RESUMEN
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
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.
Asunto(s)
Apamina/farmacología , Apamina/uso terapéutico , Ceruletida/efectos adversos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Pancreatitis/inducido químicamente , Pancreatitis/prevención & control , Enfermedad Aguda , Animales , Apamina/administración & dosificación , Ceruletida/administración & dosificación , Colecistoquinina/análogos & derivados , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos C57BL , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patologíaRESUMEN
Piperine, one of the main components of Piper longum Linn. and P. nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine has been shown to modulate the immune response, but the mechanism underlying this modulation remains unknown. Here, we examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses in bone-marrow-derived dendritic cells (BMDCs). Piperine significantly inhibited the expression of major histocompatibility complex class II, CD40 and CD86 in BMDCs in a dose-dependent manner. Furthermore, piperine treatment led to an increase in fluorescein-isothiocyanate-dextran uptake in LPS-treated dendritic cells and inhibited the production of tumour necrosis factor alpha and interleukin (IL)-12, but not IL-6. The inhibitory effects of piperine were mediated via suppression of extracellular signal-regulated kinases and c-Jun N-terminal kinases activation, but not p38 or nuclear factor-κB activation. These findings provide insight into the immunopharmacological role of piperine.
Asunto(s)
Alcaloides/farmacología , Benzodioxoles/farmacología , Diferenciación Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Animales , Células de la Médula Ósea/efectos de los fármacos , Inflamación/metabolismo , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos , Ratones , Fosforilación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Background: Poria cocos (PC), a fungus, has been used for more than 2000 years as a food and medicine in China. PC and its components have various pharmacological effects on the skin, including immunomodulatory activities, barrier function improvement, and anti-tumor effects. However, the effect of PC in aquaporin-3 (AQP3) expression, which is essential for epidermal water permeability barrier maintenance, was not reported. Methods: This study examined the mechanism through which the ethanol extract of the sclerotium of PC (EPC) promoted the expression of AQP3 in cultured human keratinocytes. Western blotting was used to investigate the expression of AQPs and the activation of phosphoinositide 3-kinase (PI3K)/Akt-related signaling molecules in HaCaT cells. Cells were treated with inhibitors of PI3K/Akt and mechanistic target of rapamycin (mTOR) prior to EPC treatment. Results: EPC promoted the expression of AQP3 in HaCaT cells without affecting AQP1 and AQP2 expression. Phosphorylated Akt levels were increased by EPC treatment, and the inhibition of PI3K by LY2940002 resulted in a reduction in EPC-induced AQP3 expression. Furthermore, EPC stimulated the phosphorylation of p70S6K and AktSer473, which are downstream targets of mTORC1 and mTORC2, respectively. The mTOR complex inhibitors, rapamycin and Torin 1, partially reduced EPC-induced AQP3 expression. Conclusion: These results suggest that EPC increased expression of AQP3, which is important for skin moisturization, by activating the PI3K/Akt/mTOR signaling pathway in human keratinocytes.
RESUMEN
The major role of inner medullary collecting duct (IMCD) cells is to maintain water and sodium homeostasis. In addition to the major role, it also participates in the protection of renal and systemic inflammation. Although IMCD cells could take part in renal and systemic inflammation, investigations on renal inflammation in IMCD cells have rarely been reported. Although berberine (BBR) has been reported to show diverse pharmacological effects, its antiinflammatory and protective effects on IMCD cells have not been studied. Therefore, in the present study, we examined the antiinflammatory and protective effects of BBR in mouse IMCD3 (mIMCD3) cells against lipopolysaccharide (LPS). An MTT assay was carried out to investigate the toxicity of BBR on mIMCD3 cells. Reverse transcription quantitativePCR and western blotting were performed to analysis proinflammatory molecules and cytokines. Mechanisms of BBR were examined by western blotting and immunocytochemistry. According to previous studies, proinflammatory molecules, such as inducible nitric oxide synthase and cyclooxygenase2, and proinflammatory cytokines, such as interleukin (IL)1ß, IL6 and tumor necrosis factorα are increased in LPSexposed mIMCD3 cells. However, the production of these proinflammatory molecules is significantly inhibited by treatment with BBR. In addition, BBR inhibited translocation of nuclear factor (NF)κB p65 from the cytosol to the nucleus, and degradation of inhibitory κBα in LPSexposed mIMCD3 cells. In conclusion, BBR could inhibit renal inflammatory responses via inhibition of NFκB signaling and ultimately contribute to amelioration of renal injury during systemic inflammation.
