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1.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206763

RESUMO

Acute pancreatitis (AP) is an inflammatory disorder, involving acinar cell death and the release of inflammatory cytokines. Currently, there are limited effective therapeutic agents for AP. Betulinic acid (BA) is a pentacyclic triterpenoid extracted from Betula platyphylla that has been shown to have anti-inflammatory effects. In this study, we aimed to investigate the effects of BA on AP and elucidate the potential underlying mechanisms. AP was induced in mice through six intraperitoneal injections of cerulein. After the last cerulein injection, the mice were sacrificed. Our results revealed that pre- and post-treatment with BA significantly reduced the severity of pancreatitis, as evidenced by a decrease in histological damage in the pancreas and lung, serum amylase and lipase activity and pancreatic myeloperoxidase activity. Furthermore, BA pretreatment reduced proinflammatory cytokine production, augmentation of chemokines, and infiltration of macrophages and neutrophils in the pancreas of AP mice. In addition, mice that were pretreated with BA showed a reduction in Iκ-Bα degradation and nuclear factor-kappa B (NF-κB) binding activity in the pancreas. Moreover, BA reduced the production of proinflammatory cytokines and NF-κB activation in pancreatic acinar cells (PACs). These findings suggest that BA may have prophylactic and therapeutic effects on AP via inhibition of the NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , NF-kappa B/metabolismo , Pancreatite/tratamento farmacológico , Triterpenos Pentacíclicos/uso terapêutico , Amilases/sangue , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Lipase/sangue , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Triterpenos Pentacíclicos/farmacologia , Peroxidase/metabolismo , Transdução de Sinais
2.
BMJ Case Rep ; 14(7)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290025

RESUMO

Severe hypertriglyceridaemia can lead to acute pancreatitis, which is associated with maternal and perinatal mortality when it occurs in pregnancy. Rapid reduction of triglyceride levels is a primary goal in the management of severe hypertriglyceridaemia, however, there are limited safe option for treatment in pregnancy. We present a case of a woman without diabetes presenting with severe hypertriglyceridaemia in late gestation who was safely and successfully treated with insulin and review the literature surrounding the management of this important condition.


Assuntos
Diabetes Mellitus , Hipertrigliceridemia , Pancreatite , Doença Aguda , Feminino , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Insulina/uso terapêutico , Pancreatite/tratamento farmacológico , Gravidez , Gestantes
3.
Life Sci ; 280: 119704, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34111461

RESUMO

AIMS: The present study aimed to evaluate the protective action of thymol towards l-arginine-induced acute pancreatitis (AP) by studying the function of rat peritoneal immune cells. MAIN METHODS: Rat peritoneal exudate cells (PECs), obtained 24 h after the injection of l-arginine (350 mg/100 g of b.w.), were evaluated for mitochondrial activity (MTT assay), adherence capacity (methylene-blue assay), and phagocyte enzyme activity (myeloperoxidase, MPO, assay). The activity of α-amylase and free MPO, as well as the concentration of reactive oxygen species (ROS, i.e. O2-), were determined in the peritoneal exudate fluid. Also, serum α-amylase activity determination and pancreatic tissue pathohistological analysis were performed. KEY FINDING: The administered thymol (50 and 100 mg/kg, per os) caused a significant decrease in the PEC mitochondrial activity and adherence capacity when compared with these functions of PECs isolated from rats with AP. A decrease in cellular MPO activity, as well as in the levels of ROS, α-amylase, and free MPO in peritoneal exudates was found in animals treated with thymol compared to the control animals with AP. Additionally, thymol administration prevented an increase in serum α-amylase activity, accompanied by the decrease in pancreatic tissue damage that follows l-arginine application. SIGNIFICANCE: The present results showed that thymol exerts significant immunomodulatory properties and a potential to silence PEC functions in inflammatory conditions such as the AP induced by l-arginine.


