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Molecular Biology Reports Sep 2022In this study, two main research objectives were examined: (1) the cytotoxic and anticancer activities of the aqueous methanol extract from Acacia nilotica flowers on...
PURPOSE
In this study, two main research objectives were examined: (1) the cytotoxic and anticancer activities of the aqueous methanol extract from Acacia nilotica flowers on three human cancer cells, namely lung A549, breast MCF-7, and leukemia THP-1 cells, and (2) the genotoxic effects of A. nilotica extract and its influence on DNA damage induced by N-methyl-N-nitrosourea (MNU) in mice.
METHODS
Mice were orally treated with A. nilotica extract (200, 500, and 800 mg/kg for 4 days) with or without MNU (80 mg/kg intraperitoneally for 24 h).
RESULTS
In vitro experiments showed that A549 cells were the most sensitive to A. nilotica extract among the tested cell lines. A. nilotica extract inhibited A549 cell proliferation by blocking the cell cycle at the G/M phase and accumulating apoptotic cells in the sub-G/G phase in A549 cells. In vivo experiments showed that MNU induced positive and negative genotoxicity in bone marrow cells and spermatocytes, respectively. Negative genotoxicity was observed in A. nilotica extract-treated groups only. However, A. nilotica extract (800 mg/kg) remarkably increased comet tail formation in bone marrow cells. Unexpectedly, the absence of antigenotoxicity was observed in three cotreated groups with A. nilotica extract and MNU compared with the MNU-treated group. Astonishingly, cotreatment with MNU and A. nilotica extract at a dose above 200 mg/kg remarkably increased micronucleus and comet tail formation in bone marrow cells compared with the MNU-treated group.
CONCLUSIONS
A. nilotica extract possessed anticancer activity with relative genotoxic effects at high doses.
Topics: Acacia; Animals; Antineoplastic Agents; DNA Damage; Flowers; Humans; Male; Methylnitrosourea; Mice; Plant Extracts
PubMed: 35934768
DOI: 10.1007/s11033-022-07662-0 -
Nutrition and Cancer 2022Selenomethionine (SeMet) did not prevent prostate cancer in the SELECT trial and in two hormone-driven rat models. However, we have shown that daily oral bolus... (Randomized Controlled Trial)
Randomized Controlled Trial
Selenomethionine (SeMet) did not prevent prostate cancer in the SELECT trial and in two hormone-driven rat models. However, we have shown that daily oral bolus administration of next-generation selenium forms, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) at 3 mg Se/kg body weight, inhibits prostate carcinogenesis in the TRAMP and -deficient mouse models and In Vivo growth of human prostate cancer cells. Here, we determined whether these Se forms prevent prostate cancer in a chemically induced-androgen promoted carcinogenesis rat model in which SeMet was not preventive. WU rats were treated with methylnitrosourea, and one week later, slow-release testosterone implants when they were randomized to groups fed AIN-93M diet supplemented with 3 ppm selenium as MSeA or MSeC or control diet. Mean survival, tumor incidence in all accessory sex glands combined (dorsolateral and anterior prostate plus seminal vesicle) and the incidence of tumors confined to dorsolateral and/or anterior prostate were not statistically significantly different among the groups. Thus, MSeA and MSeC feeding was not preventive in this model. The contrast with the inhibitory effects of MSeA and MSeC in mouse models may be due to differences in carcinogenic mechanisms, selenium dosage, delivery mode, and pharmacokinetics or fundamental rat-mouse differences in selenium metabolism.
Topics: Androgens; Animals; Antioxidants; Carcinogenesis; Carcinogens; Diet; Disease Models, Animal; Humans; Male; Mice; Organoselenium Compounds; Prostate; Prostatic Neoplasms; Rats; Selenium; Selenocysteine; Selenomethionine
PubMed: 35762420
DOI: 10.1080/01635581.2022.2093387 -
Ecotoxicology and Environmental Safety Jul 2022N-methyl-N-nitrosourea (MNU) is a prevalent environmental carcinogen, which leads to tumors in various organs in animal models, while the mechanisms involved were still...
