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1.
Life Sci ; 241: 117118, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790686

RESUMO

AIMS: Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. MAIN METHODS: Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. KEY FINDINGS: MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. SIGNIFICANCE: MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.


Assuntos
Lesão Renal Aguda/genética , Hiperlipidemias/complicações , MicroRNAs/genética , Pancreatite/complicações , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Amilases/sangue , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hiperlipidemias/genética , Rim/patologia , Lipídeos/sangue , Lipídeos/genética , Masculino , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Pancreatite/genética , Pancreatite/patologia , Ratos Sprague-Dawley
2.
Acta Gastroenterol Belg ; 82(3): 397-400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31566327

RESUMO

BACKGROUND AND AIMS: Early prediction of severe acute pancreatitis (SAP)would be helpful for triaging patients to the appropriate level of care and intervention. The aim of this study is to compare the performance of the Change in Amylase And Body mass index (CAB) score and BISAP score for predicting SAP. PATIENTS AND METHODS: A total of 406 with AP were enrolled. The age, gender, body mass index(BMI), blood urea nitrogen determined at the time of admission and serum amylase determined on day 1 and day 2 after hospitalization were collected and analyzed statistically. RESULTS: Multivariable analysis confirmed that blood urea nitrogen (OR 1.06; 95%CI 1.03-1.09) and percentage change in amylase day 2 (OR 0.75; 95%CI 0.65-0.87) were independently associated with development of SAP. No statistically significant association was observed between BMI (OR 1.04; 95%CI 0.951.13) and severity of acute pancreatitis. The area under the receiver operating characteristic curve for Body mass index (BMI), percentage change in amylase day 2, BISAP score and CAB score were 0.57±0.05, 0.68±0.04, 0.84±0.03 and0.53±0.05, respectively. CONCLUSION: BISAP is more accurate for predicting the severity of acute pancreatitis than the CAB score.


Assuntos
Amilases/sangue , Nitrogênio da Ureia Sanguínea , Índice de Massa Corporal , Pancreatite/diagnóstico , Índice de Gravidade de Doença , Doença Aguda , Biomarcadores/sangue , Humanos , Pancreatite/classificação , Pancreatite/patologia , Admissão do Paciente/estatística & dados numéricos , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos
3.
Med Sci Monit ; 25: 6894-6904, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518341

RESUMO

BACKGROUND Acute pancreatitis (AP) has a high mortality rate and often has serious complications. The Hippo-YAP signaling pathway is mainly involved in cell proliferation and stem cell self-renewal. Recent studies have reported that YAP1 plays a crucial role in pancreatic cancer initiation and acute and chronic pancreatitis (CP). However, the role of YAP1 in AP still needs to be clarified. MATERIAL AND METHODS To assess the role of YAP1 in the progression of AP, we established a cell model of AP in AR42J cells. AR42J, a rat pancreatic acinar cell line, was stimulated with caerulein to mimic AP-like acinar cell injury. Levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-alpha) were measured by ELISA to investigate the role of YAP1 in the progression of AP. RESULTS The results showed that YAP1 and MALAT1 were the targets of miR-194 and were upregulated in caerulein-treated AR42J cells. Overexpression of MALAT1 or YAP1 can increase the levels of IL-6 and TNF-alpha secreted by AR42J cells, while miR-194 dramatically counteracts this enhancement effect. CONCLUSIONS Our results demonstrated a regulation loop among MATAL1, miR-194, and YAP1, which dynamically regulates the progression of AP, providing a new therapeutic target for treatment of this disease.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Progressão da Doença , Retroalimentação Fisiológica , MicroRNAs/metabolismo , Pancreatite/genética , Pancreatite/patologia , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Doença Aguda , Animais , Sequência de Bases , Linhagem Celular , Ceruletídeo , Citoproteção , Regulação para Baixo/genética , MicroRNAs/genética , Ligação Proteica , RNA Longo não Codificante/genética , Ratos , Regulação para Cima/genética
4.
PLoS Biol ; 17(9): e3000418, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513574

RESUMO

Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration.


