Lead and mercury 28  day exposure at small concentrations reduces smooth muscle relaxation by decreasing cGMP.
Lead and mercury 28 day exposure at small concentrations reduces smooth muscle relaxation by decreasing cGMP. Toxicol Appl Pharmacol. 2021 Jan 11;:115405 Authors: de Moura Magalhães BAB, Rodrigues LF, de Oliveira TF, Vassallo DV, Simões MR Abstract Cardiovascular diseases are among the main causes of mortality in the world. There is evidence of cardiovascular harm after exposure to low lead or mercury concentrations, but the effects of chronic exposure to the association of low doses of these toxic metals are still unknown. This work evaluated after 4 weeks, the association effects o...
Source: Toxicology and Applied Pharmacology - January 11, 2021 Category: Toxicology Authors: de Moura Magalhães BAB, Rodrigues LF, de Oliveira TF, Vassallo DV, Simões MR Tags: Toxicol Appl Pharmacol Source Type: research

Differential effects of arsenic species on Nrf2 and Bach1 nuclear localization in cultured hepatocytes.
This study aimed to explore the activation of the Nrf2 pathway upon treatment of arsenic in various forms, including inorganic and organic arsenic. Our results showed that inorganic arsenic-both As2O3 and Na2HAsO4 significantly induced the expression of Nrf2 protein and mRNA, enhanced the transcription activity of Nrf2, and induced the expression of downstream target genes. These results confirmed the inorganic arsenic-induced Nrf2 pathway activation in hepatocytes. Although all arsenic chemicals used in the study induced Nrf2 protein accumulation, the organic arsenic C2H7AsO2 did not affect the expression of Nrf2 downstre...
Source: Toxicology and Applied Pharmacology - January 9, 2021 Category: Toxicology Authors: Liu D, Xu G, Bai C, Gu Y, Wang D, Li B Tags: Toxicol Appl Pharmacol Source Type: research

Toxicant exposure during pregnancy increases protective proteins in the dam and a sexually dimorphic response in the fetus.
In this study, we examined proteomic alterations in the livers of mouse dams and their male and female fetuses induced by vinclozolin, a model antiandrogenic EDC. Dam livers upregulated nine phase I and phase II detoxification pathways and pathway analysis revealed that more pathways are significantly enriched in dam livers than in fetal livers. Phase I and II detoxification proteins are also involved in steroid and steroid hormone biosynthesis and vinclozolin likely alters steroid levels in both the dam and the fetus. The response of the fetal liver proteome to vinclozolin exposure is sexually dimorphic. Female fetal live...
Source: Toxicology and Applied Pharmacology - January 9, 2021 Category: Toxicology Authors: Rister AL, Amato CM, Nash T, McCoy MW, Bereman M, McCoy KA Tags: Toxicol Appl Pharmacol Source Type: research

Preclinical safety assessment of a therapeutic human papillomavirus DNA vaccine combined with intravaginal interleukin-7 fused with hybrid Fc in female rats.
This study was conducted to establish the toxicological profile of combination treatment with therapeutic HPV DNA vaccines (GX-188E) and the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (IL-7hyFc). GX-188E was administered intramuscularly by electroporation with or without IL-7hyFc intravaginally once per 2 weeks for 8 weeks (five times) in female Sprague-Dawley rats. Because up-regulation of immune responses and migration of antigen-specific T cells in cervicoviginal tissue were predicted as therapeutic effects, we distinguished adverse effects from therapeutic effects based on the severity...
Source: Toxicology and Applied Pharmacology - January 9, 2021 Category: Toxicology Authors: Han KH, Jang MS, Han HY, Im WJ, Jung KJ, Park KS, Choi D, Jeong HG, Kim SK, Moon KS Tags: Toxicol Appl Pharmacol Source Type: research

Effect of combined exposure to environmental aliphatic electrophiles from plants on Keap1/Nrf2 activation and cytotoxicity in HepG2 cells: A model of an electrophile exposome.
Abstract Electrophiles, ubiquitously found in the environment, modify thiol groups of sensor proteins, leading to activation of redox signaling pathways such as the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway. Nrf2 activation by exposure to single electrophiles has been established. However, the effect of exposure to a combination of electrophiles on Nrf2 activation has not been well evaluated. The current study examined whether combined exposure to electrophiles enhances the modification of thiol groups and Keap1/Nrf2 activation in HepG2 cells. Six electrophiles [...
Source: Toxicology and Applied Pharmacology - January 8, 2021 Category: Toxicology Authors: Abiko Y, Aoki H, Kumagai Y Tags: Toxicol Appl Pharmacol Source Type: research

CREB1 protects against the renal injury in a rat model of kidney stone disease and calcium oxalate monohydrate crystals-induced injury in NRK-52E cells.
In this study, we investigated the effect of cyclic AMP responsive element binding protein (CREB) 1 in a KSD model of rat and calcium oxalate monohydrate (COM) crystals-treated NRK-52E cells. Rats were pretreated with lentivirus (LV)-CREB1 vector or LV-control vector and administrated with ethylene glycol + ammonium chloride to induce KSD. It was found that CREB1 was activated in the renal tissue of non-treated KSD rats. Pretreating with LV-CREB1 vector significantly enhanced CREB1 expression in KSD rats. Biochemical analysis for serum and urine showed that upregulation of CREB1 could improve the renal function of KSD rats...
Source: Toxicology and Applied Pharmacology - January 6, 2021 Category: Toxicology Authors: Yu L, Gan X, Bai Y, An R Tags: Toxicol Appl Pharmacol Source Type: research

