Pub Date : 2022-03-06DOI: 10.1080/15376516.2022.2049412
S. Tarbali, Saeed Karami Mehrian, Shiva Khezri
Abstract Objective: During the last decades, the widespread use of silver nanoparticles (AgNPs) has been considered because of their small size and antimicrobial effects. The main concern about these particles is that they can induce oxidative stress. In this study, the dose-dependent effects of green synthesized silver nanoparticles (Green-AgNPs) were evaluated on adult male rats. Methods: Animals were injected intraperitoneally (I.P) with the vehicle (deionized water) and different doses of Green-AgNPs (50, 100, 200, and 400 ppm), daily for 21 days. For the safety assessment, body weight and organ coefficient (liver, kidney, spleen, and brain) were measured. The effects of Green-AgNPs administration on working memory, anxiety behavior, novel object recognition, and spatial memory were analyzed. The lipophilic fluorescent products (LFPs), as an indicator of oxidative stress, were also evaluated in the liver, kidney, spleen, and hippocampus. Results: After 21 days of exposure, significant changes were not observed in body weight and organ coefficients. Green-AgNPs at the doses of 100, 200, and 400 ppm caused memory impairment and anxieties as well as altered liver, kidney, spleen, and hippocampus redox status. All tissues of the exposed animals showed an increased LFPs level compared to those of the rats in the vehicle group. Conclusions: This study indicated that the consumption of Green-AgNPs in higher doses (>50 ppm), not only had negative effects on behavioral indices but also caused memory impairment in rats and was toxic. This might be due to the induction of oxidative stress demonstrated by increased LFPs levels in tissues. Graphical Abstract Cascade events after I.P. injection of different doses of Green-AgNPs in rats After I.P. administration of green synthesized AgNPs in rats, these particles can pass through endothelial cells to various organs, such as the liver, kidney, spleen, and brain. Then caused oxidative stress and increased production of free radicals in the tissues. Overload free radicals result in the initiation of lipid peroxidation and result in the production of aldehydes. Following changes in the redox state in the neurons, these events caused memory impairment in high doses of green synthesized AgNPs. Aldehydes produced are unstable and react with amino groups of proteins, amino acids, or phospholipids. Assessment of generated lipophilic fluorescent products (LFPs) as stress oxidative marker.
{"title":"Toxicity effects evaluation of green synthesized silver nanoparticles on intraperitoneally exposed male Wistar rats","authors":"S. Tarbali, Saeed Karami Mehrian, Shiva Khezri","doi":"10.1080/15376516.2022.2049412","DOIUrl":"https://doi.org/10.1080/15376516.2022.2049412","url":null,"abstract":"Abstract Objective: During the last decades, the widespread use of silver nanoparticles (AgNPs) has been considered because of their small size and antimicrobial effects. The main concern about these particles is that they can induce oxidative stress. In this study, the dose-dependent effects of green synthesized silver nanoparticles (Green-AgNPs) were evaluated on adult male rats. Methods: Animals were injected intraperitoneally (I.P) with the vehicle (deionized water) and different doses of Green-AgNPs (50, 100, 200, and 400 ppm), daily for 21 days. For the safety assessment, body weight and organ coefficient (liver, kidney, spleen, and brain) were measured. The effects of Green-AgNPs administration on working memory, anxiety behavior, novel object recognition, and spatial memory were analyzed. The lipophilic fluorescent products (LFPs), as an indicator of oxidative stress, were also evaluated in the liver, kidney, spleen, and hippocampus. Results: After 21 days of exposure, significant changes were not observed in body weight and organ coefficients. Green-AgNPs at the doses of 100, 200, and 400 ppm caused memory impairment and anxieties as well as altered liver, kidney, spleen, and hippocampus redox status. All tissues of the exposed animals showed an increased LFPs level compared to those of the rats in the vehicle group. Conclusions: This study indicated that the consumption of Green-AgNPs in higher doses (>50 ppm), not only had negative effects on behavioral indices but also caused memory impairment in rats and was toxic. This might be due to the induction of oxidative stress demonstrated by increased LFPs levels in tissues. Graphical Abstract Cascade events after I.P. injection of different doses of Green-AgNPs in rats After I.P. administration of green synthesized AgNPs in rats, these particles can pass through endothelial cells to various organs, such as the liver, kidney, spleen, and brain. Then caused oxidative stress and increased production of free radicals in the tissues. Overload free radicals result in the initiation of lipid peroxidation and result in the production of aldehydes. Following changes in the redox state in the neurons, these events caused memory impairment in high doses of green synthesized AgNPs. Aldehydes produced are unstable and react with amino groups of proteins, amino acids, or phospholipids. Assessment of generated lipophilic fluorescent products (LFPs) as stress oxidative marker.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"488 - 500"},"PeriodicalIF":3.2,"publicationDate":"2022-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46472131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-06DOI: 10.1080/15376516.2022.2049941