Assuntos
Células Acinares/metabolismo , Pâncreas/metabolismo , Pancreatite/etiologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Fibrose , Camundongos , Pâncreas/patologia , Células Estreladas do Pâncreas/fisiologia , Pancreatite/metabolismo , Pancreatite/patologia , Transdução de Sinais , Fatores de Transcrição/metabolismo
5.
Biomed Pharmacother ; 119: 109455, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541854

RESUMO

Severe acute pancreatitis (SAP) is an acute abdominal disease that can develop locally to the multiple organs. It is characterized by pancreatic tissue self-digestion, and the rapid release of inflammatory cytokines, which play a dominant role in local or even systemic inflammation. In this study, we investigate the protective effect of T-614 against SAP induced by cerulein plus LPS in mice. Biochemical markers associated with pancreatitis in serum such as inflammatory cytokines, amylase and lipase activities were measured. Related proteins of NLRP3 inflammasome and NF-κB signaling pathway were evaluated by western blotting. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to evaluate changes of inflammation in pancreatic tissue. T-614 significantly alleviated the elevation markers of pancreatitis and suppresses the pancreatic tissue damage, including histopathological and molecular manifestations. In conclusion, T-614 plays a protective role in experimental SAP mice model via anti-inflammatory effects.


Assuntos
Cromonas/uso terapêutico , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Transdução de Sinais , Sulfonamidas/uso terapêutico , Doença Aguda , Amilases/sangue , Animais , Cromonas/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lipase/sangue , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/sangue , Pancreatite/patologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia
6.
Korean J Gastroenterol ; 74(3): 175-182, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554034

RESUMO

Pancreatitis, panniculitis, and polyarthritis (PPP) syndrome is a rare but critical disease with a high mortality rate. The diagnostic dilemma of PPP syndrome is the fact that symptoms occur unexpectedly. A 48-year-old man presented with fever and painful swelling of the left foot that was initially mistaken for cellulitis and gouty arthritis. The diagnosis of PPP syndrome was made based on the abdominal CT findings and elevated pancreatic enzyme levels, lobular panniculitis with ghost cells on a skin biopsy, and polyarthritis on a bone scan. The pancreatitis and panniculitis disappeared spontaneously over time, but the polyarthritis followed its own course despite the use of anti-inflammatory agents. In addition to this case, 30 cases of PPP syndrome in the English literature were reviewed. Most of the patients had initial symptoms other than abdominal pain, leading to misdiagnosis. About one-third of them were finally diagnosed with a pancreatic tumor, of which pancreatic acinar cell carcinoma was the most dominant. They showed a mortality rate of 32.3%, associated mainly with the pancreatic malignancy. Therefore, PPP syndrome should be considered when cutaneous or osteoarticular manifestations occur in patients with pancreatitis. Active investigation and continued observations are needed for patients suspected of PPP syndrome.


Assuntos
Artrite/diagnóstico , Pancreatite/diagnóstico , Paniculite/diagnóstico , Artrite/tratamento farmacológico , Artrite/patologia , Artrite Gotosa/diagnóstico , Osso e Ossos/diagnóstico por imagem , Celulite (Flegmão)/diagnóstico , Diagnóstico Diferencial , Eritema/diagnóstico , Eritema/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/uso terapêutico , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Paniculite/tratamento farmacológico , Paniculite/patologia , Tomografia Computadorizada por Raios X
7.
Gastroenterology ; 157(6): 1660-1672.e2, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31493399

