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1.
PLoS One ; 16(1): e0242706, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33493150

RESUMO

BACKGROUND: AR42J are immortalized pancreatic adenocarcinoma cells that share similarities with pancreatic acinar cells. AR42J are often used as a cell-culture model of cerulein (CN)-induced acute pancreatitis (AP). Nevertheless, it is controversial how to treat AR42J for reliable induction of AP-like processes. Gene knockout and/or overexpression often remain challenging, as well. In this study, we demonstrate conditions for a reliable induction of proinflammatory markers upon CN treatment in AR42J and high transfection efficacy using Glyoxalase-I (Glo-I) as a target of interest. METHODS: Effects of dexamethasone (dexa) and CN on cell morphology and amylase secretion were analyzed via ELISA of supernatant. IL-6, TNF-α and NF-κB-p65 were measured via qRT-PCR, ELISA and Western Blot (WB). Transfection efficacy was determined by WB, qRT-PCR and immune fluorescence of pEGFP-N1-Glo-I-Vector and Glo-I-siRNA. RESULTS: Treatment of AR42J with 100 nm dexa is mandatory for differentiation to an acinar-cell-like phenotype and amylase production. CN resulted in secretion of amylase but did not influence amylase production. High levels of CN-induced amylase secretion were detected between 3 and 24 hours of incubation. Treatment with LPS alone or in combination with CN did not influence amylase release compared to control or CN. CN treatment resulted in increased TNF-α production but not secretion and did not influence IL-6 mRNA. CN-induced stimulation of NF-κB was found to be highest on protein levels after 6h of incubation. Transient transfection was able to induce overexpression on protein and mRNA levels, with highest effect after 12 to 24 hours. Gene-knockdown was achieved by using 30 pmol of siRNA leading to effective reduction of protein levels after 72 hours. CN did not induce amylase secretion in AR42J cell passages beyond 35. CONCLUSION: AR42J cells demonstrate a reliable in-vitro model of CN-induced AP but specific conditions are mandatory to obtain reproducible data.


Assuntos
Modelos Biológicos , Pancreatite/induzido quimicamente , Pancreatite/patologia , Animais , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Ceruletídeo , Dexametasona/farmacologia , Técnicas de Silenciamento de Genes , Interleucina-6/metabolismo , NF-kappa B/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
2.
Mol Immunol ; 130: 122-132, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33308902

RESUMO

Acinar cell necrosis is one of the most prominent pathophysiological changes of acute pancreatitis (AP). Asiaticoside (AS) is a triterpene compound with confirmed apoptosis-and necrosis-related activities. However, the specific effects of AS on AP have not been determined. In this study, we aimed to investigate the protective effect of AS on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, We found that AS administration reduced serum amylase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. And the levels of toll-like receptor 4 (TLR4) and necrotic related proteins (RIP3 and p-MLKL) of pancreatic tissue were reduced after AS administration. In addition, TLR4 deficiency eliminated the protective effect of AS on AP induced by caerulein in mice. Correspondingly, we elucidated the effect of AS in vitro and found that AS protected against pancreatic acinar cells necrosis and TAK-242 counteracted this protective effect. Meanwhile, we found that AS ameliorated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by l-arginine. Furthermore, Molecular docking results revealed interaction between AS and TLR4. Taken together, our data for the first time confirmed the protective effects of AS on AP in mice via TLR4 pathway.


Assuntos
Células Acinares/efeitos dos fármacos , Células Acinares/patologia , Pancreatite/patologia , Receptor 4 Toll-Like/genética , Triterpenos/farmacologia , Animais , Células Cultivadas , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Necrose/prevenção & controle , Pancreatite/tratamento farmacológico , Pancreatite/genética , Pancreatite/metabolismo , Transdução de Sinais/genética , Receptor 4 Toll-Like/fisiologia , Triterpenos/uso terapêutico
3.
Biochim Biophys Acta Mol Basis Dis ; 1867(1): 165987, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33039594

