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1.
Zhongguo Zhong Yao Za Zhi ; 45(6): 1423-1432, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32281357

RESUMO

The network pharmacology was used to investigate the material basis and molecular mechanism of Dachengqi Decoction(DCQD) in the treatment of acute pancreatitis(AP). Potential targets of components from DCQD and relevant pathogenic genes of AP were identified through database retrieval. Then, crucial targets were verified with relevant active chemical components via molecular docking. DAVID database was used to explore the functions and pathways involved in the treatment of AP. A total of 108 components were correlated with 28 targets. Molecular docking showed a strong binding ability of key targets and their corresponding compounds. DAVID enrichment analysis showed 438 biological process, 31 molecular functions, 17 cellular components and 96 KEGG pathways. DCQD may achieve its pharmacological effects through anti-inflammatory and anti-oxidative effects, negative regulation of apoptosis and regulation of pancreatic secretion, involving multiple signals, such as IL-17, TNF and NF-κB signaling pathway. In this study, it is the first time to use the method of network pharmacology to reveal the molecular mechanism of DCQD in the treatment of AP by multiple components and multi-signaling pathways, which provides a basis for further biological experiments of AP.


Assuntos
Pancreatite/tratamento farmacológico , Extratos Vegetais/farmacologia , Doença Aguda , Animais , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
2.
Medicine (Baltimore) ; 99(4): e18743, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977866

RESUMO

BACKGROUND: Acute pancreatitis (AP) is one of the common diseases with increasing incidence in clinical surgery and other gastrointestinal-digestive departments. Despite the rapid development of modern medicine, the overall mortality rate of AP is still high. Xuebijing (XBJ) injection (a traditional Chinese patent medicine) is a potentially effective drug for AP. This study is designed to assess the efficacy and safety of XBJ injection for AP. METHODS: We will extract data and assess methodological quality of included studies from 7 electronic databases from their inception to December 31, 2019. The primary outcomes include the mortality, surgical intervention, systemic inflammatory response syndrome (SIRS), local complications, systemic infections, gastrointestinal symptoms, and normal blood amylase recovery time. The statistical analysis will be performed using RevMan 5.3 software. RESULTS: This study will provide high-quality evidence for the efficacy of XBJ injection as an adjuvant therapy for AP. CONCLUSION: The study will provide the key evidence for clinical doctors and the development of clinical guidelines.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Pancreatite/tratamento farmacológico , Humanos , Injeções , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto , Resultado do Tratamento
3.
Gastroenterology ; 158(1): 253-269.e14, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593700

RESUMO

BACKGROUND & AIMS: Pancreatitis starts with primarily sterile local inflammation that induces systemic inflammatory response syndrome, followed by compensatory anti-inflammatory response syndrome (CARS). We investigated the mechanisms of these processes in mice and human serum. METHODS: We induced severe acute pancreatitis by partial duct ligation with caerulein stimulation or intraperitoneal injection of l-arginine in mice with deletion of interleukin (IL)12B, NLRP3, or IL18 and in mice given MCC950, a small molecule inhibitor of the NLRP3-inflammasome. Pancreata were collected from mice and analyzed by histology, and cytokine levels were measured in serum samples. We measured activation of adaptive immune responses in mice with pancreatitis by flow cytometry analysis of T cells (CD25 and CD69) isolated from the spleen. Differentiation of T-helper (Th1) cells, Th2 cells, and T-regulatory cells was determined by nuclear staining for TBET, GATA3, and FOXP3. We performed transcriptome analysis of mouse lymph nodes and bone marrow-derived macrophages after incubation with acini. We measured levels of cytokines in serum samples from patients with mild and severe acute pancreatitis. RESULTS: Activation of the adaptive immune response in mice was initiated by macrophage-derived, caspase 1-processed cytokines and required activation of NLRP3 (confirmed in serum samples from patients with pancreatitis). Spleen cells from mice with pancreatitis had increases in Th2 cells but not in Th1 cells. Bone marrow-derived macrophages secreted IL1B and IL18, but not IL12, after co-incubation with pancreatic acini. T-cell activation and severity of acute pancreatitis did not differ significantly between IL12B-deficient and control mice. In contrast, NLRP3- or IL18-deficient mice had reduced activation of T cells and no increase in Th2 cell-mediated responses compared with control mice. The systemic type 2 immune response was mediated by macrophage-derived cytokines of the IL1 family. Specifically, IL18 induced a Th2 cell-mediated response in the absence of IL12. MCC950 significantly reduced neutrophil infiltration, T-cell activation, and disease severity in mice. CONCLUSIONS: In mice with severe pancreatitis, we found systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome developed in parallel. Infiltrating macrophages promote inflammation and simultaneously induce a Th2 cell-mediated response via IL18. Inhibition of NLRP3 reduces systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome and might be used to treat patients with severe pancreatitis.