H. Hasan, S. Galal, Rania A. Ellethy
Abstract In this study, the mitigative impact of bradykinin potentiating factor (BPF) and low doses of γ-irradiation (LDR) were evaluated against doxorubicin (DOX) hepatotoxicity through Ang II/AMPK crosstalk. Rats have received a single dose of DOX (10 mg/kg, i.p.). BPF administration at a dose of 1 μg/g (b.wt./twice a week) was started one week before the administration of DOX and followed throughout the study for another consecutive week where LDR rats were subjected to two low fractions of γ-irradiation; 0.5 Gy/fraction/week up to the cumulative dose of 1 Gy at 7 days before and after doxorubicin administration. DOX produced a remarkable disturbance in serum hepatic enzymes activities, hepatic oxidative stress indices, as well as hepatic inflammatory and fibrotic markers in response to a marked elevation in hepatic angiotensin II (Ang II) together with marked depression in hepatic AMP-activated protein kinase (AMPK) expressions. The combination of BPF and LDR produced a significant improvement in all examined parameters as well as mitigates hepatic toxicity through inhibition of Ang II induced by DOX, which might also be mediated by AMPK activation. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. In conclusion, these findings shed new light on the mechanism underlying the anti-inflammatory and anti-fibrosis consequence of our remedy and support the potential use of it as a preventive and therapeutic candidate against hepatic toxicity through Ang II/AMPK crosstalk. Graphical Abstract
{"title":"Mitigative impact of bradykinin potentiating factor isolated from Androctonus amoreuxi scorpion venom and low doses of γ-irradiation on doxorubicin induced hepatotoxicity through ang II/AMPK crosstalk","authors":"H. Hasan, S. Galal, Rania A. Ellethy","doi":"10.1080/15376516.2022.2049941","DOIUrl":"https://doi.org/10.1080/15376516.2022.2049941","url":null,"abstract":"Abstract In this study, the mitigative impact of bradykinin potentiating factor (BPF) and low doses of γ-irradiation (LDR) were evaluated against doxorubicin (DOX) hepatotoxicity through Ang II/AMPK crosstalk. Rats have received a single dose of DOX (10 mg/kg, i.p.). BPF administration at a dose of 1 μg/g (b.wt./twice a week) was started one week before the administration of DOX and followed throughout the study for another consecutive week where LDR rats were subjected to two low fractions of γ-irradiation; 0.5 Gy/fraction/week up to the cumulative dose of 1 Gy at 7 days before and after doxorubicin administration. DOX produced a remarkable disturbance in serum hepatic enzymes activities, hepatic oxidative stress indices, as well as hepatic inflammatory and fibrotic markers in response to a marked elevation in hepatic angiotensin II (Ang II) together with marked depression in hepatic AMP-activated protein kinase (AMPK) expressions. The combination of BPF and LDR produced a significant improvement in all examined parameters as well as mitigates hepatic toxicity through inhibition of Ang II induced by DOX, which might also be mediated by AMPK activation. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. In conclusion, these findings shed new light on the mechanism underlying the anti-inflammatory and anti-fibrosis consequence of our remedy and support the potential use of it as a preventive and therapeutic candidate against hepatic toxicity through Ang II/AMPK crosstalk. Graphical Abstract","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"518 - 529"},"PeriodicalIF":3.2,"publicationDate":"2022-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42613860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-02DOI: 10.1080/15376516.2022.2046668
A. Aslan, Ozlem Gok, S. Beyaz, Harun Uslu, F. Erman, O. Erman, S. Baspinar
Abstract Ellagic acid (EA) has protective effect on testicular damage and this natural compound decreases oxidative damage. The present study aims to examine the preventive effect of ellagic acid (EA) against carbon tetrachloride (CCl4)-induced testicular tissue damage in rats. In testicular tissue, tumor necrosis factor-α (TNF-α), Nuclear factor erythroid-2 related factor 2 (Nrf-2), B-cell lymphoma-2 (Bcl-2), vascular endothelial growth factor (VEGF), Nuclear factor-kappa B (NF-κB), cysteine aspartic proteases (caspase-3) and protein kinase B (Akt) synthesis levels were analyzed by western blot method, reactive oxygen species (ROS) was measured by malondialdehyde (MDA) levels, Glutathione (GSH) level and catalase (CAT) by spectrophotometer. As a result, in comparison with the CCl4 group, caspase-3 and Nrf-2 protein synthesis levels increased in EA + CCl4 group, however, VEGF, Bcl-2, NF-κB, TNF-α and Akt protein synthesis levels decreased, EA application raised GSH levels and CAT activity, reduced MDA levels. In this study, in silico tools were applied to confirm the activity of EA against the cancer with macromolecules such as the above mentioned transcription factors. EA, turned out to show significant activity similarly to some cocrystal ligands, particularly against cancer. These results points out that EA can be used as a testicular damage cure drug in future.