Assuntos
Arginina/efeitos adversos , Imunidade Celular/efeitos dos fármacos , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Timol/uso terapêutico , Animais , Células Cultivadas , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Granulócitos/patologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/imunologia , Pancreatite/patologia , Cavidade Peritoneal/patologia , Ratos , Ratos Wistar
4.
BMC Gastroenterol ; 21(1): 210, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964868

RESUMO

BACKGROUND: Efficacy of pancreatic enzyme inhibitors in acute pancreatitis (AP) is unclear in China. AIMS: We aimed to present the current status of AP and evaluate the efficacy of pancreatic enzyme inhibitors in a larger population in China. METHOD: A retrospective, cross-sectional, real-world, multicenter analysis of a large dataset of patients presenting with AP from four hospitals of China over a two-year period was performed. Data were collected from the existing clinical records and the patients were grouped into medication group (somatostatin or octreotide or somatostatin and octreotide) and no medication group. Pair wise propensity score matching was performed for comparing somatostatin, octreotide and somatostatin/octreotide. The end points were incidence of disease complications, organ failure, hospitalization duration, and recovery time taken (hours) for serum amylase/serum lipase to normalcy. RESULTS: A total of 3900 patients were recruited and 2775 patients were included for analysis. A total of 1100, 661, 676 and 338 patients received either somatostatin or octreotide or somatostatin and octreotide or no medication, respectively. The incidence of complications (7.6% vs 13.6%), organ failure (4.5% vs 7.4%), and the instances of entering ICU (9.3% vs 13.3%) were higher in unmedicated group. Complications at discharge (2.91 times), organ failure (2.53 times), and hospitalization stay were higher in octreotide-treated patients compared with somatostatin-treated patients. In comparison to the octreotide group, the serum amylase/lipase recovery time was shorter in the somatostatin group. CONCLUSION: This real-world study suggested that the use of pancreatic enzyme inhibitors was positively associated with greater clinical efficacy in AP patients and somatostatin might be more effective than octreotide in real-world settings in China.


Assuntos
Pancreatite , Doença Aguda , China/epidemiologia , Estudos Transversais , Humanos , Octreotida/uso terapêutico , Pancreatite/diagnóstico , Pancreatite/tratamento farmacológico , Pancreatite/epidemiologia , Estudos Retrospectivos
5.
J Med Chem ; 64(9): 5429-5446, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33945278

RESUMO

The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.


Assuntos
Adamantano/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Doença Aguda , Adamantano/metabolismo , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Sítios de Ligação , Domínio Catalítico , Permeabilidade da Membrana Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/metabolismo , Meia-Vida , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Pancreatite/tratamento farmacológico , Ratos , Relação Estrutura-Atividade
6.
BMC Gastroenterol ; 21(1): 243, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34049483

RESUMO

BACKGROUND: Symptoms associated with acute pancreatitis can be debilitating, and treatment remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of acute pancreatitis. METHODS: Acute pancreatitis was induced in adult male C57Bl/6J mice by administering cerulein (8 injections of 50 µg/kg I.P., spaced an hour apart), with XPro1595 (10 mg/kg, S.C.) or vehicle being administered approximately 18 h after the last injection. Serum was collected 6 or 18 h after the last cerulein injection, pancreatic tissue was collected 2 and 7 days post-induction, and brain hippocampal tissue was collected at 7 days post-induction. The animal's pain level was assessed 3, 5 and 7 days post-induction. RESULTS: The induction of acute pancreatitis promoted a strong increase in serum amylase levels, which had receded back to baseline levels by the next morning. XPro1595 treatment began after amylase levels had subsided at 18 h, and prevented pancreatic immune cell infiltration, that subsequently prevented tissue disruption and acinar cell death. These improvements in pathology were associated with a significant reduction in mechanical hypersensitivity (neuropathic pain). XPro1595 treatment also prevented an increase in hippocampal astrocyte reactivity, that may be associated with the prevention of neuropathic pain in this mouse model. CONCLUSION: Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of cerulein-induced pancreatitis in mice, which provides support of its use in patients with pancreatitis.