Internal dose of vanadium in rats following repeated exposure to vanadyl sulfate and sodium orthovanadate via drinking water.
In conclusion, these data point to potential differences in absorption and disposition properties of V4+ and V5+ salts and may explain the higher sensitivity in rats following drinking water exposure to V5+ than V4+ and highlights the importance of internal dose determination in toxicology studies. PMID: 33421504 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - January 6, 2021 Category: Toxicology Authors: Harrington JM, Haines LG, Levine KE, Liyanapatirana C, Essader AS, Fernando RA, Robinson VG, Roberts GK, Stout MD, Hooth MJ, Waidyanatha S Tags: Toxicol Appl Pharmacol Source Type: research

Rifampicin impairs adipogenesis by suppressing NRF2-ARE activity in mice fed a high-fat diet.
Abstract Prolonged treatment with rifampicin (RFP), a first-line antibacterial agent used in the treatment of drug-sensitive tuberculosis, may cause various side effects, including metabolic disorders. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, also known as NRF2) plays an essential regulatory role in cellular adaptive responses to stresses via the antioxidant response element (ARE). Our previous studies discovered that NRF2 regulates the expression of CCAAT-enhancer-binding protein β (Cebpb) and peroxisome proliferator-activated receptor gamma (Pparg) in the process of adipogenesis. Here, we fo...
Source: Toxicology and Applied Pharmacology - January 4, 2021 Category: Toxicology Authors: Gao T, Lai M, Zhu X, Ren S, Yin Y, Wang Z, Liu Z, Zuo Z, Hou Y, Pi J, Chen Y Tags: Toxicol Appl Pharmacol Source Type: research

Identification of four methylation-driven genes as candidate biomarkers for monitoring single-walled carbon nanotube-induced malignant transformation of the lung.
In conclusion, these four methylation-driven genes may be candidate prognostic and diagnostic biomarkers for single-walled CNT-related lung cancer. PMID: 33387576 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 30, 2020 Category: Toxicology Authors: Xie D, Luo X Tags: Toxicol Appl Pharmacol Source Type: research

Species-specific differences in the inhibition of 11 β-hydroxysteroid dehydrogenase 2 by itraconazole and posaconazole.
Species-specific differences in the inhibition of 11β-hydroxysteroid dehydrogenase 2 by itraconazole and posaconazole. Toxicol Appl Pharmacol. 2020 Dec 30;:115387 Authors: Inderbinen SG, Zogg M, Kley M, Smieško M, Odermatt A Abstract 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) converts active 11β-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids. Disruption of 11β-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), ...
Source: Toxicology and Applied Pharmacology - December 30, 2020 Category: Toxicology Authors: Inderbinen SG, Zogg M, Kley M, Smieško M, Odermatt A Tags: Toxicol Appl Pharmacol Source Type: research

Predicting changes in renal metabolism after compound exposure with a genome-scale metabolic model.
Abstract The kidneys are metabolically active organs with importance in several physiological tasks such as the secretion of soluble wastes into the urine and synthesizing glucose and oxidizing fatty acids for energy in fasting (non-fed) conditions. Once damaged, the metabolic capability of the kidneys becomes altered. Here, we define metabolic tasks in a computational modeling framework to capture kidney function in an update to the iRno network reconstruction of rat metabolism using literature-based evidence. To demonstrate the utility of iRno for predicting kidney function, we exposed primary rat renal proximal...
Source: Toxicology and Applied Pharmacology - December 30, 2020 Category: Toxicology Authors: Rawls KD, Dougherty BV, Vinnakota KC, Pannala VR, Wallqvist A, Kolling GL, Papin JA Tags: Toxicol Appl Pharmacol Source Type: research

Molecular docking analyses of Escin as regards cyclophosphamide-induced cardiotoxicity: In vivo and in Silico studies.
This study aims to investigate whether Escin (ES) can protect against Cyclophosphamide (CPM)-induced cardiac damage. The experimental rats were categorized as Control, CPM (200 mg/kg), ES (10 mg/kg), and CPM + ES Groups, each having 6 members. Their heart tissues were stained with Hematoxylin and Eosin and the structural changes were investigated under the light microscope. The biochemical markers of ischemia modified albumin (IMA), creatine kinase (CK-MB), antioxidant activity indicators Catalase (CAT), and superoxide dismutase (SOD) activities were measured using blood samples. Besides, the effects of CPM, ES, an...
Source: Toxicology and Applied Pharmacology - December 28, 2020 Category: Toxicology Authors: Gür F, Cengiz M, Kutlu HM, Cengiz BP, Ayhancı A Tags: Toxicol Appl Pharmacol Source Type: research

