RESUMO
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.
Assuntos
Calcineurina , Catepsina B , Citocinas , Flavonoides , Camundongos Endogâmicos C57BL , Pancreatite , Animais , Pancreatite/tratamento farmacológico , Pancreatite/imunologia , Pancreatite/patologia , Pancreatite/induzido quimicamente , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Citocinas/metabolismo , Catepsina B/metabolismo , Camundongos , Masculino , Calcineurina/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Ceruletídeo , NF-kappa B/metabolismo , Pâncreas/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Transdução de Sinais/efeitos dos fármacos , Arginina/metabolismo , Modelos Animais de Doenças , Proteínas Quinases Ativadas por AMP/metabolismoRESUMO
Cannabis sativa L. has been widely used by humans for centuries for various purposes, such as industrial, ceremonial, medicinal, and food. The bioactive components of Cannabis sativa L. can be classified into two main groups: cannabinoids and terpenes. These bioactive components of Cannabis sativa L. leaf and inflorescence extracts were analyzed. Mice were systemically administered 30 mg/kg of Cannabis sativa L. leaf extract 1 h before lipopolysaccharide (LPS) administration, and behavioral tests were performed. We conducted an investigation into the oxygen saturation, oxygen tension, and degranulation of mast cells (MCs) in the deep cervical lymph nodes (DCLNs). To evaluate the anti-inflammatory effect of Cannabis sativa L. extracts in BV2 microglial cells, we assessed nitrite production and the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. The main bioactive components of the Cannabis sativa L. extracts were THCA (a cannabinoid) and ß-caryophyllene (a terpene). Cannabis sativa L. leaf extract reduced the immobility time in the forced swimming test and increased sucrose preference in the LPS model, without affecting the total distance and time in the center in the open field test. Additionally, Cannabis sativa L. leaf extract improved oxygen levels and inhibited the degranulation of MCs in DCLNs. The Cannabis sativa L. extracts inhibited IL-1ß, IL-6, TNF-α, nitrite, iNOS, and COX-2 expression in BV2 microglia cells. The efficacy of Cannabis sativa L. extracts was suggested to be due to the entourage effect of various bioactive phytochemicals. Our findings indicate that these extracts have the potential to be used as effective treatments for a variety of diseases associated with acute inflammatory responses.
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Oxidative stress, a driver of liver pathology, remains a challenge in clinical management, necessitating innovative approaches. In this research, we delved into the therapeutic potential of polyphenols for oxidative liver injury using a multiscale network analysis framework. From the Phenol-Explorer database, we curated a list of polyphenols along with their corresponding PubChem IDs. Verified target information was then collated from multiple databases. We subsequently measured the propagative effects of these compounds and prioritized a ranking based on their correlation scores for oxidative liver injury. This result underwent evaluation to discern its effectiveness in differentiating between known and unknown polyphenols, demonstrating superior performance over chance level in distinguishing these compounds. We found that lariciresinol and isopimpinellin yielded high correlation scores in relation to oxidative liver injury without reported evidence. By analyzing the impact on a multiscale network, we found that lariciresinol and isopimpinellin were predicted to offer beneficial effects on the disease by directly acting on targets such as CASP3, NR1I2, and CYP3A4 or by modulating biological functions related to the apoptotic process and oxidative stress. This study not only corroborates the efficacy of identified polyphenols in liver health but also opens avenues for future investigations into their mechanistic actions.
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Arecae pericarpium (AP), the fruit peel of the betel palm, is a traditional Oriental herbal medicine. AP is used to treat various diseases and conditions, such as ascites, edema, and urinary retention, in traditional Korean medicine. Recent studies have demonstrated its anti-obesity and antibacterial effects; however, its anti-neuroinflammatory effects have not yet been reported. Therefore, we investigated the anti-neuroinflammatory effects of AP on lipopolysaccharide (LPS)-stimulated mouse microglia in this study. To determine the anti-neuroinflammatory effects of AP on BV2 microglial cells, we examined the production of nitric oxide (NO) using Griess assay and assessed the mRNA expression levels of inflammatory mediators, such as inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, and pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, using a real-time reverse transcription-polymerase chain reaction. Furthermore, we determined the levels of mitogen-activated protein kinases and IκBα via Western blotting to understand the regulating mechanisms of AP. AP treatment decreased NO production in LPS-stimulated BV2 cells. Additionally, AP suppressed the expression of iNOS and COX-2 and the production of pro-inflammatory cytokines. AP also inhibited the activation of p38 and nuclear factor-kappa B (NF-κB) in LPS-stimulated BV2 cells. Therefore, AP exerts anti-neuroinflammatory effects via inactivation of the p38 and NF-κB pathways.