RESUMO

BACKGROUND: Protein kinase D (PKD) family, which includes PKD/PKD1, PKD2, and PKD3, has been increasingly implicated in the regulation of multiple cellular functions and human diseases. We recently reported that pharmacologic inhibition of PKD ameliorated the pathologic responses and severity of pancreatitis. However, to further investigate the importance of PKD family members in pancreatitis, it is necessary to explore the effects of pancreas-specific genetic inhibition of PKD isoform on pathology of pancreatitis. METHODS: We generated a mouse model (referred as PKD3Δpanc mice) with pancreas-specific deletion of PKD3, the predominant PKD isoform in mouse pancreatic acinar cells, by crossing Pkd3flox/flox mice with Pdx1-Cre transgenic mice which express Cre recombinase under the control of the mouse Pdx1 promoter. Pancreas-specific deletion of the PKD3 gene and PKD3 protein was confirmed by PCR and Western blot analysis. Experimental pancreatitis was induced in PKD3Δpanc and Pkd3flox/flox (control mice) littermates by intraperitoneal injections of cerulein or L-arginine. RESULTS: Compared to the control mice, PKD3Δpanc mice displayed significant attenuation in inflammation, necrosis, and severity of pancreatitis in both experimental models. PKD3Δpanc mice had markedly decreased NF-κB and trypsinogen activation, pancreatic mRNA expression of multiple inflammatory molecules, and the receptor-interacting protein kinase 1 (RIP1) activation in pancreatitis. PKD3Δpanc mice also had less pancreatic ATP depletion, increased pro-survival Bcl-2 family protein expression, and autophagy promotion. CONCLUSION: With PKD3Δpanc mouse model, we further demonstrated that PKD plays a critical role in pathobiological process of pancreatitis and PKD constitutes a novel therapeutic target to treat this disorder.


Assuntos
Deleção de Genes , Pâncreas/metabolismo , Pancreatite/metabolismo , Proteína Quinase C/deficiência , Animais , Modelos Animais de Doenças , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Necrose , Especificidade de Órgãos , Pâncreas/patologia , Pancreatite/genética , Pancreatite/patologia , Proteína Quinase C/metabolismo , Índice de Gravidade de Doença
5.
Phytomedicine ; 79: 153328, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33007730

RESUMO

BACKGROUND: Chaiqin chengqi decoction (CQCQD) is a Chinese herbal formula derived from dachengqi decoction. CQCQD has been used for the management of acute pancreatitis (AP) in the West China Hospital for more than 30 years. Although CQCQD has a well-established clinical efficacy, little is known about its bioactive ingredients, how they interact with different therapeutic targets and the pathways to produce anti-inflammatory effects. PURPOSE: Toll-like receptor 4 (TLR4) and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pro-inflammatory signaling pathways, play a central role in AP in determining the extent of pancreatic injury and systemic inflammation. In this study, we screened the bioactive ingredients using a pharmacological sub-network analysis based on the TLR4/NLRP3 signaling pathways followed by experimental validation. METHODS: The main CQCQD bioactive compounds were identified by UPLC-QTOF/MS. The TLR4/NLRP3 targets in AP for CQCQD active ingredients were confirmed through a pharmacological sub-network analysis. Mice received 7 intraperitoneal injections of cerulein (50 µg/kg; hourly) to induce AP (CER-AP), while oral gavage of CQCQD (5, 10, 15 and 20 g/kg; 3 doses, 2 hourly) was commenced at the 3rd injection of cerulein. Histopathology and biochemical indices were used for assessing AP severity, while polymerase chain reaction, Western blot and immunohistochemistry analyses were used to study the mechanisms. Identified active CQCQD compounds were further validated in freshly isolated mouse pancreatic acinar cells and cultured RAW264.7 macrophages. RESULTS: The main compounds from CQCQD belonged to flavonoids, iridoids, phenols, lignans, anthraquinones and corresponding glycosides. The sub-network analysis revealed that emodin, rhein, baicalin and chrysin were the compounds most relevant for directly regulating the TLR4/NLRP3-related proteins TLR4, RelA, NF-κB and TNF-α. In vivo, CQCQD attenuated the pancreatic injury and systemic inflammation of CER-AP and was associated with reduced expression of TLR4/NLRP3-related mRNAs and proteins. Emodin, rhein, baicalin and chrysin significantly diminished pancreatic acinar cell necrosis with varied effects on suppressing the expression of TLR4/NLRP3-related mRNAs. Emodin, rhein and chrysin also decreased nitric oxide production in macrophages and their combination had synergistic effects on alleviating cell death as well as expression of TLR4/NLRP3-related proteins. CONCLUSIONS: CQCQD attenuated the severity of AP at least in part by inhibiting the TLR4/NLRP3 pro-inflammatory pathways. Its active ingredients, emodin, baicalin, rhein and chrysin contributed to these beneficial effects.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pancreatite/tratamento farmacológico , Células Acinares/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Ceruletídeo/toxicidade , Emodina/farmacologia , Flavonoides/farmacologia , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/patologia , Células RAW 264.7 , Receptor 3 Toll-Like/antagonistas & inibidores
6.
Nat Commun ; 11(1): 4286, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855403