Assuntos
Furanos/administração & dosagem , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pancreatite/imunologia , Sulfonamidas/administração & dosagem , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Células Acinares , Imunidade Adaptativa , Animais , Arginina/toxicidade , Células Cultivadas , Ceruletídeo/toxicidade , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Interleucina-18/imunologia , Interleucina-18/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pâncreas/citologia , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Cultura Primária de Células , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Células Th2/imunologia , Células Th2/metabolismo
5.
Med Sci Monit ; 25: 7694-7701, 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31606729

RESUMO

BACKGROUND Alprostadil can inhibit inflammation and reduce inflammation-related injury in many inflammatory diseases. However, the anti-inflammatory effect of alprostadil in decreasing acute pancreatitis (AP) injury remains unknow. This study aimed to investigate the possible protective effects and mechanism of alprostadil against AP in rats. MATERIAL AND METHODS Forty healthy Sprague­Dawley rats were randomly divided into a control group, an AP group, an AP-alprostadil group, an AP-AG490 group, and an AP-(alprostadil+AG490) group. An animal model of acute pancreatitis was established. The pathological changes of the pancreases in each group were observed. We assessed levels of malondialdehyde (MDA), superoxide dismutase (SOD), and myeloperoxidase (MPO), as well as serum IL-1ß, IL-6, IL-10, and TNF-alpha. TUNEL assay was used to detect apoptosis of pancreatic cells. The proteins p-Jak2 and p-Stat3 were investigated by Western blot. RESULTS Compared with the control group, pancreatic pathological score, pancreatic apoptosis, MDA, MPO, serum IL-1ß, IL-6, and TNF-alpha levels were significantly higher in the AP group, and SOD levels were significantly decreased. Compared with the AP group, after treatment with alprostadil, AG490, and alprostadil+AG490, respectively, the pancreatic pathological score, apoptosis, MDA, MPO, serum IL-1ß, IL-6, and TNF-alpha were significantly decreased in AP rats, while SOD levels were significantly increased. The protein levels of p-JAK2 and p-STAT3 were significantly upregulated in the AP group compared with the control group, and the protein levels of p-JAK2 and p-STAT3 after treatment with alprostadil, AG490, and alprostadil+AG490 were significantly decreased, and the effect of alprostadil+AG490 was the strongest. CONCLUSIONS Alprostadil can reduce pancreatic tissue damage, delay pancreatic cell apoptosis, and reduce inflammation and anti-oxidative stress by inhibiting the JAK2/STAT3 signal pathway, thus protecting the pancreas.


Assuntos
Alprostadil/uso terapêutico , Janus Quinase 2/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Substâncias Protetoras/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células Acinares/efeitos dos fármacos , Células Acinares/metabolismo , Células Acinares/patologia , Doença Aguda , Alprostadil/farmacologia , Amilases/sangue , Animais , Apoptose/efeitos dos fármacos , Arginina , Citocinas/sangue , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/sangue , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
6.
Postepy Biochem ; 65(3): 224-230, 2019 10 01.
Artigo em Polonês | MEDLINE | ID: mdl-31643170

RESUMO

Berberine (BRB) is a compound belonging to the group of isoquinoline alkaloids of plant origin that has long been used in traditional chinese medicine (TMC). Due to, among others anti-inflammatory properties BRB is a potential therapeutic in the treatment of acute pancreatitis (OZT). In a study in the mouse model of L-arginine-induced acute pancreatitis, we showed that BRB administered by the intravenous route at 0.1 and 0.5 mg / kg body weight significantly reduces the level of myeloperoxidase activity (an indicator of inflammation) in the pancreas and lungs. Promising results point to the need for larger, randomized studies to assess the long-term efficacy and side effects of BRB therapy.


