Abstract As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis.
{"title":"Rotenone induces hepatotoxicity in rats by activating the mitochondrial pathway of apoptosis","authors":"Huan Wang, Yinzhu Jin, Yao Wang, Xue-wei Wang, Wenhui Yu, Xiaowen Jiang","doi":"10.1080/15376516.2022.2049940","DOIUrl":"https://doi.org/10.1080/15376516.2022.2049940","url":null,"abstract":"Abstract As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"510 - 517"},"PeriodicalIF":3.2,"publicationDate":"2022-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49571233","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 : 2021-02-24DOI: 10.1080/15376516.2022.2051654
Xin Gao, B. Deng, Shanshan Ran, Shugang Li
Abstract Purpose Arsenic has been reported to induce apoptosis in malignant tumor cells. Therefore, it has been investigated as a chemotherapy. From a mechanistic standpoint, the mitochondrial apoptosis pathway, mediated by GSK-3β, plays an important role in tumor cell apoptosis. Nonetheless, the regulation of GSK-3β by arsenic remains controversial. The study aimed to clarify the mechanism of GSK-3β in arsenic-induced apoptosis of tumor cells. Materials and methods We included 19 articles, which conducts the role of GSK-3β in the process of arsenic-induced tumor cell apoptosis by the meta-analysis. Results Compared with that of control group, the expression of GSK-3β (SMD= −0.92, 95% CI (−1.78, −0.06)), p-Akt (SMD= −5.46,95% CI (−8.67, −2.24)) were increased in the arsenic intervention group. Meanwhile, the combined treatment of arsenic and Akt agonists can inhibit p-GSK-3β. Using the dose and time subgroup analysis, it was shown that the low-dose (<5 μmol/L) and sub-chronic (>24 h) arsenic exposure could inhibit the expression of p-Akt (P < 0.05). In the subgroup analysis of GSK-3β sites, arsenic could inhibit p-Akt and GSK-3β (Ser9) (SMD = −0.95, 95% CI (−1.56, −0.33)). There was a positive dose-response relationship between arsenic and p-GSK-3β when the dose of arsenic was less than 8 μmol/L. The expression of Mcl-1 and pro-caspase-3 were decreased, while the loss of mitochondrial membrane potential and cleaved-caspase-3 increased significantly when arsenic stimulated GSK-3β (Ser9) (P < 0.05). Conclusion The study revealed that arsenic could induce tumor cell apoptosis, by inhibiting p-Akt/GSK-3β, and triggering the Mcl-1-dependent mitochondrial apoptosis pathway.
{"title":"The effect of GSK-3β in arsenic-induced apoptosis of malignant tumor cells: a systematic review and meta-analysis","authors":"Xin Gao, B. Deng, Shanshan Ran, Shugang Li","doi":"10.1080/15376516.2022.2051654","DOIUrl":"https://doi.org/10.1080/15376516.2022.2051654","url":null,"abstract":"Abstract Purpose Arsenic has been reported to induce apoptosis in malignant tumor cells. Therefore, it has been investigated as a chemotherapy. From a mechanistic standpoint, the mitochondrial apoptosis pathway, mediated by GSK-3β, plays an important role in tumor cell apoptosis. Nonetheless, the regulation of GSK-3β by arsenic remains controversial. The study aimed to clarify the mechanism of GSK-3β in arsenic-induced apoptosis of tumor cells. Materials and methods We included 19 articles, which conducts the role of GSK-3β in the process of arsenic-induced tumor cell apoptosis by the meta-analysis. Results Compared with that of control group, the expression of GSK-3β (SMD= −0.92, 95% CI (−1.78, −0.06)), p-Akt (SMD= −5.46,95% CI (−8.67, −2.24)) were increased in the arsenic intervention group. Meanwhile, the combined treatment of arsenic and Akt agonists can inhibit p-GSK-3β. Using the dose and time subgroup analysis, it was shown that the low-dose (<5 μmol/L) and sub-chronic (>24 h) arsenic exposure could inhibit the expression of p-Akt (P < 0.05). In the subgroup analysis of GSK-3β sites, arsenic could inhibit p-Akt and GSK-3β (Ser9) (SMD = −0.95, 95% CI (−1.56, −0.33)). There was a positive dose-response relationship between arsenic and p-GSK-3β when the dose of arsenic was less than 8 μmol/L. The expression of Mcl-1 and pro-caspase-3 were decreased, while the loss of mitochondrial membrane potential and cleaved-caspase-3 increased significantly when arsenic stimulated GSK-3β (Ser9) (P < 0.05). Conclusion The study revealed that arsenic could induce tumor cell apoptosis, by inhibiting p-Akt/GSK-3β, and triggering the Mcl-1-dependent mitochondrial apoptosis pathway.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"477 - 487"},"PeriodicalIF":3.2,"publicationDate":"2021-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48412391","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
Abstract 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":"Abstract 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.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"159-166"},"PeriodicalIF":3.2,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1681044","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.