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Guggulsterone (GS) is a phytosterol used to treat inflammatory diseases. Although many studies have examined the anti-inflammatory activities of GS, the detailed mechanisms of GS in lipopolysaccharide (LPS)-induced inflammation and endotoxemia have not yet been examined. Therefore, we investigated the anti-inflammatory effects of GS on LPS-induced inflammation. In murine peritoneal macrophages, the anti-inflammatory activity of GS was primarily mediated by heme oxygenase-1 (HO-1) induction. HO-1 induction by GS was mediated by GSH depletion and reactive oxygen species (ROS) production. The ROS generated by GS caused the phosphorylation of GSK3ß (ser9/21) and p38, leading to the translocation of nuclear factor erythroid-related factor 2 (Nrf2), which ultimately induced HO-1. In addition, GS pretreatment significantly inhibited inducible nitric oxide synthase (iNOS), iNOS-derived NO, and COX-2 protein and mRNA expression, and production of COX-derived prostaglandin PGE2, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α). In a mouse model of endotoxemia, GS treatment prolonged survival and inhibited the expression of inflammatory mediators, including IL-1ß, IL-6, and TNF-α. GS treatment also inhibited LPS-induced liver injury. These results suggest that GS-induced HO-1 could exert anti-inflammatory effects via ROS-dependent GSK (ser21/9)-p38 phosphorylation and nuclear translocation of Nrf2.
Assuntos
Endotoxemia , Lipopolissacarídeos , Animais , Camundongos , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
Chronic pancreatitis (CP) is a pancreatic inflammatory disease associated with histological changes, including fibrosis, acinar cell loss and immune cell infiltration, and leads to damage of the pancreas, which results in pain, weight loss and loss of pancreas function. Catechin or catechin hydrate (CH) has antioxidant, anticancer and immuneregulatory effects. However, unlike other catechins, the antifibrotic effects of (+)CH have not been widely studied in many diseases, including CP. Therefore, the antifibrotic effects of (+)CH against CP were evaluated in the present study. To assess the prophylactic effects of CH, (+)CH (1, 5 or 10 mg/kg) or ethanol was administered 1 h before first cerulein (50 µg/kg) injection. To assess the therapeutic effects, (+)CH (5 mg/kg) or ethanol was administered after cerulein injection for one or two weeks. In both methods, cerulein was injected intraperitoneally into mice once every hour, six times a day, four times a week, for a total of three weeks, to induce CP. The data showed that (+)CH markedly inhibited glandular destruction and inflammation during CP. Moreover, (+)CH prevented pancreatic stellate cell (PSC) activation and the production of extracellular matrix components, such as fibronectin 1 and collagens, which suggested that it may act as a novel therapeutic agent. Furthermore, the mechanism and effectiveness of (+)CH on pancreatic fibrosis were investigated in isolated PSCs. (+)CH suppressed the activation of Smad2 and fibrosis factors that act through transforming growth factorß (TGFß) or plateletderived growth factor. These findings suggest that (+)CH exhibits antifibrotic effects in ceruleininduced CP by inactivating TGFß/Smad2 signaling.