Assuntos
Berberina/uso terapêutico , Pancreatite/tratamento farmacológico , Doença Aguda/terapia , Animais , Berberina/farmacologia , Modelos Animais de Doenças , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia
7.
Medicine (Baltimore) ; 98(43): e17644, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651883

RESUMO

BACKGROUND: The aim of this study is to explore the efficacy and safety of ulinastatin for the treatment of patients with severe acute pancreatitis (SAP). METHODS: We will search randomized controlled trials which assess the efficacy and safety of ulinastatin for patients with SAP from the electronic databases of Cochrane Library, MEDILINE, EMBASE, CINAHL, PsycINFO, Scopus, CBM, Wangfang, VIP, and CNKI. All electronic databases will be searched from inception to the present with no limitations of language and publication status. Two researchers will carry out study selection, data extraction, and study quality assessment independently. Another researcher will help to resolve any disagreements between 2 researchers. RESULTS: The outcomes include overall mortality, time of hospital stay, complications of systematic or local infection, multiple organ deficiency syndrome, health related quality of life (as measured as the 36-Item Short Form Health Survey), and adverse events related to nutrition. CONCLUSION: This study will provide evidence to evaluate the efficacy and safety of ulinastatin in the treatment of patients with SAP. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019149566.


Assuntos
Glicoproteínas/uso terapêutico , Pancreatite/tratamento farmacológico , Inibidores da Tripsina/uso terapêutico , Doença Aguda , Mortalidade Hospitalar , Humanos , Tempo de Internação/estatística & dados numéricos , Pancreatite/mortalidade , Qualidade de Vida , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do Tratamento
8.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484391

RESUMO

Activated macrophages upregulate inducible nitric oxide synthase (iNOS) leading to the profuse production of nitric oxide (NO) and, eventually, tissue damage. Using macrophage NO production as a biochemical marker of inflammation, we tested different parts (flower, leaf, and stem) of the medicinal plant, Spilanthes acmella. We found that extracts prepared from all three parts, especially the flowers, suppressed NO production in RAW macrophages in response to interferon-γ and lipopolysaccharide. Follow up experiments with selected bioactive molecules from the plant (α-amyrin, ß-caryophylline, scopoletin, vanillic acid, trans-ferulic acid, and spilanthol) indicated that the N-alkamide, spilanthol, is responsible for the NO-suppressive effects and provides protection from NO-dependent cell death. Spilanthol reduced the expression of iNOS mRNA and protein and, as a possible underlying mechanism, inhibited the activation of several transcription factors (NFκB, ATF4, FOXO1, IRF1, ETS, and AP1) and sensitized cells to downregulation of Smad (TF array experiments). The iNOS inhibitory effect translated into an anti-inflammatory effect, as demonstrated in a phorbol 12-myristate 13-acetate-induced dermatitis and, to a smaller extent, in cerulein-induced pancreatitis. In summary, we demonstrate that spilanthol inhibits iNOS expression, NO production and suppresses inflammatory TFs. These events likely contribute to the observed anti-inflammatory actions of spilanthol in dermatitis and pancreatitis.


Assuntos
Dermatite/tratamento farmacológico , Dermatite/metabolismo , Macrófagos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Alcamidas Poli-Insaturadas/uso terapêutico , Animais , Sobrevivência Celular/efeitos dos fármacos , Dermatite/genética , Proteína Forkhead Box O1/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Pancreatite/genética , Peroxidase/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
9.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 562-565, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484622

RESUMO

Acute pancreatitis(AP)is an inflammatory condition of the pancreas following the activationt of pancreatic enzymes induced by a variety of factors,with or without other organ dysfunction.The production and release of inflammatory factors is generally considered as a key link during pathogenesis.Non-steroidal anti-inflammatory drugs(NSAIDs)are the most commonly applied agents for inflammatory diseases.Many studies have proved that indomethacin can reduce the risk of pancreatitis after endoscopic retrograde cholangiopancreatography;however,few high-quality evidences have demonstrated the roles of NSAIDs in treating,rather than preventing AP.Most animal experiments have shown that NSAIDs can protect organs,although the currently available findings remained inconsistent.Randomized controlled trials with large sample sizes are warranted to elucidate the roles of NSAIDs in treating AP.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Pancreatite/tratamento farmacológico , Animais , Colangiopancreatografia Retrógrada Endoscópica , Humanos , Indometacina/uso terapêutico
10.
Gastroenterology ; 157(4): e8-e9, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476298
11.
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
12.
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
13.
Mol Immunol ; 114: 620-628, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31542607

