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1.
Yuko Yamaguchi Yachiyo Fukunaga Mizuho Takagi Tsubasa Saito Kazutoshi Tamura Toru Hoshiya 《Journal of toxicologic pathology》2021,34(4):299
5-Fluorouracil (5-Fu) is a DNA-damaging agent and teratogenic in rodents. This study aimed to investigate its influence on neural progenitor cells (NPCs) in the developing fetal rat brain. Dams were intraperitoneally injected with 5-Fu (50 mg/kg b.w.) on gestation day 13 and its effects on fetal NPCs were observed from 3 to 72 hours after treatment (HAT), via periodic examination at six intervals. In NPCs of the fetal brain, the p53-labeling index (LI%) was markedly elevated at 3 HAT. Pyknosis and cleaved caspase-3-LI% also increased at 3 HAT, reaching peak values at 9 and 12 HAT. These parallel changes suggested the induction of apoptosis through a p53-mediated pathway. Pyknotic NPCs were distributed across the ventricular zone (VZ) of the telencephalic wall until 12 HAT, and became localized in the medial and dorsal layers at 12 and 48 HAT. Significant decreases in the numbers of mitotic NPCs and BrdU-LI% were noted from 3 HAT and 24 HAT, respectively. BrdU-positive NPCs were located in the ventral and middle layer at 24 and 48 HAT. p21-positive cells were detected at 12 and 24 HAT. The present results demonstrated that p53-mediated apoptosis was induced in all phases of the cell cycle of the NPCs in the early stage after 5-FU treatment. Furthermore, apoptosis of NPCs and suppression of cell proliferative activity are the events that take place in parallel leading to prominent reduction in the width of the telencephalic wall. 相似文献
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Ohira T Ando R Andoh R Nakazawa T Nishihara K Yamamoto S Nakamura N Tamura K 《Journal of toxicologic pathology》2009,22(3):167-171
Busulfan, an antineoplastic bifunctional-alkylating agent, is known to induce developmental anomalies. In the present study, we examined the distribution and sequence of pyknotic cells in rat fetal tissues exposed to busulfan. Pregnant rats on gestation day 13 were administered intraperitoneally 30 mg/kg of busulfan, and fetal tissues were examined at 6, 12, 24, 36, 48, 72 and 96 hours after treatment (HAT). Pyknosis of component cells was observed markedly in the brain, moderately in the eyes and spinal cord and mildly in the craniofacial tissue, mandible, limb buds, tail bud, ganglions, alimentary tract, lungs, kidneys, pancreas and liver. In the brain, mitotic inhibition was also detected. Most of the pyknotic cells were considered to be apoptotic cells judging from the results of TUNEL staining and electron microscopic examination. Commonly in the above-mentioned tissues, pyknotic cells began to increase at 24 HAT, peaked at 36 or 48 HAT and disappeared at 96 HAT, which is when the histological picture returned to normal in most tissues except for the brain, spinal cord and eyes. The present study clarified the outline of busulfan-induced apoptosis in rat fetuses. 相似文献
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Effect of methotrexate exposure at late gestation on development of telencephalon in rat fetal
brain
Ayano HIRAKO Satoshi FURUKAWA Takashi TAKEUCHI Akihiko SUGIYAMA 《The Journal of veterinary medical science / the Japanese Society of Veterinary Science》2016,78(2):213-220
Pregnant rats were treated with 30 mg/kg of methotrexate (MTX) on gestation day (GD) 16, and fetal brains
were examined time-dependently. On GD 20, the appearance of the telencephalon in the MTX group was different
from that in the control group, and the major axis of the telencephalon of the MTX group was shortened,
compared to that of the control group. In the sagittal section of the telencephalon in the MTX group on GD 20,
histopathological findings of deformation and narrowing of the cerebral ventricle, the disturbance of the
arrangement of the marginal cell layer of subventricular zone (SVZ) and thickening of telencephalic wall,
cortical plate and ventricular zone (VZ)/SVZ were possibly attributable to neuronal migration disorders by
MTX. Through all the experimental period, few pyknotic cells or TUNEL-positive cells were observed in the
VZ/SVZ of the telencephalic wall and striatum in the control group. On the other hand, in the VZ/SVZ of the
telencephalic wall and striatum in the MTX group, pyknotic cells or TUNEL-positive cells were observed on GD
17, and they increased significantly on GD18 and then decreased to the control levels from GD 19 onward. The
