Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 93
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Mol Med ; 44(6): 2015-2026, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638181

RESUMO

Bruceine D is one of the active components of Brucea javanica (L.) Merr., which is widely used to treat cancer in China. The aim of the present study was to evaluate the potential effect of bruceine D against non­small­cell lung cancer (NSCLC) cells and delineate its underlying mechanisms. The results indicated that treatment with bruceine D markedly inhibited the proliferation of wild­type NSCLC cells and epidermal growth factor receptor­mutant cells in a dose­ and time­dependent manner, and significantly decreased the colony­forming ability and migration of A549 cells. Hoechst 33342 staining and flow cytometric analysis demonstrated that treatment with bruceine D effectively induced apoptosis of A549 cells. In addition, the proapoptotic effect of bruceine D was found to be associated with G0­G1 cell cycle arrest, accumulation of intracellular reactive oxygen species (ROS) and malondialdehyde, depletion of glutathione levels and disruption of mitochondrial membrane potential. Additionally, pretreatment with N­acetylcysteine, a ROS scavenger, significantly attenuated the bruceine D­induced inhibition in A549 cells. Western blotting demonstrated that treatment with bruceine D significantly suppressed the expression of the anti­apoptotic proteins Bcl­2, Bcl­xL and X­linked inhibitor of apoptosis, enhanced the expression levels of apoptotic proteins Bax and Bak, and inhibited the expression of pro­caspase­3 and pro­caspase­8. Based on these results, it may be suggested that inhibition of A549 NSCLC cell proliferation by bruceine D is associated with the modulation of ROS­mitochondrial­mediated death signaling. This novel insight may provide further evidence to verify the anticancer efficacy of B. javanica, and support a role for bruceine D in the anti­NSCLC treatment.

2.
FASEB J ; 33(9): 10393-10408, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31233346

RESUMO

Isorhynchophylline (IRN), an oxindole alkaloid isolated from Uncaria rhynchophylla, elicited distinct antidepressant-like activity in mice. The present study aimed to investigate the antidepressant-like effects of IRN in chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors in mice and to illustrate its possible mechanisms of action. The mice were subjected to CUMS for 6 wk and administered with IRN (20 or 40 mg/kg) daily by oral gavage for 3 wk. The PI3K/protein kinase B (Akt) inhibitor and glycogen synthase kinase-3ß (GSK-3ß) inhibitors were used to determine the involvement of the PI3K/Akt/GSK-3ß pathway in the antidepressant-like effects of IRN in the mice. The results showed that CUMS caused depression-like behaviors in the mice, such as behavioral despair by the forced swim test (FST) and anhedonia by the sucrose preference test. In addition, CUMS could significantly reduce the levels of nerve growth factor and brain-derived neurotrophic factor but markedly increase the release of TNF-α and IL-6 in the hippocampus and cerebral cortex of the mice. Western blotting analysis showed that CUMS markedly suppressed the levels of phosphorylated GSK-3ß (Ser9) and phosphorylated Akt (Ser473) but significantly enhanced the translocation of NF-κB p65 from cytosol to nuclei in the hippocampus and cerebral cortex of the mice. CUMS could also significantly increase the NF-κB binding activity in the hippocampus and cerebral cortex of the mice, whereas IRN treatment could significantly reverse the behavioral and biochemical changes induced by CUMS in the mice. Moreover, the antidepressant-like effect of IRN was completely abolished by the PI3K/Akt inhibitor. Combination treatment with IRN and GSK-3ß inhibitors in the mice exerted a synergistic anti-immobility action in the FST. The results of mechanistic investigations indicated that the antidepressant-like action of IRN was mediated, at least in part, by enhancing neurotrophins and attenuating neuroinflammation via modulating the PI3K/Akt/GSK-3ß pathway.-Xian, Y.-F., Ip, S.-P., Li, H.-Q., Qu, C., Su, Z.-R., Chen, J.-N., Lin, Z.-X. Isorhynchophylline exerts antidepressant-like effects in mice via modulating neuroinflammation and neurotrophins: involvement of the PI3K/Akt/GSK-3ß signaling pathway.

