Fibrin gels entrapment of a doxorubicin-containing targeted polycyclodextrin: Evaluation of in vivo antitumor activity in orthotopic models of human neuroblastoma.
Abstract In vivo local antitumor activity of fibrin gels (FBGs) loaded with the poly-cyclodextrin oCD-NH2/Dox, compared to FBGs loaded with doxorubicin (Dox) or to free Dox, was evaluated in two mouse orthotopic neuroblastoma (NB) models, after positioning of the releasing devices in the visceral space. FBGs were prepared at the fibrinogen (FG) concentrations of 22 and 40 mg/ml clotted in the presence of 0.81 mM/mg FG Ca2+ and 1.32 U/mg FG thrombin. Our results indicate that FBGs loaded with oCD-NH2/Dox and applied as neoadjuvant loco-regional treatment, show an antitumor activity significantly greater than ...
Source: Toxicology and Applied Pharmacology - November 6, 2019 Category: Toxicology Authors: Viale M, Vecchio G, Maric I, Cilli M, Aprile A, Ponzoni M, Fontana V, Priori EC, Bertone V, Rocco M Tags: Toxicol Appl Pharmacol Source Type: research

Two novel peptides from ark shell protein stimulate osteoblast differentiation and rescue ovariectomy-induced bone loss.
Abstract Osteoporosis is a common bone disease resulting from imbalance between bone formation and bone resorption. Currently, anti-resorptive agents that inhibit bone resorption are the most available drugs on the market. Biosphosphonates, anti-resorptive drugs most commonly used to treat osteoporosis, are limited by their side effects for long-term contious treatment. It is important to develop appropriate therapeutic stragegies capable of promoting bone formation to counteract osteoporotic bone loss. Thus, anabolic agents that stimulate bone formation are undoubtedly of interest. Here, we purified and identifie...
Source: Toxicology and Applied Pharmacology - November 4, 2019 Category: Toxicology Authors: Oh Y, Ahn CB, Hyung JH, Je JY Tags: Toxicol Appl Pharmacol Source Type: research

Corrigendum to "Fullerene (C60) particle size implications in neurotoxicity following infusion into the hippocampi of Wistar rats" [Toxicology and Applied Toxicology 338 (2018) 197-203].
Corrigendum to "Fullerene (C60) particle size implications in neurotoxicity following infusion into the hippocampi of Wistar rats" [Toxicology and Applied Toxicology 338 (2018) 197-203]. Toxicol Appl Pharmacol. 2019 Nov 04;:114764 Authors: Kraemer ÂB, Parfitt GM, da Silva Acosta D, Bruch GE, Cordeiro MF, Marins LF, Ventura-Lima J, Monserrat JM, Barros DM PMID: 31697997 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - November 4, 2019 Category: Toxicology Authors: Kraemer ÂB, Parfitt GM, da Silva Acosta D, Bruch GE, Cordeiro MF, Marins LF, Ventura-Lima J, Monserrat JM, Barros DM Tags: Toxicol Appl Pharmacol Source Type: research

Amlexanox ameliorates acetaminophen-induced acute liver injury by reducing oxidative stress in mice.
This study was to investigate the protective mechanism of amlexanox in acetaminophen (APAP)-induced acute liver injury (ALI). Mice were intraperitoneally injected with APAP (300 mg/kg, 12 h) to induce ALI and were orally administrated with amlexanox (25, 50 and 100 mg/kg) one hour after APAP treatment. Inhibition of IKKε and TBK1 by treatment of amlexanox attenuated APAP-induced ALI as confirmed by decreased serum levels of aspartate aminotransferase and alanine aminotransferase. Furthermore, amlexanox significantly decreased hepatocellular apoptosis in injured livers of mice as evidenced by histopathologic o...
Source: Toxicology and Applied Pharmacology - November 4, 2019 Category: Toxicology Authors: Qi J, Zhou Z, Lim CW, Kim JW, Kim B Tags: Toxicol Appl Pharmacol Source Type: research

Schisandrin B attenuates renal fibrosis via miR-30e-mediated inhibition of EMT.
This study shows that miR-30e can serve as a therapeutic target in the treatment of patients with TIF and that Sch B may potentially be used in therapy against renal fibrosis. PMID: 31697999 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - November 4, 2019 Category: Toxicology Authors: Cao G, Li S, Shi H, Yin P, Chen J, Li H, Zhong Y, Diao LT, Du B Tags: Toxicol Appl Pharmacol Source Type: research

Polymer-coated nanoparticles and their effects on mitochondrial function in brain endothelial cells.
In conclusion, PCL-NP exposure changed mitochondrial respiration, especially under glucose deprivation, but did not affect mitochondrial morphology and distribution. Further studies are needed to investigate whether the functional effects are transient or long-term as this will be crucial for the use of these NPs in laser tissue soldering. PMID: 31678605 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - October 31, 2019 Category: Toxicology Authors: Bittner A, Ducray AD, Stoffel MH, Felser A, Mevissen M Tags: Toxicol Appl Pharmacol Source Type: research