phospho-Histone H3-positive rate decreased remarkedly in the VZ/SVZ of the telencephalic wall and striatum of
the MTX group on GDs 17 and 18, compared to the control group, but they recovered on and after GD 19. These
results suggested that there was a high possibility that development of the telencephalon in this period
required strong folic acid. 相似文献
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Feline lymphoma is one of the most frequently diagnosed tumors in cats. Lipotropes are dietary methyl donors that may modulate DNA methylation status and the expression of genes involved in growth and apoptosis of feline lymphoma cells. The specific objective of the study was to determine if lipotropes affect the growth of feline lymphoma cells, which entailed examining a correlation between lymphoma cell proliferation and apoptosis. F1B and FeLV-3281 cells were cultured and treated with 20 times the level of lipotropes contained in the basal culture medium. Cell growth and death and caspase 3 and tumor protein p53 activity were measured. Lipotropes were found to significantly reduce cell growth; increased cell death and caspase 3 and p53 activity was seen in F1B cells after 72 h, but the effect was minimal on FeLV-3281. These results could be useful in the development of dietary strategies for treating and preventing feline lymphoma. 相似文献
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Toko Ohira Tsubasa Saito Ryo Ando Kazutoshi Tamura Toru Hoshiya 《Journal of toxicologic pathology》2014,27(1):25-29
Busulfan is an antineoplastic bifunctional alkylating agent. We previously reported the busulfan-induced systemic histopathological changes in fetal rats and the sequence of brain lesions in fetal and infant rats. In the present study, in order to clarify the nature and sequence of busulfan-induced systemic histopathological changes in infant rats, 6-day-old male infant rats were subcutaneously administered 20 mg/kg of busulfan and histopathologically examined at 1, 2, 4, 7 and 14 days after treatment (DAT). As a result, histopathological changes characterized by pyknosis of component cells were observed in the heart, lungs, stomach, intestines, liver, kidneys, testes, epididymides, hematopoietic and lymphoid tissues, dorsal skin and femur as well as in the brain and eyes (data not shown in this paper). Such pyknosis transiently appeared until 7 DAT with prominence at 2 and/or 4 DAT in each tissue, except for the thymus, in which pyknosis peaked at 1 DAT. Most of the pyknotic nuclei were immunohistochemically positive for cleaved caspase-3, indicating that pyknotic cells were apoptotic. Different from the reports of fetal and adult rats, apoptosis was also found in cardiomyocytes and osteoblasts in infant rats. 相似文献
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A Dalman P Eftekhari‐Yazdi MR Valojerdi A Shahverdi H Gourabi E Janzamin R Fakheri F Sadeghian F Hasani 《Reproduction in domestic animals》2010,45(5):e46-e53
Cell cycle stage and synchronization of donor cells are important factors influencing the success of somatic cell nuclear transfer. This study examined whether serum starvation has any effect on specific cell death. We also studied the effects of serum starvation, culture to confluence, and full confluency (confluent + 72 h) on cell cycle characteristics and apoptosis of goat dermal fibroblast cells. The cells were obtained from the ear of a 1.5‐year‐old female goat. The following experimental groups were analysed for fibroblast cells: (i) normally growing, (ii) confluent, (iii) full confluency, (iv) cells starved for 48 h and (v) cells starved for 72 h. Analysis of cell cycle distribution by flow cytometry showed that 4.56 and 51.88% of normal cycling cells were at the G0 and G1 phases respectively. In the confluent group, 80% of the cells were arrested in the G0/G1 phase. Serum starvation for 48 and 72 h arrested 84.78% and 90.1% cells at the G0/G1 phase respectively which showed a significant difference when compared with the control group (p < 0.05). Double staining by PI and FITC distinguishes G0 phase from G1 phase. In the full confluency group, 91.53% of cells were at G0/G1 stage, but in contrast to the serum starved group, this high percentage of G0/G1 cells was mainly associated with G1 cells. Under normal culture conditions, 6.39% of cells underwent early apoptosis. In the confluent group 8.93% of cells showed early apoptosis. Serum starvation for 48 and 72 h caused early apoptosis in 8.91 and 39.83% of the cells respectively. Full confluency treatment did not increase the number of apoptotic cells significantly (8.67%). After 72 h, serum starvation significantly increased early apoptosis (p < 0.05). In conclusion, the use of full confluency is suitable for cell cycle synchronization because it arrests cells at the G0/G1 phase and also induces less apoptosis in comparison with the serum starvation group. 相似文献
