Aims: We hypothesized that critically ill patients with SARS-CoV-2 infection and insulin resistance would present a reduced Heat Shock Response (HSR), which is a pathway involved in proteostasis and anti-inflammation, subsequently leading to worse outcomes and higher inflammation. In this work we aimed: (i) to measure the concentration of extracellular HSP72 (eHSP72) in patients with severe COVID-19 and in comparison with noninfected patients; (ii) to compare the HSR between critically ill patients with COVID-19 (with and without diabetes); and (iii) to compare the HSR in these patients with noninfected individuals. Methods: Sixty critically ill adults with acute respiratory failure with SARS-CoV-2, with or without diabetes, were selected. Noninfected subjects were included for comparison (healthy, n = 19 and patients with diabetes, n = 22). Blood samples were collected to measure metabolism (glucose and HbA1c); oxidative stress (lypoperoxidation and carbonyls); cytokine profile (IL-10 and TNF); eHSP72; and the HSR (in vitro). Results: Patients with severe COVID-19 presented higher plasma eHSP72 compared with healthy individuals and noninfected patients with diabetes. Despite the high level of plasma cytokines, no differences were found between critically ill patients with COVID-19 with or without diabetes. Critically ill patients, when compared to noninfected, presented a blunted HSR. Oxidative stress markers followed the same pattern. No differences in the HSR (extracellular/intracellular level) were found between critically ill patients, with or without diabetes. Conclusions: We demonstrated that patients with severe COVID-19 have elevated plasma eHSP72 and that their HSR is blunted, regardless of the presence of diabetes. These results might explain the uncontrolled inflammation and also provide insights on the increased risk in developing type 2 diabetes after SARS-CoV-2 infection.

To evaluate the effect of preventive aerobic exercise training on sympathovagal function, cardiac function, and DNA repair capacity in a preclinical model of doxorubicin (DOX)-induced cardiomyopathy. Forty male Wistar-Kyoto rats were allocated into four groups (n = 10/group): D (DOX-treated) and C (controls) remained sedentary, and DT (DOX-trained) and CT (control-trained) performed aerobic training 4 days/week, during 4 weeks before exposure to DOX (4 mg/kg/week during 4 weeks) or saline solution. We evaluated cardiac function (echocardiography), hemodynamic and sympathovagal modulation (artery-femoral cannulation), cardiac troponin T levels, and DNA repair capacity (comet assay). Exercise training preserved ejection fraction (D: − 14.44% vs. DT: − 1.05%, p < 0.001), fractional shortening (D: − 8.96% vs. DT: − 0.27%, p = 0.025) and troponin T levels (D: 6.4 ± 3.6 vs. DT: 2.8 ± 1.7 ng/mL, p = 0.010). DOX increased heart rate variability (C: 27.7 ± 7.9 vs. D: 7.5 ± 2.2 ms², p < 0.001) and induced sympathovagal dysfunction (LF/HF, C: 0.37 ± 0.15 vs. D: 0.15 ± 0.15, p = 0.036) through exacerbation of sympathetic function (LF, C: 0.22 ± 0.01 vs. D: 0.48 ± 0.24 Hz, p = 0.019). Peripheral mononuclear blood cells of DT animals presented lower residual DNA damage (D: 43.4 ± 8.4% vs. DT: 26 ± 3.4%, p = 0.003 after 1 h). Cardioprotective effects of preventive aerobic exercise training are mediated by preservation of sympathovagal function and improvement of DNA repair capacity of peripheral blood mononuclear cells.

BACKGROUND: Interventions capable of modulating the heat shock response (HSR), such as physical exercise and heat therapy (HT), are potential therapeutic strategies for the prevention and treatment of diabetes.

Obesity constitutes a growing global health concern, affecting individuals during the aging process. Flavonoids that increase tissue NAD+ levels, such as apigenin (Api), are proposed for the treatment of obesity and age-related diseases. Thus, this study aimed to provide initial preclinical evidence of Api in this setting using middle-aged rats induced to obesity by a high-calorie diet (HCD). Forty-seven 15-month-old male Wistar rats were assigned to five groups: standard diet (SD) or HCD, each with (Api at 50 mg/kg) or without treatment (vehicle), plus vehicle control group. Obesity induction and therapeutic intervention were conducted concurrently for 88 days. Biometric, cardiac, adiposity, muscular, and blood biochemical parameters were analyzed. Eighty-eight days post HCD rats had hyperglycemia, hypertriglyceridemia, increased visceral and subcutaneous fat, and heart hypertrophy, indicating obesity and related disorders (p < 0.05 for all). The gastrocnemius of these rats exhibits reduced mass, smaller myocytes, and fibrosis (p < 0.05), indicating sarcopenia, likely caused or worsened by obesity. In parallel, preemptive Api treatment failed to prevent obesity and did not affect key adipose tissue browning genes, cardiac oxidative stress markers, or sirtuin and CD38 levels. However, it mitigated muscle loss and hypotrophy, in addition to elevating p70S6K levels in HCD-fed rats (p < 0.05 for both). These preclinical results suggest that although Api may not prevent some HCD-induced disturbances, it may attenuate age- and obesity-related atrophy via p70S6K anabolic signaling in middle-aged rats. To support clinical translation, particularly in sarcopenia subtypes, further mechanistic and therapeutic investigations on Api are required to elucidate its effects on skeletal muscle.

Background: Physical inactivity induces insulin resistance (IR) and metabolic imbalances before any significant changes in adiposity. Recent studies suggest that the beneficial effects of exercise can be potentiated if performed while fasting. This work aimed to compare the subacute effects of fed- and fasted-state single-bout exercise on biochemical parameters and cellular signaling in the metabolism. Methods: The animals were allocated into fed rest (FER), fasting rest (FAR), fed exercise (FEE), and fasting exercise (FAE) groups. The exercise protocol was a 30 min treadmill session at 60% of $\dot{\mathrm{V}}$O_2max. The fasting groups fasted for 8 h before exercise and were killed after 12 h post-exercise. Results: Soleus glycogen concentration increased only in the fasting groups, whereas the triglyceride (TGL) content increased in brown adipose tissue (BAT) and liver in the FAE. The FAE showed decreased plasma total cholesterol concentration compared withthe FAR group. Immunocontent of HSP70, SIRT1, UCP-1, and PGC1-α did not change in any tissue investigated. Conclusions: Our results indicate that physical exercise while fasting can have beneficial metabolic effects on sedentary animals. Remarkably, in the FAE group, there was a reduction in total plasma cholesterol and an increase in the capacity of BAT to metabolize and store nutrients in the form of TGLs.