NURA: A curated dataset of nuclear receptor modulators.
Abstract Nuclear receptors (NRs) are key regulators of human health and constitute a relevant target for medicinal chemistry applications as well as for toxicological risk assessment. Several open databases dedicated to small molecules that modulate NRs exist; however, depending on their final aim (i.e., adverse effect assessment or drug design), these databases contain a different amount and type of annotated molecules, along with a different distribution of experimental bioactivity values. Stemming from these considerations, in this work we aim to provide a unified dataset, NURA (NUclear Receptor Activity) datas...
Source: Toxicology and Applied Pharmacology - September 19, 2020 Category: Toxicology Authors: Valsecchi C, Grisoni F, Motta S, Bonati L, Ballabio D Tags: Toxicol Appl Pharmacol Source Type: research

Vildagliptin, a DPP-4 inhibitor, attenuates carbon tetrachloride-induced liver fibrosis by targeting ERK1/2, p38 α, and NF-κB signaling.
Vildagliptin, a DPP-4 inhibitor, attenuates carbon tetrachloride-induced liver fibrosis by targeting ERK1/2, p38α, and NF-κB signaling. Toxicol Appl Pharmacol. 2020 Sep 18;:115246 Authors: Khalil R, Shata A, Abd El-Kader EM, Sharaf H, Abdo WS, Amin NA, Saber S Abstract Mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-ĸB signaling have been recognized for their causal connection with liver fibrosis. Hence, it is encouraging to discover drugs that can modify the interactions between these signaling cascades. It has been suggested that glucagon-like peptide-1 receptors (GLP-...
Source: Toxicology and Applied Pharmacology - September 18, 2020 Category: Toxicology Authors: Khalil R, Shata A, Abd El-Kader EM, Sharaf H, Abdo WS, Amin NA, Saber S Tags: Toxicol Appl Pharmacol Source Type: research

Menthol in electronic cigarettes: A contributor to respiratory disease?
This study compared the effects of menthol on human bronchial epithelium using submerged cultures, a VITROCELL® cloud chamber that provides air liquid interface (ALI) exposure without solvents or heating, and a Cultex ALI system that delivers aerosol equivalent to that inhaled during vaping. In submerged culture, menthol significantly increased calcium influx and mitochondrial reactive oxygen species (ROS) via the TRPM8 receptor, responses that were inhibited by a TRPM8 antagonist. VITROCELL® cloud chamber exposure of BEAS-2B monolayers increased mitochondrial protein oxidation, expression of the antioxidant enzyme...
Source: Toxicology and Applied Pharmacology - September 17, 2020 Category: Toxicology Authors: Nair V, Tran M, Behar RZ, Zhai S, Cui X, Phandthong R, Wang Y, Pan S, Luo W, Pankow JF, Volz DC, Talbot P Tags: Toxicol Appl Pharmacol Source Type: research

Dosing algorithm for Tacrolimus in Tunisian Kidney transplant patients: Effect of CYP 3A4*1B and CYP3A4*22 polymorphisms.
Abstract Prescribing appropriate Tacrolimus (Tac) dosing is still a challenge for clinicians due to the interindividual variability in dose requirement and the narrow therapeutic index. Our objective is to identify potential factors that affects Tac exposure in Tunisian Kidney patients and to develop and validate a Tac dose requirement algorithm including genetic and nongenetic variables. A cross-sectional study was performed. To assess the implication of each covariate on Tac exposure, we classified the patients according to quartiles of exposure index (trough Tac concentration/Dose: C0/D). The total population w...
Source: Toxicology and Applied Pharmacology - September 16, 2020 Category: Toxicology Authors: Ben-Fredj N, Hannachi I, Chadli Z, Ben-Romdhane H, A Boughattas N, Ben-Fadhel N, Aouam K Tags: Toxicol Appl Pharmacol Source Type: research

Selection and identification of the panel of reference genes for quantitative real-time PCR normalization in rat testis at different development periods.
CONCLUSION: In this study, rat testicular GAPDH+β-actin for fetuses and GAPDH+RPL19 for infants and adolescents are recommended to be the optimal panel of reference genes. Respectively. The selected panel of reference genes was still stable under PDE condition. This study provided technical and theoretical supports for researches on testicular development toxicology. PMID: 32949581 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - September 16, 2020 Category: Toxicology Authors: Liu Y, Liu M, Zhang Q, Chen G, Wang H Tags: Toxicol Appl Pharmacol Source Type: research

Asenapine and iloperidone decrease the expression of major cytochrome P450 enzymes CYP1A2 and CYP3A4 in human hepatocytes. A significance for drug-drug interactions during combined therapy.
el WA Abstract Antipsychotics are often used in combination with other psychotropic drugs to treat a variety of psychiatric disorders, as well as in combination with other drugs taken by patients with co-morbidities. When these drugs are combined, the potential for drug-drug interaction increases, leading to side-effects, in addition to the predicted increase in effectiveness. The present study aimed at examining the effects of the three atypical neuroleptics asenapine, lurasidone and iloperidone on cytochrome P450 (CYP) expression in the human liver. The study was carried out on cryopreserved human hepatocytes. T...
Source: Toxicology and Applied Pharmacology - September 14, 2020 Category: Toxicology Authors: Danek PJ, Wójcikowski J, Daniel WA Tags: Toxicol Appl Pharmacol Source Type: research