Dipeptidyl peptidase-4 inhibitor sitagliptin induces vasorelaxation via the activation of Kv channels and PKA.
Abstract The present study investigated the vasorelaxant effects of sitagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor in aortic rings pre-contracted with phenylephrine (Phe). Sitagliptin induced vasorelaxation in a concentration-dependent manner but the inhibition of voltage-dependent K+ (Kv) channels by pretreatment with 4-aminopyridine (4-AP) effectively reduced this effect. By contrast, the inhibition of inward rectifier K+ (Kir) channels by pretreatment with barium (Ba2+), large-conductance calcium (Ca2+)-activated K+ (BKCa) channels with paxilline, and adenosine triphosphate (ATP)-sensitive K+ ...
Source: Toxicology and Applied Pharmacology - October 31, 2019 Category: Toxicology Authors: Li H, Seo MS, An JR, Jung HS, Ha KS, Han ET, Hong SH, Bae YM, Na SH, Park WS Tags: Toxicol Appl Pharmacol Source Type: research

Pharmacological and toxicological aspects of carbon nanotubes (CNTs) to vascular system: A review.
Abstract Carbon nanotubes (CNTs) are novel carbon based nanomaterials (NMs) that could be used in many areas ranging from electronics to biotechnology. The present review summarized pharmacological and toxicological aspects of CNTs to vascular systems, because the vascular systems are important targets for CNTs during manufacturing process, daily contact and biomedical uses. Functionalized CNTs could be used as novel nanoplateforms to regulate angiogenesis for cancer therapy, as well as nanocarriers to cross blood brain barrier (BBB), one of the major obstacles to prevent the entering of therapeutic substances int...
Source: Toxicology and Applied Pharmacology - October 31, 2019 Category: Toxicology Authors: Cao Y, Luo Y Tags: Toxicol Appl Pharmacol Source Type: research

Development of organoid-based drug metabolism model.
In this study, we aimed to investigate drug metabolism and toxicity based on mouse small intestinal and liver organoids derived from resident stem cells. At first, expressions and activities of CYP subfamilies (CYPs) in intestinal and liver organoids were investigated. Organoids treated with three CYPs-inducers dexamethasone (Dex), β-naphthoflavone (BNF), and 1,4-bis-2-(3, 5-dichloropyridyloxy)-benzene (TCPOBOP) were evaluated for CYPs activities. The CYPs-induced intestinal and liver organoids were confirmed to digest more docetaxel, as colon cancer cell-line survived more in CYPs-induced organoid's medium than in no...
Source: Toxicology and Applied Pharmacology - October 30, 2019 Category: Toxicology Authors: Park E, Kim HK, Jee J, Hahn S, Jeong S, Yoo J Tags: Toxicol Appl Pharmacol Source Type: research

Protective role of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in cigarette smoke-induced mitochondrial dysfunction in mice.
CONCLUSION: CS affects some of early mitochondrial genes involved in the fission/fusion process, enhancing the damage response along with altered cytokine levels. MSC + EXO combination treatment showed their protective effects. MSC + EXO combination treatment may act against these early events caused by CS exposure owing to its anti-inflammatory and other mitochondrial transfer mechanisms. PMID: 31678243 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - October 30, 2019 Category: Toxicology Authors: Maremanda KP, Sundar IK, Rahman I Tags: Toxicol Appl Pharmacol Source Type: research

Lung injury, oxidative stress and fibrosis in mice following exposure to nitrogen mustard.
Abstract Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Herein, we developed a murine model of NM-induced pulmonary toxicity with the goal of assessing inflammatory mechanisms of injury. C57Bl6/J mice were euthanized 1-28 d following intratracheal exposure to NM (0.08 mg/kg) or PBS control. NM caused progressive alveolar epithelial thickening, perivascular inflammation, bronchiolar epithelial hyperplasia, interstitial fibroplasia and fibrosis, peaking 14 d post exposure. Enlarged foamy macrophages were also observed in the lung 14 d post NM, along wit...
Source: Toxicology and Applied Pharmacology - October 30, 2019 Category: Toxicology Authors: Sunil VR, Vayas KN, Abramova EV, Rancourt R, Cervelli JA, Malaviya R, Goedken M, Venosa A, Gow AJ, Laskin JD, Laskin DL Tags: Toxicol Appl Pharmacol Source Type: research

Suppression of macrophages- Induced inflammation via targeting RAS and PAR-4 signaling in breast cancer cell lines.
In conclusion, our data support the role of piroxicam and sulindac sulfide in suppressing inflammation-driven breast cancer progression and identifies promising novel target in RAS and PAR-4 signaling. PMID: 31678245 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - October 30, 2019 Category: Toxicology Authors: Thabet NA, El-Guendy N, Mohamed MM, Shouman SA Tags: Toxicol Appl Pharmacol Source Type: research

Increasing ERK phosphorylation by inhibition of p38 activity protects against cadmium-induced apoptotic cell death through ERK/Drp1/p38 signaling axis in spermatocyte-derived GC-2spd cells.
In this study, increased intracellular and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) depolarization, and mitochondrial fragmentation and swelling were observed at 5 μM of CdCl2 exposure, resulting in increased apoptotic cell death. Moreover, CdCl2-induced cell death is closely associated with the ERK/Drp1/p38 signaling axis. Interestingly, SB203580, a p38 inhibitor, effectively prevented CdCl2-induced apoptotic cell death by reducing ∆Ψm depolarization and intracellular and mitochondrial ROS levels. Knockdown of Drp1 expression diminished CdCl2-induced mitoc...
Source: Toxicology and Applied Pharmacology - October 29, 2019 Category: Toxicology Authors: Seong JB, Bae YC, Lee HS, Huh JW, Lee SR, Lee HJ, Lee DS Tags: Toxicol Appl Pharmacol Source Type: research