{"title":"Cerebrospinal fluid neurotransmitter levels and central nervous system depression in a rat drug overdose model","authors":"Hiroshi Tsutsumi, K. Yonemitsu, Ako Sasao, Y. Ohtsu, Shota Furukawa, Y. Nishitani","doi":"10.1080/15376516.2019.1672122","DOIUrl":"https://doi.org/10.1080/15376516.2019.1672122","url":null,"abstract":"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.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"139 - 145"},"PeriodicalIF":3.2,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1672122","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41952631","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: 10.1080/15376516.2019.1669245
P. Kopa, R. Pawliczak
Abstract Objectives: This work attempts to summarize current knowledge about IQOS, the heat-not-burn tobacco products, their chemical composition and possible impact on oxidative stress and inflammatory response. Materials and Methods: The literature search was performed between January and April 2019 by a combination of terms: ‘IQOS smoking’, ‘IQOS cigarette’, ‘I quit original smoking cigarette’, ‘heat-not-burn products’, ‘HnB tobacco products’. Results: The aim of IQOS system is to minimalize the exposure of its smokers to dangerous substances present in cigarette smoke and to lower the probability of development of tobacco-related diseases. As current studies suggest, this new heat-not-burn tobacco product emits significantly lower concentrations of tar, carbonyls, VOCs, CO, free radicals or nitrosamines when compared to conventional cigarette, and thus it may reduce health risk for smokers. However, it does not eliminate this risk of development of tobacco-related diseases. Discussion: For conventional tobacco smokers the IQOS products may be an alternative option, which helps to reduce exposure to hazardous and potentially hazardous constituents. However, for never-smokers using the IQOS cigarettes may develop an addiction or increase exposition to some substances, which may increase probability of tobacco-related diseases. Moreover, emission of unexpected substances depends on device cleaning strategy and puff regiments. Conclusions: There is only limited data about IQOS effect on smokers’ health. The future investigation, especially comparison with healthy never-smokers or study of chronic exposure to IQOS, is needed.
{"title":"IQOS – a heat-not-burn (HnB) tobacco product – chemical composition and possible impact on oxidative stress and inflammatory response. A systematic review","authors":"P. Kopa, R. Pawliczak","doi":"10.1080/15376516.2019.1669245","DOIUrl":"https://doi.org/10.1080/15376516.2019.1669245","url":null,"abstract":"Abstract Objectives: This work attempts to summarize current knowledge about IQOS, the heat-not-burn tobacco products, their chemical composition and possible impact on oxidative stress and inflammatory response. Materials and Methods: The literature search was performed between January and April 2019 by a combination of terms: ‘IQOS smoking’, ‘IQOS cigarette’, ‘I quit original smoking cigarette’, ‘heat-not-burn products’, ‘HnB tobacco products’. Results: The aim of IQOS system is to minimalize the exposure of its smokers to dangerous substances present in cigarette smoke and to lower the probability of development of tobacco-related diseases. As current studies suggest, this new heat-not-burn tobacco product emits significantly lower concentrations of tar, carbonyls, VOCs, CO, free radicals or nitrosamines when compared to conventional cigarette, and thus it may reduce health risk for smokers. However, it does not eliminate this risk of development of tobacco-related diseases. Discussion: For conventional tobacco smokers the IQOS products may be an alternative option, which helps to reduce exposure to hazardous and potentially hazardous constituents. However, for never-smokers using the IQOS cigarettes may develop an addiction or increase exposition to some substances, which may increase probability of tobacco-related diseases. Moreover, emission of unexpected substances depends on device cleaning strategy and puff regiments. Conclusions: There is only limited data about IQOS effect on smokers’ health. The future investigation, especially comparison with healthy never-smokers or study of chronic exposure to IQOS, is needed.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"30 1","pages":"81 - 87"},"PeriodicalIF":3.2,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/15376516.2019.1669245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43863055","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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