{"title":"Ellagic acid inhibits proinflammatory intermediary manufacture by suppressing NF-κB/Akt, VEGF and activating Nrf-2/Caspase-3 signaling pathways in rat testicular damage: a new way for testicular damage cure and in silico approach","authors":"A. Aslan, Ozlem Gok, S. Beyaz, Harun Uslu, F. Erman, O. Erman, S. Baspinar","doi":"10.1080/15376516.2022.2046668","DOIUrl":"https://doi.org/10.1080/15376516.2022.2046668","url":null,"abstract":"Abstract Ellagic acid (EA) has protective effect on testicular damage and this natural compound decreases oxidative damage. The present study aims to examine the preventive effect of ellagic acid (EA) against carbon tetrachloride (CCl4)-induced testicular tissue damage in rats. In testicular tissue, tumor necrosis factor-α (TNF-α), Nuclear factor erythroid-2 related factor 2 (Nrf-2), B-cell lymphoma-2 (Bcl-2), vascular endothelial growth factor (VEGF), Nuclear factor-kappa B (NF-κB), cysteine aspartic proteases (caspase-3) and protein kinase B (Akt) synthesis levels were analyzed by western blot method, reactive oxygen species (ROS) was measured by malondialdehyde (MDA) levels, Glutathione (GSH) level and catalase (CAT) by spectrophotometer. As a result, in comparison with the CCl4 group, caspase-3 and Nrf-2 protein synthesis levels increased in EA + CCl4 group, however, VEGF, Bcl-2, NF-κB, TNF-α and Akt protein synthesis levels decreased, EA application raised GSH levels and CAT activity, reduced MDA levels. In this study, in silico tools were applied to confirm the activity of EA against the cancer with macromolecules such as the above mentioned transcription factors. EA, turned out to show significant activity similarly to some cocrystal ligands, particularly against cancer. These results points out that EA can be used as a testicular damage cure drug in future.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"463 - 476"},"PeriodicalIF":3.2,"publicationDate":"2022-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43735140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-01DOI: 10.1080/15376516.2019.1681043
M. A. Ibrahim, H. Ibrahim, Alaa A. Mohamed, H. G. Tammam
Abstract Several deleterious effects of Tramadol including deaths were reported especially when used in large doses. Being metabolized mainly in the liver, Tramadol have serious hepatotoxic effects. This study investigates the effect of vitamin E on Tramadol-induced hepatotoxicity in rats by evaluating the antioxidant biochemical markers, the histopathological and immunohistochemical changes.Thirty adult mature male albino rats were divided into five groups (Gs); G1: negative control; G2: received Tramadol 150 mg/kg, G 3–5: received Tramadol plus vitamin E in concentrations of 50 mg/kg, 100 mg/kg and 200 mg/kg respectively. Liver function parameters and oxidative markers in liver tissue (CAT, SOD, GSH, and MDA) were estimated. Liver samples were processed for histopathological and immunohistochemical (Caspase 3 and TNF) examinations. The results indicated that Sub-chronic administration of Tramadol resulted in impaired liver functions, increased oxidative stress parameters with decreased antioxidant capacity of liver tissues, severe hepatocellular damage (hydropic degeneration, steatosis and apoptosis) and strong immunoexpression to TNF and Caspase 3. All these effects were ameliorated with concomitant administration of vitamin E especially with high doses. The co-treatment of Tramadol-intoxicated rats with Vitamin E, especially in high doses, protects against hepatic toxicity.