N-methyl-N-nitrosourea (MNU) is a prevalent environmental carcinogen, which leads to tumors in various organs in animal models, while the mechanisms involved were still not fully understood. It is well known that anomalous angiogenesis is a key step in tumorigenesis and progression. In this study, we found that MNU induced abnormal angiogenesis which was accompanied by upregulation of rspo1, p53 and vegfaa in zebrafish embryos. Moreover, it revealed that MNU-induced ectopic sprouting of blood vessels was significantly reduced in rspo1-knockdown but not p53-knockdown embryos, indicating that rspo1 was necessary for MNU-induced abnormal angiogenesis. Additionally, pharmaceutical activation or inhibition of Wnt/β-catenin signaling pathway using (2'Z,3'E)- 6-bromoindirubin-3'-oxime or CCT036477 significantly increased or inhibited the pro-angiogenic effect of MNU on developing zebrafish embryos, which was confirmed by the effect of proliferation and migration in MNU-treated bEnd.3 cells. These data together indicated that rspo1/Wnt/β-catenin/vegfaa axis is involved in the modulation of MNU-induced anomalous angiogenesis.
Topics: Animals; Endothelial Cells; Methylnitrosourea; Mice; Neovascularization, Pathologic; Wnt Signaling Pathway; Zebrafish; beta Catenin
PubMed: 35623148
DOI: 10.1016/j.ecoenv.2022.113674 -
Journal of Toxicologic Pathology Apr 2022The retina consists of several layers, and drugs can affect the retina and choroid separately. Therefore, investigating the target layers of toxicity can provide useful...
The retina consists of several layers, and drugs can affect the retina and choroid separately. Therefore, investigating the target layers of toxicity can provide useful information pertaining to its modes of action. Herein, we compared gene expression profiles obtained via microarray analyses using samples of target layers collected via laser capture microdissection and samples of the whole globe of the eye of rats treated with -methyl--nitrosourea. Pathway analyses suggested changes in the different pathways between the laser capture microdissection samples and the whole globe samples. Consistent with the histological distribution of glial cells, upregulation of several inflammation-related pathways was noted only in the whole globe samples. Individual gene expression analyses revealed several gene expression changes in the laser capture microdissection samples, such as caspase- and glycolysis-related gene expression changes, which is similar to previous reports regarding -methyl--nitrosourea-treated animals; however, caspase- and glycolysis-related gene expressions did not change or changed unexpectedly in the whole globe samples. Analyses of the laser capture microdissection samples revealed new potential candidate genes involved in the modes of action of -methyl--nitrosourea-induced retinal toxicity. Collectively, our results suggest that specific retinal layers, which may be targeted by specific toxins, are beneficial in identifying genes responsible for drug-induced ocular toxicity.
PubMed: 35516843
DOI: 10.1293/tox.2021-0064 -
Anticancer Research May 2022Genetic and environmental factors interact to dictate the risk of cancer, and animal models are expected to provide avenues for identifying such interactions. The aim of...
BACKGROUND/AIM
Genetic and environmental factors interact to dictate the risk of cancer, and animal models are expected to provide avenues for identifying such interactions. The aim of the study was to clarify the genetic susceptibility of Copenhagen rats to spontaneous, radiation-induced, and chemically-induced mammary carcinogenesis.
MATERIALS AND METHODS
Female Copenhagen and Sprague- Dawley rats and their F hybrids were subjected at age 7 weeks to γ-irradiation or intraperitoneal injection with 1-methyl-1-nitrosourea or were not treated, and palpable mammary tumours were diagnosed histologically. Data were pooled with previous data acquired for both nontreated and irradiated Sprague-Dawley rats.
RESULTS
Radiation and 1-methyl-1-nitrosourea both significantly increased the incidence of mammary cancer in all strains. Copenhagen and F rats displayed a significantly lower incidence than Sprague-Dawley rats in all groups, with relatively higher incidence after irradiation. F rats exhibited significantly higher mammary cancer incidence than Copenhagen rats in the nontreated, but not the treated, groups. The interaction of the strain and exposure effects was suggested to be quasi-multiplicative.
CONCLUSION
Copenhagen rats display non-uniform resistance to spontaneous, radiation-induced, and chemically-induced mammary carcinogenesis with dominant inheritance over Sprague-Dawley rats.
Topics: Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Female; Humans; Mammary Neoplasms, Experimental; Methylnitrosourea; Rats; Rats, Sprague-Dawley
PubMed: 35489722
DOI: 10.21873/anticanres.15720 -
The Prostate Aug 2022There is evidence to suggest that green tea soy may have protective effects against prostate cancer, but there are several epidemiologic and clinical studies that did...
