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1.
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
2.
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
3.
Life Sci ; 259: 118268, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32800830

RESUMO

AIM: Cadmium is a persistent ubiquitous environmental toxicant that elicits several biological defects on delicate body organs. Growing evidence suggests that cadmium (Cd) may perturb signaling pathways to induce oxidative pancreatitis. Thus, we explored whether hesperidin, a flavonone, could mitigate Cd-induced oxidative stress-mediated inflammation and pancreatitis in Wistar rats. MAIN METHODS: Forty (40) rats randomly assigned to 5 groups (n = 8) were administered normal saline or hesperidin (Hsp) followed by Cd intoxication for 28 days. KEY FINDINGS: Cadmium accumulated in the pancreas of rats, and markedly decreased insulin, pancreatic superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and glutathione (GSH) level. Cadmium considerably increased malondialdehyde (MDA), serum lipase and amylase activities. Cadmium induced pancreatic pro-inflammation via over-expression of inducible nitric oxide synthase (iNOS), nuclear factor-ĸB (NF-κB), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), along with histopathological alterations. Hesperidin prominently decreased serum amylase and lipase activities, and markedly increased insulin level, pancreatic antioxidant defense mechanism, whereas iNOS, NF-κB, IL-6 and TNF-α levels significantly decreased. Changes in histology confirmed our biochemical findings. SIGNIFICANCE: Our findings suggest that Cd induced pancreatitis via pro-inflammation and oxidative stress; Hsp, thus, protects against Cd-induced pancreatitis via attenuation of oxidative stress and proinflammatory responses in pancreas.


Assuntos
Hesperidina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Cádmio/toxicidade , Catalase/metabolismo , Glutationa/metabolismo , Hesperidina/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/fisiologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/metabolismo , Substâncias Protetoras , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
4.
Nat Commun ; 11(1): 3409, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641778

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRasG12D-driven PDAC, loss of κB-Ras accelerates tumour development and shortens median survival. κB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. κB-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of κB-Ras proteins and highlight low κB-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling.


Assuntos
Células Acinares/metabolismo , Carcinoma Ductal Pancreático/genética , GTP Fosfo-Hidrolases/genética , Neoplasias Pancreáticas/genética , Pancreatite/genética , Proteínas/genética , Células Acinares/patologia , Idoso , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Metaplasia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/metabolismo , Proteínas/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteínas ral de Ligação ao GTP/genética , Proteínas ral de Ligação ao GTP/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
5.
Medicine (Baltimore) ; 99(27): e21056, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629733

RESUMO

Primary nephrotic syndrome (PNS) is one of the most common primary glomerular diseases in children. Patients complicated nephrotic syndrome with pancreatic lesions are rarely reported, and the clinical manifestations in children are atypical. This study has observed the incidence, clinical types, and prognosis of acute pancreatitis (AP) in children with primary nephrotic syndrome, and analyzed its related factors, early diagnosis, and treatment.Seven children with PNS and AP in Shanghai Children's Hospital from January 2015 to December 2017 were reviewed. The clinical data including age, height, weight, body mass index (BMI), diet, biliary tract disease, PNS durations, drugs, proteinuria, creatinine, glucose, glycated hemoglobin, amylase and lipase, albumin, cholesterol, triglyceride, ultrasound, computerized tomography (CT), renal pathology and estimated glomerular filtration rate (eGFR) were retrospectively analyzed. All patients were followed for >2 years.Ten in 589 patients with PNS were detected pancreatic lesions by abdominal ultrasound. Seven were diagnosed as AP, which the incidence was 1.2%. Only 1 of 7 patients had elevated serum amylase. Lesions of pancreas were found by ultrasound and/or enhanced CT. Four of 7 patients had been treated with tacrolimus. All patients with AP were improved after octreotide acetate injection and supportive treatment. Only 1 patient suffered recurrent AP during the relapse of PNS 10 months later.AP in children with PNS is not common, and the clinical manifestations are not typical. Abdominal ultrasound and enhanced CT are of high value in diagnosis. The adverse effects of tacrolimus should be concerned. Early diagnosis and timely treatment can be helpful for a prognosis.


