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1.
Ecotoxicol Environ Saf ; 272: 116072, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38342011

RESUMEN

Triptolide (TP) is the major bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., a traditional Chinese medicinal plant categorized within the Tripterygium genus of the Celastraceae family. It is recognized for its therapeutic potential in addressing a multitude of diseases. Nonetheless, TP is known to exhibit multi-organ toxicity, notably hepatotoxicity, which poses a significant concern for the well-being of patients undergoing treatment. The precise mechanisms responsible for TP-induced hepatotoxicity remain unresolved. In our previous investigation, it was determined that TP induces heightened hepatic responsiveness to exogenous lipopolysaccharide (LPS). Additionally, natural killer (NK) cells were identified as a crucial effector responsible for mediating hepatocellular damage in this context. However, associated activating receptors and the underlying mechanisms governing NK cell represented innate lymphoid cell (ILC) activation remained subjects of inquiry and were not yet investigated. Herein, activating receptor Killer cell lectin like receptor K1 (NKG2D) of group 1 ILCs was specifically upregulated in TP- and LPS-induced acute liver failure (ALF), and in vivo blockade of NKG2D significantly reduced group 1 ILC mediated cytotoxicity and mitigated TP- and LPS-induced ALF. NKG2D ligand UL16-binding protein-like transcript 1 (MULT-1) was found upregulated in liver resident macrophages (LRMs) after TP administration, and LRMs did exhibit NK cell activating effect. Furthermore, M1 polarization of LRMs cells was observed, along with an elevation in intracellular tumor necrosis factor (TNF)-α levels. In vivo neutralization of TNF-α significantly alleviated TP- and LPS-induced ALF. In conclusion, the collaborative role of group 1 ILCs and LRMs in mediating hepatotoxicity was confirmed in TP- and LPS-induced ALF. TP-induced MULT-1 expression in LRMs was the crucial mechanism in the activation of group 1 ILCs via MULT-1-NKG2D signal upon LPS stimulation, emphasizing the importance of infection control after TP administration.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Diterpenos , Fenantrenos , Animales , Humanos , Ratones , Subfamilia K de Receptores Similares a Lectina de Células NK , Lipopolisacáridos/toxicidad , Inmunidad Innata , Fenantrenos/toxicidad , Compuestos Epoxi/toxicidad , Células Asesinas Naturales , Macrófagos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología
2.
Sci Total Environ ; 918: 170544, 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38309367

RESUMEN

Multiple lines of evidence at whole animal, cellular and molecular levels implicate polycyclic aromatic compounds (PACs) with three rings as drivers of crude oil toxicity to developing fish. Phenanthrene (P0) and its alkylated homologs (C1- through C4-phenanthrenes) comprise the most prominent subfraction of tricyclic PACs in crude oils. Among this family, P0 has been studied intensively, with more limited detail available for the C4-phenanthrene 1-methyl-7-isopropyl-phenanthrene (1-M,7-IP, or retene). While both compounds are cardiotoxic, P0 impacts embryonic cardiac function and development through direct blockade of K+ and Ca2+ currents that regulate cardiomyocyte contractions. In contrast, 1-M,7-IP dysregulates aryl hydrocarbon receptor (AHR) activation in developing ventricular cardiomyocytes. Although no other compounds have been assessed in detail across the larger family of alkylated phenanthrenes, increasing alkylation might be expected to shift phenanthrene family member activity from K+/Ca2+ ion current blockade to AHR activation. Using embryos of two distantly related fish species, zebrafish and Atlantic haddock, we tested 14 alkyl-phenanthrenes in both acute and latent developmental cardiotoxicity assays. All compounds were cardiotoxic, and effects were resolved into impacts on multiple, highly specific aspects of heart development or function. Craniofacial defects were clearly linked to developmental cardiotoxicity. Based on these findings, we suggest a novel framework to delineate the developmental toxicity of petrogenic PAC mixtures in fish, which incorporates multi-mechanistic pathways that produce interactive synergism at the organ level. In addition, relationships among measured embryo tissue concentrations, cytochrome P4501A mRNA induction, and cardiotoxic responses suggest a two-compartment toxicokinetic model that independently predicts high potency of PAC mixtures through classical metabolic synergism. These two modes of synergism, specific to the sub-fraction of phenanthrenes, are sufficient to explain the high embryotoxic potency of crude oils, independent of as-yet unmeasured compounds in these complex environmental mixtures.