ATP and ADP enhance DNA damage repair in γ-irradiated BEAS-2B human bronchial epithelial cells through activation of P2X7 and P2Y12 receptors.
ATP and ADP enhance DNA damage repair in γ-irradiated BEAS-2B human bronchial epithelial cells through activation of P2X7 and P2Y12 receptors. Toxicol Appl Pharmacol. 2020 Sep 14;:115240 Authors: Kitabatake K, Kaji T, Tsukimoto M Abstract Agents that promote DNA repair may be useful as radioprotectants to minimize side effects such as radiation pneumonia caused by damage to normal cells during radiation therapy to treat lung cancer. We have reported that extracellular nucleotides and nucleosides are involved in the P2 or P1 receptor-mediated DNA damage response (DDR) after γ-irradiation. H...
Source: Toxicology and Applied Pharmacology - September 14, 2020 Category: Toxicology Authors: Kitabatake K, Kaji T, Tsukimoto M Tags: Toxicol Appl Pharmacol Source Type: research

Fostered Nrf2 expression antagonizes iron overload and glutathione depletion to promote resistance of neuron-like cells to ferroptosis.
Abstract Neurological diseases were often characterized by progressive neuronal death, and emerging evidences suggested that ferroptosis may be an active driver of multiple neurodegenerative diseases. However, the mechanisms underlying ferroptosis in neuron cells are unclear. Here, we demonstrated that ferroptotic stimuli caused injury in neuron-like PC12 cells by modulating the expression of proteins involved in iron metabolism and lipid peroxidation at multiple levels, such as altering iron import/export, activating ferritinophagy, and decreasing glutathione (GSH) level. Nuclear factor erythroid 2-related factor...
Source: Toxicology and Applied Pharmacology - September 13, 2020 Category: Toxicology Authors: Liu Z, Lv X, Song E, Song Y Tags: Toxicol Appl Pharmacol Source Type: research

Fatty acid nitroalkenes inhibit the inflammatory response to bleomycin-mediated lung injury.
Abstract Fatty acid nitroalkenes are reversibly-reactive electrophiles, endogenously detectable at nM concentrations, displaying anti-inflammatory actions. Nitroalkenes like 9- or 10-nitro-octadec-9-enoic acid (e.g. nitro-oleic acid, OA-NO2) pleiotropically suppress cardiovascular inflammatory responses, with pulmonary responses less well defined. C57BL/6 J male mice were intratracheally administered bleomycin (3 U/kg, ITB), to induce pulmonary inflammation and acute injury, or saline and were treated with 50 μL OA-NO2 (50 μg) or vehicle in the same instillation and 72 h post-exposure to assess ant...
Source: Toxicology and Applied Pharmacology - September 12, 2020 Category: Toxicology Authors: Wilkinson ML, Abramova E, Guo C, Gow JG, Murray A, Koudelka A, Cechova V, Freeman BA, Gow AJ Tags: Toxicol Appl Pharmacol Source Type: research

Biological effects of inhaled hydraulic fracturing sand dust. VI. Cardiovascular effects.
Abstract Hydraulic fracturing is used to access oil and natural gas reserves. This process involves the high-pressure injection of fluid to fracture shale. Fracking fluid contains approximately 95% water, chemicals and 4.5% fracking sand. Workers may be exposed to fracking sand dust (FSD) during the manipulation of the sand, and negative health consequences could occur if FSD is inhaled. In the absence of any information about its potential toxicity, a comprehensive rat animal model study (see Fedan, J.S., Toxicol Appl Pharmacol. 000, 000-000, 2020) was designed to investigate the bioactivities of several FSDs in ...
Source: Toxicology and Applied Pharmacology - September 12, 2020 Category: Toxicology Authors: Krajnak K, Kan H, Russ KA, McKinney W, Waugh S, Zheng W, Kashon ML, Johnson C, Cumpston J, Fedan JS Tags: Toxicol Appl Pharmacol Source Type: research

Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach.
Abstract Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are "old", their pharmacological and toxicological profile in SARS-CoV-2 - infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combi...
Source: Toxicology and Applied Pharmacology - September 10, 2020 Category: Toxicology Authors: Baralić K, Jorgovanović D, Živančević K, Miljaković EA, Antonijević B, Djordjevic AB, Ćurčić M, Ćosić DĐ Tags: Toxicol Appl Pharmacol Source Type: research

Chronic electronic cigarette use elicits molecular changes related to pulmonary pathogenesis.
Abstract The relative safety of chronic exposure to electronic cigarette (e-cig) aerosol remains unclear in terms of lung pathogenesis. Therefore, this study aims to evaluate gene/protein biomarkers, which are associated with cigarette-induced pulmonary injury in animals chronically exposed to nicotine containing e-cig aerosol. C57BL/6 J mice were randomly assigned to three exposure groups: e-cig, tobacco cigarette smoke, and filtered air. Lung tissues and/or paraffin embedded slides were used to evaluate gene and/or protein expressions of the CYP450 metabolism (CYP1A1, CYP2A5, and CYP3A11), oxidative stress (Nr...
Source: Toxicology and Applied Pharmacology - September 2, 2020 Category: Toxicology Authors: Marshall K, Liu Z, Olfert IM, Gao W Tags: Toxicol Appl Pharmacol Source Type: research

