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1.
Front Immunol ; 13: 968639, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059491

RESUMO

Acinar cell death and inflammatory response are two important events which determine the severity of acute pancreatitis (AP). Endoplasmic reticulum (ER) stress and necroptosis are involved in this process, but the relationships between them remain unknown. Here, we analyzed the interaction between ER stress and necroptosis and the underlying mechanisms during AP. Experimental pancreatitis was induced in Balb/C mice by caerulein (Cae) and lipopolysaccharide (LPS) or L-arginine (L-Arg) in vivo, and pancreatic acinar cells were also used to follow cellular mechanisms during cholecystokinin (CCK) stimulation in vitro. AP severity was assessed by serum amylase, lipase levels and histological examination. Changes in ER stress, trypsinogen activation and necroptosis levels were analyzed by western blotting, enzyme-linked immunosorbent assay (ELISA), adenosine triphosphate (ATP) analysis or lactate dehydrogenase (LDH) assay. The protein kinase C (PKC)α -mitogen-activated protein kinase (MAPK) -cJun pathway and cathepsin B (CTSB) activation were evaluated by western blotting. Activating protein 1 (AP-1) binding activity was detected by electrophoretic mobility shift assay (EMSA). We found that ER stress is initiated before necroptosis in CCK-stimulated acinar cells in vitro. Inhibition of ER stress by 4-phenylbutyrate (4-PBA) can significantly alleviate AP severity both in two AP models in vivo. 4-PBA markedly inhibited ER stress and necroptosis of pancreatic acinar cells both in vitro and in vivo. Mechanistically, we found that 4-PBA significantly reduced CTSB maturation and PKCα-JNK-cJun pathway -mediated AP-1 activation during AP. Besides, CTSB inhibitor CA074Me markedly blocked PKCα-JNK-cJun pathway -mediated AP-1 activation and necroptosis in AP. However, pharmacologic inhibition of trypsin activity with benzamidine hydrochloride had no effect on PKCα-JNK-cJun pathway and necroptosis in CCK-stimulated pancreatic acinar cells. Furthermore, SR11302, the inhibitor of AP-1, significantly lowered tumor necrosis factor (TNF) α levels, and its subsequent receptor interacting protein kinases (RIP)3 and phosphorylated mixed lineagekinase domain-like (pMLKL) levels, ATP depletion and LDH release rate in CCK-stimulated pancreatic acinar cells. To sum up, all the results indicated that during AP, ER stress promoted pancreatic acinar cell necroptosis through CTSB maturation, thus induced AP-1 activation and TNFα secretion via PKCα-JNK-cJun pathway, not related with trypsin activity. These findings provided potential therapeutic target and treatment strategies for AP or other cell death-related diseases.


Assuntos
Células Acinares , Catepsina B , Estresse do Retículo Endoplasmático , Necroptose , Pancreatite , Fator de Transcrição AP-1 , Células Acinares/metabolismo , Células Acinares/patologia , Doença Aguda , Trifosfato de Adenosina/metabolismo , Animais , Catepsina B/genética , Catepsina B/metabolismo , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Necroptose/genética , Necroptose/fisiologia , Pancreatite/genética , Pancreatite/metabolismo , Pancreatite/patologia , Proteína Quinase C-alfa/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Tripsina/metabolismo
2.
Front Immunol ; 13: 964622, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072587

RESUMO

Acute pancreatitis is a common critical and acute gastrointestinal disease worldwide, with an increasing percentage of morbidity. However, the gene expression pattern in peripheral blood has not been fully analyzed. In addition, the mechanism of coronavirus disease 2019 (COVID-19)-induced acute pancreatitis has not been investigated. Here, after bioinformatic analysis with machine-learning methods of the expression data of peripheral blood cells and validation in local patients, two functional gene modules in peripheral blood cells of acute pancreatitis were identified, and S100A6, S100A9, and S100A12 were validated as predictors of severe pancreatitis. Additionally, through a combination analysis of bulk sequencing and single-cell sequencing data of COVID-19 patients, a pivotal subtype of neutrophils with strong activation of the interferon-related pathway was identified as a pivotal peripheral blood cell subtype for COVID-19-induced acute pancreatitis. These results could facilitate the prognostic prediction of acute pancreatitis and research on COVID-19-induced acute pancreatitis.


