II C18,10 mm×4.6 mm,5 μm）,which was also the on-line Extraction Cartridge SPE column,by washing with 100% H2O for 1 min.The extracted sample was then eluted onto a PA II C18 column（150 mm×4.6 mm,5 μm） and separated by isocratic elution with acetonitrile-water（40：60,v/v）.The mobile phase was run at a flow rate of 1.0 mL/min,and the UV detector was set at 195 nm.Retention time of cyclophosphamide was 4.3 min and the total run-time was 6 min.The linear range of the standard curve was from 1.0 to 200 μg/mL（r2 = 0.9999）,and the limits of quantification and detection were 1.0 μg/mL（RSD10%,n = 5） and 0.3 μg/mL（RSD13%,n = 5）,respectively.Both intra-and inter-day variations were less than 5.6%.The developed method can be used for the therapeutic drug monitoring of cyclophosphamide in the clinic.
基金National Natural Science Foundation(Grant No.81272468 and 21001011)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Ministry of Education
文摘Hematological toxicity （bone marrow suppression） is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 （Nrf2） is a pivotal coordinator of cellular defensive responses against chemical insults in many tissues including bone marrow. In the present study, the effects of tert-butylhydroquinone （tBHQ） on the expression of Nrf2-regulated genes in peripheral blood cells and cyclophosphamide （CTX）-induced hematotoxicity in mice were investigated. CTX induced apoptosis of peripheral blood nucleated cells and leukopenia in mice, accompanied by mobilization of bone marrow hematopoietic cells, tBHQ treatment induced the expression of Nrf2-regulated genes such as heine oxygenase 1 （HO1） and glutamate-cysteine ligase catalytic subtmit （GCLC） in RAW264.7 mouse macrophage cells and peripheral blood cells both in vitro and in vivo. Interestingly, pretreatment with tBHQ alleviated CTX-induced mouse peripheral blood cell apoptosis and leukopenia in vivo, indicating possible involvement of Nrf2 in the protection against CTX-induced hematotoxicity. This study provides new information on the chemotherapy-induced hematotoxicity, and suggests Nrf2 could serve as a target for the development of chemoprotectants against hematotoxicity.
文摘The protective effect of a kind of purified polysaccharides extracted from Radix of Phytolacca acinosa Roxb,with a molecular weight of 10 KDa,on hematopoiesis was investigated.Average survival time of mice treated with cyclophosphamide (CY) 300 mg/kg once alone was 13.3 ± 7.2d(n=7) however,average survival time of mice treated with CY 300 mg/kg in com-bination with PAP-1 10 mg/kg,3 times/wk was 36.7± 16.4d(n=7,P<0.01).PAP-1,ip had benefi-cial effect on the recovery of the CY induced decrease of peripheral leukocyte number,and the nu-cleated bone marrow cell(BMC)number and[3￣H]TdR uptaken by BMC induced by rmGM-CSF in S180 bearing mice treated with CY,In mice,after the first ip treatment with CY 100 mg/kg on d7,the peripheral leukocyte number decreased on d9 and recovered to normal level about d13 to d15. Such recovery was accelerated by administrating PAP-1,10mg/kg, 3 times/wk.A significant in-crease of the activity to form colony in spleen(colony-forming unit in spleen, CFU-S_8, CUF-S12) in mice irradiated with 550 rad 6O￣Co γ-rays and an enhancement of proliferative response of BMC to rmGM-CSF treated with PAP-1,10mg/kg,3 times/wk, ip were observed.After PAP-1,10 mg/kg,ip once,a significant increase in the number of peripheral blood leukocytes and a rise in the serum of colony stimulating factor(CSF) were also confirmed.The types of CSF in serum were M-CSF and other hematopoietic growth factors,which were confirmed by using McAb of IL-3, GM-CSF and PcAb of M-CSF. These beneficial effects of PAP-1 on hematopoiesis may be related to its activityinducing CSFs and other hematopoietic growth factors and warrant further evaluation of its use-fulness.
