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2.
Medicine (Baltimore) ; 99(35): e21848, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871908

RESUMO

RATIONALE: Drug-induced pancreatitis (DIP) is a kind of acute pancreatitis with a relatively low incidence. There are many cases of acute pancreatitis (AP) caused by chemotherapeutic agents that have been reported. However, few reports focus on the combination of chemotherapeutic agents that induce acute pancreatitis. This article aims to retrospectively analyze a case of DIP and to explore the relationship between chemotherapeutic agents and acute pancreatitis. PATIENT CONCERNS: Here, we report a 35-year-old Chinese female patient who was diagnosed as acute myeloid leukemia with BCR/ABL expression. After induction chemotherapy of daunorubicin and cytarabine, bone marrow aspiration showed: Acute myeloid leukemia-not relieved (AML-NR). Then the regimen of homoharringtonine, cytarabine and dasatinib was started. The patient developed abdominal pain on the 14th day of chemotherapy. Laboratory tests showed elevated serum amylase (AMY) and lipase (LIPA). Computed tomography (CT) of the abdomen revealed a swollen pancreas with blurred edges and thickened left prerenal fascia. DIAGNOSIS: The patient was diagnosed as DIP by the symptoms of upper abdominal pain and the change of CT images. Other common causes of AP were excluded meanwhile. INTERVENTIONS: The chemotherapy was stopped immediately. And after fasting, fluid infusion and inhibiting the secretion of the pancreas, the symptoms were relieved. OUTCOMES: DIP relapsed when the regimen of aclacinomycin + cytarabine + G-CSF + dasatinib regimen (G-CSF (400ug/day, day 1 to 15), cytarabine (30 mg/day, day 2 to 15), aclacinomycin (20 mg/day, day 2 to 5)and dasatinib (140 mg/day, continuously)) was given, and was recovered after treatment for AP was performed. LESSONS: To choose the best treatment plan for patients, clinicians should raise awareness of DIP, and should know that chemotherapeutic agents can induce pancreatitis and the combination of chemotherapeutic agents may increase the risk of drug-induced pancreatitis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Pancreatite/induzido quimicamente , Adulto , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Feminino , Mepesuccinato de Omacetaxina/administração & dosagem , Mepesuccinato de Omacetaxina/efeitos adversos , Humanos , Pancreatite/diagnóstico por imagem , Tomografia Computadorizada por Raios X
3.
Expert Opin Pharmacother ; 21(14): 1675-1684, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32646313

RESUMO

INTRODUCTION: Severe hypertriglyceridemia (sHTG) is a complex disorder of lipid metabolism characterized by plasma levels of triglyceride (TG) greater than 885 mg/dl (>10 mmol/L). The treatment of sHTG syndromes is challenging because conventional treatments are often ineffective in reducing TG under the threshold to prevent acute pancreatitis (AP). The inhibition of APOC3, which encodes a protein involved in triglyceride (TG)-rich lipoproteins (TGRLs) removal, has been reported to be a novel target for the treatment of sHTG. Volanesorsen is a second-generation antisense oligonucleotide inhibiting apoC-III transcription/translation that has been recently approved in Europe for Familial Chylomicronemia Syndrome (FCS) treatment. AREAS COVERED: This review summarizes the evidences on the efficacy and safety of volanesorsen for the treatment of sHTG syndromes. EXPERT OPINION: Volanesorsen effectively reduces TG in sHTG through a mechanism that is mainly LPL-independent, potentially decreasing the risk of AP. Some safety concerns have been raised with the use of volanesorsen, mainly represented by the occurrence of thrombocytopenia. Due to the potential severity of side effects, some caution is needed before affirming the long-term utility of this drug. Despite this, volanesorsen currently remains the only drug that has been demonstrated effective in FCS, which otherwise remains an untreatable disease.