Assuntos
COVID-19 , Pancreatite , Doença Aguda , Biomarcadores , COVID-19/genética , Humanos , Neutrófilos/metabolismo , Pancreatite/metabolismo
3.
Mol Med ; 28(1): 106, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068514

RESUMO

BACKGROUND: Acute pancreatitis is the sudden inflammation of the pancreas. Severe cases of acute pancreatitis are potentially fatal and have no specific treatment available. Premature trypsinogen activation could initiate acute pancreatitis. However, the mechanism underlying premature trypsinogen activation is not fully understood. METHODS: In this research, a primary pancreatic acinar cell or mouse acute pancreatitis model was constructed. The effect of acid ceramidase (ASAH1), which is responsible for sphingosine production, was investigated in trypsinogen activation in vitro and in vivo. Meanwhile, the proteins regulating ASAH1 or binding to sphingosine were also detected by co-immunoprecipitation followed by mass spectrometry. RESULTS: The results showed that ASAH1 increased in acute pancreatitis. Increased ASAH1 promoted the activation of trypsinogen and cathepsin B. On the contrary, ASAH1 downregulation inhibited trypsinogen and cathepsin B. Meanwhile, ASAH1 regulated the activity of trypsin and cathepsin B through sphingosine. Additionally, E3 ligase Mind bomb homolog 1 (MIB1) decreased in acute pancreatitis resulting in the decreased binding between MIB1 and ASAH1. Exogenous MIB1 diminished the elevation in trypsin activity induced by acute pancreatitis inducer. ASAH1 increased owing to the inhibition of the proteasome degradation by MIB1. In acute pancreatitis, sphingosine was found to bind to pyruvate kinase. Pyruvate kinase activation could reduce trypsinogen activation and mitochondrial reactive oxygen species (ROS) production induced by sphingosine. CONCLUSIONS: In conclusion, during the process of acute pancreatitis, MIB1 downregulation led to ASAH1 upregulation, resulting in pyruvate kinase inhibition, followed by trypsinogen activation.


Assuntos
Pancreatite , Tripsinogênio , Ceramidase Ácida , Doença Aguda , Animais , Catepsina B/metabolismo , Modelos Animais de Doenças , Camundongos , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Piruvato Quinase , Esfingosina/efeitos adversos , Tripsina/metabolismo , Tripsinogênio/metabolismo
4.
Int J Mol Sci ; 23(18)2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36142497

RESUMO

Progressive loss and dysfunction of islet ß-cells has not yet been solved in the treatment of diabetes. Regenerating protein (Reg) has been identified as a trophic factor which is demonstrated to be associated with pancreatic tissue regeneration. We previously produced recombinant Reg3α protein (rReg3α) and proved that it protects against acute pancreatitis in mice. Whether rReg3α protects islet ß-cells in diabetes has been elusive. In the present study, rReg3α stimulated MIN6 cell proliferation and resisted STZ-caused cell death. The protective effect of rReg3α was also found in mouse primary islets. In BALB/c mice, rReg3α administration largely alleviated STZ-induced diabetes by the preservation of ß-cell mass. The protective mechanism could be attributed to Akt/Bcl-2/-xL activation and GRP78 upregulation. Scattered insulin-expressing cells and clusters with small size, low insulin density, and exocrine distribution were observed and considered to be neogenic. In isolated acinar cells with wheat germ agglutinin (WGA) labeling, rReg3α treatment generated insulin-producing cells through Stat3/Ngn3 signaling, but these cells were not fully functional in response to glucose stimulation. Our results demonstrated that rReg3α resists STZ-induced ß-cell death and promotes ß-cell regeneration. rReg3α could serve as a potential drug for ß-cell maintenance in anti-diabetic treatment.


Assuntos
Células Secretoras de Insulina , Insulinas , Ilhotas Pancreáticas , Pancreatite , Doença Aguda , Animais , Apoptose , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Pancreatite/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Aglutininas do Germe de Trigo/farmacologia
5.
Adv Protein Chem Struct Biol ; 132: 175-197, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36088075