Assuntos
Ceruletídeo , Pancreatite , Doença Aguda , Animais , Humanos , Masculino , Camundongos , Pâncreas , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Fator de Necrose Tumoral alfa
7.
J Int Med Res ; 49(5): 3000605211014798, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34034562

RESUMO

Autoimmune pancreatitis (AIP) is a unique form of pancreatitis often associated with infiltration of immunoglobulin G4-positive cells, a swollen pancreas, and diffuse narrowing of the pancreatic ducts. Unlike acute pancreatitis, AIP is rarely complicated with pseudocysts. Pancreatic calculi, a feature of ordinary chronic pancreatitis, are unusual during short-term follow-up in patients with AIP. We herein describe a 46-year-old man who initially presented with a submucosal tumor of the stomach. The patient was finally diagnosed with AIP accompanied by a pancreatic tail pseudocyst located in the gastric wall and pancreatic calculi by endoscopic ultrasonography-guided fine-needle aspiration. He underwent endoscopic retrograde cholangiopancreatography, pancreatic duct stent placement, and steroid treatment and achieved good clinical and laboratory responses. Although AIP is a common autoimmune disease that responds well to steroids, pseudocysts and pancreatic calculi are rare manifestations of AIP and should be given special attention, especially in patients with disease relapse.


Assuntos
Pancreatite Autoimune , Cálculos , Pancreatite , Doença Aguda , Cálculos/complicações , Cálculos/diagnóstico por imagem , Cálculos/cirurgia , Colangiopancreatografia Retrógrada Endoscópica , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Pancreatite/diagnóstico por imagem , Pancreatite/tratamento farmacológico
8.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1111-G1122, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33881355

RESUMO

Ketamine and xylazine (Ket/Xyl) are anesthetic agents that target neural pathways and are commonly used in combination in mouse studies. Since neural pathways can modulate acute pancreatitis severity, we asked if Ket/Xyl affect disease severity. C57BL/6 mice were treated with six hourly injections of cerulein to induce mild acute pancreatitis. Mice were also treated with and without ketamine, xylazine, and Ket/Xyl before pancreatitis induction in vivo and in vitro. Ket/Xyl pretreatment in vivo increased selected parameters of pancreatitis severity such as trypsin activity and edema; these effects were predominantly mediated by xylazine. Ket/Xyl also changed markers of autophagy. These in vivo effects of Ket/Xyl were not attenuated by atropine. The drugs had no little to no effect on pancreatitis responses in isolated pancreatic cells or lobules. These findings suggest that Ket/Xyl administration can have substantial effect on acute pancreatitis outcomes through nonmuscarinic neural pathways. Given widespread use of this anesthetic combination in experimental animal models, future studies of inflammation and injury using Ket/Xyl should be interpreted with caution.NEW & NOTEWORTHY Ketamine and xylazine anesthetic agent administration before acute pancreatitis induction in mice lead to changes in pancreatitis responses independent of acute pancreatitis induction. Future studies should consider the potential effects of anesthesia administration when studying disease processes associated with inflammation and injury.


Assuntos
Analgésicos/uso terapêutico , Ketamina/uso terapêutico , Pâncreas/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Xilazina/uso terapêutico , Analgésicos/farmacologia , Animais , Atropina/farmacologia , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Ketamina/farmacologia , Masculino , Camundongos , Resultado do Tratamento , Xilazina/farmacologia
9.
Medicine (Baltimore) ; 100(14): e25141, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832077

RESUMO

ABSTRACT: The aim of this research is to observe the effect of insulin pump combined with Ulinastatin on the levels of procalcitonin (PCT), triglycerides (TG), pentraxin-3(PTX-3), and C-X3-C motif chemokine ligand 1 (CX3CL1) in patients with diabetic ketoacidosis and pancreatitis.A total of 72 patients with diabetic ketoacidosis and pancreatitis who were admitted to our hospital from February 2016 to February 2020 were selected as the research subjects. They were divided into study groups (36 cases, given insulin pump combined Ulinastatin treatment) and control group (36 cases, given insulin pump treatment). Statistics of changes in blood amylase (AMS), blood glucose, blood ketones, glycosylated hemoglobin (HbA1c), PCT, TG, PTX-3, and chemokine CX3CL in pancreatic tissue before and after treatment.After treatment, the clinical efficacy of the study group was significantly higher than that of the control group (94.44% vs 75.00%), the difference was significant (P < .05). After treatment, the clinical symptoms (abdominal distension, abdominal pain, body temperature, blood sugar, HbA1c and blood amylase) in the study group were significantly less time-to-normal than in the control group, and the difference was significant (P < .05). After treatment, the AMS, blood sugar, HbA1c, and blood ketones of the 2 groups were all lower than before treatment, and the study group's AMS, blood sugar, HbA1c, and blood ketones were all lower In the control group, the difference was significant (P < .05). After treatment, the 2 groups of PCT, TG, PTX-3, and CX3CL were all lower than before treatment, among which the study group PCT, TG, PTX-3, and CX3CL1 were lower than the control group, the difference was significant (P < .05). After treatment, the total adverse reaction rate of the 2 groups was not significantly different (P > .05), but the total adverse reaction rate of the study group was lower than that of the control group.The combination of insulin pump and ulinastatin in the treatment of patients with diabetic ketoacidosis complicated with acute pancreatitis has a effect, which can shorten the recovery time of clinical symptoms, reduce the levels of PCT, TG, PTX-3, and CX3CL1, and has fewer adverse reactions. It is worthy of clinical application.