RESUMO

BACKGROUND & AIMS: Pancreatitis is characterized by increased influx of Ca2+ into acinar cells, by unknown mechanisms. Inhibitors of Ca2+ influx channels could be effective in treating acute pancreatitis, but these have deleterious side effects that can result in death. We investigated the expression patterns and functions of acinar cell Ca2+ channels and factors that regulate them during development of acute pancreatitis, along with changes in the channel inactivator store-operated calcium entry-associated regulatory factor (SARAF). We investigated whether SARAF is a target for treatment of acute pancreatitis and its status in human with pancreatitis. METHODS: We generated mice that expressed SARAF tagged with hemagglutinin, using CRISPR/Cas9 gene editing, and isolated acinar cells. We also performed studies with Saraf-/- mice, Sarafzf/zf mice, mice without disruption of Saraf (control mice), and mice that overexpress fluorescently labeled SARAF in acinar cells. We analyzed interactions between stromal interaction molecule 1 (STIM1) and SARAF in HEK cells stimulated with carbachol using fluorescence resonance energy transfer microscopy and immunoprecipitation. Mice were given injections of caerulein or L-arginine to induce pancreatitis. Pancreatic tissues and blood samples were collected and levels of serum amylase, trypsin, tissue damage, inflammatory mediators, and inflammatory cells were measured. We performed quantitative polymerase chain reaction analyses of pancreatic tissues from 6 organ donors without pancreatic disease (controls) and 8 patients with alcohol-associated pancreatitis. RESULTS: Pancreatic levels of Ca2+ influx channels or STIM1 did not differ significantly between acinar cells from mice with vs. without pancreatitis. By contrast, pancreatic levels of Saraf messenger RNA and SARAF protein initially markedly increased but then decreased during cell stimulation or injection of mice with caerulein, resulting in excessive Ca2+ influx. STIM1 interacted stably with SARAF following stimulation of HEK or mouse acinar cells with physiologic levels of carbachol, but only transiently following stimulation with pathologic levels of carbachol, leading to excessive Ca2+ influx. We observed reduced levels of SARAF messenger RNA in pancreatic tissues from patients with pancreatitis, compared with controls. SARAF knockout mice developed more severe pancreatitis than control mice after administration of caerulein or L-arginine, and pancreatic acinar cells from these mice had significant increases in Ca2+ influx. Conversely, overexpression of SARAF in acini reduced Ca2+ influx, eliminated inflammation, and reduced severity of acute pancreatitis. CONCLUSIONS: In mice with pancreatitis, SARAF initially increases but is then degraded, resulting in excessive, pathological Ca2+ influx by acinar cells. SARAF knockout mice develop more severe pancreatitis than control mice, whereas mice that express SARAF from a transgene in acinar cells develop less-severe pancreatitis. SARAF therefore appears to prevent pancreatic damage during development of acute pancreatitis. Strategies to stabilize or restore SARAF to acinar cells might be developed for treatment of pancreatitis.


Assuntos
Cálcio/metabolismo , Proteínas Sensoras de Cálcio Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Pâncreas/patologia , Pancreatite/patologia , Molécula 1 de Interação Estromal/metabolismo , Células Acinares/patologia , Animais , Ceruletídeo/toxicidade , Modelos Animais de Doenças , Células HEK293 , Humanos , Proteínas Sensoras de Cálcio Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Pâncreas/citologia , Pancreatite/sangue , Pancreatite/induzido quimicamente , Índice de Gravidade de Doença
8.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 575-578, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484625

RESUMO

Autoimmune pancreatitis(AIP)is radiologically characterized by sausage-like diffuse swelling of the pancreatic parenchyma but may also be found as a localized mass that is easily misdiagnosed as a pancreatic neoplasm.AIP presenting as multifocal masses is rare.Here we report a case of multifocal IgG4-related AIP,in which the lesions grew in size and finally fused to become radiologically typical.


Assuntos
Doença Relacionada a Imunoglobulina G4/diagnóstico , Pancreatite/diagnóstico , Humanos , Doença Relacionada a Imunoglobulina G4/patologia , Pâncreas/patologia , Neoplasias Pancreáticas , Pancreatite/patologia
9.
Pharm Biol ; 57(1): 595-603, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31496325