3.
Biomed Pharmacother ; 114: 108766, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901719

RESUMO

Brucea javanica is an important Chinese folk medicine traditionally used for the treatment of dysentery (also known as inflammatory bowel diseases). Brucea javanica oil emulsion (BJOE), the most common preparation of Brucea javanica, has a variety of pharmacological activities. In this follow-up investigation, we endeavored to illuminate the potential benefit of BJOE on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced Crohn's disease (CD) in rats and decipher the mechanism of action. The result illustrated that BJOE treatment significantly reduced the body weight loss, disease activity index and macroscopic scores, ameliorated shortening of colon length, arrested colonic histopathological deteriorations, lowered the histological scores in parallel to the model group. Furthermore, BJOE also decreased the levels of MPO and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-17, IL-23 and IFN-γ), and increased the levels of anti-inflammatory cytokines (IL-4, IL-10 and TGF-ß) as compared with the model group. In addition, the elevated mRNA expression of MMP-1, MMP-3 and RAGE induced by TNBS was remarkably inhibited by BJOE, SASP or AZA treatments, while the mRNA expression of PPAR-γ was significantly enhanced. Furthermore, the activation of TLR4/NF-κB signaling pathway was significantly inhibited by AZA and BJOE treatment when compared with that of TNBS-treated rats. Our study suggested that BJOE exerted superior therapeutic effect to SASP and AZA in treating TNBS-induced colitis in rats. The protective effect of BJOE may involve the inhibition of the TLR4/NF-κB-mediated inflammatory responses. These results indicated that BJOE held promising potential to be further developed into a novel candidate for the treatment of CD.


Assuntos
Brucea/química , Doença de Crohn/tratamento farmacológico , Emulsões/farmacologia , NF-kappa B/metabolismo , Óleos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Doença de Crohn/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley
4.
J Ethnopharmacol ; 234: 44-56, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30610932

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum indicum Linne (C. indicum), a healthy food and folk medicine in China for thousands of years, has been reported to exert heat-clearing and detoxifying effects and extensively applied to treat various symptoms such as inflammation diseases, hepatitis and headache. AIM OF THIS STUDY: The purpose of the present study was to investigate the protective effect of the supercritical carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) on D-galactose-induced brain and liver damage during aging process and to illuminate the underlying mechanisms. MATERIALS AND METHODS: Mice were orally administrated with CISCFE (100, 150 and 300 mg/kg) after injection with D-galactose. 24 h after the last administration, the blood samples, whole brain and liver tissues were collected for biochemical analysis, histological examination and western blot analysis. The body weight, spleen and thymus indexes, alanine transaminase (ALT), aspartate transaminase (AST), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) in brain and liver, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and necrosis factor-α (TNF-α) were detected. Besides, the expressions of Bax, Bcl-2 and cleaved caspase-3 were determined by western blot assay. RESULTS: The results indicated that CISCFE effectively increased the suppressed body weight, attenuated the decline of thymus and spleen indexes, and reduced the elevated levels of ALT and AST induced by D-gal. Furthermore, CISCFE might notably alleviate D-gal-induced abnormal alterations in structure and function of brain and liver dose-dependently via renewing normal antioxidant enzymes activities (SOD, CAT, GSH-Px), reducing MDA accumulation, decreasing inflammatory cytokines productions (IL-1ß, IL-6, TNF-α), as well as attenuating the increase of Bax/Bcl-2 ratio and cleaved caspase-3 activation in the liver and brain. CONCLUSIONS: Taken together, our present results suggested that CISCFE treatment could effectively mitigate the D-gal-induced hepatic and cerebral injury, and the underlying mechanism might be tightly related to the decreased oxidative stress, inflammation and apoptosis, indicating CISCFE might be an alternative and promising agent for the treatment of aging and age-associated brain and liver diseases.


Assuntos
Chrysanthemum/química , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Envelhecimento/patologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dióxido de Carbono/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Flores , Galactose/toxicidade , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Extratos Vegetais/administração & dosagem , Superóxido Dismutase/metabolismo
5.
Phytomedicine ; 52: 272-283, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599908

