1,4-Naphthoquinone-coated black carbon nanoparticles up-regulation POR/FTL/IL-33 axis in THP1 cells.

Black carbon (BC) is an important component of atmospheric PM 2.5 and the second largest contributor to global warming. 1,4-naphthoquinone-coated BC (1,4 NQ-BC) is a secondary particle with great research value, so we chose 1,4 NQ-BC as the research object. In our study, mitochondria and lysosomes were selected as targets to confirm whether they were impaired by 1,4 NQ-BC, label free proteomics technology, fluorescent probes, qRT-PCR and western blots were used to investigate the mechanism of 1,4 NQ-BC toxicity. We found 494 differentially expressed proteins (DEPs) in mitochondria and 86 DEPs in lysosomes using a proteomics analysis of THP1 cells after 1,4 NQ-BC exposure for 24 h. Through proteomics analysis and related experiments, we found that 1,4 NQ-BC can damage THP-1-M cells by obstructing autophagy, increasing lysosomal membrane permeability, disturbing the balance of ROS, and reducing the mitochondrial membrane potential. It is worth noting that 1,4 NQ-BC prevented the removal of FTL by inhibiting autophagy, and increased IL-33 level by POR/FTL/IL-33 axis. We first applied proteomics to study the damage mechanism of 1,4 NQ-BC on THP1 cells. Our research will enrich knowledge of the mechanism by which 1,4 NQ-BC damages human macrophages and identify important therapeutic targets and adverse outcome pathways for 1,4 NQ-BC-induced damage.

Effect of combined exposure to environmental aliphatic electrophiles from plants on Keap1/Nrf2 activation and cytotoxicity in HepG2 cells: A model of an electrophile exposome.

Electrophiles, ubiquitously found in the environment, modify thiol groups of sensor proteins, leading to activation of redox signaling pathways such as the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway. Nrf2 activation by exposure to single electrophiles has been established. However, the effect of exposure to a combination of electrophiles on Nrf2 activation has not been well evaluated. The current study examined whether combined exposure to electrophiles enhances the modification of thiol groups and Keap1/Nrf2 activation in HepG2 cells. Six electrophiles [1,2-naphthoquinone (1,2-NQ), 1,4-NQ, 1,4-benzoquinone, (E)-2-hexenal (hexenal), (E)-2-decenal, and (E)-2-butenal] were tested for S-modification of albumin in vitro and for cytotoxicity to HepG2 cells. Interestingly, a mixture of the electrophiles enhanced S-modification of albumin and cytotoxicity compared with exposure to each electrophile separately. Herein, we focused on 1,2-NQ, 1,4-NQ, and hexenal to clarify the combined effect of electrophiles on Keap1/Nrf2 activation in HepG2 cells. A concentration addition model revealed that 1,2-NQ and/or 1,4-NQ additively enhanced hexenal-mediated S-modification of GSH in vitro, whereas the cytotoxicity of hexenal was synergistically increased by simultaneous exposure of HepG2 cells to the NQs. Furthermore, an NQ cocktail (2.5 µM each) that does not activate Nrf2 enhanced hexenal-mediated Nrf2 activation. These results suggest that combined exposure to electrophiles at low concentrations induces stronger activation of redox signaling compared with exposure to each electrophile alone and worsens their cytotoxicity.

Impact of the Potential Antitumor Agent 2-(4-Hydroxyphenyl) Amino-1,4-Naphthoquinone (Q7) on Vasomotion Is Mediated by the Vascular Endothelium, But Not Vascular Smooth Muscle Cell Metabolism.