Alpinetin improves intestinal barrier homeostasis via regulating AhR/suv39h1/TSC2/mTORC1/autophagy pathway.
Abstract The injury of intestinal epithelial barrier is considered as the key pathophysiological process in response to gastrointestinal infection and inflammation, and plays an important role in the initiation and development of colitis. Alpinetin has been shown to improve intestinal barrier homeostasis under colitis condition, but the mechanism is still unclear. Here, we showed that alpinetin significantly improved transepithelial electrical resistance (TEER) in TNF-α-stimulated Caco-2 cells, which was mainly mediated by inhibiting the apoptosis. Mechanistic studies demonstrated that alpinetin markedly inc...
Source: Toxicology and Applied Pharmacology - October 29, 2019 Category: Toxicology Authors: Miao Y, Lv Q, Qiao S, Yang L, Tao Y, Yan W, Wang P, Cao N, Dai Y, Wei Z Tags: Toxicol Appl Pharmacol Source Type: research

Endocytosis mechanism in physiologically-based pharmacokinetic modeling of nanoparticles.
CONCLUSIONS: The size played an important role on the distribution and accumulation of AuNPs in various tissues. Our PBPK model was well predicted the NPs distribution in mice and human. A better understanding of these mechanisms could provide effective guides for nanomedine delivery. PMID: 31669777 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - October 26, 2019 Category: Toxicology Authors: Deng L, Liu H, Ma Y, Miao Y, Fu X, Deng Q Tags: Toxicol Appl Pharmacol Source Type: research

Involvement of PML-I in reformation of PML nuclear bodies in acute promyelocytic leukemia cells by leptomycin B.
Abstract Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation between chromosomes 15 and 17, t(15;17), results in the expression of PML-RARα fusion protein, which disrupts the normal PML nuclear bodies (PML-NBs) to micro-speckled pattern, leading to loss of their original functions. Moreover, reformation of PML-NBs in APL by arsenic is considered as one of the important step for APL treatment. Leptomycin B (LMB), a nuclear export inhibitor, is commonly used to inhibit the proteins export from the nucleus to the cytoplasm. In the present study, we found that LMB could induce the r...
Source: Toxicology and Applied Pharmacology - October 26, 2019 Category: Toxicology Authors: Wang C, De Su L, Shao YM, Chen WZ, Bu N, Hao R, Ma LY, Hussain L, Lu XY, Wang QQ, Naranmandura H Tags: Toxicol Appl Pharmacol Source Type: research

N-arylpiperazine-containing compound (C2): An enhancer of sunitinib in the treatment of pancreatic cancer, involving D1DR activation.
Abstract Previous studies showed that dopamine (DA) significantly reduces the frequency of cancer stem-like cells (CSC) and enhances the efficacy of sunitinib (SUN) in the treatment of breast cancer and non-small cell lung cancer (NSCLC). To overcome the shortcomings of DA in clinical practice, the purpose of this study was to investigate the efficacy as well as the underlying mechanism of an orally available, N-arylpiperazine-containing compound C2, in the treatment of pancreatic cancer when used alone or in combination with SUN. Our results showed that C2 and SUN exerted synergistic effects on inhibiting the gro...
Source: Toxicology and Applied Pharmacology - October 25, 2019 Category: Toxicology Authors: Su H, Xue Z, Feng Y, Xie Y, Deng B, Yao Y, Tian X, An Q, Yang L, Yao Q, Xue J, Chen G, Hao C, Zhou T Tags: Toxicol Appl Pharmacol Source Type: research

An increase in circulating B cells and B cell activation markers in peripheral blood is associated with cigarette smoking in a male cohort in Bangladesh.
Abstract In a cohort of approximately 200 Bangladeshi men, equally divided into smokers and non-smokers and equally divided by exposure to high and low levels of drinking water arsenic, we examined ex vivo a series of immune markers and immune function tests in peripheral blood mononuclear cells (PBMC). These immune parameters included PBMC cell surface markers (CSM) for B, T, monocytes, and NK cells, activated T and B cell markers, cytokine production in vitro, and analysis of CD4 subsets (Th1, Th2, Treg, and Th17 cells). We found that the effects of cigarette smoke were quite different than those associated with...
Source: Toxicology and Applied Pharmacology - October 25, 2019 Category: Toxicology Authors: Burchiel SW, Lauer FT, Factor-Litvak P, Liu X, Santella RM, Islam T, Eunus M, Alam N, Islam T, Rahman M, Ahmed A, Ahsan H, Graziano J, Parvez F Tags: Toxicol Appl Pharmacol Source Type: research

The effect of the inhalation of and topical exposure to zinc oxide nanoparticles on airway inflammation in mice.
Abstract Zinc oxide nanoparticles (ZnONPs) are widely used in the manufacturing of many commercial products. Workers exposed to ZnO particles may develop metal fume fever. Our previous study suggested that the oropharyngeal aspiration of ZnONPs could cause eosinophilic airway inflammation and increase T helper 2 (Th2) cytokine expression in the absence of allergens in mice. ZnO has been used topically as a sunscreen and a therapeutic agent for dermatological conditions. To understand whether inhalation and topically applied ZnONPs might cause or exert an adjuvant effect on the development of allergic airway inflam...
Source: Toxicology and Applied Pharmacology - October 24, 2019 Category: Toxicology Authors: Huang KL, Chang HL, Tsai FM, Lee YH, Wang CH, Cheng TJ Tags: Toxicol Appl Pharmacol Source Type: research