{"title":"Vitamin E supplementation ameliorates the hepatotoxicity induced by Tramadol: toxicological, histological and immunohistochemical study","authors":"M. A. Ibrahim, H. Ibrahim, Alaa A. Mohamed, H. G. Tammam","doi":"10.1080/15376516.2019.1681043","DOIUrl":"https://doi.org/10.1080/15376516.2019.1681043","url":null,"abstract":"Abstract Several deleterious effects of Tramadol including deaths were reported especially when used in large doses. Being metabolized mainly in the liver, Tramadol have serious hepatotoxic effects. This study investigates the effect of vitamin E on Tramadol-induced hepatotoxicity in rats by evaluating the antioxidant biochemical markers, the histopathological and immunohistochemical changes.Thirty adult mature male albino rats were divided into five groups (Gs); G1: negative control; G2: received Tramadol 150 mg/kg, G 3–5: received Tramadol plus vitamin E in concentrations of 50 mg/kg, 100 mg/kg and 200 mg/kg respectively. Liver function parameters and oxidative markers in liver tissue (CAT, SOD, GSH, and MDA) were estimated. Liver samples were processed for histopathological and immunohistochemical (Caspase 3 and TNF) examinations. The results indicated that Sub-chronic administration of Tramadol resulted in impaired liver functions, increased oxidative stress parameters with decreased antioxidant capacity of liver tissues, severe hepatocellular damage (hydropic degeneration, steatosis and apoptosis) and strong immunoexpression to TNF and Caspase 3. All these effects were ameliorated with concomitant administration of vitamin E especially with high doses. The co-treatment of Tramadol-intoxicated rats with Vitamin E, especially in high doses, protects against hepatic toxicity.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"177 - 188"},"PeriodicalIF":3.2,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1681043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41860080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-01Epub Date: 2019-10-29DOI: 10.1080/15376516.2019.1681044
Chirag N Patel, Sivakumar Prasanth Kumar, Rakesh M Rawal, Daxesh P Patel, Frank J Gonzalez, Himanshu A Pandya
The assessment of major organ toxicities through in silico predictive models plays a crucial role in drug discovery. Computational tools can predict chemical toxicities using the knowledge gained from experimental studies which drastically reduces the attrition rate of compounds during drug discovery and developmental stages. The purpose of in silico predictions for drug leads and anticipating toxicological endpoints of absorption, distribution, metabolism, excretion and toxicity, clinical adverse impacts and metabolism of pharmaceutically active substances has gained widespread acceptance in academia and pharmaceutical industries. With unrestricted accessibility to powerful biomarkers, researchers have an opportunity to contemplate the most accurate predictive scores to evaluate drug's adverse impact on various organs.A multiparametric model involving physico-chemical properties, quantitative structure-activity relationship predictions and docking score was found to be a more reliable predictor for estimating chemical toxicities with potential to reflect atomic-level insights. These in silico models provide informed decisions to carry out in vitro and in vivo studies and subsequently confirms the molecules clues deciphering the cytotoxicity, pharmacokinetics, and pharmacodynamics and organ toxicity properties of compounds. Even though the drugs withdrawn by USFDA at later phases of drug discovery which should have passed all the state-of-the-art experimental approaches and currently acceptable toxicity filters, there is a dire need to interconnect all these molecular key properties to enhance our knowledge and guide in the identification of leads to drug optimization phases. Current computational tools can predict ADMET and organ toxicities based on pharmacophore fingerprint, toxicophores and advanced machine-learning techniques.