RESUMO

BACKGROUND: Berberine (BBR) is the most abundant and major active constituent of Rhizoma Coptidis (RC), which has been widely used to treat inflammatory diseases in traditional oriental medicine. Despite BBR has been found to exhibit pronounced anti-inflammatory effect, the anti-inflammatory activities of its natural derivatives were sparsely dissected out. PURPOSE: To comparatively investigate the anti-inflammatory potential of BBR, and its natural oxoderivative (oxyberberine, OBB) and reduced derivative (dihydroberberine, DHBB) in vitro and in vivo, and delineate the possible underlying mechanism. METHODS: LC-MS/MS was used to identify the natural derivatives of BBR in RC. The potential anti-inflammatory properties of BBR and its natural derivatives were comparatively evaluated in vitro by lipopolysaccharide (LPS)-induced RAW264.7 macrophages cells, and in vivo via three typical acute inflammation murine models. Some important inflammation-related molecules were analyzed by ELISA, qRT-PCR and Western blotting. RESULTS: LC-MS/MS led to the identification of BBR, OBB and DHBB in RC ethyl acetate extract. The in vitro assay indicated that BBR, OBB and DHBB (1.25, 2.5 and 5 µM) pretreatment significantly decreased the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), prostaglandinE2 (PGE2) and nitricoxide (NO), and inhibited the mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitricoxide synthase (iNOS) in a dose-dependent manner, with relative efficiency of OBB > BBR > DHBB. Furthermore, OBB, BBR and DHBB remarkably inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 and inhibitory kappa Bα (IκBα). In vivo, BBR (20 mg/kg) and OBB (5, 10, and 20 mg/kg) pretreatment significantly ameliorated the xylene-induced ear edema, carrageenan-stimulated paw edema, and acetic acid-elicited vascular permeability in mice in a dose-dependent manner, with OBB exhibiting superior anti-inflammatory effect at the same dose (20 mg/kg). Histopathological analysis indicated that OBB and BBR could markedly attenuate the inflammatory deterioration and decrease the cellular infiltration in paw tissues. Additionally, the carrageenan-induced increases in TNF-α, IL-6, IL-1ß, PGE2 and NO productions, and COX-2 and iNOS mRNA expressions were effectually and concentration-dependently suppressed by OBB and BBR pretreatment. CONCLUSION: The anti-inflammatory activity of BBR and its natural derivatives was in the order of OBB > BBR > DHBB. OBB was for the first time found to be endowed with pronounced anti-inflammatory property, which was probably associated with suppressing the activation of NF-κB signaling pathway, and the subsequent gene expressions and productions of pro-inflammatory mediators. The results might contribute to illuminating the pharmacodynamic underpinnings of RC and provide evidence for developing OBB as a safe and promising natural lead compound in inflammation treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Animais , Berberina/análogos & derivados , Carragenina/efeitos adversos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Front Pharmacol ; 9: 1181, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386242

RESUMO

Curcumin (CUR), a promising naturally occurring dietary compound, is commonly recognized as the potential anti-inflammatory agent. While the application of CUR was hampered by its low stability and poor systemic bioavailability, it has been suggested that the biological activities of CUR are intimately related to its metabolites. In the current investigation, we aimed to comparatively explore the anti-inflammatory effects of tetrahydrocurcumin (THC), octahydrocurcumin (OHC), and CUR, and to elucidate the underlying action mechanisms on experimental mice models of acute inflammation, i.e., xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. The results showed that THC and OHC exerted significant and dose-dependent inhibitions on the formation of ear edema induced by xylene and paw edema provoked by carrageenan and inhibited the Evans blue dye leakage in peritoneal cavity elicited by acetic acid. Moreover, THC and OHC treatments were more effective than CUR in selectively inhibiting the expression of cyclooxygenase 2 (COX-2) and suppressing nuclear factor-κB (NF-κB) pathways via transforming growth factor ß activated kinase-1 (TAK1) inactivation in the carrageenan-induced mouse paw edema model.

7.
Food Chem Toxicol ; 123: 349-362, 2018 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-30423402

RESUMO

Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.

8.
Mol Immunol ; 105: 76-85, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30496979

RESUMO

Activation of NLRP3 inflammasomes is crucial in the pathological process of Ulcerative colitis (UC), which could be negatively regulated by PINK1/Parkin-driven mitophagy. Palmatine is a herb derived isoquinoline alkaloid with potent anti-inflammatory and anti-bacteria activities. In present study, we evaluated the effect of palmatine on dextran sulfate sodium (DSS)-induced mice colitis and examined whether its effect is exerted by promoting mitophagy-mediated NLRP3 inflammasome inactivation. The result showed that palmatine (40, 100 mg/kg) significantly prevented bodyweight loss and colonic shortening in DSS mice, and reduced the disease activity index and histopathologic score. The levels of MPO, IL-1ß, TNF-α and the number of F4/80+ cells in colon of DSS mice were remarkably decreased by palmatine. Moreover, palmatine suppressed NLRP3 inflammasomes activation, but enhanced the expression of the mitophagy-related proteins involving LC3, PINK1 and Parkin in colonic tissue of DSS mice. These effects was consistent with the in vitro data revealing that palmatine inhibited the activation of NLRP3 inflammasomes, while promoted the expression and mitochondrial recruitment of PINK1 and Parkin in THP-1 cell differentiated macrophages. Furthermore, the effect of palmatine on THP-1 cells was neutralized by a mitophagy inhibitor Cyclosporin A (CsA) and PINK1-siRNA. In parallel, CsA significantly attenuated the therapeutic effect of palmatine in DSS mice, illustrating that the anti-colitis effect of palmatine is closely related to mitophagy. Taken together, the current results demonstrated that palmatine protected mice against DSS-induced colitis by facilitating PINK1/Parkin-driven mitophagy and thus inactivating NLRP3 inflammasomes in macrophage.