Peptidome profiles in melamine diet-induced bladder stones in C57BL/6 mice.
In conclusion, Ndufα8 and basigin may be potential serum biomarkers for the detection of melamine diet-induced bladder stones in C57BL/6 mice. PMID: 31655076 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - October 23, 2019 Category: Toxicology Authors: Liu L, Luo M, Xiong X, Zhao L, Wang X, Ni L, Yang J, Huang C Tags: Toxicol Appl Pharmacol Source Type: research

Converting bleomycin into a prodrug that undergoes spontaneous reactivation under physiological conditions.
In this study, we converted bleomycin into a prodrug by covalently linking 2-sulfo, 9 fluorenylmethoxycarbonyl (FMS) to the primary amino side chain of bleomycin. FMS-bleomycin lost its efficacy to bind transition metal ions and therefore was converted into an inactive derivative. Upon incubation in vitro under physiological conditions, the FMS-moiety undergoes spontaneous hydrolysis, generating native bleomycin possessing full anti-bacterial potency. FMS hydrolysis and reactivation takes place with a t1/2 value of 17 ± 1 h. In silico simulation predicts a narrow therapeutic window in human patients of seven h...
Source: Toxicology and Applied Pharmacology - October 23, 2019 Category: Toxicology Authors: Cooper I, Atrakchi D, Walker MD, Horovitz A, Fridkin M, Shechter Y Tags: Toxicol Appl Pharmacol Source Type: research

The compartmentalised nature of the mechanisms governing superoxide formation and scavenging in cells exposed to arsenite.
In this study, respiration-proficient (RP) and -deficient (RD) cells were exposed to 2.5 or 10 μM arsenite to generate superoxide (O2-.) respectively in the mitochondrial respiratory chain or via NADPH oxidase activation. These treatments, while causing similar, although mitochondrial permeability transition-dependent (RP-cells) or independent (RD-cells), delayed apoptosis, surprisingly generated identical kinetics and levels of dihydrorhodamine oxidation, indicative of O2-. formation. These similarities were attributable to the involvement of a common upstream event resulting in activation of the two O2-.-generating ...
Source: Toxicology and Applied Pharmacology - October 21, 2019 Category: Toxicology Authors: Guidarelli A, Fiorani M, Cerioni L, Cantoni O Tags: Toxicol Appl Pharmacol Source Type: research

ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway.
In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process. PMID: 31639374 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - October 19, 2019 Category: Toxicology Authors: Yan H, Du J, Chen X, Yang B, He Q, Yang X, Luo P Tags: Toxicol Appl Pharmacol Source Type: research

Integrated metabolomics and network toxicology to reveal molecular mechanism of celastrol induced cardiotoxicity.
In this study, Ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS)-based metabolomics revealed clues to the mechanism of CS-induced heart injury. Palmitic acid significantly increased in plasma from CS-treated rats, and this increase resulted in oxidative stress response in vivo. Excessive ROS further activate TNF signaling pathway and caspase family, which were obtained from the KEGG enrichment analysis of network toxicology strategy. Protein expression level of caspase-3, caspase-8, bax were significantly increased by western blot. Q-PCR also showed the similar...
Source: Toxicology and Applied Pharmacology - October 17, 2019 Category: Toxicology Authors: Liu C, Zhang C, Wang W, Yuan F, He T, Chen Y, Wang Q, Huang J Tags: Toxicol Appl Pharmacol Source Type: research

Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators.
Abstract The major function of compounds with an oxime moiety attached to a quarternary nitrogen pyridinium ring is to reactivate acetylcholinesterase inhibited by organophosphorus agent (OP). However, other oxime mechanisms (e.g. modulation of cholinergic or glutamatergic receptor) may be involved in the recovery. The main disadvantage of positively charged reactivators is their low ability to penetrate into the brain although crossing the blood brain barrier could be supported via increasing the dose of administered oxime. Thus, this study presents maximal tolerated doses (MTD) for marketed oximes (TMB-4, MMB-4,...
Source: Toxicology and Applied Pharmacology - October 17, 2019 Category: Toxicology Authors: Hepnarova V, Muckova L, Ring A, Pejchal J, Herman D, Misik J, Hrabinova M, Jun D, Soukup O Tags: Toxicol Appl Pharmacol Source Type: research

Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations.
Abstract Through synthesis of two rare phosphoinositides, PtdIns(3,5)P2 and PtdIns5P, the ubiquitously expressed phosphoinositide kinase PIKfyve is implicated in pleiotropic cellular functions. Small molecules specifically inhibiting PIKfyve activity cause cytoplasmic vacuolation in all dividing cells in culture yet trigger non-apoptotic death through excessive vacuolation only in cancer cells. Intriguingly, cancer cell toxicity appears to be inhibitor-specific suggesting that additional targets beyond PIKfyve are affected. One PIKfyve inhibitor - apilimod - is already in clinical trials for treatment of B-cell ma...
Source: Toxicology and Applied Pharmacology - October 16, 2019 Category: Toxicology Authors: Ikonomov OC, Sbrissa D, Shisheva A Tags: Toxicol Appl Pharmacol Source Type: research

