Potential for Interspecies Toxicity Estimation in Soil Invertebrates

Interspecies correlation estimation (ICE) models are linear regressions that predict toxicity to a species with few data using a known toxicity value in a surrogate species. ICE models are well established for estimating toxicity to fish and aquatic invertebrates but have not been generally developed or applied to soil organisms. To facilitate the development of ICE models for soil invertebrates, a database of single chemical toxicity values was compiled from knowledgebases and reports that included 853 records encompassing 192 chemicals and 12 species. Most toxicity data for single chemicals tested in soil media were for species of earthworms, with only limited data for other species and taxa. ICE models were developed for eleven separate species pairs as least squares log-linear regressions of acute toxicity values of the same chemicals tested in both the surrogate and predicted species of soil organisms. Model uncertainty was assessed using leave one out cross-validation as the fold difference between a predicted and measured toxicity value. ICE models showed high accuracy within order (e.g., earthworm to earthworm), but less prediction accuracy in the two across-taxa models (Arthropoda to Annelida and the inverse). This study provides a proof-of-concept demonstration that ICE models can be developed for soil invertebrates.

Are PM2.5 in the Atmosphere of a Small City a Threat for Health?

A number of time series from two local PM2.5 monitoring stations were analyzed, for a small city, in North East Greece. They coincided with SARS-CoV-2 pandemic lockdowns and lifting restrictions. The aim of this analysis was to establish concentration exceedances and roughly apportion sources of the PM2.5 concentration problem. This was established by analyzing 24-h filter samples of trace elements using WD-XRF. It was found that the restrictions and their lifting did not significantly affect these concentrations. The main problems were assigned to emissions from biomass burning central heating and Saharan dust episodes. The study results indicate that even in small cities the air quality as far as PM2.5 is concerned can still be deleterious to the local population according to the WHO restricting levels but not according to the EU levels. The fact that PM2.5 is not a single chemical pollutant makes matters more complicated and renders such concentration upper levels, of little significance.

Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge

A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets (‘polypharmacology’). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.

The Biological Effects of Pharmaceuticals in the Marine Environment

Environmental pharmaceuticals represent a threat of emerging concern for marine ecosystems. Widely distributed and bioaccumulated, these contaminants could provoke adverse effects on aquatic organisms through modes of action like those reported for target species. In contrast to pharmacological uses, organisms in field conditions are exposed to complex mixtures of compounds with similar, different, or even opposing therapeutic effects. This review summarizes current knowledge of the main cellular pathways modulated by the most common classes of environmental pharmaceuticals occurring in marine ecosystems and accumulated by nontarget species—including nonsteroidal anti-inflammatory drugs, psychiatric drugs, cardiovascular and lipid regulator agents, steroidal hormones, and antibiotics—and describes an intricate network of possible interactions with both synergistic and antagonistic effects on the same cellular targets and metabolic pathways. This complexity reveals the intrinsic limits of the single-chemical approach to predict the long-term consequences and future impact of pharmaceuticals at organismal, population, and community levels. Expected final online publication date for the Annual Review of Marine Science, Volume 14 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Combined Exposure to Multiple Endocrine Disruptors and Uterine Leiomyomata and Endometriosis in US Women

BackgroundUterine leiomyomata (UL) and endometriosis (EM) are common gynecological diseases damaging the reproductive health of fertile women. Among all the potential factors, environmental endocrine-disrupting chemicals are insufficiently addressed considering the multiple pollutants and mixture exposure.MethodsWomen aged 20 to 54 years old in the National Health and Nutrition Examination Survey (NHANES) 2001-2006, having a complete measurement of ten commonly exposed endocrine-disrupting chemicals (including urinary phthalate metabolites, equol, and whole blood heavy metals) and answered questions about UL and EM were included (N=1204). Multivariable logistic regression model, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models were implemented to analyze the combined effect of chemicals on the overall association with UL and EM.ResultsIn single chemical analysis, equol (OR: 1.90, 95% CI: 1.11, 3.27) and mercury (Hg) (OR: 1.91, 95% CI: 1.14, 3.25) were found positively associated with UL in tertile 3 vs. tertile 1. In WQS regression and BKMR models, the significant positive association between WQS index and UL (OR: 2.54, 95% CI: 1.52, 4.29) was identified and the positive relationship between equol and Hg exposure and UL were further verified. Besides, the mixture evaluation models (WQS and BKMR) also found MEHP negatively associated with UL. Although none of the single chemicals in tertile 3 were significantly associated with EM, the WQS index had a marginally positive association with EM (OR: 2.01, 95% CI: 0.98, 4.15), and a significant positive association was identified in subanalysis with participants restricted to premenopausal women (OR: 2.18, 95% CI: 1.03, 4.70). MIBP and MBzP weighted high in model of EM and MEHP weighted the lowest.ConclusionComparing results from these three statistical models, the associations between equol, Hg, and MEHP exposure with UL as well as the associations of MIBP, MBzP, and MEHP exposure with EM warrant further research.