文摘OBJECTIVE To investigate the damage effect and mechanisms of cyclophosphamide(CTX)and its active metabolite derivative 4-hydroperoxycyclophosphamide(4-HC)to human neuroblas⁃toma SH-SY5Y cells.METHODS SH-SY5Y cells were treated with CTX[0(cell control),0.01,0.1,1,5,10,20,40 and 80 mmol·L^(-1)]and 4-HC[0(cell control),0.01,0.1,1,5,10,20,40 and 80μmol·L^(-1)]for 48 h.Cell confluence and morphology were observed by the IncuCyte ZOOM system.Cell viability was assessed by CCK-8 assay.Lactate dehydrogenase(LDH)release was measured by LDH assay kit.SH-SY5Y cells were treated with CTX(0,1,5,10 and 20 mmol·L^(-1))and 4-HC(0,1,5,10 and 20μmol·L^(-1))for 48 h before cell proliferation was analyzed by 5-ethynyl-2′-deoxyuridine(EdU)staining assay.Immunofluorescence was employed to assess the levels of the DNA double-strand break markerγ-H2AX and to evaluate changes in mitochondrial membrane potential.SH-SY5Y cells were treated with CTX(0,1,5 and 10 mmol·L^(-1))and 4-HC(0,1,5 and 10μmol·L^(-1))for 48 h,and the alterations in glycolysis and oxidative phosphorylation levels were analyzed using the Seahorse XFe96 Analyzer.RESULTS Compared with the cell control group,cell confluence and cell viability were significantly reduced in the CTX and 4-HC groups(P<0.01),and the half-maximal inhibitory concentrations(IC50)for CTX and 4-HC were 4.44 mmol·L^(-1) and 4.78μmol·L^(-1),respectively.The release rate of LDH was signif⁃icantly increased while the percentage of EdU+cells was significantly reduced in the CTX and 4-HC groups(P<0.01).The percentage ofγ-H2AX+cells was significantly increased and mitochondrial membrane potential significantly decreased in the CTX and 4-HC group(P<0.05).Treatment with CTX and 4-HC resulted in reduced levels of maximum glycolytic capacity,glycolytic reserve,maximal respi⁃ration,and ATP production(P<0.05).CONCLUSION CTX and 4-HC exert significant cytotoxic effects on SH-SY5Y cells by disrupting cell membrane structure,impeding cell proliferation,and reducing cell viability.The mechanisms underlying these effects may involve intracellular DNA damage,disturbance of energy metabolism and mitochondrial dysfunction.
基金National Natural Science Foundation of China (Grant No.20732001,90713004)
文摘Novel prodrugs of cyclophosphamide 1a and 1b, which comprised the galactosyl moiety, the key fraction of cyclophosphamide derivates, and the linker 4-hydroxy benzaldehyde, were synthesized. These compounds were anticipated to exhibit amplified anti-tumor activity and targeting ability.
基金The authors gratefully acknowledge the financial assistance from the Major Research Project(Project No.F-3/50/99 dated 3l-3-99)provided by the University Grants Commission(UGC),New Delhi,India
文摘Aim:To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid.Methods:The testicular△^(5),3β-hydroxysteroid dehydrogenase(HSD),17β-HSD,peroxidase and catalase activities along with the levels of malondialdehyde(MDA)and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress.The plasma testosterone(T)level was measured by immunoassay.Various germ cells at stageⅦof spermatogenic cycle were quantified from testicular stained sections.Results:Cyclophosphamide treatment results in a significant inhibition in the testicular△^(5),3β-HSD and 17β-HSD activities,a decrease in plasma T level and a diminution in the counts of various germ cells.Moreover,this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis.All these changes were reversed by ascorbic acid co-administration.Conclusion:Cyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.
基金National Natural Science Foundation of China(Grant No.20472008)the Major State Basic Research Development Program(Grant No.2004CB719900).
文摘Based on the principle of association, a novel class of cyclophosphamide bis-spiropiperazinium compounds was designed and synthesized. A new method of synthesis, separation and purification for this kind of compounds was also developed.