{"title":"A multiparametric organ toxicity predictor for drug discovery.","authors":"Chirag N Patel, Sivakumar Prasanth Kumar, Rakesh M Rawal, Daxesh P Patel, Frank J Gonzalez, Himanshu A Pandya","doi":"10.1080/15376516.2019.1681044","DOIUrl":"10.1080/15376516.2019.1681044","url":null,"abstract":"<p><p>The assessment of major organ toxicities through <i>in silico</i> predictive models plays a crucial role in drug discovery. Computational tools can predict chemical toxicities using the knowledge gained from experimental studies which drastically reduces the attrition rate of compounds during drug discovery and developmental stages. The purpose of <i>in silico</i> predictions for drug leads and anticipating toxicological endpoints of absorption, distribution, metabolism, excretion and toxicity, clinical adverse impacts and metabolism of pharmaceutically active substances has gained widespread acceptance in academia and pharmaceutical industries. With unrestricted accessibility to powerful biomarkers, researchers have an opportunity to contemplate the most accurate predictive scores to evaluate drug's adverse impact on various organs.A multiparametric model involving physico-chemical properties, quantitative structure-activity relationship predictions and docking score was found to be a more reliable predictor for estimating chemical toxicities with potential to reflect atomic-level insights. These <i>in silico</i> models provide informed decisions to carry out <i>in vitro</i> and <i>in vivo</i> studies and subsequently confirms the molecules clues deciphering the cytotoxicity, pharmacokinetics, and pharmacodynamics and organ toxicity properties of compounds. Even though the drugs withdrawn by USFDA at later phases of drug discovery which should have passed all the state-of-the-art experimental approaches and currently acceptable toxicity filters, there is a dire need to interconnect all these molecular key properties to enhance our knowledge and guide in the identification of leads to drug optimization phases. Current computational tools can predict ADMET and organ toxicities based on pharmacophore fingerprint, toxicophores and advanced machine-learning techniques.</p>","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"159-166"},"PeriodicalIF":2.8,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45436440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-02-12DOI: 10.1080/15376516.2019.1669246
R. Sankhe, M. Kinra, J. Mudgal, D. Arora, M. Nampoothiri
Abstract Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin–angiotensin–aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1–7) (Ang-(1–7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.
{"title":"Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury","authors":"R. Sankhe, M. Kinra, J. Mudgal, D. Arora, M. Nampoothiri","doi":"10.1080/15376516.2019.1669246","DOIUrl":"https://doi.org/10.1080/15376516.2019.1669246","url":null,"abstract":"Abstract Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin–angiotensin–aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1–7) (Ang-(1–7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"88 - 99"},"PeriodicalIF":3.2,"publicationDate":"2020-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1669246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42192786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-02-01DOI: 10.1080/15376516.2019.1669249
S. Hamad, M. El-Naggar
Abstract This current study aimed at detecting the potential protective role of nano-fenugreek seed on acute lung injury (ALI) induced by instillation gastric acid in male Swiss albino mice using histological and histochemical studies. Forty animals were grouped as follows: control group, HCl-treated group, low nano-fenugreek + HCl treated group, and high nano-fenugreek + HCl treated group. Pretreatment with nano-fenugreek in animal model of ALI resulted in marked ameliorations of the lung histological lesions and injury induced by HCL instillation in a dose dependent manner. It also caused inhibition in the increase of the DNA content and prevented proliferation of goblet cells induced by HCl instillation alone. In conclusion, pretreatment with Nano-fenugreek prior induction ALI could be suppress the aggregations of inflammatory cells, enhancing of DNA content, and proliferation of goblet cells induced by gastric acid in a dose dependent manner. We suggest that Nano-fenugreek may be useful in combating lung injury.
{"title":"Blocking of gastric acid induced histopathological alterations, enhancing of DNA content and proliferation of goblet cells in the acute lung injury mice models by nano-fenugreek oral administration","authors":"S. Hamad, M. El-Naggar","doi":"10.1080/15376516.2019.1669249","DOIUrl":"https://doi.org/10.1080/15376516.2019.1669249","url":null,"abstract":"Abstract This current study aimed at detecting the potential protective role of nano-fenugreek seed on acute lung injury (ALI) induced by instillation gastric acid in male Swiss albino mice using histological and histochemical studies. Forty animals were grouped as follows: control group, HCl-treated group, low nano-fenugreek + HCl treated group, and high nano-fenugreek + HCl treated group. Pretreatment with nano-fenugreek in animal model of ALI resulted in marked ameliorations of the lung histological lesions and injury induced by HCL instillation in a dose dependent manner. It also caused inhibition in the increase of the DNA content and prevented proliferation of goblet cells induced by HCl instillation alone. In conclusion, pretreatment with Nano-fenugreek prior induction ALI could be suppress the aggregations of inflammatory cells, enhancing of DNA content, and proliferation of goblet cells induced by gastric acid in a dose dependent manner. We suggest that Nano-fenugreek may be useful in combating lung injury.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"153 - 158"},"PeriodicalIF":3.2,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1669249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46973508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-02-01DOI: 10.1080/15376516.2019.1669242
