Natural Product P57 Induces Hibernation-like State through Targeting Pyridoxal Kinase

Abstract

Hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hibernation-like or torpor state in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in rodents. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly recuperated in the mice with knockout of PDXK in medial preoptic area (MPA). We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and both directly activate MPA neurons to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hibernation-like state in rodents.

Transformers: Statistical Interpretation, Architectures and Applications

“…Actually, translation is also a kind of classification issue. The encoder structure in transformer framework analyze each tokens and produce a score matrix [35], [36], [37]. The score matrix go into the decoder attention layer [38], [39] which searches for the best match for each token.…”