Role of glucocorticoids in neutrophil and endothelial adhesion molecule expression and function

Glucocorticoids are very effective inhibitors of both the acute and chronic inflammatory response. In this study the hypothesis that glucocorticoids inhibit an early component of the inflammatory response, neutrophil adhesion to endothelium, by down-regulation of adhesion molecules on neutrophils or endothelium was examined. No effect of dexamethasone on neutrophil adhesion to endothelium or of antigen expression by neutrophils or endothelium was found. The mechanism of action of glucocorticoids in the inflammatory response is probably not mediated by alterations in adhesion molecules

Identification of Cytotoxic Flavor Chemicals in Top-Selling Electronic Cigarette Refill Fluids.

We identified the most popular electronic cigarette (EC) refill fluids using an Internet survey and local and online sales information, quantified their flavor chemicals, and evaluated cytotoxicities of the fluids and flavor chemicals. "Berries/Fruits/Citrus" was the most popular EC refill fluid flavor category. Twenty popular EC refill fluids were purchased from local shops, and the ingredient flavor chemicals were identified and quantified by gas chromatography-mass spectrometry. Total flavor chemical concentrations ranged from 0.6 to 27.9 mg/ml, and in 95% of the fluids, total flavor concentration was greater than nicotine concentration. The 20 most popular refill fluids contained 99 quantifiable flavor chemicals; each refill fluid contained 22 to 47 flavor chemicals, most being esters. Some chemicals were found frequently, and several were present in most products. At a 1% concentration, 80% of the refill fluids were cytotoxic in the MTT assay. Six pure standards of the flavor chemicals found at the highest concentrations in the two most cytotoxic refill fluids were effective in the MTT assay, and ethyl maltol, which was in over 50% of the products, was the most cytotoxic. These data show that the cytotoxicity of some popular refill fluids can be attributed to their high concentrations of flavor chemicals

High concentrations of flavor chemicals are present in electronic cigarette refill fluids.

We characterized the flavor chemicals in a broad sample of commercially available electronic cigarette (EC) refill fluids that were purchased in four different countries. Flavor chemicals in 277 refill fluids were identified and quantified by gas chromatography-mass spectrometry, and two commonly used flavor chemicals were tested for cytotoxicity with the MTT assay using human lung fibroblasts and epithelial cells. About 85% of the refill fluids had total flavor concentrations >1 mg/ml, and 37% were >10 mg/ml (1% by weight). Of the 155 flavor chemicals identified in the 277 refill fluids, 50 were present at ≥1 mg/ml in at least one sample and 11 were ≥10 mg/ml in 54 of the refill fluids. Sixty-one% (170 out of 277) of the samples contained nicotine, and of these, 56% had a total flavor chemical/nicotine ratio >2. Four chemicals were present in 50% (menthol, triacetin, and cinnamaldehyde) to 80% (ethyl maltol) of the samples. Some products had concentrations of menthol ("Menthol Arctic") and ethyl maltol ("No. 64") that were 30 times (menthol) and 100 times (ethyl maltol) their cytotoxic concentration. One refill fluid contained cinnamaldehyde at ~34% (343 mg/ml), more than 100,000 times its cytotoxic level. High concentrations of some flavor chemicals in EC refill fluids are potentially harmful to users, and continued absence of any regulations regarding flavor chemicals in EC fluids will likely be detrimental to human health

Neurotrophic properties of C-terminal domain of the heavy chain of tetanus toxin on motor neuron diseases

The carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts a neuroprotective effect in neurodegenerative diseases via the activation of signaling pathways related to neurotrophins, and also through inhibiting apoptotic cell death. Here, we demonstrate that Hc-TeTx preserves motoneurons from chronic excitotoxicity in an in vitro model of amyotrophic lateral sclerosis. Furthermore, we found that PI3-K/Akt pathway, but not p21ras/MAPK pathway, is involved in their beneficial effects under chronic excitotoxicity. Moreover, we corroborate the capacity of the Hc-TeTx to be transported retrogradely into the spinal motor neurons and also its capacity to bind to the motoneuron-like cell line NSC-34. These findings suggest a possible therapeutic tool to improve motoneuron preservation in neurodegenerative diseases such as amyotrophic lateral sclerosis

Chemical Elements, Flavor Chemicals, and Nicotine in Unused and Used Electronic Cigarettes Aged 5–10 Years and Effects of pH