Asunto(s)
Petróleo , Fenantrenos , Hidrocarburos Policíclicos Aromáticos , Animales , Pez Cebra , Cardiotoxicidad , Fenantrenos/toxicidad , Relación Estructura-Actividad , Petróleo/toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad
3.
Bull Environ Contam Toxicol ; 110(3): 63, 2023 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-36917264

RESUMEN

No ecotoxicological information exists on phenanthrene (Phe) exposure in cephalopods, animals of commercial and ecological importance. This study investigated the effect of Phe on two B-esterases, Acetylcholinesterase (AChE) and Carboxylesterases (CbE), in Octopus maya embryos. Octopus embryos were exposed to different treatments: control (seawater), solvent control (seawater and DMSO 0.01%), 10 and 100 µg/L of Phe. AChE and CbE activities were measured at different developmental stages (blastula, organogenesis, and growth). B-esterase activities increased in control and solvent control as the embryos developed, showing no statistically significant differences between them. On the other hand, the embryos exposed to Phe had significant differences from controls, and between the high and low concentrations. Our results indicate that B-esterases are sensitive biomarkers of exposure to Phe in O. maya. Still, complementary studies are needed to unravel the toxicodynamics of Phe and the implications of the found inhibitory effect in hatched organisms.


Asunto(s)
Octopodiformes , Fenantrenos , Animales , Acetilcolinesterasa , Esterasas , Fenantrenos/toxicidad , Solventes
4.
Environ Sci Process Impacts ; 25(3): 594-608, 2023 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-36727431

RESUMEN

Tricyclic polycyclic aromatic hydrocarbons (PAHs) are believed to be the primary toxic components of crude oil. Such compounds including phenanthrene are known to have direct effects on cardiac tissue, which lead to malformations during organogenesis in early life stage fish. We tested a suite of 13 alkyl-phenanthrenes to compare uptake and developmental toxicity in early life stage haddock (Melanogrammus aeglefinus) embryos during gastrulation/organogenesis beginning at 2 days post fertilization via passive dosing. The alkyl-phenanthrenes were tested at their solubility limits, and three of them also at lower concentrations. Measured body burdens were linearly related to measured water concentrations. All compounds elicited one or more significant morphological defects or functional impairment, such as decreased length, smaller eye area, shorter jaw length, and increased incidence of body axis deformities and eye deformities. The profile of developmental toxicities appeared unrelated to the position of alkyl substitution, and gene expression of cytochrome 1 a (cyp1a) was low regardless of alkylation. Mortality and sublethal effects were observed below the expected range for baseline toxicity, thus indicating excess toxicity. Additionally, PAH concentrations that resulted in toxic effects here were far greater than when measured in whole crude oil exposures that cause toxicity. This work demonstrates that, while these phenanthrenes are toxic to early life stage fish, they cannot individually account for most of the developmental toxicity of crude oil, and that other compounds and/or mixture effects should be given more consideration.


Asunto(s)
Petróleo , Fenantrenos , Hidrocarburos Policíclicos Aromáticos , Contaminantes Químicos del Agua , Animales , Contaminantes Químicos del Agua/análisis , Peces/metabolismo , Fenantrenos/toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad , Hidrocarburos Policíclicos Aromáticos/metabolismo , Petróleo/análisis , Embrión no Mamífero
5.
Toxicol Lett ; 375: 21-28, 2023 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-36563867

RESUMEN

Danshen Si Wu is a Traditional Chinese Medicine used for menopausal complains. Beside tanshinone IIA (Tan IIA), Danshen also contains tanshinone I (Tan I), cryptotanshinone (CT) and dihydrotanshinone (DT). The aim of this study was to compare the biological activity of these tanshinones and to determine their cytotoxicity and genotoxicity. Purities and stabilities of the substances were analyzed by LC-DAD and LC-MS analyses. DT and CT concentrations decreased rapidly in dimethylsulfoxide and were converted to Tan I and Tan IIA, respectively. In aqueous solution concentration of all tanshinones decreased after 24 h. Tan I and Tan IIA showed dose-dependent bioactivity mediated by ERα and ERß. No cytotoxic and genotoxic effects for Tan I and Tan IIA were detected. In a yeast transactivation assay Tan I and Tan IIA showed antiandrogenic activity. A significant anabolic activity in C2C12 cells could be detected for Tan I and Tan IIA. In conclusion our data provide evidence that Tan I and Tan IIA are the most relevant bioactive tanshinones in Danshen. Our finding that all tanshinones display a certain instability in aqueous solutions is relevant when discussing their potential therapeutic benefits in humans.