RESUMO

Intracellular galectins are carbohydrate-binding proteins capable of sensing and repairing damaged lysosomes. As in the physiological conditions glycosylated moieties are mostly in the lysosomal lumen but not cytosol, it is unclear whether galectins reside in lysosomes, bind to glycosylated proteins, and regulate lysosome functions. Here, we show in gut epithelial cells, galectin-9 is enriched in lysosomes and predominantly binds to lysosome-associated membrane protein 2 (Lamp2) in a Asn(N)-glycan dependent manner. At the steady state, galectin-9 binding to glycosylated Asn175 of Lamp2 is essential for functionality of lysosomes and autophagy. Loss of N-glycan-binding capability of galectin-9 causes its complete depletion from lysosomes and defective autophagy, leading to increased endoplasmic reticulum (ER) stress preferentially in autophagy-active Paneth cells and acinar cells. Unresolved ER stress consequently causes cell degeneration or apoptosis that associates with colitis and pancreatic disorders in mice. Therefore, lysosomal galectins maintain homeostatic function of lysosomes to prevent organ pathogenesis.


Assuntos
Galectinas/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Lisossomos/metabolismo , Pâncreas/patologia , Celulas de Paneth/patologia , Células Acinares/metabolismo , Células Acinares/patologia , Animais , Autofagia/fisiologia , Colite/metabolismo , Colite/patologia , Estresse do Retículo Endoplasmático , Galectinas/genética , Células HT29 , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Lisossomos/genética , Lisossomos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pâncreas/metabolismo , Pancreatite/metabolismo , Pancreatite/patologia , Celulas de Paneth/metabolismo
7.
Pancreatology ; 20(7): 1258-1261, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32859545

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) presents with myriad extra-pulmonary manifestation and a high mortality in patients with comorbidities. Its effect on patients with pre-existing acute pancreatitis is not known. METHODS: We hereby, present 3 cases with severe acute pancreatitis with persistent respiratory failure who acquired nosocomial COVID-19 during their hospital stay after recovery from respiratory failure. Their clinical course is highlighted which reflects on pathophysiology of organ dysfunction in these 2 disease states. RESULTS: None of the 3 patients with severe acute pancreatitis who developed nosocomial COVID-19 redeveloped respiratory failure due to COVID-19 despite having recently recovered from pancreatitis induced acute hypoxemic respiratory failure. Only one patient developed SARS-CoV2 induced moderate pneumonia. CONCLUSION: These cases highlight that host responses and mechanisms of lung injury might be different in severe acute pancreatitis and COVID-19.


Assuntos
Lesão Pulmonar Aguda/etiologia , Infecções por Coronavirus/complicações , Infecção Hospitalar/complicações , Pancreatite/complicações , Pneumonia Viral/complicações , Lesão Pulmonar Aguda/patologia , Adulto , Infecções por Coronavirus/patologia , Infecção Hospitalar/patologia , Feminino , Humanos , Masculino , Pancreatite/etiologia , Pancreatite/patologia , Pandemias , Pneumonia Viral/patologia , Cobertura de Condição Pré-Existente , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Resultado do Tratamento
8.
Cancer Imaging ; 20(1): 52, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703312

