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.

Improved strategies to counter the COVID-19 pandemic: Lockdowns vs. primary and community healthcare.

COVID-19 pandemic mitigation strategies are mainly based on social distancing measures and healthcare system reinforcement. However, many countries in Europe and elsewhere implemented strict, horizontal lockdowns because of extensive viral spread in the community which challenges the capacity of the healthcare systems. However, strict lockdowns have various untintended adverse social, economic and health effects, which have yet to be fully elucidated, and have not been considered in models examining the effects of various mitigation measures. Unlike commonly suggested, the dilemma is not about health vs wealth because the economic devastation of long-lasting lockdowns will definitely have adverse health effects in the population. Furthermore, they cannot provide a lasting solution in pandemic containment, potentially resulting in a vicious cycle of consecutive lockdowns with in-between breaks. Hospital preparedness has been the main strategy used by governments. However, a major characteristic of the COVID-19 pandemic is the rapid viral transmission in populations with no immunity. Thus, even the best hospital system could not cope with the demand. Primary, community and home care are the only viable strategies that could achieve the goal of pandemic mitigation. We present the case example of Greece, a country which followed a strategy focused on hospital preparedness but failed to reinforce primary and community care. This, along with strategic mistakes in epidemiological surveillance, resulted in Greece implementing a second strict, horizontal lockdown and having one of the highest COVID-19 death rates in Europe during the second wave. We provide recommendations for measures that will reinstate primary and community care at the forefront in managing the current public health crisis by protecting hospitals from unnecessary admissions, providing primary and secondary prevention services in relation to COVID-19 and maintaining population health through treatment of non-COVID-19 conditions. This, together with more selective social distancing measures (instead of horizontal lockdowns), represents the only viable and realistic long-term strategy for COVID-19 pandemic mitigation.

E-cigarette or vaping induced lung injury: A case series and literature review.

INTRODUCTION: Recently, a rapidly increasing number of e-cigarette or vaping induced lung injury (EVALI) has been reported across the nation. Given the ongoing epidemic, it has been suggested that specific chemical substances used as additives in e-cigarettes could be highly related to EVALI. A history of vaping with positive radiographic changes and low suspicion for active infection are requirements for diagnosis but it still remains a diagnosis of exclusion. The course of the disease, mechanism of lung injury and the optimal management options need to be better understood. Here we aimed to discuss the clinical characteristics recognized in a case series of ten hospitalized EVALI patients with radiological findings of lung injury and provide an up today summary of the known literature of EVALI-induced lung injury. METHODS: A retrospective chart review was conducted on ten patients who presented to Saint Peter's University Hospital in New Brunswick, NJ from July 2019 to February 2020, with a mean hospital stay of five days. According to the CDC recommended definition of the disease, our cases met the current working definition of confirmed or probable cases of EVALI. RESULTS: Ten patients, with mean age 30.8 years (50 % male) and average years of vaping 1.708 with 60 % endorsing a simultaneous history of cannabis-related products use, went under a retrospective review. 3/10 (30 %) had documented medically-managed pulmonary disease history, 8/10 (80 %) presented with the respiratory-related chief complaint, 6/10 (60 %) presented with gastrointestinal symptoms and 7/10 (70 %) had constitutional symptoms. All patients (100 %) were found to have bilateral ground-glass opacities on chest imaging. 9/10 were admitted, 6/10 (60 %) had an oxygen saturation of <95 % requiring oxygen supplementation with 4/10 managed in the intensive care unit. CONCLUSION: EVALI patients with radiological findings of lung injury, although mainly present respiratory symptoms, may very often appear with constitutional and gastrointestinal symptoms. Based on the existing literature and our data it is argued that EVALI may be misdiagnosed and that closer monitoring is required to determine optimal diagnostic and therapeutic management of this condition. Our data and the existing literature suggest that laboratory and epidemiologic findings can be contributory for the diagnosis of the disease.

