Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation and a critical regulator of metabolic flexibility during the fasting to feeding transition. PDH is regulated via both PDH kinases (PDHK) and PDH phosphatases, which phosphorylate/inactivate and dephosphorylate/activate PDH, respectively. Our goal was to determine whether the transcription factor forkhead box O1 (FoxO1) regulates PDH activity and glucose oxidation in the heart via increasing the expression of , the gene encoding PDHK4. To address this question, we differentiated H9c2 myoblasts into cardiac myocytes and modulated FoxO1 activity, after which/PDHK4 expression and PDH phosphorylation/activity were assessed. We assessed binding of FoxO1 to the promoter in cardiac myocytes in conjunction with measuring the role of FoxO1 on glucose oxidation in the isolated working heart. Both pharmacological (1 µM AS1842856) and genetic (siRNA mediated) inhibition of FoxO1 decreased/PDHK4 expression and subsequent PDH phosphorylation in H9c2 cardiac myocytes, whereas 10 µM dexamethasone-induced /PDHK4 expression was abolished via pretreatment with 1 µM AS1842856. Furthermore, transfection of H9c2 cardiac myocytes with a vector expressing FoxO1 increased luciferase activity driven by a promoter construct containing the FoxO1 DNA-binding element region, but not in a promoter construct lacking this region. Finally, AS1842856 treatment in fasted mice enhanced glucose oxidation rates during aerobic isolated working heart perfusions. Taken together, FoxO1 directly regulates transcription in the heart, thereby controlling PDH activity and subsequent glucose oxidation rates. Although studies have shown an association between FoxO1 activity and pyruvate dehydrogenase kinase 4 expression, our study demonstrated that pyruvate dehydrogenase kinase 4 is a direct transcriptional target of FoxO1 (but not FoxO3/FoxO4) in the heart. Furthermore, we report here, for the first time, that FoxO1 inhibition increases glucose oxidation in the isolated working mouse heart.

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Highlights d Skeletal muscle SCOT expression and activity are elevated in obesity d Selective elimination of skeletal muscle SCOT activity improves glycemia in obese mice d Pimozide is a SCOT antagonist that improves glycemia in obese mice d SCOT antagonism within skeletal muscle improves glycemia by increasing PDH activity

Introduction: Favipiravir is a repurposed drug to treat coronavirus 2019 . Due to a lack of available real-world data, we assessed its effectiveness and safety in moderately to critically ill COVID-19 patients. Methods: This retrospective study was conducted in two public/specialty hospitals in Saudi Arabia. We included patients !18 years) admitted April-August 2020 with confirmed SARS-CoV-2 diagnosed by real-time polymerase chain reaction (RT-PCR) from nasopharyngeal swab. Patients received either favipiravir (1800 mg or 1600 mg twice daily loading dose, followed by 800 mg or 600 mg twice daily) or supportive-care treatment. Patients were excluded if they were outside the study period, classified as having a mild form of the disease per WHO criteria, or had an incomplete patient file. Kaplan-Meier (KM) models were used to estimate median time to discharge. Discharge ratios, progression to mechanical ventilation, and mortality outcomes were estimated across the severity spectrum using Cox proportional-hazards models. As a sensitivity analysis, we performed propensity score-matching (PSM) analysis. Results: Overall, median time to discharge was 10 days (95%CI ¼ 9-10) in the favipiravir arm versus 15 days (95%CI ¼ 14-16) in the supportive-care arm. The accelerated discharge benefit was seen across the COVID-19 spectrum of severity. The adjusted discharge ratio was 1.96 (95%CI ¼ 1.56-2.46). Progression to mechanical ventilation was slower with favipiravir (HR adj ¼ 0.10, 95%CI ¼ 0.04-0.29). There was no significant effect on mortality (HR adj ¼ 1.56, 95%CI ¼ 0.73-3.36). There was a statistically non-significant trend toward worse outcomes in the critical category (HR adj ¼ 2.80, 95%CI ¼ 0.99-7.89). Age was an independent risk factor for mortality in mechanically ventilated patients. PSM analyses confirmed these findings. Conclusion: Favipiravir was associated with clinical benefits, including accelerated discharge rate and less progression to mechanical ventilation; however, no overall mortality benefits were seen across the severity spectrum.

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