Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

Masahiro Sakagami

Second Advisor

Douglas H Sweet

Third Advisor

Sandro da Rocha

Fourth Advisor

Shijun Zhang

Fifth Advisor

Apparao Kummarapurugu


Lung fibrosis is a progressive disease with a mean survival time of 3-5 years after diagnosis. More than 50% of lung fibrosis are unknown causes. Two FDA-approved PF treatment drugs, pirfenidone (PIR) and nintedanib (NTB), can moderately slow lung function decline without enhancing survival. a Curcumin(CUR)-like derivate of Meltonion(MEL), AM24, showed more potent in inhibiting TGF-β1/PDGF-induced fibrotic conditions than CUR and MEL, better or equal anti-fibrotic activities compared to PIR and NTB, and altered the anti-fibrotic effects through collagenolytic activities; AM24 possessed the potent dual-action activities of inhibiting fibroblast activation and collagen synthesis and boosting the collagenolytic enzyme activity, at least in part by the mechanism involving the MEL receptor. In the animal lung fibrosis model, local delivery of AM24 had better therapeutic effects than systemic administration under late intervention conditions.

At 10 µM, AM24 inhibited TGF-β1 induced 1) proliferation by 85% 2) collagen qualitatively and semi-quantitatively>100%, and 3) differentiation to myofibroblast by 40%,4) migration>100%. AM24 inhibited PDGF induced 1) proliferation by 95% 2) collagen qualitatively and semi-quantitatively>100%, and 3) differentiation to myofibroblast>100%, 4) migration>100%. the AM24 treatment with local lung delivery was capable of 1) improving the exercise endurance by 70%; 2) restoring the Ashcroft score to 0; 3) lowering the collagen and hydroxyproline contents by 78% and 92%, respectively; 4) decreasing the expressions of collagen, a-SMA and TGF-b by >100%, >100%, and 80%, respectively; and notably, 5) boosting the CatL/CysC expression ratio up by 36%.


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Available for download on Tuesday, September 21, 2027