Assuntos
Rim/patologia , Síndrome Nefrótica/complicações , Síndrome Nefrótica/metabolismo , Pancreatite/metabolismo , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Incidência , Masculino , Síndrome Nefrótica/diagnóstico por imagem , Síndrome Nefrótica/fisiopatologia , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Pancreatite/diagnóstico por imagem , Pancreatite/tratamento farmacológico , Pancreatite/epidemiologia , Prognóstico , Recidiva , Estudos Retrospectivos , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico
6.
Chem Biol Interact ; 327: 109181, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32569593

RESUMO

Acute pancreatitis (AP) is a sudden pancreatic inflammation accompanied by an excessive reactive oxygen species production that provokes inflammation. The present study investigated whether carvedilol can protect against l-arginine induced AP in a rat model and studied the mechanisms associated with its protection. Rats were divided into four groups: a control group, an AP group (injected with 2 doses of l-arginine 250 mg/100 g body weight at 1 h interval, intraperitoneally) on the 22nd day of the experiment, a carvedilol group (10 mg/kg, orally) for 21 successive days, and finally a carvedilol + AP group. It was found that pretreatment with carvedilol decreased α-amylase and lipase activities as well as C-reactive protein (CRP) and malondialdehyde levels; on the other hand, it improved the reduced glutathione (GSH) level and catalase (CAT) activity. In addition, carvedilol markedly decreased all of the following biomarkers: nuclear factor kappa B (NF-κB p65), p38 mitogen-activated protein kinases (P38-MAPK), signal transducer and activator of transcription 1 (STAT1-α), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), myeloperoxidase (MPO), and phospholipase A2 (PLA2) levels that was induced by l-arginine. Finally, carvedilol noticeably down regulated the pancreatitis associated protein (PAP2) and the pancreas platelets activating factor (PAF) genes expression. In conclusion: carvedilol protected against l-arginine induced AP in rats, via the inhibition of cellular oxidative stress and inflammatory pathways that contributed to pancreas injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Carvedilol/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Animais , Arginina , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Glutationa/metabolismo , Hidrolases/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Peroxidase/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
7.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G1000-G1012, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308041

RESUMO

Trypsinogen activation is the hallmark of acute pancreatitis (AP) independent of intra-acinar NF-κB activation and inflammation. We previously found that dopamine (DA) receptor 2 (DRD2) activation controls inflammation during AP via PP2A-dependent NF-κB activation. In this study, we sought to examine whether DRD2 signaling mediates trypsinogen activation and the underlying mechanisms. Pancreatic acinar cells were stimulated with cholecystokinin-8 in vitro. AP was induced by intraperitoneal injections of caerulein and LPS or l-arginine. Pancreatitis severity was assessed biochemically and histologically. We found that activation of DRD2 by quinpirole, a potent DRD2 agonist, resulted in the reduction of trypsinogen activation and the upregulation of HSP70 in vitro and in vivo. Mechanistically, we found that quinpirole induced dephosphorylation of heat shock factor 1 (HSF1), a master transcription factor of HSP70, leading to increased nuclear translocation of HSF1 in a PP2A-dependent pathway. Furthermore, DRD2 activation restored lysosomal pH and, therefore, maintained lysosomal cathepsin B activity in a HSP70-dependent manner. VER155008, a potent HSP70 antagonist, abolished the protective effects observed with DRD2 activation in vitro and in two experimental models of AP. Our data showed that besides controlling NF-κB activation, DRD2 activation prevented trypsinogen activation during acute pancreatitis via PP2A-dependent upregulation of HSP70 and further support that DRD2 agonist could be a promising therapeutic strategy for treating AP.NEW & NOTEWORTHY The current study demonstrated that activation of DRD2 by quinpirole protects against trypsinogen activation in the in vitro and in vivo setting of acute pancreatitis by upregulating HSP70 and restoring lysosomal degradation via a PP2A-dependent manner, therefore leading to reduced pancreatic injury. These findings provide a new mechanistic insight on the protective effect of DRD2 activation in acute pancreatitis.


