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Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy in immune cells.

Biochem Pharmacol; 152: 45-59, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29551587
Canagliflozin (CAN) regulates intracellular glucose metabolism by targeting sodium-glucose co-transporter 2 (SGLT2) and intracellular glucose metabolism affects inflammation. In this study, we hypothesized that CAN might exert anti-inflammatory effects. The anti-inflammatory effects and action mechanisms of CAN were assayed in lipopolysaccharide (LPS)-induced RAW264.7 and THP-1 cells and NIH mice. Results showed that CAN significantly inhibited the production and release of interleukin (IL)-1, IL-6, or tumor necrosis factor-α (TNF-α) in the LPS-induced RAW264.7 and THP-1 cells, and mice. CAN also significantly inhibited intracellular glucose metabolism and 6-phosphofructo-2-kinase (PFK2) expression. CAN increased the levels of sequestosome-1 (SQSTM1/p62), upregulated the ratios of microtubule-associated protein 1A/1B-light chain 3 (LC3) II to I, promoted the formation of LC3 puncta, and enhanced the activities of lysosome. The inhibition of autophagy by 3-methyladenine (3-MA) reversed the effects of CAN on IL-1α levels. Increased autophagy might be associated with increased AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, p62 demonstrated good co-localization with IL-1α and possibly mediated IL-1α degradation. CAN-induced increase in p62 was dependent on the nuclear factor kappa B (NFκB) signaling pathway. These results indicated that CAN might exert anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy. Attenuated glucose metabolism by PFK2, increased autophagy flow by AMPK, and increased p62 levels by NFκB might be responsible for the molecular mechanisms of CAN. This drug might serve as a new promising anti-inflammatory drug for acute or chronic inflammatory diseases via independent hypoglycemic mechanisms. This drug might also be used as an important reference for similar drug research and development by targeting intracellular glucose metabolism and autophagy in immune cells.