Arsenic induced epigenetic changes and relevance to treatment of acute promyelocytic leukemia and beyond.
Abstract Epigenetic alterations regulate gene expression without changes in the DNA sequence. It is well-demonstrated that aberrant epigenetic changes contribute to the leukemogenesis of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) is one of the most common drugs used in the frontline treatment of APL that act through targeting and destabilizing the PML/RARα oncofusion protein. ATO together with all-trans retinoic acid (ATRA) lead to durable remission of more than 90% non-high-risk APL patients, turning APL treatment into a paradigm of oncoprotein targeted cure. Although relapse and drug resist...
Source: Toxicology and Applied Pharmacology - August 31, 2020 Category: Toxicology Authors: Maimaitiyiming Y, Wang QQ, Hsu CH, Naranmandura H Tags: Toxicol Appl Pharmacol Source Type: research

Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity.
Abstract The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assess...
Source: Toxicology and Applied Pharmacology - August 30, 2020 Category: Toxicology Authors: Miller J, Meki M, Ou Q, George SA, Gams A, Abouleisa RRE, Tang XL, Ahern BM, Giridharan GA, El-Baz A, Hill BG, Satin J, Conklin DJ, Moslehi J, Bolli R, Ribeiro AJS, Efimov IR, Mohamed TMA Tags: Toxicol Appl Pharmacol Source Type: research

Characterization of indoleamine-2,3-dioxygenase 1, tryptophan-2,3-dioxygenase, and Ido1/Tdo2 knockout mice.
Abstract Indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase 2 (TDO2) degrade tryptophan (Trp) to kynurenine (Kyn), and these enzymes have promise as therapeutic targets. A comprehensive characterization of potential safety liabilities of IDO1 and TDO2 inhibitors using knockout (KO) mice has not been assessed, nor has the dual Ido1/Tdo2 KO been reported. Here we characterized male and female mice with KOs for Ido1, Tdo2, and Ido1/Tdo2 and compared findings to the wild type (WT) mouse strain, evaluated for 14 days, using metabolomics, transcriptional profiling, behavioral analysis, spleen immunoph...
Source: Toxicology and Applied Pharmacology - August 29, 2020 Category: Toxicology Authors: Aslamkhan AG, Xu Q, Loughlin A, Vu H, Pacchione S, Bhatt B, Garfinkel I, Styring TG, LaFranco-Scheuch L, Pearson K, Reynolds S, Li J, Zhou H, Miller JR, Solban N, Bass A, Glaab WE Tags: Toxicol Appl Pharmacol Source Type: research

A novel monovalent FGFR1 antagonist: Preclinical safety profiles in rodents and non-human primates.
Abstract Blocking Fibroblast Growth Factor Receptor 1 (FGFR1) is an attractive therapeutic option for treatment of cancer subtypes with amplification and over-expression of FGFR1. Selective targeting of FGFR1 can be achieved using an antibody-based approach, as small molecule inhibitors may not discriminate between FGFR1, 2, 3 and 4 due to their highly homologous kinase domain. However, development of classical bivalent FGFR1 directed antibodies has failed due to non-tolerated body weight decreases in preclinical species. M6123 is a novel IgG-like monovalent FGFR1 specific binder with enhanced Antibody-Dependent C...
Source: Toxicology and Applied Pharmacology - August 28, 2020 Category: Toxicology Authors: Yu P, Knippel A, Onidi M, Paoletti A, Vigna E, Hellmann J, Esdar C Tags: Toxicol Appl Pharmacol Source Type: research

Metabolic profile of methylazoxymethanol model of schizophrenia in rats and effects of three antipsychotics in long-acting formulation.
This study evaluated the metabolic phenotype of a methylazoxymethanol (MAM) schizophrenia-like model together with the metabolic effects of three APs [olanzapine (OLA), risperidone (RIS) and haloperidol (HAL)] administered via long-acting formulations for 8 weeks in female rats. Body weight, feed efficiency, serum lipid profile, gastrointestinal and adipose tissue-derived hormones (leptin, ghrelin, glucagon and glucagon-like peptide 1) were determined. The lipid profile was assessed in APs-naïve MAM and control cohorts of both sexes. Body weight was not altered by the MAM model, though cumulative food intake and fee...
Source: Toxicology and Applied Pharmacology - August 28, 2020 Category: Toxicology Authors: Horska K, Kotolova H, Karpisek M, Babinska Z, Hammer T, Prochazka J, Stark T, Micale V, Ruda-Kucerova J Tags: Toxicol Appl Pharmacol Source Type: research

Integrative systems toxicology to predict human biological systems affected by exposure to environmental chemicals.
Abstract Biological systems are disturbed by several factors that are defined by the exposome. Environmental substances, including endocrine disruptors (EDs), represent the chemical exposome. These stressors may alter biological systems, that could lead to toxic health effects. Even if scientific evidence provide links between diverse environmental substances and disorders, innovative approaches, including alternative methods to animal testing, are still needed to address the complexity of the chemical mechanisms of action. Network science appears to be a valuable approach for helping to decipher a comprehensive a...
Source: Toxicology and Applied Pharmacology - August 26, 2020 Category: Toxicology Authors: Taboureau O, El M'Selmi W, Audouze K Tags: Toxicol Appl Pharmacol Source Type: research