Assuntos
Cetoacidose Diabética/tratamento farmacológico , Glicoproteínas/administração & dosagem , Insulinas/administração & dosagem , Pancreatite/tratamento farmacológico , Inibidores da Tripsina/administração & dosagem , Adulto , Idoso , Proteína C-Reativa/análise , Proteína C-Reativa/efeitos dos fármacos , Estudos de Casos e Controles , Quimiocina CX3CL1/sangue , Quimiocina CX3CL1/efeitos dos fármacos , Cetoacidose Diabética/complicações , Quimioterapia Combinada , Feminino , Humanos , Sistemas de Infusão de Insulina , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Pró-Calcitonina/sangue , Pró-Calcitonina/efeitos dos fármacos , Componente Amiloide P Sérico/análise , Componente Amiloide P Sérico/efeitos dos fármacos , Triglicerídeos/sangue
11.
Biomed Res Int ; 2021: 6621682, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33824873

RESUMO

Background: Xiaochaihu decoction (XD) has demonstrated the pharmacodynamics on acute pancreatitis. This study was aimed at investigating the material and molecular basis of Xiaochaihu decoction. Methods: Firstly, compounds of seven herbs containing XD were collected from the TCMSP, ETCM, and BATMAN-TCM databases, and the putative targets of pancreatitis were obtained from the OMIM, TTD, and GeneCards databases. Then, the PPI network was constructed according to the matching results between XD potential targets and pancreatic neoplasm targets. Furthermore, enrichment analysis on GO and KEGG by DAVID utilized bioinformatics resources. Finally, molecular docking was performed to simulate the interaction between the active compound of XD and putative targets. In an in vitro experiment, AR42J cells were induced by LPS and then treated with Quercetin (25, 50, and 100 µM) or XCHD. The IL-6, TNF-α, and IL-1ß levels were detected by ELISA kit, MAPK3 and TP53 mRNA expressions were measured by qRT-PCR, and the proteins of MAPK3 and TP53 expressions were measured by WB. Results: A total of 196 active ingredients and 91 putative targets were selected. The PPI network analysis demonstrated that Quercetin was the candidate agent and MAPK3, IL-6, and TP53 were the potential targets for the XD treatment of acute pancreatitis. The KEGG analysis revealed that pathways in cancers, TNF signaling way, and MAPK signaling way might play an important role in pancreatitis therapy. And molecular docking results showed that Quercetin combined well with MAPK3, IL-6, and TP53. An in vitro experiment indicated that XCHD and Quercetin inhibited the IL-6, TNF-α, and IL-1ß levels and MAPK3 and TP53. Conclusion: This study illustrated that XCHD and Quercetin contained in XD played an important role in the treatment of acute pancreatitis by acting on the key genes of MPAK3, IL-6, and TP53 which were associated with inflammation and apoptosis.


Assuntos
Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Medicamentos de Ervas Chinesas , Pancreatite , Transdução de Sinais/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Simulação de Acoplamento Molecular , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Pancreatite/patologia
12.
Theranostics ; 11(9): 4467-4482, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754072