Asunto(s)
Abietanos , Fenantrenos , Humanos , Abietanos/toxicidad , Abietanos/química , Fenantrenos/toxicidad , Cromatografía Liquida
6.
Toxicon ; 221: 106964, 2023 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-36372154

RESUMEN

Triptolide is a major active ingredient isolated from the traditional Chinese medicine Tripterygium wilfordii, which has anti-inflammatory, anti-cancer, and immunomodulatory effects. However, in clinical studies, triptolide has toxic side effects on the heart, kidney, liver and reproductive organs. With respect to female reproductive toxicity, damaging effects of triptolide on the ovary have been reported, but it has remained unknown whether oocytes are affected by triptolide. Therefore, this study established a concentration gradient of triptolide exposure in mice using 0 (control), 30, 60, and 90 µg triptolide/kg body weight/day administered by gavage. Triptolide administration for 28 d reduced body weight and ovarian weight and affected the developmental potential of oocytes. The triptolide-treated group exhibited meiotic failure of oocytes due to impaired spindle assembly, chromosome alignment, and tubulin stability. Triptolide was also found to induce mitochondrial dysfunction, autophagy and early apoptosis, iron homeostasis, and abnormal histone modifications. These adverse effects could be associated with oxidative stress induced by triptolide. In conclusion, our findings suggest detrimental effects of triptolide on mouse oocytes and, thus, on female reproduction.


Asunto(s)
Fenantrenos , Femenino , Ratones , Animales , Fenantrenos/toxicidad , Oocitos , Estrés Oxidativo , Apoptosis , Peso Corporal
7.
J Ethnopharmacol ; 292: 115224, 2022 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-35351577

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Triptolide (TP) exhibits extensive pharmacological activity, but its hepatotoxicity and intestinal injury are significant and limit its clinical use. AIM OF THE STUDY: To investigate the effect of gut microbiota disturbance after antibiotic pretreatment on TP-induced hepatotoxicity, intestinal injury and their mechanism. MATERIALS AND METHODS: We compared the characteristics of TP-induced hepatotoxicity and intestinal injury in mice with or without antibiotic pretreatment. The levels of cytokines in the serum, immunohistochemistry, and the pharmacokinetics of TP were determined. RESULT: Antibiotic pretreatment aggravates TP-induced hepatotoxicity and ileum/colon injury. TP induces hepatotoxicity in a dose-dependent manner after antibiotic pretreatment. Serum IL-1ß and IL-6 levels were increased in mice given oral TP after antibiotic pretreatment. TP can increase the expression of NLRP3 inflammasome in hepatocytes, and Oral TP after antibiotic pretreatment can significantly enhance its expression, but NLRP3 inflammasome no significant change in colon and ileum. The pharmacokinetic characteristics of TP are altered significantly by antibiotic pretreatment, as shown by a 145.87% increase in Cmax, a 155.11% increase in AUC0-t, a 155.1% increase in relative bioavailability, and a 15.44% delay in MRT. Moreover, TP causes hepatotoxicity in a time-dependent manner. CONCLUSIONS: Antibiotic pretreatment aggravates triptolide-induced hepatotoxicity and intestinal injury through elevated inflammatory response and promoted triptolide absorption.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Diterpenos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Fenantrenos , Animales , Antibacterianos/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Diterpenos/farmacología , Compuestos Epoxi , Inflamasomas/metabolismo , Hígado , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fenantrenos/toxicidad
8.
J Ethnopharmacol ; 289: 115090, 2022 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-35143937

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium glycosides tablets (TGT) and Tripterygium wilfordii tablets (TWT) have been used to treat autoimmune diseases clinically, however, the side effects of TWT are higher than TGT, especially for hepatotoxicity. THE AIM OF THE STUDY: This study aims to determine the mechanism of TWT-induced liver injury. MATERIALS AND METHODS: We performed metabolomic analysis of samples from mice with liver injury induced by TGT and TWT. Ppara-null mice were used to determine the role of PPARα in TWT-induced liver injury. RESULTS: The results indicated that TWT induced the accumulation of medium- and long-chain carnitines metabolism, which was associated with the disruption of PPARα-IL6-STAT3 axis. PPARα agonists fenofibrate could reverse the liver injury from TWT and TP/Cel, and its protective role could be attenuated in Ppara-null mice. The toxicity difference of TWT and TGT was due to the different ratio of triptolide (TP) and celastrol (Cel) in the tablet in which TP/Cel was lower in TWT than TGT. The hepatotoxicity induced by TP and Cel also inhibited PPARα and upregulated IL6-STAT3 axis, which could be alleviated following by PPARα activation. CONCLUSIONS: These results indicated that PPARα plays an important role in the hepatotoxicity of Tripterygium wilfordii, and PPARα activation may offer a promising approach to prevent hepatotoxicity induced by the preparations of Tripterygium wilfordii.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , PPAR alfa/genética , Extractos Vegetales/toxicidad , Tripterygium/química , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Diterpenos/química , Diterpenos/toxicidad , Compuestos Epoxi/química , Compuestos Epoxi/toxicidad , Masculino , Metabolómica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/toxicidad , Fenantrenos/química , Fenantrenos/toxicidad , Extractos Vegetales/química , Comprimidos
9.
Arch Toxicol ; 96(4): 1109-1131, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35182162

