WITHDRAWN: Naringenin attenuates slow-transit constipation by regulating the AMPK/mTOR/ULK1 signaling pathway: In vivo and in vitro studies

Area of Science:

• Gastroenterology
• Cell Biology
• Pharmacology

Background:

• Slow-transit constipation (STC) is characterized by reduced colonic motility.
• Excessive autophagy in interstitial cells of Cajal (ICCs) contributes to colonic dysmotility in STC.
• Naringenin (NAR) is known to modulate gastrointestinal motility.

Purpose of the Study:

• To investigate the regulatory role of Naringenin (NAR) in autophagy within the context of STC.
• To elucidate the underlying molecular mechanisms by which NAR affects ICCs and colonic function in STC.

Main Methods:

• Utilized Loperamide (Lop)-induced STC mouse models and L-Glutamic acid (GA)-induced rat ICC models (in vivo and in vitro).
• Employed techniques including Western blotting, RT-qPCR, co-immunoprecipitation, immunofluorescence, TEM, and IHC to analyze autophagy and signaling pathways.
• Assessed physiological effects on fecal moisture, intestinal propulsion, neurotransmitter levels, and colonic tissue pathology.

Main Results:

• NAR inhibited excessive autophagy in ICCs by partially suppressing the AMPK/mTOR/ULK1 signaling pathway, specifically reducing pT172-AMPK, pS2448-mTOR, and pS757-ULK1.
• NAR weakened the interaction between pS757-ULK1 and autophagy receptors NDP52/OPTN, preventing ULK1 degradation.
• NAR improved STC symptoms in mice, increasing fecal moisture and propulsion, balancing neurotransmitters, and ameliorating colonic damage by upregulating ANO1 and c-Kit.

Conclusions:

• Naringenin (NAR) effectively inhibits excessive autophagy in ICCs via the AMPK/mTOR/ULK1 pathway.
• NAR demonstrates therapeutic potential for treating slow-transit constipation (STC) by improving colonic dysmotility.