RESUMO

Context: Oxymatrine (OMT) has various pharmacological effects, including immune reaction regulation, anti-inflammation and anti-hypersensitive reaction. Objective: This is the first report to investigate the molecular mechanism of OMT function in l-arginine (Arg)-induced acute pancreatitis (AP) involving intestinal injury. Materials and methods: Rat pancreatic AR42J and small intestinal IEC-6 cells were treated with Arg (200-800 µM) for 48 h plus OMT (4 mg/mL) treatment. Thirty adult Wistar rats were randomly assigned to control (saline), AP (i.p. of 250 mg/100 g body weight Arg) and OMT (i.p. injection of 50 mg/kg b.w. OMT every 6 h following Arg). Both cells and rats were harvested at 48 h. Results: Arg-induced cell proliferation in both rats AR42J (EC50 633.9 ± 31.4 µM) and IEC-6 cells (EC50 571.3 ± 40.4 µM) in a dose-dependent manner, which was significantly inhibited by OMT (4 mg/mL). Meanwhile, Arg (600 µM) induced expression of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, NF-κB, IL-17A/IL-17F and IFN-γ) and activation of p-p38/p-ERK in vitro, which was reversed by OMT. In vivo, OMT (50 mg/kg) inhibited 250 mg/100 g of Arg-induced AP involving intestinal injury, including inhibiting Arg-induced inflammatory in pancreas and intestine, inhibiting Arg-induced increase of TNF-α, IL-6, IL-1ß, NF-κB and p-p38/p-ERK-MAPK signalling, and inhibiting Arg-induced increase of IL-17A/IL-17F, IFN-γ, ROR-γt and T-bet. Meanwhile, OMT inhibited Arg-induced expression of CD44 and CD55 in intestinal injury. Discussion and conclusions: OMT protects against Arg-induced AP involving intestinal injury via regulating Th1/Th17 cytokines and MAPK/NF-κB signalling, which is a promising therapeutic agent in clinics.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Íleo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Pancreatite/prevenção & controle , Quinolizinas/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Doença Aguda , Animais , Arginina , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Modelos Animais de Doenças , Íleo/imunologia , Íleo/patologia , Masculino , Pancreatite/imunologia , Pancreatite/patologia , Ratos Wistar , Células Th1/imunologia , Células Th17/imunologia
10.
Med Sci Monit ; 25: 6097-6103, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31413252

RESUMO

BACKGROUND To investigate the clinical characteristics of hypertriglyceridemia pancreatitis (HTGP) and evaluate the correlative risk factors for severe acute pancreatitis (SAP) in HTGP patients. MATERIAL AND METHODS A total of 1005 patients with acute pancreatitis (AP) admitted to Peking Union Medical College Hospital (PUMCH) from 1 Jan 2013 to 1 Aug 2018 were retrospectively reviewed. After screening, we enrolled 159 patients with HTGP and 172 with non-hypertriglyceridemia pancreatitis (NHTGP). We gathered and assessed demographic and blood biochemical information and analyzed the risk factors for SAP. RESULTS Age, serum amylase (AMY), lipase (LIP), and serum ionized calcium (Ca²âº) in the HTGP group were lower than in the NHTGP group (P<0.05), while high-sensitivity C-reactive protein (hsCRP), neutrophil-lymphocyte ratio (NLR), and body mass index (BMI) in the HTGP group were higher than in the NHTGP group (P<0.05). Among the HTGP patients, the results indicated that Ca²âº (OR=0.018, P<0.001, 95%CI: 0.002-0.129) was an independent protective factor for SAP, while higher CRP (OR=1.008, P=0.004, 95%CI: 1.003-1.013), NLR (OR=1.314, P<0.001, 95%CI: 1.161-1.488), and BMI (OR=1.597, P=0.002, 95%CI: 1.195-2.314) were independent risk factors for SAP. CONCLUSIONS Patients with HTGP had lower serum Ca²âº and higher hsCRP, NLR, and BMI, and these were associated with higher risk of developing SAP.


Assuntos
Proteína C-Reativa/metabolismo , Cálcio/sangue , Hiperlipidemias/sangue , Linfócitos/patologia , Neutrófilos/patologia , Pancreatite/sangue , Adulto , Amilases/sangue , Índice de Massa Corporal , Cálcio/metabolismo , Feminino , Humanos , Hiperlipidemias/complicações , Hipertrigliceridemia/complicações , Lipase/sangue , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Pancreatite/patologia , Estudos Retrospectivos , Fatores de Risco
11.
Mol Med Rep ; 20(4): 3027-3034, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432122