RESUMEN

Alkyl-substituted PAHs may be present in certain petroleum-derived products and in the environment and may eventually end up in consumer products, such as foodstuffs, cosmetics and pharmaceuticals. Safety concerns over possible exposure to alkylated PAHs have emerged. Bioactivation is a prerequisite for the mutagenicity and carcinogenicity of PAHs and has been extensively studied for non-substituted PAHs, while data on the bioactivation of alkyl-substituted PAHs are scarce. The present study investigated the effect of alkyl substitution on the CYP 450-mediated metabolism of phenanthrene and eight of its alkylated congeners by quantifying metabolite formation in rat and human liver microsomal incubations. Furthermore, the mutagenicity of four selected methylated phenanthrenes was compared to that of phenanthrene using the Ames test. The obtained results support the hypothesis that alkyl substitution shifts the oxidative metabolism from the aromatic ring to the alkyl side chain. Increasing the length of the alkyl chain reduced overall metabolism with metabolic conversion for 1-n-dodecyl-phenanthrene (C12) being negligible. 1- and 9-methyl-phenanthrene, in which the methyl group generates an additional bay region-like structural motif, showed mutagenicity toward Salmonella typhimurium TA98 and TA 100, whereas phenanthrene and also 2- and 3-methyl-phenanthrene, without such an additional bay region-like structural motif, tested negative. It is concluded that the position of the alkylation affects the metabolism and resulting mutagenicity of phenanthrene with the mutagenicity increasing in cases where the alkyl substituent creates an additional bay region-like structural motif, in spite of the extra possibilities for side chain oxidation.


Asunto(s)
Petróleo , Fenantrenos , Hidrocarburos Policíclicos Aromáticos , Animales , Mutagénesis , Pruebas de Mutagenicidad , Mutágenos/toxicidad , Estrés Oxidativo , Fenantrenos/toxicidad , Ratas
10.
J Ethnopharmacol ; 281: 114489, 2021 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-34363931

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Triptolide (TP), the main bioactive and toxic ingredient of Tripterygium wilfordii Hook F, causes severe toxicity, particularly for hepatotoxicity. However, the underlying mechanisms for its hepatotoxicity are not entirely clear. AIM OF THE STUDY: The purpose of the study was to explore the role of miR-155, a microRNA closely related to various liver injuries and a regulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway, in TP-induced liver injury in vitro and in vivo. MATERIALS AND METHODS: First, in vitro L02 cells were treated with different concentrations of TP. The protein levels of Nrf2 and its downstream genes Heme oxygenase1 (HO-1) were determined by Western blot. The mRNA expression of miR-155, Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and HO-1 were measured using qRT-PCR. And we transfected miR-155 inhibitor and miminc before TP treatment to determine the mRNA and/or protein levels of miR-155, Nrf2 and HO-1. Then, we further confirmed the interaction between miR-155 and Nrf2 pathway in TP-induced hepatic injury in BALB/C mice. The degree of liver injury was determined by HE staining and serum biochemical. The mRNA expression of miR-155 was examined with qRT-PCR and Nrf2 and HO-1 gene expression in liver were evaluated by immunohistochemistry and/or Western blot. RESULTS: The results showed that TP significantly induced the expression of miR-155 both in L02 cells and in rodents liver tissue, and the inhibition of miR-155 could mitigate the hepatic damages caused by TP. Further experiments demonstrated that the inhibition of miR-155 reversed the down-regulation of Nrf2 and HO-1 by TP, while the miR-155 mimic enhanced the effects of TP. Animal experiments also showed that the inhibition of miR-155 by miR-155 antagomir reversed the decrease of Nrf2 induced by TP administration. CONCLUSIONS: These results indicated that miR-155 played an important role in TP-induced hepatotoxicity by regulating the Nrf2 signaling pathway.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Diterpenos/toxicidad , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , MicroARNs/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fenantrenos/toxicidad , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Compuestos Epoxi/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , Factor 2 Relacionado con NF-E2/genética
11.
Ecotoxicol Environ Saf ; 222: 112536, 2021 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-34303043