Assuntos
Proteínas de Choque Térmico HSP72/metabolismo , Pancreatite/tratamento farmacológico , Quimpirol/farmacologia , Receptores de Dopamina D2/agonistas , Tripsinogênio/metabolismo , Animais , Ceruletídeo/farmacologia , Agonistas de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP72/genética , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Lisossomos , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/citologia , Pancreatite/metabolismo , Fosforilação , Proteína Fosfatase 2/metabolismo , Regulação para Cima
8.
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
9.
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
10.
J Pathol ; 251(1): 1-3, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32003469

RESUMO

Acute pancreatitis (AP) is an inflammatory disease of the pancreas that causes significant morbidity and mortality worldwide. Unfortunately, there is no specific treatment available to date. Several studies have previously shown that inhibitors of the PI3K/Akt axis downregulate the degree of inflammation in animal models of AP. However, studies on in vivo side-effects of such inhibitors are still lacking. In a recent issue of The Journal of Pathology, Chen, Malagola et al investigated if inhibition of Akt signaling plays a negative role in the regenerative phase of AP. They showed that treating AP mice with an Akt inhibitor (MK2206) impaired acinar regeneration and increased the development of acinar-to-ductal metaplasia. This is the first study to highlight the negative impact of an Akt inhibitor on cellular regeneration while simultaneously inhibiting inflammation in AP. The authors also suggested combining Akt activators to recover pancreatic regeneration. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Pancreatite/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doença Aguda , Animais , Humanos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Pancreatite/patologia , Transdução de Sinais/fisiologia
11.
Int J Mol Sci ; 21(1)2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31947993

RESUMO

Acute pancreatitis (AP) is a severe inflammation of the pancreas presented with sudden onset and severe abdominal pain with a high morbidity and mortality rate, if accompanied by severe local and systemic complications. Numerous studies have been published about the pathogenesis of AP; however, the precise mechanism behind this pathology remains unclear. Extensive research conducted over the last decades has demonstrated that the first 24 h after symptom onset are critical for the identification of patients who are at risk of developing complications or death. The identification of these subgroups of patients is crucial in order to start an aggressive approach to prevent mortality. In this sense and to avoid unnecessary overtreatment, thereby reducing the financial implications, the proper identification of mild disease is also important and necessary. A large number of multifactorial scoring systems and biochemical markers are described to predict the severity. Despite recent progress in understanding the pathophysiology of AP, more research is needed to enable a faster and more accurate prediction of severe AP. This review provides an overview of the available multifactorial scoring systems and biochemical markers for predicting severe AP with a special focus on their advantages and limitations.


Assuntos
Biomarcadores/sangue , Pancreatite/diagnóstico , Doença Aguda , Humanos , Interleucinas/sangue , Doenças Metabólicas/complicações , Doenças Metabólicas/patologia , Pancreatite/diagnóstico por imagem , Pancreatite/metabolismo , Prognóstico , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Fator de Necrose Tumoral alfa/sangue
12.
Mol Med Rep ; 21(3): 981-988, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922216

RESUMO

Chemerin is a novel adipokine that regulates immune responses, adipocyte differentiation, and glucose metabolism. However, the role of chemerin in pancreatogenic diabetes mellitus (PDM) remains unknown. PDM is recognized as DM occurring secondary to chronic pancreatitis or pancreatic resection due to the loss of the loss of islet cell mass. The aim of the present study was to investigate the role of chemerin in PDM by collecting blooding samples from DM patients and establishing in vivo PDM model. The present study demonstrated that chemerin levels are decreased in the serum of patients with PDM and are negatively associated with the insulin resistance (IR) status. Chemerin levels also decreased during the development of PDM in C57BL/6 mice, together with increasing serum levels of interleukin­1 and tumor necrosis factor­α and decreasing mRNA expression levels of glucose transporter 2 (GLUT2) and pancreatic and duodenal homeobox 1 (PDX1). Treatment of PDM model mice with chemerin chemokine­like receptor 1 (CMKLR1) agonist, chemerin­9, elevated the serum levels of chemerin and mRNA expression levels of GLUT2 and PDX1, leading to the alleviation of glucose intolerance and IR in these animals. Together, the accumulated data indicated that chemerin may exert a protective function in PDM, perhaps by regulating perhaps by regulating GLUT2 and PDX1 expression, and that the restoration of the chemerin/CMKLR1 pathway may represent a novel therapeutic strategy for PDM.