RESUMO

Various inflammatory abnormalities of the pancreas can mimic pancreatic ductal adenocarcinoma (PDAC) at cross-sectional imaging. Misdiagnosis of PDAC at imaging may lead to unnecessary surgery. On the other hand, chronic pancreatitis (CP) bears a greater risk of developing PDAC during the course of the disease. Thus, differentiation between mass-forming chronic pancreatitis (MFCP) and PDAC is important to avoid unnecessary surgery and not to delay surgery of synchronous PDAC in CP.Imaging features such as the morphology of the mass including displacement of calcifications, presence of duct penetrating, sign appearance of duct stricturing, presence or absence of vessel encasement, apparent diffusion coefficient (ADC) value and intravoxel incoherent motion (IVIM) at diffusion-weighted imaging (DWI), fluorodeoxyglucose (FDG) uptake in PET/CT, and mass perfusion parameters can help to differentiate between PDAC and MFCP. Correct interpretation of imaging features can appropriately guide biopsy and surgery, if necessary. This review summarizes the relevant computed tomography (CT) and magnetic resonance imaging (MRI) features that can help the radiologist to come to a confident diagnosis and to guide further management in equivocal cases.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Neoplasias Pancreáticas/diagnóstico por imagem , Pancreatite/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Carcinoma Ductal Pancreático/patologia , Diagnóstico Diferencial , Humanos , Neoplasias Pancreáticas/patologia , Pancreatite/patologia
9.
Life Sci ; 256: 117985, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32562692

RESUMO

AIMS: To assess the combination therapy of anti-CD20 mabs and adenovirus-mediated interleukin-10 (IL-10) gene delivery on the prevention of type 1 diabetes (T1D) in non-obese diabetes (NOD) mice. MAIN METHODS: In present study, we simultaneously blocked the B cell interactions and recovered the Th cell subset proportion by using through anti-CD20 Mab and adenovirus-mediated gene delivery of IL-10, respectively. After 9 consecutive days of combination therapy, various measurements, including hematoxylin-eosin staining (HE), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling assay (TUNEL), immunohistochemistry, ELISA, PCR and western blot were applied to further assess the efficacy. KEY FINDINGS: The results suggested that the combination intervention reduced the T1D-associated morbidity of NOD mice, promote insulin secretion, control blood glucose and ease pancreatitis. Moreover, the combination therapy might play a protective role in pancreatic ß cells by suppressing the expression of TNF-α and Fas, blocking the Caspase-8 and Caspase-3 apoptotic pathways and activating the Bcl-2 anti-apoptotic pathway. Finally, the combination intervention may up-regulate the gene expression of CK-19 and PDX-1 and further accelerate the differentiation and proliferation of pancreatic ß cells. SIGNIFICANCE: Therefore, the combination intervention with anti-CD20 mabs and the IL-10 gene plays a role in the prevention of T1D to some extent in NOD mice.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos CD20/administração & dosagem , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Interleucina-10/administração & dosagem , Pancreatite/tratamento farmacológico , Adenoviridae/genética , Animais , Anticorpos Monoclonais/genética , Antígenos CD20/genética , Apoptose/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Quimioterapia Combinada , Feminino , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pancreatite/genética , Pancreatite/patologia
10.
Surg Clin North Am ; 100(3): 565-580, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32402301

RESUMO

Solid tumors of the pancreas encompass a variety of diagnoses with treatments ranging from observation to major abdominal surgery. Pancreatic ductal adenocarcinoma remains one of the most common and most lethal of these differential of diagnoses and requires a multimodality approach through a multidisciplinary team of specialists. This article reviews the classification, clinical presentation, and workup in differentiating solid tumors of the pancreas and serves as an additional tool for general surgeons faced with such a clinical finding, from a surgical oncology perspective.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Linfoma/cirurgia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Colangiopancreatografia Retrógrada Endoscópica , Diagnóstico Diferencial , Detecção Precoce de Câncer , Endossonografia , Humanos , Linfoma/diagnóstico , Linfoma/patologia , Imagem por Ressonância Magnética , Estadiamento de Neoplasias , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Pancreatectomia/métodos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreatite/diagnóstico , Pancreatite/mortalidade , Pancreatite/patologia , Pancreatite/cirurgia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Taxa de Sobrevida , Tomografia Computadorizada por Raios X
11.
Adv Clin Exp Med ; 29(5): 587-595, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32459401