Assuntos
Catequina , Pancreatopatias , Pancreatite Crônica , Animais , Camundongos , Catequina/farmacologia , Ceruletídeo , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/tratamento farmacológico , Pâncreas , Etanol/efeitos adversosRESUMO
Acute kidney injury (AKI) is a major side effect of cisplatin, a crucial anticancer agent. Therefore, it is necessary to develop drugs to protect against cisplatin-induced nephrotoxicity. Ojeoksan (OJS), a traditional blended herbal prescription, is mostly used in Korea; however, there are no reports on the efficacy of OJS against cisplatin-induced AKI. To investigate the reno-protective effect of OJS on AKI, we orally administered 50, 100, and 200 mg/kg of OJS to mice 1 h before intraperitoneal injection with 20 mg/kg of cisplatin. OJS inhibited the increase of blood urea nitrogen (BUN) and serum creatinine (SCr) levels and reduced histological changes in the kidney, like loss of brush borders, renal tubular necrosis, and cast formation. Administration of OSJ reduced the levels of pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. In addition, OJS inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways in cisplatin-induced AKI. These results suggest that OJS attenuates cisplatin-induced AKI by downregulating the MAPK and NF-κB pathways.
Assuntos
Injúria Renal Aguda , Antineoplásicos , Camundongos , Animais , NF-kappa B/metabolismo , Cisplatino/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Creatinina , Interleucina-6/metabolismo , Transdução de Sinais , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Rim/metabolismo , Antineoplásicos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Citocinas/metabolismoRESUMO
Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis. Fraxinus rhynchophylla (FR) reportedly exhibits anti-inflammatory, antioxidative and antitumor activities. Although FR possesses numerous properties associated with the regulation of diverse diseases, the effects of FR on CP remain unknown. Herein, we examined the effects of FR on CP. For CP induction, mice were intraperitoneally administered cerulein (50 µg/kg) 6 times a day, 4 days per week for 3 weeks. FR extract (100 or 400 mg/kg) or saline (control group) was intraperitoneally injected 1 hour before the first cerulein injection. After 3 weeks, the pancreas was harvested for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the antifibrogenic effects and regulatory mechanisms of FR. Administration of FR significantly inhibited histological damage in the pancreas, increased pancreatic acinar cell survival, decreased PSC activation and collagen deposition, and decreased pro-inflammatory cytokines. Moreover, FR treatment inhibited the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, fibronectin 1, and decreased pro-inflammatory cytokines in isolated PSCs stimulated with transforming growth factor (TGF)-ß. Furthermore, FR treatment suppressed the phosphorylation of Smad 2/3 but not of Smad 1/5 in TGF-ß-stimulated PSCs. Collectively, these results suggest that FR ameliorates pancreatic fibrosis by inhibiting PSC activation during CP.
Assuntos
Fraxinus , Pancreatite Crônica , Animais , Ceruletídeo/metabolismo , Ceruletídeo/farmacologia , Ceruletídeo/uso terapêutico , Colágeno/metabolismo , Colágeno/farmacologia , Colágeno/uso terapêutico , Fibrose , Humanos , Camundongos , Pâncreas/patologia , Pancreatite Crônica/tratamento farmacológico , Pancreatite Crônica/metabolismo , Pancreatite Crônica/patologia , Casca de Planta/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
Acute pancreatitis (AP) is an inflammatory disorder, involving acinar cell death and the release of inflammatory cytokines. Currently, there are limited effective therapeutic agents for AP. Betulinic acid (BA) is a pentacyclic triterpenoid extracted from Betula platyphylla that has been shown to have anti-inflammatory effects. In this study, we aimed to investigate the effects of BA on AP and elucidate the potential underlying mechanisms. AP was induced in mice through six intraperitoneal injections of cerulein. After the last cerulein injection, the mice were sacrificed. Our results revealed that pre- and post-treatment with BA significantly reduced the severity of pancreatitis, as evidenced by a decrease in histological damage in the pancreas and lung, serum amylase and lipase activity and pancreatic myeloperoxidase activity. Furthermore, BA pretreatment reduced proinflammatory cytokine production, augmentation of chemokines, and infiltration of macrophages and neutrophils in the pancreas of AP mice. In addition, mice that were pretreated with BA showed a reduction in Iκ-Bα degradation and nuclear factor-kappa B (NF-κB) binding activity in the pancreas. Moreover, BA reduced the production of proinflammatory cytokines and NF-κB activation in pancreatic acinar cells (PACs). These findings suggest that BA may have prophylactic and therapeutic effects on AP via inhibition of the NF-κB signaling pathway.
