The differing effects of a dual acting regulator on SIRT1.

SIRT1 is an NAD+-dependent protein deacetylase that has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism, and neurodegeneration. There is great interest in understanding the regulation of SIRT1 to better understand SIRT1-related diseases and to better design therapeutic approaches that target SIRT1. There are many known protein and small molecule activators and inhibitors of SIRT1. One well-studied SIRT1 regulator, resveratrol, has historically been regarded as a SIRT1 activator, however, recent studies have shown that it can also act as an inhibitor depending on the identity of the peptide substrate. The inhibitory nature of resveratrol has yet to be studied in detail. Understanding the mechanism behind this dual behavior is crucial for assessing the potential side effects of STAC-based therapeutics. Here, we investigate the detailed mechanism of substrate-dependent SIRT1 regulation by resveratrol. We demonstrate that resveratrol alters the substrate recognition of SIRT1 by affecting the K M values without significantly impacting the catalytic rate (k cat). Furthermore, resveratrol destabilizes SIRT1 and extends its conformation, but the conformational changes differ between the activation and inhibition scenarios. We propose that resveratrol renders SIRT1 more flexible in the activation scenario, leading to increased activity, while in the inhibition scenario, it unravels the SIRT1 structure, compromising substrate recognition. Our findings highlight the importance of substrate identity in resveratrol-mediated SIRT1 regulation and provide insights into the allosteric control of SIRT1. This knowledge can guide the development of targeted therapeutics for diseases associated with dysregulated SIRT1 activity.

Arterial Monitoring in Hypertensive Emergencies: Significance for the Critical Care Resuscitation Unit.

INTRODUCTION: Blood pressure measurement is important for treating patients. It is known that there is a discrepancy between cuff blood pressure vs arterial blood pressure measurement. However few studies have explored the clinical significance of discrepancies between cuff (CPB) vs arterial blood pressure (ABP). Our study investigated whether differences in CBP and ABP led to change in management for patients with hypertensive emergencies and factors associated with this change. METHODS: This prospective observational study included adult patients admitted between January 2019-May 2021 to a resuscitation unit with hypertensive emergencies. We defined clinical significance of discrepancies as a discrepancy between CBP and ABP that resulted in change of clinical management. We used stepwise multivariable logistic regression to measure associations between clinical factors and outcomes. RESULTS: Of 212 patients we analyzed, 88 (42%) had change in management. Mean difference between CBP and ABP was 17 milligrams of mercury (SD 14). Increasing the existing rate of antihypertensive infusion occurred in 38 (44%) patients. Higher body mass index (odds ratio [OR] 1.04, 95% confidence Interval [CI] 1.0001-1.08, P-value <0.05) and history of peripheral arterial disease (OR 0.16, 95% CI 0.03-0.97, P-value <0.05) were factors associated with clinical significance of discrepancies. CONCLUSION: Approximately 40% of hypertensive emergencies had a clinical significance of discrepancy warranting management change when arterial blood pressure was initiated. Further studies are necessary to confirm our observations and to investigate the benefit-risk ratio of ABP monitoring.

Discrepancy Between Invasive and Noninvasive Blood Pressure Measurements in Patients with Sepsis by Vasopressor Status.

INTRODUCTION: Blood pressure (BP) monitoring is an essential component of sepsis management. The Surviving Sepsis Guidelines recommend invasive arterial BP (IABP) monitoring, although the benefits over non-invasive BP (NIBP) monitoring are unclear. This study investigated discrepancies between IABP and NIBP measurement and their clinical significance. We hypothesized that IABP monitoring would be associated with changes in management among patients with sepsis requiring vasopressors. METHODS: We performed a retrospective study of adult patients admitted to the critical care resuscitation unit at a quaternary medical center between January 1-December 31, 2017. We included patients with sepsis conditions AND IABP monitoring. We defined a clinically significant BP discrepancy (BPD) between NIBP and IABP measurement as a difference of > 10 millimeters of mercury (mm Hg) AND change of BP management to maintain mean arterial pressure ≥ 65 mm Hg. RESULTS: We analyzed 127 patients. Among 57 (45%) requiring vasopressors, 9 (16%) patients had a clinically significant BPD vs 2 patients (3% odds ratio [OR] 6.4; 95% CI: 1.2-30; P = 0.01) without vasopressors. In multivariable logistic regression, higher Sequential Organ Failure Assessment (SOFA) score (OR 1.33; 95% CI: 1.02-1.73; P = 0.03) and serum lactate (OR 1.27; 95% CI: 1.003-1.60, P = 0.04) were associated with increased likelihood of clinically significant BPD. There were no complications (95% CI: 0-0.02) from arterial catheter insertions. CONCLUSION: Among our population of septic patients, the use of vasopressors was associated with increased odds of a clinically significant blood pressure discrepancy between IABP and NIBP measurement. Additionally, higher SOFA score and serum lactate were associated with higher likelihood of clinically significant blood pressure discrepancy. Further studies are needed to confirm our observations and investigate the benefits vs the risk of harm of IABP monitoring in patients with sepsis.

Complication of vasopressor infusion through peripheral venous catheter: A systematic review and meta-analysis.

BACKGROUND: Vasopressors are mainstay treatment for patients in shock and are usually infused through central venous catheters (CVCs). However, CVCs are associated with risk of infection or delay from the needs of confirmation of placement. Infusing vasopressor through peripheral venous catheter (PIVs) could be an alternative in the Emergency Departments (ED) but data regarding complications is inconclusive. We performed a random-effects meta-analysis to assess literature involving prevalence of complications from infusing vasopressors via PIVs. METHODS: We searched PubMed, EMBASE and Scopus databases from beginnings to 02/02/2020 to identify relevant randomized control trials, cohort, case-control studies. We excluded case reports. Authors assessed studies' quality with Newcastle-Ottawa Scale and Cochrane Risk of Bias tool. Kappa score was used to assess interrater agreement. Outcome was complications as direct results from infusing vasopressors through PIVs. RESULTS: We identified 325 articles and included 9 studies after reviewing 16 full text articles. Our analysis included 1835 patients whose mean age was 63 (Standard Deviation 12) years and 48% was female. There were 122 (7%) complications, of which 117 (96%) were minor. The meta-analysis with random effects showed the pooled prevalence of complications as 0.086 (95%CI 0.031-0.21). Studies reporting infusion safety guidelines had significantly lower prevalence of complications (0.029, 95%CI 0.018-0.045), compared to those not reporting a safety guideline (0.12, 95%CI 0.038-0.30, p = 0.024). CONCLUSION: There was low prevalence of complications as a direct result from infusing vasopressors through PIVs. Studies with safety guidelines were associated with significantly lower prevalence of complications. Further studies are needed to confirm our observations.