Diosgenin alleviates hypercholesterolemia via SRB1/CES-1/CYP7A1/FXR pathway in high-fat diet-fed rats.
Abstract Phytosterol diosgenin (DG) exhibits cholesterol-lowering properties. Few studies focused on the underlying mechanism of DG attenuation of hypercholesterolemia by promoting cholesterol metabolism. To investigate the roles of SRB1/CES-1/CYP7A1/FXR pathways in accelerating cholesterol elimination and alleviating hypercholesterolemia, a rat model of hypercholesterolemia was induced by providing a high-fat diet (HFD). Experimental rat models were randomly divided into a normal control (Con) group, HFD group, low-dose DG (LDG) group (150 mg/kg/d), high-dose DG (HDG) group (300 mg/kg) and Simvastatin (Sim) g...
Source: Toxicology and Applied Pharmacology - December 28, 2020 Category: Toxicology Authors: Yu L, Lu H, Yang X, Li R, Shi J, Yu Y, Ma C, Sun F, Zhang S, Zhang F Tags: Toxicol Appl Pharmacol Source Type: research

Malformations and mortality in zebrafish early stages associated with elevated caspase activity after 24  h exposure to MS-222.
Malformations and mortality in zebrafish early stages associated with elevated caspase activity after 24 h exposure to MS-222. Toxicol Appl Pharmacol. 2020 Dec 25;:115385 Authors: Félix LM, Luzio A, Antunes L, Coimbra AM, Valentim A Abstract Tricaine methanesulfonate (MS-222) is a commonly used anaesthetic agent for immobilization of aquatic species. However, delayed development and malformations have been observed in 24 hpf (hours post-fertilization) zebrafish embryos after long-term immobilization. Still, no comprehensive study has been described regarding zebrafish exposure to MS-222 dur...
Source: Toxicology and Applied Pharmacology - December 25, 2020 Category: Toxicology Authors: Félix LM, Luzio A, Antunes L, Coimbra AM, Valentim A Tags: Toxicol Appl Pharmacol Source Type: research

Co-administration of Luteolin mitigated toxicity in rats' lungs associated with doxorubicin treatment.
Abstract Doxorubicin (DOX), is a drug against lung malignancies with undesirable side effect including oxidative, inflammatory and apoptotic effects. Luteolin (LUT), present in fruits and vegetables is pharmacologically active against oxido-inflammatory and apoptotic responses. The present study examined the effect of LUT on DOX-induced lungs and blood dysfunction in Wistars rat (sex: male; 10 weeks old, 160 ± 5 g). Randomly grouped (n = 10) rats were treated as follows: control, LUT alone (100 mg/kg; per os), DOX (2 mg/kg; i. p), and co-treated rats with LUT (50 or 1...
Source: Toxicology and Applied Pharmacology - December 24, 2020 Category: Toxicology Authors: Owumi SE, Nwozo SO, Arunsi UO, Oyelere AK, Odunola OA Tags: Toxicol Appl Pharmacol Source Type: research

The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition.
In this study, human nonmalignant prostate epithelial RWPE-1 cells were cocultured with testosterone (TE) -exposed prostate stromal fibroblasts WPMY-1 cells (TE-WPMY-1). The survival rate, epithelial-mesenchymal transition (EMT) and collagen deposition of RWPE-1 were observed. The expression profiles of circRNAs, lncRNAs and mRNAs in WPMY-1-derived exosome-like vesicles (WPMY-1-exo) were explored by high-throughput RNA sequencing. Firstly, both TE-WPMY-1 and TE-WPMY-1-exo significantly promoted RWPE-1 cells proliferation. Secondly, 41 circRNAs, 132 lncRNAs and 1057 mRNAs were differentially expressed (DE) between TE-WPMY-1...
Source: Toxicology and Applied Pharmacology - December 24, 2020 Category: Toxicology Authors: Chen J, Rong N, Liu M, Xu C, Xiong Q, Lei Y Tags: Toxicol Appl Pharmacol Source Type: research

Low dose spironolactone-mediated androgen-adiponectin modulation alleviates endocrine-metabolic disturbances in letrozole-induced PCOS.
Abstract Polycystic ovarian syndrome (PCOS), is a multifactorial endocrine disorder in women of reproductive age. It usually associates with metabolic disorders (MDs), which aggravates the risk of infertility, cardiometabolic events and associated comorbidities in women with PCOS. Adiponectin, a circulating protein produced by adipocytes, which has been suggested to inversely correlate with MDs. Spironolactone, a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. Herein, we investigated the effects of low dose spironolactone (LDS) and the role of adiponecti...
Source: Toxicology and Applied Pharmacology - December 21, 2020 Category: Toxicology Authors: Olaniyi KS, Oniyide AA, Adeyanju OA, Ojulari LS, Omoaghe AO, Olaiya OE Tags: Toxicol Appl Pharmacol Source Type: research

Autoantibodies in outbred Swiss Webster mice following exposure to gold and mercury.
In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl2) in drinking w...
Source: Toxicology and Applied Pharmacology - December 20, 2020 Category: Toxicology Authors: Amirhosseini M, Alkaissi H, Hultman PA, Havarinasab S Tags: Toxicol Appl Pharmacol Source Type: research

Astaxanthin attenuates alcoholic cardiomyopathy via inhibition of endoplasmic reticulum stress-mediated cardiac apoptosis.
This study highlights that administration of AST ablated chronic excessive ethanol consumption-induced cardiomyopathy by suppressing cardiac ER stress and subsequent apoptosis. PMID: 33352188 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 19, 2020 Category: Toxicology Authors: Wang W, Liu T, Liu Y, Yu L, Yan X, Weng W, Lu X, Zhang C Tags: Toxicol Appl Pharmacol Source Type: research

