RESUMEN
Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/ß-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.
Asunto(s)
Calcineurina , Catepsina B , Citocinas , Flavonoides , Ratones Endogámicos C57BL , Pancreatitis , Animales , Pancreatitis/tratamiento farmacológico , Pancreatitis/inmunología , Pancreatitis/patología , Pancreatitis/inducido químicamente , Flavonoides/farmacología , Flavonoides/uso terapéutico , Citocinas/metabolismo , Catepsina B/metabolismo , Ratones , Masculino , Calcineurina/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Ceruletida , FN-kappa B/metabolismo , Páncreas/patología , Páncreas/efectos de los fármacos , Páncreas/inmunología , Transducción de Señal/efectos de los fármacos , Arginina/metabolismo , Modelos Animales de Enfermedad , Proteínas Quinasas Activadas por AMP/metabolismoRESUMEN
Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation and fibrosis. Currently, there are no drugs for the treatment of pancreatic fibrosis associated with CP. Piperine, a natural alkaloid found in black pepper, has been reported to show antiinflammatory, antioxidative, and antitumor activities. Although piperine exhibits numerous properties in regards to the regulation of diverse diseases, the effects of piperine on CP have not been established. To investigate the effects of piperine on CP in vivo, we induced CP in mice through the repetitive administration of cerulein (50 µg/kg) six times at 1h intervals, 5 times per week, for a total of 3 weeks. In the pretreatment groups, piperine (1, 5, or 10 mg/kg) or corn oil were administrated orally at 1 h before the first cerulein injection, once a day, 5 times a week, for a total of 3 weeks. In the posttreatment groups, piperine (10 mg/kg) or corn oil was administered orally at 1 or 2 week after the first cerulein injection. Pancreases were collected for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the antifibrogenic effects and regulatory mechanisms of piperine. Piperine treatment significantly inhibited histological damage in the pancreas, increased the pancreatic acinar cell survival, reduced collagen deposition and reduced proinflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as αsmooth muscle actin (αSMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)ß in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGFßinduced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGFß/SMAD2/3 signaling during CP.
Asunto(s)
Alcaloides/uso terapéutico , Antiinflamatorios/uso terapéutico , Benzodioxoles/uso terapéutico , Pancreatitis Crónica/tratamiento farmacológico , Piperidinas/uso terapéutico , Alcamidas Poliinsaturadas/uso terapéutico , Proteínas Smad/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosis , Ratones , Ratones Endogámicos C57BL , Páncreas/efectos de los fármacos , Páncreas/inmunología , Páncreas/patología , Pancreatitis Crónica/inmunología , Pancreatitis Crónica/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Acute pancreatitis (AP) is an inflammatory disease of the pancreas, which, in its most severe form, is associated with multi-organ failure and death. Loganin, a major iridoid glycoside obtained from Corni fructus, has been shown to have anti-inflammatory and anti-shock effects. However, the effects of loganin on AP have not been determined. Pre-treatment of loganin reduced pancreatic damage and AP-associated lung injury and attenuated the severity of AP, as evidenced by (1) a reduction in several biochemical parameters (pancreatic weight to body weight ratio, myeloperoxidase activity, and level of amylase) and (2) production of pro-inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. However, post-treatment of loganin failed to improve pancreatic damage and biochemical parameters of AP, but could inhibit the AP-induced elevation of IL-1ß and TNF-α significantly. In addition, cerulein-induced activation of nuclear factor (NF)-κB was inhibited in the pancreas by administration of loganin. In conclusion, these results suggest that loganin exhibits an anti-inflammatory effect in cases of AP and its pulmonary complications through inhibition of NF-κB activation.
