RESUMO
Acute lung injury (ALI) is an inflammatory process, and has high incidence and mortality. ALI and the acute respiratory distress syndrome are two common complications worldwide that result in acute lung failure, sepsis, and death. Pro-inflammatory substances, such as cytokines and chemokines, are responsible for activating the body's defense mechanisms and usually mediate inflammatory processes. Therefore, the research of substances that decrease the uncontrolled response of organism is seen as potential for patients with ALI. Octyl gallate (OG) is a phenolic compound with therapeutic actions namely antimicrobial, antiviral, and antifungal. In this study, we evaluated its action on lipopolysaccharide (LPS)-activated alveolar macrophages RAW 264.7 cells and ALI in male mice. Our results demonstrated protective effects of OG in alveolar macrophages activated with LPS and mice with ALI. The OG treatment significantly decreased the inflammatory markers in both studies in vitro and in vivo. The data suggested that OG can act as an anti-inflammatory agent for ALI.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ácido Gálico/análogos & derivados , Inflamação/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Ácido Gálico/farmacologia , Humanos , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/genética , Lesão Pulmonar/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7RESUMO
Baccharis anomala DC. (BA) is a plant species found in the tropical regions of South America and is widely used for its hepatoprotective effects, as well as for the treatment of gastrointestinal diseases. Studies have recently reported its antioxidant and anti-inflammatory potential. BA extract can reverse the activated phenotype of hepatic stellate cells (HSC), which plays a central role in extracellular matrix (ECM) deposition in the development of liver fibrosis. Thus, this study aimed to evaluate the effects of the treatment with BA extract on liver fibrosis in a CCl4-induced liver fibrosis model in BALB/c mice. Methanolic extract was obtained from BA leaves, a gas chromatography/mass spectrometry (GC/MS) to detect the compounds present was performed, and then administered by intraperitoneal injection in Balb/C mice at a concentration of 50 and 100 mg/kg together with the administration of CCl4 for inducing liver fibrosis. After 10 weeks, blood analysis, histopathology, oxidative stress, as well as protein and gene expression in the hepatic tissue were performed. Treatment with BA extract was able to reduce profibrotic markers by reducing the expression of α-SMA and Col-1 proteins, as well as reducing the formation of free radicals and lipid peroxidation. (BA extract showed anti-inflammatory effects in the liver by suppressing NF-kB activation and reducing gene expression of signaling targets (IL-6 and iNOS). The data obtained showed that BA extract has antifibrotic and anti-inflammatory effects.
Assuntos
Baccharis , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Baccharis/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Fígado , Inflamação/metabolismo , Matriz Extracelular/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
Acute lung injury (ALI) is a disease of high prevalence and is characterized by the excessive production of inflammatory mediators in the lungs of people sick. Inflammation is the major characteristic of ALI and studies report that inhibition of inflammatory cytokines could be an alternative treatment. Statins such as Simvastatin (SV) are known to their use for cholesterol reduction but also for inflammatory and immunoregulatory processes. In this study, we evaluated the effects of SV on LPS-induced alveolar macrophages and in ALI mice model. Our study has demonstrated the protective effects of SV on LPS-activated alveolar macrophages RAW 264.7 and LPS-induced ALI in mice. SV treatment significantly inhibited the alveolar macrophages activation by decreasing the iNOS, IL-1ß, and IL-6 gene expression in vitro and in vivo. The treatment also decreased the inflammatory cells migration and the cytokines gene expression. Our findings suggest that SV can act as an anti-inflammatory agent for acute lung injury.
Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , Animais , Camundongos , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Sinvastatina/efeitos adversos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Pulmão/metabolismo , Citocinas/metabolismoRESUMO
Acute lung injury (ALI) is a life-threatening acute inflammatory disease with high rates of morbidity and mortality worldwide. 4-Allyl-2,6-dimethoxyphenol (methoxyeugenol), a phenylpropanoid from a synthetic source, exhibits strong anti-inflammatory activity, but its effects on the inflammation of ALI have not yet been reported. In our study, the anti-inflammatory effects of methoxyeugenol were investigated on RAW 264.7 cells and a mice model of ALI. Our results showed that methoxyeugenol (7.5 and 30 µM) attenuated the proliferation and gene expression of interleukin (IL)-6 in LPS-stimulated RAW 264.7 cells. In a mice model of ALI induced with LPS, methoxyeugenol exhibited a significant protective effect, based on influx reduction of macrophages and neutrophils into the lungs; reduction in release of the cytokines IL-6, TNF-α, and IL-10; and in reactive oxygen species (ROS) formation. We show that the anti-inflammatory effects of methoxyeugenol are associated with the suppression of the NFκB signaling pathway. Moreover, we demonstrated for the first time that a phenolic compound, from a synthetic source, protects against lung tissue inflammation and promotes a reduction of NET formation. These findings provided evidence for the use of methoxyeugenol as a new strategy to control inflammation in ALI disease.