Pesticides, cognitive functions and dementia: A review.

Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person's quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer's disease.

Effects of single and combined toxic exposures on the gut microbiome: Current knowledge and future directions.

Human populations are chronically exposed to mixtures of toxic chemicals. Predicting the health effects of these mixtures require a large amount of information on the mode of action of their components. Xenobiotic metabolism by bacteria inhabiting the gastrointestinal tract has a major influence on human health. Our review aims to explore the literature for studies looking to characterize the different modes of action and outcomes of major chemical pollutants, and some components of cosmetics and food additives, on gut microbial communities in order to facilitate an estimation of their potential mixture effects. We identified good evidence that exposure to heavy metals, pesticides, nanoparticles, polycyclic aromatic hydrocarbons, dioxins, furans, polychlorinated biphenyls, and non-caloric artificial sweeteners affect the gut microbiome and which is associated with the development of metabolic, malignant, inflammatory, or immune diseases. Answering the question 'Who is there?' is not sufficient to define the mode of action of a toxicant in predictive modeling of mixture effects. Therefore, we recommend that new studies focus to simulate real-life exposure to diverse chemicals (toxicants, cosmetic/food additives), including as mixtures, and which combine metagenomics, metatranscriptomics and metabolomic analytical methods achieving in that way a comprehensive evaluation of effects on human health.

Adverse and hormetic effects in rats exposed for 12 months to low dose mixture of 13 chemicals: RLRS part III.

The aim of the current study was to evaluate the effects of a mixture of thirteen common chemicals on rats, after a one-year exposure to doses around the acceptable daily intake (ADIs), using blood and urinary tests. The influence of low doses of the mixture on weight gain, water consumption, feed consumption and feed efficiency, biochemistry parameters, haematological parameters, blood lymphocytes subsets, serum inflammation profile and urine parameters was evaluated. Our mixture caused a moderate monotonic increase of the males' appetite and a non-monotonic increase of anabolism and a monotonic increase of appetite for the females. Regarding biochemical parameters, the exposure to the test mixture caused non-monotonic increases of AST and ALT, a decrease of PChE in males and plausibly a monotonic biliary obstruction in both sexes. Monocytes significantly increased in low dose groups of both sexes. A significant decrease of all the lymphocytes subclasses and an increased expression of TNF-α protein associated with an increased expression of IFN-γ protein observed in various groups. It became apparent that after twelve months of exposure very low doses of the tested mixture had both non-monotonic and monotonic harmful effects on different levels on rats.

Neuroprotective effects of Scrophularia buergeriana extract against glutamate-induced toxicity in SH-SY5Y cells.

The aim of this study was to investigate the antioxidant and anti­apoptotic activities, as well as the underlying mechanisms of action, of Scrophularia buergeriana (S. buergeriana) extract (SBE) in glutamate­induced SH­SY5Y cell death. The roots of S. buergeriana were extracted with 70% ethanol, and standardized SBE was used in this study. To induce cytotoxicity, the SH­SY5Y cells were exposed to glutamate for 3 h, or pre­treated with SBE for 1 h, and subsequently incubated with glutamate for 3 h. The neuroprotective effects were assessed by measuring cell viability and the total glutathione contents using commercial kits. The antioxidant and anti­apoptotic mechanisms of action of SBE were evaluated by western blot analysis. The results confirmed that glutamate­induced toxicity was caused by reactive oxygen species (ROS) production, leading to oxidative stress and DNA damage, thus leading to cell death. However, treatment of the SH­SY5Y cells with SBE significantly increased the viability of the cells exposed to glutamate by upregulating the levels of antioxidant proteins, such as superoxide dismutase (SOD)1, SOD2 and glutathione peroxidase­1 (GPx­1), and directly enhancing the total glutathione contents. Furthermore, SBE attenuated DNA impairment and decreased B­cell lymphoma-2 (Bcl­2)­associated X protein (Bax), cleaved caspase­3 and cleaved poly(adenosine diphosphate (ADP)­ribose) polymerase (PARP) activation. In addition, SBE upregulated Bcl­2 expression via p38 mitogen­activated protein kinases (MAPKs). On the whole, the findings of this study demonstrated that SBE exerts neuroprotective effects against glutamate­induced cell toxicity through its antioxidant and anti­apoptotic activities.