Cytotoxicity and oxidative stress induced by nickel and titanium ions from dental alloys on cells of gastrointestinal tract.
Abstract The aim was to explore the biological effect of nickel (Ni) and titanium (Ti) ions released from dental alloys. NiTi alloy were exposed to 40 mL of artificial saliva (pH = 4.8, t = 37 °C). The dynamics of Ni and Ti ions release during corrosion were recorded on the 3th, 7th and 14th day. Biological effect of Ni and Ti ions released from alloy was explored on cell lines of human tongue CAL 27, liver Hep G2 and colon Caco-2. Neutral Red uptake assay for the estimation of cell viability/cytotoxicity and 2',7'-dichlorofluorescein diacetate fluorimetric assay for reactive oxygen species were us...
Source: Toxicology and Applied Pharmacology - October 16, 2019 Category: Toxicology Authors: Rincic Mlinaric M, Durgo K, Katic V, Spalj S Tags: Toxicol Appl Pharmacol Source Type: research

Urban air pollution induces redox imbalance and epithelium hyperplasia in mice cornea.
Abstract The aim of the study was to evaluate the time course of the effects of urban air pollutants on the ocular surface, focusing on the morphological changes, the redox balance, and the inflammatory response of the cornea. 8-week-old mice were exposed to urban or filtered air (UA-group and FA-group, respectively) in exposure chambers for 1, 2, 4, and 12 weeks. After each time, the eyes were enucleated and the corneas were isolated for biochemical analysis. UA-group corneas exhibited a continuous increase in NADPH oxidase-4 levels throughout the exposure time, suggesting an increased production of reactive ox...
Source: Toxicology and Applied Pharmacology - October 16, 2019 Category: Toxicology Authors: Lasagni Vitar RM, Hvozda Arana AG, Janezic NS, Marchini T, Tau J, Martinefski M, Tesone AI, Racca L, Reides CG, Tripodi V, Evelson PA, Berra A, Llesuy SF, Ferreira SM Tags: Toxicol Appl Pharmacol Source Type: research

Growth and neurite stimulating effects of the neonicotinoid pesticide clothianidin on human neuroblastoma SH-SY5Y cells.
We examined further the effects of CTD on neuronal differentiation by measuring neurite outgrowth. Exposure to CTD (1-100 μM) significantly increased the number of cells within 24 h of culture. The nAChRs antagonists, mecamylamine and SR16584, inhibited this effect, suggesting human α3β4 nAChRs could be targets of neonicotinoids. We observed a transient intracellular calcium influx and increased phosphorylation of extracellular signal-regulated kinase 1/2 shortly after exposure to CTD. Transcriptome analysis revealed that CTD down-regulated genes involved in neuronal function (e.g., formation of filopodia...
Source: Toxicology and Applied Pharmacology - October 15, 2019 Category: Toxicology Authors: Hirano T, Minagawa S, Furusawa Y, Yunoki T, Ikenaka Y, Yokoyama T, Hoshi N, Tabuchi Y Tags: Toxicol Appl Pharmacol Source Type: research

A novel ALK inhibitor ZYY inhibits Karpas299 cell growth in vitro and in a nude mouse xenograft model and induces protective autophagy.
In this study, we investigated the antitumor effect of ZYY, a novel ALK inhibitor, showing a strong growth inhibitory effect on Karpas299 cells in vitro and in vivo. Specifically, ZYY significantly reduced the mRNA and protein expression of ALK and its downstream signaling proteins in Karpas299 cells. Furthermore, ZYY induced G1 phase arrest and promoted apoptosis in Karpas299 cells. Furthermore, we demonstrated that ZYY-induced apoptosis was mainly related to the mitochondria-dependent endogenous pathway. In vitro studies further showed that ZYY induced autophagy in Karpas299 cells, along with increased levels of the auto...
Source: Toxicology and Applied Pharmacology - October 13, 2019 Category: Toxicology Authors: Shen J, Wang J, Du J, Wang L, Zhou X, Chang X, Li Z, Zhai X, Zuo D, Wu Y Tags: Toxicol Appl Pharmacol Source Type: research

Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart.
CONCLUSIONS AND IMPLICATIONS: To our knowledge, this is the first pre-clinical study to show that Tiotropium bromide induces Ca2+ signalling via CaMKII and L-type Ca2+ channels to result in cell damage. This has significant clinical impact due to long term use of TB in COPD patients, and warrants assessment of cardiac drug safety. PMID: 31618660 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - October 13, 2019 Category: Toxicology Authors: Cassambai S, Mee CJ, Renshaw D, Hussain A Tags: Toxicol Appl Pharmacol Source Type: research

Coenzyme Q10 mitigates ionizing radiation-induced testicular damage in rats through inhibition of oxidative stress and mitochondria-mediated apoptotic cell death.
Abstract Radiotherapy is a common treatment modality for cancer patients; however, its use is limited by decreasing the probability of fertility in male cancer survivors. Therefore, this study aimed to define the capability of coenzyme Q10 (CoQ10), a potent stimulator of mitochondrial function, in attenuating ionizing radiation (IR)-induced spermatogenesis impairments. Male Sprague Dawley rats were exposed to a single dose of ϒ-rays (10 Gy) and/or treated with CoQ10 (10 mg/kg, orally, for 2 consecutive weeks). IR mediated irregular seminiferous tubules, which were emerged with typical morphological chara...
Source: Toxicology and Applied Pharmacology - October 13, 2019 Category: Toxicology Authors: Said RS, Mohamed HA, Kamal MM Tags: Toxicol Appl Pharmacol Source Type: research

Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes.
Abstract Recent developments of novel targeted therapies are contributing to the increased long-term survival of cancer patients; however, drug-induced cardiotoxicity induced by cancer drugs remains a serious problem in clinical settings. Nevertheless, there are few in vitro cell-based assays available to predict this toxicity, especially from the aspect of morphology. Here, we developed a simple two-dimensional (2D) morphological assessment system, 2DMA, to predict drug-induced cardiotoxicity in cancer patients using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with image-based high-conte...
Source: Toxicology and Applied Pharmacology - September 15, 2019 Category: Toxicology Authors: Matsui T, Miyamoto K, Yamanaka K, Okai Y, Kaushik EP, Harada K, Wagoner M, Shinozawa T Tags: Toxicol Appl Pharmacol Source Type: research

Corrigendum to "Wogonin inhibits tumor angiogenesis via degradation of HIF-1 α protein" [Toxicology and Applied Pharmacology 271 (2013) 144-145].
Corrigendum to "Wogonin inhibits tumor angiogenesis via degradation of HIF-1α protein" [Toxicology and Applied Pharmacology 271 (2013) 144-145]. Toxicol Appl Pharmacol. 2019 Sep 14;:114762 Authors: Song X, Yao J, Wang F, Zhou M, Zhou Y, Wang H, Wei L, Zhao L, Li Z, Lu N, Guo Q PMID: 31526815 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - September 14, 2019 Category: Toxicology Authors: Song X, Yao J, Wang F, Zhou M, Zhou Y, Wang H, Wei L, Zhao L, Li Z, Lu N, Guo Q Tags: Toxicol Appl Pharmacol Source Type: research

WZ3146 inhibits mast cell Lyn and Fyn to reduce IgE-mediated allergic responses in vitro and in vivo.
In this study, we investigated the inhibitory effect of WZ3146, N-[3-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide, and the mechanisms of its actions on the MC activation and IgE-mediated allergic response by using three types of MCs such as rat basophilic leukemia (RBL)-2H3 cells, mouse bone marrow mast cells (BMMCs), and human Laboratory of Allergic Diseases 2 (LAD2) cells. WZ3146 inhibited antigen-stimulated degranulation in a dose-dependent manner (IC50, ~ 0.35 μM for RBL-2H3 cells; ~ 0.39 μM for BMMCs; ~ 0.41 for LAD2 cells). WZ3146 also suppressed the production of h...
Source: Toxicology and Applied Pharmacology - September 14, 2019 Category: Toxicology Authors: Park YH, Kim DK, Kim HS, Lee D, Lee MB, Min KY, Jo MG, Lee JE, Kim YM, Choi WS Tags: Toxicol Appl Pharmacol Source Type: research

Chemotherapeutic doses of arsenic trioxide delays hepatic regeneration by oxidative stress and hepatocyte apoptosis in partial hepatectomy rat.
This study concludes that ATO at a chemotherapeutic concentration augments oxidative stress and hepatocytes apoptosis, thereby delays liver regeneration potential and could affect the outcome of liver transplantation. PMID: 31525389 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - September 13, 2019 Category: Toxicology Authors: Nithyananthan S, Thirunavukkarasu C Tags: Toxicol Appl Pharmacol Source Type: research

PEGylated gold nanorods are not cytotoxic to human endothelial cells but affect kruppel-like factor signaling pathway.
Abstract Gold (Au) nanomaterials (NMs), particularly those with PEG surface functionalization, are generally considered to be biocompatible for biomedical applications due to relatively low cytotoxicity. Herein, we investigated the toxicity of PEGylated Au nanorods (NRs) to human umbilical vein endothelial cells (HUVECs), a commonly used in vitro model for human endothelium. We found a previously unknown effect that up to 10 μg/mL Au NRs, albeit not cytotoxic, decreased the mRNA and protein levels of kruppel-like factor 2 (KLF2), a transcription factor with well-documented vasoprotective effects. The results ...
Source: Toxicology and Applied Pharmacology - September 12, 2019 Category: Toxicology Authors: Li X, Tang Y, Chen C, Qiu D, Cao Y Tags: Toxicol Appl Pharmacol Source Type: research

Lipidomes of brain from rats acutely intoxicated with diisopropylfluorophosphate identifies potential therapeutic targets.
In this study, we characterized the profiles of lipid mediators, important players in neuroinflammation, in the rat model of acute DFP intoxication. The profiles of lipid mediators were monitored in three different regions of the brain (cortex, hippocampus, and cerebellum) at 0, 1, 3, 7, 14, and 28 days post-exposure. The distribution pattern of lipid mediators was distinct in the three brain regions. In the cerebellum, the profile is dominated by LOX metabolites, while the lipid mediator profiles in cortex and hippocampus are dominated by COX metabolites followed by LOX and CYP 450 metabolites. Following acute DFP intox...
Source: Toxicology and Applied Pharmacology - September 12, 2019 Category: Toxicology Authors: Yang J, Bruun DA, Wang C, Wan D, Reynolds CB, Phu K, Inceoglu B, Lein PJ, Hammock BD Tags: Toxicol Appl Pharmacol Source Type: research