Assuntos
Apolipoproteína C-III/antagonistas & inibidores , Hipertrigliceridemia/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Europa (Continente) , Humanos , Hiperlipoproteinemia Tipo I/tratamento farmacológico , Hipertrigliceridemia/sangue , Hipertrigliceridemia/metabolismo , Lipoproteínas/sangue , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos , Pancreatite/induzido quimicamente , Pancreatite/prevenção & controle , Trombocitopenia/induzido quimicamente , Trombocitopenia/prevenção & controle , Triglicerídeos/sangue
4.
Radiología (Madr., Ed. impr.) ; 62(3): 229-242, mayo-jun. 2020. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-194221

RESUMO

El tratamiento del cáncer ha avanzado drásticamente en las últimas décadas. Un mayor conocimiento de la biología tumoral ha propiciado el desarrollo de nuevos fármacos anticancerígenos, llamados "terapias dirigidas". Estos fármacos tienen como diana vías de señalización específicas necesarias para el desarrollo del cáncer. Más novedosa es aún la inmunoterapia. Estos nuevos agentes se pueden clasificar en diferentes grupos, principalmente según su mecanismo de acción: inhibidores de VEGF o antiangiogénicos, inhibidores de EGFR, inhibidores de mTOR, inhibidores de CTLA-4, inhibidores de PD-1/PD-L1, etc. Todas estas nuevas terapias traen consigo nuevos efectos adversos que el radiólogo debe conocer. Entender el mecanismo molecular de las terapias dirigidas y reconocer sus efectos adversos es esencial para una correcta valoración radiológica y para proporcionar un tratamiento apropiado


The treatment of cancer has improved drastically in recent decades. Better understanding of tumor biology has enabled the development of new treatments, called targeted therapy. These drugs target specific signaling pathways that are necessary for the development of cancer. Immunotherapy is even more novel. These new agents can be classified into different groups, mainly according to their mechanism of action: VEGF inhibitors or anti-angiogenic agents, EGFR inhibitors, mTOR inhibitors, CTLA-4 inhibitors, or PD-1/PD-L1 inhibitors, etc. All these new treatments are accompanied by new adverse effects that radiologists need to know. Understanding the molecular mechanisms of targeted therapies and knowing their adverse effects are vital to imaging assessment and ensuring appropriate treatment


Assuntos
Humanos , Radioterapia/métodos , Radioterapia/efeitos adversos , Neoplasias/radioterapia , Imunoterapia/efeitos adversos , Radioterapia/normas , Anticorpos Monoclonais , Pancreatite/induzido quimicamente
5.
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
6.
Metabolism ; 109: 154295, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32553739

RESUMO

INTRODUCTION: The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents. OBJECTIVE: This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review. DISCUSSION: DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer. CONCLUSION: Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Neoplasias Pancreáticas/induzido quimicamente , Pancreatite/induzido quimicamente , Resultado do Tratamento
7.
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
8.
Adv Exp Med Biol ; 1244: 271-276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301021

RESUMO

Immune checkpoint inhibitors (ICIs) are increasingly used for multiple cancer types. Hepatotoxicity is a reported adverse event of ICI treatment. It can present as asymptomatic elevation of aspartate transaminase and alanine transaminase or symptomatic hepatitis with fever, malaise, and even death in rare cases. The diagnosis of ICI-induced hepatitis is made after exclusion of other etiologies based on medical history, laboratory evaluation, and imaging and histological findings. Treatment of ICI-induced hepatitis consists of ICI discontinuation and immunosuppression in severe cases. Pancreatic injury as asymptomatic lipase elevation or acute pancreatitis-like disease with abdominal pain and evidence on imaging has been documented as a toxicity of ICI therapy. Appropriate treatment of pancreatitis still needs further investigation. Few cases, reports, and series documented cholecystitis and cholangitis as possible adverse events related to ICI therapy as well.


Assuntos
Hepatite/etiologia , Imunoterapia/efeitos adversos , Neoplasias/terapia , Pancreatite/induzido quimicamente , Doença Aguda , Humanos , Neoplasias/imunologia
9.
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
11.
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
12.
J Oncol Pharm Pract ; 26(6): 1533-1537, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32054410