9.
Phytomedicine ; 50: 196-204, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30466979

RESUMO

BACKGROUND: Sinapis Semen is derived from the dried mature seeds of Sinapis alba L. or Brassica juncea (L.) Czern. et Coss. Traditionally, the seeds from S. alba are called "White Sinapis Semen" while those from B. juncea are called "Yellow Sinapis Semen". PURPOSE: The present study aimed to compare the chemical composition and the anti-inflammatory effects of 50% aqueous ethanol extracts of the White Sinapis Semen (EWSS) and Yellow Sinapis Semen (EYSS) using both acute (12-O-tetradecanoylphorbol-acetate (TPA)- and arachidonic acid (AA)-induced mouse ear edema) and chronic (multiple applications of croton oil (CO)) inflammatory models. METHODS: The anti-inflammatory effects of EWSS and EYSS were determined by measuring the ear thickness and myeloperoxidase (MPO) activity. The anti-inflammatory mechanism was explored by measuring the protein and mRNA levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6 in the ear of the TPA-treated mice. RESULTS: The results showed that both EWSS and EYSS significantly decreased the ear thickness in both the TPA- and AA-induced acute models, as well as in the CO-induced chronic model. In addition, EWSS and EYSS could markedly inhibit the MPO activity in the ears of TPA-, AA- or CO-treated mice. Moreover, EWSS and EYSS also remarkably inhibited the protein and mRNA levels of TNF-α and IL-6 in the ears of TPA-treated mice. Comparatively, EWSS exerted more potent anti-inflammatory effect than that of EYSS. CONCLUSION: Our results revealed that both EWSS and EYSS are effective anti-inflammatory agents against acute and chronic inflammatory processes, and EWSS possess more potent anti-inflammatory effect than EYSS. The anti-inflammatory effect of the two herbs may be mediated, at least in part, by suppressing the mRNA expression of a panel of inflammatory mediators including TNF-α, IL-6 and IL-1ß.

10.
Food Funct ; 9(11): 5891-5902, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30375606

RESUMO

Acetaminophen (APAP) is commonly used to relieve pain and fever in a clinical setting, but its excessive use can lead to serious hepatotoxicity. Our previous study demonstrated that polydatin (PD) can effectively attenuate d-galactose- and alcohol-induced hepatotoxicity, however, its effect on APAP-induced hepatotoxicity is still unknown. In this study, we explore the protective effect and potential mechanism of PD against APAP-induced hepatotoxicity in mice. The results indicate that PD effectively improves the survival of mice with APAP-induced hepatotoxicity, significantly alleviating histopathologic alterations in the liver, and decreasing the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). PD significantly and dose-dependently reduces oxidative stress by lowering the content of oxidized glutathione (GSSG), reactive oxygen species (ROS), nitric oxide (NO) and malonaldehyde (MDA), while enhancing the hepatic activities of glutathione (GSH), glutathione peroxidase (GSH-Px) and the GSH/GSSG ratio. Meanwhile, PD also substantially inhibits the levels and mRNA expressions of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (NOX2). Additionally, PD markedly arrests apoptosis by assuaging TUNEL-positive hepatocytes and the apoptotic index, decreasing the levels and expression of cytochrome c (CytC), cleaved-caspase-9, apoptotic protease activating factor 1 (Apaf-1), cleaved-caspase-3, and Bax and increasing the level and expression of Bcl-2. Overall, PD pretreatment shows a potent protective effect against APAP-induced hepatotoxicity by relieving oxidative stress and inhibiting apoptosis.

