The brain-liver cholinergic anti-inflammatory pathway and viral infections.

Efferent cholinergic signaling is a critical and targetable source of immunoregulation. The vagus nerve (VN) is the primary source of cholinergic signaling in the body, and partially innervates hepatic functionality through the liver-brain axis. Virus-induced disruption of cholinergic signaling may promote pathogenesis in hepatotropic and neurotropic viruses. Therefore, restoring VN functionality could be a novel therapeutic strategy to alleviate pathogenic inflammation in hepatotropic and neurotropic viral infections alike. In this minireview, we discuss the physiological importance of cholinergic signaling in maintaining liver-brain axis homeostasis. Next, we explore mechanisms by which the VN is perturbed by viral infections, and how non-invasive restoration of cholinergic signaling pathways with bioelectronic medicine (BEM) might ameliorate hepatic inflammation and neuroinflammation in certain viral infections.

Methamphetamine induces transcriptional changes in cultured HIV-infected mature monocytes that may contribute to HIV neuropathogenesis.

HIV-associated neurocognitive impairment (HIV-NCI) persists in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy. HIV-NCI significantly impacts quality of life, and there is currently no effective treatment for it. The development of HIV-NCI is complex and is mediated, in part, by the entry of HIV-infected mature monocytes into the central nervous system (CNS). Once in the CNS, these cells release inflammatory mediators that lead to neuroinflammation, and subsequent neuronal damage. Infected monocytes may infect other CNS cells as well as differentiate into macrophages, thus contributing to viral reservoirs and chronic neuroinflammation. Substance use disorders in PWH, including the use of methamphetamine (meth), can exacerbate HIV neuropathogenesis. We characterized the effects of meth on the transcriptional profile of HIV-infected mature monocytes using RNA-sequencing. We found that meth mediated an upregulation of gene transcripts related to viral infection, cell adhesion, cytoskeletal arrangement, and extracellular matrix remodeling. We also identified downregulation of several gene transcripts involved in pathogen recognition, antigen presentation, and oxidative phosphorylation pathways. These transcriptomic changes suggest that meth increases the infiltration of mature monocytes that have a migratory phenotype into the CNS, contributing to dysregulated inflammatory responses and viral reservoir establishment and persistence, both of which contribute to neuronal damage. Overall, our results highlight potential molecules that may be targeted for therapy to limit the effects of meth on HIV neuropathogenesis.

Mitochondrial Dysfunction and the Glycolytic Switch Induced by Caveolin-1 Phosphorylation Promote Cancer Cell Migration, Invasion, and Metastasis.

Cancer cells often display impaired mitochondrial function, reduced oxidative phosphorylation, and augmented aerobic glycolysis (Warburg effect) to fulfill their bioenergetic and biosynthetic needs. Caveolin-1 (CAV1) is a scaffolding protein that promotes cancer cell migration, invasion, and metastasis in a manner dependent on CAV1 phosphorylation on tyrosine-14 (pY14). Here, we show that CAV1 expression increased glycolysis rates, while mitochondrial respiration was reduced by inhibition of the mitochondrial complex IV. These effects correlated with increased reactive oxygen species (ROS) levels that favored CAV1-induced migration and invasion. Interestingly, pY14-CAV1 promoted the metabolic switch associated with increased migration/invasion and augmented ROS-inhibited PTP1B, a phosphatase that controls pY14 levels. Finally, the glycolysis inhibitor 2-deoxy-D-glucose reduced CAV1-enhanced migration in vitro and metastasis in vivo of murine melanoma cells. In conclusion, CAV1 promotes the Warburg effect and ROS production, which inhibits PTP1B to augment CAV1 phosphorylation on tyrosine-14, thereby increasing the metastatic potential of cancer cells.

The Scope and Impact of the COVID-19 Pandemic on Neuroemergent Patient Transfers, Clinical Care and Patient Outcomes.

Introduction: The SARS-CoV-2 (COVID-19) pandemic continues to substantially alter previously established clinical practice patterns and has transformed patient care in American healthcare. However, studies to evaluate the impact of COVID-19 on neuroemergent patient care and associated clinical outcomes are limited. Herein, we describe the impact of COVID-19 on the Neuroemergency Transfer Program (NTP) - a novel, urban, high volume interhospital patient transfer program. Objective: To evaluate and describe the clinical impact of the COVID-19 pandemic on the NTP. Study Design: A single-center retrospective study of prospectively collected consecutive neuroemergent patient transfer data between 2018-2021 was analyzed. Adult patients were divided based upon transfer date into a Pre-COVID (PCOV) or COVID cohort. Patient demographics, transfer characteristics and clinical data and outcomes were analyzed. Results: 3,096 patients were included for analysis. Mean age at transfer in the PCOV and COVID cohorts were 62.4 ± 0.36 and 61.1 ± 0.6 years. A significant decrease in mean transfers per month was observed between cohorts (PCOV = 97.8 vs. COV = 68.2 transfers/month, p < 0.01). Total transfer time in the PCOV cohort was 155.1 ± 3.4 min which increased to 169.3 ± 12.8 min in the COVID cohort (p = 0.13). Overall mean transfer distance was significantly longer in the PCOV cohort at 22.0 ± 0.4 miles vs. 20.3 ± 0.67 miles in the COV cohort (p = 0.03). The relative frequency of transfer diagnoses was unchanged between cohorts. A significant increase in mean inpatient length of stay was noted, 7.9 ± 0.15 days to 9.6 ± 0.33 days in the PCOV vs. COVID cohorts (p < 0.01). Ultimately, no difference in the frequency of good vs. poor clinical outcome were noted between the PCOV (79.8% and 19.4%) vs. COV (78.8% and 20.4%) cohorts. Conclusion: The impact of COVID-19 on current healthcare dynamics are far reaching. Here, we show a significant decrease in interhospital patient transfers and increased length of stay between a Pre-COVID and COVID cohort. Further work to better elucidate the specific interplay of clinical contributors to account for these changes is indicated.