Assuntos
Quimiocinas/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pancreatite , Transdução de Sinais , Adulto , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pancreatite/metabolismo , Pancreatite/patologia
13.
Oxid Med Cell Longev ; 2020: 8172714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998444

RESUMO

High-fat diet (HFD) often increases oxidative stress and enhances inflammatory status in the body. Toll-like receptor 4 (TLR4) is widely expressed in the pancreatic tissues and plays an important role in pancreatitis. This study is aimed at investigating the effect of HFD on acute pancreatitis (AP) and the role of TLR4-mediated necroptosis and inflammation in this disease. Weight-matched rats were allocated for an 8-week feeding on the standard chow diet (SCD) or HFD, and then, the AP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at an indicated time point after modeling. Additionally, inhibition of TLR4 signaling by TAK-242 in HFD rats with AP was conducted in vivo. The results showed that the levels of serum free fatty acid (FFA) in HFD rats were higher than those in SCD rats. Moreover, HFD rats were more vulnerable to AP injury than SCD rats, as indicated by more serious pathological damage and much higher pancreatic malondialdehyde (MDA) and lipid peroxidation (LPO) levels as well as lower pancreatic superoxide dismutase (SOD) activities and reduced glutathione (GSH) contents and more intense infiltration of MPO-positive neutrophils and CD68-positive macrophages. In addition, HFD markedly increased the expressions of TLR4 and necroptosis marker (RIP3) and aggravated the activation of NF-κB p65 and the expression of TNF-α in the pancreas of AP rats at indicated time points. However, TLR4 inhibition significantly attenuated the structural and functional damage of the pancreas induced by AP in HFD rats, as indicated by improvement of the above indexes. Taken together, these findings suggest that HFD exacerbated the extent and severity of AP via oxidative stress, inflammatory response, and necroptosis. Inhibition of TLR4 signaling by TAK-242 alleviated oxidative stress and decreased inflammatory reaction and necroptosis, exerting a protective effect during AP in HFD rats.


Assuntos
Gorduras na Dieta/efeitos adversos , Necroptose/efeitos dos fármacos , Pancreatite/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Gorduras na Dieta/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pancreatite/patologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores
14.
Clin Biochem ; 77: 54-56, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31899279

RESUMO

BACKGROUND: Despite widespread recommendations to favor lipase over amylase in the diagnosis and management of acute pancreatitis, many routine hospital laboratories still offer amylase testing. This study sought to evaluate and compare ordering patterns of amylase and lipase in patients with acute pancreatitis. METHODS: We analyzed 438 patients with acute pancreatitis admitted to our hospital. Data collection included pancreatitis etiology and management as well as biochemical profiles of amylase and lipase. We compared serial ordering patterns, degree of biomarker elevation, and normalization kinetics. RESULTS: All patients had at least one lipase ordered during their admission, and only 51 patients (12%) had at least one amylase ordered. On average, lipase was elevated 5 times higher above its respective upper reference limit than amylase at admission. Pancreatitis etiology was skewed toward gallstones in the amylase group as compared to the lipase only group (69% vs. 43%), and surgical patients (laparoscopic cholecystectomy) were more likely to have amylase ordered and/or trended. CONCLUSIONS: Amylase measurement was not necessary in the diagnosis and management of 88% of patients with acute pancreatitis. Of patients for whom amylase was ordered, it was common for these patients to be those referred to surgical procedures, possibly because amylase normalization may be documented faster than that of lipase.