Food ingredient safety evaluation: Utility and relevance of toxicokinetic methods.
Abstract The use of toxicokinetic (TK) data is becoming more prevalent in the evaluation of food ingredient safety as more TK information is being incorporated in safety data packages. Data demonstrating "1) the extent of absorption, 2) tissue distribution, 3) pathways and rates of metabolism, and 4) rate(s) of elimination" of food ingredients and their metabolites of intermediate and high toxicological potential may be useful for planning and designing toxicity studies, selecting doses for toxicity studies, addressing species differences, and understanding the potential modes of action to evaluate their...
Source: Toxicology and Applied Pharmacology - September 12, 2019 Category: Toxicology Authors: Kabadi SV, Zang Y, Fisher JW, Smith N, Whiteside C, Aungst J Tags: Toxicol Appl Pharmacol Source Type: research

Identification of differentially expressed genes and networks related to hepatic lipid dysfunction.
Abstract A range of chemical exposures that resulted in the specific pathology of hepatic lipid dysfunction in rats were selected from DrugMatrix, a publicly available toxicogenomic database. Raw microarray data collected from these exposures were further analyzed using bioinformatic tools to generate a differentially expressed genes (DEGs) dataset associated with hepatic lipid dysfunction. Further analysis of the DEGs dataset resulted in 324 upregulated genes, and 275 genes that were down regulated. Meanwhile, 36 genes were either up regulated or down regulated in different chemical treatments. All identified gen...
Source: Toxicology and Applied Pharmacology - September 11, 2019 Category: Toxicology Authors: Abedini JA, Handa S, Edwards S, Chorley B, El-Masri H Tags: Toxicol Appl Pharmacol Source Type: research

Carvedilol protects against hepatic ischemia reperfusion injury in high-fructose high-fat diet-fed mice: Role of G protein-coupled receptor kinase 2 and 5.
In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect. PMID: 31518596 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - September 10, 2019 Category: Toxicology Authors: Mohammed SG, Ibrahim IAAE, Mahmoud AAA, Mahmoud MF Tags: Toxicol Appl Pharmacol Source Type: research

Role of polypyrimidine tract-binding protein 1/yin yang 2 signaling in regulating vascular smooth muscle cell proliferation and neointima hyperplasia.
Abstract Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular restenosis. We investigated whether polypyrimidine tract-binding protein 1 (PTBP1), a novel regulator of cell proliferation and differentiation, is implicated in VSMC proliferation and neointima hyperplasia responding to injury. C57BL/6 J mice of 10-12 weeks old were randomly divided into sham and carotid artery injury group. Primary VSMCs obtained from thoracic aortas of 10- to 12-week-old mice were treated with physiological saline and platelet derived growth factor-BB (PDGF-BB). Adenovirus expressing shCon, shP...
Source: Toxicology and Applied Pharmacology - September 6, 2019 Category: Toxicology Authors: Wang Z, Gan X, Qiu C, Yang D, Sun X, Zeng Z Tags: Toxicol Appl Pharmacol Source Type: research

Iron chelation by deferasirox confers protection against concanavalin A-induced liver fibrosis: A mechanistic approach.
Abstract Hepatic iron overload is one of the causative factors for chronic liver injury and fibrosis. The present study aimed to investigate the potential antifibrotic effect of the iron chelator; deferasirox (DFX) in experimentally-induced liver fibrosis in rats. Male Sprague-Dawley rats were administered concanavalin A (Con A) and/or DFX for 6 consecutive weeks. Con A injection induced significant hepatotoxicity as was evident by the elevated transaminases activity, and decreased albumin level. Also, it disturbed the iron homeostasis through increasing C/EBP homologous protein (CHOP), decreasing phosphorylated c...
Source: Toxicology and Applied Pharmacology - September 6, 2019 Category: Toxicology Authors: Adel N, Mantawy EM, El-Sherbiny DA, El-Demerdash E Tags: Toxicol Appl Pharmacol Source Type: research

Rapamycin attenuates liver injury caused by vinyl chloride metabolite chloroethanol and lipopolysaccharide in mice.
Abstract Vinyl chloride (VC) is a prevalent environmental toxicant that is rapidly metabolized within the liver. Its metabolites have been shown to directly cause hepatic injury at high exposure levels. We have previously reported that VC metabolite, chloroethanol (CE), potentiates liver injury caused by lipopolysaccharide (LPS). Importantly, that study showed that CE alone, while not causing damage per se, was sufficient to alter hepatic metabolism and increase mTOR phosphorylation in mice, suggesting a possible role for the mTOR pathway. Here, we explored the effect of an mTOR inhibitor, rapamycin, in this model...
Source: Toxicology and Applied Pharmacology - September 6, 2019 Category: Toxicology Authors: Lang AL, Krueger AM, Schnegelberger RD, Kaelin BR, Rakutt MJ, Chen L, Arteel GE, Beier JI Tags: Toxicol Appl Pharmacol Source Type: research

