The clinical application of chemodynamic therapy is impeded by the insufficient intracellular H2O2 level in tumor tissues. Herein, we developed a supramolecular nanoparticle via a simple one‐step ...supramolecular polymerization‐induced self‐assembly process using platinum (IV) complex‐modified β‐cyclodextrin‐ferrocene conjugates as supramolecular monomers. The supramolecular nanoparticles could dissociate rapidly upon exposure to endogenous H2O2 in the tumor and release hydroxyl radicals as well as platinum (IV) prodrugs in situ, which is reduced into cisplatin to significantly promote the generation of H2O2 in the tumor tissue. Thus, the supramolecular nanomedicine overcomes the limitation of conventional chemodynamic therapy via the self‐augmented cascade radical generation and drug release. In addition, dissociated supramolecular nanoparticles could be readily excreted from the body via renal clearance to effectively avoid systemic toxicity and ensure long term biocompatibility of the nanomedicine. This work may provide new insights on the design and development of novel supramolecular nanoassemblies for cascade chemo/chemodynamic therapy.
We reported a one‐pot supramolecular polymerization‐induced self‐assembly approach to fabricate H2O2‐responsive nanomedicine with highly controllable drug loading and rapid clearance for self‐augmented synergistic chemo/chemodynamic cancer therapy.
While conventional parameters used to detect hepatotoxicity in drug safety assessment studies are generally informative, the need remains for parameters that can detect the potential for ...hepatotoxicity at lower doses and/or at earlier time points. Previous work has shown that metabolite profiling (metabonomics/metabolomics) can detect signals of potential hepatotoxicity in rats treated with doxorubicin at doses that do not elicit hepatotoxicity as monitored with conventional parameters. The current study extended this observation to the question of whether such signals could be detected in rats treated with compounds that can elicit hepatotoxicity in humans (i.e., drug-induced liver injury, DILI) but have not been reported to do so in rats. Nine compounds were selected on the basis of their known DILI potential, with six other compounds chosen as negative for DILI potential. A database of rat plasma metabolite profiles, MetaMap®Tox (developed by metanomics GmbH and BASF SE) was used for both metabolite profiles and mode of action (MoA) metabolite signatures for a number of known toxicities. Eight of the nine compounds with DILI potential elicited metabolite profiles that matched with MoA patterns of various rat liver toxicities, including cholestasis, oxidative stress, acetaminophen-type toxicity and peroxisome proliferation. By contrast, only one of the six non-DILI compounds showed a weak match with rat liver toxicity. These results suggest that metabolite profiling may indeed have promise to detect signals of hepatotoxicity in rats treated with compounds having DILI potential.
Abstract Objective This study was performed to evaluate the biocompatibility of nine types of pure metal ingots (Ag, Al, Cr, Cu, Mn, Mo, Nb, V, Zr) and 36 experimental titanium (Ti) alloys containing ...5, 10, 15, and 20 wt% of each alloying element. Methods The cell viabilities for each test group were compared with that of CP-Ti using the WST-1 test and agar overlay test. Results The ranking of pure metal cytotoxicity from most potent to least potent was as follows: Cu > Al > Ag > V > Mn > Cr > Zr > Nb > Mo > CP-Ti. The mean cell viabilities for pure Cu, Al, Ag, V, and Mn were 21.6%, 25.3%, 31.7%, 31.7%, and 32.7%, respectively, which were significantly lower than that for the control group ( p < 0.05). The mean cell viabilities for pure Zr and Cr were 74.1% and 60.6%, respectively ( p < 0.05). Pure Mo and Nb demonstrated good biocompatibility with mean cell viabilities of 93.3% and 93.0%, respectively. The mean cell viabilities for all the Ti-based alloy groups were higher than 80% except for Ti–20Nb (79.6%) and Ti–10V (66.9%). The Ti–10Nb alloy exhibited the highest cell viability (124.8%), which was higher than that of CP-Ti. Based on agar overlay test, pure Ag, Cr, Cu, Mn, and V were ranked as ‘moderately cytotoxic’, whereas the rest of the tested pure metals and all Ti alloys, except Ti–10V (mild cytotoxicity), were ranked as ‘noncytotoxic’. Significance The results obtained in this study can serve as a guide for the development of new Ti-based alloy implant systems.
Neonicotinoid insecticides are environmentally persistent and highly water-soluble, and thus are prone to leaching into surface waters where they may negatively affect non-target aquatic insects. ...Most of the research to date has focused on imidacloprid, and few data are available regarding the effects of other neonicotinoids or their proposed replacements (butenolide insecticides). The objective of this study was to assess the toxicity of six neonicotinoids (imidacloprid, thiamethoxam, acetamiprid, clothianidin, thiacloprid, and dinotefuran) and one butenolide (flupyradifurone) to Hexagenia spp. (mayfly larvae). Acute (96-h), water-only tests were conducted, and survival and behaviour (number of surviving mayflies inhabiting artificial burrows) were assessed. Acute sublethal tests were also conducted with imidacloprid, acetamiprid, and thiacloprid, and in addition to survival and behaviour, mobility (ability to burrow into sediment) and recovery (survival and growth following 21 d in clean sediment) were measured. Sublethal effects occurred at much lower concentrations than survival: 96-h LC50s ranged from 780 μg/L (acetamiprid) to >10,000 μg/L (dinotefuran), whereas 96-h EC50s ranged from 4.0 μg/L (acetamiprid) to 630 μg/L (thiamethoxam). Flupyradifurone was intermediate in toxicity, with a 96-h LC50 of 2000 μg/L and a 96-h EC50 of 81 μg/L. Behaviour and mobility were impaired significantly and to a similar degree in sublethal exposures to 10 μg/L imidacloprid, acetamiprid, and thiacloprid, and survival and growth following the recovery period were significantly lower in mayflies exposed to 10 μg/L acetamiprid and thiacloprid, respectively. A suite of effects on mayfly swimming behaviour/ability and respiration were also observed, but not quantified, following exposures to imidacloprid, acetamiprid, and thiacloprid at 1 μg/L and higher. Imidacloprid concentrations measured in North American surface waters have been found to meet or exceed those causing toxicity to Hexagenia, indicating that environmental concentrations may adversely affect Hexagenia and similarly sensitive non-target aquatic species.