Subchronic toxicity evaluation of glucosamine and glucosamine in combination with chondroitin sulfate in obese Zucker rats.
Abstract D-Glucosamine is a widely consumed dietary supplement used to promote joint health and treat osteoarthritis. It also stimulates intracellular hexosamine flux and increases transforming growth factor β1 (TGFβ1) mRNA expression and insulin resistance in animal studies. The effects of D-glucosamine exposure were investigated in obese Zucker rats. Male (leprfa/leprfa) Zucker rats were exposed to 30, 120, 300 and 600 mg D-glucosamine HCl per kg/day either alone or with chondroitin sulfate (24, 96, 240 and 480 mg/kg/day respectively) for 90 days. After 4 weeks exposure, these doses produced Cm...
Source: Toxicology and Applied Pharmacology - December 17, 2020 Category: Toxicology Authors: Leakey JEA, Ali AA, Babb AR, Badgley HL, Davis KJ, Juliar BE, Leakey TI, Lewis SM, Patton RE, Seng JE Tags: Toxicol Appl Pharmacol Source Type: research

T4-mediated rescue of aortic malformations in hypothyroid rats indicates maternal thyroid status can affect great vessel development.
Abstract Pexacerfont is a corticotrophin-releasing factor subtype 1 receptor (CRF-1) antagonist developed for potential treatment of anxiety and stress-related disorders. In male rats, pexacerfont caused hepatic enzyme induction leading to increased thyroxine (T4) clearance. When administered to pregnant rats on gestation day 6 to 15, pexacerfont at 300 mg/kg/day (30× mean AUC in humans at 100 mg/day) produced similar effects on thyroid homeostasis with serum T4 and thyroid-stimulating hormone levels that were 0.3-0.5× and 3.3-3.7× of controls, respectively. At this dose, fetuses of pexacerfo...
Source: Toxicology and Applied Pharmacology - December 16, 2020 Category: Toxicology Authors: Augustine-Rauch K, Liaw JJ, Graziano M Tags: Toxicol Appl Pharmacol Source Type: research

Chronic cannabidiol treatment reduces the carbachol-induced coronary constriction and left ventricular cardiomyocyte width of the isolated hypertensive rat heart.
In conclusion, due to its modest beneficial effect in hypertension and its adverse effects in normotensive hearts, caution should be taken when using CBD as a drug in therapy. PMID: 33338514 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 15, 2020 Category: Toxicology Authors: Pędzińska-Betiuk A, Weresa J, Schlicker E, Harasim-Symbor E, Toczek M, Kasacka I, Gajo B, Malinowska B Tags: Toxicol Appl Pharmacol Source Type: research

An investigation of systemic exposure to bisphenol AF during critical periods of development in the rat.
In conclusion, these data demonstrate considerable gestational and lactational transfer of parent aglycone from the mother to offspring. Since the ontogeny of conjugating enzymes in humans is similar to that of rodents, the data from rodent BPAF studies may be useful in predicting human risk from exposure to BPAF. PMID: 33338515 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 15, 2020 Category: Toxicology Authors: Waidyanatha S, Collins BJ, Cunny H, Aillon K, Riordan F, Turner K, McBride S, Betz L, Sutherland V Tags: Toxicol Appl Pharmacol Source Type: research

Generating adverse outcome pathway (AOP) of inorganic arsenic-induced adult male reproductive impairment via integration of phenotypic analysis in comparative toxicogenomics database (CTD) and AOP wiki.
CONCLUSION: This study applied computational and bioinformatics methods in generating AOPs for arsenic reproductive toxicity, which identified the imperative roles of testosterone reduction, response to ROS, spermatogenesis and give a global view about their internal association. Furthermore, this study helped address the existing knowledge gaps for future experimental verification. PMID: 33338516 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 15, 2020 Category: Toxicology Authors: Chai Z, Zhao C, Jin Y, Wang Y, Zou P, Ling X, Yang H, Zhou N, Chen Q, Sun L, Chen W, Ao L, Cao J, Liu J Tags: Toxicol Appl Pharmacol Source Type: research

Non-dioxin-like polychlorinated biphenyl 19 has distinct effects on human Kv1.3 and Kv1.5 channels.
Abstract Polychlorinated biphenyls (PCBs) are persistent and serious organic pollutants and can theoretically form 209 congeners. PCBs can be divided into two categories: dioxin-like (DL) and non-DL (NDL). NDL-PCBs, which lack aryl hydrocarbon receptor affinity, have been shown to perturb the functions of Jurkat T cells, cerebellar granule cells, and uterine cells. Kv1.3 and Kv1.5 channels are important in immune and heart functions, respectively. We investigated the acute effects of 2,2',6-trichlorinated biphenyl (PCB19), an NDL-PCB, on the currents of human Kv1.3 and Kv1.5 channels. PCB19 acutely blocked the Kv1...
Source: Toxicology and Applied Pharmacology - December 11, 2020 Category: Toxicology Authors: Kim JH, Hwang S, Jo SH Tags: Toxicol Appl Pharmacol Source Type: research