Assuntos
Amilases/metabolismo , Colecistectomia Laparoscópica/métodos , Pancreatite/diagnóstico , Adulto , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/enzimologia , Pancreatite/metabolismo , Pancreatite/cirurgia
15.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 64-71, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31889183

RESUMO

Previous studies have shown that during severe acute pancreatitis (SAP) attacks, hydrogen sulfide (H2S) is released in the colon. However, the roles played by H2S in regulating enteric nerves remain unclear. In this study, we examined the association between SAP-induced H2S release and loss of intestinal motility, and also explored the relevant mechanism in enteric nerve cells. A rat SAP model was constructed and enteric nerve cells were prepared. Intestinal mobility was evaluated by measuring the number of bowel movements at indicated time points and by performing intestinal propulsion tests. The production of inflammatory cytokines during a SAP attack was quantified by ELISA, and the levels of cystathionine-γ-lyase (CSE) and cystathionine-ß-synthase (CBS) were examined by immunohistochemistry and western blot analysis. In vivo studies showed that PI3K/Akt/Sp1 signaling in enteric nerve cells was blocked, confirming the mechanism of endogenous H2S formation by western blot analysis and immunofluorescence. Our results also showed that rats with SAP symptoms had reduced intestinal motility. Furthermore, PI3K/Akt/Sp1 signaling was triggered and CSE expression was up-regulated, and these changes were associated with H2S formation in the colon. In addition, propargylglycine reduced the levels of inflammatory cytokines and suppressed the release of H2S. Enteric nerve cells that were incubated with LY294002 and transfected with a Sp1-knockdown vector displayed decreased levels of CSE production, which led to a decrease in H2S production. These results suggest that SAP symptoms suppressed the intestinal motility of rats via the release of H2S in enteric nerve cells, which was dependent on the inflammation-induced PI3K/Akt/Sp1 signaling pathway.


Assuntos
Movimento Celular , Sistema Nervoso Entérico/patologia , Sulfeto de Hidrogênio/metabolismo , Neurônios/metabolismo , Pancreatite/metabolismo , Animais , Cromonas/farmacologia , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Citocinas/metabolismo , Motilidade Gastrointestinal , Técnicas de Silenciamento de Genes , Inflamação/metabolismo , Masculino , Morfolinas/farmacologia , Pancreatite/induzido quimicamente , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Ácido Taurocólico/efeitos adversos , Ácido Taurocólico/farmacologia , Transfecção
16.
Cell Mol Life Sci ; 77(9): 1811-1825, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31363815

RESUMO

Premature intrapancreatic trypsinogen activation is widely regarded as an initiating event for acute pancreatitis. Previous studies have alternatively implicated secretory vesicles, endosomes, lysosomes, or autophagosomes/autophagolysosomes as the primary site of trypsinogen activation, from which a cell-damaging proteolytic cascade originates. To identify the subcellular compartment of initial trypsinogen activation we performed a time-resolution analysis of the first 12 h of caerulein-induced pancreatitis in transgenic light chain 3 (LC3)-GFP autophagy reporter mice. Intrapancreatic trypsin activity increased within 60 min and serum amylase within 2 h, but fluorescent autophagosome formation only by 4 h of pancreatitis in parallel with a shift from cytosolic LC3-I to membranous LC3-II on Western blots. At 60 min, activated trypsin in heavier subcellular fractions was co-distributed with cathepsin B, but not with the autophagy markers LC3 or autophagy protein 16 (ATG16). Supramaximal caerulein stimulation of primary pancreatic acini derived from LC3-GFP mice revealed that trypsinogen activation is independent of autophagolysosome formation already during the first 15 min of exposure to caerulein. Co-localization studies (with GFP-LC3 autophagosomes versus Ile-Pro-Arg-AMC trypsin activity and immunogold-labelling of lysosomal-associated membrane protein 2 [LAMP-2] versus trypsinogen activation peptide [TAP]) indicated active trypsin in autophagolysosomes only at the later timepoints. In conclusion, during the initiating phase of caerulein-induced pancreatitis, premature protease activation develops independently of autophagolysosome formation and in vesicles arising from the secretory pathway. However, autophagy is likely to regulate overall intracellular trypsin activity during the later stages of this disease.