Mincong Huang, Jie Su, Zhaohuan Lou, Feng Xie, W. Pan, Zhengbiao Yang, Liqiang Gu, Fang Xie, Zhiwei Xu, Lili Zhang, Fang Liu, Huimin Lai, Lijiang Zhang, Nengming Lin
Abstract In standard nonclinical drug safety evaluation studies, limitations exist in predicting the clinical risk of a drug based only on data from healthy animals. To obtain more comprehensive toxicological information on norisoboldine (NOR), we conducted an exploratory study using C57BL/6 mice in addition to healthy mice as models of dextran sodium sulfate (DSS) colitis to evaluate the safety of NOR. The healthy mice and DSS colitis mice were exposed to 30 or 90 mg NOR/kg body weight or water for 15 days. Compared with the model control group, 90 mg/kg of NOR aggravated the symptoms and colonic lesions of the DSS colitis mice and even caused death in two animals. No significant adverse effects were observed in the healthy mice. These different toxic reactions to NOR in the healthy and DSS colitis mice indicate that NOR toxicity varies by status among animals and suggests that the DSS colitis mouse model may be more susceptible, accurate and comprehensive in evaluating the safety of NOR. In conclusion, 90 mg/kg of NOR may be safe for healthy mice but not for DSS colitis mice. The DSS colitis mouse model, with many features similar to those of human colitis patients, may be a novel choice to counteract the deficiencies of using healthy mice to evaluate the safety of anti-inflammatory bowel disease (IBD) drugs, and further research is required.
{"title":"Application of a DSS colitis model in toxicologically assessing norisoboldine","authors":"Mincong Huang, Jie Su, Zhaohuan Lou, Feng Xie, W. Pan, Zhengbiao Yang, Liqiang Gu, Fang Xie, Zhiwei Xu, Lili Zhang, Fang Liu, Huimin Lai, Lijiang Zhang, Nengming Lin","doi":"10.1080/15376516.2019.1669242","DOIUrl":"https://doi.org/10.1080/15376516.2019.1669242","url":null,"abstract":"Abstract In standard nonclinical drug safety evaluation studies, limitations exist in predicting the clinical risk of a drug based only on data from healthy animals. To obtain more comprehensive toxicological information on norisoboldine (NOR), we conducted an exploratory study using C57BL/6 mice in addition to healthy mice as models of dextran sodium sulfate (DSS) colitis to evaluate the safety of NOR. The healthy mice and DSS colitis mice were exposed to 30 or 90 mg NOR/kg body weight or water for 15 days. Compared with the model control group, 90 mg/kg of NOR aggravated the symptoms and colonic lesions of the DSS colitis mice and even caused death in two animals. No significant adverse effects were observed in the healthy mice. These different toxic reactions to NOR in the healthy and DSS colitis mice indicate that NOR toxicity varies by status among animals and suggests that the DSS colitis mouse model may be more susceptible, accurate and comprehensive in evaluating the safety of NOR. In conclusion, 90 mg/kg of NOR may be safe for healthy mice but not for DSS colitis mice. The DSS colitis mouse model, with many features similar to those of human colitis patients, may be a novel choice to counteract the deficiencies of using healthy mice to evaluate the safety of anti-inflammatory bowel disease (IBD) drugs, and further research is required.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"107 - 114"},"PeriodicalIF":3.2,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1669242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43825170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-02-01DOI: 10.1080/15376516.2019.1672122
Hiroshi Tsutsumi, K. Yonemitsu, Ako Sasao, Y. Ohtsu, Shota Furukawa, Y. Nishitani
Abstract A neuropsychiatric drug overdose impairs physiological function via central nervous system (CNS) depression. In drug-related deaths, only the drug concentration can currently provide information regarding CNS depression in victims. In this study, using a drug overdose model, we investigated the ability of neurotransmitters in the cerebrospinal fluid (CSF) to serve as biomarkers for CNS depression. Four groups of rats were orally administered diazepam (200 mg/kg) and/or phenobarbital (100 mg/kg) or vehicle. In a hot plate test performed to assess physiological impairment, drug-administered animals showed prolongation of the response latency. Serum drug concentrations were also sufficient to observe the effect of drug overdose. The levels of benzoyl-derivatized neurotransmitters were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis. Noradrenaline, adrenaline, serotonin, melatonin, phosphoethanolamine, and histamine levels in the CSF decreased as the response latencies in the hot plate test increased. These reduced CSF neurotransmitter levels may represent physiological dysfunction through CNS depression.