RESUMO

BACKGROUND: Disturbances in pancreatic microcirculation, beginning with vasoconstriction, are crucial in early pancreatitis and progression to necrotizing pancreatitis. Thus, vascular-targeted treatment aiming to restore a sufficient level of microcirculation through vasodilation would possibly reduce the severity of pancreatitis. Lidocaine is an anti-arrhythmic and local anesthetic drug, which also acts as a vasodilator at higher concentrations. OBJECTIVES: To evaluate the efficacy of intra-arterial infusion of lidocaine into the celiac trunk in treatment of cerulein-induced acute pancreatitis. MATERIAL AND METHODS: Wistar rats (n = 20) were randomly divided into 2 equal groups: the control group (NaCl group, n = 10) and the study group (lidocaine group, n = 10). All subjects underwent surgical intervention with intra-arterial infusion of 0.9% NaCl (control group) or 1% lidocaine hydrochloride (study group) into the celiac trunk. Blood samples were collected 5 times at regular intervals from each rat for amylase and lipase measurements. Histopathological analysis of the pancreas was performed. RESULTS: A total number of 16 rats (control group n = 7, study group n = 9) were included. In the postoperative course, the study group (lidocaine group) revealed lower values of serum amylase and lipase levels compared to the control group (NaCl group), except the values at the 1st treatment point, which appeared 1 h after intraoperative drug injection. Significantly lower treatment endpoint levels of pancreatic enzymes were seen in the lidocaine group. Moreover, no differences were observed between the 1st and the last treatment point in the control group; however, these differences were significant for both enzymes in the study group. Histopathology revealed reduced pancreatitis severity in the study group compared to the controls. CONCLUSIONS: Intra-arterial lidocaine infusion into the celiac trunk decreases pancreatitis severity. What is more, this study demonstrates the relevance of early vasodilation in the therapy of acute pancreatitis.


Assuntos
Ceruletídeo/efeitos adversos , Lidocaína/administração & dosagem , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Ceruletídeo/uso terapêutico , Infusões Intra-Arteriais , Lidocaína/uso terapêutico , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/patologia , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
14.
PLoS One ; 15(4): e0231883, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302358

RESUMO

OBJECTIVE: A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations. METHODS: A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency. RESULTS: Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis. DISCUSSION: Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations. REGISTRATION: CRD42017060473.


Assuntos
Pancreatite/patologia , Preparações Farmacêuticas/classificação , Doença Aguda , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Pancreatite/induzido quimicamente
15.
Med Sci Monit ; 26: e920684, 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32283546

RESUMO

BACKGROUND Acute pancreatitis (AP) is a symptom of sudden pancreas inflammation, which causes patients severe suffering. In general, fibroblast growth factor (FGF) levels are increased and amylase and lipase activities are elevated during AP pathogenesis, but protein concentration are low. However, the mechanism through which FGF signaling regulates AP pathogenesis remains elusive. MATERIAL AND METHODS The concentrations of PGE2, TNF-alpha, sCRP, FGF1, and FGF2 in the serum samples of the AP group and healthy control group were detected by enzyme-linked immunosorbent assay. In addition, IkappaBalpha and p-IkappaBalpha levels were analyzed in the serum samples. Subsequently, the AP rat model was established, and FGF1, FGF2, anti-FGF1, and anti-FGF2 antibodies and Bay11-7082 were injected into AP rats. TNF-alpha, PAI-1 JNK, p-JNK, IkappaBalpha, and p-IkappaBalpha levels were also examined. RESULTS Results showed that levels of PGE2, TNF-alpha, sCRP, p-IkappaBalpha, FGF1, and FGF2, as well as amylase and lipase activity were increased in patients with AP compared with those in healthy people. In addition, protein concentrations were lower in patients with AP than in the healthy group. Activation of FGF signaling by injecting FGF1 or FGF2 also inhibited AP-induced inflammation response in the pancreas and increased amylase and lipase activities, as well as protein concentration. However, the injection of FGF1 and FGF2 antibodies accelerated AP-mediated inflammation responses in the serum. In addition, Bay11-7082 injection inhibited AP activation of inflammation response and amylase and lipase activities. Protein concentration were also increased in AP rats. CONCLUSIONS FGF signaling protects against AP-mediated damage by inhibition of AP-activating inflammatory responses.


