Abstract Objectives Cross sectional surveys have reported that alcohol consumption has skyrocketed during the COVID-19 pandemic. Chronic alcohol use triggers systemic inflammation which leads to neuroinflammation and neurodegeneration. In the present study, we hypothesize that alcohol consumption and cytokine elevation during inflammatory conditions synergistically increase amyloid-beta precursor protein (APP) expression and worsens Alzheimer’s disease (AD) pathology. Methods QIAGEN Ingenuity Pathway Analysis (IPA) was employed to conduct network meta-analysis on the molecular mechanisms underlying ethanol (EtOH) influence on APP expression and AD in inflammatory conditions including COVID-19, inflammation of respiratory system, organ, absolute anatomical region, body cavity, joint, respiratory system component, gastrointestinal tract, large intestine, liver, central nerve system, and lung. IPA tools were utilized to identify the molecules associated with EtOH, inflammatory conditions and the common molecules between them. Results Simulation activity of EtOH, mimicking exposure to alcohol, upregulated the APP expression and augmented AD pathology in all inflammatory conditions including COVID-19. Our studies identified six molecules including ADORA2A, Cytokine, IFN-gamma, IL1-beta, Immunoglobulin and TNF, which concurrently contribute to increased APP expression and AD progression upon EtOH simulation in all diseases studied. Conclusions The present study has revealed molecular mechanisms underlying alcohol augmentation of AD in COVID-19 and other diseases of inflammation.
Alcohol is the most widely used addictive substance. Severe alcohol abuse is diagnosed as "alcohol use disorder" (AUD). A common and harmful drinking pattern is binge drinking that elevates a person's blood alcohol concentration to ≥ 0.08%. Such drinking may be an early indicator of AUD. Opioid misuse and dependence have become worldwide crises. Patterned consumption of various opioids can develop into opioid use disorder (OUD). An intertwined epidemic exists between opioid abuse, alcohol addiction, and binge drinking. Currently, studies on the interaction of AUD and OUD are limited and the underlying mechanisms linking these disorders remains unclear. We reviewed studies on AUD and OUD and utilized Ingenuity Pathway Analysis (IPA) to identify mechanisms of AUD and OUD interaction and potential gene targets for therapeutic agents. According to IPA Canonical Pathways Analysis, Gamma-aminobutyric Acid (GABA) Receptor Signaling, Neuroinflammation Signaling Pathway, Opioid Signaling Pathway and Dopamine-DARPP32 Feedback in cAMP Signaling are potential contributors to the interaction of AUD and OUD.
Abstract Objectives During physical and psychosocial development, many adolescents engage in binge alcohol drinking. Ethanol (EtOH) is the key chemical in alcoholic beverages. EtOH intoxication impairs locomotor behaviors. We previously found that binge treatment with EtOH (BE) causes spleen atrophy, leading to immune dysregulation. With these premises, we hypothesized that BE-induced spleen atrophy is correlated with compromised locomotion and behaviors in adolescence. Methods We exposed F344 rats to either 3 days of BE (mimicking college drinking) or water following pubertal onset. 24 h following the last BE, we assessed behaviors using ANY-Maze, focusing on locomotor activity, freezing, and thigmotaxis, before spleen collection. Correlation analysis and Linear Regression analysis quantified BE’s effects on behavior. In parallel, we used GEO2R to obtain differentially expressed genes (DEGs) from public dataset GSE49028 (B6129Sf2/J mice were given BE) and identified signaling pathways in the prefrontal cortex (PFC) involved in BE compromising locomotion and increasing anxiety. Results BE significantly decreased spleen size. Interestingly, we found that BE exposure had a gender-dependent impact, affecting males more than females. Furthermore, functional analysis of the dataset identified several targets of interest including the downregulation of BDNF as a critical regulator of behavioral deficit following BE treatment. Conclusions Using data-driven discovery and hypothesis-testing investigation to integrate these two studies, we provide an understanding of the underlying biological mechanism of BE-induced spleen atrophy-associated behavioral impairments through the genetic alterations in the PFC. Our findings will help develop a potent, powerful cocktail of reagents to treat behavioral impairment in those who binge drink.
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