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Mesenteric adipose tissue B lymphocytes promote intestinal injury in severe Acute pancreatitis by mediating enteric pyroptosis

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 300-309页

作者： Qing Huang Jia-Wen Liu Hai-Bin Dong Zheng-Jie Wei Jin-Zhe Liu Yu-Tang Ren Xuan Jiang Bo Jiang Department of Gastroenterology Beijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua UniversityBeijing 102218China

Background:Visceral adipose tissue(VAT)has been linked to the severe Acute pancreatitis(SAP)prognosis,although the underlying mechanism remains unclear.It has been reported that pyroptosis worsens SAP.The present study aimed to verify whether mesenteric adipose tissue(MAT,a component of VAT)can cause secondary intestinal injury through the pyroptotic pathway.Methods:Thirty-six male Sprague Dawley(SD)rats were divided into six different groups.Twelve rats were randomly divided into the SAP and control groups.We monitored the changes of MAT and B lymphocytes infiltration in MAT of SAP rats.Twelve SAP rats were injected with MAT B lymphocytes or phosphate buffer solution(PBS).The remaining twelve SAP rats were first injected with MAT B lymphocytes,and then with MCC950(NLRP3 inhibitor)or PBS.We collected blood and tissue samples from pancreas,gut and MAT for analysis.Results:Compared to the control rats,the SAP group showed inflammation in MAT,including higher expression of tumor necrosis factor(TNF-α)and interleukin-6(IL-6),lower expression of IL-10,and histological changes.Flow cytometry analysis revealed B lymphocytes infiltration in MAT but not T lymphocytes and macrophages.The SAP rats also exhibited intestinal injury,characterized by lower expression of zonula occludens-1(ZO-1)and occludin,higher levels of lipopolysaccharide and diamine oxidase,and pathological changes.The expression of NLRP3 and n-GSDMD,which are responsible for pyroptosis,was increased in the intestine of SAP rats.The injection of MAT B lymphocytes into SAP rats exacerbated the inflammation in MAT.The upregulation of pyroptosis reduced tight junction in the intestine,which contributed to the SAP progression,including higher inflammatory indicators and worse histological changes.The administration of MCC950 to SAP+MAT B rats downregulated pyroptosis,which subsequently improved the intestinal barrier and ameliorated inflammatory response of SAP.Conclusions:In SAP,MAT B lymphocytes aggravated local inflammation,and promoted the injury to the int

关键词： Acute pancreatitis Mesenteric adipose tissue B lymphocyte Intestinal barrier Pyroptosis

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Rheum palmatum L. and Salvia miltiorrhiza Bge. Alleviates Acute pancreatitis by Regulating Th17 Cell Differentiation: An Integrated Network Pharmacology Analysis, Molecular Dynamics Simulation and Experimental Validation

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Chinese Journal of Integrative Medicine 2024年第5期30卷 408-420页

作者： FENG Min-chao LUO Fang HUANG Liang-jiang LI Kai CHEN Zu-min LI Hui YAO Chun QIN Bai-jun CHEN Guo-zhong The First Clinical Medical College Guangxi University of Traditional Chinese MedicineNanning 530000China Guangxi Key Laboratory of Molecular Biology of Traditional Chinese Medicine and Preventive Medicine Nanning 530000China Graduate School Guangxi University of Traditional Chinese MedicineNanning 530000China Department of Gastroenterology the First Affiliated Hospital of Guangxi University of Traditional Chinese MedicineNanning 530023China