RESUMO

The exocrine pancreas produces enzymes involved in the digestive process whereas endocrine pancreas mainly regulates glucose metabolism. Diseases of the exocrine pancreas are characterized by high morbidity and mortality. Acute pancreatitis is a painful disease in which pancreatic secretory proteins are prematurely activated causing the digestion of the gland. Pancreatic adenocarcinoma is one of the most malignant cancers due to its resistance to treatment, its late diagnosis and high capacity for metastasis. Autophagy is a catabolic process that aims at degrading cytoplasmic contents and damaged organelles, to preserve cell viability and homeostasis. VMP1 is a transmembrane protein that plays a key role in triggering autophagy and being part of the autophagosome membrane. A specific type of selective autophagy pathway called zymophagy protects the pancreas against self-digestion in the setting of acute pancreatitis by sequestering intracellularly activated zymogen granules. Mitophagy is also responsible for maintaining pancreatitis as a mild disease by preserving mitochondrial function. Dysregulation of these selective autophagic processes by pancreatitis itself constitutes a risk factor for development of severe disease. In pancreatic adenocarcinoma, VMP1 mediated autophagy promotes cancer cell survival and resistance to chemotherapy. Therefore, it is relevant to highlight a role for controlling VMP1 expression and targeting VMP1 molecular pathways to improve exocrine pancreatic diseases prognosis.


Assuntos
Adenocarcinoma/metabolismo , Autofagia , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas , Doença Aguda , Adenocarcinoma/patologia , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/metabolismo
6.
Biochem Biophys Res Commun ; 630: 118-124, 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36155057

RESUMO

Acute pancreatitis (AP) is an inflammatory disorder of pancreas and common digestive diseases, effective drug for AP is few. As an analog of active center of Reg3α, the biological activities of HTD4010 are similar to Reg3α. This study aimed to explore whether HTD4010 could decrease the inflammatory response and pancreatic injury in hypertriglyceridemic-AP (HTG-AP), and explore underlying mechanisms. This study was shown that the administration of HTD4010 could decrease the inflammatory response, reduce acinar cell injury (both apoptosis and necroptosis) and damage of lung tissue in HTG-AP. Moreover, HTD4010 down-regulated the expression of TLR4 and NF-κB protein. These results showed that HTD4010 could alleviate the severity of AP possibly by TLR4/NF-κB signaling pathway in HTG-AP.


Assuntos
NF-kappa B , Pancreatite , Doença Aguda , Animais , Modelos Animais de Doenças , Camundongos , NF-kappa B/metabolismo , Pâncreas/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Peptídeos/metabolismo , Receptor 4 Toll-Like/metabolismo
7.
Oxid Med Cell Longev ; 2022: 4499219, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35927992

RESUMO

Acute pancreatitis (AP) is an inflammatory disease that is associated with trypsinogen activation, mitochondrial dysfunction, cell death, and inflammation. Dopamine D2 receptor (DRD2) plays an essential role in alleviating AP, while it is unclear whether it is involved in regulating acinar cell necroptosis. Here, we found that DRD2 agonist quinpirole alleviated acinar cell necroptosis via inhibiting cathepsin B (CTSB). Moreover, CTSB inhibition by CA-074Me ameliorated AP severity by reducing necroptosis. Notably, knockdown of TFAM reversed the therapeutic effect of either quinpirole or CA-074Me. We identified a new mechanism that DRD2 signaling inhibited CTSB and promoted the expression of mitochondrial transcription factor A(TFAM), leading to reduction of ROS production in AP, which attenuated acinar cell necroptosis ultimately. Collectively, our findings provide new evidence that DRD2 agonist could be a new potential therapeutic strategy for AP treatment.


Assuntos
Pancreatite , Células Acinares/metabolismo , Doença Aguda , Animais , Catepsina B/metabolismo , Proteínas de Ligação a DNA , Proteínas de Grupo de Alta Mobilidade , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais , Necroptose , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Quimpirol , Espécies Reativas de Oxigênio , Receptores de Dopamina D2/metabolismo , Fatores de Transcrição
8.
Mol Med Rep ; 26(4)2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35946453