RESUMEN

As a widely existing traditional Chinese medicine component, TP (triptolide) has serious reproductive toxicity which causes severe damage to the reproductive system and limits its application prospect. TP and MET (metformin) have shown great potential in combined with each other in anticancer and anti-inflammatory. Whether metformin can resist the reproductive toxicity caused by triptolide, the effects of MET on TP-induced reproductive capacity has not been reported. In this study, metformin was used to investigate the therapeutic effect on reproductive toxicity induced by TP in rat. The results showed that metformin had significant therapeutic effects on oxidative stress damage, destruction of the blood-testosterone barrier and apoptosis. And it proved that its therapeutic effect is mainly to restore the structural and functional stability of testis through antioxidant stress. It will provide guidance for the treatment of reproductive toxicity caused by TP and the adjuvant detoxification of TP application.


Asunto(s)
Diterpenos , Metformina , Fenantrenos , Animales , Diterpenos/toxicidad , Compuestos Epoxi/toxicidad , Masculino , Metformina/toxicidad , Fenantrenos/toxicidad , Ratas , Testículo
12.
Mar Pollut Bull ; 169: 112560, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34091251

RESUMEN

Coral reefs are keystone coastal ecosystems that can be exposed to petroleum hydrocarbons from multiple sources, and when selecting spill response methods to limit environmental damages, corals represent one of the highest valued resources for protection. Because previous research to characterize the sensitivity of coral species to petroleum hydrocarbon exposures is limited, a continuous-flow passive dosing system and toxicity testing protocol was designed to evaluate the acute effects of two representative petroleum compounds, toluene and phenanthrene, on five coral species: Acropora cervicornis, Porites astreoides, Siderastera siderea, Stephanocoenia intersepta, and Solenastrea bournoni. Using analytically confirmed exposures, sublethal and lethal endpoints were calculated for each species, and used as model inputs to determine critical target lipid body burdens (CTLBBs) for characterizing species sensitivity. Further, quantification of the time-dependent toxicity of single hydrocarbon exposures is described to provide model inputs for improved simulation of spill impacts to corals in coastal tropical environments.


Asunto(s)
Antozoos , Contaminación por Petróleo , Petróleo , Fenantrenos , Contaminantes Químicos del Agua , Animales , Arrecifes de Coral , Ecosistema , Hidrocarburos , Petróleo/toxicidad , Contaminación por Petróleo/análisis , Fenantrenos/toxicidad , Tolueno , Contaminantes Químicos del Agua/toxicidad
13.
J Hazard Mater ; 418: 126302, 2021 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-34118541

RESUMEN

Phenanthrene (PHE) is an important organic compound, which is widespread in the soil environment and exhibits potential threats to soil organisms. Toxic effects of PHE to earthworms have been extensively studied, but toxic mechanisms on PHE-induced cytotoxicity and oxidative stress at the molecular and cellular levels have not been reported yet. Therefore, we explored the cytotoxicity and oxidative stress caused by PHE in earthworm coelomocytes and the interaction mechanism between PHE and the major antioxidant enzymes SOD/CAT. It was shown that high-dose PHE exposure induced the intracellular reactive oxygen species (ROS) generation, mediated lipid peroxidation, reduced total antioxidant capacity (T-AOC) in coelomocytes, and triggered oxidative stress, thus resulted in a strong cytotoxicity at higher concentrations (0.6-1.0 mg/L). The intracellular SOD/CAT activity in cells after PHE exposure were congruent with that in molecular levels, which the activity of SOD enhanced and CAT inhibited. Spectroscopic studies showed the SOD/CAT protein skeleton and secondary structure, as well as the micro-environment of aromatic amino acids were changed after PHE binding. Molecular docking indicated PHE preferentially docked to the surface of SOD. However, the key residues Tyr 357, His 74, and Asn 147 for activity were in the binding pocket, indicating PHE more likely to dock to the active center of CAT. In addition, H-bonding and hydrophobic force were the primary driving force in the binding interaction between PHE and SOD/CAT. This study indicates that PHE can induce cytotoxicity and oxidative damage to coelomocytes and unearthes the potential effects of PHE on earthworms.


