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Heliyon Apr 2021Methylguanidine, an originator of carcinogenic methylnitrosourea, has been found in many animal meats and processed stored food often in high concentration. The present...
Methylguanidine, an originator of carcinogenic methylnitrosourea, has been found in many animal meats and processed stored food often in high concentration. The present study was designed to understand the multiple dose effect of N-methyl-N-nitrosourea (MNU), an end product of methylguanidine, in Swiss albino mice fertility as well as cancer induction. Accordingly, a total of five experimental groups of animal (female Swiss albino mice) were taken, considering group-I as vehicle control and group-II-V as treatment groups (whereas group-II-Vwere treated with single to quadruple doses of 50 mg/kg of MNU respectively in a three weeks interval). After accomplishment of MNU injection, each female mice was mated with male mice to check the fertility efficiency. The results of the study indicated that, mice treated with highest number of MNU doses were 42.85% less efficient in getting pregnant than the control mice. There were noted changes in body weight, food and water intake upon MNU-exposure compared to control group. A significant increase in cumulative weight of vital female organs like uterus and ovary were also observed in mice injected with quadruple doses of MNU (50 mg/kg) compared to control mice. The findings of the study suggest the direct effect of MNU in pregnancy, without any cancer incidence in the vital female organs of Swiss albino mice.
PubMed: 33912714
DOI: 10.1016/j.heliyon.2021.e06738 -
Food and Chemical Toxicology : An... May 2021alpha-Glycosyl Isoquercitrin (AGIQ), is used in Japan as a food additive and was granted generally recognized as safe (GRAS) status in 2005 (FEMA) and 2007 (FDA). The...
alpha-Glycosyl Isoquercitrin (AGIQ), is used in Japan as a food additive and was granted generally recognized as safe (GRAS) status in 2005 (FEMA) and 2007 (FDA). The safety and toxicity information for AGIQ is sparse and therefore, the carcinogenicity potential of AGIQ was examined in the CByB6F1-Tg(HRAS)2Jic (rasH2) model. One hundred female and male rasH2 mice, each, were allocated to one of four designated dose groups; 0 (control)%, 1.5%, 3.0% or 5.0% AGIQ. Animals were administered the diets for six months and an additional 10 females and 10 males, each, were administered a positive control, N-methyl-N-nitrosourea (MNU). Body weights and clinical observations were collected. A full screen necropsy, organ weights, clinical chemistry, urinalysis and histopathology were performed. The positive control animals elicited appropriate responses specific to this strain (rasH2) of mice. There were statistically significant sporadic non-dose-dependent changes in clinical chemistries without corresponding pathological correlation. No microscopic AGIQ-related findings were noted; the range of pathology observations were all considered background findings, either specific to rasH2 mice or common to inbred strains of mice. Therefore, under the study conditions, the no-observed-adverse-effect level (NOAEL) was determined to be more than 5.0% (7215.4 mg/kg BW/day in male mice and 14685.5 mg/kg/day in female mice).
Topics: Animals; Body Weight; Carcinogenicity Tests; Dose-Response Relationship, Drug; Feeding Behavior; Female; Food Additives; Male; Methylnitrosourea; Mice; Mice, Transgenic; No-Observed-Adverse-Effect Level; Organ Size; Quercetin
PubMed: 33771599
DOI: 10.1016/j.fct.2021.112103 -
Biomedicine & Pharmacotherapy =... Jun 2021Combretastatin A-4 (CA-4) received significant interest as a potential anticancer agent in recent years. Several CA-4 analogs were synthesized and investigated to...
UNLABELLED
Combretastatin A-4 (CA-4) received significant interest as a potential anticancer agent in recent years. Several CA-4 analogs were synthesized and investigated to enhance the activity or solve the in vivo decreased activity of CA-4.
AIM
The present study aims to investigate the chemotherapeutic and the antiproliferative effects of the mono and the dual therapy of the newly synthesized CA-4 analogs OMA1520 and OMA1774 against hepatocellularcarcinoma (HCC) induced in male adult rats by N-methylnitrosourea (MNU).