RESUMO

Recent studies have proven that the overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also duct cells, however, pancreatic duct contribution in acinar cells homeostasis is poorly known and the molecular mechanisms leading to acinar insult and acute pancreatitis (AP) are unclear. Our previous work also showed that S100A9 protein level was notably increased in AP rat pancreas through iTRAQ-based quantitative proteomic analysis. Therefore, we investigated the actions of injured duct cells on acinar cells and the S100A9-related effects and mechanisms underlying AP pathology in the present paper. Methods: In this study, we constructed S100A9 knockout (s100a9-/-) mice and an in vitro coculture system for pancreatic duct cells and acinar cells. Moreover, a variety of small molecular inhibitors of S100A9 were screened from ChemDiv through molecular docking and virtual screening methods. Results: We found that the upregulation of S100A9 induces cell injury and inflammatory response via NLRP3 activation by targeting VNN1-mediated ROS release; and loss of S100A9 decreases AP injury in vitro and in vivo. Moreover, molecular docking and mutant plasmid experiments proved that S100A9 has a direct interaction with VNN1 through the salt bridges formation of Lys57 and Glu92 residues in S100A9 protein. We further found that compounds C42H60N4O6 and C28H29F3N4O5S can significantly improve AP injury in vitro and in vivo through inhibiting S100A9-VNN1 interaction. Conclusions: Our study showed the important regulatory effect of S100A9 on pancreatic duct injury during AP and revealed that inhibition of the S100A9-VNN1 interaction may be a key therapeutic target for this disease.


Assuntos
Amidoidrolases/metabolismo , Calgranulina B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ductos Pancreáticos/metabolismo , Pancreatite/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Acinares/efeitos dos fármacos , Células Acinares/metabolismo , Animais , Linhagem Celular , Proteínas Ligadas por GPI/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular/métodos , Ductos Pancreáticos/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia
13.
Phytomedicine ; 85: 153525, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33740732

RESUMO

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that is associated with substantial morbidity and mortality. Chaiqin chengqi decoction (CQCQD) has been proven clinically to be an effective treatment for AP for decades in West China Hospital. Quality control for CQCQD containing many hundreds of characteristic phytochemicals poses a challenge for developing robust quality assessment metrics. PURPOSE: To evaluate quality consistency of CQCQD with a multi-strategy based analytical method, identify potential quality-markers (Q-markers) based on drug properties and effect characteristics, and endeavor to establish CQCQD as a globally-accepted medicine. METHODS: A typical analysis of constitutive medicinal plant materials was performed following the Chinese Pharmacopoeia. The extraction process was optimized through an orthogonal array (L9(34)) to evaluate three levels of liquid to solid ratio, soaking time, duration of extraction, and the number of extractions. An ultra-high-performance liquid chromatography (UHPLC) fingerprinting combined with absolute quantitation of multi chemical marker compounds, coupled with similarity, hierarchical clustering analysis (HCA), and principal component analyses (PCA) were performed to evaluate 10 batches of CQCQD. On the basis of systematic analysis of fundamental features of CQCQD in treating AP, the potential Q-marker screen was proposed through detection of quality transfer and efficacy for chemical markers. UHPLC coupled with quadrupole orbitrap mass spectrometry were used to determine compounds in medicinal materials, decoctions and plasma. Network pharmacology and taurolithocholic acid 3-sulfate induced pancreatic acinar cell death were used to evaluate the correlation between chemical markers and anti-pancreatitis activity. A cerulein induced AP murine model was used to validate quality assessed CQCQD batches at clinically-equivalent dose. The effective content of chemical markers was predicted using linear regression analysis on quantitative information between validated batches and the other batches. RESULTS: The chemical markers and other physical and chemical indices in the original materials met Chinese Pharmacopoeia standards. A total of 22 co-existing fingerprint peaks were selected and the similarity varied between 0.946 and 0.990. Batch D10 possessed the highest similarity index. HCA classified the 10 batches into 2 main groups: 7 batches represented by D10 and 3 batches represented by D1. During the initial Q-marker screen stage, 22 compounds were detected in both plant materials and decoctions, while 13 compounds were identified in plasma. Network pharmacology predicted the potential targets and pathway of AP related to the 22 compounds. All 10 batches showed reduced necrosis below 60% with the best effect achieved by D10 (~40%). The spectrum-efficacy relationship analyzed by Pearson correlation analysis indicated that emodin, rhein, aloe emodin, geniposide, hesperridin, chrysin, syringin, synephrine, geniposidic acid, magnolol, physcion, sinensetin, and baicalein showed positive correlation with pancreatic acinar cell death protection. Similar to the in vitro evaluation, batch D10 significantly reduced total histopathological scores and biochemical severity indices at a clinically-equivalent dose but batch D1 did not. The content of naringin, narirutin and baicalin in batches D1, D5 and D9 consistently exceeds the upper limit of the predicted value. Eight markers whose lower limit is predicted to be close to 0 contributed less to the material basis for AP protection. CONCLUSION: Despite qualified materials used for CQCQD preparation, the clinical effect depends on appropriate content range of Q-markers. Emodin, rhein, aloe emodin, magnolol, hesperidin, synephrine, baicalein, and geniposide are considered as vital Q-markers in the primary screen. This study proposed a feasible platform for producing highly consistent batches of CQCQD in future study.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Pancreatite/tratamento farmacológico , Controle de Qualidade , Células Acinares/efeitos dos fármacos , Doença Aguda , Animais , Ceruletídeo , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/normas , Camundongos , Necrose/patologia , Pâncreas/efeitos dos fármacos , Pancreatite/induzido quimicamente
14.
World J Gastroenterol ; 27(9): 794-814, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33727771

