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Our study explores the role of cancer-derived extracellular exosomes (EXs), particularly focusing on collagen alpha-3 (VI; COL6A3), in facilitating tumor dissemination and metastasis in epithelial ovarian cancer (EOC). We found that COL6A3 is expressed in aggressive ES2 derivatives, SKOV3 overexpressing COL6A3 (SKOV3/COL6A3), and mesenchymal-type ovarian carcinoma stromal progenitor cells (MSC-OCSPCs), as well as their EXs, but not in less aggressive SKOV3 cells or ES2 cells with COL6A3 knockdown (ES2/shCOL6A3). High COL6A3 expression correlates with worse overall survival among EOC patients, as evidenced by TCGA and GEO data analysis. In vitro experiments showed that EXs from MSC-OCSPCs or SKOV3/COL6A3 cells significantly enhance invasion ability in ES2 or SKOV3/COL6A3 cells, respectively (both, p <0.001). In contrast, ES2 cells with ES2/shCOL6A3 EXs exhibited reduced invasion ability (p < 0.001). In vivo, the average disseminated tumor numbers in the peritoneal cavity were significantly greater in mice receiving intraperitoneally injected SKOV3/COL6A3 cells than in SKOV3 cells (p < 0.001). Furthermore, mice intravenously (IV) injected with SKOV3/COL6A3 cells and SKOV3/COL6A3-EXs showed increased lung colonization compared to mice injected with SKOV3 cells and PBS (p = 0.007) or SKOV3/COL6A3 cells and PBS (p = 0.039). Knockdown of COL6A3 or treatment with EX inhibitor GW4869 or rapamycin-abolished COL6A3-EXs may suppress the aggressiveness of EOC. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide, and its pathophysiology is characterized by oxidative stress and inflammation. Despite extensive research, effective treatments for TBI remain elusive. Recent studies highlighted the critical interplay between TBI and circadian rhythms, but the detailed regulation remains largely unknown. Motivated by the observed sustained decrease in Rev-erbα after TBI, we aimed to understand the critical role of Rev-erbα in the pathophysiology of TBI and determine its feasibility as a therapeutic target. Using a mouse model of TBI, we observed that TBI significantly downregulates Rev-erbα levels, exacerbating inflammatory and oxidative stress pathways. The regulation of Rev-erbα with either the pharmacological activator or inhibitor bidirectionally modulated inflammatory and oxidative events, which in turn influenced neurobehavioral outcomes, highlighting the protein's protective role. Mechanistically, Rev-erbα influences the expression of key oxidative stress and inflammatory regulatory genes. A reduction in Rev-erbα following TBI likely contributes to increased oxidative damage and inflammation, creating a detrimental environment for neuronal survival and recovery which could be reversed via the pharmacological activation of Rev-erbα. Our findings highlight the therapeutic potential of targeting Rev-erbα to mitigate TBI-induced damage and improve outcomes, especially in TBI-susceptible populations with disrupted circadian regulation. [ABSTRACT FROM AUTHOR]

Background: Platelets, a type of anucleated cell, play a crucial role in cardiovascular diseases (CVDs). Therefore, targeting platelet activation is essential for mitigating CVDs. Endogenous agonists, such as collagen, activate platelets by initiating signal transduction through specific platelet receptors, leading to platelet aggregation. Eugenol, primarily sourced from clove oil, is known for its antibacterial, anticancer, and anti-inflammatory properties, making it a valuable medicinal agent. In our previous study, eugenol was shown to inhibit platelet aggregation induced by collagen and arachidonic acid. We concluded that eugenol exerts a potent inhibitory effect on platelet activation by targeting the PLCγ2–PKC and cPLA2-TxA2 pathways, thereby suppressing platelet aggregation. In our current study, we found that eugenol significantly inhibits NF-κB activation. This led us to investigate the relationship between the NF-κB and cPLA2 pathways to elucidate how eugenol suppresses platelet activation. Methods: In this study, we prepared platelet suspensions from the blood of healthy human donors to evaluate the inhibitory mechanisms of eugenol on platelet activation. We utilized immunoblotting and confocal microscopy to analyze these mechanisms in detail. Additionally, we assessed the anti-thrombotic effect of eugenol by observing fluorescein-induced platelet plug formation in the mesenteric microvessels of mice. Results: For immunoblotting and confocal microscopy studies, eugenol significantly inhibited NF-κB-mediated signaling events stimulated by collagen in human platelets. Specifically, it reduced the phosphorylation of IKK and p65 and prevented the degradation of IκBα. Additionally, CAY10502, a cPLA2 inhibitor, significantly reduced NF-κB-mediated signaling events. In contrast, BAY11-7082, an IKK inhibitor, did not affect collagen-stimulated cPLA2 phosphorylation. These findings suggest that cPLA2 acts as an upstream regulator of NF-κB activation during platelet activation. Furthermore, both BAY11-7082 and CAY10502 significantly reduced the collagen-induced rise in intracellular calcium levels. In the animal study, eugenol demonstrated potential as an anti-thrombotic agent by significantly reducing platelet plug formation in fluorescein-irradiated mouse mesenteric microvessels. Conclusion: Our study uncovered a novel pathway in platelet activation involving the cPLA2-NF-κB axis, which plays a key role in the antiplatelet effects of eugenol. These findings suggest that eugenol could serve as a valuable and potent prophylactic or therapeutic option for arterial thrombosis. [ABSTRACT FROM AUTHOR]

We develop a tractable nonparametric model for the time-varying reproductive rate of infectious diseases that combines the structure of a deterministic compartmental model and a stochastic model for incidence data. We use Bayesian inference to estimate, with uncertainty, the reproductive rate of the Coronavirus 2019 outbreak in the U.S. states of California, Florida, Michigan, New Mexico, New York, and Texas from January 2020 to March 2022. Employing the inferred reproductive rates, we estimate the posterior distribution of the time-varying reproduction numbers for each state. Compering the time-varying reproduction numbers across the states, we identify some epidemic waves, potentially driven from changes in human behavior and virus mutations. [ABSTRACT FROM AUTHOR]