Assuntos
Anti-Inflamatórios/uso terapêutico , NF-kappa B/metabolismo , Pancreatite/tratamento farmacológico , Triterpenos Pentacíclicos/uso terapêutico , Amilases/sangue , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Lipase/sangue , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Triterpenos Pentacíclicos/farmacologia , Peroxidase/metabolismo , Transdução de Sinais , Ácido BetulínicoRESUMO
Nardostachys spp. have been widely used in Asia as a folk medicine. In particular, the extracts of Nardostachys jatamansi, a species that grows in China, India, and Tibet, have been used to treat mental disorders, hyperlipidemia, hypertension, and convulsions. In this investigation, the potential of 20% aqueous ethanol extract of N. jatamansi (NJ20) as a botanical drug was explored by chemically investigating its constituents and its anti-neuroinflammatory effects on lipopolysaccharide- (LPS-) induced in vitro and in vivo models. Nine secondary metabolites were isolated and identified from NJ20, and quantitative analysis of these metabolites revealed desoxo-narchinol A as the major constituent. In LPS-challenged cells, pretreatment with NJ20 inhibited the LPS-induced excessive production of proinflammatory mediators, such as nitric oxide, prostaglandin E2, interleukin- (IL-) 1ß, IL-6, and tumor necrosis factor-α. NJ20 also attenuated the overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2. Additionally, pre-intraperitoneal injection of NJ20 downregulated the mRNA overexpression of IL-1ß, IL-6, and iNOS in the prefrontal cortex, hypothalamus, and hippocampus of the LPS-stimulated C57BL/c mouse model. Chemical and biological investigations of NJ20 revealed that it is a potential inhibitor of LPS-induced neuroinflammatory responses in microglial cells and mouse models. The major active constituent of NJ20, desoxo-narchinol A, demonstrated anti-neuroinflammatory effects. Hence, our findings indicate that NJ20 may be a promising herbal mixture for developing a functional product and/or herbal drug for treating neuroinflammatory diseases.
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Cisplatin is the most widely used chemotherapeutic agent. However, it often causes nephrotoxicity, which results in acute kidney injury (AKI). Therefore, we urgently need a drug that can reduce the nephrotoxicity induced by cisplatin. Loganin is a major iridoid glycoside isolated from Corni fructus that has been used as an anti-inflammatory agent in various pathological models. However, the renal protective activity of loganin remains unclear. In this study, to examine the protective effect of loganin on cisplatin-induced AKI, male C57BL/6 mice were orally administered with loganin (1, 10, and 20 mg/kg) 1 h before intraperitoneal injection of cisplatin (10 mg/kg) and sacrificed at three days after the injection. The administration of loganin inhibited the elevation of blood urea nitrogen (BUN) and creatinine (CREA) in serum, which are used as biomarkers of AKI. Moreover, histological kidney injury, proximal tubule damages, and renal cell death, such as apoptosis and ferroptosis, were reduced by loganin treatment. Also, pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, reduced by loganin treatment. Furthermore, loganin deactivated the extracellular signal-regulated kinases (ERK) 1 and 2 during AKI. Taken together, our results suggest that loganin may attenuate cisplatin-induced AKI through the inhibition of ERK1/2.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Cisplatino/efeitos adversos , Iridoides/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Morte Celular/efeitos dos fármacos , Creatinina/sangue , Citocinas/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Acute pancreatitis (AP) refers to inflammation in the pancreas, which may lead to death in severe cases. Coenzyme Q10 (Q10), generally known to generate energy, plays an important role as an anti-oxidant and anti-inflammatory effector. Here, we showed the effect of Q10 on inflammatory response in murine AP model. For this study, we induced AP by injection of cerulein intraperitoneally or pancreatic duct ligation (PDL) in mice. The level of cytokines and digestive enzymes were measured in pancreas, and blood. All pancreatic tissues were excised for investigation such as histological changes, infiltration of immune cells. Administration of Q10 attenuated the severity of AP and its associated pulmonary complication as shown by reduction of acinar cell death, parenchymal edema, inflammatory cell infiltration and alveolar thickening in both cerulein-induced AP and PDL-induced AP. Moreover, reduction of the cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α were observed in pancreas and pancreatic acinar cells by Q10. Furthermore, Q10 reduced the infiltration of immune cells such as monocytes and neutrophils and augmentation of chemokines such as CC chemokine-2 (CCL2) and C-X-C chemokine-2 (CXCL2) in pancreas of AP mice. In addition, Q10 deactivates the phosphorylation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in pancreas. In conclusion, these observations suggest that Q10 could attenuate the pancreatic damage and its associated pulmonary complications via inhibition of inflammatory cytokines and inflammatory cell infiltration and that the deactivation of ERK and JNK by Q10 might contribute to the attenuation of AP.
