T. R. R. Lima, Estela de Oliveira Lima, J. Delafiori, Rodrigo Ramos Catharino, J. L. Viana de Camargo, L. C. Pereira
{"title":"Molecular signatures associated with diuron exposure on rat urothelial mitochondria","authors":"T. R. R. Lima, Estela de Oliveira Lima, J. Delafiori, Rodrigo Ramos Catharino, J. L. Viana de Camargo, L. C. Pereira","doi":"10.1080/15376516.2022.2062271","DOIUrl":"https://doi.org/10.1080/15376516.2022.2062271","url":null,"abstract":"Abstract Diuron, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, is a worldwide used herbicide whose biotransformation gives rise to the metabolites, 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous studies indicate that diuron and/or its metabolites are toxic to the bladder urothelium of the Wistar rats where, under certain conditions of exposure, they may induce successively urothelial cell degeneration, necrosis, hyperplasia and eventually tumors. The hypothesis was raised that the molecular initiating event (MIE) of this Adverse Outcome Pathway is the mitochondrial toxicity of those compounds. Therefore, this study aimed to investigate in vitro the metabolic alterations resulting from urothelial mitochondria isolated from male Wistar rats exposure to diuron, DCPMU and DCA at 10 and 100 µM. A non-targeted metabolomic analysis using mass spectrometry showed discriminative clustering among groups and alterations in the intensity abundance of membrane-associated molecules phosphatidylcholine, phosphatidylinositol and phosphatidylserine, in addition to methylhexanoyl-CoA and, particularly for diuron 100 µM, dehydro-L-gulonate, all of them involved in critical mitochondrial metabolism. Collectively, these data indicate the mitochondrial dysfunction as an MIE that triggers cellular damage and death observed in previous studies.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"628 - 635"},"PeriodicalIF":3.2,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43716828","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}
H. Aboutalebi, F. Alipour, A. Ebrahimzadeh-Bideskan
{"title":"The protective effect of co-administration of platelet-rich plasma (PRP) and pentoxifylline (PTX) on cyclophosphamide-induced premature ovarian failure in mature and immature rats","authors":"H. Aboutalebi, F. Alipour, A. Ebrahimzadeh-Bideskan","doi":"10.1080/15376516.2022.2057264","DOIUrl":"https://doi.org/10.1080/15376516.2022.2057264","url":null,"abstract":"Abstract Cyclophosphamide (CP), as an antineoplastic agent, causes premature ovarian failure (POF) due to ovarian toxicity and subsequent infertility in women. Platelet-rich plasma (PRP) has accumulated significant attention in regenerative medicine. Pentoxifylline (PTX) as a methylxanthine derivative has been shown to have antioxidant and antiapoptotic properties. The aim of this study was to evaluate the protective effect of PRP and PTX on CP-induced POF. Fifty mature and immature female rats were assigned into five groups: control, CP (75 mg/kg, intraperitoneal [ip] on days 1 and 10 to induce POF), CP + PRP (200 μl, ip, half an hour after CP injection on day 1 and 10), CP + PTX (50 mg/kg, orally, half an hour after CP injection daily for 21 day), and CP + PRP + PTX. At the end of experiments on day 21, measurement of body weight, ovarian parameters (ovarian volume, follicular granulosa cell layers diameter, oocyte diameter, and the number of granulosa cells), measurement of ovarian hormone in sera for estradiol (E2), and anti-Mullerian hormone (AMH), as well as biochemical assessment were performed. The results showed that CP significantly reduced the ovarian parameters, E2, AMH, superoxide dismutase (SOD) activity and increased Malondialdehyde (MDA) levels compared to the control group (p < 0.001). Our results also indicated that all histomorphometric parameters and biochemical markers in CP-induced POF, were preserved close to normal by PRP and PTX treatments in both mature and immature rats (p < 0.001). Therefore, it is concluded that the co-administration of PRP and PTX can protect the ovary from CP-induced POF. Graphical Abstract","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"588 - 596"},"PeriodicalIF":3.2,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45848105","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}
{"title":"Implications for herbal polypharmacy: coumarin-induced hepatotoxicity increased through common herbal phytochemicals astragaloside IV and atractylenolide I","authors":"Susan M. Britza, I. Musgrave, R. Byard","doi":"10.1080/15376516.2022.2057267","DOIUrl":"https://doi.org/10.1080/15376516.2022.2057267","url":null,"abstract":"Abstract Hepatotoxicity is a well-known adverse effect of many substances, with toxicity often resulting from interactions of drugs with other drug-like substances. With the increased availability of complementary and alternative medicines, including herbal medicines, the likelihood of adverse interactions between drugs and drug-like substances in herbs increases. However, the impact of potential herb-herb interactions is little understood. To assess the potential of two cytochrome P450 enzyme modulating phytochemicals common to many herbal medicines, atractylenolide I (ATR-I) and astragaloside IV (AST-IV), to interact with coumarin, another phytochemical common in many foods, a hepatocyte function model with a liver carcinoma cell line, HepG2, was exposed to these agents. To determine the effects of cytochrome P450 modulation by these phytochemicals certain cells were induced with rifampicin to induce cytochrome P450. Increasing concentrations of ATR-I combined with a fixed, nontoxic concentration of coumarin (200 µM), demonstrated significant additive interactions. 