Doxycycline (DOX), a derivative of tetracycline, is a broad-spectrum antibiotic that exhibits a number of therapeutic activities in addition to its antibacterial properties. For example, DOX has been used in the management of a number of diseases characterized by chronic inflammation. One potential mechanism by which DOX inhibits the progression of these diseases is by reducing oxidative stress, thereby inhibiting subsequent lipid peroxidation and inflammatory responses. Herein, we tested the hypothesis that DOX directly scavenges reactive oxygen species (ROS) and inhibits the formation of redox-mediated malondialdehyde-acetaldehyde (MAA) protein adducts. Using a cell-free system, we demonstrated that DOX scavenged reactive oxygen species (ROS) produced during the formation of MAA-adducts and inhibits the formation of MAA-protein adducts. To determine whether DOX scavenges specific ROS, we examined the ability of DOX to directly scavenge superoxide and hydrogen peroxide. Using electron paramagnetic resonance (EPR) spectroscopy, we found that DOX directly scavenged superoxide, but not hydrogen peroxide. Additionally, we found that DOX inhibits MAA-induced activation of Nrf2, a redox-sensitive transcription factor. Together, these findings demonstrate the under-recognized direct antioxidant property of DOX that may help to explain its therapeutic potential in the treatment of conditions characterized by chronic inflammation and increased oxidative stress.

Obesity-induced insulin resistance is a risk factor for diabetes and cardiovascular disease. However, the mechanisms underlying endothelial senescence in obesity, and how it impacts obesity-induced insulin resistance remain incompletely understood. In this study, transcriptome analysis revealed that the long non-coding RNA (lncRNA) Maternally expressed gene 3 (Meg3) is one of the top differentially expressed lncRNAs in the vascular endothelium in diet-induced obese mice. Meg3 knockdown induces cellular senescence of endothelial cells characterized by increased senescence-associated β–galactosidase activity, increased levels of endogenous superoxide, impaired mitochondrial structure and function, and impaired autophagy. Moreover, Meg3 knockdown causes cellular senescence of hepatic endothelium in diet-induced obese mice. Furthermore, Meg3 expression is elevated in human nonalcoholic fatty livers and nonalcoholic steatohepatitis livers, which positively correlates with the expression of CDKN2A encoding p16, an important hallmark of cellular senescence. Meg3 knockdown potentiates obesity-induced insulin resistance and impairs glucose homeostasis. Insulin signaling is reduced by Meg3 knockdown in the liver and, to a lesser extent, in the skeletal muscle, but not in the visceral fat of obese mice. We found that the attenuation of cellular senescence of hepatic endothelium by ablating p53 expression in vascular endothelium can restore impaired glucose homeostasis and insulin signaling in obesity. In conclusion, our data demonstrate that cellular senescence of hepatic endothelium promotes obesity-induced insulin resistance, which is tightly regulated by the expression of Meg3. Our results suggest that manipulation of Meg3 expression may represent a novel approach to managing obesity-associated hepatic endothelial senescence and insulin resistance.

Substantial, involved, and expensive efforts to promote the dissemination of scientific knowledge and career interest in Science, Technology, Engineering, and Mathematics (STEM) are enthusiastically supported by many scientific, federal, and local organizations. The articulated underlying goals for these efforts include an enhanced public understanding of science and science-related policy, an increased diversity in STEM careers, and an increase in the future STEM workforce. This effort is primarily driven by an underperformance of the United States that includes poor test performance and limited number of students pursuing STEM degrees. Despite this investment, attitudes toward STEM have not notably changed. The goal of this project was to determine students’ attitudes toward STEM in response to a previously established scientific outreach event. This event was used to address three common goals in STEM outreach: STEM literacy, diversity and inclusion, and career preparedness. We found there was a notable difference in the attitudes toward scientific activities and interest in pursuing a “Science Career” after participation in this event. Strikingly, interest in hypothesis development, the keystone of all STEM disciplines, was the least liked of all the activities offered during the event. Our data suggest that events designed to enhance interest in pursuing a STEM career may benefit from different elements compared with events designed to increase understanding of STEM literacy concepts, such as hypothesis development.

Background: Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) remain at risk for developing neurocognitive impairment primarily due to systemic inflammation that persists despite virologic suppression, albeit the mechanisms underlying such inflammation are poorly understood. Methods: Herein, we evaluate the predictive capacity of the mitochondrial redox environment on circulating neuro-and T-lymphocyte-related inflammation and concomitant cognitive function in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-theart systems biology approaches including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance (EPR) spectroscopy to measure superoxide levels, antioxidant activity assays, and Meso Scale multiplex technology to quantify inflammatory proteins in the periphery. Findings: We observed disturbances in mitochondrial function and the redox environment in PLWH compared to controls, which included reduced mitochondrial capacity (t(76) = À1.85, p = 0.034, 95% CI: À1,À0.13), elevated levels of superoxide (t(75) = 1.70, p = 0.047, 95% CI: 8.01 E 3, 1) and alterations in antioxidant defense mechanisms (t(74) = 1.76, p = 0.041, 95% CI: À710.92, 1). Interestingly, alterations in both superoxide-and hydrogen peroxide-sensitive redox environments were differentially predictive of neuro-, but not T-lymphocyte-related inflammatory profiles in PLWH and controls, respectively (ps < 0.026). Finally, when accounting for superoxide-sensitive redox pathways, neuroinflammatory profiles significantly predicted domain-specific cognitive function across our sample (b = À0.24, p = 0.034, 95% CI: À0.09, À0.004 for attention; b = À0.26, p = 0.018, 95% CI: À0.10, À0.01 for premorbid function).Interpretation: Our results suggest that precursors to neuroinflammation apparent in PLWH (i.e., mitochondrial function and redox environments) predict overall functionality and cognitive dysfunction and importantly, may serve as a proxy for characterizing inflammation-related functional decline in the future.

No abstract