文摘Objective: Cyclophosphamide(CP) is commonly used to treat some cancers, but its clinical efficacy is also linked with testicular toxicity. We investigated the effects of aqueous extract(AE) and methanolic extract(ME) of Helichrysum odoratissimum for reducing CP-induced reproductive toxicity in male rats.Methods: In addition to a normal control(group 1), drugs or vehicles were administered orally to seven groups(n = 5) of rats that had already received 4-weeks of pre-treatment with CP(5 mg/[kgád], per oral administration);group 2 received CP + distilled water(10 m L/[kgád]);group 3 received CP + 5% tween 80(10 m L/[kgád]);group 4 received CP + clomiphene citrate(0.25 mg/[kgád]);groups 5 and 6 received CP + AE(50 and 100 mg/[kgád]) and groups 7 and 8 received CP + ME(50 and 100 mg/[kgád]). Animals were sacrificed on day 15, and body and sexual organ weights, sperm characteristics, testosterone level and testicular histology were evaluated.Results: The CP-treated group showed a significant reduction(P < 0.001) in the body and seminal vesicle weights, testosterone level, sperm count, sperm motility and sperm viability, but elevated(P < 0.001)sperm morphological abnormalities and testicular structure alterations, compared to the control group.Interestingly, these detrimental effects of CP were reversed by treatment with H. odoratissimum extracts.For instance, both extracts and all doses of H. odoratissimum significantly increased the sperm count(P < 0.001), sperm motility(AE, 50 mg/kg, P < 0.05;ME, 50 and 100 mg/kg, P < 0.05) and sperm viability(AE, 50 mg/kg, P < 0.001;ME, 50 and 100 mg/kg, P < 0.001) compared to the CP group. H. odoratissimum also improved plasmatic and intratesticular testosterone levels and prevented histological alterations of the testes.Conclusion: H. odoratissimum might be considered as an alternative drug to alleviate/prevent reproductive damage in cancer patients receiving CP chemotherapy.
基金Supported by Research Topic of Traditional Chinese Medicine and Ethnic Medicine Technology in Guizhou Provincial Administration of Traditional Chinese Medicine(No.QZYY2017-005)Guiyang Science and Technology Bureau Fund National Base Cultivation Project(Zhuke Contract[2017] 30-39)the Foundation of Innovation and Talent Team of the Higher Education of Guizhou province(No.2015 51)
文摘OBJECTIVE: To investigate the therapeutic effects of Jiazhu decoction (JZD) in combination with cyclophosphamide (CTX) on the growth of breast cancer in mice and to explore the possible molecular mechanisms of action. METHODS: BALB/c mice were randomly divided into four groups of 10 (untreated model group, JZD group, CTX group, and JZD + CTX group) and subcutaneously injected with 4T1 mouse breast cancer cells. Tumors were allowed to establish for ~7 d before initiation of treatment with CTX (100 mg/kg every week by intraperitoneal injection) and/or JZD (0.015 mL of 1.65 g/mL crude drug, administered daily by gavage). The model group received equivalent volumes of vehicle on the same schedules. Tumor volumes were measured every 3 d. Mice were sacrificed after 3 weeks of treatment, and tumors were excised and subjected to RT-qPCR and western blot analysis to evaluate expression of the Wnt/β-catenin signaling pathway components β-catenin, c-Myc, and cyclin D1 at the mRNA and protein levels. RESULTS: The mean tumor volume was smaller and the growth rate was slower in the CTX and JZD + CTX groups compared with the model group (P < 0.05), and in the JZD + CTX group compared with the CTX and JZD groups (P < 0.05). Tumor growth was inhibited by 35.4% and 48.1% by CTX and JZD + CTX treatment, respectively (P < 0.001). The expression of β-catenin, c-Myc, and cyclin D1 mRNA and protein in tumors was significantly lower in mice treated with JZD or JZD + CTX compared with the untreated mice (P < 0.05), and was significantly lower in mice treated with JZD + CTX compared with either JZD or CTX alone (P < 0.05). CONCLUSION: JZD inhibited the growth of mouse breast cancer cells in vivo, possibly by reducing the expression of β-catenin, c-Myc, and cyclin D1. Combination therapy with JZD plus CTX had a more potent inhibitory effect on breast cancer growth compared with either agent alone.