11.
Int J Nanomedicine ; 13: 5887-5907, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319255

RESUMO

Background: Bruceine D (BD) is a major bioactive component isolated from the traditional Chinese medicinal plant Brucea javanica which has been widely utilized to treat dysentery (also known as ulcerative colitis [UC]). Methods: To improve the water solubility and absolute bioavailability of BD, we developed a self-nanoemulsifying drug delivery system (SNEDDS) composing of MCT (oil), Solutol HS-15 (surfactant), propylene glycol (co-surfactant) and BD. The physicochemical properties and pharmacokinetics of BD-SNEDDS were characterized, and its anti-UC activity and potential mechanism were evaluated in TNBS-induced UC rat model. Results: The prepared nanoemulsion has multiple beneficial aspects including small mean droplet size, low polydispersity index (PDI), high zeta potential (ZP) and excellent stability. Transmission electron microscopy showed that nanoemulsion droplets contained uniform shape and size of globules. Pharmacokinetic studies demonstrated that BD-SNEDDS exhibited enhanced pharmacokinetic parameters as compared with BD-suspension. Moreover, BD-SNEDDS significantly restored the colon length and body weight, reduced disease activity index (DAI) and colon pathology, decreased histological scores, diminished oxidative stress, and suppressed TLR4, MyD88, TRAF6, NF-κB p65 protein expressions in TNBS-induced UC rat model. Conclusion: These results demonstrated that BD-SNEDDS exhibited highly improved oral bioavailability and advanced anti-UC efficacy. In conclusion, our current results provided a foundation for further research of BD-SNEDDS as a potential complementary therapeutic agent for UC treatment.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Quassinas/uso terapêutico , Animais , Disponibilidade Biológica , Colite Ulcerativa/patologia , Liberação Controlada de Fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Nanopartículas/química , Nanopartículas/ultraestrutura , Óleos/química , Tamanho da Partícula , Transição de Fase , Quassinas/química , Quassinas/farmacocinética , Quassinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Solubilidade
12.
Pharmacol Res ; 137: 34-46, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30243842

RESUMO

Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg-1) and the positive drug Sulfasalazine (SASP, 200 mg kg-1) were orally administered for 7 days. Disease activity index (DAI) was evaluated on day 8, and colonic tissues were collected for biochemistry analysis. The fecal microbiota was characterized by high-throughput Illumina MiSeq sequencing. And plasma metabolic changes were detected by UPLC-MS. Our results showed that Pal treatment significantly reduced DAI scores and ameliorated colonic injury in mice with DSS-induced colitis. Mucosal integrity was improved and cell apoptosis was inhibited. Moreover, gut microbiota analysis showed that mice received Pal-treatment have higher relative abundance of Bacteroidetes and Firmicutes, but reduced amount of Proteobacteria. Moreover, Pal not only suppressed tryptophan catabolism in plasma, but also decreased the protein expression of indoleamine 2,3-dioxygenase 1 (IDO-1, the rate-limiting enzyme of tryptophan catabolism) in colon tissue. This is consolidated by molecular docking, which suggested that Pal is a potent IDO-1 inhibitor. Taken together, our findings demonstrate that Pal ameliorated DSS-induced colitis by mitigating colonic injury, preventing gut microbiota dysbiosis, and regulating tryptophan catabolism, which indicated that Pal has great therapeutic potential for colitis.

13.
J Med Food ; 21(9): 887-898, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30109956

RESUMO

Angelica sinensis (AS, Danggui in Chinese) is an important herbal component of various traditional formulae for the management of asthenia and its tonic effects. Although AS has been shown to ameliorate cognitive damage and nerve toxicity in D-galactose (D-gal)-elicited senescent mice brain, its effects on liver and kidney injury have not yet been explored. In this work, mice were subjected to hypodermic injection with D-gal (200 mg/kg) and orally gavaged with AS (20, 40, or 80 mg/kg) once a day for 8 successive weeks. Results revealed that AS significantly improved liver and kidney function as assessed by organ index and functional parameters. In addition, AS pretreatment effectively ameliorated the histological deterioration. AS attenuated the MDA level and markedly enhanced the activities and gene expressions of antioxidative enzymes, namely Cu, Zn-SOD, CAT, and GPx. Furthermore, AS markedly inhibited the D-gal-mediated increment of expressions of inflammatory cytokines iNOS, COX-2, IκBα, p-IκBα, and p65 and promoted the IκBα expression level in both hepatic and renal tissues. In sum, AS pretreatment could effectively guard the liver and kidney of mice from D-gal-induced injury, and the underlying mechanism was deemed to be intimately related to attenuating oxidative response and inflammatory stress.