BACKGROUND
There is evidence to suggest that green tea soy may have protective effects against prostate cancer, but there are several epidemiologic and clinical studies that did not identify such an effect. We tested the notion of protective effects in a rat model of prostate carcinogenesis that has been predictive of the effects of selenium and vitamin E in randomized clinical trials and a human prostate cancer xenograft model in nude mice and rat prostate tumor cells transplanted in immune-competent syngeneic animals.
METHODS
Prostate cancer was induced in rats with methylnitrosourea and testosterone and tumor incidence was determined. Subcutaneous tumor growth was measured resulting from injected cells isolated from rat prostate cancers grafted in syngeneic animals and from the prostate-specific antigen (PSA)-producing human prostate cancer PC346 xenografted in nude mice. Brewed decaffeinated green tea infusion or caffeinated green tea extract and the same 300 mg/ml concentration of caffeine were provided in drinking water of the rats and nude mice.
RESULTS
Caffeinated green tea extract and caffeine provided in drinking water did not modify the induction of prostate cancer in the rat model compared with control rats. The same drinking water treatments also did not affect the growth and PSA production of PC346 human prostate cancer xenografts in nude mice and the growth of two transplantable rat prostate cancer tumor lines in Wistar Firth rats. Brewed green tea infusion as drinking water did also not affect tumor growth in these xeno- and allograft models.
CONCLUSION
These animal studies with drinking water exposure to green tea and caffeine do not support the idea that green tea is protective against prostate cancer.
Topics: Animals; Caffeine; Carcinogenesis; Disease Models, Animal; Drinking Water; Heterografts; Humans; Male; Mice; Mice, Nude; Plant Extracts; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Rats; Rats, Wistar; Tea
PubMed: 35485427
DOI: 10.1002/pros.24364 -
International Journal of... 2022Angiogenesis is the process of new vascular formation, which is derived from various factors. For suppressing cancer cell growth, targeting angiogenesis is one of the...
Angiogenesis is the process of new vascular formation, which is derived from various factors. For suppressing cancer cell growth, targeting angiogenesis is one of the therapeutic approaches. Vascular endothelial growth factor family receptors, including Flt-1, Flk-1 and Flt-4, have been found to play an essential role in regulating angiogenesis. Rapamycin is a macrolide compound with anti-proliferative properties, while platelet factor-4 (PF-4) is an antiangiogenic ELR-negative chemokine. Rapamycin inhibits mTOR ligands activation, thus suppressing cell proliferation, while PF-4 inhibits cell proliferation through several mechanisms. In the present study, we evaluated the effects of rapamycin and platelet factor-4 toward breast carcinoma at the proteomic and genomic levels. A total of 60 N-Methyl-N-Nitrosourea-induced rat breast carcinomas were treated with rapamycin, platelet factor-4 and rapamycin+platelet factor-4. The tumours were subsequently subjected to immunohistochemical protein analysis and polymerase chain reaction gene analysis. Protein analysis was performed using a semiquantitative scoring method, while the mRNA expression levels were analysed based on the relative expression ratio. There was a significant difference in the protein and mRNA expression levels for the selected markers. In the rapamycin+platelet factor-4-treated group, the Flt-4 marker was downregulated, whereas there were no differences in the expression levels of other markers, such as Flt-1 and Flk-1. On the other hand, platelet factor-4 did not exhibit a superior angiogenic inhibiting ability in this study. Rapamycin is a potent antiangiogenic drug; however, platelet factor-4 proved to be a less effective drug of anti-angiogenesis on rat breast carcinoma model.
Topics: Angiogenesis Inhibitors; Animals; Female; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Methylnitrosourea; Platelet Factor 4; Rats, Sprague-Dawley; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Rats
PubMed: 35037503
DOI: 10.1177/20587384211059673 -
Scientific Reports Dec 2021Retinal prosthesis is regarded as the treatment for vision restoration in the blind with retinal degeneration (RD) due to the loss of photoreceptors. A strategy for...