Time-to-treatment window and cross-sex potential of β2-adrenergic receptor-induced mitochondrial biogenesis-mediated recovery after spinal cord injury.
Time-to-treatment window and cross-sex potential of β2-adrenergic receptor-induced mitochondrial biogenesis-mediated recovery after spinal cord injury. Toxicol Appl Pharmacol. 2020 Dec 11;:115366 Authors: Scholpa NE, Simmons EC, Crossman JD, Schnellmann RG Abstract Mitochondrial dysfunction is a well-characterized consequence of spinal cord injury (SCI). We previously reported that treatment with the FDA-approved β2-adrenergic receptor agonist formoterol beginning 8 h post-SCI induces mitochondrial biogenesis (MB) and improves body composition and locomotor recovery in female mice. To dete...
Source: Toxicology and Applied Pharmacology - December 11, 2020 Category: Toxicology Authors: Scholpa NE, Simmons EC, Crossman JD, Schnellmann RG Tags: Toxicol Appl Pharmacol Source Type: research

Soybean lectin induces autophagy through P2RX7 dependent activation of NF- κB-ROS pathway to kill intracellular mycobacteria.
Conclusion Taken together, these results conclude that SBL induced autophagy exerts an anti-mycobacterial effect in P2RX7-NF-κB dependent manner through the generation of ROS. General significance This study has provided a novel anti-mycobacterial role of SBL, which may play an important role in devising new therapeutic interventions. PMID: 33301752 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 7, 2020 Category: Toxicology Authors: Mishra A, Behura A, Kumar A, Ghosh A, Naik L, Mawatwal S, Mohanty SS, Mishra A, Saha S, Bhutia SK, Singh R, Dhiman R Tags: Toxicol Appl Pharmacol Source Type: research

Semaphorin 4A antibody alleviates arsenic-induced hepatotoxicity in mice via inhibition of AKT2/NF- κB inflammatory signaling.
In conclusion, the anti-Sema 4A antibody antagonizes arsenic-induced hepatotoxicity in mice and may be involved in the inhibitions of AKT2/NF-κB and NLRP3 inflammatory signaling mediated synergistically by Sema 4A or Sema 3A and their receptor NRP-1. PMID: 33290778 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 5, 2020 Category: Toxicology Authors: Yang Y, Wang Q, Wang W, Wei S, Zeng Q, Zhang A Tags: Toxicol Appl Pharmacol Source Type: research

Anacardic 6-pentadecyl salicylic acid induces apoptosis in breast cancer tumor cells, immunostimulation in the host and decreases blood toxic effects of taxol in an animal model.
s L, Vega L Abstract Many antineoplastic agents induce myelosuppression and leukopenia as secondary effects in patients. The development of anticancer agents that simultaneously provoke antitumor immune response represents an important therapeutic advance. The administration of 6-pentadecyl salicylic acid (6SA) contributes to the antitumor immunity using 4 T1 breast cancer cells in Balb/c female mice, with Taxol as a positive control and in cotreatment with 6SA (6SA + Taxol; CoT). Our results show that 6SA reduces tumor volume and size by inducing caspase-8-mediated apoptosis without reducing tumor infiltrat...
Source: Toxicology and Applied Pharmacology - December 5, 2020 Category: Toxicology Authors: Gnanaprakasam JNR, López-Bañuelos L, Vega L Tags: Toxicol Appl Pharmacol Source Type: research

Death by histone deacetylase inhibitor quisinostat in tongue squamous cell carcinoma via apoptosis, pyroptosis, and ferroptosis.
Abstract Tongue cancer is one of the most common oral malignancies. Quisinostat is a histone deacetylase inhibitor with antitumor activity. The aim of this study was to evaluate the effects of quisinostat on the viability of tongue squamous cell carcinoma (TSCC) cells (CAL-27, TCA-8113) in vitro and in vivo. Cell viability, cell morphological observation, scratch wound-healing assay, transwell migration assay, transmission electron microscope, flow cytometry and cellular reactive oxygen species were assessed in vitro. The results showed that quisinostat can significantly inhibit the viability, growth and migration...
Source: Toxicology and Applied Pharmacology - December 5, 2020 Category: Toxicology Authors: Wang X, Liu K, Gong H, Li D, Chu W, Zhao D, Wang X, Xu D Tags: Toxicol Appl Pharmacol Source Type: research

Astragaloside IV protects against retinal iron overload toxicity through iron regulation and the inhibition of MAPKs and NF- κB activation.
In conclusion, the results show that AS-IV has significant protective effects against retinal iron overload toxicity and suggest that iron regulation and the inhibition of MAPKs and NF-κB activation might be mechanisms underlying the effects of AS-IV. PMID: 33285147 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - December 4, 2020 Category: Toxicology Authors: Song Q, Zhao Y, Yang Y, Han X, Duan J Tags: Toxicol Appl Pharmacol Source Type: research