2-Hydroxy-5-(3,5,7-Trihydroxy-4-Oxo-4H-Chromen-2-yl)Phenyl (E)-3-(4-Hydroxy-3-Methoxyphenyl)Acrylate: Synthesis, In Silico Analysis and In Vitro Pharmacological Evaluation

Quercetin and ferulic acid are two phytochemicals extensively represented in the plant kingdom and daily consumed in considerable amounts through diets. Due to a common phenolic structure, these two molecules share several pharmacological properties, e.g., antioxidant and free radical scavenging, anti-cancer, anti-inflammatory, anti-arrhythmic, and vasorelaxant. The aim of the present work was the combination of the two molecules in a single chemical entity, conceivably endowed with more efficacious vasorelaxant activity. Preliminary in silico studies herein described suggested that the new hybrid compound bound spontaneously and with high affinity on the KCa1.1 channel. Thus, the synthesis of the 3′-ferulic ester derivative of quercetin was achieved and its structure confirmed by 1H- and 13C-NMR spectra, HSQC and HMBC experiments, mass spectrometry, and elementary analysis. The effect of the new hybrid compound on vascular KCa1.1 and CaV1.2 channels revealed a partial loss of the stimulatory activity that characterizes the parent compound quercetin. Therefore, further studies are necessary to identify a better strategy to improve the vascular properties of this flavonoid.

Curcumin, Resveratrol and Cannabidiol as natural key-prototypes in drug design for neuroprotective agents

: Nowadays, neurodegenerative diseases (NDs), such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), represent a great challenge for different scientific fields, such as neuropharmacology, medicinal chemistry, molecular biology, and medicine, once all these pathologies remain incurable, with high socio-economic impacts and high costs for governmental health services. Due to their severity and multifactorial pathophysiological complexity, the available approved drugs for clinics have not yet shown adequate effectiveness in disease-modifying effects, with very restricting options in the therapeutic arsenal, which highlight the permanent need for continued drug discovery efforts in Academia and Industry. In this context, natural products, such as curcumin (1), resveratrol (2), and cannabidiol (CBD, 3) have been recognized as important sources of inspiration, promising chemical entities, prototype models, and starting materials for medicinal organic chemistry. Once their molecular architecture, multifunctional properties and single chemical diversity could address the discovery, optimization, and development of innovative drug candidates with improved pharmacodynamics and pharmacokinetics compared to the known drugs, there may be a real chance of discovering novel effective drugs to combat NDs. In this review, we report the most recent efforts of medicinal chemists worldwide, published in the scientific literature available in PubMed, SCOPUS, and Web of Sciences database, during the last 10 years of research devoted to the exploration of curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) as starting materials or privileged scaffolds in the design of multi-target directed ligands (MTDLs) with potential therapeutic properties against NDs.

Chiral Polythiophenes: Part I: Syntheses of Monomeric Precursors

The purpose of this mini-review is to comprehensively present the synthetic approaches used for the preparation of non-racemic mono- and multi-substituted thiophenes, which, in turn, can be applied as precursors for the synthesis of chiral polythiophenes isolated as a single chemical entity or having supramolecular thin-layer architectures.

Probing the Nature of Chemical Bonds by Atomic Force Microscopy

The nature of the chemical bond is important in all natural sciences, ranging from biology to chemistry, physics and materials science. The atomic force microscope (AFM) allows to put a single chemical bond on the test bench, probing its strength and angular dependence. We review experimental AFM data, covering precise studies of van-der-Waals-, covalent-, ionic-, metallic- and hydrogen bonds as well as bonds between artificial and natural atoms. Further, we discuss some of the density functional theory calculations that are related to the experimental studies of the chemical bonds. A description of frequency modulation AFM, the most precise AFM method, discusses some of the experimental challenges in measuring bonding forces. In frequency modulation AFM, forces between the tip of an oscillating cantilever change its frequency. Initially, cantilevers were made mainly from silicon. Most of the high precision measurements of bonding strengths by AFM became possible with a technology transfer from the quartz watch technology to AFM by using quartz-based cantilevers (“qPlus force sensors”), briefly described here.