Uncovering the toxicity mechanisms of a series of carboxylic acids in liver cells through computational and experimental approaches.

Hepatotoxicity poses a significant concern in drug design due to the potential liver damage that can be caused by new drugs. Among common manifestations of hepatotoxic damage is lipid accumulation in hepatic tissue, resulting in liver steatosis or phospholipidosis. Carboxylic derivatives are prone to interfere with fatty acid metabolism and cause lipid accumulation in hepatocytes. This study investigates the toxic behaviour of 24 structurally related carboxylic acids in hepatocytes, specifically their ability to cause accumulation of fatty acids and phospholipids. Using high-content screening (HCS) assays, we identified two distinct lipid accumulation patterns. Subsequently, we developed structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR) models to determine relevant molecular substructures and descriptors contributing to these adverse effects. Additionally, we calculated physicochemical properties associated with lipid accumulation in hepatocytes and examined their correlation with our chemical structure characteristics. To assess the applicability of our findings to a wide range of chemical compounds, we employed two external datasets to evaluate the distribution of our QSAR descriptors. Our study highlights the significance of subtle molecular structural variations in triggering hepatotoxicity, such as the presence of nitrogen or the specific arrangement of substitutions within the carbon chain. By employing our comprehensive approach, we pinpointed specific molecules and elucidated their mechanisms of toxicity, thus offering valuable insights to guide future toxicology investigations.

Yield and Chemical Characteristics of Salvia hispanica L. (Chia) Oil from Native Seeds from Four Provenances of Guatemala.

INTRODUCTION: Chia (Salvia hispanica L.) is a plant from the Lamiaceae family that has been used as ancestral food, medicine, and oil, with culinary, artistic, and religious purposes by most of the Mesoamerican civilizations. Native from Mesoamerica, introduced into South America, Australia, and Europe, it is presently consumed as a nutritional and functional food. OBJECTIVE: This research aims to characterize ancient native cultivars from four provenances in Guatemala to recommend their direct consumption by the population as well as to establish its trade. METHOD: Seed samples were collected in four places where they have been cultivated for several generations. The oil was obtained by expression and analyzed chemically by gas chromatography following standard qualitative and quantitative methods. RESULTS: Variations in oil yield and some of the characteristic parameters of the phytochemical analysis were obtained. In general, the profile was similar to most of the reported data in the literature, with the saturated fatty acids (8.54-9.25%) relatively lower than the references (7.95-11.45%) but a higher concentration of unsaturated fatty oils, particularly of omega-3 (64.68-68.62%). CONCLUSION: The oil from native cultivars contains high quantities of omega-3, which might help pregnant women during gestation and to control other conditions such as metabolic syndrome, particularly in low- and middle-income populations where these seeds are consumed regularly. The suggestion is made to encourage the cultivation and use of these ancestral seeds with the possibility of commercialization abroad with an appellation of origin label.

Factors that influence the quality of metabolomics data in in vitro cell toxicity studies: a systematic survey.

REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) is a global strategy and regulation policy of the EU that aims to improve the protection of human health and the environment through the better and earlier identification of the intrinsic properties of chemical substances. It entered into force on 1st June 2007 (EC 1907/2006). REACH and EU policies plead for the use of robust high-throughput "omic" techniques for the in vitro investigation of the toxicity of chemicals that can provide an estimation of their hazards as well as information regarding the underlying mechanisms of toxicity. In agreement with the 3R's principles, cultured cells are nowadays widely used for this purpose, where metabolomics can provide a real-time picture of the metabolic effects caused by exposure of cells to xenobiotics, enabling the estimations about their toxicological hazards. High quality and robust metabolomics data sets are essential for precise and accurate hazard predictions. Currently, the acquisition of consistent and representative metabolomic data is hampered by experimental drawbacks that hinder reproducibility and difficult robust hazard interpretation. Using the differentiated human liver HepG2 cells as model system, and incubating with hepatotoxic (acetaminophen and valproic acid) and non-hepatotoxic compounds (citric acid), we evaluated in-depth the impact of several key experimental factors (namely, cell passage, processing day and storage time, and compound treatment) and instrumental factors (batch effect) on the outcome of an UPLC-MS metabolomic analysis data set. Results showed that processing day and storage time had a significant impact on the retrieved cell's metabolome, while the effect of cell passage was minor. Meta-analysis of results from pathway analysis showed that batch effect corrections and quality control (QC) measures are critical to enable consistent and meaningful estimations of the effects caused by compounds on cells. The quantitative analysis of the changes in metabolic pathways upon bioactive compound treatment remained consistent despite the concurrent causes of metabolomic data variation. Thus, upon appropriate data retrieval and correction and by an innovative metabolic pathway analysis, the metabolic alteration predictions remained conclusive despite the acknowledged sources of variability.

Durability Performance Indices for Cement-Based Mortars.

Corrosion-induced damaged structures are generally repaired using locally available materials. Nevertheless, determining the durability of the repair materials to be used is necessary to forecast its service life after being placed on the damaged structure. In previous investigations, the most commonly used durability indices are saturated electrical resistivity (ρS), ultrasonic pulse velocity (UPV), total void content (TVC), water capillary absorption (WCA), rapid chloride permeability (RCP), and compressive strength (fc). Four repair mortar types were evaluated. For each mortar type, 5 × 5 cm2 cubes, 5 × 10 cm2 (small) cylinders, and 10 × 20 cm2 (large) cylinders were made from each mortar evaluated. On the basis of the present results, the durability design of mortars should consider not only the mechanical strength, but also the durability index values to define its durability performance. According to the empirical correlations obtained between all durability indices, ρS vs. RCP, TVC vs. WCA, and RCP vs. WCA were the ones with higher correlation coefficient. These correlations could be used for mortar mixture durability forecasting.