RESUMO

INTRODUCTION: Actionable mutations are tested as standard of care for all new metastatic non-small cell lung cancers. Tumors harboring an anaplastic lymphoma kinase mutation respond to tyrosine kinase inhibitors targeting anaplastic lymphoma kinase pathway. Patients are monitored for common adverse effects, although we occasionally encounter unexpected side effects. CASE REPORT: A 52-year-old male presented with a right hilar lung mass, and workup revealed a stage IIIA adenocarcinoma. He underwent treatment with concurrent chemoradiation; however, disease recurred one year later with a right hilar mass and contralateral mediastinal lymphadenopathy, biopsy of which resulted positive for adenocarcinoma. Molecular analysis showed anaplastic lymphoma kinase rearrangement and alectinib was started. Six months into therapy, he presented with hematochezia, nausea, and epigastric pain and was diagnosed with acute pancreatitis. Triglyceride level resulted above the measurable level at >5680mg/dL, thought to be the inciting event of pancreatitis.Management and outcome: Despite treatment with intravenous hydration, insulin infusion, and antibiotics, he decompensated with development of respiratory failure, shock requiring intensive care. Therapeutic plasmapheresis was initiated due to persistently elevated triglyceride. Following the third plasmapheresis, triglyceride level decreased to 359 mg/dL. With aggressive multidisciplinary management, he made a complete recovery. Follow-up imaging studies at three and six months show a stable mass-like abnormality in the right hilum without evidence of disease progression. DISCUSSION: Prior to starting alectinib, our patient's triglyceride level was 420 mg/dL. While he consumed alcohol, he had no other traditional risk factor. To our knowledge, this is the first reported case of hypertriglyceridemia-induced acute pancreatitis related to treatment with an anaplastic lymphoma kinase inhibitor.


Assuntos
Antineoplásicos/efeitos adversos , Carbazóis/efeitos adversos , Hipertrigliceridemia/induzido quimicamente , Pancreatite/induzido quimicamente , Piperidinas/efeitos adversos , Doença Aguda , Adenocarcinoma/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/administração & dosagem , Biópsia , Carbazóis/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
13.
Am J Case Rep ; 21: e921241, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32037393

RESUMO

BACKGROUND Degenerative disc disease of the lumbar spine can be associated with spinal canal and neuroforaminal stenosis, resulting in severe pain. Conservative approaches to treatment are generally recommended initially, especially in the elderly. Epidural corticosteroid injections can provide significant but temporary pain relief and are a commonly performed procedure in pain management. Pancreatitis caused by corticosteroids is unusual and the prognosis typically is good. CASE REPORT A 73-year-old woman presented with severe intractable back pain 1 week after lumbar epidural steroid injection for symptomatic spinal stenosis. Imaging confirmed severe multi-level degenerative disc disease of the lumbar spine resulting in severe canal and bilateral neuroforaminal stenosis. Because of abdominal pain and nausea, an abdominal CT and labs were performed, revealing evidence of pancreatic inflammation. CONCLUSIONS Lumbar epidural steroid injection may be a risk factor for developing steroid-induced pancreatitis.


Assuntos
Glucocorticoides/efeitos adversos , Injeções Epidurais , Dor Lombar/tratamento farmacológico , Pancreatite/induzido quimicamente , Estenose Espinal/tratamento farmacológico , Idoso , Feminino , Glucocorticoides/administração & dosagem , Humanos
14.
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
15.
Int Immunopharmacol ; 80: 106136, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31991372

RESUMO

Garlic (Allium sativum) - derived organosulfur compound diallyl disulfide (DADS) possesses antioxidant, anti-inflammatory and anti-cancer effects. This study was aimed to investigate the anti-inflammatory role and the underlying molecular mechanisms of DADS in cerulein-induced acute pancreatitis (AP) and associated lung injury. Administration of DADS significantly attenuated the severity of pancreatic and pulmonary inflammation by inhibiting cerulein induced serum amylase, myeloperoxidase activity (MPO) and histological changes in pancreas and lung. Furthermore, the anti-inflammatory effect of DADS was associated with the decrease in tumor necrosis factor (TNF)-α,cystathionine-γ-lyase (CSE), preprotachykinin A (PPTA), neurokinin-1-receptor (NK1R) expression and hydrogen sulfide (H2S) production in both pancreas and lung. In addition, DADS reduced caerulein-induced I-κB degradation and subsequent translocation of NF-κB in the pancreas and lung. These results show for the first time that in AP, DADS exhibits an anti-inflammatory effect by inhibiting CSE/H2S and SP/NK1R signaling and NF-кB pathway.


