Fig. 2

Heat shock response in healthy and in insulin resistant state. In insulin sensitive state, activation of insulin signalling will lead in inhibition of the enzyme GSK-3β (by phosphorylation). In this case, activation of HSR, when stimulated, is normal and HSP72 can maintain NF-κB inhibition, thus an inflammatory balance. Obesity (adipose tissue expansion) and physical inactivity initiates a chronic low-grade inflammation that spread to all tissues. The inflammatory mediators (cytokines, TLR ligands and others) can induce the activation of NF-κB and JNK, leading to ROS/RNS overproduction (by increase activity and expression of inflammatory enzymes) and inhibition of insulin signalling. In the presence of insulin resistance, GSK-3β become activated and inhibits HSF1 activity and expression, resulting in a blunted HSR. Under this circumstance, no inhibition over NF-κB results in amplification of inflammation and no resolution, causing a vicious inflammatory cycle. Heat therapy (hot water immersion or sauna) and exercise can activate HSR and ameliorates insulin signalling and inflammation. Two potential alternative therapies that may be applied to restore HSR and reduce inflammation in SARS-CoV-2 infected patients is the rationale use of antipyretic drugs (allowing increases in temperature, thus improving HSR) and the use of HSR activator drugs, such as the BGP-15