Objective: To identify the core targets of Rheum palmatum L. and Salvia miltiorrhiza Bge.,(Dahuang-Danshen, DH-DS) and the mechanism underlying its therapeutic efficacy in Acute pancreatitis(AP)using a network pharmacology approach and validate the findings in animal experiments. Methods: Network pharmacology analysis was used to elucidate the mechanisms underlying the therapeutic effects of DH-DS in AP. The reliability of the results was verified by molecular docking simulation and molecular dynamics simulation.Finally, the results of network pharmacology enrichment analysis were verified by immunohistochemistry,Western blot analysis and real-time quantitative PCR, respectively. Results: Sixty-seven common targets of DH-DS in AP were identified and mitogen-activated protein kinase 3(MAPK3), Janus kinase 2(JAK2), signal transducer and activator of transcription 3(STAT3), protein c-Fos(FOS) were identified as core targets in the protein interaction(PPI) network analysis. Gene ontology analysis showed that cellular response to organic substance was the main functions of DH-DS in AP, and Kyoto Encyclopedia of Genes and Genomes analysis showed that the main pathway included Th17 cell differentiation. Molecular docking simulation confirmed that DH-DS binds with strong affinity to MAPK3, STAT3 and FOS. Molecular dynamics simulation revealed that FOS-isotanshinone Ⅱ and STAT3-dan-shexinkum d had good binding capacity. Animal experiments indicated that compared with the AP model group, DH-DS treatment effectively alleviated AP by inhibiting the expression of interleukin-1β, interleukin-6 and tumor necrosis factor-α, and blocking the activation of Th17 cell differentiation(P<0.01). Conclusion: DH-DS could inhibit the expression of inflammatory factors and protect pancreatic tissues,which would be functioned by regulating Th17 cell differentiation-related m RNA and protein expressions.

关键词： Rheum palmatum L. Salvia miltiorrhiza Bge. molecular docking simulation network pharmacology Acute pancreatitis Th17 cell differentiation

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Etiology and classification of Acute pancreatitis in children admitted to ICU using the Pediatric Sequential Organ Failure Assessment (pSOFA) score

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Hepatobiliary & Pancreatic Diseases International 2023年第3期22卷 317-322页

作者： Vratislav Smolka Marie Rohanova Miroslav Seda Eva Karaskova Oksana Tkachyk Martin Zapalka Jana Volejnikova Department of Pediatrics Faculty of Medicine and DentistryPalacky University and University Hospital OlomoucI.P.Pavlova 185/6Olomouc 77900Czech Republic

Background:Pediatric Acute pancreatitis(AP)is rare but increasing.Severe AP is associated with higher morbidity and mortality.However,there are no universally accepted prognostic criteria for AP.Methods:This retrospective study included children with AP admitted to an intensive care unit(ICU)of our tertiary pediatric center between January 2009 and December 2018.The severity of organ dysfunction in AP was assessed according to the modified Atlanta criteria using the Pediatric Sequential Organ Failure Assessment(p SOFA)and Computed Tomography Severity Index(CTSI).Results:Seventy acute episodes of AP were evaluated in 55 children with primary pancreatitis.In addition,secondary AP was diagnosed in 15 patients originally admitted to ICU for different indications.Mild AP[no organ dysfunction,normal computed tomography(CT)finding]was the most prevalent(64/85 episodes in 49 children),followed by moderate AP(15 children;p SOFA 2-9 points,CTSI 3-4 points on admission).Severe AP(p SOFA 4-17 points,CTSI 6-10 points)was diagnosed in 6 children with traumatic or secondary AP.The most frequent etiologies of primary AP episodes were idiopathic(39%)and biliary(31%).Children with idiopathic AP had frequent relapses and comorbidities.Hereditary AP was typically mild,but presented with high pancreatic enzyme levels and recurrence rates.Admission at ICU and an interval without enteral nutrition(EN)were relatively short in drug-induced AP and relatively long in secondary and traumatic AP.Endoscopic retrograde cholangiopancreatography(ERCP)was performed in 13 patients with biliary AP and in 4 patients with traumatic AP.No AP-related death was observed.Conclusion:p SOFA score accurately reflects the severity and prognosis of AP in children.

关键词： Acute pancreatitis Children Organ dysfunction Prognosis pSOFA score

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ALKBH5 suppresses autophagic flux via N6-methyladenosine demethylation of ZKSCAN3 mRNA in Acute pancreatitis

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World Journal of Gastroenterology 2024年第12期30卷 1764-1776页

作者： Tao Zhang Shuai Zhu Geng-Wen Huang Department of General Surgery Xiangya HospitalCentral South UniversityChangsha 410005HunanChina. National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410005HunanChina.