Inhibition of notch enhances the anti-atherosclerotic effects of LXR agonists while reducing fatty liver development in ApoE-deficient mice.
Abstract Liver X receptor (LXR) activation can achieve satisfactory anti-atherosclerotic activity, but can also lead to the development of fatty liver and hypertriglyceridemia. In contrast, Notch inhibition can suppress both atherosclerosis and the hepatic accumulation of lipids. In the present study, we sought to assess whether combining LXR ligand agonists (T317) with Notch receptor inhibitors (DAPT) would lead to enhanced anti-atherosclerotic activity while overcoming the adverse events associated with LXR ligand agonist therapy. The impact of the combined T317 + DAPT therapeutic regimen on atherosclerosis, fat...
Source: Toxicology and Applied Pharmacology - August 24, 2020 Category: Toxicology Authors: Hao Y, Wang X, Zhang F, Wang M, Wang Y, Wang H, Du Y, Wang T, Fu F, Gao Z, Zhang L Tags: Toxicol Appl Pharmacol Source Type: research

Comparative toxicokinetics of bisphenol S in rats and mice following gavage administration.
Abstract Bisphenol S (BPS) is a component of polyether sulfone used in a variety of industrial applications and consumer products. We investigated the plasma toxicokinetic (TK) behavior of free (unconjugated parent) and total (parent and conjugated) BPS in rats and mice following a single gavage administration (34, 110, or 340 mg/kg). In male rats, BPS was rapidly absorbed with free BPS maximum concentration (Cmax) reached at ≤2.27 h. Elimination of free BPS in male rats was dose-dependent with estimated half-lives of 5.77-11.9 h. Cmax and area under the concentration versus time curve (AUC) increased wit...
Source: Toxicology and Applied Pharmacology - August 24, 2020 Category: Toxicology Authors: Waidyanatha S, Black SR, Silinski M, Sutherland V, Fletcher BL, Fernando RA, Fennell TR Tags: Toxicol Appl Pharmacol Source Type: research

Oxymatrine ameliorates Imiquimod-induced psoriasis pruritus and inflammation through inhibiting heat shock protein 90 and heat shock protein 60 expression in keratinocytes.
Abstract In this work, we aimed to investigate whether oxymatrine exerts its anti-pruritic and anti-inflammatory efficacy in the imiquimod-induced psoriasis mice and the related mechanism. We established the psoriasis model by applying the imiquimod ointment topically and oxymatrine was injected intraperitoneally as the treatment. The behavior and skin morphology results indicated that oxymatrine inhibits imiquimod-induced pruritus alleviating keratinization of skin and inflammatory infiltration. Moreover, we examined the expression of various indicators and found heat shock protein (HSP) 90 and 60 upregulated in ...
Source: Toxicology and Applied Pharmacology - August 21, 2020 Category: Toxicology Authors: Xiang X, Tu C, Li Q, Wang W, Huang X, Zhao Z, Xiong H, Mei Z Tags: Toxicol Appl Pharmacol Source Type: research

Paris saponin II-induced paraptosis-associated cell death increased the sensitivity of cisplatin.
Abstract Paris Saponin II (PSII) has been regarded as an effective and imperative component isolated from Rhizoma Paridis saponins (RPS) and exhibited strong anti-tumor effects on a variety of cancer. Our results revealed that human non-small lung cancer cell lines NCI-H460 and NCI-H520 were exposed to 1 μM of PSII, which inhibited the proliferation of lung cancer cells and activated apoptosis, autophagy and paraptosis. PSII induced paraptosis-associated cell death prior to apoptosis and autophagy. It induced paraptosis based on ER stress through activation of the JNK pathway. Meanwhile, PSII increased the cy...
Source: Toxicology and Applied Pharmacology - August 21, 2020 Category: Toxicology Authors: Man S, Lv P, Cui J, Liu F, Peng L, Ma L, Liu C, Gao W Tags: Toxicol Appl Pharmacol Source Type: research

Triclosan disrupts immune cell function by depressing Ca2+ influx following acidification of the cytoplasm.
Abstract Triclosan (TCS) is an antimicrobial agent that was effectively banned by the FDA from hand soaps in 2016, hospital soaps in 2017, and hand sanitizers in 2019; however, TCS can still be found in a few products. At consumer-relevant, non-cytotoxic doses, TCS inhibits the functions of both mitochondria and mast cells, a ubiquitous cell type. Via the store-operated Ca2+ entry mechanism utilized by many immune cells, mast cells undergo antigen-stimulated Ca2+ influx into the cytosol, for proper function. Previous work showed that TCS inhibits Ca2+ dynamics in mast cells, and here we show that TCS also inhibits...
Source: Toxicology and Applied Pharmacology - August 21, 2020 Category: Toxicology Authors: Sangroula S, Baez Vasquez AY, Raut P, Obeng B, Shim JK, Bagley GD, West BE, Burnell JE, Kinney MS, Potts CM, Weller SR, Kelley JB, Hess ST, Gosse JA Tags: Toxicol Appl Pharmacol Source Type: research

Toxicological implication of prostaglandin transporter SLCO2A1 inhibition by cigarette smoke in exacerbation of lung inflammation.
We reported that bleomycin (BLM)-induced pulmonary fibrosis was exacerbated in the prostaglandin transporter gene (Slco2a1)-deficient mice (Slco2a1(-/-)). Because cigarette smoke (CS) contributes to creating a profibrotic milieu in the respiratory region, the present study aimed to investigate the impact of CS on SLCO2A1-associated pathogenesis in the lungs of BLM-instilled mice. Bronchoalveolar lavage (BAL) fluid cell analysis indicated more severe inflammation in Slco2a1(-/-) on day 5 after BLM intratracheal instillation, and Slco2a1 deletion increased mRNA expression of pro-inflammatory cytokines (Tnf-α and Il-1&b...
Source: Toxicology and Applied Pharmacology - August 20, 2020 Category: Toxicology Authors: Nakanishi T, Sakiyama S, Takashima H, Honda R, Shumba MN, Nakamura Y, Kasahara K, Tamai I Tags: Toxicol Appl Pharmacol Source Type: research

PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor coordination-associated side effects in neuropathic pain model.
This study therefore sought to explore the ability of PCC-0105002, a novel PSD95-nNOS small molecule inhibitor, to alter pain sensitivity in rodent neuropathic pain models. Firstly, the IC50 of PCC-0105002 for PSD95 and NOS1 binding activity was determined using an AlphaScreen assay kit. Then, we examined the effects of PCC-0105002 in the mouse formalin test and in the rat spinal nerve ligation (SNL) model, and explored the ability of PCC-0105002 to mediate analgesia and to effect motor coordination in a rota-rod test. Moreover, the mechanisms whereby PCC-0105002 mediates analgesia was explored via western blotting, Golgi ...
Source: Toxicology and Applied Pharmacology - August 20, 2020 Category: Toxicology Authors: Li C, Su C, Wang Z, Han R, Wang Y, Wang H, Tian J, Gao Y Tags: Toxicol Appl Pharmacol Source Type: research

Commentary - a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars and intended copy biologics in treating chemotherapy associated febrile neutropenia.
Abstract Filgrastim, human white cell growth factor, Granulocyte colony-stimulating factor (G-CSF), is a core medicine in the WHO list of Essential Medicines. For this reason, recent reporting of statistically significant safety and efficacy differences between reference and Biosimilar brands of filgrastim by Rastogi and the Indian Pharmacopoeia Commission in Toxicology and Applied Pharmacology in 2020 is of great concern [Shruti Rastogi et al. Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decad...
Source: Toxicology and Applied Pharmacology - August 18, 2020 Category: Toxicology Authors: Cornes PG, Muenzberg M Tags: Toxicol Appl Pharmacol Source Type: research

Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPAR α mice fed an American diet.
The objectives of this study were to generate a new model for examining PFAS-induced dyslipidemia and to conduct molecular studies to better define mechanism(s) of action. We tested the hypothesis that perfluorooctanoic acid (PFOA) exposure at a human-relevant level dysregulates expression of genes controlling cholesterol homeostasis in livers of mice expressing human PPARα (hPPARα). Female and male hPPARα and PPARα null mice were fed a diet based on the "What we eat in America" analysis and exposed to PFOA in drinking water (8 μM) for 6 weeks. This resulted in a serum PFOA concentr...
Source: Toxicology and Applied Pharmacology - August 18, 2020 Category: Toxicology Authors: Schlezinger JJ, Puckett H, Oliver J, Nielsen G, Heiger-Bernays W, Webster TF Tags: Toxicol Appl Pharmacol Source Type: research

Salinomycin promotes T-cell proliferation by inhibiting the expression and enzymatic activity of immunosuppressive indoleamine-2,3-dioxygenase in human breast cancer cells.
Abstract Indoleamine 2,3 dioxygenase (IDO) is upregulated in many tumor types, including breast cancer, and plays a reputable role in promoting tumor immune tolerance. The importance of the immunosuppressive mechanism of IDO by suppressing T-cell function has garnered profound interest in the development of clinical IDO inhibitors. Herein, we established a screening method with cervical HeLa cells to induce IDO expression using interferon-γ (IFN-γ). After screening our chemical library, we found that salinomycin potently inhibited IFN-γ-stimulated kynurenine synthesis with IC50 values of 3.36-4.6...
Source: Toxicology and Applied Pharmacology - August 18, 2020 Category: Toxicology Authors: Ebokaiwe AP, Njoya EM, Sheng Y, Zhang Z, Sheng L, Zhou Z, Qiang Z, Ting P, Hussein AA, Zhang G, Lu X, Li L, Wang F Tags: Toxicol Appl Pharmacol Source Type: research

Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer.
This study provides preclinical proof-of-concept that combined treatment of EZH2 inhibitor with AR antagonist results in synergistic anticancer effects opening new possibilities for treatment of CRPC tumors. PMID: 32805266 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - August 14, 2020 Category: Toxicology Authors: Shankar E, Franco D, Iqbal O, Moreton S, Kanwal R, Gupta S Tags: Toxicol Appl Pharmacol Source Type: research

Cardiopulmonary function and dysregulated cardiopulmonary reflexes following acute oleoresin capsicum exposure in rats.
Abstract Cardiopulmonary functions such as respiratory depression, severe irritation, inflamed respiratory tract, hyperventilation and, tachycardia are the most affected ones when it comes to the riot control agent oleoresin capsicum (OC) exposure. However, no studies have been done to elucidate the mechanism underlying deterioration of the combined cardiopulmonary functions. Parameters such as acute respiratory, cardiac, parameters and ultrasonography (USG) measurements were investigated in an in vivo setup using Wistar rats at 1 h and 24 h post inhalation exposure to 2%, 6% and 10% OC, whereas, cell migratio...
Source: Toxicology and Applied Pharmacology - August 14, 2020 Category: Toxicology Authors: Patowary P, Pathak MP, Kishor S, Roy PK, Das S, Chattopadhyay P, Zaman K Tags: Toxicol Appl Pharmacol Source Type: research

