Hippocampal astrocytes induce sex-dimorphic effects on memory.

Astrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the effects of astrocytic receptors are dependent on sex. We leveraged in vivo gene editing and chemogenetics to examine the roles of astrocytic receptors in spatial memory and other processes. We show that reductions in metabotropic glutamate receptor 3 (mGluR3), the main astrocytic glutamate receptor in adults, impair memory in females but enhance memory in males. Similarly, increases in astrocytic mGluR3 levels have sex-dependent effects and enhance memory in females. mGluR3 manipulations also alter spatial search strategies during recall in a sex-specific manner. In addition, acute chemogenetic stimulation of Gi/o-coupled or Gs-coupled receptors in hippocampal astrocytes induces bidirectional and sex-dimorphic effects on memory. Thus, astrocytes are sex-dependent modulators of cognitive function and may promote sex differences in aging and disease.

Recent updates on biomarkers of exposure and systemic toxicity in e-cigarette users and EVALI.

Electronic nicotine delivery systems (ENDS), or e-cigarettes, are emerging tobacco products that produce aerosols by heating e-liquids, which most often consist of propylene glycol and vegetable glycerin along with various flavoring compounds, bypassing the combustion that occurs in the use of traditional tobacco cigarettes. These products have seen a drastic increase in popularity in recent years both as smoking cessation devices as well as among younger generations, due in large part to the widespread perception among consumers that e-cigs are significantly less harmful to health than traditional tobacco cigarettes. Due to the novelty of ENDS as well as their rapidly increasing use, research into biomarkers of e-cig exposure and toxicity have lagged behind their popularity, leaving important questions about their potential toxicity unanswered. Research into potential biomarkers of acute and chronic e-cig use, and e-cigarette- or vaping-associated lung injury is necessary for informing both clinical and regulatory decision-making. We aim to provide an updated review of recent research into potential circulating, genomic, transcriptomic, and epigenetic biomarkers of exposure to and toxicity of e-cigs. We additionally highlight research areas that warrant additional study to gain a better understanding of health risks associated with ENDS use, as well as to provide validation of existing data and methods for measuring and analyzing e-cig-associated biomarkers in human and animal biofluids, tissues, and cells. This review also highlights ongoing efforts within the WNY Center for Research on Flavored Tobacco for research into novel biomarkers in extracellular vesicles that may be associated with short- and long-term ENDS use.

E-cigarette-induced pulmonary inflammation and dysregulated repair are mediated by nAChR α7 receptor: role of nAChR α7 in SARS-CoV-2 Covid-19 ACE2 receptor regulation.

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.

Systemic biomarkers in electronic cigarette users: implications for noninvasive assessment of vaping-associated pulmonary injuries.

BACKGROUND: Electronic cigarettes (e-cigs) were introduced as electronic nicotine delivery systems, and have become very popular in the USA and globally. There is a paucity of data on systemic injury biomarkers of vaping in e-cig users that can be used as a noninvasive assessment of vaping-associated lung injuries. We hypothesised that characterisation of systemic biomarkers of inflammation, anti-inflammatory, oxidative stress, vascular and lipid mediators, growth factors, and extracellular matrix breakdown may provide information regarding the toxicity of vaping in e-cig users. METHODS: We collected various biological fluids, i.e. plasma, urine, saliva and exhaled breath condensate (EBC), measured pulmonary function and vaping characteristics, and assessed various biomarkers in e-cig users and nonusers. RESULTS: The plasma samples of e-cig users showed a significant increase in biomarkers of inflammation (interleukin (IL)-1ß, IL-6, IL-8, IL-13, interferon (IFN)-γ, matrix metalloproteinase-9, intercellular cell adhesion molecule-1) and extracellular matrix breakdown (desmosine), and decreased pro-resolving lipid mediators (resolvin D1 and resolvin D2). There was a significant increase in growth factor (endothelial growth factor, vascular endothelial growth factor, ß-nerve growth factor, platelet-derived growth factor-AA, stem cell factor, hepatocyte growth factor and placental growth factor) levels in plasma of e-cig users versus nonusers. E-cig users showed a significant increase in levels of inflammatory biomarker IFN-γ, oxidative stress biomarker 8-isoprostane and oxidative DNA damage biomarker 8-oxo-dG in urine samples, and of inflammatory biomarker IL-1ß in saliva samples. EBC showed a slight increase in levels of triglycerides and 8-isoprostane in e-cig users compared with normal nonusers. CONCLUSION: E-cig users have increased levels of biomarkers of inflammation and oxidative stress, reduced pro-resolving anti-inflammatory mediators, and endothelial dysfunction, which may act as risk factors for increasing susceptibility to systemic diseases. The identified noninvasive biomarkers can be used for determining e-cig vaping-associated lung injuries, and for regulatory and diagnostic aspects of vaping in humans.

Dysregulated repair and inflammatory responses by e-cigarette-derived inhaled nicotine and humectant propylene glycol in a sex-dependent manner in mouse lung.

Nicotine inhalation via electronic cigarettes (e-cigs) is an emerging concern. However, little is known about the acute toxicity in the lungs following inhalation of nicotine-containing e-cig aerosols. We hypothesized that acute exposure to aerosolized nicotine causes lung toxicity by eliciting inflammatory and dysregulated repair responses. Adult C57BL/6J mice were exposed 2 h daily for 3 days to e-cig aerosols containing propylene glycol (PG) with or without nicotine. Acute exposure to nicotine-containing e-cig aerosols induced inflammatory cell influx (neutrophils and CD8a+ T-lymphocytes), and release of pro-inflammatory cytokines in bronchoalveolar lavage fluid in a sex-dependent manner. Inhalation of e-cig aerosol containing PG alone significantly augmented the lung levels of various homeostasis/repair mediators (PPARγ, ADRP, ACTA2, CTNNB1, LEF1, ß-catenin, E-cadherin, and MMP2) in a sex-dependent manner when compared to air controls. These findings were accompanied by an increase in protein abundance and altered gene expression of lipogenic markers (PPARγ, ADRP) and myogenic markers (fibronectin, α-smooth muscle actin and ß-catenin), suggesting a dysregulated repair response in mouse lungs. Furthermore, exposure to nicotine containing e-cig aerosols or PG alone differentially affected the release of pro-inflammatory cytokines in healthy and COPD human 3D EpiAirway tissues. Overall, acute exposure to nicotine containing e-cig aerosols was sufficient to elicit a pro-inflammatory response and altered mRNA and protein levels of myogenic, lipogenic, and extracellular matrix markers in mouse lung in a sex-dependent manner. Thus, acute exposure to inhaled nicotine via e-cig leads to dysregulated repair and inflammatory responses, which may lead to airway remodeling in the lungs.