Interaction of Synthetic Cannabinoid Receptor Agonists with Cannabinoid Receptor I: Insights into Activation Molecular Mechanism.

Synthetic cannabinoid receptor agonists (SCRAs) have become a wide group of new psychoactive substances since the 2010s. For the last few years, the X-ray structures of the complexes of cannabinoid receptor I (CB1) with SCRAs as well as the complexes of CB1 with its antagonist have been published. Based on those data, SCRA-CB1 interactions are analyzed in detail, using molecular modeling and molecular dynamics simulations. The molecular mechanism of the conformational transformation of the transmembrane domain of CB1 caused by its interaction with SCRA is studied. These conformational changes allosterically modulate the CB1-Gi complex, providing activation of the Gi protein. Based on the X-ray-determined structures of the CB1-ligand complexes, a stable apo conformation of inactive CB1 with a relatively low potential barrier of receptor activation was modeled. For that model, molecular dynamic simulations of SCRA binding to CB1 led to the active state of CB1, which allowed us to explore the key features of this activation and the molecular mechanism of the receptor's structural transformation. The simulated CB1 activation is in accordance with the previously published experimental data for the activation at protein mutations or structural changes of ligands. The key feature of the suggested activation mechanism is the determination of the stiff core of the CB1 transmembrane domain and the statement that the entire conformational transformation of the receptor to the active state is caused by a shift of alpha helix TM7 relative to this core. The shift itself is caused by protein-ligand interactions. It was verified via steered molecular dynamics simulations of the X-ray-determined structures of the inactive receptor, which resulted in the active conformation of CB1 irrespective of the placement of agonist ligand in the receptor's active site.

Replication of chromosomal loci involved in Parkinson's disease: A quantitative synthesis of GWAS.

INTRODUCTION: Parkinson's disease is a neurodegenerative disorder with a complex etiology coming from interactions between genetic and environmental factors. Research on Parkinson's disease genetics has been an effortful struggle, while new technologies and novel study designs served as indispensable boosters. Until now, 90 loci and 20 disease-causing gene mutations have been identified. In this study we describe a novel non-parametric approach to GWAS meta-analysis and its application in PD genetics. METHODS: A literature search was conducted to identify Genome-Wide Association Studies (GWAS) regarding Parkinson's disease. We applied predefined inclusion criteria and extracted the reported SNPs and their respective position and statistical significance. We divided all chromosomes in approximately equal genetic distance segments called bins and recorded the most significant SNP from each bin and each study and ranked them in terms of their p-value. Ranks from each bin were summed, averaged and added in a heterogeneity-based analysis using the METRADISC-XL software. Weighted and unweighted analysis was performed. RESULTS: Five-hundred and forty-three SNPs and their respective p-values from 15 studies were matched in their corresponding bins. The METRADISC-XL analysis resulted in 7 bins with a significant p-value. A bin on chromosome 4 where the SNCA gene is located found with genome-wide significant association with Parkinson's Disease. CONCLUSION: This is the first time a non-parametric method is applied in GWAS meta-analysis. The results add some insight on the overall understanding of Parkinson's disease genetics and serve as a first step of further convergent analysis with Genome-wide linkage studies.

Parkinson's disease and pesticides: Are microRNAs the missing link?

Parkinson's disease (PD) is a common neurodegenerative disorder that leads to significant morbidity and decline in the quality of life. It develops due to loss of dopaminergic neurons in the substantia nigra pars compacta, and among its pathogenic factors oxidative stress plays a critical role in disease progression. Pesticides are a broad class of chemicals widely used in agriculture and households for the protection of crops from insects and fungi. Several of them have been incriminated as risk factors for PD, but the underlying mechanisms have yet to be fully understood. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in regulating mRNA translation and protein synthesis. miRNA levels have been shown to be affected in several diseases as well. Since the studies on the association between pesticides and PD have yet to reach definitive conclusions, here we review recent evidence on deregulated microRNAs upon pesticide exposure, and attempt to find an overlap between miRNAs deregulated in PD and pesticides, as a missing link between the two, and enhance future research in this direction.