The concentrations of elements/metals, nicotine, flavor chemicals and acids were compared in the e-liquids of unused and used first-generation electronic cigarettes (ECs) that were stored for 5–10 years. Metal analysis was performed using inductively coupled plasma optical emission spectroscopy; nicotine and flavor chemical analyses were performed using gas chromatography/mass spectroscopy. Of the 22 elements analyzed, 10 (aluminum, chromium, copper, iron, lead, nickel, selenium, silicon, tin, zinc) were often found in the e-liquids. Five elements had the highest average concentrations: copper (1161.6 mg/L), zinc (295.8 mg/L), tin (287.6 mg/L), nickel (71.1 mg/L), and lead (50.3 mg/L). Nicotine concentrations were always lower than label concentrations indicated. Of the 181 flavor chemicals analyzed, 11 were detected in at least one sample, with hydroxyacetone being present in all samples. In used products, some flavor chemicals appeared to be by-products of heating. E-liquids with the highest concentrations of acids and the lowest pH levels also had the highest concentrations of elements/metals. Metal concentrations in e-liquids increased after use in some products, and some metal concentrations, such as nickel, were high enough to be a health concern. Leachates from discarded ECs could contribute toxic metals/chemicals to the environment, supporting the need for better regulation of atomizer design, composition, and disposal

Ethyl Maltol, Vanillin, Corylone and other Conventional Confectionery-related Flavour Chemicals Dominate in Some E-cigarette Liquids Labelled ‘tobacco’ flavoured

Background The increased popularity of electronic cigarettes (e-cigarettes) has been linked to the abundance of flavoured products that are attractive to adolescents and young adults. In the last decade, e-cigarette designs have evolved through four generations that include modifications in battery power, e-cigarette liquid (e-liquid) reservoirs and atomiser units. E-liquids have likewise evolved in terms of solvent use/ratios, concentration and number of flavour chemicals, use of nicotine salts and acids, the recent increased use of synthetic cooling agents and the introduction of synthetic nicotine. Our current objective was to evaluate and compare the evolving composition of tobacco-flavoured e-liquids over the last 10 years. Methods Our extensive database of flavour chemicals in e-liquids was used to identify trends and changes in flavour chemical composition and concentrations. Results Tobacco-flavoured products purchased in 2010 and 2011 generally had very few flavour chemicals, and their concentrations were generally very low. In tobacco-flavoured refill fluids purchased in 2019 and Puff Bar Tobacco e-cigarettes, the total number and concentration of flavour chemicals were higher than expected. Products with total flavour chemicals \u3e10 mg/mL contained one to five dominant flavour chemicals (\u3e1 mg/mL). The most frequently used flavour chemicals in tobacco e-liquids were fruity and caramellic. Conclusions There is a need for continuous surveillance of e-liquids, which are evolving in often subtle and harmful ways. Chemical constituents of tobacco flavours should be monitored as they clearly can be doctored by manufacturers to have a taste that would appeal to young users

TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy

<p>Abstract</p> <p>Background</p> <p>Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA).</p> <p>Results</p> <p>TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1^G93Amice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords.</p> <p>Conclusion</p> <p>These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.</p

Hyperexcitability in young iPSC-derived C9ORF72 mutant motor neurons is associated with increased intracellular calcium release

S.B. was supported by a Motor Neuron Disease Association studentship (WadeMartins/Oct13/867-792) and D.A.B was supported by the Monument Trust Discovery Award (J-1403) from Parkinson’s UK. The work was supported by the Medical Research Council Dementias Platform UK Stem Cell Network (Grant MR/M024962/1 to RW-M).A large hexanucleotide repeat expansion in the C9ORF72 gene is the most prevalent cause of amyotrophic lateral sclerosis (ALS). To better understand neuronal dysfunction during ALS progression, we studied motor neuron (MN) cultures derived from iPSC lines generated from C9ORF72 (C9) expansion carriers and unaffected controls. C9 and control MN cultures showed comparable mRNA levels for MN markers SMI-32, HB9 and ISL1 and similar MN yields (> 50% TUJ1/SMI-32 double-positive MNs). Using whole-cell patch clamp we showed that C9-MNs have normal membrane capacitance, resistance and resting potential. However, immature (day 40) C9-MNs exhibited a hyperexcitable phenotype concurrent with increased release of calcium (Ca2+) from internal stores, but with no changes to NaV and KV currents. Interestingly, this was a transient phenotype. By day 47, maturing C9-MNs demonstrated normal electrophysiological activity, displaying only subtle alterations on mitochondrial Ca2+ release. Together, these findings suggest the potential importance of a developmental component to C9ORF72-related ALS.Publisher PDFPeer reviewe