Asunto(s)
Oligoquetos , Fenantrenos , Animales , Catalasa/metabolismo , Simulación del Acoplamiento Molecular , Oligoquetos/metabolismo , Estrés Oxidativo , Fenantrenos/toxicidad , Superóxido Dismutasa/metabolismo
14.
Aquat Toxicol ; 235: 105823, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33906022

RESUMEN

Oil and gas exploration in the Arctic can result in the release of polycyclic aromatic hydrocarbons (PAHs) into relatively pristine environments. Following the recent spill of approximately 17 500 tonnes of diesel fuel in Norilsk, Russia, May 2020, our study focussed on the effects of phenanthrene, a low molecular weight PAH found in diesel and crude oil, on the isolated atrial and ventricular myocytes from the heart of the polar teleost, the Navaga cod (Eleginus nawaga). Acute exposure to phenanthrene in navaga cardiomyocytes caused significant action potential (AP) prolongation, confirming the proarrhythmic effects of this pollutant. We show AP prolongation was due to potent inhibition of the main repolarising current, IKr, with an IC50 value of ~2 µM. We also show a potent inhibitory effect (~55%) of 1 µM phenanthrene on the transient IKr currents that protects the heart from early-after-depolarizations and arrhythmias. These data, along with more minor effects on inward sodium (INa) (~17% inhibition at 10 µM) and calcium (ICa) (~17% inhibition at 30 µM) currents, and no effects on inward rectifier (IK1 and IKAch) currents, demonstrate the cardiotoxic effects exerted by phenanthrene on the atrium and ventricle of navaga cod. Moreover, we report the first data that we are aware of on the impact of phenanthrene on atrial myocyte function in any fish species.


Asunto(s)
Gadiformes/fisiología , Miocitos Cardíacos/efectos de los fármacos , Fenantrenos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Potenciales de Acción/efectos de los fármacos , Animales , Regiones Árticas , Peces , Miocitos Cardíacos/fisiología , Petróleo , Hidrocarburos Policíclicos Aromáticos/toxicidad , Sodio/farmacología
15.
Environ Sci Pollut Res Int ; 27(36): 45270-45281, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32789631

RESUMEN

Deep-water column micronekton play a key role in oceanic food webs and represent an important trophic link between deep- and shallow-water ecosystems. Thus, the potential impacts of sub-surface hydrocarbon plumes on these organisms are critical to developing a more complete understanding of ocean-wide effects resulting from deep-sea oil spills. This work was designed to advance the understanding of hydrocarbon toxicity in several ecologically important deep-sea micronekton species using controlled laboratory exposures aimed at determining lethal threshold exposure levels. The current study confirmed the results previously determined for five deep-sea micronekton by measuring lethal threshold levels for phenanthrene between 81.2 and 277.5 µg/L. These results were used to calibrate the target lipid model and to calculate a critical target lipid body burden for each species. In addition, an oil solubility model was used to predict the acute toxicity of MC252 crude oil to vertically migrating crustaceans, Janicella spinacauda and Euphausiidae spp., and to compare the predictions with results of a 48-h constant exposure toxicity test with passive-dosing. Results confirmed that the tested deep-sea micronekton appear more sensitive than many other organisms when exposed to dissolved oil, but baseline stress complicated interpretation of results.


Asunto(s)
Contaminación por Petróleo , Petróleo , Fenantrenos , Contaminantes Químicos del Agua , Animales , Ecosistema , Océanos y Mares , Petróleo/análisis , Petróleo/toxicidad , Contaminación por Petróleo/análisis , Fenantrenos/toxicidad , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad
16.
J Pharm Pharmacol ; 72(12): 1854-1864, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32478421

RESUMEN

OBJECTIVES: We aimed to determine the diurnal rhythm of Tripterygium wilfordii (TW) hepatotoxicity and to investigate a potential role of metabolism and pharmacokinetics in generating chronotoxicity. METHODS: Hepatotoxicity was determined based on assessment of liver injury after dosing mice with TW at different circadian time points. Circadian clock control of metabolism, pharmacokinetics and hepatotoxicity was investigated using Clock-deficient (Clock-/- ) mice. KEY FINDINGS: Hepatotoxicity of TW displayed a significant circadian rhythm (the highest level of toxicity was observed at ZT2 and the lowest level at ZT14). Pharmacokinetic experiments showed that oral gavage of TW at ZT2 generated higher plasma concentrations (and systemic exposure) of triptolide (a toxic constituent) compared with ZT14 dosing. This was accompanied by reduced formation of triptolide metabolites at ZT2. Loss of Clock gene sensitized mice to TW-induced hepatotoxicity and abolished the time-dependency of toxicity that was well correlated with altered metabolism and pharmacokinetics of triptolide. Loss of Clock gene also decreased Cyp3a11 expression in mouse liver and blunted its diurnal rhythm. CONCLUSIONS: Tripterygium wilfordii chronotoxicity was associated with diurnal variations in triptolide pharmacokinetics and circadian expression of hepatic Cyp3a11 regulated by circadian clock. Our findings may have implications for improving TW treatment outcome with a chronotherapeutic approach.


