Oxidant-dependent antioxidant activity of polydopamine films: The chemistry-morphology interplay

Polydopamine (PDA) films allow to functionalize almost all materials with a conformal and chemically active coating. These coatings can react with reducible metallic cations and with all kinds of molecules carrying nucleophilic groups. Recently, our team extended PDA chemistry to a vast repertoire of oxidants and to acidic conditions. However, the influence of changes in the method of PDA deposition on the properties of the obtained coatings, in particular the antioxidant properties, have not been sufficiently explored. It is anticipated that the antioxidant properties should depend on the film preparation method. A combination of experimental techniques, atomic force microscopy, cyclic voltammetry and X ray photoelectron spectroscopy are used to relate the antioxidant properties of PDA films to their structural features and to their chemical composition. It is demonstrated that the antioxidant properties of PDA films are not only dependent on the type of the employed oxidant – which can be expected to affect a variable density of oxidizable groups on the surface of PDA - but also on the oxidant film morphology and roughness

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Pharmacokinetic aspects of retinal drug delivery

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.Peer reviewe

Inhibition of neuronal nitric oxide synthase by 6-nitrocatecholamines, putative reaction products of nitric oxide with catecholamines under oxidative stress conditions.

6-Nitrodopamine and 6-nitronoradrenaline (6-nitronorepinephrine), putative products of the nitric oxide (NO)-dependent nitration of dopamine and noradrenaline, are reported to be reversible, competitive inhibitors of neuronal nitric oxide synthase (nNOS) with Ki values of 45 and 52 μM resp. The nitrocatecholamines inhibited H2O2 prodn. in the absence of L-arginine and tetrahydrobiopterin (BH4) (the IC50 values for 6-nitrodopamine and 6-nitronoradrenaline were 85 and 55 μM resp.) but without affecting cytochrome c redn. The apparent Ki values for nitrocatecholamine inhibition of enzyme activation by BH4 were 18 μM for 6-nitrodopamine and 40 μM for 6-nitronoradrenaline. Both nitrocatecholamines antagonized the dimerization of nNOS induced by BH4 and by L-arginine, the effect being reversed by BH4 (more than 10 μM) and L-arginine (e.g., 100 μM). Overall, these results suggest that nitrocatecholamines interfere with nNOS activity by binding to the enzyme in the proximity of the substrate and BH4-binding sites near the heme group

The first expedient entry to the human melanogen 2-S-cysteinyldopa exploiting the anomalous regioselectivity of 3,4-dihydroxycinnamic acid-thiol conjugation.

The first convenient synthesis of 2-S-cysteinyl-3,4-dihydroxyphenylalanine (2-S-cysteinyldopa) in 30% overall yield is reported, which capitalizes on the anomalous regiochemistry of the oxidative coupling of 3,4-dihydroxycinnamic acid derivatives with thiol compounds, leading to 2-S rather than the usual 5-S conjugates. (C) 2007 Elsevier Ltd. All rights reserved

Free radical oxidation of coriolic acid (13-(S)-hydroxy-9Z,11E-octadecadienoic acid

The reaction of (13S,9Z,11E)-13-hydroxy-9,11-octadecadienoic acid, one of the major peroxidn. products of linoleic acid and an important physiol. mediator, with the Fenton reagent (Fe2+/EDTA/H2O2) was investigated. In phosphate buffer, pH 7.4, the reaction proceeded with >80% substrate consumption after 4 h to give a defined pattern of products, the major of which were isolated as Me esters and were subjected to complete spectral characterization. The less polar product was identified as (9Z,11E)-13-oxo-9,11-octadecadienoate Me ester (40% yield). Based on 2D NMR anal. the other two major products were formulated as (11E)-9,10-epoxy-13-hydroxy-11-octadecenoate Me ester (15% yield) and (10E)-9-hydroxy-13-oxo-10-octadecenoate Me ester (10% yield). Mechanistic expts., including deuterium labeling, were consistent with a free radical oxidn. pathway involving as the primary event H-atom abstraction at C-13, as inferred from loss of the original S configuration in the reaction products. Overall, these results provide the first insight into the products formed by oxidn. of (13S,9Z,11E)-13-hydroxy-9,11-octadecadienoic acid with the Fenton reagent, and hint at novel formation pathways of the hydroxyepoxide and hydroxyketone of potential (patho)physiol. relevance in settings of oxidative stress

Biomimetic nitration of the linoleic acid metabolite 13-hydroxyoctadecadienoic acid: isolation and spectral characterization of novel chain-rearranged epoxy nitro derivatives

Nitration of unsatd. fatty acids is a (patho)physiol. important pathway of lipid modification induced by nitric oxide-derived species. We report herein on the unexpected chain rearrangement undergone by (13S,9Z,11E)-13-hydroxyoctadeca-9,11-dienoic acid (I), a linoleic acid metabolite, when exposed to nitrating agents of biol. relevance. At pH 7.4 and at room temp., reaction of I with peroxynitrite (ONOO-) as well as Fe2+-EDTA/H2O2/NO2- and horseradish peroxidase/H2O2/NO2- led to the formation of two nitration products, which could be isolated as the Me esters and were identified as diastereoisomeric Me (12S)-10,11-epoxy-12-hydroxy-9-(nitromethyl)heptadecanoates by extensive 1H, 13C, 15N NMR and MS anal