RESUMO

Curcumin has been demonstrated to reduce markers of inflammation during acute pancreatitis (AP). However, the underlying mechanisms of the protective effects of curcumin are unknown. In the present study the effects of curcumin in an AP animal model and cell models was examined and the underlying mechanisms were investigated. An AP animal model was established by injection of 5% sodium taurocholate into the biliopancreatic duct of rats, and the cell model was established by treatment with 0.5 nM cerulein with an optimal concentration of lipopolysaccharide in AR42J rat pancreatic cancer cells. Amylase activity and arterial blood gas composition were assessed by automatic biochemical and blood gas analyzers. Pathological alteration of the pancreas was determined by hematoxylin and eosin staining. Interleukin (IL­6), tumor necrosis factor (TNF)­α and C­reactive protein (CRP) levels were measured by ELISA. Cell viability was determined by Cell Counting Kit­8 and protein expression levels were assessed by western blotting. Curcumin reduced the ascites volume after 12 and 24 h, the weight of pancreas after 12, 24 and 36 h of surgery, but also attenuated injury to the pancreas. Serum expression levels of TNF­α and CRP were reduced by curcumin. In addition, curcumin decreased the cell viability, amylase activity and the phosphorylation of p38 in AR42J cells, but did not affect the intracellular levels of IL­6 and TNF­α. Curcumin may lower the severity and inflammatory response via the mitogen­activated protein kinase­signaling pathway, to some extent. However, future studies are required to fully understand the protective effects of curcumin on AP.


Assuntos
Curcumina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pâncreas/metabolismo , Pancreatite , Animais , Proteína C-Reativa/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Interleucina-6/metabolismo , Pâncreas/patologia , Pancreatite/metabolismo , Pancreatite/patologia , Pancreatite/prevenção & controle , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
12.
Int Immunopharmacol ; 75: 105821, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437787

RESUMO

Mounting evidence has demonstrated that acute pancreatitis (AP) is one of the causes of multiple organ damage. NADPH (nicotinamide adenine dinucleotide phosphate) act as a substrate of NADPH oxidase (NOX) to generate reactive oxygen species (ROS), but the role NADPH oxidase signaling pathway plays in AP-induced acute lung injury remains unclear. Apocynin, an inhibitor of NOX, is highly effective in suppressing the production of ROS. Here, we used rat model of severe acute pancreatitis (SAP) to explore whether the NOX inhibitor apocynin produced protective effects in against SAP-induced lung injury via inhibition of inflammation and oxidation. We observed that apocynin significantly attenuated severe acute pancreatitis-induced increase of NOX2, NOX4 and ROS expressions in lung tissues. In addition, the phosphorylation and degradation of IκBα, and the nuclear localization of NF-κB p65 in SAP-induced lung injury were also inhibited after using apocynin. Simultaneously, down-regulation of NOX suppressed the levels of inflammasome proteins including NLRP3, ASC, pro-Caspase-1 and cleaved-Caspase-1 in the lung. Serum levels of TNF-α, interleukin (IL)-1ß and IL-6 were also reduced. Our findings suggest that beyond anti-oxidative effects, apocynin may also have anti-inflammatory effects by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis. Therefore, apocynin may have therapeutic potential in the treatment of SAP and SAP-induced lung injury.


Assuntos
Acetofenonas/farmacologia , Lesão Pulmonar Aguda/imunologia , Anti-Inflamatórios/farmacologia , Inflamassomos/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pancreatite/imunologia , Acetofenonas/uso terapêutico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Citocinas/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/complicações , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Ratos Wistar , Espécies Reativas de Oxigênio/imunologia , Transdução de Sinais/efeitos dos fármacos
13.
J Vet Med Sci ; 81(10): 1492-1495, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31406036

RESUMO

An 11-year-old, castrated male, Yorkshire Terrier was presented with acute vomiting after chicken bone ingestion. The dog had been diagnosed with hyperadrenocorticism previously and showed acute splenomegaly and signs of systemic inflammatory response syndrome during hospitalization. On diagnostic imaging, acute splenic vein thrombosis was found, concurrent with pancreatitis and gastritis. The spleen showed marked enlargement and hypoechoic lacy appearances on ultrasonography, mimicking splenic torsion. On the histopathologic report, only splenic hemorrhage and congestion with large splenic vein thrombosis were identified. After splenectomy, the dog completely recovered and was discharged.