Asunto(s)
Berberina/farmacología , Inflamación/tratamiento farmacológico , Riñón/efectos de los fármacos , Factor de Transcripción ReIA/genética , Animales , Línea Celular , Ciclooxigenasa 2/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Interleucina-1beta/genética , Interleucina-6/genética , Riñón/patología , Lipopolisacáridos/toxicidad , Ratones , FN-kappa B/genética , Óxido Nítrico Sintasa/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Our previous report revealed that Gardenia jasminoides (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1[Formula: see text]g/kg) or saline (control group) were intraperitoneally injected 1[Formula: see text]h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC in vivo and in vitro. In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.
Asunto(s)
Ceruletida/efectos adversos , Gardenia/química , Pancreatitis Crónica/tratamiento farmacológico , Pancreatitis Crónica/prevención & control , Fitoterapia , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Animales , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Fibrosis , Inyecciones Intraperitoneales , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones Endogámicos C57BL , Páncreas/patología , Células Estrelladas Pancreáticas/patología , Pancreatitis Crónica/inducido químicamente , Pancreatitis Crónica/patología , Extractos Vegetales/aislamiento & purificaciónRESUMEN
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 6â¯h. HP (0.5, 5 or 10â¯mg/kg, i.p.) was administered 1â¯h prior to and 1, 3 or 5â¯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.
Asunto(s)
Ceruletida/farmacología , Furanos/farmacología , Lignanos/farmacología , Nardostachys/química , Páncreas/efectos de los fármacos , Pancreatitis/inducido químicamente , Pancreatitis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Citocinas/metabolismo , Femenino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Páncreas/metabolismo , Pancreatitis/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
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
Heme oxygenase-1 (HO-1) has an anti-inflammatory action in acute pancreatitis (AP). However, its mechanism of action and natural compounds/drugs to induce HO-1 in pancreas are not well understood. In this study, we investigated the regulatory mechanisms of HO-1 during AP using desoxo-narchinol-A (DN), the natural compound inducing HO-1 in the pancreas. Female C57/BL6 Mice were intraperitoneally injected with supramaximal concentrations of cerulein (50⯵g/kg) hourly for 6â¯h to induce AP. DMSO or DN was administered intraperitoneally, then mice were sacrificed 6â¯h after the final cerulein injection. Administration of DN increased pancreatic HO-1 expression through activation of activating protein-1, mediated by mitogen-activated protein kinases. Furthermore, DN treatment reduced the pancreatic weight-to-body weight ratio as well as production of digestive enzymes and pro-inflammatory cytokines. Inhibition of HO-1 by tin protoporphyrin IX abolished the protective effects of DN on pancreatic damage. Additionally, DN treatment inhibited neutrophil infiltration into the pancreas via regulation of chemokine (C-X-C motif) ligand 2 (CXCL2) by HO-1. Our results suggest that DN is an effective inducer of HO-1 in the pancreas, and that HO-1 regulates neutrophil infiltration in AP via CXCL2 inhibition.
Asunto(s)
Quimiocina CXCL2/metabolismo , Hemo-Oxigenasa 1/metabolismo , Neutrófilos/fisiología , Páncreas/metabolismo , Pancreatitis/metabolismo , Enfermedad Aguda , Amilasas/sangre , Animales , Ceruletida/administración & dosificación , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Naftoles/metabolismo , Infiltración Neutrófila , Páncreas/patología , Pancreatitis/patologíaRESUMEN
Inflammasomes promote the production of pro-inflammatory cytokines, such as interleukin (IL)-1ß and IL-18, which are the representative mediators of inflammation. Abnormal activation of inflammasomes leads to the development of inflammatory diseases such as acute pancreatitis (AP). In this study, we demonstrate the inhibitory effects of a new natural compound fraxinellone on inflammasome formation and examine the role of inflammasomes in a mouse model of AP. AP was induced with hourly intraperitoneal injections of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50⯵g/kg) for 6â¯h. Mice were sacrificed 6â¯h after the final cerulein injection. Blood and pancreas samples were obtained for further experiments. Intraperitoneal injection of fraxinellone significantly inhibited the pancreatic activation of multiple inflammasome molecules such as NACHT, LRR and PYD domains-containing protein 3 (NLRP3), PY-CARD, caspase-1, IL-18, and IL-1ß during AP. In addition, fraxinellone treatment inhibited pancreatic injury, elevation in serum amylase and lipase activities, and infiltration of inflammatory cells such as neutrophils and macrophages but had no effect on pancreatic edema. To investigate whether inflammasome activation leads to the infiltration of inflammatory cells, we used parthenolide, a well-known natural inhibitor, and IL-1 receptor antagonist mice. The inhibition of inflammasome activation by pharmacological/or genetic modification restricted the infiltration of inflammatory cells, but not edema, consistent with the results observed with fraxinellone. Taken together, our study highlights fraxinellone as a natural inhibitor of inflammasomes and that inflammasome inhibition may lead to the suppression of inflammatory cells during AP.