Retinal prosthesis is regarded as the treatment for vision restoration in the blind with retinal degeneration (RD) due to the loss of photoreceptors. A strategy for retinal prosthesis is to electrically activate surviving neurons. The retina's response to electrical stimulation in a larger RD model has not been studied yet. Therefore, in this study, we investigated electrically evoked retinal responses in a previously validated N-methyl-N-nitrosourea (MNU)-induced porcine RD model. Electrically evoked responses were evaluated based on the number of retinal ganglion cell (RGC) spikes via multichannel recordings. Stimulation pulses were applied to degenerative and wild-type retinas with pulse modulation. Compared to wild-type retinas, degenerative retinas showed higher threshold values of pulse amplitude and pulse duration. The rate of increase in the number of RGC spikes relative to stimulus intensity was lower in degenerative retinas than in normal retinas. In severely degenerated retinas, few RGCs showed electrically evoked spikes. Our results suggest that the degenerative porcine retina requires a higher charge than the normal porcine retina. In the early stage of RD, it is easier to induce RGC spikes through electrical stimulation using retinal prosthesis; however, when the degeneration is severe, there may be difficulty recovering patient vision.
Topics: Animals; Disease Models, Animal; Electric Stimulation; Evoked Potentials, Visual; Female; Methylnitrosourea; Retinal Degeneration; Retinal Ganglion Cells; Swine; Swine, Miniature
PubMed: 34921172
DOI: 10.1038/s41598-021-03439-w -
Clinical & Translational Oncology :... May 2022The aim of this study was to investigate the involvement of the SDF-1/CXCR4 axis in the process of BMMSC homing in prostate cancer (PCa) in vivo and in vitro.
PURPOSE
The aim of this study was to investigate the involvement of the SDF-1/CXCR4 axis in the process of BMMSC homing in prostate cancer (PCa) in vivo and in vitro.
METHODS
After verification of BMMSCs, we fixed the concentration gradient of SDF-1 for BMMSC cultivation to analyze CXCR4 expression by qRT-PCR and flow cytometric analysis. Furthermore, we developed a non-contact co-culture system and explored the participation of the SDF-1/CXCR4 axis in PCa using qRT-PCR, flow cytometry, and ELISA. In addition, A green fluorescent protein (GFP)-transplanted methylnitrosourea (MNU)-induced PCa mouse model was established to investigate the CXCR4 expression in vivo.
RESULTS
The CXCR4 expression was up-regulated with the increase in SDF-1 concentrations, and elevated SDF-1 had a significant promoting effect on cell proliferation and migration in BMMSCs. Moreover, the CXCR4 expression of BMMSCs was significantly increased in the non-contact co-culture model with vascular endothelial cells (VECs), and analysis of this model also showed that the proliferation and migration of BMMSCs were promoted in the presence of VECs. The ELISA assay showed that the SDF-1 levels in the co-culture model at 48 h were significantly increased. Twenty of the GFP-transplanted mice were divided into a PCa group and a control group, and four GFP-transplanted mice were observed to have prostate tumorigenesis. It also showed that CXCR4 was obviously increased in the prostate tissue of PCa mice.
CONCLUSION
Our findings suggest that BMMSCs could home and promote the proliferation and migration of PCa through the SDF-1/CXCR4 axis in vivo and in vitro.
Topics: Animals; Bone Marrow Cells; Cell Movement; Chemokine CXCL12; Endothelial Cells; Humans; Male; Mesenchymal Stem Cells; Mice; Prostatic Neoplasms; Receptors, CXCR4; Signal Transduction
PubMed: 34855138
DOI: 10.1007/s12094-021-02740-4 -
STAR Protocols Dec 2021N-Methyl-N-nitrosourea, an N-nitroso compound converted from dietary nitrite by , causes somatic mutations in epithelial cells and induces gastric premalignancy. Here,...
N-Methyl-N-nitrosourea, an N-nitroso compound converted from dietary nitrite by , causes somatic mutations in epithelial cells and induces gastric premalignancy. Here, we describe a detailed protocol for induction of gastric tumor and analysis of tumor phenotypes in mice. This model can be widely used for studying the initiation and growth of gastric cancer. For complete details on the use and execution of this protocol, please refer to Li et al. (2021).
Topics: Animals; Male; Methylnitrosourea; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Stomach; Stomach Neoplasms
PubMed: 34585155
DOI: 10.1016/j.xpro.2021.100814