Modulation of PARP activity by Monomethylarsonous (MMA+3) acid and uranium in mouse thymus.
Abstract Arsenic exposure is well established to impair the function of zinc finger proteins, including PARP-1. Previous studies from our lab show that early developing T cells in the thymus are very sensitive to arsenite (As+3)-induced genotoxicity mediated through PARP-1 inhibition. Additionally, it has been shown that uranium (in the form of uranyl acetate, UA) also suppresses PARP-1 activity in HEK cells. However, very little is known about whether the As+3 metabolite, monomethylarsonous acid (MMA+3), also inhibits PARP-1 activity and if this is modified by combined exposures with other metals, such as uranium...
Source: Toxicology and Applied Pharmacology - December 3, 2020 Category: Toxicology Authors: Medina S, Zhou X, Lauer FT, Zhang H, Liu KJ, Lewis J, Burchiel SW Tags: Toxicol Appl Pharmacol Source Type: research

Uranium directly interacts with the DNA repair protein poly (ADP-ribose) polymerase 1.
Abstract People living in southwest part of United States are exposed to uranium (U) through drinking water, air, and soil. U is radioactive, but independent of this radioactivity also has important toxicological considerations as an environmental metal. At environmentally relevant concentrations, U is both mutagenic and carcinogenic. Emerging evidence shows that U inhibits DNA repair activity, but how U interacts with DNA repair proteins is still largely unknown. Herein, we report that U directly interacts with the DNA repair protein, Protein Poly (ADP-ribose) Polymerase 1 (PARP-1) through direct binding with the...
Source: Toxicology and Applied Pharmacology - December 3, 2020 Category: Toxicology Authors: Zhou X, Xue B, Medina S, Burchiel SW, Liu KJ Tags: Toxicol Appl Pharmacol Source Type: research

Ethyl maltol enhances copper mediated cytotoxicity in lung epithelial cells.
Abstract Ethyl maltol (EM) is a flavoring agent commonly used in foods that falls under the generally recognized as safe category. Is added to many commercial e-cigarette vaping fluids and has been detected in the aerosol. Considering that EM facilitates heavy metal transport across plasma membranes, and that heavy metals have been detected in aerosols generated from e-cigarettes, this study examines whether EM enhances heavy metal mediated toxicity. A decrease in viability was observed in the Calu-6 and A549 lung epithelial cell lines co-exposed to EM and copper (Cu) but no decrease was observed after co-exposure...
Source: Toxicology and Applied Pharmacology - November 30, 2020 Category: Toxicology Authors: Durrani K, El Din SA, Sun Y, Rule AM, Bressler J Tags: Toxicol Appl Pharmacol Source Type: research

CoQ10 protects against acetaminophen-induced liver injury by enhancing mitophagy.
In this study, we further investigated the CoQ10 therapeutic effects on APAP-overdose liver injury. C57BL/6 J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 1.5 h after APAP treatment. The results showed that hepatic CoQ10 levels were decreased during the APAP-induced hepatotoxicity and preceded serum ALT elevation. Treatment of CoQ10 significantly improved the liver injury induced by APAP. Moreover, CoQ10 treatment decreased the ROS levels and promoted the antioxidative related gene expression in APAP overdose mice. Importantly, results showed that even tho...
Source: Toxicology and Applied Pharmacology - November 30, 2020 Category: Toxicology Authors: Zhang P, Chen S, Tang H, Fang W, Chen K, Chen X Tags: Toxicol Appl Pharmacol Source Type: research

Arsenic metabolism differs between child and adult patients during acute arsenic poisoning.
Abstract Epidemiological studies on chronic arsenic poisoning have clarified the relationship between various adverse effects and methylation efficiency or methylation capacity. However, no study has similarly investigated such effects on patients with acute arsenic poisoning. In the present work, we studied 61 patients with acute oral arsenic poisoning occurring after consumption of an arsenic trioxide-laced meal (curry soup). The cohort included children (defined as under 15 year old [y/o], n = 22) and adults (over 16 y/o, n = 39) whose urinary arsenic profiles were analyzed. None of these patients had...
Source: Toxicology and Applied Pharmacology - November 29, 2020 Category: Toxicology Authors: Yamauchi H, Takata A Tags: Toxicol Appl Pharmacol Source Type: research

Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibiting TLR4-NF- κB-NLRP3 pathway in hepatic ischemia/reperfusion injury.
Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibiting TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury. Toxicol Appl Pharmacol. 2020 Nov 29;:115340 Authors: El-Sisi AEE, Sokar SS, Shebl AM, Mohamed DZ, Abu-Risha SE Abstract BACKGROUND AND AIM: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whethe...
Source: Toxicology and Applied Pharmacology - November 29, 2020 Category: Toxicology Authors: El-Sisi AEE, Sokar SS, Shebl AM, Mohamed DZ, Abu-Risha SE Tags: Toxicol Appl Pharmacol Source Type: research

Ozone-induced changes in oxidative stress parameters in brain regions of adult, middle-age, and senescent Brown Norway rats.
Abstract A critical part of community based human health risk assessment following chemical exposure is identifying sources of susceptibility. Life stage is one such susceptibility. A prototypic air pollutant, ozone (O3) induces dysfunction of the pulmonary, cardiac, and nervous systems. Long-term exposure may cause oxidative stress (OS). The current study explored age-related and subchronic O3-induced changes in OS in brain regions of rats. To build a comprehensive assessment of OS-related effects of O3, a tripartite approach was implemented focusing on 1) the production of reactive oxygen species (ROS) [NADPH Qu...
Source: Toxicology and Applied Pharmacology - November 26, 2020 Category: Toxicology Authors: Kodavanti PRS, Valdez M, Richards JE, Agina-Obu DI, Phillips PM, Jarema KA, Kodavanti UP Tags: Toxicol Appl Pharmacol Source Type: research

