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OBJECTIVE To investigate the proliferation effect of di(2-ethylhexyl) phthalate (DEHP) on prostate in aged rats at the environmental exposure dose and the possible mechanism.METHODS Thirty-two male Sprague-Dawley rats,aged 1.5 years,were randomly divided into 4 groups (8 rats per group) and treated with DEHP (30,90 and 270 μg· kg-1,ig) and vehicle once daily respectively for 4 weeks.All the animals were anesthetized with pentobarbital sodium and sacrificed on the day subsequent to the last treatment.① Abdominal aortic blood samples were collected,and serum estradiol (E2),testosterone (T) and prolactin (PRL) levels were assayed by ELISA.② The prostate tissues were dissected and categorized into different lobes,weighed and measured.The prostate relative mass was calculated.③ The morphological changes were detected by HE staining and prostate epithelial height was analyzed with microscopic image analysis software.RESULTS Compared with vehicle control group,the prostate relative mass,dorsolateral prostate mass,and dorsolateral prostate index in DEHP 270 μg· kg-1 group were significantly higher (P＜0.05).The height of the ventral prostate epithelium in DEHP 30,90 and 270 μg· kg-1 groups was increased significantly (P＜0.01),so was the height of dorsal prostate epithelium in DEHP 270 μg· kg-1 group (P＜0.01).There were no significant changes in levels of E2,PRL or T in DEHP 30,90 and 270 μg· kg-1 groups,but the ratios of E2/T in DEHP 30 and 270 μμg· kg-1 groups were increased significantly (P＜0.05).CONCLUSION Low-dose DEHP could promote the proliferation of prostatic hyperplasia in the aged rats,which might be associated with the relative levels of endogenous hormone.
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OBJECTIVE To study the changes in inflammatory factors caused by prostatitis.METHODS SD rats were castrated under sterile conditions.E2 0.25 mg· kg-1+ T 0.25,0.5 and 1.0 mg· kg-1 were given sc for 30 d,respectively.Serum samples were taken and levels of E2,T and dihydrotestosterone (DHT) were detected by ELISA.Pathological changes of prostate tissue were observed by HE staining.The expressions of tumor necrosis factor-alpha (TNF-α),cyclooxygenase-2 (COX-2) and macrophage inflammatory protein 1alpha (MIP-1α) in prostate were detected by immunohistochemistry.RESLULTS ELISA detection showed that E2 levels were significantly increased [(80±7) ng· L-1,P＜0.01] in E2 0.25 mg· kg-1 group and that T levels were significantly decreased [111 ±6 vs (111 ±5) nmol· L-1,P＜0.05]in E20.25 mg ·kg-1 and E2+T 0.25 mg·kg-1 groups compared with the sham-operated group.E2 was significantly increased [(80±7) ng· L-1,P＜0.01] in E20.25 mg· kg-1 groups compared with the castrated control.The sham and castrated control showed normal glandular epithelium without leukocyte infiltration.In E2 0.25 mg·kg-1 group,extensive infiltration of inflammatory cells was found in the glandular lumens,suggesting the occurrence of chronic prostatitis.In each E2+T groups,fewer inflammatory cells were noted in the stroma around glands.The expressions of TNF-m COX-2 and MIP-1α in sham group were negative or low,while those of castrated control and E2 0.25 mg· kg-1 groups were high,especially in E2 0.25 mg· kg-1 group.The expressions of TNF-α,COX-2 and MIP-1α in each E2+T group were significantly decreased.CONCLUSION Testosterone can inhibit prostatitis and the expression of inflammatory factors,such as TNF-α,COX-2 and MIP-1 α,in castrated SD rats initiated by estrogen.
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There is an increasing demand for neonatal and juvenile animal toxicity studies during the research and development of new drugs. In this paper,we discussed general evaluation parameters of pediatric non-clinical safety with pediatric drugs,such as growth and development and food intake,and paramenters of other organs and systems, such as the central nervous system,reproductive system, behavior evaluation in combination with our own experience. In addition,the characteristics of non-clin?ical safety evaluation of new traditional Chinese medicine materia medica used for juvenile animals were analyzed. This paper is intended reference for non-clinical safety evaluation of pediatric drugs and to gain some experience related to formulation of new guidelines.
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In current research and development of new drugs,the demand for toxicological study using neonatal and juvenile animals is becoming increasingly urgent. In this paper,we discussed the characteristics,importance and necessity of nonclinical safety evaluation for pediatric drugs,considerations for research design,selection of animal species and age,route and duration of drug administration and evaluation indexes. In addition,the characteristics of nonclinical safety evaluation of new traditional Chinese materia medica used for children were analyzed. It is hoped that these studies will not only provide support and reference for nonclinical safety evaluation of pediatric drugs but help accumulate material in formulating relevant guidelines.