ABSTRACT: Vasomotion is defined as rhythmic oscillations in arterial diameter that regulate the blood flow and blood pressure. Because antitumor treatment may impair vascular functions and increase the blood pressure, we sought to evaluate whether a new naphthoquinone derivative, postulated as an antitumor agent, manifests adverse effects on vascular function. In this article, we evaluated the toxicity of 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) and its effects on vascular vasomotion in 3 models of vascular structure: endothelial cells, aortic ring, and smooth muscle cells. Although showing nontoxic effects, Q7 inhibited the formation of capillary-like structures of the EA.hy926 endothelial cell line grown on Matrigel. In exvivo experiments with aortic rings precontracted with phenylephrine (PE, 10-6 M), Q7 (10-5 M) significantly (P < 0.05) reduced vascular rhythmic contractions induced by the acetylcholine (ACh; 10-7-10-5 M), whereas sodium nitroprusside (a nitric oxide donor; 10-8 M) recovered the vasomotion. Furthermore, Q7 (10-5 M) did not decrease KCl-induced vascular rhythmic contractions in the aortic rings precontracted with BaCl2 (a nonselective K+ channel blocker; 10-3 M). Vascular smooth muscle cells (A7r5) preincubated with Q7 (10-5 M) for 3 hours also demonstrated a reduced glucose uptake. However, the Adenosine Triphosphate content was unaffected, suggesting that the rapid reduction in vasomotion observed in vascular reactivity experiments did not involve cellular metabolism but may be due to faster mechanisms involving endothelial nitric oxide and K+ channels leading to oscillations in intracellular Ca2+. In summary, the naphthoquinone derivative Q7 presents low cytotoxicity yet may alter the endothelial cell response and vasomotion in the absence of changes in smooth muscle cell metabolism.

Exploration of Benzo[b]carbazole-6,11-diones as anticancer agents: Synthesis and studies of hTopoIIα inhibition and apoptotic effects.

Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoIIα inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative CN and Pd-catalyzed CC bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoIIα inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- κß signaling cascade, relatively less cytotoxicity to normal cells, and hTopoIIα inhibition with more efficiency compared to an anticancer drug etoposide.

Cytotoxicity and antigenotoxicity evaluation of acetylshikonin and shikonin.

Shikonin (SH) is used as a red pigment for food coloring and cosmetics, and has cytotoxic activity towards cancer cells. However, due to strong toxicity SH has limited potential as an anticancer drug. Acetylshikonin (ASH) is one of the SH derivatives with promising anticancer potential. In present study, we attempted to evaluate and compare the cytotoxicity of SH and ASH towards a normal cell line (V79) and in addition to evaluate their antigenotoxic activity. The evaluation was made with the use of the set of cytotoxicity assays with V79 line and the micronucleus test in vitro performed using clinafloxacin (CLFX), ethyl methanesulfonate (EMS) as direct genotoxins and cyclophosphamide (CPA) as indirect genotoxin. For CPA and EMS the simultaneous protocol was used and for CLFX three different variants were performed: pretreatment, simultaneous, and post-treatment. A higher cytotoxic effect was observed for SH. The EC50 values obtained for SH were approximately twofold lower compared to that of ASH. Moreover, ASH exhibited an antigenotoxic potential against CPA-induced genotoxicity, whereas SH has no activity. However, ASH increased the EMS-induced genotoxicity, when SH exhibited no effect. Both compounds decreased the genotoxicity of CLFX in pretreatment and simultaneous protocol. Based on the results of the present study it can be concluded that ASH is less cytotoxic than SH to normal cells and has comparable antigenotoxic potential.

Naphthoquinone-Dopamine Hybrids Inhibit α-Synuclein Aggregation, Disrupt Preformed Fibrils, and Attenuate Aggregate-Induced Toxicity.

Accumulation and aggregation of the intrinsically disordered protein α-synuclein (α-Syn) into amyloid fibrils are hallmarks of a series of heterogeneous neurodegenerative disorders, known as synucleinopathies and most notably Parkinson's disease (PD). The crucial role of α-Syn aggregation in PD makes it an attractive target for the development of disease-modifying therapeutics that would inhibit α-Syn aggregation or disrupt its preformed fibrillar assemblies. To this end, we have designed and synthesized two naphthoquinone-dopamine-based hybrid small molecules, NQDA and Cl-NQDA, and demonstrated their ability to inhibit in vitro amyloid formation by α-Syn using ThT assay, CD, TEM, and Congo red birefringence. Moreover, these hybrid molecules efficiently disassembled preformed fibrils of α-Syn into nontoxic species, as evident from LUV leakage assay. NQDA and Cl-NQDA were found to have low cytotoxicity and they attenuated the toxicity induced by α-Syn towards SH-SY5Y neuroblastoma cells. NQDA was found to efficiently cross an in vitro human blood-brain barrier model. These naphthoquinone-dopamine based derivatives can be an attractive scaffold for therapeutic design towards PD.