Assuntos
Compostos Alílicos/farmacologia , Anti-Inflamatórios/farmacologia , Dissulfetos/farmacologia , Lesão Pulmonar/tratamento farmacológico , Pancreatite/tratamento farmacológico , Compostos Alílicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Ceruletídeo/toxicidade , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Dissulfetos/uso terapêutico , Humanos , Sulfeto de Hidrogênio/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/imunologia , Masculino , Camundongos , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/imunologia , Receptores da Neurocinina-1/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Substância P/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165685, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953217

RESUMO

Progression of acute pancreatitis (AP) into a severe form usually results in a life-threatening condition with multiple organ dysfunction, and in particular acute lung injury (ALI), often contributes to the majority of AP-associated deaths. Increasing evidence has shown that uncontrolled activation of the immune system with rapid production of inflammatory cytokines play a dominant role in this process. As an intracellular inflammatory signaling platform, the NOD-like receptor protein 3 (NLRP3) inflammasome, is recently reported to be involved in the pathogenesis of AP progression, however, the relationship between NLRP3 inflammasome activation and AP-associated lung injury remains unclear yet. Here, we show that NLRP3 inflammasome activation and subsequent pyroptosis in alveolar macrophages (AMs) is responsible for the lung injury secondary to AP. In addition, plasma-derived exosomes from AP mice is capable of triggering NLRP3-dependent pyroptosis in AMs. Inhibition of exosome release or uptake in vivo by inhibitors substantially suppresses AMs pyroptosis and thereby alleviates AP-induced pulmonary lesion. Collectively, the current work reveals for the first time the involvement of NLRP3-dependent pyroptosis induced by plasma exosomes in the pathogenesis of AP-induced ALI, suggesting that the exosome-mediated NLRP3 inflammatory pathway is a potential therapeutic target for the treatment of lung injury during AP.


Assuntos
Lesão Pulmonar Aguda/imunologia , Exossomos/metabolismo , Inflamassomos/imunologia , Macrófagos Alveolares/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pancreatite/complicações , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Animais , Arginina/administração & dosagem , Arginina/toxicidade , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Exossomos/imunologia , Humanos , Macrófagos Alveolares/imunologia , Masculino , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pancreatite/sangue , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Piroptose/imunologia
17.
Int Immunopharmacol ; 80: 106128, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978799

RESUMO

OBJECTIVE: Bone marrow-derived mesenchymal stem cells (BMSCs) are effective in the treatment of severe acute pancreatitis (SAP), but their therapeutic effects could still be improved. In order to optimize the clinical application of BMSCs, we adopted the strategy of resveratrol (Res) pretreatment of BMSCs (Res-BMSCs) and applied it to a rat model of sodium taurocholate (NaT)-induced acute pancreatitis. METHODS: SAP was induced by injection of 3% NaT into the pancreatic duct and successful induction of SAP occurred after 12 h. Rats were treated with BMSCs, Res or BMSCs primed with Res at 40 mmol/L, Vandetanib (ZD6474) daily oral dosages of 50 mg/kg vandetanib. RESULTS: Res stimulated BMSCs to secrete vascular endothelial growth factor A (VEGFA), activated the downstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and inhibited pancreatic cell apoptosis. In addition, conditioned medium (CM) from Res-BMSCs enhanced the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro, increased resistance to apoptosis and promoted the expression of angiogenesis-related proteins CD31, VEGF and VEGFR2 in pancreatic tissue, but Vandetanib partly abolished these effects by blocking the VEGFA- mediated pathway. CONCLUSION: Resveratrol-preprocessed BMSCs can activate the PI3K/AKT signaling pathway in pancreatic cells and HUVECs through paracrine release of VEGFA; thus, achieving the therapeutic effect of resisting apoptosis of pancreatic cells and promoting regeneration of damaged blood vessels. Res pretreatment may be a new strategy to improve the therapeutic effect of BMSCs on SAP.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Pancreatite/terapia , Resveratrol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Células-Tronco Mesenquimais/metabolismo , Necrose/induzido quimicamente , Necrose/imunologia , Necrose/patologia , Necrose/terapia , Pâncreas/irrigação sanguínea , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/diagnóstico , Pancreatite/imunologia , Comunicação Parácrina/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Piperidinas/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/administração & dosagem , Ratos , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Ácido Taurocólico/toxicidade , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
World J Gastroenterol ; 26(1): 35-54, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31933513