Assuntos
Doenças do Cão , Gastrite/veterinária , Pancreatite/veterinária , Esplenectomia/veterinária , Síndrome de Resposta Inflamatória Sistêmica/veterinária , Trombose Venosa/veterinária , Doença Aguda , Animais , Doenças do Cão/patologia , Doenças do Cão/cirurgia , Cães , Gastrite/complicações , Gastrite/patologia , Masculino , Pancreatite/complicações , Pancreatite/patologia , Veia Esplênica/patologia , Síndrome de Resposta Inflamatória Sistêmica/complicações , Ultrassonografia , Trombose Venosa/complicações , Trombose Venosa/cirurgia
14.
Oxid Med Cell Longev ; 2019: 4363672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281575

RESUMO

The present study was conducted to investigate the effect and potential mechanism of hypoxia-inducible factor-1α (HIF-1α) genetic inhibition plus glutamine (Gln) supplementation on necrosis-apoptosis imbalance during acute pancreatitis (AP), with a specific focus on the regulations of intracellular energy metabolism status. Wistar rats and AR42J cells were used to establish AP models. When indicated, a HIF-1α knockdown with or without a Gln supplementation was administered. In vivo, local and systemic inflammatory injuries were assessed by serum cytokine measurement, H&E staining, and transmission electron microscope (TEM) observation of pancreatic tissue. In vitro, intracellular energy metabolism status was evaluated by measuring the intracellular adenosine triphosphate (ATP), lactic acid, and Ca2+ concentrations and the mitochondrial potential. In addition, changes in the apoptotic activity were analyzed using TUNEL staining in vivo and an apoptosis assay in vitro. HIF-1α knockdown alleviated AP-related inflammatory injury as indicated by the measurements of serum cytokines and examinations of TEM and H&E staining of pancreatic tissues. HIF-1α knockdown played an antioxidative role against AP-related injuries by preventing the increase in the intracellular Ca2+ concentration and the decrease in the mitochondrial membrane potential and subsequently by suppressing the glycolysis pathway and increasing energy anabolism in AR42J cells after AP induction. Apoptosis was significantly upregulated when HIF-1α was knocked down before AP induction due to an attenuation of the translocation of nuclear factor-kappa B to the nuclei. Furthermore, these merits of HIF-1α knockdown in the relief of the metabolic stress and upregulation of apoptosis were more significant when Gln was administered concomitantly. In conclusion, Gln-supplemented HIF-1α knockdown might be promising for the future management of AP by relieving the intracellular energy stress, thereby attenuating the predominance of necrosis over apoptosis.


Assuntos
Glutamina/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pancreatite/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Técnicas de Silenciamento de Genes , Glutamina/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Necrose , Pancreatite/genética , Pancreatite/patologia , Ratos , Ratos Wistar
15.
Pancreatology ; 19(5): 646-652, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31301995

RESUMO

BACKGROUND & AIM: Ascites in patients with acute pancreatitis (AP) is understudied although recent literature hints at its evident role in the final outcome. This study was planned to study the characteristics of ascites in patients of AP and its effect on the disease course and outcome. METHODS: Consecutive patients of AP were studied and patients with or without ascites were evaluated for the baseline parameters and severity assessment. Ascites was quantified and fluid analyzed for its characteristics. Intraabdominal pressure (IAP) was monitored. The various outcome parameters were compared between the two groups of patients with and without ascites. RESULTS: Of the cohort of 213 patients, 82 (38.5%) developed ascites. Ascites group had significantly higher rates of organ failure (p = 0.001), necrosis (p=<0.001) and higher severity assessment scores. The ascites group had significantly longer hospital and ICU stay and higher ventilator days compared to the non-ascites group. Mortality was also higher in the ascites group (34.1% vs 8.45; p = 0.001). Majority of patients with ascites had moderate to gross ascites (75.6%), low serum ascites albumin gradient (87.8%) with low amylase levels (71.9%). Sub-group analysis in ascites group showed that patients with fatal outcome had higher rates of moderate to gross ascites, higher baseline IAP and lower reduction in IAP after 48 h. Moderate to gross ascites and grades of intra-abdominal hypertension (IAH) were significant predictors of mortality (AUC - 0.76). CONCLUSION: AP patients with ascites have a more severe disease with poorer outcome. Higher degrees of ascites and IAH grades are significant predictors of mortality.