METHODS
50 male rats were divided into 5 groups of 10 animals in each group. Group I: normal healthy control; group II: MNU treated group, group III: MNU animals treated by OMA1520, group IV: MNU animals treated by OMA1774, and group V: MNU animals treated by both OMA1520 and OMA1774. The rats were assessed for liver cancer progression or inhibition by evaluating the histopathological, immunohistochemical, biochemical, and antioxidant enzyme status.
RESULTS
The present work indicated that OMA1520 and OMA1774 possessed substantial chemotherapeutic efficiency against HCC. The histological and immunohistochemical examinations of liver tissues confirmed the biochemical sera data. Also, they diminished the cytotoxic effects of MNU and restored the normal histological hepatic architecture. Both analogs restored the normal levels of liver enzymes and functions and revealed potential antioxidant effects. OMA1520 and OMA1774 reduced the inflammatory and tumor markers' elevated expressions in serum.
CONCLUSION
Substantial evidence in our results suggests that both CA-4 analogs could be possible alternative anticancer agents, and their co-administration provides a synergistic activity.
Topics: Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Carcinoma, Hepatocellular; HL-60 Cells; Hep G2 Cells; Humans; Liver Neoplasms, Experimental; MCF-7 Cells; Male; Molecular Docking Simulation; Rats; Triazoles
PubMed: 33752057
DOI: 10.1016/j.biopha.2021.111417 -
Biological Trace Element Research Dec 2021Glutathione-related enzymes belong to the protection mechanism of the cells against harmful oxidative damage and chemicals. Glutathione S-transferase (GST) is frequently...
Glutathione-related enzymes belong to the protection mechanism of the cells against harmful oxidative damage and chemicals. Glutathione S-transferase (GST) is frequently over-expressed in various cancer cells and is involved in drug resistance. Chlorophyllin is an antioxidant molecule interfering with the GST P1-1 activity. The purpose of this study is to evaluate the short- and long-term protective effects of chlorophyllin as an antioxidant molecule on DNA damage, antioxidant enzyme activities, trace elements, and minerals in chemically induced breast cancer model in vivo. In our study, N-methyl-N-nitrosourea (MNU) was used for inducing breast carcinogenesis in female Sprague-Dawley rats. A total of 36 rats were divided into groups as short term and long term. Each group was divided into four sub-groups as control group received physiological saline solution (n = 3), Chl group (n = 5) received chlorophyllin, MNU group (n = 5) was administered MNU, and Chl + MNU group (n = 5) was treated with both chlorophyllin and MNU. Results illustrated that chlorophyllin had a significant anti-genotoxic effect in the short term, and glutathione-related enzyme activities were protected by chlorophyllin treatment in MNU-induced breast cancer model. Additionally, MNU administration impaired mineral and trace element levels including Na, Mg, K, Fe, Zn, and Co in the liver, kidney, spleen, heart, and tumor tissues; however, adverse effects of MNU were recovered upon chlorophyllin treatment in the indicated tissues of the rats. In conclusion, chlorophyllin can be used as an antioxidant molecule to ameliorate adverse effects of MNU by enhancing antioxidant enzyme activities and regulating trace element and mineral balance in several organs and tumor tissue in the breast cancer model.
Topics: Animals; Antioxidants; Chlorophyllides; Female; Methylnitrosourea; Neoplasms; Rats; Rats, Sprague-Dawley
PubMed: 33624221
DOI: 10.1007/s12011-021-02585-6 -
Journal of Biochemical and Molecular... May 2021Gastric carcinoma is one of the most aggressive types of cancer that ranks fifth among all cancer incidences and third in cancer mortality. As it exhibits a prolonged...