Analysis of the intricate effects of polyunsaturated fatty acids and polyphenols on inflammatory pathways in health and disease.

Prevention and treatment of non-communicable diseases (NCDs), including cardiovascular disease, diabetes, obesity, cancer, Alzheimer's and Parkinson's disease, arthritis, non-alcoholic fatty liver disease and various infectious diseases; lately most notably COVID-19 have been in the front line of research worldwide. Although targeting different organs, these pathologies have common biochemical impairments - redox disparity and, prominently, dysregulation of the inflammatory pathways. Research data have shown that diet components like polyphenols, poly-unsaturated fatty acids (PUFAs), fibres as well as lifestyle (fasting, physical exercise) are important factors influencing signalling pathways with a significant potential to improve metabolic homeostasis and immune cells' functions. In the present manuscript we have reviewed scientific data from recent publications regarding the beneficial cellular and molecular effects induced by dietary plant products, mainly polyphenolic compounds and PUFAs, and summarize the clinical outcomes expected from these types of interventions, in a search for effective long-term approaches to improve the immune system response.

Behavioral impacts of a mixture of six pesticides on rats.

Pesticides can potentially contribute to the development of numerous neurodegenerative diseases. This study evaluates the effects of a six-pesticide mixture at doses around the no-observed-adverse-effectlevels (0 × NOAEL, control) and 0.25, 1 and 5 × NOAEL on behavior of Wistar rats. After 3, 6 and 12 months, rats were observed for neurobehavioral changes using the techniques of elevated plus maze and universal problemchamber, and the experiment was conducted thrice. The 3-month exposure revealed a decrease in the cognitive ability at the dose of 5 × NOAEL, and a dose-dependent research activity and anxiety. The 6-month exposurerevealed non-monotonic effects on the cognitive ability, with a decrease by 0.25 and 5 × NOAEL, as well as non-monotonic effects on anxiety, withan increase by 0.25 and 1 × NOAEL. A decrease was also observed in research activity at 5 × NOAEL. However, the 12-month exposure resulted to an increase in cognitive ability by 0.25 × NOAEL and in anxiety by 1 × NOAEL, as well as to a dose-dependent research activity. Repeating the trial showed that the cognitive ability increased from one trial to another, while the researching activity decreased and the anxiety increased by 0× NOAEL. In the groups exposed to pesticides mixture, the trends were different, showing that the exposure to pesticides combined with repeated trials, also influence the response of the animals. The resultsdemonstrate the occurrence of several dose-dependent behavioral responses, with negative effects occurring at doses that are considered safe. This study provides novel insights about time-dependent mixtures biology, and an important perspective to consider when conducting risk assessments.

An imazamox-based herbicide causes apoptotic changes in rat liver and pancreas.

We studied the acute toxicity of an imazamox-based herbicide at 12, 24 and 36 mg/kg body (bw) weight imazamox equivalent dose on the liver and pancreatic tissue in Sprague Dawley rats. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, glucose, calcium as well as creatinine, were determined in blood samples, which were collected after 24, 48 and 72 h exposure. Caspase 3 and anti-insulin expression and immunopositivity were evaluated using in situ hybridization and immunohistochemistry, respectively. The imazamox-based herbicide evaluated in this study induced toxic effects even from the lowest dose tested (12 mg/kg bw). The two highest doses caused a statistically significant cytotoxicity on the Langerhans islet cells. Necrotic and degenerative changes were detected in hepatocytes at the two highest doses. Imazamox is considered to be poorly toxic to the liver. Nevertheless, the imazamox-based herbicide formulation tested here reduced the size of the ß-islet cells, induced an elevation in serum glucose and calcium. Our data shows that commercial formulations of imazamox containing various co-formulants can have hepatic and pancreatic toxic effects.