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Cuadrado and colleagues first showed that GSK-3 inhibits NRF2 activity, but the identification of sites in NRF2 that are phosphorylated by GSK-3 was achieved several years later using two-dimensional electrophoresis and mass spectrometry: GSK-3 phosphorylates a group of Ser residues at the level of DSGIS motif in the Neh6 domain of NRF2, and this event represents the signal for the recognition by the adapter protein -TrCP, that targets NRF2 for ubiquitination and proteasomal degradation in a KEAP1-independent manner [150, 151]

The delivery system matters enormously

Semaglutide and tirzepatide may decrease the absorption of other oral medicines due to the delayed gastric-emptying effect

However, adequate fluid intake is essentialpatients should consume at least 8 ounces of water with each dose to prevent paradoxical worsening of constipation or potential bowel obstruction

Some patients find that a slower titration schedule, increasing every six to eight weeks instead of four, eliminates most GI problems