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Prostate cancer is the most common cancer among males in the United states,and the incidence has risen dramatically in recent years in China. Lymph node metastasis is a strong predictor of the metastatic potential and poor outcome of prostate cancer. Animal models of human prostate cancer lymphatic metastasis can be used to study the pathogenesis and metastatic mechanisms of prostate cancer,and evaluate the efficacy of new drugs for lymphatic metastasis of prostate cancer. This paper reviews commonly-used animal models of human prostate cancer lymphatic metastasis,including xenograft mouse models,genetically engineered mouse models,rat models and canine models,analyzes their advantages and disadvantages,presents their functions and characteristics,introduces the applications of cancer stem cells in these models and test methods of these models,and highlights the main problems to be solved.
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OBJECTIVE To compare the difference of methods for active systemic anaphylactic reaction induced by breviscapine injection between ″Pharmacopoeia″ 2010 edition, an Attached ⅫG in Traditional Chinese Medicine lnjection Safety Test Application Guidelines ″ Anaphylactic Reaction Test″(thereafter referred to as the method of ″Pharmacopoeia″) and the Traditional Chinese Medicine, Natural Medicine lmmune Toxicity (Anaphylaxis, Anaphylactic Reaction of Light) Technology Guiding Principles in the 2005 Version (thereafter referred to as the method of ″Guiding Principle″) and provide reference for non-clinical safety evaluation of drugs. METHODS According to the methods of ″Pharmacopoeia″and ″Guiding Principle″, respectively, the effect of breviscapine injection on active systemic anaphylactic reaction of guinea pigs was investigated. The guinea pigs were divided into four groups, negative control group, positive control group, breviscapine injection 5 and 50 mg.kg-1 groups. ln the sensitization phase, the guinea pigs were ip administrered with breviscapine injection 0.5 mL each every other day for 3 times. The dose was 5 and 50 mg.kg-1 , respectively. For the method of ″Pharmacopoeia″, on the 14th and 21st days after the first sensitization, the guinea pigs were iv administrered with breviscapine injec-tion 1 mL. For the method of ″Guiding Principle″, the guinea pigs were provocated on the 12th day after the first sensitization. Each group was studied by observing the symptom of anaphylactic reaction and immune time. RESULTS For the method of ″Pharmacopoeia″, on the 14th day after the first sensitization, there was 1 guinea pig with sneezing and (or) the nose-scratching at different time in the 5 mg.kg-1 group. ln the 50 mg.kg-1 group, there was one or two cases of sneezing and (or) 1 case of nose-scratc-hing. The 5 and 50 mg.kg-1 dose groups conformed to the regulations. On the 21st day after the first sensitization, trembling occurred in the 5 mg.kg-1 group, with 1 or 2 guinea pigs sneezing and ( or) scratching the nose. There were 4 guinea pigs (4/ 4) with sneezing 1 and 3 times, cough once or twice, 1 scratching nose and urination at different time, and 1 guinea pigs (1/ 4) appeared 3 times consecutive sneezing and shivering in 50 mg.kg-1 group. The 5 mg.kg-1 group conformed to the regulations, while the 50 mg.kg-1 group did not. For the method of ″Guiding Principle″, the 5 mg.kg-1 group was weak positive or positive, with different degrees of symptoms of an anaphylactic reaction, including 3 guinea pigs scratched nasal symptoms. And the 50 mg.kg-1 group of anaphylactic symptoms including scratc-hing nose, sneezing, coughing and (or) urination, showed positive. CONCLUSION During the active systemic anaphylactic reaction of drugs non-clinical safety evaluation of drugs the advantage of either method should be brought into play. The method of ″ Pharmacopoeia″ may be used for preliminary screening of test samples. ln case pf suspected reactions, the method of ″Guiding Principle″ should be used for more detailed observations.
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Objective To investigate the effect of testosterone on mitotic orientation in rat prostate epithelial cells and the relative differential gene expression.Methods Twenty SPF male SD rats were divided into 2 groups at random and then subjected to castration.One group of rats was administrated with testosterone 3.7 mg daily for 30 days and the control group was only injected with olive oil.Microscopic analysis was performed using immunohistochemistry.Differential gene expression analysis was conducted by gene microarray and RT-PCR techniques.Results In the testosterone-adminis-trated group, there was a significant mitosis orientation parallel to the basement membrane.But in the control group, mito-sis orientation was oriented perpendicular to the basement membrane.Using the gene microarray and RT-PCR techniques, the cell proliferation genes such as Ran, Tgm4 and Wnt2 in Wnt signal pathway were up-regulated in the testosterone group.Conversely, suppressor cell proliferation genes such as Dkk3 and Fas were down-regulated.Conclusions Mitotic orientation of prostate epithelia cells is changed after testosterone administration.Wnt signal pathway and AR singling path-way also have an influence on the mitosis orientation and cell proliferation.
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Elements, including experimental personnel, facili-ties, equipment, apparatus, technology and skills, are essential to carrying out pre-clinical reproductive toxicity research. As to a study , authenticity , normativity , scientificity and innovativeness guarantee the success. These four elements are independent of each other,but mutually supported. Authenticity and scientificity are the footstone and soul, respectively, for drug non-clinical re-productive toxicity research. Normativity guarantees authenticity and scientificity, and innovativeness relies on authenticity. Nor-mativity and scientificity ensure the reliability and dynamics of experimental results which perhaps is an effective way accessing innovation.