Assuntos
Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Inflamação/metabolismo , Pancreatite/patologia , Transdução de Sinais , Doença Aguda , Adulto , Amilases/metabolismo , Animais , Proteína C-Reativa/análise , Estudos de Casos e Controles , Dinoprostona/sangue , Feminino , Fator 1 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Inflamação/patologia , Lipase/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidor de NF-kappaB alfa/sangue , Nitrilos/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonas/farmacologia , Fator de Necrose Tumoral alfa/sangue
16.
Iran J Immunol ; 17(1): 52-63, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32224541

RESUMO

BACKGROUND: Tim-3 has been considered as an ideal target for the immunotherapy of inflammation, but it is unclear whether Tim-3 also plays an important role in acute pancreatitis (AP), as well. OBJECTIVE: To identify the immunomodulatory effects and mechanisms of Tim-3 action in the early stages of severe acute pancreatitis in mice. METHODS: Male BALB/c mice were randomly divided into sham injection group, severe acute pancreatitis group, and anti-Tim-3 treated group. Histopathological scores of the pancreas were calculated, pancreatic myeloperoxidase (MPO) activity was assessed. The concentrations of serum IL-6, IL-10, and TNF-α were evaluated by ELISA method. Quantitative RT-PCR was performed to detect the transcripts of Tim-3, IL-6, IL-10, TNF-α, and TLR4 in peritoneal macrophages. The levels of peritoneal macrophages Tim-3, TLR4, MyD88, and NF-kB p65 were measured by western blot analysis. RESULTS: The pathological scores of the anti-Tim-3 treated group (11.5 ± 1.3) significantly increased compared with the sham (1.3 ± 0.5) and SAP groups (6.9 ± 1.0). Furthermore, the downregulation of Tim-3 significantly aggravated mouse pancreatic tissue damage. It was further shown that Tim-3 negatively regulated the production of pro-inflammatory cytokines, IL-6 and TNF-α, as well as anti-inflammatory cytokine IL-10. Of note, the negative regulation of inflammatory cytokines by Tim-3 was mediated by the activation of TLR4/MyD88 NF-kB signaling pathway. CONCLUSION: Our study showed that Tim-3 might play an important role in the development of AP through regulating the inflammatory response.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/imunologia , Pancreatite/imunologia , Pancreatite/patologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C
17.
Presse Med ; 49(1): 104015, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234378

RESUMO

The diagnosis and treatment of pancreatic and biliary tract involvement in IgG4 disease can be challenging for physicians. A French series shows that the pancreas is the most frequently involved organ in systemic IgG4 disease. Pancreatitis may be found in more than 50% of patients with IgG4 disease and the biliary tract is involved in one third. Pancreatic or biliary involvement may be isolated, metachronous or synchronous of other IgG4-related organ injuries. Pancreatitis related to IgG4 disease is called autoimmune pancreatitis (AIP) type 1. The diagnosis is mainly suspected in the presence of symptoms and morphological features. Changes observed on conventional imaging are not typical and are usually similar to lesions observed in autoimmune pancreatitis type 2. AIP type 1 can also sometimes have a clinical or morphological presentation that mimics pancreatic cancer, especially pseudo-tumoral forms, associated with obstructive jaundice, weight loss and fatigue. Thus, the first challenge is to confirm the diagnosis of autoimmune pancreatitis and to exclude cancer. The AIP type must then be determined to decide on the most appropriate treatment.


Assuntos
Doenças Biliares/diagnóstico , Doença Relacionada a Imunoglobulina G4/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Pancreatite/diagnóstico , Fatores Etários , Idoso , Doenças Biliares/tratamento farmacológico , Doenças Biliares/patologia , Biomarcadores/sangue , Diagnóstico Diferencial , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/classificação , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Doença Relacionada a Imunoglobulina G4/patologia , Icterícia/etiologia , Masculino , Neoplasias Pancreáticas/patologia , Pancreatite/classificação , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Fatores Sexuais , Esteroides/uso terapêutico
18.
Biochem Biophys Res Commun ; 525(3): 620-625, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32115146