BACKGROUND Increasing evidence has demonstrated that N6-methyladenosine(m6A)RNA modification plays an essential role in a wide range of pathological conditions.Impaired autophagy is a critical hallmark of Acute pancreatitis(AP).AIM To explore the role of the m6A modification of ZKSCAN3 in the regulation of autophagy in AP.METHODS The AP mouse cell model was established by cerulein-treated mouse pancreatic acinar cells(MPC-83),and the results were confirmed by the levels of amylase and inflammatory factors.Autophagy activity was evaluated by specific identification of the autophagy-related microstructure and the expression of autophagy-related genes.ZKSCAN3 and ALKBH5 were knocked down to study the function in AP.A m6A RNA binding protein immunoprecipitation assay was used to study how the m6A modification of ZKSCAN3 mRNA is regulated by ALKBH.RESULTS The increased expression of amylase and inflammatory factors in the supernatant and the accumulation of autophagic vacuoles verified that the AP mouse cell model was established.The downregulation of LAMP2 and upregulation of LC3-II/I and SQSTM1 demonstrated that autophagy was impaired in AP.The expression of ZKSCAN3 was upregulated in AP.Inhibition of ZKSCAN3 increased the expression of LAMP2 and decreased the expression of the inflammatory factors,LC3-II/I and SQSTM1.Furthermore,ALKBH5 was upregulated in AP.Knockdown of ALKBH5 downregulated ZKSCAN3 expression and restored decreased autophagic flux in AP.Notably,the bioinformatic analysis revealed 23 potential m6A modification sites on ZKSCAN3 mRNA.The m6A modification of ZKSCAN3 mRNA was significantly decreased in AP.Knockdown of ALKBH5 increased the modification of ZKSCAN3 mRNA,which confirmed that ALKBH5 upregulated ZKSCAN3 expression in a m6A-dependent manner.CONCLUSION ALKBH5 inhibits autophagic flux through m6A demethylation of ZKSCAN3 mRNA in AP,thereby aggravating the severity of the disease.

关键词： Acute pancreatitis Autophagy ZKSCAN3 N6-methyladenosine ALKBH5

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Development and validation of a nomogram for predicting survival in patients with Acute pancreatitis

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世界急诊医学杂志(英文) 2023年第1期14卷 44-48页

作者： Xiao-guang Zhu Jia-mei Jiang Yong-xia Li Jing Gao Wei Wu Qi-ming Feng Department of Emergency Medicine Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai 200233China

BACKGROUND:Acute pancreatitis(AP)is a complex and heterogeneous disease.We aimed to design and validate a prognostic nomogram for improving the prediction of short-term survival in patients with AP.METHODS:The clinical data of 632 patients with AP were obtained from the Medical Information Mart for Intensive Care(MIMIC)-IV database.The nomogram for the prediction of 30-day,60-day and 90-day survival was developed by incorporating the risk factors identified by multivariate Cox analyses.RESULTS:Multivariate Cox proportional hazard model analysis showed that age(hazard ratio[HR]=1.06,95%confidence interval[95%CI]1.03-1.08,Pacute Physiology Score II(HR=1.04,95%CI 1.02-1.06,P<0.001)were independent predictors of 90-day mortality in patients with AP.A prognostic nomogram model for 30-day,60-day,and 90-day survival based on these variables was built.Receiver operating characteristic(ROC)curve analysis demonstrated that the nomogram had good accuracy for predicting 30-day,60-day,and 90-day survival(area under the ROC curve:0.796,0.812,and 0.854,respectively;bootstrap-corrected C-index value:0.782,0.799,and 0.846,respectively).CONCLUSION:The nomogram-based prognostic model was able to accurately predict 30-day,60-day,and 90-day survival outcomes and thus may be of value for risk stratification and clinical decision-making for critically ill patients with AP.

关键词： Acute pancreatitis Risk factor Prognosis

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Aggressive versus controlled fluid resuscitation in Acute pancreatitis: A systematic review and meta-analysis of randomized controlled trials

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Chinese Medical Journal 2023年第10期136卷 1166-1173页

作者： Kun He Lin Gao Zihan Yang Yuelun Zhang Tianrui Hua Wenmo Hu Dong Wu Lu Ke Department of Gastroenterology State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Critical Care Medicine Center of Severe Acute Pancreatitis(CSAP)Jinling HospitalMedical School of Nanjing UniversityNanjingJiangsu 210010China Department of Internal Medicine Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Medical Research Center State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China National Institute of Healthcare Data Science Nanjing UniversityNanjingJiangsu 210010China