Exposure to silver nanoparticles primes mast cells for enhanced activation through the high-affinity IgE receptor.
Abstract Mast cells are a key effector cell in type I allergic reactions. It has been shown that environmental exposures such as diesel exhaust and heavy metals exacerbate mast cell degranulation and activation. Today, the use of engineered nanomaterials (ENMs) is rapidly expanding and silver nanoparticles (AgNP) are one of the mostly widely utilized ENMs, primarily for their antimicrobial properties, and are being incorporated into many consumer and biomedical products. We assessed whether pre-exposure of bone marrow-derived mast cells (BMMCs) to 20 nm AgNPs enhanced degranulation and activation to an allergen ...
Source: Toxicology and Applied Pharmacology - September 5, 2019 Category: Toxicology Authors: Alsaleh NB, Mendoza RP, Brown JM Tags: Toxicol Appl Pharmacol Source Type: research

High- and low- selenium diets affect endocrine energy balance during early programming.
les F Abstract High- and low- Se diets received by dams during gestation and lactation are related to insulin resistance in their pups. High-Se diet leads to an increase in serum insulin levels, which does not function properly, and an anabolic process. Low-Se diet is related to very low insulin values and an extreme catabolic energy imbalance. Selenoproteins have been implicated directly in the general endocrine regulation of appetite and energy homeostasis. To obtain information concerning how Se intake by dams is involved in regulating endocrine energy balance in progeny, three experimental groups of dam rats w...
Source: Toxicology and Applied Pharmacology - September 5, 2019 Category: Toxicology Authors: Ojeda ML, Carreras O, Díaz-Castro J, Murillo ML, Nogales F Tags: Toxicol Appl Pharmacol Source Type: research

Cortisol disruption and transgenerational alterations in the expression of stress-related genes in zebrafish larvae following fluoxetine exposure.
Abstract Fluoxetine (FLX), the active ingredient in well-known therapeutic drugs such as Prozac, is highly prescribed worldwide to treat affective disorders even among pregnant women and adolescents. Given that FLX readily crosses the placenta, a fetus from a treated pregnant woman is potentially at risk from unintended effects of the chemical. Moreover, FLX reaches aquatic ecosystems at biologically active levels through sewage release, so fish may also be inadvertently affected. We previously demonstrated that FLX exposure to environmentally- (Low FLX lineage; LFL) and human- (High FLX lineage; HFL) relevant con...
Source: Toxicology and Applied Pharmacology - August 30, 2019 Category: Toxicology Authors: Vera-Chang MN, Moon TW, Trudeau VL Tags: Toxicol Appl Pharmacol Source Type: research

Dexmedetomidine attenuates the induction and reverses the progress of 6-hydroxydopamine- induced parkinsonism; involvement of KATP channels, alpha 2 adrenoceptors and anti-inflammatory mechanisms.
CONCLUSION: Our findings indicate that DEX attenuates the induction and reverses the progress of 6-OHDA- induced Parkinsonism through activation of KATP channels and α2-adrenoceptors, respectively. Through activation of α2-adrenoceptors, DEX also exerts anti-inflammatory effect which is possibly another mechanism underlying the DEX's antiparkinsonism effect. PMID: 31476326 [PubMed - as supplied by publisher] (Source: Toxicology and Applied Pharmacology)
Source: Toxicology and Applied Pharmacology - August 30, 2019 Category: Toxicology Authors: Minaei A, Haghdoost-Yazdi H Tags: Toxicol Appl Pharmacol Source Type: research

The comparative effects of high dose atorvastatin and proprotein convertase subtilisin/kexin type 9 inhibitor on the mitochondria of oxidative muscle fibers in obese-insulin resistant female rats.
Abstract The present study aimed to compare the effects of high dose atorvastatin and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on the mitochondrial function in oxidative muscle fibers in obese female rats. Female Wistar rats were fed with either a normal diet (ND: n = 12) or a high-fat diet (HFD: n = 36) for a total of 15 weeks. At week 13, ND-fed rats received a vehicle, and HFD-fed rats were divided to three groups to receive either a vehicle, 40 mg/kg/day of atorvastatin, or 4 mg/kg/day of PCSK9 inhibitor (SBC-115076) for 3 weeks. Soleus muscles were investigated to asse...
Source: Toxicology and Applied Pharmacology - August 29, 2019 Category: Toxicology Authors: Thonusin C, Apaijai N, Jaiwongkam T, Kerdphoo S, Arunsak B, Amput P, Palee S, Pratchayasakul W, Chattipakorn N, Chattipakorn SC Tags: Toxicol Appl Pharmacol Source Type: research

Thromboxane A2 receptor signaling in endothelial cells attenuates monocrotaline-induced liver injury.
In this study, we explored the role of TP signaling in a monocrotaline (MCT)-induced mouse model of SOS. Relative to wild-type (WT) mice, TP-deficient (TP-/-) mice exhibited more severe MCT-liver injury, as indicated by elevated levels of alanine aminotransferase (ALT) and coagulative necrosis. Extensive accumulation of platelets in the liver was observed in both WT and TP-/- mice. TP expression co-localized with CD31-positive LSECs. MCT treatment caused LSEC destruction, concomitant with elevated expression of matrix metalloproteinases (MMPs) and adhesion molecules in WT mice, and LSEC damage was further exacerbated in TP...
Source: Toxicology and Applied Pharmacology - August 27, 2019 Category: Toxicology Authors: Otaka F, Ito Y, Inoue T, Ohkubo H, Nishizawa N, Kojo K, Betto T, Yamane S, Narumiya S, Koizumi W, Majima M Tags: Toxicol Appl Pharmacol Source Type: research