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•Toxicity of neonicotinoid and butenolide insecticides was assessed in Hexagenia.•Differences in toxicity occurred among compounds and endpoints (>2700-fold).•Behaviour and mobility endpoints were more sensitive than lethality.•Acute acetamiprid and thiacloprid exposures caused long-term impacts.•Effects of imidacloprid were observed at environmentally relevant concentrations.
The sublethal toxicity of neonicotinoids to Hexagenia varies 160-fold, with imidacloprid, acetamiprid, and thiacloprid being the most toxic.
Pesticide impacts are usually discussed in the context of applied amounts while disregarding the large but environmentally relevant variations in substance-specific toxicity. Here, we systemically ...interpret changes in the use of 381 pesticides over 25 years by considering 1591 substance-specific acute toxicity threshold values for eight nontarget species groups. We find that the toxicity of applied insecticides to aquatic invertebrates and pollinators has increased considerably-in sharp contrast to the applied amount-and that this increase has been driven by highly toxic pyrethroids and neonicotinoids, respectively. We also report increasing applied toxicity to aquatic invertebrates and pollinators in genetically modified (GM) corn and to terrestrial plants in herbicide-tolerant soybeans since approximately 2010. Our results challenge the claims of a decrease in the environmental impacts of pesticide use.
•Exposure to EDCs is associated with global DNA demethylation in murine N2A neuroblastoma cells.•Adipocyte differentiation in vitro is accompanied by global DNA demethylation.•Flame retardant BDE47 ...increases adipocyte differentiation in murine 3T3-L1 cells.•TBT induces both global DNA demethylation and adipocyte differentiation in vitro.
Recent studies suggest that endocrine disrupting chemicals (EDCs) may form a risk factor for obesity by altering energy metabolism through epigenetic gene regulation. The goal of this study is to investigate the effects of a range of EDCs with putative obesogenic properties on global DNA methylation and adipocyte differentiation in vitro. Murine N2A and human SK-N-AS neuroblastoma cells and murine preadipocyte fibroblasts (3T3-L1) were exposed to tributyltin (TBT), diethylstilbestrol (DES), bisphenol A (BPA), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153), hexachlorobenzene (HCB), hexabromocyclododecane (HBCD), 2,2′,4,4′-tetrabrominated diphenyl ether (BDE-47) , perfluorinated octyl acid (PFOA) and perfluorinated octyl sulfonate (PFOS). A modest decrease in global DNA methylation was observed in N2A cells exposed to 10μM DES, BPA, TCDD, BDE-47, PCB-153 and 1μM HCB, but no changes were found in the human SK-N-AS cells. We reveal for the first time that BDE-47 increases adipocyte differentiation in a dose-dependent manner (2.5–25μM). Adipocyte differentiation was also enhanced by TBT (⩾10nM) and BPA (>10μM) and inhibited by TCDD (⩾0.1nM). The other chemicals showed either modest or no effects on adipocyte differentiation at the concentrations tested (PFOA, PFOS and HBCD at 10μM; PCB-153, 3.4μM and HCB, 1μM). This study demonstrates that selected EDCs can induce functional changes in murine adipocyte differentiation in vitro which are accompanied by decreased global DNA methylation.
•Mixtures of similar MoA chemicals increased BDNF levels and neurite outgrowth.•Mixtures of similar MoA chemicals decreased synapse formation and electrical activity.•Synergistic effects on ...synaptogenesis features was predicted by mathematical modelling.•Some of the DNT effects observed in hiPSC-neurons/astrocytes recapitulate ASD features.•In vitro assays combined with mathematical modelling enable DNT testing of chemical mixtures.
Prenatal and postnatal co-exposure to multiple chemicals at the same time may have deleterious effects on the developing nervous system. We previously showed that chemicals acting through similar mode of action (MoA) and grouped based on perturbation of brain derived neurotrophic factor (BDNF), induced greater neurotoxic effects on human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes compared to chemicals with dissimilar MoA. Here we assessed the effects of repeated dose (14 days) treatments with mixtures containing the six chemicals tested in our previous study (Bisphenol A, Chlorpyrifos, Lead(II) chloride, Methylmercury chloride, PCB138 and Valproic acid) along with 2,2′4,4′-tetrabromodiphenyl ether (BDE47), Ethanol, Vinclozolin and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)), on hiPSC-derived neural stem cells undergoing differentiation toward mixed neurons/astrocytes up to 21 days. Similar MoA chemicals in mixtures caused an increase of BDNF levels and neurite outgrowth, and a decrease of synapse formation, which led to inhibition of electrical activity. Perturbations of these endpoints are described as common key events in adverse outcome pathways (AOPs) specific for DNT. When compared with mixtures tested in our previous study, adding similarly acting chemicals (BDE47 and EtOH) to the mixture resulted in a stronger downregulation of synapses. A synergistic effect on some synaptogenesis-related features (PSD95 in particular) was hypothesized upon treatment with tested mixtures, as indicated by mathematical modelling. Our findings confirm that the use of human iPSC-derived mixed neuronal/glial models applied to a battery of in vitro assays anchored to key events in DNT AOP networks, combined with mathematical modelling, is a suitable testing strategy to assess in vitro DNT induced by chemical mixtures.
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