PHNQ from Evechinus chloroticus Sea Urchin Supplemented with Calcium Promotes Mineralization in Saos-2 Human Bone Cell Line.

Polyhydroxylated naphthoquinones (PHNQs), known as spinochromes that can be extracted from sea urchins, are bioactive compounds reported to have medicinal properties and antioxidant activity. The MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay showed that pure echinochrome A exhibited a cytotoxic effect on Saos-2 cells in a dose-dependent manner within the test concentration range (15.625-65.5 µg/mL). The PHNQ extract from New Zealand sea urchin Evechinus chloroticus did not induce any cytotoxicity within the same concentration range after 21 days of incubation. Adding calcium chloride (CaCl2) with echinochrome A increased the number of viable cells, but when CaCl2 was added with the PHNQs, cell viability decreased. The effect of PHNQs extracted on mineralized nodule formation in Saos-2 cells was investigated using xylenol orange and von Kossa staining methods. Echinochrome A decreased the mineralized nodule formation significantly (p < 0.05), while nodule formation was not affected in the PHNQ treatment group. A significant (p < 0.05) increase in mineralization was observed in the presence of PHNQs (62.5 µg/mL) supplemented with 1.5 mM CaCl2. In conclusion, the results indicate that PHNQs have the potential to improve the formation of bone mineral phase in vitro, and future research in an animal model is warranted.

Induction of Oxidative Stress and Mitochondrial Dysfunction by Juglone Affects the Development of Bovine Oocytes.

Juglone, a major naphthalenedione component of walnut trees, has long been used in traditional medicine as an antimicrobial and antitumor agent. Nonetheless, its impact on oocyte and preimplantation embryo development has not been entirely clarified. Using the bovine model, we sought to elucidate the impact of juglone treatment during the in vitro maturation (IVM) of oocytes on their maturation and development of embryos. Results showed a severe reduction in oocyte nuclear maturation and cumulus expansion and a significant increase in mitochondrial dysfunction and reactive oxygen species (ROS) levels in cumulus-oocyte complexes (COCs) treated with juglone (12.5, 25.0, and 50.0 µM). In addition, RT-qPCR showed downregulation of the expansion-related (HAS2, TNFAIP6, PTX3, and PTGS2) and mitochondrial (ATPase6 and ATP5F1E) genes in juglone-treated COCs. Moreover, the development rates of day 4 total cleavage and 8-16 cell stage embryos, as well as day 8 blastocysts, were significantly reduced following exposure to juglone. Using immunofluorescence, the apoptotic marker caspase-9 was overexpressed in oocytes exposed to juglone (25.0 µM) compared to the untreated control. In conclusion, our study reports that exposing bovine oocytes to 12.5-50.0 µM of juglone can reduce their development through the direct induction of ROS accumulation, apoptosis, and mitochondrial dysfunction.

Efficacy of lapachol on treatment of cutaneous and visceral leishmaniasis.

