RESUMO
Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.
RESUMO
BACKGROUND: On March 11, 2020, the New Mexico Governor declared a public health emergency in response to the COVID-19 pandemic. The New Mexico medical advisory team contacted University of New Mexico (UNM) faculty to form a team to consolidate growing information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease to facilitate New Mexico's pandemic management. Thus, faculty, physicians, staff, graduate students, and medical students created the "UNM Global Health COVID-19 Intelligence Briefing." OBJECTIVE: In this paper, we sought to (1) share how to create an informative briefing to guide public policy and medical practice and manage information overload with rapidly evolving scientific evidence; (2) determine the qualitative usefulness of the briefing to its readers; and (3) determine the qualitative effect this project has had on virtual medical education. METHODS: Microsoft Teams was used for manual and automated capture of COVID-19 articles and composition of briefings. Multilevel triaging saved impactful articles to be reviewed, and priority was placed on randomized controlled studies, meta-analyses, systematic reviews, practice guidelines, and information on health care and policy response to COVID-19. The finalized briefing was disseminated by email, a listserv, and posted on the UNM digital repository. A survey was sent to readers to determine briefing usefulness and whether it led to policy or medical practice changes. Medical students, unable to partake in direct patient care, proposed to the School of Medicine that involvement in the briefing should count as course credit, which was approved. The maintenance of medical student involvement in the briefings as well as this publication was led by medical students. RESULTS: An average of 456 articles were assessed daily. The briefings reached approximately 1000 people by email and listserv directly, with an unknown amount of forwarding. Digital repository tracking showed 5047 downloads across 116 countries as of July 5, 2020. The survey found 108 (95%) of 114 participants gained relevant knowledge, 90 (79%) believed it decreased misinformation, 27 (24%) used the briefing as their primary source of information, and 90 (79%) forwarded it to colleagues. Specific and impactful public policy decisions were informed based on the briefing. Medical students reported that the project allowed them to improve on their scientific literature assessment, stay current on the pandemic, and serve their community. CONCLUSIONS: The COVID-19 briefings succeeded in informing and guiding New Mexico policy and clinical practice. The project received positive feedback from the community and was shown to decrease information burden and misinformation. The virtual platforms allowed for the continuation of medical education. Variability in subject matter expertise was addressed with training, standardized article selection criteria, and collaborative editing led by faculty.
RESUMO
Current diets contain an increasing amount of salt and high fructose corn syrup, but it remains unclear as to how dietary salt and fructose affect organ function at the molecular level. This study aimed to test the hypothesis that consumption of high salt and fructose diets would increase tissue-specific expression of two critical osmotically-regulated genes, nuclear factor of activated T-cells 5 (NFAT5) and aldose reductase (AR). Fifty Sprague-Dawley rats were placed on a control, 4% NaCl, 8% NaCl, or 64% fructose diet for eight weeks. Fourteen different tissue samples were harvested and snap-frozen, followed by RNA purification, cDNA synthesis, and NFAT5 and AR gene expression quantification by real-time PCR.Our findings demonstrate that NFAT5 and AR expression are up-regulated in the kidney medulla, liver, brain, and adipose tissue following consumption of a high salt diet. NFAT5 expression is also up-regulated in the kidney cortex following consumption of a 64% fructose diet. These findings highlight the kidney medulla, liver, brain, and adipose tissue as being "salt-responsive" tissues and reveal that a high fructose diet can lead to enhanced NFAT5 expression in the kidney cortex. Further characterization of signaling mechanisms involved could help elucidate how these diets affect organ function long term.