RESUMO

Acute pancreatitis is a severe inflammatory disease of the pancreas. In experimental acute pancreatitis, cerulein induces the expression of interleukin­6 (IL­6) by activating Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 in pancreatic acinar cells. Ligands of peroxisome proliferator activated receptor­Î³ (PPAR­Î³) and suppressor of cytokine signaling (SOCS) 3 inhibit IL­6 expression by suppressing JAK2/STAT3 in cerulein­stimulated pancreatic acinar AR42J cells. Lutein, an oxygenated carotenoid, upregulates and activates PPAR­Î³ to regulate inflammation in a renal injury model. The present study aimed to determine whether lutein activated PPAR­Î³ and induced SOCS3 expression in unstimulated AR42J cells, and whether lutein inhibited activation of JAK2/STAT3 and IL­6 expression via activation of PPAR­Î³ and SOCS3 expression in cerulein­stimulated AR42J cells. The anti­inflammatory mechanism of lutein was determined using reverse transcription­quantitative PCR, western blot analysis and enzyme­linked immunosorbent assay in AR42J cells stimulated with or without cerulein. In another experiment, cells were treated with lutein and the PPAR­Î³ antagonist GW9662 or the PPAR­Î³ agonist troglitazone prior to cerulein stimulation to determine the involvement of PPAR­Î³ activation. The results indicated that lutein increased PPAR­Î³ and SOCS3 levels in unstimulated cells. Cerulein increased phospho­specific forms of JAK2 and STAT3, and mRNA and protein expression of IL­6, but decreased SOCS3 levels in AR42J cells. Cerulein­induced alterations were suppressed by lutein or troglitazone. GW9662 alleviated the inhibitory effect of lutein on JAK2/STAT3 activation and IL­6 expression in cerulein­stimulated cells. In conclusion, lutein inhibited the activation of JAK2/STAT3 and reduced IL­6 levels via PPAR­Î³­mediated SOCS3 expression in pancreatic acinar cells stimulated with cerulein.


Assuntos
Ceruletídeo , Pancreatite , Células Acinares/metabolismo , Doença Aguda , Humanos , Interleucina-6/metabolismo , Luteína , PPAR gama/genética , PPAR gama/metabolismo , Pancreatite/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Troglitazona
9.
Drug Des Devel Ther ; 16: 2479-2495, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35941928

RESUMO

Background: Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas without specific treatment. Shenmai injection (SMI) was reported to eliminate the severity of experimental AP. This study aimed to explore the mechanisms underlying the synergistic protective effects of SMI on AP based on network pharmacology and experimental validation. Methods: Network pharmacology analysis and molecular docking based on identified components were performed to construct the potential therapeutic targets and pathways. The principal components of SMI were detected via ultra-high-performance liquid chromatography-coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Effect of SMI and the identified components on cellular injury and IL6/STAT3 signaling was assessed on mouse pancreatic acinar cell line 266-6 cells. Finally, 4% sodium taurocholate (NaT) was used to induce AP model to assess the effects of SMI in treating AP and validate the potential molecular mechanisms. Results: By searching the TCMSP and ETCM databases, 119 candidate components of SMI were obtained. UHPLC-QTOF/MS analysis successfully determined the representative components of SMI: ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D. Fifteen hub targets and eight related pathways were obtained to establish the main pharmacology network. Subnetwork analysis and molecular docking indicated that the effects of these four main SMI components were mostly related to the interleukin (IL) 6/STAT3 pathway. In vitro, SMI, ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D increased the cell viability of NaT-stimulated mouse pancreatic acinar 266-6 cells and decreased IL6 and STAT3 expression. In vivo, 10 mL/kg SMI significantly alleviated the pancreatic histopathological changes and the expression of IL6 and STAT3 in the AP mice. Conclusion: This study demonstrated SMI may exert anti-inflammatory effects against AP by suppressing IL6/STAT3 activation, thus providing a basis for its potential use in clinical practice and further study in treating AP.


Assuntos
Medicamentos de Ervas Chinesas , Pancreatite , Doença Aguda , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Combinação de Medicamentos , Interleucina-6 , Camundongos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Pancreatite/metabolismo
10.
Pancreas ; 51(5): 469-475, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35835099

RESUMO

OBJECTIVES: Severe acute pancreatitis (SAP) is the most serious subtype of acute pancreatitis, manifested as multiple-organ failure resulting in high morbidity and mortality. Based on the role of tripartite motif-containing protein 29 (TRIM29) in immune responses, we aimed to explore its effect on SAP. METHODS: Peripheral blood monocyte cells from the SAP or non-SAP patients, as well as bone marrow-derived macrophages from wild-type, TRIM29 -/- , or stimulator of interferon genes (STING) -/- mice after injecting 50 mg/kg of cerulein to induce SAP, were isolated to analyze the role of TRIM29 and STING in the SAP. RESULTS: Tripartite motif-containing protein 29 was significantly reduced in SAP patients. Compared with wild-type mice, TRIM29 deficiency mice displayed more severe symptom of acute pancreatitis after cerulein injection, which were lost in TRIM29 -/- STING -/- mice. Moreover, interferon and its related genes, as well as STING degradation, were decreased in TRIM29 -/- mice. CONCLUSIONS: Our study demonstrated that TRIM29 negatively regulated the severity of SAP by degrading STING at its downstream, suggesting that TRIM29 and STING might serve as therapeutic targets for SAP.