300 µM ATR-I produced a 31% reduction in cell viability (p < 0.01) with coumarin in rifampicin uninduced cells. In rifampicin-induced cells, ATR-I (100–300 µM) produced a significant reduction in cell viability (p < 0.01) with coumarin (200 µM). AST-IV with fixed coumarin (200 µM) showed 27% toxicity at 300 µM AST-IV in rifampicin uninduced cells (p < 0.05) and 30% toxicity in rifampicin induced cells (p < 0.05). However, when fixed coumarin and AST-IV were combined with increasing concentrations of ATR-I no further significant increase in toxicity was observed (p > 0.05). These results demonstrate the potential toxic interactive capabilities of common traditional Chinese herbal medicine phytochemicals and underline the potential importance of coumarin-mediated toxicity.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"606 - 615"},"PeriodicalIF":3.2,"publicationDate":"2022-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44260297","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}
{"title":"Chronic oral exposure of aluminum chloride in rat modulates molecular and functional neurotoxic markers relevant to Alzheimer’s disease","authors":"M. Dey, R. Singh","doi":"10.1080/15376516.2022.2058898","DOIUrl":"https://doi.org/10.1080/15376516.2022.2058898","url":null,"abstract":"Abstract Aluminum is an environmentally abundant potential neurotoxic agent that may result in oxidative damage to a range of cellular biomarkers. The potential sources of aluminum accumulation in the body include drinking water, food, medicines, vaccines, and aluminum cookware utensils, etc. The accumulation of aluminum in the brain is reported to be associated with cholinergic dysfunction, oxidative stress and neuronal damage, which may ultimately cause Alzheimer’s disease. Since chronic exposure to aluminum leads to its accumulation in the brain, so this study was done by a long-term (24 weeks) low dose (20 mg/kg) oral exposure of aluminum chloride in rats. In this chronic model, we have evaluated the major hallmarks of Alzheimer’s disease including amyloid-beta (Aβ1–42) and phosphorylated-tau (p231-tau) protein in brain tissue. Furthermore, we evaluated the level of acetyl cholinesterase activity, inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and oxidative stress biomarkers in the rat brain in this model. The neurobehavioral parameters were also assessed in animals by using spontaneous locomotor activity, passive avoidance, rotarod test and novel object recognition test to evaluate alteration in learning, memory and muscle co-ordination. We found that chronic oral exposure to aluminum chloride causes a significant increase in structural hallmarks such as Aβ1–42 and p231-tau levels along with pro-inflammatory cytokines (TNF-α and IL-6), oxidative stress, and a decrease in antioxidant markers such as GSH and catalase in the brain tissue. These biomarkers significantly affected neurobehavioral parameters in animals. This study provides a mechanistic understanding of chronic aluminum-induced neuronal toxicity in the brain with relevance to Alzheimer’s disease.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"616 - 627"},"PeriodicalIF":3.2,"publicationDate":"2022-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46410488","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}
Lakshmi Jaya Madhuri B, Neelima Ayyalasomayajula, Lokesh Murumulla, P. K. Dixit, C. Suresh
{"title":"Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and Parkin in Pb and β-amyloid peptide induced toxicity","authors":"Lakshmi Jaya Madhuri B, Neelima Ayyalasomayajula, Lokesh Murumulla, P. K. Dixit, C. Suresh","doi":"10.1080/15376516.2022.2054749","DOIUrl":"https://doi.org/10.1080/15376516.2022.2054749","url":null,"abstract":"Abstract Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer’s Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/Parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and Parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and Parkin in cells exposed to Pb and β–amyloid peptides, both Aβ (25-35) and Aβ (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aβ peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and β–amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/Parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"559 - 568"},"PeriodicalIF":3.2,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59851344","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}
A. Toropov, A. Toropova, P. Achary, M. Rasková, I. Raška