Background:Early fluid resuscitation is one of the fundamental treatments for Acute pancreatitis(AP),but there is no consensus on the optimal fluid rate.This systematic review and meta-analysis aimed to compare the efficacy and safety of aggressive vs.controlled fluid resuscitation(CFR)in AP.Methods:The Cochrane Central Register of Controlled Trials(CENTRAL),MEDLINE,Embase,and Web of Science databases were searched up to September 30,2022,for randomized controlled trials(RCTs)comparing aggressive with controlled rates of early fluid resuscitation in AP patients without organ failure on admission.The following keywords were used in the search strategy:"pancreatitis,""fluid therapy,""fluid resuscitation,"and"randomized controlled trial."There was no language restriction.The Grading of Recommendations Assessment,Development and Evaluation(GRADE)framework was used to assess the certainty of evidence.Trial sequential analysis(TSA)was used to control the risk of random errors and assess the conclusions.Results:A total of five RCTs,involving 481 participants,were included in this study.For primary outcomes,there was no significant difference in the development of severe AP(relative risk[RR]:1.87,95%confidence interval[CI]0.95-3.68;P=0.07;n=437;moderate quality of evidence)or hypovolemia(RR:0.98,95%CI:0.32-2.97;P=0.97;n=437;moderate quality of evidence)between the aggressive and CFR groups.A significantly higher risk of fluid overload(RR:3.25,95%CI:1.53-6.93;P<0.01;n=249;low quality of evidence)was observed in the aggressive fluid resuscitation(AFR)group than the controlled group.Additionally,the risk of intensive care unit admission(P=0.02)and the length of hospital stay(P<0.01)as partial secondary outcomes were higher in the AFR group.TSA suggested that more studies were required to draw precise conclusions.Conclusion:For AP patients without organ failure on admission,CFR may be superior to AFR with respect to both efficacy and safety outcomes.Registration:PROSPERO;https://www.***.york.***.uk/PROSPERO/;CRD 42022363945.

关键词： Acute pancreatitis Aggressive fluid resuscitation Controlled fluid resuscitation Efficacy Safety Systemic review

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Prevalence and prognosis of Acute pancreatitis in critically ill patients with COVID-19

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Hepatobiliary & Pancreatic Diseases International 2023年第4期22卷 399-402页

作者： Dongju Kang SuHo Park Changkyo Oh YuJin Kim JinBae Kim SangHoon Park Myung Seok Lee JaeKeun Park Department of Internal Medicine Kangnam Sacred Heart HospitalHallym University College of MedicineSeoul 07441Korea

Background:Coronavirus disease 2019(COVID-19)is a global pandemic issue.In addition to the well-known respiratory and fever symptoms,gastrointestinal symptoms have also been reported.This study aimed to evaluate the prevalence and prognosis of patients with COVID-19 infection complicated with Acute pancreatitis in intensive care unit(ICU).Methods:This was a retrospective observational cohort study,and patients aged 18 years or older,ad-mitted into the ICU in a single tertiary center from January 1,2020,to April 30,2022 were enrolled.Patients were identified by electronic medical records and reviewed manually.The primary outcome was the prevalence of Acute pancreatitis among ICU patients with COVID-19.The secondary outcomes were the length of hospital stay,need for mechanical ventilation(MV),need for continuous renal replacement therapy(CRRT),and in-hospital mortality.Results:A total of 4133 patients,admitted into the ICU,were screened.Among these patients,389 were infected by COVID-19,and 86 were diagnosed with Acute pancreatitis.COVID-19 positive patients were more likely to present with Acute pancreatitis than COVID-19 negative patients(odds ratio=5.42,95%confidence interval:2.35-6.58,PAcute pancreatitis patients with and without COVID-19 infection.Conclusions:Severe COVID-19 infections may cause acute pancreas damage in critically ill patients.How-ever,the prognosis may not differ between Acute pancreatitis patients with and without COVID-19 infec-tion.