14.
Front Pharmacol ; 9: 615, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962947

RESUMO

Bleomycin (BLM) is a broad spectrum anti-tumor drug and inducing pulmonary fibrosis. As an anti-tumor drug without immunosuppression, it is urgent to find a drug that reduces the side effects of BLM. Scutellarin (SCU), a flavone extracted from Erigeron breviscapus (Vant.) Hand-Mazz, has anti-inflammatory activity and ability to inhibit tumor cell growth, migration, and invasion. However, the combined role of SCU and BLM treatment in tumor is unclear. This study aimed to investigate the possible effect and related mechanisms of BLM combined with SCU in the treatment of tumor through in vivo and in vitro experiments. In vivo experiments showed that BLM combined with SCU in the treatment of mice bearing H22 ascites tumor prolonged the survival time, alleviated BLM-induced pulmonary fibrosis, reduced the production of TNF-α; IL-6, and the levels of MDA and MPO. BLM combined with SCU increased the apoptotic rate of H22 ascites cells and the levels of cleaved-caspases-3 and -8. Furthermore, BLM combined with SCU increased the protein expression of p53 and gene expression of miR-29b, and decreased the expression of TGF-ß1. In vitro experiment results showed that BLM combined with SCU inhibited the viability of H22 cells and MRC-5 cells, promoted H22 cell apoptosis, up-regulated the protein expression of p53 and down-regulated the protein expression of α-SMA and collagen-I in MRC-5 cells. These experimental results suggested that SCU could enhance the anti-tumor effect of BLM and reduce BLM-induced pulmonary fibrosis, indicating SCU as a potential adjuvant for BLM in the future.

15.
Int Immunopharmacol ; 62: 15-22, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29966943

RESUMO

Pogostone (PO), a major component of Pogostemon cablin, displays potent protective effects against lipopolysaccharide-induced acute lung injury (ALI) in mice. This study aimed to investigate the protective effect of PO on TNF-α-induced cell injury in human alveolar epithelial cells in vitro and its underlying mechanism. The cell viability was measured using the MTS method. The cell apoptosis was determined using flow cytometry. The activities of reactive oxygen species (ROS) were detected using a fluorescence microscope. The pro-inflammatory cytokines and antioxidant genes were assessed using reverse transcription-polymerase chain reaction. The protein expression of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα), and nuclear factor-kappa B (NF-κB) p65 was analyzed using the Western blot analysis. PO alleviated cell apoptosis and inhibited ROS production. It alleviated TNF-α-induced cell injury, suppressed the levels of inflammatory cytokines [interleukin (IL)-6, IL-1ß, and IL-8], and enhanced the expression of antioxidant genes (quinine oxidoreductase 1, glutamate cysteine ligase catalytic subunit, heme oxygenase-1). It increased the expression of Keap1 and promoted the activation of Nrf2. However, the phosphorylation of IκBα and the nuclear expression of NF-κB p65 decreased. The anti-inflammatory and antioxidant effects of PO were abrogated following Nrf2 and NF-κB p65 knockdown. The results indicated a protective effect of PO against TNF-α-induced cell injury in A549 cells by modulating the balance between Nrf2 and NF-κB p65 signaling pathways. They verified PO as a promising anti-inflammatory adjuvant drug for treating ALI.

16.
PLoS One ; 13(3): e0194069, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29538417

RESUMO

Ulcerative colitis (UC) is a chronic relapsing disease without satisfactory treatments, in which intestinal inflammation and disrupted intestinal epithelial barrier are two main pathogeneses triggering UC. Berberrubine (BB) is deemed as one of the major active metabolite of berberine (BBR), a naturally-occurring isoquinoline alkaloid with appreciable anti-UC effect. This study aimed to comparatively investigate the therapeutic effects of BB and BBR on dextran sodium sulfate (DSS)-induced mouse colitis model, and explore the potential underlying mechanism. Results revealed that BB (20 mg/kg) produced a comparable therapeutic effect as BBR (50 mg/kg) and positive control sulfasalazine (200 mg/kg) by significantly reducing the disease activity index (DAI) with prolonged colon length and increased bodyweight as compared with the DSS group. BB treatment was shown to significantly ameliorate the DSS-induced colonic pathological alternations and decreased histological scores. In addition, BB markedly attenuated colonic inflammation by alleviating inflammatory cell infiltration and inhibiting myeloperoxidase (MPO) and cytokines (TNF-α, IFN-γ, IL-1ß, IL-6, IL-4 and IL-10) productions in DSS mice. Furthermore, BB treatment substantially upregulated the expression of tight junction (TJ) proteins (zonula occludens-1, zonula occludens-2, claudin-1, occludin) and mRNA expression of mucins (mucin-1 and mucin-2), and decreased the Bax/Bcl-2 ratio. In summary, BB exerted similar effect to its analogue BBR and positive control in attenuating DSS-induced UC with much lower dosage and similar mechanism. The protective effect observed may be intimately associated with maintaining the integrity of the intestinal mucosal barrier and mitigating intestinal inflammation, which were mediated at least partially, via favorable modulation of TJ proteins and mucins and inhibition of inflammatory mediators productions in the colonic tissue. This is the first report to demonstrate that BB possesses pronounced anti-UC effect similar to BBR and sulfasalazine with much smaller dosage. BB might have the potential to be further developed into a promising therapeutic option in the treatment of UC.