Application of Force to a Syndecan-4 Containing Complex With Thy-1-αVß3 Integrin Accelerates Neurite Retraction.

Inflammation contributes to the genesis and progression of chronic diseases, such as cancer and neurodegeneration. Upregulation of integrins in astrocytes during inflammation induces neurite retraction by binding to the neuronal protein Thy-1, also known as CD90. Additionally, Thy-1 alters astrocyte contractility and movement by binding to the mechano-sensors αVß3 integrin and Syndecan-4. However, the contribution of Syndecan-4 to neurite shortening following Thy-1-αVß3 integrin interaction remains unknown. To further characterize the contribution of Syndecan-4 in Thy-1-dependent neurite outgrowth inhibition and neurite retraction, cell-based assays under pro-inflammatory conditions were performed. In addition, using Optical Tweezers, we studied single-molecule binding properties between these proteins, and their mechanical responses. Syndecan-4 increased the lifetime of Thy-1-αVß3 integrin binding by interacting directly with Thy-1 and forming a ternary complex (Thy-1-αVß3 integrin + Syndecan-4). Under in vitro-generated pro-inflammatory conditions, Syndecan-4 accelerated the effect of integrin-engaged Thy-1 by forming this ternary complex, leading to faster neurite retraction and the inhibition of neurite outgrowth. Thus, Syndecan-4 controls neurite cytoskeleton contractility by modulating αVß3 integrin mechano-receptor function. These results suggest that mechano-transduction, cell-matrix and cell-cell interactions are likely critical events in inflammation-related disease development.

AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells.

: The renin-angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling axis that promotes metastasis in melanoma, colon, and breast cancer cells. Here, we evaluated whether the antimetastatic effect of AT2R is connected to inhibition of this pathway. We found that murine melanoma B16F10 cells expressed AT2R, while MDAMB-231 human breast cancer cells did not. AT2R activation blocked migration, transendothelial migration, and metastasis of B16F10(cav-1) cells, and this effect was lost when AT2R was silenced. Additionally, AT2R activation reduced transendothelial migration of A375 human melanoma cells expressing CAV1. The relevance of AT2R was further underscored by showing that overexpression of the AT2R in MDA-MB-231 cells decreased migration. Moreover, AT2R activation increased non-receptor protein tyrosine phosphatase 1B (PTP1B) activity, decreased phosphorylation of CAV1 on tyrosine-14 as well as Rab5/Rac1 activity, and reduced lung metastasis of B16F10(cav-1) cells in C57BL/6 mice. Thus, AT2R activation reduces migration, invasion, and metastasis of cancer cells by PTP1B-mediated CAV1 dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway. In doing so, these observations open up interesting, novel therapeutic opportunities to treat metastatic cancer disease.

Estudio de la actividad procoagulante de las plaquetas en el síndrome de Bernard Soulier / Procoagulant activity of platelets study in the Bernard Soulier's syndrome

En el síndrome de Bernard soulier (SBS) han sido demostradas alteraciones específicas que dan lugar a un trastorno en la adhesividad plaquetaria. También se le han atribuido otros defectos que condicionan una alteración en el actividad procoagulante de sus mismas plaquetas, los cuales no han logrado definirse satisfactoriamente. En el presente trabajo se estduió el efecto procoagulante de las plaquetas, en cuatro pacientes con SBS, comparándolo con los resultados en controles sanos y enfermos trombocitopénica, para tal fin se efectuaron modificaciones en el cosumo de protrombina (CP) y tiempo de recalcificación del plasma, para evaluar el efecto de la trombocitopenia y el de plasmas con deficiencias intensas y específicas de factores de coagulación V, VIII y XI sobre el mecanismo procoagulante de las plaquetas con SBS. Los resultados observados difieren de los informados por otros investigadores, pues no se detectó ningún defecto en la actividad procoagulante en las plaquetas de los pacientes con SBS, considerando que su actividad procoagulante es normal, o bien, que existan variante de dicho síndrome