Asunto(s)
Antiinflamatorios/uso terapéutico , Benzofuranos/uso terapéutico , Inflamasomas/metabolismo , Inflamación/tratamiento farmacológico , Macrófagos/inmunología , Neutrófilos/inmunología , Pancreatitis/tratamiento farmacológico , Enfermedad Aguda , Animales , Movimiento Celular/efectos de los fármacos , Ceruletida/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVES: We set out to examine whether berberine (BBR) might affect the severity of pancreatitis and pancreatitis-associated lung injury in choline-deficient ethionine-supplemented (CDE) diet-induced severe acute pancreatitis. METHODS: Severe acute pancreatitis was induced by feeding a CDE diet for 3 days. Berberine was administered intraperitoneally during CDE diet. Mice were killed on days 1, 2, and 3 after the onset of CDE diet. The severity of pancreatitis was assessed by evaluating changes to the pancreas and lung and survival rate. Blood, pancreas, and lung were harvested for further examination. Furthermore, the regulating mechanisms of BBR were evaluated on the pancreas. RESULTS: Administration of BBR significantly inhibited histological damage to the pancreas and lung and decreased serum level of amylase and lipase, myeloperoxidase activity, cytokine production, and the mortality rate. Furthermore, administration of BBR inhibited activation of nuclear factor kappa B, c-Jun N-terminal kinases, and p38 in the pancreas during CDE diet. CONCLUSIONS: These findings suggest that BBR attenuates the severity of pancreatitis by inhibiting activation of nuclear factor kappa B, c-Jun N-terminal kinase, and p38 and that BBR could be used as a beneficial agent to regulate AP.
Asunto(s)
Berberina/farmacología , Lesión Pulmonar/prevención & control , Pulmón/efectos de los fármacos , Páncreas/efectos de los fármacos , Pancreatitis Aguda Necrotizante/prevención & control , Amilasas/sangre , Animales , Colina/aislamiento & purificación , Dieta/efectos adversos , Etionina/administración & dosificación , Femenino , Lipasa/sangre , Pulmón/metabolismo , Pulmón/patología , Lesión Pulmonar/mortalidad , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Páncreas/metabolismo , Páncreas/patología , Pancreatitis Aguda Necrotizante/etiología , Pancreatitis Aguda Necrotizante/mortalidad , Fitoterapia/métodos , Tasa de SupervivenciaRESUMEN
Acute pancreatitis (AP) is a life-threatening disease. Berberine (BBR), a well-known plant alkaloid, is reported to have anti-inflammatory activity in many diseases. However, the effects of BBR on AP have not been clearly elucidated. Therefore, the present study aimed to investigate the effects of BBR on cerulein-induced AP in mice. AP was induced by either cerulein or l-arginine. In the BBR treated group, BBR was administered intraperitoneally 1h before the first cerulein or l-arginine injection. Blood samples were obtained to determine serum amylase and lipase activities and nitric oxide production. The pancreas and lung were rapidly removed for examination of histologic changes, myeloperoxidase (MPO) activity, and real-time reverse transcription-polymerase chain reaction. Furthermore, the regulating mechanisms of BBR were evaluated. Treatment of mice with BBR reduced pancreatic injury and activities of amylase, lipase, and pancreatitis-associated lung injury, as well as inhibited several inflammatory parameters such as the expression of pro-inflammatory cytokines and inducible nitric oxide synthesis (iNOS). Furthermore, BBR administration significantly inhibited c-Jun N-terminal kinase (JNK) activation in the cerulein-induced AP. Deactivation of JNK resulted in amelioration of pancreatitis and the inhibition of inflammatory mediators. These results suggest that BBR exerts anti-inflammatory effects on AP via JNK deactivation on mild and severe acute pancreatitis model, and could be a beneficial target in the management of AP.
