Benzopyran hydrazones with dual PPARα/γ or PPARα/δ agonism and an anti-inflammatory effect on human THP-1 macrophages.

Peroxisome proliferator-activated receptors (PPARs) play a major role in regulating inflammatory processes, and dual or pan-PPAR agonists with PPARγ partial activation have been recognised to be useful to manage both metabolic syndrome and metabolic dysfunction-associated fatty liver disease (MAFLD). Previous works have demonstrated the capacity of 2-prenylated benzopyrans as PPAR ligands. Herein, we have replaced the isoprenoid bond by hydrazone, a highly attractive functional group in medicinal chemistry.

Synthesis of 2-aminopropyl benzopyran derivatives as potential agents against triple-negative breast cancer.

Synthesis of three series of 2-aminopropyl derivatives containing a benzopyran nucleus was performed to evaluate their performance against triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-436) and normal breast epithelial cells (MCF10A). For the three series, the cytotoxic activity was as follows: -methylated derivatives (tertiary amines) 5b, 6b, and 7b > secondary amine benzopyrans 5, 6, and 7 > quaternary amine salts 5c, 6c, and 7c > free phenolic derivatives 5a, 6a, and 7a. The structure-activity relationship showed the importance of the presence of an amine group and a -fluorobenzyloxy substituent in the chromanol ring (IC values from 1.

Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity.

Background And Purpose: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements.

Experimental Approach: BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARβ/δ and PPARγ.

Synthesis and biological studies of "Polycerasoidol" and "trans-δ-Tocotrienolic acid" derivatives as PPARα and/or PPARγ agonists.

2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARα/γ agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-δ-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6-hydroxy-dihydrobenzopyran) scaffold.

Synthesis of 2-Prenylated Alkoxylated Benzopyrans by Horner-Wadsworth-Emmons Olefination with PPARα/γ Agonist Activity.

We have synthesized series of 2-prenylated benzopyrans as analogues of the natural polycerasoidol, a dual PPARα/γ agonist with anti-inflammatory effects. The prenylated side chain consists of five or nine carbons with an α-alkoxy-α,β-unsaturated ester moiety. Prenylation was introduced via the Grignard reaction, followed by Johnson-Claisen rearrangement, and the α-alkoxy-α,β-unsaturated ester moiety was introduced by the Horner-Wadsworth-Emmons reaction.

1-(2'-Bromobenzyl)-6,7-dihydroxy--methyl-tetrahydroisoquinoline and 1,2-Demethyl-nuciferine as Agonists in Human D Dopamine Receptors.

Certain D-like dopamine receptor (DR) agonists are useful therapeutically as antiparkinsonian drugs, whereas D-like DR antagonists or partial agonists are proven effective as antipsychotics. Two isoquinoline derivatives, 1-(2'-bromobenzyl)-6,7-dihydroxy--methyl-tetrahydroisoquinoline (Br-BTHIQ, ) and 1,2-demethyl-nuciferine (aporphine, ), were herein synthesized, and their dopaminergic affinity in cloned human DR, DR, and DR subtypes and their behavior as agonists/antagonists were evaluated. They showed affinity values () for hD, hD, and hD DR within the nanomolar range.

Micronuclei Detection by Flow Cytometry as a High-Throughput Approach for the Genotoxicity Testing of Nanomaterials.

Thousands of nanomaterials (NMs)-containing products are currently under development or incorporated in the consumer market, despite our very limited understanding of their genotoxic potential. Taking into account that the toxicity and genotoxicity of NMs strongly depend on their physicochemical characteristics, many variables must be considered in the safety evaluation of each given NM. In this scenario, the challenge is to establish high-throughput methodologies able to generate rapid and robust genotoxicity data that can be used to critically assess and/or predict the biological effects associated with those NMs being under development or already present in the market.

Synthesis of benzopyran derivatives as PPARα and/or PPARγ activators.

We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski's rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism.

The Comet Assay as a Tool to Detect the Genotoxic Potential of Nanomaterials.

The interesting physicochemical characteristics of nanomaterials (NMs) has brought about their increasing use and, consequently, their increasing presence in the environment. As emergent contaminants, there is an urgent need for new data about their potential side-effects on human health. Among their potential effects, the potential for DNA damage is of paramount relevance.

Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti-inflammatory activity.

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect.

Effects of differently shaped TiONPs (nanospheres, nanorods and nanowires) on the in vitro model (Caco-2/HT29) of the intestinal barrier.

Background: The biological effects of nanoparticles depend on several characteristics such as size and shape that must be taken into account in any type of assessment. The increased use of titanium dioxide nanoparticles (TiONPs) for industrial applications, and specifically as a food additive, demands a deep assessment of their potential risk for humans, including their abilities to cross biological barriers.

Methods: We have investigated the interaction of three differently shaped TiONPs (nanospheres, nanorods and nanowires) in an in vitro model of the intestinal barrier, where the coculture of Caco-2/HT29 cells confers inherent intestinal epithelium characteristics to the model (i.

Ethical Challenges of Early Identification of Advanced Chronic Patients in Need of Palliative Care: The Catalan Experience.

Palliative care must be early applied to all types of advanced chronic and life limited prognosis patients, present in all health and social services. Patients' early identification and registry allows introducing palliative care gradually concomitant with other measures. Patients undergo a systematic and integrated care process, meant to improve their life quality, which includes multidimensional assessment of their needs, recognition of their values and preferences for advance care planning purposes, treatments review, family care, and case management.

Titanium dioxide nanoparticles translocate through differentiated Caco-2 cell monolayers, without disrupting the barrier functionality or inducing genotoxic damage.

