Impact of hydrocarbon extraction on heavy metal concentrations in lowland paca (Cuniculus paca) from the Peruvian Amazon.

Oil has been extracted from the Western Amazon since the 1920s, leading to severe environmental contamination due to frequent occurrence oil spills and the dumping of produced water. Local inhabitants, along with environmental and human rights organizations, have reported the adverse effects of oil-related pollution on their livelihoods and the ecosystems they depend on. Here, we study accumulation of oil-related heavy metals in wildlife, and its subsequent incorporation into the trophic chain. We analysed the concentration of 14 heavy metals (Cd, Cr, Hg, As, Ni, V, Ba, Se, Be, Fe, Cu, Zn, Mn, Al) in liver samples from 78 lowland pacas (Cuniculus paca) hunted for subsistence in an oil-polluted area from the northern Peruvian Amazon where oil has been extracted since the 1970s (n = 38), and two control areas, the Yavari-Mirín River basin (n = 20), and the Pucacuro River basin (n = 20). Pacas in the oil-polluted area have significantly higher concentrations of Cd (P < 0.01) and Ba (P < 0.0001) compared to those in control areas, suggesting bioaccumulation of oil-related pollution. Conversely, Se levels were significantly lower in the oil-polluted area (P < 0.0001), likely due to the sequestration of Se by other heavy metals, particularly Cd. Additionally, minor variations in other heavy metals, e.g., Fe and Zn, were observed in pacas from the oil-polluted area, whereas control areas showed higher concentrations of Ni and Cu. Mn and Al levels did not significantly differ between the study areas. These results underscore the impact of oil extraction on the absorption and assimilation of heavy metals in wildlife, point at oil activities as the source of the high and unsafe blood Cd levels reported for the indigenous population of the studied oil extraction area and raise concerns about the long-term health risks from oil extraction posed to local Indigenous People who rely on subsistence hunting.

Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases.

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

First evidences of Amazonian wildlife feeding on petroleum-contaminated soils: A new exposure route to petrogenic compounds?

Videos recorded with infrared camera traps placed in petroleum contaminated areas of the Peruvian Amazon have shown that four wildlife species, the most important for indigenous peoples' diet (lowland tapir, paca, red-brocket deer and collared peccary), consume oil-contaminated soils and water. Further research is needed to clarify whether Amazonian wildlife's geophagy can be a route of exposure to petrogenic contamination for populations living in the vicinity of oil extraction areas and relying on subsistence hunting.

Oil pollution in soils and sediments from the Northern Peruvian Amazon.

Oil has been extracted from the Northern Peruvian Amazon for over four decades. However, few scientific studies have assessed the impacts of such activities in the environment and health of indigenous communities in the region. We have investigated the occurrence of petrogenic hydrocarbon pollution in soils and sediments from areas favoured as hunting or fishing grounds by local indigenous inhabitants. The study was conducted in one of the most productive oil blocks in Peru, located in the headwaters of the Amazon river. Soils and river sediments, in the vicinity of oil extraction and processing infrastructure, contained an oil pollution signature as attested by the occurrence of hopanes and steranes. Given the lack of any other significant source of oil pollution in the region, the sources of hydrocarbons are likely to be the activities of the oil industry in the oil block, from voluntary discharges or accidental spills. Spillage of produced water was commonplace until 2009. Moreover, petrogenic compounds were absent in control samples in sites far removed from any oil infrastructure in the oil block. Our findings suggest that wildlife and indigenous populations in this region of the Amazon are exposed to the ingestion of oil polluted soils and sediments. The data obtained supports previous claims that the local spillage of oil and produced waters in the water courses in the Corrientes and Pastaza basins could have eventually reached the main water course of the Amazon.

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases.

The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure-activity relationships and structure-property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.

Discovery of a novel class of zwitterionic, potent, selective and orally active S1P1 direct agonists.

Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural-activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.

Plastic-embedded semithin cross-sections as a tool for high-resolution immunofluorescence analysis of the neuromuscular junction molecules: Specific cellular location of protease-activated receptor-1.

In the neuromuscular junction (NMJ), three cellular elements (nerve ending, postsynaptic muscle component, and teloglial Schwann cell) are closely juxtaposed and functionally interdependent. It is important to determine the precise location of the relevant molecules involved in structural stability and neurotransmission at the three cellular components of this synapse in order to understand the molecular mechanisms underlying NMJ formation, maintenance, and functionality. In this paper, we show that plastic-embedded 0.5-mum semithin cross-sections from whole-mount multiple-immunofluorescence-stained muscles provide a simple and sensitive high-resolution procedure for analyzing the cellular and subcellular distribution of molecules at the NMJ. We have used this procedure to resolve the location of protease-activated receptor 1 (PAR-1). Previously, by immunohistochemistry we had detected PAR-1 in muscle fibers concentrated in the synaptic area but could not determine whether PAR-1 is expressed only in the muscle fiber at the NMJ. Our present results demonstrate that PAR-1 is concentrated in the postsynaptic region but not in the presynaptic terminal and that the labelling pattern for PAR-1 overlapped with Schwann cell staining.