RESUMO

BACKGROUND: Acute pancreatitis (AP) and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis. The validated caerulein- (CAE) induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study. AIM: To determine efficacy of acetyl-L-carnitine (ALC) to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis. METHODS: Pancreatitis was induced with 6 hly intraperitoneal (i.p.) injections of CAE (50 µg/kg), 3 d a week for 6 wk in male C57BL/6J mice. Starting in week 4, mice received either vehicle or ALC until experiment's end. Mechanical hyper-sensitivity was assessed with von Frey filaments. Heat hypersensitivity was determined with the hotplate test. Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests. Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1 (Iba1). RESULTS: Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies, indicating ongoing pain. Treatment with ALC attenuated inflammation-induced hypersensitivity, but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted. Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls. Treatment with ALC resulted in increased numbers of rearing activity events, but time spent in "safety" was not changed. After all the abdominal injections, pancreata were translucent if excised at experiment's end and opaque if excised on the subsequent day, indicative of spontaneous healing. Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC. Microglial Iba1 immunostaining was significantly increased in hippocampus, thalamus (intralaminar nuclei), hypothalamus, and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves. CONCLUSION: CAE-induced pancreatitis caused increased pain-related behaviors, pancreatic fibrosis, and brain microglial changes. ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.


Assuntos
Ceruletídeo , Pancreatite , Acetilcarnitina , Doença Aguda , Animais , Encéfalo , Ceruletídeo/toxicidade , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia , Dor , Pâncreas , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico
15.
Medicine (Baltimore) ; 100(8): e24808, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663099

RESUMO

BACKGROUND: Previous studies have showed that anti-acid therapy with proton pump inhibitors (PPIs) can inhibit pancreatic secretion and it may be used in treating acute pancreatitis (AP). But at present, there is no systematic reviews for the evidence and the therapeutic effectiveness and safety of anti-acid therapy with PPIs in AP were not unclear. Therefore, we will undertake a systematic review of the literature to summarize previous evidence regarding this topic, in order to clarify the effectiveness and safety of anti-acid therapy with PPIs in AP. METHODS: We will search the EMBASE, WANFANG DATA, Web of Knowledge, China National Knowledge Infrastructure, PubMed, ClinicalTrials.gov and Cochrane Library from inception to June 30,2021 to retrieve relevant studies using the search strategy: ("Proton pump inhibitors" OR "PPI" OR "PPIs" OR "Omeprazole" OR "Tenatoprazole" OR "Pantoprazole" OR "acid suppression therapy" OR "acid suppression drugs") AND ("pancreatitis" OR "pancreatitides"). Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic. RESULTS: This study assessed the efficiency and safety of proton pump inhibitors for treating acute pancreatitis. CONCLUSIONS: This study will provide reliable evidence-based evidence for the clinical application of PPIs for treating AP. ETHICS AND DISSEMINATION: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.