Assuntos
Pancreatite , Fatores de Transcrição/metabolismo , Doença Aguda , Animais , Ceruletídeo , Interferons , Macrófagos/metabolismo , Camundongos , Pancreatite/induzido quimicamente , Pancreatite/genética , Pancreatite/metabolismo , Fatores de Transcrição/genética
11.
BMC Complement Med Ther ; 22(1): 189, 2022 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-35842665

RESUMO

BACKGROUND: hyperlipidemia acute pancreatitis (HTG-AP) is a major hidden danger affecting human health, however, whether there is a protective effect of resveratrol on HTG-AP is unclear. Therefore our study was aimed to investigate the preventive effect and the underlying mechanism of resveratrol in the HTG-AP mice model. METHODS: This research was divided into two parts. In the first part, mice were adaptively fed with normal chow or HFD for 6 weeks. From the second week, resveratrol-treated mice were in intragastric administration with resveratrol (45 mg/kg/d) for 4 weeks. In the second part, the procedures were the same as the first part. After the last intragastric administration with resveratrol, all mice were intraperitoneal injections of cerulean. RESULTS: We found resveratrol effectively inhibited pancreatic pathological injury in the HFD, AP, and HTG-AP mice. Resveratrol reduced the LPS, IL-6, TNF-α, and MCP-1 expressions in the HFD mice. Resveratrol also reduced TNF-α, MDA, and MCP-1 expressions and increased SOD and T-AOC expressions in the AP and HTG-AP mice. Furthermore, resveratrol suppressed the NF-κB pro-inflammatory signaling pathway in pancreatic tissues in the AP and HTG-AP mice. Moreover, resveratrol improved the gut microbiota in the HFD mice. CONCLUSION: The resveratrol pre-treatment could attenuate pancreas injury, inflammation, and oxidative stress in the HTG-AP mice, via restraining the NF-κB signaling pathway and regulating gut microbiota. Therefore, Our study proved that the resveratrol pre-treatment had a preventive effect on HTG-AP.


Assuntos
Microbioma Gastrointestinal , Pancreatite , Doença Aguda , Animais , Ceruletídeo/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Humanos , Camundongos , NF-kappa B/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Resveratrol/efeitos adversos , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
12.
Front Immunol ; 13: 913178, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774796

RESUMO

Severe acute pancreatitis (SAP), one of the most serious abdominal emergencies in general surgery, is characterized by acute and rapid onset as well as high mortality, which often leads to multiple organ failure (MOF). Acute lung injury (ALI), the earliest accompanied organ dysfunction, is the most common cause of death in patients following the SAP onset. The exact pathogenesis of ALI during SAP, however, remains unclear. In recent years, advances in the microbiota-gut-lung axis have led to a better understanding of SAP-associated lung injury (PALI). In addition, the bidirectional communications between intestinal microbes and the lung are becoming more apparent. This paper aims to review the mechanisms of an imbalanced intestinal microbiota contributing to the development of PALI, which is mediated by the disruption of physical, chemical, and immune barriers in the intestine, promotes bacterial translocation, and results in the activation of abnormal immune responses in severe pancreatitis. The pathogen-associated molecular patterns (PAMPs) mediated immunol mechanisms in the occurrence of PALI via binding with pattern recognition receptors (PRRs) through the microbiota-gut-lung axis are focused in this study. Moreover, the potential therapeutic strategies for alleviating PALI by regulating the composition or the function of the intestinal microbiota are discussed in this review. The aim of this study is to provide new ideas and therapeutic tools for PALI patients.