Assuntos
Ascite/patologia , Pancreatite/patologia , Doença Aguda , Adulto , Amilases/metabolismo , Líquido Ascítico/química , Líquido Ascítico/patologia , Estudos de Coortes , Feminino , Humanos , Hipertensão Intra-Abdominal/etiologia , Hipertensão Intra-Abdominal/fisiopatologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Pancreatite/mortalidade , Pancreatite/terapia , Paracentese , Valor Preditivo dos Testes , Resultado do Tratamento
16.
In Vivo ; 33(4): 1133-1141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280202

RESUMO

BACKGROUND/AIM: This study investigated the anti-inflammatory effect of apigenin in an experimental model of acute pancreatitis. Inflammatory response was reflected by tissue expression of the cytokine TNF-α coupled with histological examination. MATERIALS AND METHODS: Wistar rats were divided into three groups: Sham-group animals underwent laparotomy only, without any other interventions. Control-group animals underwent laparotomy and bilio-pancreatic duct ligation to induce pancreatitis without apigenin administration. Apigenin group animals were further treated with apigenin. Euthanasia was performed at 6, 12, 24, 48 and 72 h post-operatively. RESULTS: Over-expression of TNF-α in relation to postoperative time was observed in the control group (p<0.001). In the apigenin group, under-expression of TNF-α in relation to postoperative time was observed (p<0.013). At 72 h, apigenin reduced pancreatic TNF-α expression and prevented pancreatic necrosis. CONCLUSION: Apigenin slows progression and reduces severity of acute pancreatitis. Apigenin may serve as an adjunct to a more successful therapeutic strategy in acute pancreatitis.


Assuntos
Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Pancreatite/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença Aguda , Animais , Biomarcadores , Imuno-Histoquímica , Masculino , Pancreatite/tratamento farmacológico , Pancreatite/etiologia , Pancreatite/patologia , Ratos , Fatores de Tempo
17.
Gastroenterology ; 157(5): 1413-1428.e11, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31352001

RESUMO

BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.


Assuntos
Células Acinares/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Transformação Celular Neoplásica/metabolismo , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Intraductais Pancreáticas/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células Acinares/patologia , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/prevenção & controle , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Regulação para Baixo , Fatores de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Mutação , PPAR gama/genética , PPAR gama/metabolismo , Cisto Pancreático/genética , Cisto Pancreático/metabolismo , Cisto Pancreático/patologia , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/prevenção & controle , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/prevenção & controle , Pancreatite/genética , Pancreatite/metabolismo , Pancreatite/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Medicine (Baltimore) ; 98(28): e16435, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305468

RESUMO

RATIONALE: Mucinous cystic neoplasms (MCNs) are pancreatic mucin-producing cystic lesions with a distinctive ovarian-type stroma. The diagnosis is generally easy in typical cases; however, differential diagnosis is difficult in others such as in the case we report herein. PATIENT CONCERNS: A 27-year-old woman with sudden onset of epigastric pain was referred to our hospital for suspected acute pancreatitis. Contrast-enhanced computed tomography revealed a 25-mm cystic lesion in the pancreas and a low density area with delayed enhancement at the right upper side of the cystic lesion. DIAGNOSES: During its clinical course, the cystic lesion underwent various morphological changes. Eventually, it presented typical findings of MCNs, and could be accurately diagnosed. INTERVENTIONS: Laparoscopic distal pancreatectomy was performed on the patient by preserving the spleen. OUTCOMES: The patient revealed no symptoms till 1 year after the operation. LESSONS: This case of MCN with intriguing short-term morphological changes was associated with recurrent pancreatitis. A combination of imaging modalities is essential for accurate diagnosis of MCNs, and follow-up with serial imaging might be useful for certain unusual lesions.