Assuntos
Berberina/análogos & derivados , Colite/tratamento farmacológico , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Animais , Berberina/farmacologia , Colite/induzido quimicamente , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo
17.
Phytomedicine ; 39: 111-118, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29433672

RESUMO

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are most widely used as effective anti-inflammatory agents. However, their clinical application brings about inevasible gastrointestinal side effects. Pogostemon cablin is a traditional herbal medicine used for the treatment of gastrointestinal diseases in China. One of its representative components, the tricyclic triterpenoid ß-patchoulone (ß-PAE) has demonstrated great anti-inflammatory activity and gastroprotective effect against ethanol-induced gastric injury, but its protective effect against gastric ulcer induced by indomethacin is still unknown. PURPOSE: To assess the protective effect of ß-PAE against ulcer produced by indomethacin and reveal the underlying pharmacological mechanism. STUDY DESIGN: We used an indomethacin-induced gastric ulcer model of rats in vivo. METHODS: Gastroprotective activity of ß-PAE (10, 20, 40 mg/kg, i.g.) was estimated via indomethacin-induced gastric ulcer model in rats. Histopathological and histochemical assessment of ulcerated tissues were performed. Protein and mRNA expression were determined by Elisa, Western blotting and qRT-PCR. RESULTS: ß-PAE could inhibit ulcer formation. Histopathological and histochemical assessment macroscopically demonstrated that ß-PAE alleviates indomethacin-induced gastric ulceration in dose-dependent manner. After administration of ß-PAE, elevated tumor necrosis factor -α level was significantly decreased and the phosphorylation of JNK and IκB was markedly inhibited. ß-PAE suppressed the levels of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule and monocyte chemoattractant protein 1, as well as myeloperoxidase. Meanwhile, ß-PAE increased cyclooxygenase enzyme activities (COX-1 and COX-2) to enhance the production of prostaglandin E2. Proangiogenic protein, vascular endothelial growth factor and its receptor fms-like tyrosine kinase-1 mRNA expression were promoted while anti-angiogenic protein, endostatin-1 and its receptor ETAR mRNA expression were decreased. CONCLUSION: ß-PAE may provide gastroprotection in indomethacin-induced gastric ulcer in rats by reducing inflammatory response and improving angiogenesis.


Assuntos
Indometacina/efeitos adversos , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Indutores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/farmacologia , Dinoprostona/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Masculino , Pogostemon/química , Ratos Sprague-Dawley , Úlcera Gástrica/patologia , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Mol Med ; 41(3): 1447-1454, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29328398

RESUMO

Colorectal cancer (CRC) is a common and life­threatening type of malignant cancer, which is associated with a high mortality rate. Cisplatin (CDDP) is a commonly used chemotherapy drug with significant side effects. Brusatol (BR) is one of the principal chemical compounds isolated from the Chinese herb Bruceae Fructus, which has been reported to markedly inhibit the proliferation of numerous cancer cell lines. The present study aimed to investigate the possible synergistic anticancer effects of CDDP combined with BR on CT­26 cells, and to evaluate the underlying mechanisms of action. The growth inhibitory effects of BR, CDDP, and BR and CDDP cotreatment on CT­26 cells were assessed by MTT assay. Cell apoptosis were determined by flow cytometry and western blot analysis. The results indicated that compared with single­agent treatment, cotreatment of CT­26 cells with CDDP and BR synergistically inhibited cell proliferation and increased cellular apoptosis. Furthermore, treatment of CT­26 cells with CDDP and BR resulted in a marked increase in the release of cytosolic cytochrome c, decreased expression of procaspase­3 and procaspase­9, and upregulation of the B­cell lymphoma 2 (Bcl­2)­associated X protein/Bcl­2 ratio compared with treatment with BR or CDDP alone. These results strongly suggested that the combination of CDDP and BR was able to produce a synergistic antitumor effect in CRC cells, thus providing a solid foundation for further development of this combination regimen into an effective therapeutic method for CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Neoplasias Colorretais/patologia , Quassinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Citocromos c/metabolismo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Quassinas/química , Proteína X Associada a bcl-2/metabolismo
19.
Mol Med Rep ; 17(1): 789-800, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115625