Assuntos
Lesão Pulmonar Aguda , Microbioma Gastrointestinal , Pancreatite , Doença Aguda , Lesão Pulmonar Aguda/patologia , Translocação Bacteriana , Microbioma Gastrointestinal/fisiologia , Humanos , Pancreatite/etiologia , Pancreatite/metabolismo
13.
Ann Clin Lab Sci ; 52(3): 416-425, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35777802

RESUMO

MicroRNA-146a-5p (miR-146a-5p) has been shown to mediate the inflammatory responses and autophagy in many diseases; however, its role in acute pancreatitis (AP) is not clear. OBJECTIVE: To determine the expression and role of miR-146a-5p in taurolithocholic acid-3-sulphate (TLCs) induced-AR42J cell model of AP. METHODS: Quantitative reverse transcription polymerase chain reaction, western blot, enzyme linked immunosorbent assay (ELISA), miRNA mimics or vectors or small interfering RNAs transfection and dual-luciferase reporter assay were employed in this study. RESULTS: miR-146a-5p was concentration-dependently decreased; while, interleukin-1 receptor associated kinase 1 (IRAK1) and tumor necrosis factor receptor associated factor 6 (TRAF6) were concentration-dependently increased after TLCs treatment. TLCs induced high levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and impaired autophagy characterized as increased of LC3-II/I and decreased expression of p62. Overex-presion of miR-146a-5p and knockdown of IRAK1/TRAF6 inhibited TLCs-induced inflammation and autophagy. Luciferase assay confirmed miR-146a-5p can directly target IRAK1 and TRAF6. The expression of p-NF-κB p65 was increased by TLCs, decreased by miR-146a-5p overexpression and IRAK1/ TRAF6 knockdown but increased after upregulation of IRAK1/TRAF6. CONCLUSIONS: Overexpression of miR-146a-5p ameliorates inflammation and autophagy in TLCs-treated AR42J cells by inhibiting IRAK1/ TRAF6/NF-κB pathway.


Assuntos
MicroRNAs , Pancreatite , Doença Aguda , Autofagia/genética , Autofagia/fisiologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Pancreatite/genética , Pancreatite/metabolismo , Transdução de Sinais/genética , Fator 6 Associado a Receptor de TNF/metabolismo
14.
Nutrients ; 14(13)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35807771

RESUMO

Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/- mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.


Assuntos
Diosgenina , Pancreatite , Doença Aguda , Animais , Apoptose , Arginina/farmacologia , Proteínas de Transporte , Diosgenina/efeitos adversos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Proteínas Serina-Treonina Quinases , Tiorredoxinas/metabolismo
15.
Comput Math Methods Med ; 2022: 8801484, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844444

RESUMO

Objective: The lack of certain trace elements such as selenium, molybdenum, magnesium or related nutrients in the soil, water quality and food in the disease area, which caused disturbance of myocardium metabolism and resulted in injury and necrosis. The aim of the study was to explore the mechanism of ibuprofen alleviating myocardial injury caused by acute pancreatitis (AP). Method: We have established AP cell model and rat model. HE staining is used for histological examination. ELISA is used to determine the levels of proinflammatory cytokines (TNF-α and IL-6) and markers of myocardial injury (LDH and CK-MB). qRT-PCR and Western blot are used to analyze the mRNA and protein levels of related genes. Results: The expression level of AIM2 was significantly increased in AP cells; downregulation of AIM2 alleviated inflammation and myocardial injury induced by AP cells; ibuprofen could inhibit the expression of AIM2 and alleviate inflammation and myocardial injury induced by AP cells. In vivo experiments have found that ibuprofen can inhibit the expression of AIM2 to alleviate myocardial injury in AP rat. Conclusion: Ibuprofen can alleviate myocardial injury caused by acute pancreatitis by inhibiting the expression of AIM2.


Assuntos
Proteínas de Ligação a DNA , Ibuprofeno , Pancreatite , Doença Aguda , Animais , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Ibuprofeno/farmacologia , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/genética , Pancreatite/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
16.
Drug Saf ; 45(9): 929-939, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35788538

RESUMO

Adverse drug reactions (ADRs) affecting the pancreas are a heterogeneous group of side effects that cause damage to pancreatic cells. Various mechanisms such as hypersensitization, sphincter of Oddi constriction, direct cytotoxic and metabolic effects on pancreatic cells, and dose-dependent idiosyncrasy lead to intrapancreatic activation of pancreatic enzymes resulting in drug-induced acute pancreatitis. Several medications have been linked with the development of pancreatic cancer. Pancreatic cancer may result from proinflammatory, proliferative, and antiapoptotic effects. Diabetogenic effect of drugs, which is understood as impairment of insulin secretion, may occur due to direct destruction of ß cells, systemic toxicity affecting pancreatic islets and cell membrane glucose transporters, induction of Th1-type autoimmune response, and impairment of voltage-gated calcium channels in ß cells, endoplasmic reticulum stress, and insulin signaling. A better understanding of ADRs that affect the pancreas may contribute to improving the awareness of clinicians and patients and reducing potential harmful side effects of implemented therapies.