Leishmaniasis is one of the most important neglected diseases worldwide. It is a life-threatening disease and causes significant morbidity, long-term disability, and early death. Treatment involves disease control or use of intervention measures, although the currently used drugs require long-lasting therapy, and display toxicity and reduced efficacy. The use of natural products isolated from plants, such as lapachol, an abundant naphthoquinone naturally occurring in South American Handroanthus species (Tabebuia, Bignoniaceae), is a promising option for the treatment of leishmaniasis. In this study, we investigated the leishmanicidal activity of lapachol in vitro and in vivo against Leishmania infantum and L. amazonensis, causative agents of visceral and cutaneous leishmaniasis, respectively. Low cytotoxicity in HepG2 cells (3405.8 ±â€¯261.33 µM), good anti-Leishmania activity, and favorable selectivity indexes (SI) against promastigotes of both L. amazonensis (IC50 = 79.84 ±â€¯9.10 µM, SI = 42.65) and L. infantum (IC50 = 135.79 ±â€¯33.04 µM, SI = 25.08) were observed. Furthermore, anti-Leishmania activity assays performed on intracellular amastigotes showed good activity for lapachol (IC50 = 191.95 µM for L. amazonensis and 171.26 µM for L. infantum). Flow cytometric analysis demonstrated that the cytotoxic effect of lapachol in Leishmania promastigotes was caused by apoptosis-like death. Interestingly, the in vitro leishmanicidal effect of lapachol was confirmed in vivo in murine models of visceral and cutaneous leishmaniasis, as lapachol (25 mg/kg oral route for 24 h over 10 days) was able to significantly reduce the parasitic load in skin lesions, liver, and spleen, similar to amphotericin B, the reference drug. These results reinforce the therapeutic potential of lapachol, which warrants further investigations as an anti-leishmaniasis therapeutic.

Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through up-regulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J2 (PGJ2) or tert-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H2O2-induced IL-11 production, 1,2-NQ, but not 15d-PGJ2 or tBHQ, elicited prolonged ERK activation. Conversely, inhibition of the ERK pathway by a MEK inhibitor completely blocked 1,2-NQ-induced IL-11 production at both protein and mRNA levels, further substantiating an intimate cross-talk between ERK activation and 1,2-NQ-induced IL-11 production. Promoter analysis of the Il11 gene revealed that two AP-1 sites were essential for 1,2-NQ-induced promoter activities. Among various members of the AP-1 family, Fra-1 was up-regulated by 1,2-NQ, and its up-regulation was blocked by a MEK inhibitor. Although NRF2 was not required for H2O2-induced IL11 up-regulation, NRF2 was essential for 1,2-NQ-induced IL11 up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of FOSL1 Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in Il11ra1-/- mice compared with Il11ra1+/- mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.

Antibacterial naphthoquinone derivatives targeting resistant strain Gram-negative bacteria in biofilms.

The aims of this study were the planning, synthesis and in vitro evaluation of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Gram-negative and Gram-positive strains, searching for potential lead compounds against bacterial biofilm formation. A series of 12 new analogs of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones were synthesized by adding a thiol and different substituents to a ο-quinone methide using microwave irradiation. The compounds were tested against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. simulans ATCC 27851, S. epidermidis ATCC 12228 and a hospital Methicillin-resistant S. aureus (MRSA) strain), as well as Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa ATCC 15442, Proteus mirabilis ATCC 15290, Serratia marcescens ATCC 14756, Klebsiella pneumoniae ATCC 4352 and Enterobacter cloacae ATCC 23355) strains, using the disk diffusion method. Ten compounds showed activity mainly against Gram-negative strains with a minimal inhibitory concentration (MIC = 4-64 µg/mL) within the Clinical and Laboratory Standards Institute (CLSI) levels. The biofilm inhibition data showed compounds, 9e, 9f, 9j and 9k, are anti-biofilm molecules when used in sub-MIC concentrations against P. aeruginosa ATCC 15442 strain. Compound (9j) inhibited biofilm formation up to 63.4% with a better profile than ciprofloxacin, which is not able to prevent biofilm formation effectively. The reduction of P. aeruginosa ATCC 15442 mature biofilms was also observed for 9e and 9k. The structure modification applied in the series resulted in 12 new naphthoquinones with antimicrobial activity against Gram-negative bacteria strains (E. coli ATCC 25922, P. aeruginosa ATCC 27853 and ATCC 15442). Four compounds decreased P. aeruginosa biofilm formation effectively.

Expressions of some antioxidant genes in SH-SY5Y cells treated with ß-lapachone, morphine and electromagnetic field.