Asunto(s)
Proteínas CLOCK/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Ritmo Circadiano/efectos de los fármacos , Diterpenos/toxicidad , Hígado/efectos de los fármacos , Fenantrenos/toxicidad , Extractos Vegetales/toxicidad , Tripterygium/toxicidad , Activación Metabólica , Animales , Proteínas CLOCK/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Diterpenos/aislamiento & purificación , Diterpenos/farmacocinética , Compuestos Epoxi/aislamiento & purificación , Compuestos Epoxi/farmacocinética , Compuestos Epoxi/toxicidad , Hígado/metabolismo , Hígado/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fenantrenos/aislamiento & purificación , Fenantrenos/farmacocinética , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacocinética , Toxicocinética
17.
Biomed Pharmacother ; 129: 110427, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32574974

RESUMEN

Triptolide is a multi-functional natural small molecular compound extracted from a traditional Chinese medicinal herb. Triptolide and its derivatives exhibit cytotoxicity through inducing DNA damage, therefore increasing sensitivity to DNA-damage based chemotherapy or radiotherapy in different types of cells. However, the regulatory mechanism of genotoxicity by triptolide, and the loss of genome integrity induced by triptolide are not fully understood. Here, we measured the effects of triptolide on genome integrity in a human fibroblast line HCA2-hTERT using the neutral comet assay. We demonstrated that treating cells with triptolide induced genomic instability in HCA2-hTERT cells. Furthermore, we observed the accumulation of γH2AX foci in triptolide treated cells than control cells at 24 h post ionizing radiation. Further mechanistic studies indicated that triptolide inhibited the enzymatic activity of DNA-PKcs, the critical nonhomologous end joining factor. In vitro kinase activity assays showed that triptolide suppressed the kinase activity of DNA-PKcs and molecular docking also predicted a potential interaction between triptolide and DNA-PKcs. As a consequence, we found that triptolide treatment enhanced the interaction between DNA-PKcs and KU80 and hampered the following recruitment of 53BP1. Altogether, our finding provides a new perspective about the toxicity of triptolide in non-cancer cells and highlights the necessity of taking genome effects of triptolide and its derivatives into consideration in the future clinical and research applications.


Asunto(s)
Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Diterpenos/toxicidad , Fibroblastos/efectos de los fármacos , Inestabilidad Genómica/efectos de los fármacos , Fenantrenos/toxicidad , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular , Proteína Quinasa Activada por ADN/genética , Proteína Quinasa Activada por ADN/metabolismo , Compuestos Epoxi/toxicidad , Fibroblastos/enzimología , Fibroblastos/patología , Histonas/metabolismo , Humanos , Autoantígeno Ku/metabolismo , Fosforilación , Telomerasa/genética , Telomerasa/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo
18.
Eur J Med Chem ; 190: 112079, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-32028140

RESUMEN

A series of novel triptolide/furoxans hybrids were designed and synthesized as analogues of triptolide, which is a naturally derived compound isolated from the thunder god vine (Tripterygium wilfordii Hook. F). Some of these synthesized compounds exhibited antiproliferative activities in the nanomolar range. Among them, compound 33 exhibited both good antiproliferative activity and NO-releasing ability and the acute toxicity of compound 33 decreased more than 160 times (LD50 = 160.9 mg/kg) than triptolide. Moreover, compound 33 significantly inhibited the growth of melanoma at a low dose (0.3 mg/kg) and showed strong anti-inflammatory activity in vitro and in vivo. These results indicate that compound 33 could be a promising candidate for further study.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos/uso terapéutico , Diterpenos/uso terapéutico , Donantes de Óxido Nítrico/uso terapéutico , Fenantrenos/uso terapéutico , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/toxicidad , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Proliferación Celular/efectos de los fármacos , Diterpenos/síntesis química , Diterpenos/toxicidad , Diseño de Fármacos , Compuestos Epoxi/síntesis química , Compuestos Epoxi/uso terapéutico , Compuestos Epoxi/toxicidad , Femenino , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Estructura Molecular , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/toxicidad , Fenantrenos/síntesis química , Fenantrenos/toxicidad , Células RAW 264.7 , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Toxicol Lett ; 318: 1-11, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31618665