关键词： Acute pancreatitis COVID-19 Coronavirus infections Intensive care unit

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Ferroptosis and its emerging roles in Acute pancreatitis

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Chinese Medical Journal 2022年第17期135卷 2026-2034页

作者： Hongyao Li Yujie Lin Ling Zhang Jing Zhao Peiwu Li Department of Emergency Lanzhou University Second HospitalLanzhou UniversityLanzhouGansu 730030China

Acute pancreatitis(AP)is a common and potentially life-threatening pancreatic inflammatory disease.Although it is usually self-limiting,up to 20%of patients will develop into severe AP.It may lead to systemic inflammatory response syndrome and multiple organ dysfunction,affecting the lungs,kidneys,liver,heart,etc.Surviving patients usually have sequelae of varying degrees,such as chronic hyperglycemia after AP(CHAP),pancreatic exocrine insufficiency,and chronic pancreatitis.Lacking specific target treatments is the main reason for high mortality and morbidity,which means that more research on the pathogenesis of AP is needed.Ferroptosis is a newly discovered regulated cell death(RCD),originally described in cancer cells,involving the accumulation of iron and the depletion of plasma membrane polyunsaturated fatty acids,and a caspase-independent RCD.It is closely related to neurological diseases,myocardial infarction,ischemia/reperfusion injury,cancer,etc.Research in the past years has also found the effects of ferroptosis in AP,pancreatic cancer,and AP complications,such as acute lung injury and acute kidney injury.This article reviews the research progress of ferroptosis and its association with the pathophysiological mechanisms of AP,trying to provide new insight into the pathogenesis and treatment of AP,facilitating the development of better-targeted drugs.

关键词： Acute pancreatitis Ferroptosis RCD Autophagy GPX4 PUFAs Regulated cell death

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Should we perform decompressive laparotomy during severe Acute pancreatitis with intra-abdominal hypertension below 25 mmHg: Only the gut knows

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WORLD JOURNAL OF GASTROINTESTINAL SURGERY 2024年第5期16卷 1470-1473页

作者： Vieille, Thibault Crotet, Melissa Turco, Celia Monasterolo, Paul Winiszewski, Hadrien Piton, Gael Besancon Univ Hosp Med Intens Care Unit 3 Bd Fleming F-25000 Besancon France Vesoul Hosp Intens Care Unit F-70000 Vesoul France Besancon Univ Hosp Dept Digest Surg Oncol Liver Transplantat Unit F-25000 Besancon France Sorbonne Univ Ctr Rech St Antoine CRSA Inserm UMRS 938 10041NY212 Paris France Nord Franche Comte Hosp Intens Care Unit F-90400 Trevenans France

We suggest that during severe Acute pancreatitis (SAP) with intra-abdominal hypertension, practitioners should consider decompressive laparotomy, even with intra-abdominal pressure (IAP) below 25 mmHg. Indeed, in this setting, non-occlusive mesenteric ischemia (NOMI) may occur even with IAP below this cutoff and lead to transmural necrosis if abdominal perfusion pressure is not promptly restored. We report our experience of 18 critically ill patients with SAP having undergone decompressive laparotomy of which one third had NOMI while IAP was mostly below 25 mmHg.

关键词： Acute pancreatitis Abdominal compartment syndrome Decompressive laparotomy Mesenteric ischemia Intra-abdominal pressure Abdominal perfusion pressure ABDOMINAL COMPARTMENT SYNDROME

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Laser speckle contrast imaging for monitoring of acutepancreatitis at ischemia-reperfusion injury of thepancreas in rats

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Journal of Innovative Optical Health Sciences 2022年第1期15卷 90-102页

作者： P.A.Dyachenko(Timoshina) A.N.Bashkatov D.A.Alexandrov V.I.Kochubey V.V.Tuchin Saratov State University SaratovRussia Laboratories of Biophotonics and Laser Molecular Imaging and Machine Learning National Research Tomsk State University TomskRussia Saratov State Medical University SaratovRussia Institute of Precision Mechanics and Control Russian Academy of SciencesRussia A.N.Bach Institute of Biochemistry Research Center of Biotechnology of the Russian Academy of Sciences MoscowRussia

The influence of ischemia-reperfusion(I/R)action on pancreatic blood flow(PBF)and the development of Acute pancreatitis(AP)in laboratory rats is evaluated in vivo by using the laser speckle contrast imaging(LSCI).Additionally,the optical properties in norm and under condition of AP in rats were assessed using a modied integrating sphere spectrometer and inverse Monte Carlo(IMC)software.The results of the experimental study of microcirculation of the pancreas in 82 rats in the ischemic model are presented.The data obtained conrm the fact that local ischemia and changes in the blood°ow velocity of the main vessels cause and provoke Acute pancreatitis.

关键词： Laser speckles contrast of speckle images adaptive algorithm microcirculation blood flow Acute pancreatitis pancreas rats optical properties integrating sphere spectroscopy

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