Cisplatin-induced hair cell loss in zebrafish neuromasts is accompanied by protein nitration and Lmo4 degradation.
Abstract Generation of reactive oxygen species, a critical factor in cisplatin-induced ototoxicity, leads to the formation of peroxynitrite, which in turn results in the nitration of susceptible proteins. Previous studies indicated that LMO4, a transcriptional regulator, is the most abundantly nitrated cochlear protein after cisplatin treatment and that LMO4 nitration facilitates ototoxicity in rodents. However, the role of this mechanism in regulating cisplatin-induced hair cell loss in non-mammalian models is unknown. As the mechanosensory hair cells in the neuromasts of zebrafish share many features with mammal...
Source: Toxicology and Applied Pharmacology - November 24, 2020 Category: Toxicology Authors: Shahab M, Rosati R, Meyers D, Sheilds J, Crofts E, Baker T, Jamesdaniel S Tags: Toxicol Appl Pharmacol Source Type: research

Andrographolide inhibits IL-1 β release in bone marrow-derived macrophages and monocyte infiltration in mouse knee joints induced by monosodium urate.
Andrographolide inhibits IL-1β release in bone marrow-derived macrophages and monocyte infiltration in mouse knee joints induced by monosodium urate. Toxicol Appl Pharmacol. 2020 Nov 23;:115341 Authors: Lo CW, Lii CK, Hong JJ, Chuang WT, Yang YC, Huang CS, Chen HW Abstract Andrographolide (AND) is the major diterpenoid in A. paniculata with wide clinical application and has been shown to be a potent anti-inflammatory agent. Gout is the leading inflammatory disease of the joints, and the deposition of urate in the articular cavity attracts immune cells that release inflammatory cytokines. Monosodi...
Source: Toxicology and Applied Pharmacology - November 23, 2020 Category: Toxicology Authors: Lo CW, Lii CK, Hong JJ, Chuang WT, Yang YC, Huang CS, Chen HW Tags: Toxicol Appl Pharmacol Source Type: research

A transcriptomic overview of lung and liver changes one day after pulmonary exposure to graphene and graphene oxide.
This study explores transcriptomic differences in the lung and liver after pulmonary exposure to two GBM with similar physical properties, but different surface chemistry. Female C57BL/6 mice were exposed by a single intratracheal instillation of 0, 18, 54 or 162 μg/mouse of graphene oxide (GO) or reduced graphene oxide (rGO). Pulmonary and hepatic changes in the transcriptome were profiled to identify commonly and uniquely perturbed functions and pathways by GO and rGO. These changes were then related to previously analyzed toxicity endpoints. GO exposure induced more differentially expressed genes, affected more fun...
Source: Toxicology and Applied Pharmacology - November 20, 2020 Category: Toxicology Authors: Poulsen SS, Bengtson S, Williams A, Jacobsen NR, Troelsen JT, Halappanavar S, Vogel U Tags: Toxicol Appl Pharmacol Source Type: research

Gender differences and dose proportionality in the toxicokinetics of udenafil and its active metabolite following oral administration in rodents.
This study thus demonstrates gender and species differences with regard to the toxicokinetic profiles of udenafil and its active metabolite N-dealkylated udenafil after oral administration of udenafil to mice and rats of both sexes. Our findings suggest the possibility of gender differences in the toxicokinetics of udenafil in humans and suggests that further study is needed in this cohort. PMID: 33221319 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - November 19, 2020 Category: Toxicology Authors: Lee JH, Lee DY, Kang KK, Jeong EJ, Staatz CE, Baek IH Tags: Toxicol Appl Pharmacol Source Type: research

Diets enriched with coconut, fish, or olive oil modify peripheral metabolic effects of ozone in rats.
In conclusion, CO-, FO-, and OO-enriched diets modified ozone-induced metabolic changes in a diet-specific manner, which could contribute to altered peripheral energy homeostasis. PMID: 33217375 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - November 17, 2020 Category: Toxicology Authors: Snow SJ, Henriquez AR, Fenton JI, Goeden T, Fisher A, Vallanat B, Angrish M, Richards JE, Schladweiler MC, Cheng WY, Wood CE, Tong H, Kodavanti UP Tags: Toxicol Appl Pharmacol Source Type: research

Examining the evidence of non-monotonic dose-response in androgen receptor agonism high-throughput screening assay.
Abstract Modern high-throughput screening (HTS) techniques allow to determine in vitro bioactivity of tens of thousands of chemicals within a relatively short period of time and tested compounds are usually interpreted as either active or inactive. The interpretation is mostly based on the assumption of monotonic dose-response. This approach ignores potential abnormal dose-response relationships, such as non-monotonic dose-response (NMDR). NMDR presents a serious challenge to toxicologists and pharmacologists, since they undermine the usefulness of such concepts as lowest-observed-adverse-effect level (LOAEL) and ...
Source: Toxicology and Applied Pharmacology - November 17, 2020 Category: Toxicology Authors: Klimenko K Tags: Toxicol Appl Pharmacol Source Type: research