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Pub Date : 2020-02-01DOI: 10.1080/15376516.2019.1669243
A. Famurewa, Chima A. Ekeleme-Egedigwe, E. David, C. Eleazu, A. M. Folawiyo, N. Obasi
Abstract Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with hepatotoxicity – a source of worry to clinicians. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM hepatotoxicity. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced hepatotoxicity in female Wistar rats. Rats were subjected to oral pretreatment of Zn (100 mg/kg body weight (b.w.)/day) for 14 days against hepatic toxicity induced by single intraperitoneal administration of TAM (50 mg/kg b.w.) on day 13. TAM markedly elevated serum liver enzymes, whereas total protein and albumin considerably reduced. TAM caused prominent depletion of hepatic-reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity. Also, TAM significantly increased malondialdehyde (MDA) level. Further, it raised liver levels of tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by the liver histopathological alterations. The mechanistic inflammatory expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-ĸB), and expression of caspase-3 protein prominently increased. Zinc supplementation significantly modulated serum liver function markers, antioxidant enzymes, and GSH and MDA levels. Zinc downregulated the expression of cytokines, NO, iNOS, NF-ĸB and caspase-3, and ameliorated histopathological changes. Zinc protects against TAM-induced hepatotoxicity; it may serve as an adjuvant supplement for female patients undergoing TAM chemotherapy.
他莫昔芬(TAM)自1977年获得美国食品和药物管理局批准以来，一直用于乳腺癌化疗。然而，TAM治疗伴随着肝毒性，这是临床医生担心的一个来源。氧化应激和炎症是TAM肝毒性的主要机制。在这项研究中，我们探讨了锌(Zn)的补充是否可以预防tam引起的雌性Wistar大鼠肝毒性。大鼠口服锌(100 mg/kg体重/天)预处理14天，第13天单次腹腔注射TAM (50 mg/kg体重/天)诱导肝毒性。TAM显著提高血清肝酶，而总蛋白和白蛋白显著降低。TAM引起肝还原性谷胱甘肽(GSH)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GPx)活性明显降低。此外，TAM显著提高丙二醛(MDA)水平。肝组织病理学改变证实，其可提高肝脏肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6)和一氧化氮(NO)水平。诱导型一氧化氮合酶(iNOS)和核因子κ B (NF-ĸB)的机制性炎症表达以及caspase-3蛋白的表达显著升高。补充锌可显著调节血清肝功能指标、抗氧化酶、谷胱甘肽和丙二醛水平。锌下调细胞因子、NO、iNOS、NF-ĸB和caspase-3的表达，改善组织病理改变。锌可以防止tam引起的肝毒性;可作为女性TAM化疗患者的辅助补充。
{"title":"Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats","authors":"A. Famurewa, Chima A. Ekeleme-Egedigwe, E. David, C. Eleazu, A. M. Folawiyo, N. Obasi","doi":"10.1080/15376516.2019.1669243","DOIUrl":"https://doi.org/10.1080/15376516.2019.1669243","url":null,"abstract":"Abstract Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with hepatotoxicity – a source of worry to clinicians. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM hepatotoxicity. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced hepatotoxicity in female Wistar rats. Rats were subjected to oral pretreatment of Zn (100 mg/kg body weight (b.w.)/day) for 14 days against hepatic toxicity induced by single intraperitoneal administration of TAM (50 mg/kg b.w.) on day 13. TAM markedly elevated serum liver enzymes, whereas total protein and albumin considerably reduced. TAM caused prominent depletion of hepatic-reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity. Also, TAM significantly increased malondialdehyde (MDA) level. Further, it raised liver levels of tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by the liver histopathological alterations. The mechanistic inflammatory expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-ĸB), and expression of caspase-3 protein prominently increased. Zinc supplementation significantly modulated serum liver function markers, antioxidant enzymes, and GSH and MDA levels. Zinc downregulated the expression of cytokines, NO, iNOS, NF-ĸB and caspase-3, and ameliorated histopathological changes. Zinc protects against TAM-induced hepatotoxicity; it may serve as an adjuvant supplement for female patients undergoing TAM chemotherapy.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"115 - 123"},"PeriodicalIF":3.2,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1669243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43215844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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