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Background Glaucoma in humans is a second leading cause of irreversible vision loss in the world and can affect all age groups as well as all populations. The precise mechanism of retinal ganglion cell (RGC) death and progressive degeneration of optic nerve in glaucoma is not understood. It has been suggested that apoptosis is the common pathway that leads to the death of RGCs in glaucoma and that neurotrophin 4 (NTF4) protein plays a role in the protection of RGCs by activating tyrosine kinase receptors. Additionally, one previous study suggested that p53 codon 72 polymorphism (R72P) might have a greater susceptibility to apoptosis in some ethnic population. Glaucoma also occurs in dogs, and the primary glaucoma in beagles is inherited as an autosomal recessive trait. Although recently a candidate gene has been isolated, the mechanism underlying RGC death is not understood. Method To understand whether the same p53 and NTF4 pathway mechanism is involved in a beagle model of glaucoma, we have isolated NTF4 gene from dog and analyzed both p53 and NTF4 genes for mutations in glaucomatous animals. Results Our analyses failed to identify any disease-causing mutations in both genes with the exception of two polymorphisms in NTF4 gene. However, these are not pathogenic changes because they are also present in normal animals and are not segregated with the disease. Conclusion These results suggest that impaired neurotrophin signaling or compromised trophic support to the retina and p53-mediated apoptosis may not be the underlying mechanism of RGCs death in a beagle model of glaucoma. 相似文献
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This study examines apoptosis and viral neuropathogenesis in a murine model infected with vesicular stomatitis virus (VSV). VSV induces apoptotic cell death in cultured cell lines, raising the possibility that apoptosis of infected neurons and other target cells may contribute to disease and mortality. To determine whether or not VSV induces apoptosis in neural tissues, mice were inoculated intranasally with VSV. At 24, 48, 72, 96, and 120 hours postinfection, brain tissues were assayed for the presence of viral RNA by in situ hybridization and viral antigen by immunohistochemistry. Apoptosis was identified by in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling and electron microscopy. Viral replication and lesions were observed predominantly in central nervous system neurons. Apoptotic cell death was restricted to the same regions of the brain in which infected cells and tissue injury were identified. Results suggest that VSV-induced apoptosis is a mechanism causing cell death, tissue injury, and mortality in VSV-infected mice. 相似文献
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Pagnini U Montagnaro S Sanfelice di Monteforte E Pacelli F De Martino L Roperto S Florio S Iovane G 《Veterinary immunology and immunopathology》2005,103(3-4):283-293
Programmed cell death (PCD), or apoptosis, is initiated in response to various stimuli, including virus infection. A number of studies have shown that deregulation of apoptosis is an important feature of virus-induced immunosuppression for various viral diseases. In the present study, CapHV-1 was found to cause apoptosis in mitogen-stimulated as well as nonstimulated caprine peripheral blood mononuclear cells (PBMC). Apoptotic index, as quantified by fluorescent dyes, revealed a significant increase in the percentage of apoptotic cells at 24 and 48 h postinfection as compared to their respective noninfected controls. Apoptosis specific internucleosomal laddering in DNA from CapHV-1 infected PBMC was seen in agarose gel electrophoresis. No DNA fragmentation was observed in control noninfected PBMC. Virus-induced apoptosis was reduced by Z-VAD-FMK, an aspecific caspase inhibitor, by AC-DEVD-CHO (caspase-3-specific) and AC-VEID-CHO (caspase-6-specific) treatment. PCD in CapHV-1 infected peripheral blood mononuclear cells occurs at the G0/G1 phase of the cell cycle. However, penetration of virus particles and infection was not required for PCD, as UV-inactivated CapHV-1 induced apoptosis of mitogen-stimulated bovine peripheral blood mononuclear cells in vitro. 相似文献
