The first X-ray crystal structures of nickel(II) and copper(II) salphen metal complexes bound to a quadruplex DNA are presented. Two structures have been determined and show that these ...salphen–metal complexes bind to human telomeric quadruplexes by end-stacking, with the metal in each case almost in line with the potassium ion channel. Quadruplex and duplex DNA binding is presented for these two and other related salphen complexes, all with side-chains terminating in pyrrolidino end-groups and differing patterns of substitution on the salphen core. The crystal structures are able to provide rationalizations for the structure–activity data, and in particular for the superior quadruplex-binding of the nickel complexes compared to that of the copper-containing ones. The complexes show significant antiproliferative activity for the compounds in a panel of cancer cell lines. They also show telomerase inhibitory activity in the telomerase TRAP-LIG assay.
Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington’s disease (HD), ...periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.
Background
Allergic contact dermatitis has been described as a type IV reaction caused by antigen‐specific T cells. Central roles for CD8+ cytotoxic T cells as effector cells and CD4+ T cells as ...regulatory cells have been suggested. T helper (Th) 2 and Th1 cytokines have been implicated; however, the nature of the allergen influences the Th response.
Objective
To determine the types of T cells and cytokines expressed in patients allergic to p‐phenylenediamine (PPD).
Methods
Serial skin biopsies of areas with positive patch test reactions in 29 PPD‐sensitized patients were collected. T cell markers and cytokine expression were analysed by flow cytometry and quantitative reverse transcription polymerase chain reaction in both skin and peripheral blood mononuclear cells (PBMCs) of sensitized patients.
Results
We observed increased expression of T cell markers and Th2/Th9‐associated cytokines in both skin and stimulated PBMCs of PPD‐allergic patients. Moreover, interleukin (IL)‐9 was mainly produced by Th9 cells, in both skin and PBMCs. Further investigations showed that Il9r‐deficient mice were more affected in a PPD contact hypersensitivity model than wild‐type mice.
Conclusion
We did not confirm the preclinical presence of CD8+ T cells. However, the expression of different T cell markers positively correlated with patch test reactions. IL‐9 expression was strongly upregulated and directly related to patch test severity. In addition, we showed that IL‐9 has an anti‐inflammatory role in a mouse model of PPD contact hypersensitivity.
Urban stormwater runoff frequently contains the car tire transformation product 6PPD-quinone, which is highly toxic to juvenile and adult coho salmon (Onchorychus kisutch). However, it is currently ...unclear if embryonic stages are impacted. We addressed this by exposing developing coho salmon embryos starting at the eyed stage to three concentrations of 6PPD-quinone twice weekly until hatch. Impacts on survival and growth were assessed. Further, whole-transcriptome sequencing was performed on recently hatched alevin to address the potential mechanism of 6PPD-quinone-induced toxicity. Acute mortality was not elicited in developing coho salmon embryos at environmentally measured concentrations lethal to juveniles and adults, however, growth was inhibited. Immediately after hatching, coho salmon were sensitive to 6PPD-quinone mortality, implicating a large window of juvenile vulnerability prior to smoltification. Molecularly, 6PPD-quinone induced dose-dependent effects that implicated broad dysregulation of genomic pathways governing cell–cell contacts and endothelial permeability. These pathways are consistent with previous observations of macromolecule accumulation in the brains of coho salmon exposed to 6PPD-quinone, implicating blood–brain barrier disruption as a potential pathway for toxicity. Overall, our data suggests that developing coho salmon exposed to 6PPD-quinone are at risk for adverse health events upon hatching while indicating potential mechanism(s) of action for this highly toxic chemical.
Opisthorchiasis, caused by the foodborne trematode
, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao People's Democratic Republic, ...pharmacokinetic samples were obtained from 125 adult and adolescent
-infected patients treated with 400 mg tribendimidine following the design of a sparse sampling scheme at 20 min and 2, 7.75, 8, and 30 h after treatment using dried blood spot sampling. Pharmacokinetic data for the metabolites deacetylated amidantel (dADT) and acetylated dADT (adADT) were pooled with data from two previous ascending-dose trials and evaluated using nonlinear mixed-effects modeling. The observed pharmacokinetic data were described using a flexible transit absorption model for the active metabolite dADT, followed by one-compartment disposition models for both metabolites. Significant covariates were age, body weight, formulation, and breaking of the enteric coating on the tablets. There were significant associations between
cure and both the dADT maximum concentration and the area under the concentration-time curve (
< 0.001), with younger age being associated with a higher probability of cure. Modeling and simulation of exposures in patients with different weight and age combinations showed that an oral single dose of 400 mg tribendimidine attained therapeutic success in over 90% of adult patients. Our data confirmed that tribendimidine could be a valuable novel alternative to the standard treatment, praziquantel, for the treatment of
infections.
