ABSTRACT
Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity, but it also sheds light on the mechanism of its action. Pyruvate's prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.
ABSTRACT
Purpose: RECOVERY, ACTT-1, and ACTT-2 trials have demonstrated that utilization of dexamethasone, remdesivir, or a combination of remdesivir with baricitinib leads to mortality benefit and faster time to recovery, respectively. However, no studies have investigated the benefit of triple therapy of dexamethasone, remdesivir, and baricitinib. We investigate the benefits of triple therapy compared to dual therapy of dexamethasone with remdesivir in patients with severe COVID-19 on HFNC. Materials and Methods: A retrospective data analysis was performed on patients with severe COVID-19 requiring HFNC and evaluated for hospital discharge status, requirement of mechanical ventilation, length of stay, and days on HFNC. Results: Among 191 patients with severe COVID-19, 81 patients received dexamethasone, remdesivir, and baricitinib. Patients receiving triple therapy had a significant survival benefit (HR 0.52; P=0.042). Treatment with triple therapy vs. dual therapy also trended towards less requirement of mechanical ventilation (OR 0.66; P=0.26). There was no significant change in length of stay (mean 13.74 vs. 13.31; P=0.74) or days on HFNC (mean 8.95 vs. 7.28 days, P=0.16). Conclusions: The use of dexamethasone, remdesivir, and baricitinib in patients with severe COVID-19 requiring HFNC was associated with a significant survival benefit in comparison to dual therapy of dexamethasone with remdesivir.