{"title":"The searching for agents for Alzheimer’s disease treatment via the system of self-consistent models","authors":"A. Toropov, A. Toropova, P. Achary, M. Rasková, I. Raška","doi":"10.1080/15376516.2022.2053918","DOIUrl":"https://doi.org/10.1080/15376516.2022.2053918","url":null,"abstract":"Abstract Robust quantitative structure-activity relationships (QSARs) for hBACE-1 inhibitors (pIC50) for a large database (n = 1706) are established. New statistical criteria of the predictive potential of models are suggested and tested. These criteria are the index of ideality of correlation (IIC) and the correlation intensity index (CII). The system of self-consistent models is a new approach to validate the predictive potential of QSAR-models. The statistical quality of models obtained using the CORAL software (http://www.insilico.eu/coral) for the validation sets is characterized by the average determination coefficient R2 v= 0.923, and RMSE = 0.345. Three new promising molecular structures which can become inhibitors hBACE-1 are suggested.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"549 - 557"},"PeriodicalIF":3.2,"publicationDate":"2022-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45725599","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}
{"title":"Combinative ex vivo studies and in silico models ProTox-II for investigating the toxicity of chemicals used mainly in cosmetic products","authors":"Priyanka Banerjee, O. C. Ulker","doi":"10.1080/15376516.2022.2053623","DOIUrl":"https://doi.org/10.1080/15376516.2022.2053623","url":null,"abstract":"Abstract Human data on remains sparse and of varying quality and reproducibility. Ex vivo experiments and animal experiments currently is the most preferred way to predict the skin sensitization approved by the regulatory agencies across the world. However, there is a constant need and demand to reduce animal experiments and provide the scope of alternative methods to animal testing. In this study, we have compared the predictive performance of the published computational tools such as ProTox-II, SuperCYPsPred with the data obtained from ex-vivo experiments. From the results of the retrospective analysis, it can be observed that the computational predictions are in agreement with the experimental results. The computational models used here are generative models based on molecular structures and machine learning algorithms and can be applied also for the prediction of skin sensitization. Besides prediction of the toxicity endpoints, the models can also provide deeper insights into the molecular mechanisms and adverse outcome pathways (AOPs) associated with the chemicals used in cosmetic products.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"542 - 548"},"PeriodicalIF":3.2,"publicationDate":"2022-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47984282","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}
Veysel Parlak, Bunyamin Ozgeris, A. Uçar, A. ÇİLİNGİR YELTEKİN, F. B. Ozgeris, O. Caglar, G. Alak, H. Turkez, M. Atamanalp
{"title":"Hematotoxic, oxidative and genotoxic damage in rainbow trout (Oncorhynchus mykiss) after exposure to 3-benzoylpyridine","authors":"Veysel Parlak, Bunyamin Ozgeris, A. Uçar, A. ÇİLİNGİR YELTEKİN, F. B. Ozgeris, O. Caglar, G. Alak, H. Turkez, M. Atamanalp","doi":"10.1080/15376516.2022.2049413","DOIUrl":"https://doi.org/10.1080/15376516.2022.2049413","url":null,"abstract":"Abstract Pyridine is a basic heterocyclic organic compound. The pyridine ring is present in many important compounds, including agricultural chemicals, medicines and vitamins. Due to their widespread industrial use, bioaccumulation and non-target toxic effects are being considered as a great risk to human and environmental health. In this study, we aimed to evaluate the hematological, oxidative and genotoxic damage potentials by different concentrations (1, 1.5, and 2 g/L) of the ketone 3-Benzoylpyridine (3BP) on rainbow trout (Oncorhynchus mykiss). Alterations in the biomarker levels of oxidative DNA damage (8-hydroxy-2′-deoxyguanosine (8-OHdG)), apoptosis (Caspase-3), malondialdehyde (MDA) as well as antioxidant enzyme activities including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), myeloperoxidase (MPO), paraoxonase (PON), and arylesterase (AR) were assessed in brain, liver, gill and blood tissues. Acetylcholinesterase (AChE) activity was also determined in brain tissue. In addition, we analyzed micronucleus (MN) rates and hematological indices of total erythrocyte count (RBC), total leukocyte count (WBC), hemoglobin (Hb), hematocrit (Hct), total platelet count (PLT), mean cell hemoglobin concentration (MCHC), mean cell hemoglobin (MCH), and mean cell volume (MCV) in blood. LC50-96h value of 3BP was calculated as 5.2 g/L from the data obtained. A significant decrease in brain AChE activity was determined in clear time and dose dependent manners. While SOD, CAT, GPx, PON, and AR levels were decreased, MDA, MPO, 8-OHdG and Caspase-3 levels were increased in all tissues (p < 0.05). Again, the 3BP led to increases of MN formation at all applied concentrations in the rates of between 45.4 and 72.7%. Significant differences (p < 0.05) were found out in between all studied hematology parameters between 3BP-exposed and the control fish. In conclusion, ours study firstly indicated that the treatment doses of 3BP induced distinct hematological and oxidative alterations as well as genotoxic damage in rainbow trout.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"501 - 509"},"PeriodicalIF":3.2,"publicationDate":"2022-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44602591","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}
{"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}
{"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}