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Notably, the cold-induced white-to-brown conversion was demonstrated to arise also when the adrenergic cascade is blocked, highlighting that white adipocytes directly sense temperature variations 54

doi: 10.1038/s41392-021-00470-1 133 KangI.ChangM

Increased BBB permeability mediated by elevated endothelin-1 (ET-1) is a key mechanism of PH [92,93,94], and ET-1 receptor antagonists like bosentan not only alleviate PH symptoms but also exert neuroprotective effects by modulating BBB function [95, 96]

Blockade of the adenosine axis enhances the expression of CD8+ T cells and IFN-, reduces the number of Tregs and MDSCs, thereby augmenting antitumor immune responses (109)

Moreover, unbound volume of distribution in the brain parenchymal cells (V u,cell ) estimated using the brain homogenate method and cerebral microdialysis can be combined with V u,brain to estimate unbound (pro)drug concentration ratio in intra- and extracellular compartments of the brain (K p,uu,cell ) (87)