Asunto(s)
Iridoides/uso terapéutico , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Pancreatitis/metabolismo , Pancreatitis/prevención & control , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Iridoides/farmacología , Ratones , Ratones Endogámicos C57BL , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéuticoRESUMEN
Lupeol is a triterpenoid commonly found in fruits and vegetables and is known to exhibit a wide range of biological activities, including antiinflammatory and anti-cancer effects. However, the effects of lupeol on acute pancreatitis specifically have not been well characterized. Here, we investigated the effects of lupeol on cerulein-induced acute pancreatitis in mice. Acute pancreatitis was induced via an intraperitoneal injection of cerulein (50 µg/kg). In the lupeol treatment group, lupeol was administered intraperitoneally (10, 25, or 50 mg/kg) 1 h before the first cerulein injection. Blood samples were taken to determine serum cytokine and amylase levels. The pancreas was rapidly removed for morphological examination and used in the myeloperoxidase assay, trypsin activity assay, and real-time reverse transcription polymerase chain reaction. In addition, we isolated pancreatic acinar cells using a collagenase method to examine the acinar cell viability. Lupeol administration significantly attenuated the severity of pancreatitis, as was shown by reduced pancreatic edema, and neutrophil infiltration. In addition, lupeol inhibited elevation of digestive enzymes and cytokine levels, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and interleukin (IL)-6. Furthermore, lupeol inhibited the cerulein-induced acinar cell death. In conclusion, these results suggest that lupeol exhibits protective effects on cerulein-induced acute pancreatitis.
Asunto(s)
Antiinflamatorios/farmacología , Ceruletida , Pancreatitis/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Extractos Vegetales , Enfermedad Aguda , Amilasas , Animales , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Inyecciones Intraperitoneales , Lipasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Páncreas/efectos de los fármacos , Pancreatitis/inducido químicamente , Peroxidasa/metabolismo , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Guggulsterone (GS), a plant steroid and a compound found at high levels in Commiphora myrrha, exhibits anti-inflammatory, anti-cancer, and cholesterol-lowering effects. However, the potential of GS to ameliorate acute pancreatitis (AP) is unknown. The aim of this study was to evaluate the effects of GS on cerulein-induced AP. AP was induced by intraperitoneally injecting supramaximal concentrations of the stable cholecystokinin analog cerulein (50 µg/kg) hourly for 6 h. In the GS-treated group, GS was administered intraperitoneally (10, 25, or 50mg/kg) 1 h before the first cerulein injection. Mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to measure serum lipase levels and evaluate cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examinations, flow cytometry analysis, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction analysis. Pre-treatment with GS attenuated cerulein-induced histological damage, reduced pancreas weight/body weight ratio, decreased serum lipase levels, inhibited infiltrations of macrophages and neutrophils, and suppressed cytokine production. Additionally, GS treatment suppressed the activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) in the pancreas in cerulein-induced pancreatitis. In conclusion, our results suggest that GS attenuates AP via deactivation of ERK and JNK.
Asunto(s)
Antiinflamatorios/uso terapéutico , Ceruletida/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Pancreatitis/tratamiento farmacológico , Pregnenodionas/uso terapéutico , Enfermedad Aguda , Animales , Antiinflamatorios/administración & dosificación , Western Blotting , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Inyecciones Intraperitoneales , Lipasa/sangre , Ratones Endogámicos C57BL , Páncreas/efectos de los fármacos , Páncreas/inmunología , Páncreas/patología , Pancreatitis/enzimología , Pancreatitis/inmunología , Pregnenodionas/administración & dosificaciónRESUMEN
OBJECTIVES: We aimed to evaluate the anti-inflammatory and inhibitory effects of Lithospermum erythrorhizon (LE) on cerulein-induced acute pancreatitis (AP) in a mouse model. METHODS: Acute pancreatitis was induced via intraperitoneal injection of cerulein (50 µg/kg) every hour for 6 times. In the LE, water extract (100, 250, or 500 mg/kg) was administered intraperitoneally 1 hour before the first injection of cerulein. Six hours after AP, blood, the pancreas, and the lung were harvested for further examination. In addition, pancreatic acinar cells were isolated using a collagenase method, and then, we investigated the acinar cell viability and cytokine productions. RESULTS: Treatment with LE reduced pancreatic damage and AP-associated lung injury and attenuated the severity of AP, as evidenced by the reduction in neutrophil infiltration, serum amylase and lipase levels, trypsin activity, and proinflammatory cytokine expression. In addition, treatment with LE inhibited high mobility group box 1 expression in the pancreas during AP. In accordance with in vivo data, LE inhibited the cerulein-induced acinar cell death, cytokine productions, and high-mobility group box 1 expression. Furthermore, LE also inhibited the activation of p38 mitogen-activated protein kinases. CONCLUSIONS: These results suggest that LE plays a protective role during the development of AP by inhibiting the activation of p38.