Assuntos
Pancreatite/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , 2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Humanos , Omeprazol/uso terapêutico , Pantoprazol/uso terapêutico , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Projetos de Pesquisa
16.
Medicine (Baltimore) ; 100(8): e24863, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663109

RESUMO

BACKGROUND: Liuhedan is a famous traditional Chinese medicine (TCM) formula used to treat acute pancreatitis (AP) in China. However, there is no systematic reviews for the evidence and the therapeutic effectiveness and safety of Liuhedan for treating AP. The aim of this study is to summarize previous evidence, assessing the efficacy and safety of Liuhedan in the treatment of AP. METHODS: We will search the EMBASE, WANFANG DATA, Web of Knowledge, CNKI, PubMed, ClinicalTrials.gov and Cochrane Library from inception to June 30, 2021 to retrieve relevant studies using the search strategy: ("Liuhedan" OR "Liuhe Pill" OR "Liu-He-Dan") AND ("pancreatitis" OR "pancreatitides"). Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic. RESULTS: This study assessed the efficiency and safety of Liuhedan for treating acute pancreatitis. CONCLUSIONS: This study will provide reliable evidence-based evidence for the clinical application of Liuhedan for treating AP. ETHICS AND DISSEMINATION: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Pancreatite/tratamento farmacológico , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
17.
Life Sci ; 277: 119435, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33781829

RESUMO

AIMS: Acute pancreatitis (AP) is a common inflammatory disorder with high incidence and mortality. AMPK-SIRT1 pathway is involved in a variety of diseases, but its role in AP remains elusive. This study was aimed to explore the role of AMPK-SIRT1 pathway in AP. MAIN METHODS: AP models in vivo and vitro were constructed by intraperitoneal administration of L-arginine and caerulein-stimulated respectively. Rat serum amylase, IL-6 and TNF-α were determined by ELISA. The expression levels of AMPK, SIRT1, Beclin-1, LC3 and p62 were determined by qRT-PCR and western blot. The number of autophagosome was checked by transmission electron microscope. KEY FINDINGS: Compared with NC rats, serum amylase, IL-6 and TNF-α were increased in AP rats. The expressions of AMPK and SIRT1 were decreased, while Beclin-1, LC3II/Iratio and p62 were markedly increased in AP rats. After activation of AMPK by metformin, expressions of p-AMPKα, SIRT1 were significantly raised, while expressions of Beclin-1, LC3 II/I, p62, TNF-α, IL-6 were reduced, and the number of autophagosome was decreased significantly in caerulein-stimulated AR42J cells. The inhibition of AMPK by compound C obtained opposite results. SIGNIFICANCE: During AP occurrence, p-AMPK and SIRT1 were down-regulated, leading to the accumulation of p62, increase of autophagic vacuoles, damage of autophagy, and the occurrence of inflammation. It hinted that activation of AMPK restored impaired autophagy and inhibited inflammation reaction by up-regulating SIRT1. Our findings might provide important theoretical basis for explaining the pathogenesis of AP and investigating therapeutic target to treat and prevent AP.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Ceruletídeo/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/prevenção & controle , Pancreatite/patologia , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Apoptose , Inflamação/metabolismo , Inflamação/patologia , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/genética
18.
Transfusion ; 61(2): 537-545, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33616967

RESUMO

BACKGROUND: Therapeutic plasma exchange (TPE) is often used to decrease serum triglyceride levels in hypertriglyceridemic pancreatitis (HTGP), although there is a lack of high-quality data directly attributing improved clinical outcomes to TPE. There are currently no large studies evaluating the treatment of HTGP without TPE. STUDY DESIGN AND METHODS: This study retrospectively analyzes clinical and laboratory outcomes of 115 encounters at Massachusetts General Hospital (MGH) wherein a HTGP patient was treated without TPE and compares these outcomes to those of HTGP patients in the literature treated with TPE. RESULTS: After management without TPE, the median reduction in serum triglycerides was 48% (IQR 29%-63%) on day one and 74% (IQR 60%-84%) on day two in 115 episodes of acute HTGP. The reductions were comparable to those reported in several large published case series after a course of TPE (65.8% to 81% reduction). In 25 episodes among 24 patients, treatment included admission to an intensive care unit. There was no significant difference in mortality or rates of local complication, mechanical ventilation, or use of vasoactive medication or renal replacement therapy between this ICU subset and published cohorts (all P > .05). CONCLUSIONS: HTGP patients who do not receive TPE do not experience inferior outcomes compared to patients in the literature treated with TPE. The added value of TPE in HTGP, if any exists, needs to be demonstrated in controlled trials.