Ligustilide inhibits the proliferation of non-small cell lung cancer via glycolytic metabolism.
Abstract Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. The abnormal activation of glycolytic metabolism and PTEN/AKT signaling in NSCLC cells are highly correlated with their proliferation abilities and viability. Ligustilide is one of the major bioactive components of multiple Chinese traditional medicine including Angelica sinensis and Ligusticum. Ligustilide exposure inhibits the proliferation and viability of multiple cancer cell lines in vitro. However, the impact of ligustilide to the progression of NSCLC and its detailed pharmacological mechanisms remain ...
Source: Toxicology and Applied Pharmacology - November 16, 2020 Category: Toxicology Authors: Jiang X, Zhao W, Zhu F, Wu H, Ding X, Bai J, Zhang X, Qian M Tags: Toxicol Appl Pharmacol Source Type: research

Famciclovir leads to failure of hematopoiesis, but may have the benefit of relieving myeloid expansion in MDS-like zebrafish.
This study reveals that FCV functions as a double-edged sword, with hematotoxicity at a high level, but that appropriate FCV treatment may be beneficial for the treatment of MDS. PMID: 33207248 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - November 15, 2020 Category: Toxicology Authors: Li J, Meng P, Zhou R, Zhang Y, Lin Q Tags: Toxicol Appl Pharmacol Source Type: research

2,5-Hexanedione influences primordial follicular development in cultured neonatal mouse ovaries by interfering with the PI3K signaling pathway via miR-214-3p.
Abstract The mechanisms by which 2,5-hexanedione (2,5-HD) exposure adversely affects reproduction are unclear. In the present study, whole neonatal mouse ovaries were exposed to 2,5-HD in vitro and then assessed for progesterone levels to determine the effects of this compound on ovary function. Ovarian histomorphological analyses were performed to assess the effects of 2,5-HD on follicular development, and PI3K signaling pathway was evaluated to elucidate the molecular mechanisms of 2,5-HD-mediated toxicity on follicular development. The results showed that after ovarian exposure to 2,5-HD in vitro, the percentag...
Source: Toxicology and Applied Pharmacology - November 13, 2020 Category: Toxicology Authors: Zeng J, Sun Y, Li X, Zhu J, Zhang W, Lu W, Weng Y, Liu J Tags: Toxicol Appl Pharmacol Source Type: research

Biological effects of inhaled hydraulic fracturing sand dust. I. Scope of the investigation.
Abstract Hydraulic fracturing ("fracking") is a process in which subterranean natural gas-laden rock is fractured under pressure to enhance retrieval of gas. Sand (a "proppant") is present in the fracking fluid pumped down the well bore to stabilize the fissures and facilitate gas flow. The manipulation of sand at the well site creates respirable dust (fracking sand dust, FSD) to which workers are exposed. Because workplace exposures to FSD have exceeded exposure limits set by OSHA, a physico-chemical characterization of FSD along with comprehensive investigation of the potential early adverse ...
Source: Toxicology and Applied Pharmacology - November 9, 2020 Category: Toxicology Authors: Fedan JS Tags: Toxicol Appl Pharmacol Source Type: research

Inhibition of thrombospondin-1 reduces glutathione activity and worsens acute liver injury during acetaminophen hepatotoxicity in mice.
Abstract Acetaminophen (N-Acetyl-p-Aminophenol or APAP)-induced hepatotoxicity is the most common cause of acute liver failure in the United States and Western Europe. Previous studies have shown that TGFβ1 is elevated during APAP-induced hepatotoxicity and promotes liver injury by reducing liver regeneration while inducing hepatocyte senescence. At this time, little is known about the role of proteins that activate latent TGFβ1 and their effects during APAP-induced hepatotoxicity. Thrombospondin-1 (TSP1) is a homotrimeric protein that can not only activate latent TGFβ1 but can also interact with ot...
Source: Toxicology and Applied Pharmacology - November 8, 2020 Category: Toxicology Authors: Frampton G, Reddy P, Jefferson B, Ali M, Khan D, McMillin M Tags: Toxicol Appl Pharmacol Source Type: research

Down-regulation of Survivin and Bcl-2 concomitant with the activation of caspase-3 as a mechanism of apoptotic death in KG1a and K562 cells upon exposure to a derivative from ciprofloxacin family.
Abstract Ciprofloxacin derivatives belong to a family of antibiotics called fluoroquinolones. Recently, these compounds have been recommended for the treatment of cancer. In the present study, we assessed the cytotoxicity of several new synthetic ciprofloxacin derivatives and the apoptosis-inducing activity of the most efficient derivative in two human myeloid leukemia K562 and KG1-a cell lines. Among the prepared ciprofloxacin derivatives, 1-cyclopropyl-7-(4-(2-((3,7-dimethyloct-6-en-1-yl)oxy)-2-oxoethyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4dihydroquinoline-3-carboxylic acid (4-DMOCP) was more active compound with I...
Source: Toxicology and Applied Pharmacology - November 7, 2020 Category: Toxicology Authors: Eslami F, Mahdavi M, Babaei E, Hussen BM, Mostafavi H, Shahbazi A Tags: Toxicol Appl Pharmacol Source Type: research