Asunto(s)
Antiinflamatorios/farmacología , Ceruletida , Lithospermum/química , Páncreas/efectos de los fármacos , Pancreatitis/prevención & control , Extractos Vegetales/farmacología , Enfermedad Aguda , Animales , Antiinflamatorios/aislamiento & purificación , Biomarcadores/sangre , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocinas/sangre , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activación Enzimática , Femenino , Proteína HMGB1/metabolismo , Mediadores de Inflamación/sangre , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Pancreatitis/sangre , Pancreatitis/inducido químicamente , Pancreatitis/patología , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Acute pancreatitis (AP) is a complicated disease which is largely undiscovered. Fisetin, a natural flavonoid from fruits and vegetables, has been shown to have anti-inflammatory, antioxidant, and anti-cancer activities in various disease models. However, the effects of fisetin on AP have not been determined. Pre- and post- treatment of mice with fisetin reduced the severity of AP and pancreatitis-associated lung injury and inhibited several biochemical parameters (pancreatic weight to body weight ratio, amylase, lipase, and myeloperoxidase activity) and production of inflammatory cytokines. In pancreatic acinar cells, fisetin also inhibited cell death and production of inflammatory cytokines. In addition, fisetin inhibited activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB in vivo and in vitro. In conclusion, these results suggest that fisetin exhibits anti-inflammatory effect on AP and could be a beneficial agent in the treatment of AP and its pulmonary complications.
Asunto(s)
Ceruletida/efectos adversos , Regulación hacia Abajo/efectos de los fármacos , Flavonoides/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Pancreatitis/patología , Transducción de Señal/efectos de los fármacos , Células Acinares/efectos de los fármacos , Células Acinares/patología , Enfermedad Aguda , Administración Oral , Animales , Activación Enzimática/efectos de los fármacos , Femenino , Flavonoides/administración & dosificación , Flavonoides/uso terapéutico , Flavonoles , Inyecciones Intraperitoneales , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Páncreas/efectos de los fármacos , Páncreas/patología , Pancreatitis/inducido químicamente , Pancreatitis/tratamiento farmacológico , Pancreatitis/prevención & controlRESUMEN
It has been previously shown that Nardostachys jatamansi (NJ) exhibits anti-inflammatory properties against lipopolysaccharide (LPS) challenges. However, the potency of NJ constituents against LPS-induced inflammatory responses has not been examined. In this present study, we determined which NJ extract fractions exhibit inhibitory effects against LPS-induced inflammatory responses. Among the NJ fractions, NJ-1, NJ-3, NJ-4, and NJ-6 inhibited LPS-induced production of NO. The NJ-3, NJ-4, and NJ-6 fractions also inhibited the production of cytokines, such as IL-1 ß , IL-6, and TNF- α . However, NJ-1, NJ-3, NJ-4, and NJ-6 showed differential inhibitory mechanisms against LPS-induced inflammatory responses. NJ-1, NJ-3, and NJ-4 inhibited LPS-induced activation of c-jun NH2-terminal kinase (JNK) and p38 but did not affect activation of extracellular signal-regulated kinase (ERK) or NF- κ B. On the other hand, NJ-6 inhibited activation of MAPKs and NF- κ B. In addition, in vivo experiments revealed that administration of NJ-1, NJ-3, NJ-4, and NJ-6 reduced LPS-induced endotoxin shock, with NJ-6 especially showing a marked protective effect. Taken together, these results provide the evidence for the potential of selective NJ fractions against LPS-induced inflammation. Thus, it will be advantageous to further isolate and determine single effective compounds from these potent fractions.
RESUMEN
BACKGROUND/AIM: We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP. METHODS: AP was induced via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 µg/kg) every hour for 6 times. In the apamin treatment group, apamin was administered subcutaneously (10, 50, or 100 µg/kg) at both 18 and 1 h before the first cerulein injection. The mice were sacrificed at 6 h after the final cerulein injection. Blood samples were obtained to determine serum amylase and lipase levels, as well as cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examination, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction. Furthermore, we isolated the pancreatic acinar cells to specify the role of apamin in AP. RESULTS: Pre-treatment with apamin inhibited histological damage, pancreatic weight/body weight ratio, serum level of amylase and lipase, MPO activity, and cytokine production. In addition, apamin treatment significantly inhibited cerulein-induced pancreatic acinar cell death. Furthermore, apamin treatment inhibited the cerulein-induced activation of c-Jun NH2-terminal kinases (JNK). CONCLUSIONS: These results could suggest that apamin could protect against AP by inhibition of JNK activation.