Assuntos
Heparina/uso terapêutico , Hipertrigliceridemia/complicações , Insulina/uso terapêutico , Pancreatite/tratamento farmacológico , Troca Plasmática , Adulto , Pré-Escolar , Cuidados Críticos , Quimioterapia Combinada , Feminino , Humanos , Hipertrigliceridemia/sangue , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pancreatite/sangue , Pancreatite/etiologia , Utilização de Procedimentos e Técnicas , Terapia de Substituição Renal/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricos , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Triglicerídeos/sangue , Vasodilatadores/uso terapêutico
19.
Gene ; 778: 145469, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33539941

RESUMO

Acute Pancreatitis (AP) refers to the inflammatory state of the pancreatic mass caused by an abnormal release of digestive enzymes characterized by pancreatic acinar cell injury. It is mainly caused by gallstones, which primarily block sphincter of Oddi opening into the duodenum, heavyalcohol use, systemic diseases, etc. Stimulator of interferon genes known as STING uniquely senses the apoptotic and necrotic DNA fragments. Through the expression of TMEM173 (transmembrane protein 173) or STING protein in macrophages, downstream signaling pathways are activated in AP and are responsible for promoting inflammation. STING elicits a cascade of downstream signaling events such as activation of TBK1, IRF-3 phosphorylation, and IFN-ß production along with other cytokines, which result in the excessive manufacture of the type-I IFNs and different kinds of proinflammatory cytokines that take part in the immune defense system of the host. Research findings suggest that STING regulates an array of innate immunity pathways, and the absence of proper treatment measures for AP provides the opportunity of evaluating STING as a striking therapeutic target for AP associated inflammation. Although the understanding of STING hyperactivation and its association with inflammation is relative of recent interest among researchers, extensive studies are going on to identify inhibitors that can directly target STING and inhibits the downstream signaling in AP. Therefore, this review aims to collectively compile the available pieces of evidence, which could help to better understand the role of STING signaling in AP and its promising role as a therapeutic target.


Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pancreatite/metabolismo , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Terapia de Alvo Molecular , Pancreatite/tratamento farmacológico , Pancreatite/genética , Transdução de Sinais/efeitos dos fármacos
20.
Int Immunopharmacol ; 94: 107486, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33639566

RESUMO

BACKGROUND: Docosahexaenoic acid-derived protectin D1 (PD1) was identified critical in the resolution of inflammation in vivo, where it modulates the innate immune response and stimulates resolution. Acute pancreatitis (AP) is characterized by local pancreatic inflammation with mild forms whereas systemic inflammation with severe forms. Herein we investigate the impact of PD1 in murine models of pancreatitis. METHODS: Three independent AP models, which induced in male mice via intraperitoneal injection of caerulein, L-arginine or pancreatic duct ligation, were used to confirm the protective effect of PD1. Infiltrationsof neutrophils and macrophages in pancreas were detected by flow cytometry and immunohistochemistry. In vitro and in vivo neutrophil extracellular traps formation was detected by immunofluorescence staining. Expression of peptidylarginine deiminase 4 (PAD4) in activated neutrophils was evaluated by western blotting. RESULTS: Systemic treatment with PD1 reduced serum activities of amylase and lipase, blunted the concentrations of tumor necrosis factor-α and interleukin-6 in serum and protected against pancreas histologic damage in three AP models. PD1 also prolonged the survival in the pancreatic duct ligation model. Moreover, pancreatic infiltrationofneutrophils and neutrophil CitH3 expression were reduced after PD1 administration. In vitro studies revealed PD1 decreased supernatant cell-free DNA and CitH3 levels and downregulated PAD4 expression in mouse bone-marrow derived neutrophils. However, in the caerulein mice pretreated with GSK484 hydrochloride, an inhibitor of PAD4, PD1 treatment showed no more protective effect. CONCLUSIONS: PD1 ameliorates AP by decreasing early infiltration of neutrophils into the pancreas and neutrophil extracellular traps formation through PAD4. These results supply the foundation to consider PD1 as a therapy for AP.


Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Armadilhas Extracelulares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/farmacologia , Armadilhas Extracelulares/imunologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos ICR , Neutrófilos/imunologia , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/imunologia , Pancreatite/patologia , Proteína-Arginina Desiminase do Tipo 4/imunologia
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