ß-Lapachone (ß-Lap), morphine (Mor), and electromagnetic field (EMF) generate reactive oxygen species. The goal of the present study was to examine the effects of Mor and EMF, in combination with ß-Lap on the cell growth inhibition and expression of several antioxidant genes. The 0.50 mT intensity of 50 Hz EMF and two exposure conditions ("15 min field-on/15 min field-off" and "30 min field-on continuously") on SH-SY5Y cells were used. The effects of Mor and EMF, in combination with ß-Lap on cell growth inhibition and the expression levels of several antioxidant genes (NQO1, NQO2, SOD1, SOD2, CAT, GSTO1, GSTM2, GSTM3, GSTP1, MGST1, MGST3) in SH-SY5Y cells were measured. The relative mRNA levels were calculated according to the [Formula: see text]. Whereas NQO1 mRNA level decreased in the "15 min field-on/15 min field-off" condition, the expression level of NQO2 was increased. Both NQO1 and NQO2 expressions increased in Mor treated cells. IC50 values of ß-Lap in combination with Mor, EMF, and "Mor + EMF" were higher than cells treated only with ß-Lap. The NQO1 expression level in the cells treated with ß-Lap was higher than the other treatments, indicating that ß-Lap induces the expression of NQO1. Moreover, multiple linear regression analysis indicated that NQO1 mRNA levels were associated positively with ß-Lap and negatively with EMF. At least in part, the mRNA levels of NQO1 were associated with IC50 values of ß-Lap in designed treatments. There is a negative association between mRNA levels of NQO1 and IC50 values of ß-Lap but not NQO2.

Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells.

Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.

Evaluation on the leishmanicidal activity of 2-N,N'-dialkylamino-1,4-naphthoquinone derivatives.

Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. In this study was evaluated in vitro leishmanicidal activity of 2-N,N'-dialkylamino-1,4-naphthoquinone derivatives, covering a series of fourteen 2-N-morpholino-, 2-N-thiomorpholino, 2-N-piperidino, 2-N-(N4-methyl)-piperazino naphthoquinones (1a-n) derived from nor-lapachol and lawsone, belong to some other di-alkyaminoderivatives. At the cytotoxicity assay on peritoneal macrophages, the compounds possessing larger alkyl groups and N-methyl-piperazino moiety (1d, 1h, 1i and 1k), showed toxic effects similar to the standard drug used pentamidine. However, the other compounds of the series showed no deleterious effect on the host cell. Meanwhile, these cytotoxic derivatives (1d, 1h and 1i) had pronounced leishmanicidal activity against L. amazonensis promastigotes, and treatments with six other compounds (1d, 1e, 1f, 1h, 1k and 1n) had significant effect leishmanicidal against L. chagasi promastigotes. In the assay against L. chagasi amastigotes, eight compounds (1a, 1b, 1c, 1d, 1h, 1i, 1k and 1m) showed significant activity. Moreover, the compounds (1a, 1b, 1c, and 1m) showed effect against amastigotes of L. chagasi and not being toxic to the host cell. These data show the derivatives as promising substances for research leishmanicidal activity.

Improvement of cyanobacterial-killing biologically derived substances (BDSs) using an ecologically safe and cost-effective naphthoquinone derivative.

In previous studies, naphthoquinone (NQ) compounds have been shown to be effective, selective, and ecologically safe algicides for controlling harmful algal blooming species (HABs) or winter bloom species, such as Stephanodiscus hantzschii. However, there are no reports on NQ-based algicides for use with cyanobacterial blooming species. In this study, we developed 31 NQ compounds to investigate algicides for mitigating cyanobacterial blooms. In addition, to better apply these compounds in the field, we reduced the number of production steps to develop a cost-effective algicide. In preliminary testing, we screened NQ compounds that showed the best algicidal activity on target cyanobacteria, including Aphanizomenon, Dolichospermum, Microcystis, Oscillatoria, and Nostoc species. The compound NQ 2-0 showed the highest algicidal activity (90%) at a low concentration (≥1µM) on target algae. These were very limiting algicidal effects of 1µM NQ 2-0 observed against non-target algae, such as diatoms (Stephanodiscus hantzschii, Cyclotella meneghiniana, Synedra acus, and Aulacoseira granulata) or green algae (Cosmarium bioculatum and Scenedesmus quadricauda), and the effect did not exceed 15-25% (except against S. quadricauda). NQ 2-0 (1µM) showed no eco-toxicity, as represented by the survival rates of Pseudokirchneriella subcapitata (100%), Daphnia magna (100%), and Danio rerio (100%). Additionally, a chronic eco-toxicity assessment showed no toxicity toward the survival, growth or reproduction of D. magna. Moreover, NQ 2-0 quickly dissipated from field water samples and had a half-life of approximately 3.2 days. These results suggest that NQ 2-0 could be a selective and ecologically safe algicide to mitigate harmful cyanobacterial blooms.