文摘In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its combination with cyclophosphamide （CP） （50 mg/kg） were separately dissolved in tap water at 500, 1000, 2000, and 4000 mg/kg. Onions （A. cepa） were suspended in the solutions and controls for 48 h in the dark. Root tips were prepared for microscopic evaluation. 2,2-Diphenyl-l-picrylhydrazyl （DPPH） free radicals＇ scavenging power of the extract was tested using butylated hydroxyanisole （BHA） and butylated hydroxytoluene （BHT） as standards. Water extract of Myristica fragrans scavenged free radicals better than BHA, but worse than BHT. The extract alone, as well as in combination with CP suppressed cell division, and induced chromosomal aberrations that were insignificantly different from the negative control （P≤0.05）. However, cytotoxic and mutagenic actions of CP were considerably suppressed. The observed effects on cell division and chromosomes of A. cepa may be principally connected to the antioxidant properties of the extract. The obtained results suggest mitodepressive and antimutagenic potentials of water extract of the leaves of M. fragrans as desirable properties of a promising anticancer agent.
基金supported by grants from the National Natural Science Foundation of China(21566024)。
文摘The main purpose of this study was to investigate the improvement effect of Mesona chinensis Benth polysaccharide(MP)on cyclophosphamide(CTX)induced liver injury in mice.To explore metabolic profile of liver tissue and feces among normal group,CTX-induced group and MP management group based on metabolomics method by using UPLC-Q-TOF/MS.The results showed that MP could alleviate liver injury and promote the production of short chain fatty acids(SCFAs),with the best dose of 200 mg/kg·body weight(bw).The principal component analysis(PCA)and orthogonal partial least squares discriminant analysis(OPLSDA)scores plots of the liver and feces samples showed a clear separation among normal,model and highdose of MP(MPH).There were 18 endogenous metabolites in liver and 29 endogenous metabolites in feces,which were mainly involved in 8 metabolic pathways:taurine and hypotaurine metabolism,phenylalanine metabolism,α-linolenic acid metabolism,tricarboxylic acid(TCA)cycle,phenylalanine,tyrosine and tryptophan biosynthesis,arachidonic acid metabolism,sphingolipid metabolism as well as tryptophan metabolism.Moreover,a common metabolite arachidonic acid was observed in liver and feces samples.These endogenous metabolites may be considered to be MP’s response to liver protection.It will help to further understand the mechanism of MP and provide a basis for further research.
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.
基金This study was supported by grants from the National Natural Science Foundation of China(No.81772257)the Guangdong Provincial Natural Science Foundation of China(No.2018A030313697).
文摘Spermatogenic dysfunction caused by cyclophosphamide(CP)chemotherapy has seriously influenced the life quality of patients.Unfortunately,treatments for CP-induced testicular spermatogenic dysfunction are limited,and the molecular mechanisms are not fully understood.For the first time,here,we explored the effects of bone marrow mesenchymal stem cell-derived exosomes(BMSC-exos)on CP-induced testicular spermatogenic dysfunction in vitro and in vivo.BMSC-exos could be taken up by spermatogonia(GC1-spg cells).CP-injured GC1-spg cells and BMSC-exos were cocultured at various doses,and then,cell proliferation was measured using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay.In addition,photophosphorylation of extracellular-regulated kinase(ERK),p38 mitogen-activated protein kinase(p38MAPK),and protein kinase B(AKT)proteins was evaluated by western blotting as well as apoptosis in GC1-spg cells measured using flow cytometry.Treatment with BMSC-exos enhanced cell proliferation and reduced apoptosis of CP-injured GCI-spg cells.Phosphorylated levels of ERK,AKT,and p38MAPK proteins were reduced in CP-injured spermatogonia when co-treated with BMSC-exos,indicating that BMSC-exos acted against the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.In experiments in vivo,CP-treated rats received BMSC-exos by injection into the tail vein,and testis morphology was compared between treated and control groups.Histology showed that transfusion of BMSC-exos inhibited the pathological changes in CP-injured testes.Thus,BMSC-exos could counteract the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.The findings provide a potential treatment for CP-induced male spermatogenic dysfunction using BMSC-exos.