Asunto(s)
Antiinflamatorios/farmacología , Berberina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Pancreatitis Aguda Necrotizante/patología , Animales , Western Blotting , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Técnica del Anticuerpo Fluorescente , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Liver metastasis is the main cause of death from colorectal cancer. Alcohol consumption impacts liver function and is suggested to be an independent risk factor for liver metastasis of colorectal cancer, but no experimental evidence supporting this hypothesis has been demonstrated to date. In this study, we investigated the effect of alcohol intake on liver metastasis. We examined colon cancer cell spread from the spleen in mice provided with water (control group), alcohol for 4 weeks before tumor injection (prealcohol), alcohol for 3 weeks after tumor injection (postalcohol), or alcohol throughout the 7-week study (alcohol). Alcohol intake significantly increased hepatic metastatic burden in the prealcohol (2.4-fold, P < 0.001), postalcohol (2.0-fold, P < 0.01), and alcohol groups (2.2-fold, P < 0.001). A fluorescence-based metastasis tracking assay also confirmed an alcohol-induced increase in the abundance of tumor cells in the liver (2.5-fold, P < 0.001). Investigation of the host microenvironment revealed an alcohol-induced inflammatory response marked by elevated TNFα, IL1ß, IL6, and IFNγ protein levels, as well as increased expression of intercellular molecule-1 (ICAM1) in hepatic tissues after 4 weeks of alcohol consumption. Moreover, the peripheral blood of mice provided with alcohol for 4 weeks exhibited reduced natural killer and CD8(+) T-cell counts. Collectively, our findings suggest that chronic alcohol consumption accelerates liver metastasis of colorectal cancer cells through alterations to the liver microenvironment and inactivation of immune surveillance. Cancer Res; 76(7); 1698-704. ©2016 AACR.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Neoplasias del Colon/etiología , Hígado/patología , Consumo de Bebidas Alcohólicas/patología , Animales , Proliferación Celular , Enfermedad Crónica , Neoplasias del Colon/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Metástasis de la NeoplasiaRESUMEN
Guggulsterone (GS) is a phytosterol that has been used to treat inflammatory diseases such as colitis, obesity, and thrombosis. Although many previous studies have examined activities of GS, the effect of GS on lipopolysaccharide (LPS)-induced inflammatory responses in mouse inner medullary collecting duct-3 (mIMCD-3) cells have not been examined. Therefore, here, we investigated the anti-inflammatory action of GS on mIMCD-3 cells exposed to LPS. LPS treatment on mIMCD-3 cells produced pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) significantly; however, GS treatment significantly inhibited the production of pro-inflammatory molecules. In addition, GS inhibited the degradation of Iκ-Bα and translocation of NF-κB on mIMCD-3 cells. These results suggest that GS could inhibit inflammatory responses in collecting duct cells which could contribute to kidney injury during systemic infection.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Antiinflamatorios/farmacología , Túbulos Renales Colectores/inmunología , Pregnenodionas/farmacología , Receptor Toll-Like 4/inmunología , Animales , Línea Celular , Ciclooxigenasa 2/biosíntesis , Femenino , Inflamación/tratamiento farmacológico , Interleucina-6/biosíntesis , Túbulos Renales Colectores/citología , Lipopolisacáridos , Macrófagos Peritoneales/inmunología , Ratones , Ratones Endogámicos C57BL , Inhibidor NF-kappaB alfa/metabolismo , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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
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
We previously reported that Nardostachys jatamansi (NJ) exhibits anti-inflammatory activity against lipopolysaccharide (LPS). However, the active compound in NJ is unknown. Therefore, here, we examined the effects of desoxo-narchinol-A (DN) isolated from NJ against LPS-induced inflammation. To demonstrate the anti-inflammatory effect of DN against LPS, we used two models; murine endotoxin shock model for in vivo model, and peritoneal macrophage responses for in vitro. In endotoxin shock model, DN was administrated intraperitoneally 1h before LPS challenge, then we evaluated mice survival rates and organ damages. Pretreatment with DN (0.05mg/kg, 0.1mg/kg, or 0.5mg/kg) dramatically reduced mortality in a murine LPS-induced endotoxin shock model. Furthermore, DN inhibited tissue injury and production of pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α), in the liver and lung. In in vitro macrophage model, we examined the inflammatory mediators and regulatory mechanisms such as mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB). DN inhibited the production of inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and its derivative nitric oxide (NO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), IL-1ß, IL-6 and TNF-α and H3 protein acetylation in murine peritoneal macrophages. DN also inhibited p38 activation, but not extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), and NF-κB. These results suggest that DN from NJ exhibits protective effects against LPS-induced endotoxin shock and inflammation through p38 deactivation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Naftoles/farmacología , Nardostachys/química , Choque Séptico/prevención & control , Animales , Citocinas/biosíntesis , Activación Enzimática/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/efectos de los fármacos , Naftoles/aislamiento & purificación , Choque Séptico/inducido químicamente , Choque Séptico/patología , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacosRESUMEN
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
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.