Synergistic effect of carbon nuclei and polyaromatic hydrocarbons on respiratory and immune responses.

Particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5 ) is generally composed of carbon nuclei associated with various organic carbons, metals, ions and biological materials. Among these components, polyaromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) and quinones have detrimental effects on airway epithelial cells and immunodisrupting effects, which leads to the exacerbation of respiratory allergies. The effects of PAHs and the carbon nuclei, separately as well as in combination, remain to be established. We investigated the effects of BaP, 9,10-phenanthroquinone (9,10-PQ), and 1,2-napthoquinone (1,2-NQ) and their combined effects with heated diesel exhaust particle (H-DEP) as carbon nuclei of typical PM2.5 . We exposed human airway epithelial cells (BEAS-2B), murine bone marrow-derived antigen-presenting cells (APCs), and murine splenocytes to BaP, 9,10-PQ, or 1,2-NQ in the presence and absence of H-DEP. Several important inflammatory cytokines and cell surface molecules were measured. PAHs alone did not have apparent cytotoxic effects on BEAS-2B, whereas combined exposure with H-DEP induced noticeable detrimental effects which mainly reflected the action of H-DEP itself. BaP increased CD86 expression as an APC surface molecule regardless of the presence or absence of H-DEP. None of the BaP, 9,10-PQ, or 1,2-NQ exposure alone or their combined exposure with H-DEP resulted in any significant activation of splenocytes. These results suggest that PAHs and carbon nuclei show additive effects, and that BaP with the carbon nuclei may contribute to exacerbations of allergic respiratory diseases including asthma by PM2.5 , especially via antigen-presenting cell activation.

[Dangerous cosmetic products in Germany : Analysis of the RAPEX database of the European Commission]. / Gefährliche Kosmetikprodukte in Deutschland : Analyse der RAPEX-Datenbank der Europäischen Kommission.

BACKGROUND: Cosmetic products are subject to the European Cosmetics Regulation: They shall not harm human health when used under "normal or reasonably foreseeable conditions". Hazardous cosmetic products are reported by the EU Member States to the EU Commission and are listed in the database of the European Rapid Alert System RAPEX. MATERIAL AND METHODS: The reports from Germany on dangerous cosmetic products from the years 2005-3/2017 in the European RAPEX database were systematically analyzed. RESULTS: During the study period, 157 dangerous cosmetic products were reported from Germany. The most common product categories were bleaching creams (24.2%) because of the content of hydroquinone, mercury or corticosteroids, creams/lotions/gels (10.8%) mainly due to microbiological contamination, henna products (10.2%) because of sensitizing concentrations of paraphenylene diamine, and nail adhesives (8.9%) because of high levels of methyl methacrylate. CONCLUSIONS: Hazardous cosmetic products appear to be rare in view of the high market volume of cosmetics, even though the total number of official investigations the RAPEX reports based on is not known. Dermatologists should inform the competent monitoring authorities in case of a suspected harm to health caused by dangerous cosmetic products so that the products can be examined and, if necessary, withdrawn from the market.

Adverse Outcome Pathway (AOP) Informed Modeling of Aquatic Toxicology: QSARs, Read-Across, and Interspecies Verification of Modes of Action.