Gastric carcinoma is one of the most aggressive types of cancer that ranks fifth among all cancer incidences and third in cancer mortality. As it exhibits a prolonged asymptomatic condition and high recurrence rate, it is a great challenge to treat gastric cancer. Traditional medicine that utilizes herbal phytochemicals to treat various diseases is a potent alternative for current allopathic treatment. Hence, we evaluated the potency of a phytochemical bilobalide for treating gastric cancer in in vitro and in vivo models. Bilobalide, a sesquiterpenoid, is present in the Ginkgo biloba plant that belongs to the family of Ginkgoaceae. The cytotoxicity effect of bilobalide was evaluated in both gastric cancer (AGS) cells and normal gastric epithelial cells. Apoptosis-inducing property of bilobalide against the AGS cell line was analyzed with different fluorescent staining techniques and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and cell cycle analysis was carried out by flow cytometry. The in vivo studies were assessed with N-methyl-N-nitrosourea (MNU)-induced gastric cancer in rats. Serum-specific gastric markers were quantified and histopathological analysis of stomach tissue was performed. The expression of target-signaling molecules was analyzed by a reverse-transcription polymerase chain reaction. The in vitro results proved that bilobalide effectively suppressed the AGS cell growth and induced cell death by nuclear damage and apoptosis induction. The bilobalide treatment effectively arrested the cell cycle of AGS cells via inhibiting the PI3K-signaling pathway. Our in vivo results also confirmed that the bilobalide persuasively inhibited the MNU-induced gastric carcinoma via inhibiting the thioredoxin-fold family proteins and inflammatory markers' expression. Overall, our results authentically prove that bilobalide possesses therapeutic potency to cure gastric carcinoma.
Topics: Animals; Apoptosis; Bilobalides; Cell Line, Tumor; Cell Proliferation; Ginkgo biloba; Humans; Male; Methylnitrosourea; Neoplasms, Experimental; Plant Extracts; Rats; Rats, Wistar; Stomach Neoplasms
PubMed: 33511709
DOI: 10.1002/jbt.22723 -
Asian Pacific Journal of Cancer... Jan 2021Testicular cancer is a public health problem. The goal of this study was to demonstrate the efficacy of quercetin treatment on N-nitroso-N-methyl-urea (MNU)-induced...
BACKGROUND
Testicular cancer is a public health problem. The goal of this study was to demonstrate the efficacy of quercetin treatment on N-nitroso-N-methyl-urea (MNU)-induced testicular carcinogenesis alone or in combination with cisplatin-treatment.
METHODS
In total 70 adult male albino rats were categorized into six groups, control, quercetin-treatment (10 mg/kg body weight), cisplatin-treatment (2 mg/kg. body weight), cisplatin and quercetin-treatment, MNU-treatment, MNU plus quercetin-treatment and MNU plus quercetin and cisplatin-treatment. Treatment with quercetin and/or cisplatin was performed after 2 months of MNU induced testicular carcinogenesis. The studied groups were euthanized and sacrificed and their testes were examined for gene expression, biochemical, histological and immunohistochemically analysis, inflammation and apoptosis of germ cells.
RESULTS
The fertility of the rats subjected to MNU carcinogenesis was impaired following cisplatin and/or quercetin-treatment. Cisplatin-treatment reduced the fertility rate and improved after quercetin-treatment. Quercetin-treatment decreased the sharp increase in RNA expression of BAX and MPO in both cisplatin-toxicated testes and after MNU carcinogenesis induction. In addition, the testicular levels of testosterone and SOD increased in parallel with depletion of MDA, IL-6, AFP and caspase-3 levels in MNU and/or cisplatin-treatment after -quercetin-treatment. The testicular structure of the cisplatin-treated group recovered their dividing germ and sperm differentiation after-quercetin-treatment. While, there was a great appearance of flourishing germ cell of MNU carcinogenesis post quercetin therapy, there was still a lack of sperm differentiation. Conclusion: Quercetin-treatment showed increased cisplatin activity and decreased testicular carcinogenesis due to anti-neoplastic and antioxidant activities.
Topics: Alkylating Agents; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Biomarkers, Tumor; Carcinogenesis; Cell Proliferation; Cisplatin; Drug Synergism; Drug Therapy, Combination; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Male; Methylnitrosourea; Quercetin; Rats; Rats, Wistar; Testicular Neoplasms
PubMed: 33507682
DOI: 10.31557/APJCP.2021.22.1.75 -
Drug Delivery Dec 2021Retinal degeneration (RD) refers to a group of blinding retinopathies leading to the progressive photoreceptor demise and vision loss. Treatments against this...