Correction to: Population-Based Analysis of Cluster Headache-Associated Genetic Polymorphisms.

The original version of this article unfortunately contained mistakes in author group section.

Population-Based Analysis of Cluster Headache-Associated Genetic Polymorphisms.

Cluster headache is a disorder with increased hereditary risk. Associations between cluster headache and polymorphism rs2653349 of the HCRTR2 gene have been demonstrated. The less common allele (A) seems to reduce disease susceptibility. The polymorphism rs5443 of the GNB3 gene positively influences triptan treatment response. Carriers of the mutated T allele are more likely to respond positively compared to C:C homozygotes, when treated with triptans. DNA was extracted from buccal swabs obtained from 636 non-related Southeastern European Caucasian individuals and was analyzed by real-time PCR. Gene distribution for the rs2653349 was G:G = 79.1%, G:A = 19.2%, and A:A = 1.7%. The frequency of the wild-type G allele was 88.7%. The frequencies for rs5443 were C:C = 44.0%, C:T = 42.6%, and T:T = 13.4%. The frequency of the wild-type C allele was 65.3%. The frequency distribution of rs2653349 in the Southeastern European Caucasian population differs significantly when compared with other European and East Asian populations, and the frequency distribution of rs5443 showed a statistically significant difference between Southeastern European Caucasian and African, South Asian, and East Asian populations. For rs2653349, a marginal statistically significant difference between genders was found (p = 0.080) for A:A versus G:G and G:A genotypes (OR = 2.78), indicating a higher representation of male homozygotes for the protective mutant A:A allele than female. No statistically significant difference was observed between genders for rs5443. Cluster headache pathophysiology and pharmacotherapy response may be affected by genetic factors, indicating the significant role of genotyping in the overall treatment effectiveness of cluster headaches.

Staphylococcus aureus colonisation in patients from a primary regional hospital.

Staphylococcus aureus (SA or S. aureus) is a common pathogen that leads to local and systemic infections in communitarian and hospitalised patients. Staphylococcus colonizing nasal or pharyngeal sites can become virulent and cause severe infections. In this study, we collected 322 pharyngeal exudates and 142 nasal exudates from hospitalised and outpatients for screening purposes. The carriage rates in the pharynx were 27.06% for S. aureus, 11.55% for methicillin­resistant S. aureus (MRSA) and 5.61% for methicillin­oxacillin resistant S. aureus (MORSA). The carriage rates in the nose were 35.38% for S. aureus, 18.46% for MRSA and 13.85% for MORSA. The median multiple antibiotic resistance (MAR) index of SA was 33.33%. The MAR of MRSA was significantly higher than that of methicillin-susceptible strains (MSSA) (45.45% vs. 18.75%, P<0.0001) and the MAR of MORSA was 57.14%. Hierarchical clustering analysis revealed differences in the resistance of methicillin-sensitive, MRSA and MORSA strains. On the whole, our study demonstrates the pattern of distribution of nasal and pharyngeal colonisation with SA, MRSA and MORSA in adults vs. children, inpatients vs. outpatients, ICU patients vs. non­ICU patients, and females vs. males, which can be used for adjusting the screening and decontamination protocols in a hospital. SA is a pervasive pathogen with constantly changing trends in resistance and epidemiology and thus requires constant monitoring in healthcare facilities.

CYP polymorphisms and pathological conditions related to chronic exposure to organochlorine pesticides.