We demonstrate a rationally designed fluorescent and colorimetric dual-readout strategy for the highly sensitive, quantitative determination of inorganic pyrophosphatase (PPase) activity, a key ...hydrolytic enzyme involved in a variety of metabolic processes. Inspired by the selective oxidative and chromogenic reaction of o-phenylenediamine (OPD) with Cu(2+), the special inhibitory effects of pyrophosphate (PPi) on the oxidative ability of Cu(2+), and the specific hydrolysis of PPi into orthophosphate by PPase, a convenient small molecule OPD-based analytical system was developed for Cu(2+)/PPi recognition and PPase activity assay. We have confirmed that Cu(2+) acts as the oxidant in the reaction and the main chromogenic product of OPD is 2,3-diaminophenazine (usually called OPDox) in the assay by combining the ESI-MS, (1)H NMR, and XPS spectra analysis. Direct electrochemical insights into the Cu(2+)-triggered and PPi-inhibited mechanism were performed by cyclic voltammetry characterizations of the Cu(2+) in the absence and presence of PPi for the first time. Furthermore, the proposed analytical system with clear response mechanism exhibits a promising outlook for the PPase activity assay in real biological samples and inhibitor screening.
Tire tread particles (TTP) are environmentally prevalent microplastics and generate toxic aqueous leachate. We determined the total carbon and nitrogen leachate concentrations and chemical profiles ...from micron (∼32 μm) and centimeter (∼1 cm) TTP leachate over 12 days. Dissolved organic carbon (DOC) and total dissolved nitrogen (TDN) were used to measure the concentration of leached compounds. Nontargeted chemical analysis by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC/TOF-MS) was used to compare the chemical profiles of leachates. After leaching for 12 days, DOC was 4.0 times higher in the micron TTP leachate than in the centimeter TTP leachate, and TDN was 2.6 times higher. The total GC×GC/TOF-MS chromatographic feature peak area was 2.9 times greater in the micron TTP leachate than the centimeter TTP leachate, and similarly, the total relative abundance of 54 tentatively identified compounds was 3.3 times greater. We identified frequently measured tire-related chemicals, such as 6PPD, N-cyclohexyl-N′-phenylurea (CPU), and hexa(methoxymethyl)melamine (HMMM), but nearly 50% of detected chemicals were not previously reported in tire literature or lacked toxicity information. Overall, the results demonstrate that smaller TTP have a greater potential to leach chemicals into aquatic systems, but a significant portion of these chemicals are not well-studied and require further risk assessment.
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•Using nontargeted GC × GC/TOF-MS, we detected 60 compounds in tire leachate.•Micron TTP leached 4x and 2.6x more DOC and TDN, respectively, than centimeter-size TTP.•38% of compounds were significantly more abundant in the micron TTP leachate.•∼50% of identified TTP leachate constituents were not previously described in tire literature.
Nitroreductase activities are positively associated with the hypoxic level of tumors, making it an attractive target for tumor detection. Herein, we have developed a ...2,5-bis(methylsulfinyl)-1,4-diaminobenzene based probe (BBP), which is a nitroreductase (NTR) responsive fluorescent probe and can rapidly detect NTRs with high sensitivity and specificity. The BBP showed not only a selective response to NTRs over other biological reductants, but also high sensitivity to NTRs and could detect as low as 20 ng mL-1 NTRs. Furthermore, the BBP responded rapidly to NTRs in as fast as 10 minutes, enabling real-time monitoring of the production levels of NTRs. Most importantly, the BBP could identify NTR activities in 2D cell monolayers, 3D tumor spheroids, and even solid tumors in mice. Particularly, the BBP could monitor the early tumor formation and treatment response via measuring NTR activities. Overall, the BBP appears to be an ideal imaging probe for the detection of solid tumors, and possesses great potential in a broad range of diagnostic and therapeutic applications in the clinic.
Summary
Background
Contact allergy in children is becoming increasingly recognized as a cause of eczema. The causal agents may change with time, but there are few comparative data for this age group.
...Objectives
To compare data from the past 10 years with a similar study from the previous decade.
Methods
Between 2005 and 2014, 500 consecutive children who had been patch tested at Leeds Teaching Hospitals were identified, and the results were reviewed.
Results
Twenty‐seven per cent (134 cases) of children had one or more positive patch test findings. The mean ± standard deviation age of patients with a positive test reaction was 11.9 ± 4.1 years, which was significantly higher than that of patients with a negative result (10.9 ± 4.0 years) (p = 0.01; Mann–Whitney U‐test). No significant relationship between sex and a positive patch test result was found (p = 0.48, chi‐squared). Allergy to nickel was the most frequent finding, although this accounted for 18%, rather than 33% (1995–2004), of all positive reactions. The next most common allergens included fragrance mix 1 (17%), p‐phenylenediamine (16%), and methylchloroisothiazolinone/methylisothiazolinone (6%).
Conclusions
Although the overall incidence of contact allergy in our paediatric population is static, there has been a significant change in the allergens detected, probably as a result of changes in European legislation and cosmetic product use in children.
p‐Phenylenediamine (PPD) (1,4‐diaminobenzene; CAS no. 106‐50‐3) is well known as key allergen in hair dye‐related allergic contact dermatitis. PPD can be N‐acetylated to the non‐sensitizing compounds ...mono‐PDD (MAPPD) and diacetyl‐PPD (DAPPD) by N‐acetyltransferase 1 (NAT1) in keratinocytes,1 and outside the skin also by N‐acetyltransferase 2 (NAT2).2 When investigating the elicitation response modification by NAT1 and NAT2 genotypes, we showed that genotypes containing the rapid acetylator allele NAT1*10 and individuals homozygous for the rapid acetylator allele NAT2*4 were under‐represented among PPD‐sensitized cases.3 Here, we evaluated this finding by investigating two well‐characterized highly sensitive cases with a longstanding history of allergic contact dermatitis caused by dyes.
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