Evidence map›Paper›PMID 33690904›Full record

ArticleAlcoholism, clinical and experimental research2021

Differential cytotoxicity, ER/oxidative stress, dysregulated AMPKα signaling, and mitochondrial stress by ethanol and its metabolites in human pancreatic acinar cells.

Mukund P Srinivasan, Kamlesh K Bhopale, Anna A Caracheo, Lata Kaphalia, Gopalakrishnan Loganathan, Appakalai N Balamurugan, Cristiana Rastellini, Bhupendra S Kaphalia

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alcoholism, clinical and experimental research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed, 1 pooled it
2.7field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 1 country.

Mukund P SrinivasanDepartment of Pathology, The University of Texas Medical Branch, Galveston, TX, USA.ORCID 0000-0002-3307-2305
Kamlesh K BhopaleDepartment of Pathology, The University of Texas Medical Branch, Galveston, TX, USA.
Anna A CaracheoDepartment of Pathology, The University of Texas Medical Branch, Galveston, TX, USA.
Lata KaphaliaDepartment of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, USA.ORCID 0000-0003-1038-7758
Gopalakrishnan LoganathanDepartment of Surgery, University of Louisville, Louisville, KY, USA.
Appakalai N BalamuruganDepartment of Surgery, University of Louisville, Louisville, KY, USA.
Cristiana RastelliniDepartment of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, USA.
Bhupendra S KaphaliaDepartment of Pathology, The University of Texas Medical Branch, Galveston, TX, USA.ORCID 0000-0002-3794-0392
The University of Texas Medical Branch at Galveston · USCincinnati Children's Hospital Medical Center · USUniversity of Louisville · US

Funding

Role of Alcohol Metabolism in Alcoholic Chronic PancreatitisR01AA025850 · NIAAA · UNIVERSITY OF TEXAS MED BR GALVESTON · PI KAPHALIA, BHUPENDRA S · 2017 to 2021
$1.7M
AMPK Signaling and Chronic Alcoholic PancreatitisR21AA024699 · NIAAA · UNIVERSITY OF TEXAS MED BR GALVESTON · PI KAPHALIA, BHUPENDRA S · 2016 to 2017
$407k
NIAAA NIH HHS AA24699NIAAA NIH HHS AA25850NIAAA NIH HHS R01 AA025850NIAAA NIH HHS R21 AA024699
6 · The paper itself

Abstract

backgroundAlcoholic chronic pancreatitis (ACP) is a serious inflammatory disorder of the exocrine pancreatic gland. A previous study from this laboratory showed that ethanol (EtOH) causes cytotoxicity, dysregulates AMPKα and ER/oxidative stress signaling, and induces inflammatory responses in primary human pancreatic acinar cells (hPACs). Here we examined the differential cytotoxicity of EtOH and its oxidative (acetaldehyde) and nonoxidative (fatty acid ethyl esters; FAEEs) metabolites in hPACs was examined to understand the metabolic basis and mechanism of ACP.

methodsWe evaluated concentration-dependent cytotoxicity, AMPKα inactivation, ER/oxidative stress, and inflammatory responses in hPACs by incubating them for 6 h with EtOH, acetaldehyde, or FAEEs at clinically relevant concentrations reported in alcoholic subjects using conventional methods. Cellular bioenergetics (mitochondrial stress and a real-time ATP production rate) were determined using Seahorse XFp Extracellular Flux Analyzer in AR42J cells treated with acetaldehyde or FAEEs.

resultsWe observed concentration-dependent increases in LDH release, inactivation of AMPKα along with upregulation of ACC1 and FAS (key lipogenic proteins), downregulation of p-LKB1 (an oxidative stress-sensitive upstream kinase regulating AMPKα) and CPT1A (involved in β-oxidation of fatty acids) in hPACs treated with EtOH, acetaldehyde, or FAEEs. Concentration-dependent increases in oxidative stress and ER stress as measured by GRP78, unspliced XBP1, p-eIF2α, and CHOP along with activation of p-JNK1/2, p-ERK1/2, and p-P38MAPK were present in cells treated with EtOH, acetaldehyde, or FAEEs, respectively. Furthermore, a significant decrease was observed in the total ATP production rate with subsequent mitochondrial stress in AR42J cells treated with acetaldehyde and FAEEs.

conclusionsEtOH and its metabolites, acetaldehyde and FAEEs, caused cytotoxicity, ER/oxidative and mitochondrial stress, and dysregulated AMPKα signaling, suggesting a key role of EtOH metabolism in the etiopathogenesis of ACP. Because oxidative EtOH metabolism is negligible in the exocrine pancreas, the pathogenesis of ACP could be attributable to the formation of FAEEs and related pancreatic acinar cell injury.

Indexed as

AcetaldehydeAcetyl-CoA CarboxylaseAcinar CellsAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesCarnitine O-PalmitoyltransferaseCell SurvivalCentral Nervous System DepressantsEndoplasmic Reticulum StressEstersEthanolHumansMitochondriaMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinase 8ACACA protein, humanAcetaldehydeAcetyl-CoA CarboxylaseAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesCarnitine O-PalmitoyltransferaseCentral Nervous System DepressantsCPT1A protein, humanEstersEthanolMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinase 8Mitogen-Activated Protein Kinase 9STK11 protein, humanacetaldehydealcoholic pancreatitisAMPKαER stressfatty acid ethyl estershuman pancreatic acinar cells

Identifiers

PMID33690904
PMCPMC8544284
OpenAlexW3134915388

What OpenQuestion holds

Textmetadata
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.