Assuntos
Neoplasias Pancreáticas , Pancreatite , Doença Aguda , Humanos , Insulina , Secreção de Insulina , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/metabolismo
17.
Mol Med Rep ; 26(2)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35730599

RESUMO

Cerulein­induced pancreatitis resembles human acute pancreatitis in terms of pathological events, such as enzymatic activation and inflammatory cell infiltration in the pancreas. Cerulein is a cholecystokinin analog that increases levels of reactive oxygen species (ROS) and interleukin­6 (IL­6) expression level in pancreatic acinar cells. Serum levels of resistin, which is secreted from adipocytes, are reportedly higher in patients with acute pancreatitis than in healthy individuals. Previously, it was shown that the adipokine resistin can aggravate the cerulein­induced increase in ROS levels and IL­6 expression level in pancreatic acinar cells. Peroxisome proliferator­activated receptor­gamma (PPAR­Î³) is a key regulator of the transcription and expression of antioxidant enzymes, including heme oxygenase 1 (HO­1) and catalase. α­lipoic acid, a naturally occurring dithiol antioxidant, can prevent cerulein­induced pancreatic damage in rats. In the present study, it was aimed to investigate whether α­lipoic acid can attenuate the cerulein/resistin­induced increase in IL­6 expression and ROS levels via PPAR­Î³ activation in pancreatic acinar AR42J cells. The anti­inflammatory mechanism of α­lipoic acid was determined using reverse transcription­quantitative PCR, western blot analysis, enzyme­linked immunosorbent assay, immunofluorescence staining and fluorometry. Treatment with cerulein and resistin increased ROS levels and IL­6 expression level, which were inhibited by α­lipoic acid in pancreatic acinar cells. α­lipoic acid increased the nuclear translocation and expression level of PPAR­Î³ and the expression levels of its target genes: HO­1 and catalase. The PPAR­Î³ antagonist GW9662 and HO­1 inhibitor zinc protoporphyrin reversed the inhibitory effect of α­lipoic acid on cerulein/resistin­induced increase in ROS and IL­6 levels. In conclusion, α­lipoic acid inhibits the cerulein/resistin­induced increase in ROS production and IL­6 expression levels by activating PPAR­Î³ and inducing the expression of HO­1 and catalase in pancreatic acinar cells.


Assuntos
Pancreatite , Ácido Tióctico , Células Acinares/metabolismo , Doença Aguda , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Catalase/metabolismo , Ceruletídeo/toxicidade , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Resistina/metabolismo , Ácido Tióctico/farmacologia
18.
Apoptosis ; 27(7-8): 521-530, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35612769

RESUMO

The animal models of traumatic pancreatitis (TP) were established to evaluate the specific mechanisms by which umbilical cord mesenchymal stem cell-derived exosomes (ucMSC-Ex) exert therapeutic effects. Sixty four rats were randomly divided into eight groups, including TP groups with three different degrees and relevant groups with ucMSC-Ex treated. The degrees of pancreatic tissue injury were evaluated by Histological Examination. Furthermore, enzyme-linked immunosorbent assay were applied to evaluate the activity of pancreatic enzymes and levels of inflammatory factors in serum. Finally, the apoptotic effects of each group were evaluated by TUNEL, western blot (WB), and real time fluorescence quantitative polymerase chain reaction (RT-qPCR). The pancreatic histopathological score and serum amylase and lipase levels gradually increased in various degrees of TP and the levels in the treatment group were all significantly decreased. The apoptosis index gradually increased in each TP group and significantly decreased in the treatment group in TUNEL results. WB and RT-qPCR showed the same trend, that bax and caspase-3 gradually increased and bcl-2 gradually decreased in TP groups. Compared with TP groups, the expression of bax and caspase-3 were lower while bcl-2 expression was higher in the treatment group. ucMSC-Ex suppressed the inflammatory response and inhibited pancreatic acinar cell apoptosis to promote repair of injured pancreatic tissue.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Pancreatite , Animais , Apoptose , Caspase 3/genética , Caspase 3/metabolismo , Células-Tronco Mesenquimais/metabolismo , Pancreatite/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Cordão Umbilical , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Immunopharmacol Immunotoxicol ; 44(5): 757-765, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35616237