Assuntos
Adenocarcinoma Mucinoso/patologia , Pâncreas/patologia , Cisto Pancreático/patologia , Neoplasias Pancreáticas/patologia , Pancreatite/patologia , Adenocarcinoma Mucinoso/complicações , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/cirurgia , Adulto , Progressão da Doença , Feminino , Humanos , Pâncreas/diagnóstico por imagem , Pâncreas/cirurgia , Cisto Pancreático/complicações , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Pancreatite/complicações , Pancreatite/diagnóstico por imagem , Pancreatite/cirurgia , Recidiva
19.
PLoS One ; 14(6): e0217633, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211768

RESUMO

Acute pancreatitis (AP) is acute inflammation of the pancreas, mainly caused by gallstones and alcohol, driven by changes in communication between cells. Heparin-binding proteins (HBPs) play a central role in health and diseases. Therefore, we used heparin affinity proteomics to identify extracellular HBPs in pancreas and plasma of normal mice and in a caerulein mouse model of AP. Many new extracellular HBPs (360) were discovered in the pancreas, taking the total number of HBPs known to 786. Extracellular pancreas HBPs form highly interconnected protein-protein interaction networks in both normal pancreas (NP) and AP. Thus, HBPs represent an important set of extracellular proteins with significant regulatory potential in the pancreas. HBPs in NP are associated with biological functions such as molecular transport and cellular movement that underlie pancreatic homeostasis. However, in AP HBPs are associated with additional inflammatory processes such as acute phase response signalling, complement activation and mitochondrial dysfunction, which has a central role in the development of AP. Plasma HBPs in AP included known AP biomarkers such as serum amyloid A, as well as emerging targets such as histone H2A. Other HBPs such as alpha 2-HS glycoprotein (AHSG) and histidine-rich glycoprotein (HRG) need further investigation for potential applications in the management of AP. Pancreas HBPs are extracellular and so easily accessible and are potential drug targets in AP, whereas plasma HBPs represent potential biomarkers for AP. Thus, their identification paves the way to determine which HBPs may have potential applications in the management of AP.


Assuntos
Biomarcadores/sangue , Pancreatite/genética , Proteoma/genética , alfa-2-Glicoproteína-HS/genética , Animais , Modelos Animais de Doenças , Heparina/genética , Homeostase , Humanos , Camundongos , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite/sangue , Pancreatite/patologia , Ligação Proteica/genética , Proteínas/genética , Proteômica/métodos , Proteína Amiloide A Sérica/metabolismo
20.
Pancreatology ; 19(5): 638-645, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31204259

RESUMO

BACKGROUND: /Objectives: Evaluation of the local and systemic effects of aging on the severity of acute pancreatitis (AP) in an experimental rat model in elderly animals. METHODS: AP was induced in Wistar rats by intraductal 2.5% taurocholate injection and divided into two groups: Young (3 month old) and Aged (18 month old). Two and 24 h after AP induction blood samples were collected for determinations of amylase, AST, ALT, urea, creatinine, glucose, and of plasma I-FABP. TNF-α and IL-6 levels were determined in serum and ascitic fluid. Liver mitochondrial function and malondialdehyde (MDA) contents, pancreas histological analysis, and pulmonar myeloperoxidade (MPO) activity were performed. Bacterial translocation was evaluated by bacterial cultures of pancreas. RESULTS: A significant increase in serum amylase, AST, ALT, urea, creatinine, glucose, I-FABP, and IL-6 levels, and a reduction in serum and ascitic fluid TNF-α levels were observed in the aged group compared to the young group. Liver mitochondrial dysfunction, MDA contents, and pulmonary MPO activity were increased in the Aged AP group compared to the Young AP group. Positive bacterial cultures obtained from pancreas tissue in aged group were significantly increased compared to the young group. Acinar necrosis was also increased in aged AP group when compared to young AP group. CONCLUSION: Aging worsens the course of acute pancreatitis evidenced by increased local and systemic lesions and increased bacterial translocation.


Assuntos
Envelhecimento/patologia , Pancreatite/patologia , Doença Aguda , Animais , Citocinas/sangue , Proteínas de Ligação a Ácido Graxo/metabolismo , /fisiopatologia , Peroxidação de Lipídeos , Masculino , Mitocôndrias Hepáticas/metabolismo , Necrose , Oxirredução , Pancreatite/cirurgia , Peroxidase/metabolismo , Fosforilação , Ratos , Ratos Wistar
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