The widespread use of titanium dioxide nanoparticles (TiO NPs) in commercial food products makes intestinal cells a suitable target. Accordingly, we have used the human colon adenocarcinoma Caco-2 cells to detect their potential harmful effects. Caco-2 cells can differentiate in to enterocytic-like cells, forming consistent cell monolayers and are used as a model of the intestinal barrier.

Assessing the effects of silver nanoparticles on monolayers of differentiated Caco-2 cells, as a model of intestinal barrier.

Since ingestion is one of the main routes of entry of nanoparticles (NPs) in our organism, simple and fast in vitro models of the intestinal barrier can be helpful to evaluate NPs risk. The human colon adenocarcinoma Caco-2 cell line has been extensively used due to its ability to differentiate, forming a well-structured cell monolayer. In this study, we have used these differentiated cells as a model of intestinal barrier to evaluate a wide set of effects caused by exposure to silver nanoparticles (AgNPs) with an average size of 7.

Exploring the usefulness of the complex in vitro intestinal epithelial model Caco-2/HT29/Raji-B in nanotoxicology.

The use of in vitro barrier models is gaining relevance as an alternative to animal studies in risk assessment, pharmacokinetic, and toxicological studies in general. These models permit an easier evaluation of the underlying mechanisms taking place at the molecular and cellular levels on the barrier site. Here, we report several methodological modifications of the three-dimensional in vitro intestinal epithelial model Caco-2/HT29/Raji-B for its successful application in the Nanotoxicology field.

Effects of cerium oxide nanoparticles on differentiated/undifferentiated human intestinal Caco-2 cells.

Since ingestion constitute one of the main routes of nanoparticles (NPs) exposure, intestinal cells seems to be a suitable choice to evaluate their potential harmful effects. Caco-2 cells, derived from a human colon adenocarcinoma, have the ability to differentiate forming consistent cell monolayer structures. For these reasons Caco-2 cells, both in their undifferentiated or differentiated state, are extendedly used.

[Find your 1%: prevalence and mortality of a community cohort of people with advanced chronic disease and palliative needs].

Objective: To determine the prevalence and profiles of people with advanced chronic diseases in Primary Care and to analyse the elements related to their mortality in order to orient strategies for improvement in this level of care.

Design: An observational, analytical and prospective study during 3 years conducted on a cohort of patients with palliative needs.

Location: Three Primary Care teams of Osona (Catalonia).

Long-term effects of silver nanoparticles in caco-2 cells.

The high success of silver nanoparticles (AgNPs), mainly associated with their proved antimicrobial properties, has led to an increasing spread in our close environment. Although many studies have been carried out to detect potential toxicity of AgNPs, most of them have been developed under unrealistic exposure conditions. In terms of human risk, the evaluation of long-term exposures to subtoxic doses of NPs remains a challenge.

Frozen dispersions of nanomaterials are a useful operational procedure in nanotoxicology.

The variability observed in nanoparticle (NP) dispersions can affect the reliability of the results obtained in short-term tests, and mainly in long-term experiments. In addition, obtaining a good dispersion is time-consuming and acts as a bottleneck in the development of high-throughput screening methodologies. The freezing of different aliquots from a stock dispersion would overcome such limitations, but no studies have explored the impact of freezing thawing the samples on the physico-chemical and biological properties of the nanomaterial (NM).

Utility of the NECPAL CCOMS-ICO tool and the Surprise Question as screening tools for early palliative care and to predict mortality in patients with advanced chronic conditions: A cohort study.

Background: The Surprise Question (SQ) identifies patients with palliative care needs. The NECPAL CCOMS-ICO (NECPAL) tool combines the Surprise Question with additional clinical parameters for a more comprehensive assessment. The capacity of these screening tools to predict mortality is still unknown.

[Living with advanced chronic obstructive pulmonary disease: The impact of dyspnoea on patients and caregivers].

Aim: To understand the experiences of patients and caregivers living with advanced chronic obstructive pulmonary disease, the impact of their symptoms and care needs arising from a functional, emotional, and social context.

Design: Qualitative study. Phenomenological perspective.

The Catalonia WHO Demonstration Project of Palliative Care: Results at 25 Years (1990-2015).

In 2015, the World Health Organization (WHO) Demonstration Project on Palliative Care in Catalonia (Spain) celebrated its 25th anniversary. The present report describes the achievements and progress made through this project. Numerous innovations have been made with regard to the palliative care (PC) model, organization, and policy.

Antioxidant and anti-genotoxic properties of cerium oxide nanoparticles in a pulmonary-like cell system.

Cerium oxide nanoparticles (CeO2-NP) present two different oxidation states what can suppose an auto-regenerative redox cycle. Potential applications of CeO2-NP to quench reactive oxygen species (ROS) in biological systems are currently being investigated. In this context, CeO2-NP may represent a novel agent to protect cells and tissues against oxidative damage by its regenerative free radical-scavenging properties.

Identifying patients with chronic conditions in need of palliative care in the general population: development of the NECPAL tool and preliminary prevalence rates in Catalonia.

Palliative care (PC) has focused on patients with cancer within specialist services. However, around 75% of the population in middle-income and high-income countries die of one or more chronic advanced diseases. Early identification of such patients in need of PC becomes crucial.

Prevalence and characteristics of patients with advanced chronic conditions in need of palliative care in the general population: a cross-sectional study.

Background: Of deaths in high-income countries, 75% are caused by progressive advanced chronic conditions. Palliative care needs to be extended from terminal cancer to these patients. However, direct measurement of the prevalence of people in need of palliative care in the population has not been attempted.