Assuntos
Autofagia , Ceruletídeo/toxicidade , Pancreatite/patologia , Tripsina/metabolismo , Tripsinogênio/metabolismo , Animais , Autofagossomos/metabolismo , Endossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Vesículas Secretórias/metabolismo
17.
Redox Biol ; 28: 101324, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539805

RESUMO

Acute pancreatitis is an inflammatory process of the pancreatic gland that may lead to dysregulation of the trans-sulfuration pathway. The aims of this work were firstly to study the methionine cycle as well as the trans-sulfuration pathway using metabolomic and proteomic approaches identifying the causes of this dysregulation in an experimental model of acute pancreatitis; and secondly to reveal the effects of S-adenosylmethionine administration on these pathways. Acute pancreatitis was induced by cerulein in mice, and a group of animals received S-adenosylmethionine treatment. Cerulein-induced acute pancreatitis rapidly caused marked depletion of methionine, S-adenosylmethionine, 5'-methylthioadenosine, cystathionine, cysteine, and glutathione levels in pancreas, but S-adenosylhomocysteine and homocysteine remained unchanged. Protein steady-state levels of S-adenosylhomocysteine-hydrolase and cystathionine gamma-lyase diminished but methylthioadenosine phosphorylase levels increased in pancreas with acute pancreatitis. Although cystathionine ß-synthase protein levels did not change with acute pancreatitis, Nos2 mRNA and protein levels were markedly up-regulated and caused tyrosine nitration of cystathionine ß-synthase in pancreas. S-adenosylmethionine administration enhanced Nos2 mRNA expression and cystathionine ß-synthase nitration and triggered homocysteine accumulation in acute pancreatitis. Furthermore, S-adenosylmethionine administration promoted enrichment of the euchromatin marker H3K4me3 in the promoters of Tnf-α, Il-6, and Nos2 and enhanced the mRNA up-regulation of these genes. Accordingly, S-adenosylmethionine administration increased inflammatory infiltrate and edema in pancreas with acute pancreatitis. In conclusion, tyrosine-nitration of cystathionine ß-synthase blockades the trans-sulfuration pathway in acute pancreatitis promoting homocysteine accumulation upon S-adenosylmethionine treatment.


Assuntos
Ceruletídeo/efeitos adversos , Cistationina beta-Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Pancreatite/metabolismo , Animais , Cistationina/metabolismo , Cisteína/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Homocisteína/metabolismo , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/etiologia , S-Adenosilmetionina/administração & dosagem , Regulação para Cima
18.
J Pediatr Hematol Oncol ; 42(1): 63-64, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593004

RESUMO

Pancreatitis is a common complication of many pediatric oncology drugs - most commonly asparaginase, followed by pentamidine, mercaptopurine, corticosteroids, and trimethoprim-sulfamethoxazole. Cytarabine-associated pancreatitis is not often mentioned in the pediatric oncology literature. We report the case of a 10-year-old female with acute myeloid leukemia who developed cytarabine-associated pancreatitis.


Assuntos
Citarabina , Leucemia Mieloide Aguda , Pancreatite , Criança , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/patologia
19.
Endocr J ; 67(1): 95-98, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31597815

