Meptazinol Hydrochloride

Contaminants of emerging concern receive increasing attention in the Arctic environment. The aim of this study was to screen for chemicals of emerging Arctic concern (CEACs) in different types of Arctic samples including biota, air and human serum. We used a combination of gas chromatography (GC) and liquid chromatography (LC) with high resolution mass spectrometry (HRMS) for suspect and non-target screening (NTS). Suspect screening of 25 CEACs was based on published in-silico approaches for the identification of CEACs and revealed tetrabromophthalic anhydride (TBPA) in pilot whale and air, albeit with low detection frequencies (17 and 33%, respectively). An NTS workflow detected 49, 42, 31 and 30 compounds in pilot whale, ringed seal, air, and human serum, respectively, at confidence level 2 and 3. Although legacy POPs still dominated the samples, 64 CEACs were tentatively identified and further assessed for persistence (P), bioaccumulation (B), mobility (M), toxicity (T), and long-range transport potential (LRTP). While four PBT compounds were identified, 37 PMT substances dominated among these 64 compounds. Our study indicated that many chemicals of potential risk might be present in Arctic samples and would benefit from confirmation and further studies of their transport to and accumulation in the Arctic environment.

The pathogenesis of Alzheimer’s disease (AD) involves multiple pathophysiological processes. Oxidative stress is a major cause of AD-associated neuronal injury. The current research was designed to examine whether a novel (-)-meptazinol-serotonin hybrid (Mep-S) with potent antioxidant activity and additional inhibitory properties for acetylcholinesterase (AChE) activity could attenuate oxidative neuronal damage and cognitive deficits. In human SH-SY5Y cells, Mep-S suppressed H2O2-induced apoptosis by restoring mitochondrial membrane potential and inhibiting caspase-3 activation. Meanwhile, it attenuated oxidative stress elicited by H2O2 through lessening generation of reactive oxygen species as well as enhancing production of glutathione (GSH) and activity of superoxide dismutase (SOD). Mechanistically, Mep-S promoted nuclear translocation of a transcription factor nuclear factor E2-related factor-2 (Nrf2) in H2O2-challenged cells. This effect was accompanied by reduction in Kelch-like ECH-associated protein-1 (Keap1) levels as well as augmentation of Akt phosphorylation and expression of heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1 (NQO-1). Molecular docking analysis revealed that Mep-S may disrupt the protein-protein interactions between Keap1 and Nrf2. In an in vivo mouse model, Mep-S attenuated scopolamine-caused cognitive deficits with inhibition of apoptotic neuronal death and brain AChE activity. Furthermore, the scopolamine-induced impairment of total antioxidant capacity and reduction in SOD1, SOD2, and γ-glutamate-cysteine ligase expression in the brain were counteracted by Mep-S, accompanied by decreased Keap1 levels, increased Akt catalytic subunit and Nrf2 phosphorylation, and decreased Nrf2, HO-1, and NQO-1 expression. Collectively, our results suggest that Mep-S ameliorates apoptotic neuronal death and memory dysfunction associated with oxidative stress by regulating the Nrf2/antioxidant enzyme pathway through inactivating Keap1 and phosphorylating Nrf2 via Akt activation. Therefore, Mep-S may be a potential lead for multitarget neuroprotective agents to treat AD-like symptoms.