PMID- 36098401
OWN - NLM
STAT- MEDLINE
DCOM- 20221021
LR  - 20231002
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Print)
IS  - 0193-1857 (Linking)
VI  - 323
IP  - 4
DP  - 2022 Oct 1
TI  - Urolithin A attenuates severity of chronic pancreatitis associated with continued 
      alcohol intake by inhibiting PI3K/AKT/mTOR signaling.
PG  - G375-G386
LID - 10.1152/ajpgi.00159.2022 [doi]
AB  - Heavy alcohol consumption is the dominant risk factor for chronic pancreatitis 
      (CP); however, treatment and prevention strategies for alcoholic chronic 
      pancreatitis (ACP) remains limited. The present study demonstrates that ACP 
      induction in C57BL/6 mice causes significant acinar cell injury, pancreatic 
      stellate cell (PSC) activation, exocrine function insufficiency, and an increased 
      fibroinflammatory response when compared with alcohol or CP alone. Although the 
      withdrawal of alcohol during ACP recovery led to reversion of pancreatic damage, 
      continued alcohol consumption with established ACP perpetuated pancreatic injury. 
      In addition, phosphokinase array and Western blot analysis of ACP-induced mice 
      pancreata revealed activation of the phosphatidylinositol 3 kinase 
      (PI3K)/AKT/mammalian target of rapamycin (mTOR) and cyclic AMP response element 
      binding protein (CREB) signaling pathways possibly orchestrating the 
      fibroinflammatory program of ACP pathogenesis. Mice treated with urolithin A (Uro 
      A, a gut-derived microbial metabolite) in the setting of ACP with continued 
      alcohol intake (during the recovery period) showed suppression of AKT and P70S6K 
      activation, and acinar damage was significantly reduced with a parallel reduction 
      in pancreas-infiltrating macrophages and proinflammatory cytokine accumulation. 
      These results collectively provide mechanistic insight into the impact of Uro A 
      on attenuation of ACP severity through suppression of PI3K/AKT/mTOR signaling 
      pathways and can be a useful therapeutic approach in patients with ACP with 
      continuous alcohol intake.NEW & NOTEWORTHY Our novel findings presented here 
      demonstrate the utility of Uro A as an effective therapeutic agent in attenuating 
      alcoholic chronic pancreatitis (ACP) severity with alcohol continuation after 
      established disease, through suppression of the PI3K/AKT/mTOR signaling pathway.
FAU - Mehra, Siddharth
AU  - Mehra S
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Srinivasan, Supriya
AU  - Srinivasan S
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Singh, Samara
AU  - Singh S
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Zhou, Zhiqun
AU  - Zhou Z
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Garrido, Vanessa
AU  - Garrido V
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Silva, Iago De Castro
AU  - Silva IC
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Totiger, Tulasigeri M
AU  - Totiger TM
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Dosch, Austin R
AU  - Dosch AR
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Dai, Xizi
AU  - Dai X
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
FAU - Dawra, Rajinder K
AU  - Dawra RK
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
AD  - Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
FAU - Jala, Venkatakrishna Rao
AU  - Jala VR
AD  - Department of Microbiology and Immunology, University of Louisville, Louisville, 
      Kentucky.
FAU - Shi, Chanjuan
AU  - Shi C
AD  - Department of Pathology, Duke University School of Medicine, Durham, North 
      Carolina.
FAU - Datta, Jashodeep
AU  - Datta J
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
AD  - Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
FAU - VanSaun, Michael
AU  - VanSaun M
AD  - Department of Cancer Biology, University of Kansas Medical Center, Kansas City, 
      Kansas.
FAU - Merchant, Nipun
AU  - Merchant N
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
AD  - Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
FAU - Nagathihalli, Nagaraj
AU  - Nagathihalli N
AUID- ORCID: 0000-0003-2373-3293
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, 
      Florida.
AD  - Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
LA  - eng
SI  - figshare/10.6084/m9.figshare.20532144
GR  - R01 CA161976/CA/NCI NIH HHS/United States
GR  - P30 ES030283/ES/NIEHS NIH HHS/United States
GR  - T32 CA211034/CA/NCI NIH HHS/United States
GR  - R03 CA249401/CA/NCI NIH HHS/United States
GR  - P30 CA240139/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220913
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 1143-70-0 (3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - 0 (Cytokines)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Proto-Oncogene Proteins c-akt/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism/pharmacology
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Mice, Inbred C57BL
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Signal Transduction
MH  - *Pancreatitis, Alcoholic/pathology
MH  - Sirolimus/pharmacology
MH  - Cytokines/pharmacology
MH  - Alcohol Drinking
MH  - Mammals/metabolism
PMC - PMC9602784
OTO - NOTNLM
OT  - PI3K/AKT/mTOR
OT  - alcoholic pancreatitis
OT  - fibrosis
OT  - inflammation
OT  - urolithin A
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2022/09/14 06:00
MHDA- 2022/10/22 06:00
PMCR- 2023/10/01
CRDT- 2022/09/13 08:02
PHST- 2022/09/14 06:00 [pubmed]
PHST- 2022/10/22 06:00 [medline]
PHST- 2022/09/13 08:02 [entrez]
PHST- 2023/10/01 00:00 [pmc-release]
AID - GI-00159-2022 [pii]
AID - 10.1152/ajpgi.00159.2022 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2022 Oct 1;323(4):G375-G386. doi: 
      10.1152/ajpgi.00159.2022. Epub 2022 Sep 13.