RESUMO

BACKGROUND: Abdominal paracentesis drainage (APD) is a safe and effective strategy for severe acute pancreatitis (SAP) patients. However, the effects of APD treatment on SAP-associated cardiac injury remain unknown. AIM: To investigate the protective effects of APD on SAP-associated cardiac injury and the underlying mechanisms. METHODS: SAP was induced by 5% sodium taurocholate retrograde injection in Sprague-Dawley rats. APD was performed by inserting a drainage tube with a vacuum ball into the lower right abdomen of the rats immediately after SAP induction. Morphological staining, serum amylase and inflammatory mediators, serum and ascites high mobility group box (HMGB) 1, cardiac-related enzymes indexes and cardiac function, oxidative stress markers and apoptosis and associated proteins were assessed in the myocardium in SAP rats. Nicotinamide adenine dinucleotide phosphate oxidase activity and mRNA and protein expression were also examined. RESULTS: APD treatment improved cardiac morphological changes, inhibited cardiac dysfunction, decreased cardiac enzymes and reduced cardiomyocyte apoptosis, proapoptotic Bax and cleaved caspase-3 protein levels. APD significantly decreased serum levels of HMGB1, inhibited nicotinamide adenine dinucleotide phosphate oxidase expression and ultimately alleviated cardiac oxidative injury. Furthermore, the activation of cardiac nicotinamide adenine dinucleotide phosphate oxidase by pancreatitis-associated ascitic fluid intraperitoneal injection was effectively inhibited by adding anti-HMGB1 neutralizing antibody in rats with mild acute pancreatitis. CONCLUSION: APD treatment could exert cardioprotective effects on SAP-associated cardiac injury through suppressing HMGB1-mediated oxidative stress, which may be a novel mechanism behind the effectiveness of APD on SAP.


Assuntos
Traumatismos Cardíacos/fisiopatologia , Traumatismos Cardíacos/terapia , Estresse Oxidativo/fisiologia , Pancreatite/terapia , Paracentese/métodos , Abdome , Doença Aguda , Animais , Modelos Animais de Doenças , Traumatismos Cardíacos/etiologia , Miocárdio , Pancreatite/induzido quimicamente , Pancreatite/complicações , Ratos , Ratos Sprague-Dawley , Ácido Taurocólico
19.
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
20.
Gastroenterology ; 158(4): 1083-1094, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31751559

RESUMO

BACKGROUND & AIMS: Mutations in the human serine protease 1 gene (PRSS1), which encodes cationic trypsinogen, can accelerate its autoactivation and cause hereditary or sporadic chronic pancreatitis. Disruption of the locus that encodes cationic trypsinogen in mice (T7) causes loss of expression of the protein, but only partially decreases the severity of secretagogue-induced acute pancreatitis and has no effect on chronic pancreatitis. We investigated whether trypsinogen becomes pathogenic only when its activation is promoted by mutation. METHODS: We generated mice with knock-in of the p.K24R mutation (called T7K24R mice), which is analogous to human PRSS1 mutation p.K23R. We gave T7K24R and C57BL/6N (control) mice repeated injections of cerulein to induce pancreatitis. Plasma amylase activity, pancreatic edema, and myeloperoxidase content in pancreas and lungs were quantified. We expressed mutant and full-length forms of PRSS1 in Escherichia coli and compared their autoactivation. RESULTS: The p.K24R mutation increased autoactivation of T7 5-fold. T7K24R mice developed no spontaneous pancreatitis. T7K24R mice given cerulein injections had increased pancreatic activation of trypsinogen and more edema, infiltration of lung and pancreas by inflammatory cells, and plasma amylase activity compared with control mice given cerulein injections. Injection of cerulein for 2 days induced progressive pancreatitis in T7K24R mice, but not in control mice, with typical features of chronic pancreatitis. CONCLUSIONS: Introduction of a mutation into mice that is analogous to the p.K23R mutation in PRSS1 increases pancreatic activation of trypsinogen during secretagogue-induced pancreatitis. Higher pancreatic activity of trypsin increases the severity of pancreatitis, even though loss of trypsin activity does not prevent pancreatitis in mice.


Assuntos
Mutação , Pancreatite Crônica/enzimologia , Pancreatite/enzimologia , Tripsina/genética , Tripsinogênio/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/enzimologia , Pancreatite/induzido quimicamente , Pancreatite/genética , Pancreatite Crônica/genética , Secretagogos/efeitos adversos , Índice de Gravidade de Doença
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