Retinal degeneration (RD) refers to a group of blinding retinopathies leading to the progressive photoreceptor demise and vision loss. Treatments against this debilitating disease are urgently needed. Intraocular delivery of exosomes represents an innovative therapeutic strategy against RD. In this study, we aimed to determine whether the subretinal delivery of RPE-derived exosomes (RPE-Exos) can prevent the photoreceptor death in RD. RD was induced in C57BL6 mice by MNU administration. These MNU administered mice received a single subretinal injection of RPE-Exos. Two weeks later, the RPE-Exos induced effects were evaluated via functional, morphological, and behavior examinations. Subretinal delivery of RPE-Exos efficiently ameliorates the visual function impairments, and alleviated the structural damages in the retina of MNU administered mice. Moreover, RPE-Exos exert beneficial effects on the electrical response of the inner retinal circuits. Treatment with RPE-Exos suppressed the expression levels of inflammatory factors, and mitigated the oxidative damage, indicating that subretinal delivery of RPE-Exos constructed a cytoprotective microenvironment in the retina of MNU administered mice. Our data suggest that RPE-Exos have therapeutic effects against the visual impairments and photoreceptor death. These findings will enrich our knowledge of RPE-Exos, and highlight the discovery of a promising medication for RD.
Topics: Alkylating Agents; Animals; Apoptosis; Biological Products; Calpain; Caspase 3; Disease Models, Animal; Electroretinography; Exosomes; Inflammation; Injections, Intraocular; Interleukin-1beta; Interleukin-6; Malondialdehyde; Methylnitrosourea; Mice; Oxidative Stress; Photoreceptor Cells, Vertebrate; Proto-Oncogene Proteins c-bcl-2; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Tomography, Optical Coherence; Tumor Necrosis Factor-alpha; Vision, Ocular; bcl-2-Associated X Protein
PubMed: 33501868
DOI: 10.1080/10717544.2020.1870584 -
Scientific Reports Jan 2021We aimed to develop an outer retinal degeneration pig model induced by temporary intravitreal loading of N-methyl-N-nitrosourea (MNU) during vitrectomy. In a preliminary...
We aimed to develop an outer retinal degeneration pig model induced by temporary intravitreal loading of N-methyl-N-nitrosourea (MNU) during vitrectomy. In a preliminary experiment involving 5 mini-pig cases to determine the appropriate concentration of MNU, the vitreous cavity of each eye was filled with 4, 8, 10, 12, or 16 mg/mL MNU for 10 min, which was then replaced with a balanced salt solution. Multimodal examinations including spectral-domain optical coherence tomography (OCT) images and full-field electroretinography (ffERG) were obtained at baseline and week 2, week 6, and week 12. The retinal degeneration was classified according to the amplitudes of a dark adaptive (DA) 10.0 a-wave amplitude. The degree of moderate retinal degeneration was defined as DA 10.0 a-wave amplitude ≥ 10% and < 60% of baseline amplitude. The degree of severe degeneration was defined as DA 10.0 a-wave amplitude < 10% of baseline amplitude, noise, or flat signal. Hematoxylin and eosin staining and immunohistochemistry were performed at week 12. The main experiments were conducted first with 10 cases of 5 mg/mL and later with 13 cases of 10 mg/mL. In the preliminary experiment, degree of outer retinal degeneration increased with MNU concentration. Use of 4, 8, 10, 12, and 16 mg/mL MNU showed no, moderate, severe, severe, and atrophic changes, respectively. In the main experiments, there were 9 cases of moderate retinal degeneration and 1 case of severe degeneration in 5 mg/mL MNU group. Two cases of moderate degeneration and 11 of severe degeneration were recorded in 10 mg/mL group. Mean thickness of total retina, inner nuclear layer, and outer nuclear layer decreased at week 2 in both groups. The mean amplitudes on ffERG decreased at week 2. The ffERG and OCT findings did not change from week 2 to week 6 or week 12. The results of staining supported those of ffERG and OCT. Temporal MNU loading in a vitrectomized pig-eye model induced customized outer retinal degeneration with changing the concentration of MNU.
Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroretinography; Intravitreal Injections; Methylnitrosourea; Retinal Degeneration; Swine; Swine, Miniature; Tomography, Optical Coherence; Vitrectomy
PubMed: 33420119
DOI: 10.1038/s41598-020-79437-1 -
Journal of Environmental Pathology,... 2020Gastric cancer is the most typical oncological illness globally. Though the incidence of gastric cancer has dropped dramatically over the last few years, the survival...
Gastric cancer is the most typical oncological illness globally. Though the incidence of gastric cancer has dropped dramatically over the last few years, the survival rate is yet concerning due to poor diagnostic strategy. The etiology of gastric cancer is majorly associated with dietary factors. For this reason, application of nontoxic natural agents with anticancer effects for patients is needed. Diosmin has been commonly utilized to treat various diseases both traditionally and now clinically. However, its effect on gastric carcinogenesis remains unclear. The effects of diosmin were used to evaluate how N-methyl-N-nitrosourea (MNU) induces gastric carcinogenesis in rats. The general and gross assessment of MNU in experimental animals was tabulated. Biological tumor markers (gastrin, ALP, LDH, and γ-GT) were examined. Oxidative markers (LPO) and antioxidative markers (GSH, vitamin E, and vitamin C) were determined. In addition, inflammatory cytokines (thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2) were explored and justified with histopathological studies. Overall, the results showed positive anticancer activity demonstrated by improved body weight, reduced tumor rate, decreased oxidative marker value by increased antioxidative rate, and suppressed tumor biomarkers and inflammatory cytokines. The histopathological analysis was congruent with the data observed. Our conclusion that diosmin exerts its anticancer activity by up-regulation of antioxidants which might be responsible for amelioration of oxidative stress and inflammatory cytokines in carcinogenesis to prevent gastric cancer.
Topics: Animals; Biomarkers; Carcinogenesis; Cytokines; Diosmin; Gastric Mucosa; Male; Methylnitrosourea; Oxidative Stress; Rats; Rats, Wistar; Stomach Neoplasms
PubMed: 33389909
DOI: 10.1615/JEnvironPatholToxicolOncol.2020035653 -
Journal of Environmental Pathology,... 2020Gastric cancer (GC) may arise in any region of the stomach. Poorly diagnosed GC results in almost one million mortalities annually worldwide. Kirenol is a bioactive...
BACKGROUND
Gastric cancer (GC) may arise in any region of the stomach. Poorly diagnosed GC results in almost one million mortalities annually worldwide. Kirenol is a bioactive compound present in the Sieges beckia sps.
OBJECTIVE
In this current, we investigate the anticancer capacity of kirenol against the MNG-stimulated GC in rats via modulating the antioxidants status and inhibition of NF-κB cascade.
METHODOLOGY
GC was provoked in the rats via supplementing 100 mg/kg of MNU through the intragastric route for 16 weeks concomitantly with 30 mg/kg of kirenol treatment. The body weight, tumor volume, and incidence of all animals were tabulated every week. The status of gastrin, ALP, LDH, and γ-GT was studied through the ELISA tests. The lipid peroxidation, enzymatic, and nonenzymatic antioxidants were determined via standard procedures. Expression of thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2 was studied through RT-PCR. The gastric mucosa was analyzed microscopically.
RESULTS
Kirenol treatment appreciably improved the body weight and diminished the tumor volume and incidences in the MNG-challenged rats. The lipid peroxidation was diminished and the enzymatic and non-enzymatic antioxidants were improved by the kirenol treatment. Kirenol suppressed the status of serum markers of GC and gastrin, ALP, LDH, and γ-GT. The mRNA expression of thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2 was downregulated via the kirenol in the MNG-challenged rats. Histopathological analysis result also confirmed the therapeutic role of kirenol.
CONCLUSION
These findings proved that the kirenol appreciably prevented the MNG-triggered GC in rats and it may become a potential drug for the GC treatment in the future.
Topics: Animals; Biomarkers; Dinoprostone; Diterpenes; Gastric Mucosa; Interleukin-6; Lipid Peroxidation; Male; Methylnitrosourea; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Stomach Neoplasms; Tumor Necrosis Factor-alpha
PubMed: 33389906
DOI: 10.1615/JEnvironPatholToxicolOncol.2020035475