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Nomegestrol acetate, 19-norprogesterone de ri vatives, has been used for oral contraception. Recently, studies showed that nom egestrol was a selective estrogen enzyme modulator (SEEM). Nomegestrol is capabl e of inhibiting estrone sulfatase and 17-beta-hydroxysteroid dehydrogenase (17 beta-HSD) and increasing the activity of sulfotransferase,which will provide a new option in the treatment of breast cancer. In addition, nomegestrol has stro ng reversal effects on multidrug resistance in breast cancer cells. In vitro, nomegestrol also exhibits as an inhibitor on endometrial proliferation in uter us. These advances will be introduced in the present review.
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Objective: In the present study we observed the general pattern of the adaptive response of thymocyte apoptosis and cell cycle progression induced by low dose radiation (LDR). Methods: Kunming male mice were irradiated with the inductive dose (D1, 75 mGy) and the challenging dose (D2, 1.5 Gy). The intervals between D1 and D2 were 3, 6, 12, 24 and 60 hours. The changes of thymocyte apoptotic bodies (TAB) and cell cycle progression were measured with flow cytometry with the thymocytes cultured for 4, 20 and 44 hours, respectively, 18 hours after irradiation with D2. Results: When the intervals between D1 and D2 were 3, 6 and 12 hours, the percentages of TAB in the D1 + D2 groups in the thymocytes cultured for 4 and 20 hours were significantly lower than those in the D2 groups (P<0.05) and the percentages of G0/G1 and G2 + M phase cells decreased in varying degrees, while the percentages of S phase cells increased significantly (P<0.05 or P<0.01). Conclusion: The results mentioned above indicate that when the mice were irradiated with 75 mGy (D1, 12.5 mGy/min) 3～12 hours before 1.5 Gy (D2, 0.285 Gy/min) exposure, the adaptive response of apoptosis and cell cycle progression may be induced with the thymocytes cultured for 4 and 20 hours after whole-body irradiation with D2.
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Background and Purpose:Prostate cancer is one of the most common cancers and the second leading cause of cancer-related death in Europan and North American males.The incidence of prostate cancer has also been increasing during the past few decades in China.It is widely accepted that this heterogeneity,which results from the tumor progression driven largely by genomic instability(genetic and/or epigenetic alterations)of tumor cells in primary tumor,endows specific populations of tumor cells with the unique character needed for invasion,migration,and metastasis colony formation in other organs and only these subpopulations possessing thost character can survive the potentially destructive journey from the primary tumor to the sites of metastases.The purpose of the present study was to explore the genes associated with invasion and metastasis of human prostate cancer cell line PC-3M in nude mice.Methods:After PC-3M cells were inoculated into orthotopic site(prostate) in a male nude mouse for two months,tumor cells were isolated from the primary tumor and lymph node metastasis,separately.Cell invasion and adhesion ability in vitro were first compared between two cells.Then metastasis-related genes differentially expressed between them were analyzed by utilizing cDNA microarray technique.Results:The in vitro cell invasion and adhesion potential of tumor cells from lymph node metastasis was significantly higher than those from primary tumor by 2.5 fold and 1.5 fold,respectively.Metastasis-related genes differentially expressed between those two sublines were identified,all of them were up-regulated in the tumor cells from lymph node metastasis and could be categorilized: 1.genes encoding cellular matrix-degrading proteolytic enzyme including cathepsin and MMP.2.genes encoding transcription factors.3.genes related to heterotypic adhesion of tumor cells.4.genes encoding cell surface receptors.Conclusions:There are significant differences in invasion and adhesion potential between cells from primary tumor and those from lymph node metastasis.Some differentially expressed molecules might be playing pivotal roles in promoting tumor cells to migrate from primary tumors to distant metastases,which may be helpful to elucidate the possible mechanism of metastasis in prostate cancer.
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Objective: To investigate the anti-tumor efficiency of B16 melanoma HACs in vivo and in vitro.Methods: Tris-HCI extract and Sephacryl S-200 gel filtration were applied to prepare B16 HACs, and the cytolokicity of specific CTL induced by HACs was tested. Results: The 41, 47 and 53 tube HACs obtained by gel filtration could decrease the tumor incidences, delay the time of tumor development and decrease the mortalitites of mice.Conclusion:60 ~ 97 kD HACs from B16 melanoma cytosol have the activites of inhibiting tumor and could be used in effective anti-tumor therapy.
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It was argued whether bisphenol A(BPA) can induce reproductive toxicity to male,so in the present paper the recently published articles on the reproductive toxicity induced by BPA to male were reviewed.It was indicated that BPA has no obvious embryotoxicity,but BPA can directly induce the reproductive toxicity to male reproductive system,and the testis and prostate were the main target organs of BPA.Even low level BPA exposure could produce toxic effects.