Histone deacetylase 3-selective inhibitor RGFP966 ameliorates impaired glucose tolerance through β-cell protection.
In this study, low-dose streptozotocin (STZ)-induced pre-diabetic mice were used to test the regulatory ability of RGFP966 in blood glucose and insulin. We isolated the islets both from normal C57BL/6 J mice and KKAy mice with spontaneous type 2 diabetes to determine the potency of RGFP966 on glucose-stimulated insulin secretion. NIT-1 pancreatic β-cells induced by sodium palmitate (PA) were applied to identify the protective effects of RGFP966 against β-cell apoptosis. The results showed that administration of RGFP966 in the pre-diabetic mice not only significantly reduced hyperglycemia, promoted phase I insul...
Source: Toxicology and Applied Pharmacology - August 12, 2020 Category: Toxicology Authors: Lei L, Bai G, Wang X, Liu S, Xia J, Wu S, Huan Y, Shen Z Tags: Toxicol Appl Pharmacol Source Type: research

Epigenetic repression of AT2 receptor is involved in β cell dysfunction and glucose intolerance of adult female offspring rats exposed to dexamethasone prenatally.
In conclusion, continuous epigenetic repression of AT2R before and after birth may be involved in β cell dysfunction and glucose intolerance of the PDE adult female offspring. PMID: 32791177 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - August 10, 2020 Category: Toxicology Authors: Kou H, Gui S, Dai Y, Guo Y, Wang H Tags: Toxicol Appl Pharmacol Source Type: research

IL-33/ST2 signaling modulates Afghanistan particulate matter induced airway hyperresponsiveness in mice.
We present for the first time that APM may increase AHR, one of the features of asthma, in part through the IL-33/ST2/RGS2 pathway. PMID: 32777237 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - August 7, 2020 Category: Toxicology Authors: Berman R, Kopf KW, Min E, Huang J, Downey GP, Alam R, Chu HW, Day BJ Tags: Toxicol Appl Pharmacol Source Type: research

Implications of miRNAs on TGF- β/TAK1/mTOR pathway in mediating the renoprotective effects of pentoxifylline against cisplatin-induced nephrotoxicity in rats.
Implications of miRNAs on TGF-β/TAK1/mTOR pathway in mediating the renoprotective effects of pentoxifylline against cisplatin-induced nephrotoxicity in rats. Toxicol Appl Pharmacol. 2020 Aug 07;:115184 Authors: El Magdoub HM, Schaalan MF, Rahmo RM, Farag DB, Khedr LH Abstract CIS-mediated nephrotoxicity is induced via transforming growth factor-beta (TGF-β) and TGF-β-activated kinase (TAK1). TGF-β and TAK1 are known to interact with microRNA-let-7b and microRNA-26b, respectively. Additionally, TGF-β1 is reported to down-regulate the autophagy marker microtubule-associated prot...
Source: Toxicology and Applied Pharmacology - August 7, 2020 Category: Toxicology Authors: El Magdoub HM, Schaalan MF, Rahmo RM, Farag DB, Khedr LH Tags: Toxicol Appl Pharmacol Source Type: research

Enhanced in vivo targeting of estrogen receptor alpha signaling in murine mammary adenocarcinoma by nilotinib/rosuvastatin novel combination.
Abstract The development of resistance to endocrine therapy of estrogen receptor alpha (ERα)-positive breast cancer is inevitable, necessitating the introduction of alternative treatment strategies. Therefore, the current study was carried out to investigate the in vivo efficacy and tolerability of nilotinib/rosuvastatin novel combination against ERα-positive breast carcinoma. Results showed that treatment of tumor-bearing mice with nilotinib/rosuvastatin exerted a significant antitumor activity. Mechanistically, the combination treatment efficiently inhibited the in vivo ERα protein expression, ...
Source: Toxicology and Applied Pharmacology - August 6, 2020 Category: Toxicology Authors: Goda AE, Elsisi AE, Sokkar SS, Abdelrazik NM Tags: Toxicol Appl Pharmacol Source Type: research

Hydroxyl functionalized multi-walled carbon nanotubes modulate immune responses without increasing 2009 pandemic influenza A/H1N1 virus titers in infected mice.
We reported that exposure of lung cells and mice to pristine single-walled CNTs (SWCNTs) leads to significantly increased influenza virus H1N1 strain A/Mexico/4108/2009 (IAV) titers in concert with repressed antiviral immune responses. In the present study, we investigated if hydroxylated multi-walled CNTs (MWCNTs), would result in similar outcomes. C57BL/6 mice were exposed to 20 μg MWCNTs on day 0 and IAV on day 3 and samples were collected on day 7. We investigated pathological changes, viral titers, immune-related gene expression in lung tissue, and quantified differential cell counts and cytokine and chemokine le...
Source: Toxicology and Applied Pharmacology - August 6, 2020 Category: Toxicology Authors: Chen H, Humes ST, Rose M, Robinson SE, Loeb JC, Sabaraya IV, Smith LC, Saleh NB, Castleman WL, Lednicky JA, Sabo-Attwood T Tags: Toxicol Appl Pharmacol Source Type: research

Hesperetin protects against palmitate-induced cellular toxicity via induction of GRP78 in hepatocytes.
In conclusion, hesperetin protected against palmitate-induced hepatic cell death via activation of the sXBP1/GRP78 signaling pathway, thus inhibiting palmitate-induced ER stress. Moreover, high concentrations of hesperetin induce ER stress and subsequently cause cell death in hepatocytes. PMID: 32763355 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - August 5, 2020 Category: Toxicology Authors: Geng Y, Wu Z, Buist-Homan M, Blokzijl H, Moshage H Tags: Toxicol Appl Pharmacol Source Type: research