Assuntos
Lesão Pulmonar Aguda , Armadilhas Extracelulares , Pneumonia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/prevenção & controle , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Studies have shown interest in nutraceuticals for the prevention of liver diseases. Methoxyeugenol, is a molecule found in foods, such as nutmeg (Myristica fragrans Houtt.) and Brazilian red propolis. These two sources of methoxyeugenol, propolis and nutmeg, are used in folk medicine for the treatment of hepatic and gastrointestinal disorders, although little is known about their effects on the prevention of liver fibrosis. Natural PPAR (Peroxisome proliferator-activated receptor) agonists would represent unique molecules for therapy, considering the lack of therapeutics to treat liver fibrosis in chronic liver disease. Thus, investigation on new alternatives are necessary, including the search for natural compounds from renewable and sustainable sources. Liver fibrosis is a pathological process characterized by an exacerbated cicatricial response in the hepatic tissue, which compromises liver function. Therefore, inhibition of HSC (hepatic stellate cell) activation and hepatocyte damage are considered major strategies for the development of new anti-fibrotic treatments. AIM OF THE STUDY: This study aimed to investigate the effects of methoxyeugenol treatment on HSC phenotype modulation in human and murine cells, hepatocyte damage prevention, and protective effects in vivo, in order to evaluate its therapeutic potential for liver fibrosis prevention. METHODS: We investigated the effects of methoxyeugenol in (i) in vitro models using human and murine HSC and hepatocytes, and (ii) in vivo models of CCl4 (carbon tetrachloride) -induced liver fibrosis in mice. RESULTS: We herein report that methoxyeugenol decreases HSC activation through the activation of PPAR-É£, ultimately inducing a quiescent phenotype highlighted by an increase in lipid droplets, loss of contraction ability, and a decrease in the proliferative rate and mRNA expression of fibroblast markers. In addition, methoxyeugenol prevented hepatocytes from oxidative stress damage. Moreover, in mice submitted to chronic liver disease through CCl4 administration, methoxyeugenol decreased the inflammatory profile, liver fibrosis, mRNA expression of fibrotic genes, and the inflammatory pathway signaled by NF-kB (Nuclear factor kappa B). CONCLUSION: We propose methoxyeugenol as a novel and potential therapeutic approach to treat chronic liver disease and fibrosis.
Assuntos
Eugenol/análogos & derivados , Eugenol/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , NF-kappa B/metabolismo , PPAR gama/metabolismo , Animais , Intoxicação por Tetracloreto de Carbono , Linhagem Celular , Eugenol/química , Eugenol/uso terapêutico , Análise de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação , Cirrose Hepática/induzido quimicamente , Masculino , Camundongos , NF-kappa B/genética , Estresse Oxidativo , PPAR gama/genéticaRESUMO
Potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65) is a potent inhibitor of the uridine phosphorylase 1 (UPP1) enzyme. Its non-ionized analog has already demonstrated biological properties by reducing adverse effects caused by the chemotherapeutic 5-fluorouracil (5-FU). In addition, it has been demonstrated that uridine inhibits inflammation and fibrosis in bleomycin lung injury, decreasing collagen production. The purpose of this study was to investigate the in vitro and in vivo effects of CPBMF65 on activated hepatic stellate cells (HSC) and on carbon tetrachloride-induced liver fibrosis in mice. After incubation with CPBMF65, decreased cell proliferation and phenotype reversion were observed in vitro. In addition, CPBMF65 promoted a protective effect on tetrachloride-induced liver fibrosis in mice, demonstrated by its antifibrotic and anti-inflammatory actions. The results of the present study indicate that the UPP1 inhibitor (CPBMF65) may have potential as a novel therapeutic agent for the treatment of liver fibrosis.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Uridina Fosforilase/antagonistas & inibidores , Animais , Tetracloreto de Carbono/toxicidade , Linhagem Celular Transformada , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células Estreladas do Fígado/enzimologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Uridina Fosforilase/metabolismoRESUMO
Octyl gallate (OG) is an antioxidant commonly used in food, although there is no definition of its acceptable daily intake. There are reports in vitro and in vivo showing that food additives and drugs can alter lipid metabolism. Lipid droplet accumulation in hepatic cells is one of the main findings in the unregulated lipid metabolism and is strongly related to the development of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of OG on lipid metabolism in the hepatocellular carcinoma cell line (HepG2). The results have shown, for the first time, that treatment with OG increased the overall amount of lipids, the triglyceride concentration, the lipid droplet area, and SREBP-1c and PPAR-γ gene expression. Taken together, the findings indicate that OG induces lipid droplet accumulation in HepG2 cells through the regulation of SREBP-1c and PPAR-γ gene expression without involving mTOR/S6K1 and may contribute to NAFLD when used as a food additive.
RESUMO
The incidence of hepatocellular carcinoma (HCC) keeps rising year by year, and became the second leading cause of cancer-related death. Some studies have found that liraglutide, a GLP-1 analog, may decrease the tumor cells proliferation. Due to this, the aim of this work is to investigate the antiproliferative potential of exenatide, another GLP-1 analog. Cell proliferation was assessed by direct count with Trypan blue dye exclusion. Flow cytometry was used to determinate autophagy and nuclear staining. Morphometric analysis was used to verify senescence and apoptosis. The mechanism that induced cell growth inhibition was analyzed by Western Blot. Treatment with exenatide significantly decreases cell proliferation and increases autophagy, both in relation to control and liraglutide. In addition, mTOR inhibition was greater in cells treated with exenatide. In relation to chronic treatment, exenatide does not allow cellular regrowth by preventing some resistance mechanism that the cells can acquire. These results suggest that exenatide has a potent anti-proliferative activity via mTOR modulation and, among the GLP-1 analogs tested, could be in the future an alternative for HCC treatment.