RESUMO

BACKGROUND: Fentanyl is an analgesic used against pancreatitis-related pain, while whether it ameliorates severe acute pancreatitis (SAP) has yet to be checked. This study aims to determine fentanyl-delivered effect on SAP and the mechanism underlying this effect. METHODS: Rat SAP models were established, following fentanyl treatment. The serum activity of amylase (AMY), lipase (LIP), and diamine oxidase (DAO) was detected by enzyme-linked immunosorbent assay (ELISA). Histological examination was performed in the pancreatic and intestinal tissues with hematoxylin-eosin staining. After transfection with matrix metalloproteinase (MMP) 9 overexpression plasmids, Caco-2 monolayers were treated with fentanyl and subsequently exposed to lipopolysaccharide (LPS). The transepithelial electrical resistance (TEER) value was determined in rat intestinal mucosa through an Ussing chamber assisted by Analyze & Acquire, and in Caco-2 cell monolayers through a voltohmmeter. Intestinal mucosa and paracellular permeabilities were determined by fluorescein isothiocyanate (FITC)-labeled dextran assay. The expressions of ZO-1, Occludin, MMP9, Fas and Fas ligand (FasL) in rat intestinal mucosa and/or Caco-2 monolayers were analyzed by qRT-PCR or/and western blot. RESULTS: Fentanyl alleviated SAP-related histological alterations in the pancreas and intestines, reduced the elevated levels of SAP-related AMY, LIP, and DAO, but promoted the levels of ZO-1 and Occludin. In SAP rats and Caco-2 monolayers, SAP-related or LPS-induced TEER value decreases, permeability increases, and increases in the expressions of MMP9, Fas, and FasL were reversed partly by fentanyl. Notably, MMP9 overexpression could reverse the above fentanyl-delivered in vitro effects. CONCLUSIONS: Fentanyl alleviates intestinal mucosal barrier damage in rats with SAP by inhibiting the MMP9/FasL/Fas pathway.


Assuntos
Amina Oxidase (contendo Cobre) , Pancreatite , Doença Aguda , Amina Oxidase (contendo Cobre)/metabolismo , Amina Oxidase (contendo Cobre)/farmacologia , Amilases/metabolismo , Amilases/farmacologia , Animais , Células CACO-2 , Dextranos/efeitos adversos , Dextranos/metabolismo , Amarelo de Eosina-(YS)/efeitos adversos , Amarelo de Eosina-(YS)/metabolismo , Proteína Ligante Fas/efeitos adversos , Proteína Ligante Fas/metabolismo , Fentanila/efeitos adversos , Fentanila/metabolismo , Fluoresceína-5-Isotiocianato/efeitos adversos , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Humanos , Mucosa Intestinal , Lipase/metabolismo , Lipopolissacarídeos/farmacologia , Metaloproteinase 9 da Matriz , Ocludina/metabolismo , Ocludina/farmacologia , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Ratos
20.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 34(3): 329-332, 2022 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-35574757

RESUMO

Acute pancreatitis (AP) is a common and potentially threatening disease of the pancreas, and some patients eventually develop to severe acute pancreatitis (SAP). Symptomatic support therapies such as rehydration therapy and anti-infection are still the main treatments. Lacking specific therapies is the main reason for the high mortality of AP patients, especially those with SAP. Premature trypsinogen activation is the most important pathologic cellular event in the pathogenesis of AP. The release of trypsin can cause self-digestion inside and outside of acinar cells, especially the release of cathepsin B can also cause a caspase-unrelated regulatory cell death (RCD) known as necroptosis, which is closely related to the development and prognosis of AP. Therefore, it is necessary to further study the mechanism of necroptosis in the occurrence and development of AP. This article reviews the mechanism of necroptosis and the research progress related to AP, in an attempt to provide a new understanding of the pathogenesis and treatment of AP, and promote the better target drug development.


Assuntos
Pancreatite , Células Acinares/metabolismo , Células Acinares/patologia , Doença Aguda , Humanos , Necroptose , Pâncreas , Pancreatite/metabolismo
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