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人端粒酶逆转录酶(hTERT)基因对山羊胎儿成纤维细胞的影响 总被引：2，自引：1，他引：1
利用包含人端粒酶逆转录酶（hTERT）基因的真核表达载体pCI-neo-hTERT转染山羊胎儿成纤维细胞,筛选阳性克隆扩大培养,并对转染阳性细胞分别进行RT-PCR检测,倍性分析,细胞周期检测和细胞凋亡检测,以观察该基因对山羊胎儿成纤维细胞的影响。试验结果表明,筛选出的阳性细胞现已传至第50代;RT-PCR检测,端粒酶基因成功整合到山羊胎儿成纤维细胞并持续表达;倍性分析结果显示,转基因第50代细胞呈正常二倍体;对细胞周期进行分析,结果显示转基因第50代细胞较未转染第30代细胞有较高的S期,说明该细胞DNA合成旺盛,具有很强的增殖能力;细胞凋亡检测结果发现,转基因第50代细胞中凋亡细胞的比例明显少于转染第30代山羊胎儿成纤维细胞。这些试验结果均表明,hTERT能增加山羊胎儿成纤维细胞体外培养的代数,并保持细胞良好的形态及较强的增殖能力。 相似文献
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Sterility in male hypogonadic (hgn/hgn) rats results from congenital testicular dysplasia caused by a single recessive gene hgn on rat chromosome 10. We recently identified an insertion mutation in the Spag5/astrin gene of hgn/hgn rats that may cause defective proliferation of immature Sertoli cells in the postnatal hgn/hgn testis. Since the pathological alterations were present in the testes at birth, we examined the involvement of defective mitosis and apoptotic cell death in embryonic development of hgn/hgn testes. Testicular hypoplasia was apparent at embryonic day (ED) 18.5. Immunostaining of hgn/hgn testes at ED 21.5 with antibody to GATA-4, which is specific for fetal Sertoli cells in the seminiferous cords, showed that the significant decrease in the number of fetal Sertoli cells was accompanied by a two fold increase in their mitotic index and abnormal mitosis and apoptosis. Prior to this, we observed a decrease in the number of BrdU-labeled cells, an increase in the number of TUNEL-positive apoptotic cells, and presence of MIS-positive apoptotic cells in hgn/hgn testes on ED 17.5 and 18.5. These results suggest that the Spag5 mutation may cause a reduction in mitotic activity and an increase in apoptosis of fetal Sertoli cells in hgn/hgn testes. 相似文献
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本研究旨在观察羊驼睾丸的出生后发育和精子发生过程中的细胞凋亡及凋亡相关蛋白Bcl2和Caspase3 的定位.取材新生、12月龄和24月龄羊驼的睾丸,用TUNEL法检测睾丸发育和精子发生过程的细胞凋亡,用免疫组织化学技术检测凋亡相关蛋白Bcl2和Caspase3在羊驼出生后发育和精子发生过程中的定位.结果显示在新生羊驼睾丸未检测到TUNEL阳性细胞,Caspase3和Bcl2表达于间质细胞,提示在新生期凋亡蛋白参与间质细胞凋亡的调节,为曲精小管的发育提供空间;12月龄羊驼睾丸TUNEL阳性细胞定位于曲精小管中央部分,Caspase3 和Bcl2定位于间质细胞和曲精小管中央生殖细胞,提示在青春期(12月龄)羊驼睾丸,细胞凋亡和凋亡相关蛋白参与曲精小管管腔形成的调节;24月龄羊驼睾丸TUNEL阳性细胞定位于精原细胞、精母细胞和精子细胞,Caspase3 和Bcl2定位于间质细胞和各个发育阶段的生精细胞,Caspase3阳性细胞在精原细胞最高,向精母细胞和精子细胞逐渐减少,Bcl2在精原细胞弱阳性表达,在血睾屏障以内的曲精小管近腔室部分呈弥散性强阳性表达,提示在性成熟(24月龄)羊驼睾丸精子发生过程中,细胞凋亡主要发生于精原细胞和早期精母细胞,Bcl2可能抑制精母细胞之后生殖细胞的凋亡.结果提示在羊驼睾丸出生后发育和精子发生过程中存在细胞凋亡现象;凋亡蛋白Caspase3和Bcl2参与羊驼睾丸发育和精子发生过程中细胞凋亡的调节. 相似文献
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We developed a real-time PCR assay for measuring relative quantities (RQ) of p53 tumor suppressor mRNA in the whitefish (Coregonus lavaretus, Salmonidae, Teleostei). Real-time PCR primers for the p53 gene were designed from a region that was found to be conserved among salmonid p53 genes. To test for the usefulness of the assay we performed a treatment study, using benzo[a]pyrene (B[a]P) a putative p53-inducer. Two groups of hatchery raised whitefish, with an average body mass of 15 g and total length of 12 cm were either given an intraperitoneal injection (10 mg x kg(-1)) of B[a]P in corn oil (2 mg B[a]P ml(-1) corn oil) or corn oil alone (Control). After treatment (48 h, 7 degrees C), two random fish from each group were anesthetized and the liver, head kidney and brain were collected for mRNA isolation and analysis. In the control fish, relative quantification analysis based on the p53 mRNA levels in liver (RQ=1.00) showed higher basal levels of p53 mRNA in the head kidney (RQ= 1.69), and lower in the brain (RQ=0.41). In all three tissues sampled, p53 mRNA was affected by treatment with B[a]P. Liver tissue showed the greatest induction (RQ=1.53) from base levels (RQ=1.00), followed by brain (RQ=1.36), and head kidney (RQ=1.23). These results confirm that p53 mRNA is generally present at lower levels in differentiated tissues (liver and brain) than in those tissues with cell lines (head kidney), and demonstrate that p53 is moderately inducible by B[a]P in the whitefish. The approach presented here has the advantage of providing rapid and accurate measures of p53 induction in various tissues of fish responding to PAH contaminant exposure. 相似文献