RESUMO

Acute pancreatitis (AP) is a severe inflammatory condition of the pancreas, with no specific treatment available. We have previously reported that Nardostachys jatamansi (NJ) ameliorates cerulein-induced AP. However, the specific compound responsible for this inhibitory effect has not been identified. Therefore, in the present study, we focused on a single compound, 8α-hydroxypinoresinol (HP), from NJ. The aim of this study was to determine the effect of HP on the development of pancreatitis in mice and to explore the underlying mechanism(s). AP was induced by the injection of cerulein (50 µg/kg/h) for 6 h. HP (0.5, 5 or 10 mg/kg, i.p.) was administered 1 h prior to and 1, 3 or 5 h after the first cerulein injection, with vehicle- and DMSO-treated groups as controls. Blood samples were collected to determine serum levels of amylase, lipase, and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) assays, cytokine assays, and assessment of nuclear factor (NF)-κB activation. The lungs were removed for morphological examination and MPO assays. Administration of HP dramatically improved pancreatic damage and pancreatitis-associated lung damage and also reduced amylase and lipase activities in serum. Moreover, administration of HP reduced the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in the pancreas and serum during AP. In addition, the administration of HP inhibited degradation of inhibitory κ-Bα (Iκ-Bα), NF-κB p65 translocation into nucleus and NF-κB binding activity in the pancreas. Our results suggest that HP exerted therapeutic effects on pancreatitis and these beneficial effects may be due to the inhibition of NF-κB activation.


Assuntos
Ceruletídeo/farmacologia , Furanos/farmacologia , Lignanas/farmacologia , Nardostachys/química , Pâncreas/efeitos dos fármacos , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Animais , Citocinas/metabolismo , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/metabolismo , Pancreatite/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Adv Clin Exp Med ; 28(8): 1059-1066, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31414732

RESUMO

BACKGROUND: It is well-known that severe acute pancreatitis (SAP) due to infection is mainly caused by intestinal bacterial translocation. The intestinal barrier is tasked with preventing intestinal pathogenic bacteria and toxins from reaching the parenteral tissues through the intestinal wall. Therefore, maintaining intestinal barrier function may be the key to preventing damage from acute pancreatitis (AP). The phosphatidylinositol 3-kinase/protein kinase B pathway (PI3K/PKB) plays a role in AP. However, the exact effect of PI3K/PKB on injury associated with SAP has not yet been found. OBJECTIVES: The present study was aimed at investigating the impact of wortmannin (WT), a PI3K/PKB inhibitor, on intestinal barrier function in SAP rats. MATERIAL AND METHODS: The rats were divided into 3 groups: 1) the Sham Surgery group (SS), whose duodenum and pancreas were flipped 3 times (n = 18); 2) the pancreatitis group (SAP), who were injected through retrograde pancreatic duct injection with 5% sodium taurocholate (n = 18); and 3) the WSAP intervention group (SAP+WT). Serum alpha-amylase levels, plasma endogenous endotoxin, hematoxylin-eosin (H&E) staining, intestinal mucosa electron microscopy, intestinal permeability, and expression of p-PKB (phosphorylated protein kinase B) were measured. RESULTS: In our findings under an electron microscope, the SAP group presented cell edema and mitochondrial vacuolated degeneration, sparsely arranged microvilli, tight junction damage, and widening, while the WSAP group exhibited less change and lower pancreas scores (7.4 ±1.14, 10.2 ±1.48 and 12.0 ±1.58 for 3 h, 6 h and 12 h, respectively) (p < 0.05). Furthermore, the plasma endogenous endotoxin levels and Evans blue content of the WSAP group was significantly lower at all timepoints than in the SAP group (p < 0.05). Western blotting showed that p-PKB expression was lower in the WSAP group than in the SAP group (p < 0.05). Our study suggests that WT relieves intestinal permeability changes in SAP rats and may be dose-dependent. CONCLUSIONS: The PI3K/PKB signal pathway may involve SAP-related intestinal injuries and WT may relieve SAP intestinal injuries through the PI3K/PKB pathway.