RESUMEN

Triptolide (TP), a principal bioactive component extracted from traditional Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted wide attention of its therapeutic effects on inflammation and autoimmune diseases. However, the therapeutic application of TP is hindered by severe cardiomyocyte toxicity and narrow therapeutic window. We previously identified that the p53 was an indispensable contributor in TP-induced myocardial injury. p53 has an inhibitory effect on IKKß-NF-κB pathway that regulates glucose transporters (GLUT) expression. Based on these evidences, we speculate that p53 mediates TP-disturbed glucose uptake by blocking IKKß-NF-κB signaling. This study focused on the effect of TP on cardiac glucose uptake and the role of p53 in glucose metabolism in cardiomyocytes, and p53 -/- mice. TP treatment depressed glucose consumption and ATP production resulting in myocardial damage. Incubation with ATP (5 mM) remarkably decreased the cellular damage. Immunoblotting and immunofluorescence identified that TP suppressed glucose uptake by restricting IKKß-NF-κB signaling activation, GLUT1 and GLUT4 expression. p53 inhibition alleviated the cell damage and the compromise of glucose uptake. Mechanistically, p53 antagonist PFTα abolished TP-induced the inhibition of IKKß, IκBα phosphorylation, p65 nuclear translocation, and GLUT1, GLUT4 expression. Consistently, in acute heart injury models, p53 deficiency upregulated IKKß-NF-κB activation and GLUT1, GLUT4 protein levels which was also indicated as amelioration of heart histological injury after 1.2 mg kg-1 TP administration. The present findings indicate that TP-induced p53 overactivation suppresses glucose uptake by inhibiting IKKß-NF-κB pathway and downregulating NF-κB-dependent GLUT1 and GLUT4 expression.


Asunto(s)
Diterpenos/toxicidad , Glucosa/metabolismo , Cardiopatías/inducido químicamente , Quinasa I-kappa B/metabolismo , Miocitos Cardíacos/efectos de los fármacos , FN-kappa B/metabolismo , Fenantrenos/toxicidad , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Cardiotoxicidad , Línea Celular , Metabolismo Energético/efectos de los fármacos , Compuestos Epoxi/toxicidad , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Cardiopatías/genética , Cardiopatías/metabolismo , Cardiopatías/patología , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética
20.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3468-3477, 2019 Aug.
Artículo en Chino | MEDLINE | ID: mdl-31602911

RESUMEN

Tripterygium wilfordii multiglycoside( GTW),an extract derived from T. wilfordii,has been used for rheumatoid arthritis and other immune diseases in China. However its potential hepatotoxicity has not been investigated completely. Firstly,the content of triptolid( TP) in GTW was 0. 008% confirmed by a LC method. Then after oral administration of GTW( 100,150 mg·kg-1) and TP( 12 µg·kg-1) in female Wistar rats for 24 h,it was found that 150 mg·kg-1 GTW showed more serious acute liver injury than 12 µg·kg-1 TP,with the significantly increased lever of serum ALT,AST,TBA,TBi L,TG and bile duct hyperplasia even hepatocyte apoptosis. The expression of mRNA and proteins of liver bile acid transporters such as BSEP,MRP2,NTCP and OATP were down-regulated significantly by GTW to inhibit bile acid excretion and absorption,resulting in cholestatic liver injury. Moreover,GTW was considered to be involved in hepatic oxidative stress injury,although it down-regulated SOD1 and GPX-1 mRNA expression without significant difference in MDA and GSH levels. In vitro,we found that TP was the main toxic component in GTW,which could inhibit cell viability up to 80% in Hep G2 and LO2 cells at the dose of 0. 1 µmol·L-1. Next a LC-MS/MS method was used to detect the concentration of triptolid in plasma from rats,interestingly,we found that the content of TP in GTW was always higher than in the same amount of TP,suggesting the other components in GTW may affect the TP metabolism. Finally,we screened the substrate of p-glycoprotein( p-gp) in Caco-2 cells treated with components except TP extrated from GTW,finding that wilforgine,wilforine and wilfordine was the substrate of p-gp. Thus,we speculated that wilforgine,wilforine and wilfordine may competitively inhibit the excretion of TP to bile through p-gp,leading to the enhanced hepatotoxity caused by GTW than the same amount of TP.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Diterpenos/toxicidad , Medicamentos Herbarios Chinos/toxicidad , Glicósidos/toxicidad , Fenantrenos/toxicidad , Tripterygium/toxicidad , Animales , Células CACO-2 , Cromatografía Liquida , Compuestos Epoxi/toxicidad , Femenino , Humanos , Hígado/efectos de los fármacos , Extractos Vegetales/toxicidad , Ratas , Ratas Wistar , Espectrometría de Masas en Tándem
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