Alternative approaches have been promoted to reduce the number of vertebrate and invertebrate animals required for the assessment of the potential of compounds to cause harm to the aquatic environment. A key philosophy in the development of alternatives is a greater understanding of the relevant adverse outcome pathway (AOP). One alternative method is the fish embryo toxicity (FET) assay. Although the trends in potency have been shown to be equivalent in embryo and adult assays, a detailed mechanistic analysis of the toxicity data has yet to be performed; such analysis is vital for a full understanding of the AOP. The research presented herein used an updated implementation of the Verhaar scheme to categorize compounds into AOP-informed categories. These were then used in mechanistic (quantitative) structure-activity relationship ((Q)SAR) analysis to show that the descriptors governing the distinct mechanisms of acute fish toxicity are capable of modeling data from the FET assay. The results show that compounds do appear to exhibit the same mechanisms of toxicity across life stages. Thus, this mechanistic analysis supports the argument that the FET assay is a suitable alternative testing strategy for the specified mechanisms and that understanding the AOPs is useful for toxicity prediction across test systems.

Cratoxylum formosum Extract Protects against Amyloid-Beta Toxicity in a Caenorhabditis elegans Model of Alzheimer's Disease.

Amyloid-ß, one of the hallmarks of Alzheimer's disease, is toxic to neurons and causes cell death in the brain. Oxidative stress is known to play an important role in Alzheimer's disease, and there is strong evidence linking oxidative stress to amyloid-ß. The herbal plant "Tiew kon" (Cratoxylum formosum ssp. pruniflorum) is an indigenous vegetable that is grown in Southeast Asia. Many reports suggested that the twig extract from C. formosum possesses an antioxidant property. The purpose of this study was to investigate the protective effect of the twig extract from C. formosum against amyloid-ß toxicity using the transgenic Caenorhabditis elegans model. This study demonstrated that the extract significantly delayed amyloid-ß-induced paralysis in the C. elegans model of Alzheimer's disease. Using a genetic approach, we found that DAF-16/FOXO transcription factor, heat shock factor 1, and SKN-1 (Nrf2 in mammals) were required for the extract-mediated delayed paralysis. The extract ameliorated oxidative stress by reducing the level of H2O2, which appeared to account for the protective action of the extract. The extract possesses antioxidant activity against juglone-induced oxidative stress as it was shown to increase survival of the stressed worms. In addition, C. formosum decreased the expression of the heat shock protein-16.2 gene which was induced by thermal stress, indicating its ability to reduce cellular stress. The results from this study support the C. elegans model in the search for disease-modifying agents to treat Alzheimer's disease and indicate the potential of the extract from C. formosum ssp. pruniflorum as a source for the development of anti-Alzheimer's drugs.

Stability of ß-Lapachone upon Exposure to Various Stress Conditions: Resultant Efficacy and Cytotoxicity.

Even though ß-lapachone is a promising compound with antitumor, antiinflammatory, antineoplastic, and wound-healing effects, there are still issues concerning its chemical stability and degradation mechanisms. The objective of this study was to obtain degradation profiles of ß-lapachone and evaluate its chemical stability under various stress conditions. Moreover, the correlation between stability and efficacy was evaluated. The degradation study of ß-lapachone was performed using heat, acid, base, oxidation, and light conditions. Kinetics and degradation profiles were investigated with HPLC and LC-MS. The stability indicated in the LC method was validated according to the International Conference on Harmonization guidelines. Human dermal fibroblast (HDF) cells were cultured with the standard and its degraded samples in the cellular activity and cytotoxicity test. ß-Lapachone was relatively unstable upon exposure to light, and its photodegradation was accelerated with high relative humidity. Three degradants were identified, and their degradation followed zero-order kinetics. It was shown to degrade to phthalic acid under oxidative conditions, and the degradation kinetics were dependent on the concentration of hydrogen peroxide. Two degradation products were identified upon exposure to basic conditions, which followed first-order kinetics. ß-Lapachone was relatively stable under acidic and thermal conditions. It increased the synthesis of collagen compared with the control. However, as the contents decreased, the synthesis of collagen also decreased in the photodegraded samples. ß-Lapachone did not exert cytotoxic effects at the effective concentration in the cytotoxicity test. Therefore, in order to ensure efficacy and safety, the chemical stability of ß-lapachone needs to be controlled carefully while considering instability mechanisms.