RESUMO

The circadian clock, a biochemical oscillator, plays a fundamental role in health and diseases. Ferroptosis, a type of regulated cell death driven by oxidative stress, is a prominent feature in iron-induced tissue injury. However, whether an impaired circadian clock contributes to ferroptosis-induced sterile inflammation remains unknown. Here, we show that the circadian transcription factor ARNTL (also known as BMAL1) protects against experimental acute pancreatitis through blocking the ferroptosis-mediated release of HMGB1, a mediator of sterile inflammation. We utilized a Cre/LoxP system to generate mice with a specific depletion of Arntl in the pancreas (Pdx1-Cre;Arntlflox/flox). These Arntl-deficient mice developed l-arginine-induced acute pancreatitis more rapidly than controls, with increased mortality, tissue injury, neutrophil infiltration, and HMGB1 release. In contrast, the administration of liproxstatin-1 (a ferroptosis inhibitor) or anti-HMGB1 neutralizing antibody attenuated the development of acute pancreatitis in the Arntl-deficient mice. Mechanistically, pancreatic ARNTL is a key regulator of the expression of multiple antioxidant or membrane repair systems (e.g., SLC7A11, GPX4, SOD1, TXN, NFE2L2, and CHMP5) to suppress ferroptotic tissue injury. Collectively, these findings uncover a novel link between the circadian clock and ferroptotic response in inflammation and pancreatic injury.


Assuntos
Relógios Circadianos , Ferroptose , Inflamação/patologia , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/metabolismo , Animais , Arginina , Proteína HMGB1/metabolismo , Camundongos Knockout , Pâncreas/patologia , Pancreatite/patologia
19.
Biol Pharm Bull ; 43(3): 509-515, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115510

RESUMO

Acute pancreatitis (AP) is one kind of acute surgical abdominal disease in the world. It causes intestinal damage with subsequent bacterial migration, endotoxemia and secondary pancreatic infections. In this investigation, we determined that edaravone (EDA) reduces pancreatic and intestinal injury after AP in mice. This was demonstrated by a reduction in histological score, apoptosis, interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α, along with obstructing activation of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NFκB). Our study results suggested that EDA exerts its protective effects against pancreatic and intestinal injury after AP via regulation of the TLR4/NFκB pathway. Our findings provide the basis for EDA to treat AP-induced pancreatic and intestinal injury, even might develop as a potential therapy for other inflammatory diseases.


Assuntos
Edaravone/farmacologia , Intestinos/patologia , NF-kappa B/metabolismo , Pâncreas/patologia , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Animais , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pancreatite/patologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Proc Natl Acad Sci U S A ; 117(12): 6622-6629, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32156729

RESUMO

A more comprehensive understanding of the molecular mechanisms underlying pancreatic diseases, including pancreatitis and cancer, is essential to improve clinical management. MEN1 has established roles in epigenetic regulation and tumor suppression in the endocrine pancreas; however, intriguing recent data suggest MEN1 may also function in the exocrine pancreas. Using physiologically relevant genetic mouse models, we provide direct evidence that Men1 is essential for exocrine pancreas homeostasis in response to inflammation and oncogenic stress. Men1 loss causes increased injury and impaired regeneration following acute caerulein-induced pancreatitis, leading to more severe damage, loss of the normal acinar compartment, and increased cytokeratin 19-positive metaplasias and immune cell infiltration. We further demonstrate the Men1 protein is stabilized in response to insult, and loss of Men1 is associated with the overexpression of proinflammatory Jund target genes, suggesting that loss of Men1-mediated repression of Jund activity is, at least in part, responsible for the impaired response. Finally, we demonstrate that Men1 loss significantly accelerates mutant Kras-dependent oncogenesis. Combined, this work establishes Men1 as an important mediator of pancreas homeostasis in vivo.


Assuntos
Carcinogênese/patologia , Homeostase , Inflamação/patologia , Pâncreas Exócrino/patologia , Neoplasias Pancreáticas/patologia , Pancreatite/patologia , Proteínas Proto-Oncogênicas/fisiologia , Animais , Biomarcadores/análise , Carcinogênese/imunologia , Carcinogênese/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diferenciação Celular , Feminino , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Pâncreas Exócrino/imunologia , Pâncreas Exócrino/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Pancreatite/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética
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