A Signaling Crosstalk between BMP9 and HGF/c-Met Regulates Mouse Adult Liver Progenitor Cell Survival.

During chronic liver disease, hepatic progenitor cells (HPC, oval cells in rodents) become activated, proliferate, and differentiate into cholangiocytes and/or hepatocytes contributing to the final outcome of the regenerative process in a context-dependent fashion. Here, we analyze the crosstalk between the hepatocyte growth factor (HGF)/c-Met signaling axis, key for liver regeneration, and bone morphogenetic protein (BMP)9, a BMP family ligand that has emerged as a critical regulator of liver pathology. Our results show that HGF/c-Met signaling blocks BMP9-mediated apoptotic cell death, while it potentiates small mothers against decapentaplegic (SMAD)1 signaling triggered by BMP9 in oval cells. Interestingly, HGF-induced overactivation of SMAD1, -5, -8 requires the upregulation of TGF-ß type receptor activin receptor-like kinase (ALK)1, and both ALK1 and SMAD1 are required for the counteracting effect of HGF on BMP9 apoptotic activity. On the other hand, we also prove that BMP9 triggers the activation of p38MAPK in oval cells, which drives BMP9-apoptotic cell death. Therefore, our data support a model in which BMP9 and HGF/c-Met signaling axes establish a signaling crosstalk via ALK1 that modulates the balance between the two pathways with opposing activities, SMAD1 (pro-survival) and p38 mitogen-activated protein kinases (p38MAPK; pro-apoptotic), which determines oval cell fate. These data help delineate the complex signaling network established during chronic liver injury and its impact on the oval cell regenerative response.

Proteomic profiling, functional characterization, and immunoneutralization of the venom of Porthidium porrasi, a pitviper endemic to Costa Rica.

The genus Porthidium includes nine pitviper species inhabiting Mexico, Central America, and northern South America. Porthidium porrasi is a species endemic to the Southwest of Costa Rica, for which no information on its venom was available. In this study, the proteomic composition and functional activities of P. porrasi venom are described. The most abundant venom proteins were identified as metalloproteinases (36.5%). In descending order of abundance, proteins belonging to the disintegrin, phospholipase A2, serine proteinase, C-type lectin/lectin-like, vascular endothelial growth factor, Cysteine-rich secretory protein, L-amino acid oxidase, phospholipase B, and phosphodiesterase families were also identified. P. porrasi venom showed a weak lethal potency in mice (10 µg/g body weight by intraperitoneal route), induced marked hemorrhage and edema, and weak myotoxic effect. These in vivo activities, as well as those assayed in vitro (proteolytic and phospholipase A2 activities) correlated with compositional data. A comparison of P. porrasi venom with those of three other Porthidium species studied to date reveals a generally conserved compositional and functional pattern in this pitviper genus. Importantly, the lethal effect of P. porrasi venom in mice was adequately cross-neutralized by a heterospecific polyvalent antivenom, supporting its use in the treatment of eventual envenomings by this species.

Perioperative and long-term all-cause mortality in patients with diabetes who underwent a lower extremity amputation.

INTRODUCTION: Long-term mortality of patients with diabetes who undergo lower extremity amputation (LEA) has not been reported in Spain. METHODS: The retrospective cohort included all subjects who underwent LEAs from January 1, 2005 to December 31, 2015 in San Jorge Hospital, Huesca, Spain. Live status of every patient up to September 2017 and the date of death were retrieved using the national death index. RESULTS: The series included 203 patients: 116 patients (57.1%) underwent a minor amputation and 87 patients (42.9%) underwent a major amputation. Twenty-five patients (12.3%) died in the perioperative period. Significant risk factors of perioperative mortality were undergoing an above-the-knee amputation, postoperative cardiac complications, age >74 years and acute renal failure. Survival rates at 1, 3, and 5 years were 90.6, 72.8, and 55.5% in patients who underwent a minor amputation compared with 70.8, 41.3, and 34.4% in patients who underwent a major amputation, respectively. Log-rank test between the two groups was χ2 = 12.7 (p < 0.01). CONCLUSIONS: Long-term survival was worse in patients who underwent a major amputation with a 5-year mortality of 65.6%. This mortality is worse than what has been reported for some types of common malignancies.

Evaluation of an automatic dry eye test using MCDM methods and rank correlation.

Dry eye is an increasingly common disease in modern society which affects a wide range of population and has a negative impact on their daily activities, such as working with computers or driving. It can be diagnosed through an automatic clinical test for tear film lipid layer classification based on color and texture analysis. Up to now, researchers have mainly focused on the improvement of the image analysis step. However, there is still large room for improvement on the machine learning side. This paper presents a methodology to optimize this problem by means of class binarization, feature selection, and classification. The methodology can be used as a baseline in other classification problems to provide several solutions and evaluate their performance using a set of representative metrics and decision-making methods. When several decision-making methods are used, they may offer disagreeing rankings that will be solved by conflict handling in which rankings are merged into a single one. The experimental results prove the effectiveness of the proposed methodology in this domain. Also, its general purpose allows to adapt it to other classification problems in different fields such as medicine and biology.