Formation of lamellar body-like structure may be an initiator of didecyldimethylammonium chloride-induced toxic response.
In this study, we identified the possible pulmonary toxic response and mechanism using human bronchial epithelial (BEAS-2B) cells and mice. First, cell viability decreased sharply at a 4 μg/mL of concentration. The volume of intracellular organelles and the ROS level reduced, leading to the formation of apoptotic bodies and an increase of the LDH release. Secretion of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and matrix metalloproteinase-1 also significantly increased. More importantly, lamellar body-like structures were formed in both the cells and mice exposed to DDAC, and the expression of both...
Source: Toxicology and Applied Pharmacology - August 4, 2020 Category: Toxicology Authors: Park EJ, Seong E, Kang MS, Lee GH, Kim DW, Han JS, Lim HJ, Lee SH, Han HY Tags: Toxicol Appl Pharmacol Source Type: research

Intermittent fasting ameliorates PM2.5 exposure-induced abnormalities in glycaemic control.
This study, therefore, tested whether intermittent fasting ameliorates PM2.5 exposure-induced abnormalities in glycaemic control. To this end, C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) for 16 weeks and concurrently subject to ad libitum feeding or intermittent fasting. The food intake assessment showed that CAP exposure transiently reduced food intake in ad libitum fed mice, but persistently reduced food intake in intermittently fasted mice. In contrast, CAP exposure persistently promoted mouse weight gain in ad libitum fed mice, while intermittent fasting blocked this C...
Source: Toxicology and Applied Pharmacology - August 3, 2020 Category: Toxicology Authors: Wei W, Tang L, Chen M, Chen S, Zhou H, Ying Z Tags: Toxicol Appl Pharmacol Source Type: research

Corrigendum to 'P-Glycoprotein activation by 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5) in rat distal ileum: Ex vivo and in vivo studies' [Toxicology and Applied Pharmacology 386 (2020) 114832].
, Remião F PMID: 32750377 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - August 1, 2020 Category: Toxicology Authors: Rocha-Pereira C, Ghanem CI, Silva R, Casanova AG, Duarte-Araújo M, Gonçalves-Monteiro S, Sousa E, de Lourdes Bastos M, Remião F Tags: Toxicol Appl Pharmacol Source Type: research

Natural alkaloid 8-oxo-epiberberine inhibited TGF- β1-triggred epithelial-mesenchymal transition by interfering Smad3.
In conclusion, OPB inhibited TGF-β1-induced EMT possibly by interfering with Smad3. OPB might have therapeutic potentials for the treatment of metastatic cancers. PMID: 32745479 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - July 31, 2020 Category: Toxicology Authors: Liu X, Zhang Y, Zhou GJ, Hou Y, Kong Q, Lu JJ, Zhang Q, Chen X Tags: Toxicol Appl Pharmacol Source Type: research

Endocrine-disrupting chemicals rapidly affect intercellular signaling in Leydig cells.
This study addresses a specific role of testicular gap junctional intercellular communication (GJIC) between adjacent prepubertal Leydig cells in endocrine disruption and male reproductive toxicity. Organochlorine pesticides (lindane, methoxychlor, DDT), industrial chemicals (PCB153, bisphenol A, nonylphenol and octylphenol) as well as personal care product components (triclosan, triclocarban) rapidly dysregulated GJIC in murine Leydig TM3 cells. The selected GJIC-inhibiting EDCs (methoxychlor, triclosan, triclocarban, lindane, DDT) caused the immediate GJIC disruption by the relocation of gap junctional protein connexin 4...
Source: Toxicology and Applied Pharmacology - July 30, 2020 Category: Toxicology Authors: Yawer A, Sychrová E, Labohá P, Raška J, Jambor T, Babica P, Sovadinová I Tags: Toxicol Appl Pharmacol Source Type: research

NADPH-quinone oxidoreductase-1 mediates Benzo-[a]-pyrene-1,6-quinone-induced cytotoxicity and reactive oxygen species production in human EA.hy926 endothelial cells.
This study, demonstrated that BP-1,6-Q diminishes NQO1 enzyme activity in a dose-dependent manner in human EA.hy926 endothelial cells. The decrease in the NQO1 enzyme causes potentiation in BP-1,6-Q-mediated toxicity in EA.hy926 endothelial cells. The enhancement of NQO1 in endothelial cells showed cytoprotection against BP-1,6-Q-induced cellular toxicity, lipid, and protein damage suggesting an essential role of NQO1 in cytoprotection against BP-1,6-Q toxicity. Using various biochemical assays and genetic approaches, results from this study further demonstrated that NQO1 also plays a crucial role in BP-1,6-Q-induced produ...
Source: Toxicology and Applied Pharmacology - July 30, 2020 Category: Toxicology Authors: Shukla H, Gaje G, Koucheki A, Lee HY, Sun X, Trush MA, Zhu H, Li YR, Jia Z Tags: Toxicol Appl Pharmacol Source Type: research