RESUMO

A 59-year-old woman unaware of having diabetes was transferred due to coma. Upon discovery at home, her consciousness on the Glasgow Coma Scale was E1V2M4, BP 95/84 mmHg, body temperature 34.7°C. On arrival at ER, height was 1.63 m, weight 97 kg, plasma glucose (PG) 1,897 mg/dL, HbA1c 13.6%, osmolality 421 mosm/kg, arterial pH 7.185, lactate 6.34 mmol/L, ß-hydroxybutyrate 7.93 mmol/L. With saline and regular insulin infusion, PG was lowered to 1,440 mg/dL at 2 hours and then to 250 mg/dL by Day 3, and consciousness normalized by Day 5. On admission, serum immunoreactive insulin (IRI) was undetectable (<0.03 U/mL), C-peptide immunoreactivity (CPR) undetectable (<0.003 ng/mL), and anti-glutamic acid decarboxylase antibody negative. Following the above-described treatment, fasting PG was 186 mg/dL and CPR 1.94 ng/mL, respectively, on Day 14; 2-h post-breakfast PG 239 mg/dL and CPR 6.28 ng/mL, respectively, on Day 18. The patient discharged on Day 18 with 1,800 kcal diet, 32 U insulin glargine and 40 mg gliclazide. Fifteen months later at outpatient clinic, her HbA1c was 6.9% and 2-h post-breakfast PG 123 mg/dL and CPR 5.30 ng/dL with 750 mg metformin, 10 mg gliclazide and 18 U insulin glargine. Transient, but total cessation of insulin secretion was documented in a patient with type 2 diabetes under severe metabolic decompensation. Swift, sustained recovery of insulin release indicated that lack of insulin at the time of emergency was due to secretory failure, i.e., unresponsive exocytotic machinery or depletion of releasable insulin, rather than loss of beta cells.


Assuntos
Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Coma Diabético/metabolismo , Insulina/metabolismo , Acidose Láctica/complicações , Acidose Láctica/metabolismo , Acidose Láctica/terapia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Coma Diabético/etiologia , Coma Diabético/terapia , Feminino , Hidratação , Hemoglobina A Glicada/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hiperglicemia/terapia , Hipoglicemiantes/uso terapêutico , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Cetose/complicações , Cetose/metabolismo , Cetose/terapia , Pessoa de Meia-Idade , Pancreatite/etiologia , Pancreatite/metabolismo
20.
Dig Dis Sci ; 65(6): 1720-1732, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31724100

RESUMO

BACKGROUND AND AIMS: The present study aimed to identify the differential expressed genes that are related to acute pancreatitis. METHODS: Microarray datasets GSE109227 and GSE3644 were downloaded from the public database and analyzed to screen the genes. Afterward, integrated analysis of these genes were performed, including gene ontology and pathway enrichment analysis, protein-protein interaction network construction, expression level evaluation in human organs, relevant miRNAs and TFs prediction, and prognosis values of hub genes in pancreatic carcinoma. RESULTS: A total number of 93 differential expressed genes were screened from the datasets, and EGFR, CDH1, ACTB, CD44, and VCL were identified as hub DEGs. Functional enrichment analysis demonstrated that these genes were mostly enriched in biological processes such as cell adhesion, platelet aggregation, glycoprotein binding, and also involved in multiple pathways included adherent junction, proteoglycans in cancer, bacterial invasion of epithelial cells, focal adhesion, Rap1 signaling pathway, regulation of actin cytoskeleton, and pathways in cancers. The five hub genes were all expressed in human pancreas organs with various levels. Hub gene-related network investigation predicted core miRNAs including hsa-mir-16-5p and main TFs like SOX9 with close interactions with these hub genes. Survival analysis also indicated that the high expression of EGFR, CDH1, ACTB, CD44, and VCL were significantly associated with poor prognosis in pancreatic carcinoma. CONCLUSIONS: The study suggested that hub genes EGFR, CDH1, ACTB, CD44, and VCL may play vital role in the pathogenesis of acute pancreatitis and may serve as potential biomarkers to facilitate future acute pancreatitis diagnosis and treatment.


Assuntos
Regulação da Expressão Gênica/fisiologia , Redes Reguladoras de Genes , Análise de Sequência com Séries de Oligonucleotídeos , Pancreatite/metabolismo , Carcinoma/metabolismo , Mineração de Dados , Bases de Dados Factuais , Bases de Dados de Proteínas , Humanos , Neoplasias Pancreáticas/metabolismo , Transcriptoma
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