Assuntos
Anti-Inflamatórios/uso terapêutico , Pancreatite/tratamento farmacológico , Ubiquinona/análogos & derivados , Animais , Anti-Inflamatórios/farmacologia , Ceruletídeo , Citocinas/genética , Citocinas/imunologia , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Pancreatite/patologia , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
OBJECTIVES: In this study, we investigated the anti-inflammatory effects of silymarin on cerulein-induced acute pancreatitis (AP) in mice. METHODS: Cerulein (50 µg/kg) was injected intraperitoneally once hourly for 6 hours to induce AP. To investigate the prophylactic effects of silymarin, dimethyl sulfoxide or silymarin (25, 50, and 100 mg/kg) was injected intraperitoneally 1 hour before cerulein injection. To investigate the therapeutic effects of silymarin, dimethyl sulfoxide or silymarin (100 mg/kg) was injected intraperitoneally 1, 3, or 5 hours after the first cerulein injection. Blood, pancreas, and lungs were harvested 6 hours after the last cerulein injection. RESULTS: Pre- and posttreatment with silymarin decreased the pancreas weight/body weight ratio and serum amylase activity. Furthermore, silymarin treatment inhibited pancreas and lung injury and neutrophil infiltration during cerulein-induced AP. In addition, silymarin inhibited increased secretion of proinflammatory cytokines such as interleukin 1ß, interleukin 6, and tumor necrosis factor α. Finally, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB were activated by cerulein, and only p38 in MAPK was inhibited by silymarin. CONCLUSIONS: These findings suggest that silymarin attenuates the severity of AP through inhibition of p38 MAPKs and that silymarin could be a potential prophylactic and therapeutic agent for the treatment of AP.
Assuntos
Pâncreas/efeitos dos fármacos , Pancreatite/prevenção & controle , Índice de Gravidade de Doença , Silimarina/farmacologia , Doença Aguda , Amilases/sangue , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Ceruletídeo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Silimarina/administração & dosagemRESUMO
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.
Assuntos
Berberina/farmacologia , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Fator de Transcrição RelA/genética , Animais , Linhagem Celular , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Rim/patologia , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/genética , Óxido Nítrico Sintase/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
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 fármacosRESUMO
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.
Assuntos
Alcaloides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzodioxóis/uso terapêutico , Pancreatite Crônica/tratamento farmacológico , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Proteínas Smad/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Modelos Animais de Doenças , Feminino , Fibrose , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite Crônica/imunologia , Pancreatite Crônica/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
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 DoençaRESUMO
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.
Assuntos
Anti-Inflamatórios/uso terapêutico , Benzofuranos/uso terapêutico , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Macrófagos/imunologia , Neutrófilos/imunologia , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Movimento Celular/efeitos dos fármacos , Ceruletídeo/administração & dosagem , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Berberina/farmacologia , Lesão Pulmonar/prevenção & controle , Pulmão/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pancreatite Necrosante Aguda/prevenção & controle , Amilases/sangue , Animais , Colina/isolamento & purificação , Dieta/efeitos adversos , Etionina/administração & dosagem , Feminino , Lipase/sangue , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/mortalidade , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite Necrosante Aguda/etiologia , Pancreatite Necrosante Aguda/mortalidade , Fitoterapia/métodos , Taxa de SobrevidaRESUMO
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.