Effects of silver nanoparticles on T98G human glioblastoma cells.
rb MA Abstract Nanotechnology has been well developed in recent decades because it provides social progress and welfare. Consequently, exposure of population is increasing and further increases in the near future are forecasted. Therefore, assessing the safety of applications involving nanoparticles is strongly advisable. We assessed the effects of silver nanoparticles at a non-cytotoxic concentration on the performance of T98G human glioblastoma cells mainly by an omic approach. We found that silver nanoparticles are able to alter several molecular pathways related to inflammation. Cellular repair and regeneratio...
Source: Toxicology and Applied Pharmacology - July 30, 2020 Category: Toxicology Authors: Fuster E, Candela H, Estévez J, Arias AJ, Vilanova E, Sogorb MA Tags: Toxicol Appl Pharmacol Source Type: research

Natriuretic peptides and echocardiographic parameters in Mexican children environmentally exposed to arsenic.
CONCLUSIONS: In this study, we showed associations between plasma BNP and arsenic exposure. Our results support the importance of reducing childhood arsenic exposure, which may have cardiovascular effects early in life. PMID: 32738329 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - July 29, 2020 Category: Toxicology Authors: Torres-Arellano JM, Osorio-Yañez C, Sánchez-Peña LC, Ayllon-Vergara JC, Arreola-Mendoza L, Aguilar-Madrid G, Del Razo LM Tags: Toxicol Appl Pharmacol Source Type: research

Upregulation of ubiquitinated proteins and their degradation pathway in muscle atrophy induced by cisplatin in mice.
In conclusion, ubiquitin and ubiquitinated proteins are upregulated in cisplatin-induced muscle atrophy. Cisplatin-induced ubiquitinated proteins are degraded by the 26 s proteasome pathway. PMID: 32738330 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - July 29, 2020 Category: Toxicology Authors: Sakai H, Ikeno Y, Tsukimura Y, Inomata M, Suzuki Y, Kon R, Ikarashi N, Chiba Y, Yamada T, Kamei J Tags: Toxicol Appl Pharmacol Source Type: research

A novel bile acid analog, A17, ameliorated non-alcoholic steatohepatitis in high-fat diet-fed hamsters.
In conclusion, a novel bile acid analog A17 was identified to ameliorate NASH in HF-fed hamsters. The potential mechanisms could be contributed to reducing FA uptake, stimulating FA oxidation and relieving inflammation. PMID: 32738331 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - July 29, 2020 Category: Toxicology Authors: Wang Y, Zhu Y, Niu J, Deng Q, Guo S, Jiang H, Peng Z, Xue Y, Peng H, Xuan L, Pan G Tags: Toxicol Appl Pharmacol Source Type: research

Effects of ablation and activation of Nrf2 on bile acid homeostasis in mice.
In this study, activation of Nrf2 was achieved either pharmacologically by CDDO-imidazolide (CDDO-Im) or genetically through a "gene dose-response" model consisting of Nrf2-null, wild-type (WT), Keap1-knockdown (Keap1-KD), and Keap1-hepatocyte knockout (Keap1-HKO) mice. In WT mice, CDDO-Im increased bile flow and decreased hepatic BAs, which was associated with a down-regulation of the canalicular BA efflux transporter Bsep and an increase in biliary BA excretion. In contrast, hepatic Bsep and biliary BA excretion were not altered in Keap1-KD or Keap1-HKO mice, suggesting that Nrf2 is not important for regulating...
Source: Toxicology and Applied Pharmacology - July 29, 2020 Category: Toxicology Authors: Zhang Y, Lickteig AJ, Liu J, Csanaky IL, Klaassen CD Tags: Toxicol Appl Pharmacol Source Type: research

Epigenetic upregulation of galanin-like peptide mediates deoxynivalenol induced-growth inhibition in pituitary cells.
In this study, we report the important role of GALP during DON-induced growth inhibition in the rat pituitary tumour cell line GH3. DON was found to increase the expression of GALP through hypomethylationin the promoter region of the GALP gene and upregulate the expression of proinflammatory factors, while downregulate the expression of growth hormone (GH). Furthermore, GALP overexpression promoted proinflammatory cytokines, including TNF-α, IL-1β, IL-11 and IL-6, and further reduced cell viability and cell proliferation, while the inhibitory effect of GALP was the opposite. The expression of GALP and insulin li...
Source: Toxicology and Applied Pharmacology - July 29, 2020 Category: Toxicology Authors: Liu A, Hu S, Wu Q, Ares I, Martínez M, Martínez-Larrañaga MR, Anadón A, Wang X, Martínez MA Tags: Toxicol Appl Pharmacol Source Type: research

The utility of a differentiated preclinical liver model, HepaRG cells, in investigating delayed toxicity via inhibition of mitochondrial-replication induced by fialuridine.
Abstract During its clinical development fialuridine caused liver toxicity and the death of five patients. This case remains relevant due to the continued development of mechanistically-related compounds against a back-drop of simple in vitro models which remain limited for the preclinical detection of such delayed toxicity. Here, proteomic investigation of a differentiated, HepaRG, and proliferating, HepG2 cell model was utilised to confirm the presence of the hENT1 transporter, thymidine kinase-1 and -2 (TK1, TK2) and thymidylate kinase, all essential in order to reproduce the cellular activation and disposition...
Source: Toxicology and Applied Pharmacology - July 27, 2020 Category: Toxicology Authors: Jolly CE, Douglas O, Kamalian L, Jenkins RE, Beckett AJ, Penman SL, Williams DP, Monshouwer M, Simic D, Snoeys J, Park BK, Chadwick AE Tags: Toxicol Appl Pharmacol Source Type: research