EC pharmacology and toxicology最新文献

Alzheimer's disease (AD) is the most common form of senile dementia and it is characterized by cognitive, motor and memory impairments. AD neuropathology includes toxic biomarkers, such as Aβ amyloid protein buildup between neurons disrupting connections, tau protein fibrillization and neuronal demise. These biomarkers are exacerbated with exposure to environmental borne or man-made nanoparticles or engineered nanomaterials (ENMs) as these nanoparticles are becoming more widely adopted for industrial applications. Studies suggest a link between nanoparticle exposure and neurotoxic responses, thus suggesting a contribution to AD pathology. This review summarizes research in the field of nanoparticles in terms of neurotoxic changes in the nervous system, as well as its relation to AD pathology. Studies involving silver, silica, copper oxide and iron oxide nanoparticles in mice suggest ranging neurotoxic reactions, such as disrupted neural connections, neuroinflammation, neuron cell death, redox stress, impairment of the blood-brain barrier (BBB), decrease in motor performance, demyelination of axons, decrease in long-term potentiation (LTP) and damage to DNA and brain structures. This review also examines beneficial effects of certain nanoparticles as potential therapeutic or diagnostic tools for AD.

Methylene diphenyl diisocyanate (MDI), the most abundantly produced diisocyanate worldwide, is among the best recognized chemical causes of occupational asthma. The bulk of synthesized MDI, the 4,4' isomer, has been the focus of most biochemical research to date. The biological reactivity of other MDI isomers (2,2' and 2,4'), present at concentrations approaching 50% in some commercial products, remains less clear. We hypothesized 2,2' and 2,4' MDI react with glutathione (GSH), a major anti-oxidant of the lower airways, similarly to 4,4' MDI, and that the products could be characterized using a combination of LC-UV-MS and MS/MS. Purified 2,2' and 2,4' MDI isomers were mixed with GSH in pH-buffered aqueous phase at 37°C and reaction products were analyzed at varying time points. Within minutes, S-linked bis(GSH)-MDI conjugates were detectable as the dominant [M+H]⁺ ion, with an 865.25 m/z and more intense [M+2H]²⁺ ions of the same nominal mass. Upon longer reaction, [M+H]+ ions with greater retention times and the 558.17 m/z expected for mono(GSH)-MDI reaction products were observed, and exhibited MS/MS collision-induced dissociation (CID)-fragmentation patterns consistent with cyclized structures. Compared with 4,4' MDI, 2,2' and 2,4' isomers exhibit similar rapid reactivity with GSH and formation of bis(GSH)-MDI conjugates, but greater formation of cyclized mono(GSH) conjugates following extended reaction times (10 minutes to 2 hours). Further translational studies will be required to determine if the present in vitro findings extend to the complex lower airway microenvironment in vivo.

The monoamine neurotransmitter serotonin (5-HT) plays a role in many physiological responses by interacting with various receptor subtypes. The 5-HT_2C receptor subtype is a 7-transmembrane, G protein-coupled receptor (GPCR) that is involved in neuronal excitability, spatial learning, mood, and appetite. The microorganism Chromobacterium violaceum produces a purple pigment, violacein, which can be extracted and purified. Violacein has antibiotic, antileishmanial, antifungal and antitumoral properties in various cancer cell lines. Violacein is derived from the amino acid tryptophan as is 5-HT and therefore, the two have similar chemical structures. However, no one has reported the activity of violacein at 5-HT receptors. Therefore the Fentress lab decided to investigate whether or not violacein had an effect on 5-HT_2C receptor trafficking. Human Embryonic Kidney (HEK) 293 cells expressing fluorescently-tagged 5-HT_2C receptor were treated with 5-HT, violacein, water or vehicle and then cells were fixed and visualized with fluorescent microscopy. Violacein treatment did not cause receptor internalization. Recent studies suggest that the 5-HT_2C receptor can activate the JAK/STAT pathway. To see if violacein can modulate this pathway, HEK 293 cells expressing 5-HT_2C receptor were treated with either 5-HT, violacein, or pretreated with violacein followed by incubation with 5-HT. Phosphorylation states of JAK2 and STAT3 were examined by immunoblotting. Results determined that 5-HT_2C receptor activation had no effect on JAK2 phosphorylation and that violacein blocked STAT3 phosphorylation. Primary radioligand binding determined that violacein has a low affinity for 5-HT_2C receptor but has a higher affinity for adrenergic receptors. Future studies will examine G protein-coupling by measuring phosphoinositide hydrolysis and cAMP assay to investigate adrenergic pathways.

Recent studies indicate that hyperbaric oxygen therapy (HBOT), a well-established therapy for decompression illness, could be a potential therapy for Alzheimer's disease (AD). However, due to oxygen toxicity i.e., increased oxidative stress implicated in HBOT, the risk and benefit of HBOT for AD patients need to be further assessed clinically.

Drug development pipeline inefficiency has called for more novel solutions and cutting-edge technologies. Artificial intelligence (AI)-based methods including different machine- and deep-learning algorithms have been employed for virtual drug screening. With the continuous refinement of algorithms, improvement of computing hardware, and increased availability of molecular datasets for drug development, it is certainly a prime time for AI-powered virtual drug screening.