The association between genetic variations in the cytochrome P450 (CYP) family genes and pathological conditions related to long-term exposure to organochlorine compounds (OCs) deserves further elucidation. OCs are persistent organic pollutants with bioaccumulative and lipophilic characteristics. They can act as endocrine disruptors and perturb cellular mechanisms. Prolonged exposure to OCs has been associated with different pathological manifestations. CYP genes are responsible for transcribing enzymes essential in xenobiotic metabolism. Therefore, polymorphisms in these genetic sequences a. alter the metabolic pathways, b. induce false cellular responses, and c. may provoke pathological conditions. The main aim of this review is to define the interaction between parameters a, b and c at a mechanistic/molecular level, with references in clinical cases.

Environmental exposure to organophosphorus nerve agents.

Exposure to organophosphorus nerve agents, the most deadly chemical warfare agents, is possible in a variety of situations, such as destruction of chemical warfare agents, terrorist attacks, armed conflicts or accidents in research laboratories and storage facilities. Hundreds of thousands of tons of chemical munitions were disposed of at the sea in the post World War II period, with European, Russian, Japanese and US coasts being the most affected. Sulfur mustard, Lewisite and nerve agents appear to be the most frequently chemical warfare agents disposed of at the sea. Addressing the overall environmental risk, it has been one of the priorities of the world community since that time. Aside from confirming exposure to nerve agents in the alleged use for forensic purposes, the detection and identification of biological markers of exposure are also needed for the diagnosis and treatment of poisoning, in addition to occupational health monitoring for specific profiles of workers. When estimating detrimental effects of acute or potential chronic sub-lethal doses of organophosphorus nerve agents, released accidentally or intentionally into the environment, it is necessary to understand the wide spectra of physical, chemical and toxicological properties of these agents, and predict their ultimate fate in environmental systems.

Soyasaponin Ag inhibits α­MSH­induced melanogenesis in B16F10 melanoma cells via the downregulation of TRP­2.

Saponins, which are glycosylated, represent a diverse group of biologically functional products in plants. In the present study, we investigated the effects of soyasaponin Ag, a secondary metabolite extracted from soybean, on α­melanocyte-stimulating hormone (α­MSH)­induced melanin synthesis in B16F10 mouse melanoma cells and the underlying molecular mechanisms. To elucidate the mechanisms through which soyasaponin Ag inhibits melanin synthesis, we performed cellular tyrosinase activity assays and analyzed the expression of the melanogenesis­related genes, tyrosinase, tyrosinase­related protein (TRP)­1 and TRP­2. We demonstrated that soyasaponin Ag inhibited α­MSH­induced melanin synthesis in melanoma cells. Of note, soyasaponin Ag had no inhibitory effect on intracellular tyrosinase activity. However, soyasaponin Ag inhibited TRP­2 expression in a dose­dependent manner. Therefore, the depigmenting effect of soyasaponin Ag may be due to the inhibition of tyrosinase expression or the enhancement of tyrosinase degradation. Moreover, soyasaponin Ag did not exert any toxic on B16F10 mouse melanoma cells, suggesting that soyasaponin is a safe component for use in skin care cosmetic formulations that are used for skin whitening.

Neuroendocrine factors: The missing link in non­melanoma skin cancer (Review).

Non­melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun­protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun­exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well­known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene­related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α­melanocyte­stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.

Update on radionuclide therapy in oncology.

Unstable isotopes and their capacity to emit ionizing radiation have been employed in clinical practice not only for diagnostic, but also for therapeutic purposes, with significant contribution in several fields of medicine and primarily in the management of oncologic patients. Their efficacy is associated with their ability to provide the targeted delivery of ionizing radiation for a determined duration. These compounds can be used for curative or palliative treatment, as well as for a diagnostic-therapeutic (theranostic) approach. This review summarises the most recent trends in radionuclide treatment for several malignancies, including prostate cancer, neuroendocrine tumours, and hematological and thyroid malignancies, in which radionuclide-based therapies have been employed with high effectiveness.