Assuntos
Mucosa Intestinal , Pancreatite , Fosfatidilinositol 3-Quinases , Wortmanina , Doença Aguda , Animais , Mucosa Intestinal/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Wortmanina/farmacologia
15.
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
17.
Int J Mol Med ; 44(4): 1563-1573, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432106

RESUMO

Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Icariin (ICA), a flavonoid glycoside, has been reported to have several pharmacological effects; however, the anti­inflammatory effects of ICA against AP require further study. Therefore, we aimed to investigate the effect of ICA on cerulein­induced AP. In the present study, AP was induced by intraperitoneally administering a supramaximal concentration of cerulein (50 µg/kg/h) for 6 h. ICA was also administered intraperitoneally, and mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to determine serum amylase and lipase levels. The pancreas and lung were rapidly removed for histological examination, and the analysis of myeloperoxidase activity. In addition, reverse transcription­quantitative polymerase chain reaction was conducted to analyze the expression of inflammatory cytokines in pancreatic tissues. Our results revealed that the administration of ICA prevented an increase in the pancreas weight/body weight ratio of mice and serum digestive enzyme levels. ICA treatment also inhibited cerulein­induced histological injury and neutrophil infiltration of the pancreas and lung. In addition, ICA suppressed the production of pro­inflammatory cytokines, including interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α in the pancreas. Furthermore, ICA administration was observed to inhibit p38 activation during cerulein­induced AP. Inhibition of p38 activation resulted in alleviated pancreatitis. Collectively, our results suggested that ICA exhibits anti­inflammatory effects in cerulein­induced AP via the inhibition of p38.


Assuntos
Ceruletídeo/efeitos adversos , Flavonoides/farmacologia , Pancreatite/etiologia , Pancreatite/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Amilases/sangue , Animais , Biomarcadores , Modelos Animais de Doenças , Feminino , Lipase/sangue , Lipase/metabolismo , Camundongos , NF-kappa B/metabolismo , Pancreatite/diagnóstico , Pancreatite/tratamento farmacológico , Índice de Gravidade de Doença
19.
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
20.
Trials ; 20(1): 463, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358032

RESUMO

BACKGROUND: Differentiating infection from inflammation in acute pancreatitis is difficult, leading to overuse of antibiotics. Procalcitonin (PCT) measurement is a means of distinguishing infection from inflammation as levels rise rapidly in response to a pro-inflammatory stimulus of bacterial origin and normally fall after successful treatment. Algorithms based on PCT measurement can differentiate bacterial sepsis from a systemic inflammatory response. The PROCalcitonin-based algorithm for antibiotic use in Acute Pancreatitis (PROCAP) trial tests the hypothesis that a PCT-based algorithm to guide initiation, continuation and discontinuation of antibiotics will lead to reduced antibiotic use in patients with acute pancreatitis and without an adverse effect on outcome. METHODS: This is a single-centre, randomised, controlled, single-blind, two-arm pragmatic clinical and cost-effectiveness trial. Patients with a clinical diagnosis of acute pancreatitis will be allocated on a 1:1 basis to intervention or standard care. Intervention will involve the use of a PCT-based algorithm to guide antibiotic use. The primary outcome measure will be the binary outcome of antibiotic use during index admission. Secondary outcome measures include: safety non-inferiority endpoint all-cause mortality; days of antibiotic use; clinical infections; new isolates of multiresistant bacteria; duration of inpatient stay; episode-related mortality and cause; quality of life (EuroQol EQ-5D); and cost analysis. A 20% absolute change in antibiotic use would be a clinically important difference. A study with 80% power and 5% significance (two-sided) would require 97 patients in each arm (194 patients in total): the study will aim to recruit 200 patients. Analysis will follow intention-to-treat principles. DISCUSSION: When complete, PROCAP will be the largest randomised trial of the use of a PCT algorithm to guide initiation, continuation and cessation of antibiotics in acute pancreatitis. PROCAP is the only randomised trial to date to compare standard care of acute pancreatitis as defined by the International Association of Pancreatology/American Pancreatic Association guidelines to patients having standard care but with all antibiotic prescribing decisions based on PCT measurement. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number, ISRCTN50584992. Registered on 7 February 2018.


Assuntos
Algoritmos , Antibacterianos/uso terapêutico , Técnicas de Apoio para a Decisão , Monitoramento de Medicamentos/métodos , Pancreatite/tratamento farmacológico , Pró-Calcitonina/sangue , Antibacterianos/efeitos adversos , Antibacterianos/economia , Biomarcadores/sangue , Tomada de Decisão Clínica , Ensaios Clínicos Fase III como Assunto , Redução de Custos , Análise Custo-Benefício , Custos de Medicamentos , Monitoramento de Medicamentos/economia , Inglaterra , Humanos , Pancreatite/sangue , Pancreatite/diagnóstico , Pancreatite/economia , Ensaios Clínicos Pragmáticos como Assunto , Valor Preditivo dos Testes , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento
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