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A lupus erythematosus-like syndrome is common after prolonged use A lupus-like syndrome occurs in 20-25% of patients on procainamde for more than one year

M.NielsenK

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The title for Figure 4 should be reconsidered as the term "mutually opposite signal modulation" is unclear and/or does not reflect the description to follow. Response: We have replaced the term mutually opposite signal modulation with: amplification of MC3R signaling and attenuation of GHSR1a signaling For Figure 5, the figure legend should clarified if 5-HT2c-GHSR1a dimerization produces reduced Ca++ accumulation with (as appears to be implied by the figure) or without ligand for each receptor. Response: To make it clearer that the 5-HT2C ligand is not required, while the ghrelin ligand is, we have changed the description to read: When dimerized with 5-HT2C, GHSR1a displays a 65% reduction in ghrelin-induced Ca2+ accumulation, with this effect not requiring the presence of a 5-HT2C ligand. Reviewer #2: The review includes an excellent explanation of GSHR1a dimerization with other receptors at the cellular and molecular level and also does a good job of explaining technical aspects of this type of work

In summary, the accumulation of TMAO will not only increase oxidative stress and endothelial cell damage and permeability but also lead to an increase endothelial-derived NOS expression (56), thereby aggravating disease progression