RESUMO

Silymarin has been used in the treatment of a number of liver diseases for a long time, but its efficacy in preventing triptolide induced acute hepatotoxicity has not been reported previously. The present study aimed to assess the protective effect of silymarin against triptolide (TP)-induced hepatotoxicity in rats. Rats were orally administrated with silymarin (50, 100 and 200 mg/kg) for 7 days and received intraperitoneal TP (2 mg/kg) on the day 8. Hepatic injuries were comprehensively evaluated in terms of serum parameters, morphological changes, oxidative damage, inflammation and apoptosis. The results demonstrated that TP-induced increases in serum parameters, including alanine transaminase, aspartate aminotransferase, alkaline phosphatase, total cholesterol and γ-glutamyl transpeptidase, which were determined using a biochemical analyzer, and histopathological alterations and hepatocyte apoptosis as determined by hematoxylin and eosin and TUNEL staining, respectively, were prevented by silymarin pretreatment in a dose-dependent manner. TP-induced depletions in the activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, glutathione S-transferase and catalase, and glutathione levels, were also significantly reversed by silymarin, as determined using specific kits. Additionally, silymarin dose-dependently exhibited inhibitory effects on malonaldehyde content in the liver. The production of proinflammatory cytokines was investigated using ELISA kits, and the results demonstrated that silymarin dose-dependently inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and IL-1ß in the liver. To determine the mechanism of silymarin, western blot analysis was performed to investigate the protein expression of phosphorylated (p)-p38 and p-c-Jun N-terminal kinase (JNK) of the TNF-α induced inflammatory response and apoptotic pathways. Silymarin significantly blocked p38 and JNK phosphorylation and activation. Additionally, the expression of the proapoptotic proteins cytochrome c, cleaved caspase-3 and Bcl-2-associated X was also reduced following treatment with silymarin, as determined by ELISA, western blotting and immunohistochemistry, respectively. In conclusion, silymarin was demonstrated to dose-dependently protect rat liver from TP-induced acute hepatotoxicity, with the high dose (200 mg/kg) achieving a superior effect. This protective effect may be associated with the improvement of antioxidant and anti-inflammatory status, as well as the prevention of hepatocyte apoptosis. Therefore, silymarin may have the potential to be applied clinically to prevent TP-induced acute hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diterpenos/toxicidade , Fenantrenos/toxicidade , Substâncias Protetoras/farmacologia , Silimarina/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Diterpenos/química , Compostos de Epóxi/química , Compostos de Epóxi/toxicidade , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fenantrenos/química , Substâncias Protetoras/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Silimarina/química
20.
Artigo em Inglês | MEDLINE | ID: mdl-29250126

RESUMO

Excessive alcohol consumption leads to serious liver injury, associating with oxidative stress and inflammatory response. Previous study has demonstrated that polydatin (PD) exerted antioxidant and anti-inflammatory effects and attenuated ethanol-induced liver damage, but the research remained insufficient. Hence, this experiment aimed to evaluate the hepatoprotective effect and potential mechanisms of PD on ethanol-induced hepatotoxicity. Our results showed that PD pretreatment dramatically decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in the serum, suppressed the malonaldehyde (MDA) and triglyceride (TG) content and the production of reactive oxygen species (ROS), and enhanced the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), andalcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH), paralleled by an improvement of histopathology alterations. The protective effect of PD against oxidative stress was probably associated with downregulation of cytochrome P450 2E1 (CYP2E1) and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target gene haem oxygenase-1 (HO-1). Moreover, PD inhibited the release of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) via downregulating toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) p65. To conclude, PD pretreatment protects against ethanol-induced liver injury via suppressing oxidative stress and inflammation.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA