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1.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3330-3334, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602891

RESUMO

Triptolide( TP) is isolated from the traditional Chinese medicine Tripterygium wilfordii,which exhibits notable immuneregulative effect. Th17 cells involve in inflammatory response and Treg cells contribute to immune tolerance. They both play an important role in immune response. Previous studies have investigated that TP induced hepatic Th17/Treg imbalance. However,the effect of TP on spleen Th17/Treg cells remains unclear. Therefore,the aim of present study was to investigate the effect of TP on Th17/Treg cells in spleen. In this study,the effect of TP on the proliferation of splenic lymphocyte was detected by cytotoxicity test in vitro. After different concentrations of TP( 2. 5,5,20,40 nmol·L~(-1)) were given to splenic lymphocyte,cytokines secreted from the supernatant of splenic lymphocyte were detected by cytometric bead array,and the expression of suppressor of cytokine signaling( SOCS) mRNA was detected by qRT-PCR. Female C57 BL/6 mice were continuously observed for 24 h after treatment of 500 µg·kg-1 TP. The effects of TP on the splenic tissue structure and the percentage of Th17/Treg cells were examined. The results showed that the IC50 of TP was19. 6 nmol·L~(-1) in spleen lymphocytes. TP inhibited the secretion of IL-2 and IL-10 and induced the expression of SOCS-1/3 mRNA in spleen lymphocytes at the dosage of 2. 5 and 5 nmol·L~(-1) after 24 h in vitro. Administration of TP at dosage of 500 µg·kg-1 had no significant spleen toxicity in vivo. TP treatment increased the percentage of Th17 cells after 12 h and inhibited the proportion of Treg cells after 12 and 24 h. In conclusion,TP reduced the secretion of IL-2 and IL-10 through SOCS-1/3 signaling pathway,thereby induced the percentage of Th17 cells and inhibited the percentage of Treg cells.


Assuntos
Diterpenos/farmacologia , Fenantrenos/farmacologia , Baço/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Células Th17/citologia , Animais , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Baço/citologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
2.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3374-3383, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602898

RESUMO

Traditional Chinese medicine Tripterygium wilfordii Hook.f( TWHF) is a natural botanical drug in China. It has complex chemical compositions and has been used for a long history. TWHF was used as an insecticide to protect crops at early stage,and it was later found to have significant effects in the treatment of rheumatoid arthritis,attaining great concerns. With further researches,it was found that TWHF can treat various diseases in the medical field due to a variety of pharmacological activities such as anti-cancer,neuroprotection,anti-inflammatory and immune-suppressing,particularly. Multiple extracts of TWHF have unique immunosuppressive function,playing an immune role through multi-target and multi-channel,with significant effect in the treatment of autoimmune diseases. As an immune-suppressing drug,TWHF is worthy of in-depth research due to its broad application prospects. While achieving good clinical efficacy,reports about its toxic effects to multiple systems of the body are also increasing,greatly hindering its clinical application. In order to fully understand the immune-suppressing function of TWHF and reduce or avoid the occurrence of toxic and side effects,we summarized recent progress of TWHF on the immune organs,cells and factors in recent years,as well as the pharmacology and toxic effects,hoping to provide a scientific and reasonable reference for its wider use in clinical treatment.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Sistema Imunitário/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tripterygium/química , Artrite Reumatoide/tratamento farmacológico , Humanos
3.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3468-3477, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602911

RESUMO

Tripterygium wilfordii multiglycoside( GTW),an extract derived from T. wilfordii,has been used for rheumatoid arthritis and other immune diseases in China. However its potential hepatotoxicity has not been investigated completely. Firstly,the content of triptolid( TP) in GTW was 0. 008% confirmed by a LC method. Then after oral administration of GTW( 100,150 mg·kg-1) and TP( 12 µg·kg-1) in female Wistar rats for 24 h,it was found that 150 mg·kg-1 GTW showed more serious acute liver injury than 12 µg·kg-1 TP,with the significantly increased lever of serum ALT,AST,TBA,TBi L,TG and bile duct hyperplasia even hepatocyte apoptosis. The expression of mRNA and proteins of liver bile acid transporters such as BSEP,MRP2,NTCP and OATP were down-regulated significantly by GTW to inhibit bile acid excretion and absorption,resulting in cholestatic liver injury. Moreover,GTW was considered to be involved in hepatic oxidative stress injury,although it down-regulated SOD1 and GPX-1 mRNA expression without significant difference in MDA and GSH levels. In vitro,we found that TP was the main toxic component in GTW,which could inhibit cell viability up to 80% in Hep G2 and LO2 cells at the dose of 0. 1 µmol·L-1. Next a LC-MS/MS method was used to detect the concentration of triptolid in plasma from rats,interestingly,we found that the content of TP in GTW was always higher than in the same amount of TP,suggesting the other components in GTW may affect the TP metabolism. Finally,we screened the substrate of p-glycoprotein( p-gp) in Caco-2 cells treated with components except TP extrated from GTW,finding that wilforgine,wilforine and wilfordine was the substrate of p-gp. Thus,we speculated that wilforgine,wilforine and wilfordine may competitively inhibit the excretion of TP to bile through p-gp,leading to the enhanced hepatotoxity caused by GTW than the same amount of TP.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Diterpenos/toxicidade , Medicamentos de Ervas Chinesas/toxicidade , Glicosídeos/toxicidade , Fenantrenos/toxicidade , Tripterygium/toxicidade , Animais , Células CACO-2 , Cromatografia Líquida , Compostos de Epóxi/toxicidade , Feminino , Humanos , Fígado/efeitos dos fármacos , Extratos Vegetais/toxicidade , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem
4.
J Biochem Mol Toxicol ; 33(11): e22394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557376

RESUMO

Triptolide (TP), a major active ingredient of Tripterygium wilfordii, exerts potent immunosuppressive effects in the treatment of rheumatoid arthritis but is not widely used in clinical practice due to its multiorgan toxicity, particularly hepatotoxicity, nephrotoxicity, and reproductive toxicity. An LC-MS/MS approach was employed to explore the endocrine-disrupting effects of TP. The endocrine-disrupting effects of various concentrations (0-100 nM) of TP for 48 hour were firstly investigated using an in vitro model (H295R cell line). It was found that TP did not decrease cell viability. The transcriptional levels of steroidogenic enzymes in H295R cells were assessed by quantificational real-time polymerase chain reaction. The possible adrenal and endocrine effects of oral administration of TP (0, 50, and 500 µg/kg) for 28 days on both normal and collagen-induced arthritis (CIA) rats were also explored. The serum and adrenal tissue hormone levels (corticosterone and progesterone) and adrenal histopathology were analyzed, with the results that TP significantly decreased the level of cortisol in H295R cells and the level of plasma corticosterone in both normal and CIA rats. Histological alterations in adrenal cortex were observed at the dose of 500 µg/kg. Exposure to TP for 48 hour had an obvious inhibitory effect on the messenger RNA transcript levels of HSD3B2, CYP21A2, CYP17A1, and CYP11B1, which is essential for the synthesis of corticosteroids. In a word, TP leads to the disorder of corticosteroid synthesis and secretion, and corticosteroid may be a potential biomarker for the treatment of multiorgan toxicity of TP.

5.
Chin J Nat Med ; 17(5): 372-380, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31171272

RESUMO

Macrophages play an important role in inflammation, and excessive and chronic activation of macrophages leads to systemic inflammatory diseases, such as atherosclerosis and rheumatoid arthritis. In this paper, we explored the anti-inflammatory effect of broussonin E, a novel phenolic compound isolated from the barks ofBroussonetia kanzinoki, and its underlying molecular mechanisms. We discovered that Broussonin E could suppress the LPS-induced pro-inflammatory production in RAW264.7 cells, involving TNF-α, IL-1ß, IL-6, COX-2 and iNOS. And broussonin E enhanced the expressions of anti-inflammatory mediators such as IL-10, CD206 and arginase-1 (Arg-1) in LPS-stimulated RAW264.7 cells. Further, we demonstrated that broussonin E inhibited the LPS-stimulated phosphorylation of ERK and p38 MAPK. Moreover, we found that broussonin E could activate janus kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3. Downregulated pro-inflammatory cytokines and upregulated anti-inflammatory factors by broussonin E were abolished by using the inhibitor of JAK2-STAT3 pathway, WP1066. Taken together, our results showed that broussonin E could suppress inflammation by modulating macrophages activation statevia inhibiting the ERK and p38 MAPK and enhancing JAK2-STAT3 signaling pathway, and can be further developed as a promising drug for the treatment of inflammation-related diseases such as atherosclerosis.

6.
Chin J Nat Med ; 16(9): 653-664, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30269842

RESUMO

Triptolide (TP) induces severe liver injury, but its hepatotoxicity mechanisms are still unclear. Inflammatory responses may be involved in the pathophysiology. Neutrophils are the first-line immune effectors for sterile and non-sterile inflammatory responses. Thus, the aim of the present study was to investigate the neutrophilic inflammatory response in TP-induced liver injury in C57BL/6 mice. Our results showed that neutrophils were recruited and accumulated in the liver, which was parallel to or slightly after the development of liver injury. Neutrophils induced release of myeloperoxidase and up-regulation of CD11b, which caused cytotoxicity and hepatocyte death. Hepatic expressions of CXL1, TNF-α, IL-6, and MCP1 were increased significantly to regulate neutrophils recruitment and activation. Up-regulation of toll like receptors 4 and 9 also facilitated neutrophils infiltration. Moreover, neutrophils depletion using an anti-Gr1 antibody showed mild protection against TP overdose. These results indicated that neutrophils accumulation might be the secondary response, not the cause of TP-induced liver injury. In conclusion, the inflammatory response including neutrophil infiltration may play a role in TP-induced hepatotoxicity, but may not be severe enough to cause additional liver injury.

7.
Acta Pharmacol Sin ; 39(12): 1847-1854, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30013034

RESUMO

Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 µg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP-induced liver injury when their NKT cells were depleted by injection of anti-NK1.1 mAb (200 µg, i.p.) on days -2 and -1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-γ, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury.

8.
Biomed Pharmacother ; 103: 1557-1566, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864943

RESUMO

Triptolide is the major bioactive component isolated from the Chinese Medicinal plant Tripterygium wilfordii. Despite the growing interest and the plethora of reports discussing the pharmacological activity of this diterpenoid, no clear consensus regarding its cellular targets and full mechanism of action has been reached. In the present work, a combined in vitro and in silico approach was used to evaluate the biological activity of Triptolide on Non-small cell lung cancer (NSCLC). In vitro, Triptolide treatment induced apoptosis in NSCLC cell lines and down-regulated the phosphorylation of AKT, mTOR, and p70S6K. Triptolide also impacted cellular glycolysis as well as the antioxidant response through the impairment of glucose utilization, HKII, glutathione, and NRF2 levels. Molecular docking results examined the possible interactions between Triptolide and AKT and predicted an allosteric binding to AKT-1 structure. Molecular dynamics simulations were further used to evaluate the stability of the complex formed by Triptolide's best conformer and AKT. These findings provide an insightful approach to the anticancer effect of Triptolide against NSCLC and highlight a possible new role for AKT/mTOR HKII inhibition.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Diterpenos/farmacologia , Neoplasias Pulmonares/patologia , Fenantrenos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Glutationa/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fenantrenos/química , Fosfatidilinositol 3-Quinases/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Phytomedicine ; 40: 140-147, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29496166

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies associated with high mortality rate worldwide. We previously reported that pristimerin inhibits cell growth and induces apoptosis in CRC cells. HYPOTHESIS/PURPOSE: To further understand the molecular mechanism by which pristimerin elicits its anticancer activities on colon cancer cells, we investigated its effect on nuclear factor-κB (NF-κB) signaling pathway. STUDY DESIGN: This study consisted of both in vitro and in vivo experiments involving HCT-116 cell line and xenograft mouse model. Molecular techniques such as qRT-PCR, western blotting and immunofluorescence were used to demonstrate pristimerin in vitro effect on NF-κB signaling pathway; whereas it's in vivo activity was analyzed by western blot and immunohistochemistry on tumor tissues. RESULTS: Our in vitro results on HCT-116 cells showed that pristimerin inhibited IKK phosphorylation, IкB-α degradations and IкB-α phosphorylation in both dose- and time- dependent manners, which caused suppression of NF-кB p65 phosphorylation, nuclear translocation and accumulation of NF-кB. Moreover, pristimerin was found to inhibit both constitutive activated-NF-кB and tumor necrosis factor-α (TNF-α)- and lipopolysaccharide (LPS)-induced activation of NF-кB signaling pathway. Furthermore, our in vivo results on xenograft animal model revealed that pristimerin inhibited tumor growth mainly through suppressing NF-кB activity in tumor tissues. CONCLUSION: Pristimerin antitumor activities were mainly mediated through inhibition of NF-кB signaling pathway in colon tumor cells. These findings further explain that pristimerin has the therapeutic potential for targeting colon cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , NF-kappa B/metabolismo , Triterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Células HCT116 , Humanos , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos BALB C , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Triterpenos/administração & dosagem , Fator de Necrose Tumoral alfa/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Biomater Appl ; 32(8): 1090-1104, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29357775

RESUMO

Magnetic mesoporous silica nanospheres (MMSN) were prepared and the surface was modified with cancer cell-specific ligand folic acid. Calcium carbonate was then employed as acid-activated gatekeepers to cap the mesopores of the MMSN, namely, MMSN-FA-CaCO3. The formation of the MMSN-FA-CaCO3 was proved by several characterization techniques, viz. transmission electron microscopy, zeta potential measurement, Fourier transform infrared spectroscopy, BET surface area measurement, and UV-Vis spectroscopy. Daunomycin was successfully loaded in the MMSN-FA-CaCO3 and the system exhibited sensitive pH stimuli-responsive release characteristics under blood or tumor microenvironment. Cellular uptake by folate receptor (FR)-overexpressing HeLa cells of the MMSN-FA-CaCO3 was higher than that by non-folated-conjugated ones. Intracellular-uptake studies revealed preferential uptake of these nanoparticles into FR-positive [FR(+)] HeLa than FR-negative [FR(-)]A549 cell lines. DAPI stain experiment showed high apoptotic rate of MMSN-FA-DNM-CaCO3 to HeLa cells. The present data suggest that the CaCO3 coating and folic acid modification of MMSN are able to create a targeted, pH-sensitive template for drug delivery system with application in cancer therapy.

12.
Biomed Pharmacother ; 95: 1777-1788, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28962083

RESUMO

AIM: The aim of this study is to examine the effects of cordycepin (CRD) on LPS-induced inflammatory response in macrophages and further investigate the underlying molecular mechanisms. METHODS: Cultured mouse RAW264.7 macrophages and human THP-1-derived macrophages were used in this study. The mRNA and protein expression levels of cytokine IL-1ß, IL-6, TNF-α, and MCP-1 were detected by real time RT-PCR, ELISA and Western blot, respectively. The activation of NOD-Like Receptor Protein 3 (NLRP3) inflammasome was analyzed with Western blot analysis and immunofluorescence staining. The ERK1/2 activation was assessed by Western blot analysis. RESULTS: The results demonstrated that pretreatment with CRD (6.25, 12.5, 25, 50µmol/L) dose-dependently inhibited LPS-induced expression of proinflammatory cytokines (IL-1ß, IL-6, TNF-α, MCP-1) and cyclooxygenase 2 (COX-2) in mouse RAW264.7 cells. Similar results were obtained in human THP-1-derived macrophages with CRD. Furthermore, CRD remarkably inhibited LPS-induced activation of the NLRP3 inflammasome and ERK1/2 signaling pathway in RAW264.7 cells. CONCLUSION: CRD exerts anti-inflammatory effects in LPS-induced murine and human macrophages at least in part by inhibiting the activation of NLRP3 inflammasome and ERK1/2 signaling pathway as well as inhibition of COX2-mediated inflammatory response.


Assuntos
Desoxiadenosinas/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Western Blotting , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Desoxiadenosinas/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Inflamassomos/metabolismo , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
13.
Chin J Nat Med ; 15(5): 341-346, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28558869

RESUMO

Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology, characterized by prostatic enlargement coincident with distinct alterations in tissue histology. In the present study, we investigated whether triptolide can prevent testosterone-induced prostatic hyperplasia in rats. Castration was performed via the scrotal route after urethane aesthesia. BPH was induced in experimental groups by daily subcutaneous injections of testosterone propionate (TP) for two weeks. Triptolide was administered daily by oral gavage at a dose of 100 and 50 µg·kg-1 for 2 weeks, along with the TP injections. On day 14, the animals were humanely killed by cervical dislocation after aesthesia. Prostates were excised, weighed, and used for histological studies. Testosterone and dihydrotestosterone (DHT) levels in serum and prostate were measured. The results showed that triptolide significantly reduced the prostate weight, and the testosterone and DHT levels in both the serum and prostate. Histopathological examination also showed that triptolide treatment suppressed TP-induced prostatic hyperplasia. In conclusion, triptolide effectively inhibits the development of BPH induced by testosterone in a rat model.


Assuntos
Diterpenos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Fenantrenos/administração & dosagem , Hiperplasia Prostática/tratamento farmacológico , Tripterygium/química , Androgênios/sangue , Animais , Compostos de Epóxi/administração & dosagem , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Hiperplasia Prostática/sangue , Hiperplasia Prostática/fisiopatologia , Ratos , Ratos Sprague-Dawley , Testosterona/sangue
14.
J Ethnopharmacol ; 207: 92-99, 2017 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-28576579

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Baeckea frutescens L. is commonly used as a folk medicinal material. There are nineteen components in its volatile oil, including Pcymol which has effects of eliminating phlegm, relieving asthma and antiviral. This study was aimed to investigate the anti-infectious inflammatory activities of Baeckea frutescens L. and its conponents and analyzing the mechanisms. MATERIALS AND METHODS: The anti-infectious inflammation of Baeckea frutescens L. were studied by using macrophage activating lipopeptide-2 (MALP-2)-stimulated RAW264.7 cell model in vitro. Secretion of nitric oxide (NO), expression of inducible NO synthase (iNOS) and cytokines were detected as classic inflammatory index. Expression of Myeloid differentiation factor 88 (MyD88), degradation of inhibitory κBα (IκBα) and nuclear translocation of NF-κB p65 were further investigated. RESULTS: The results suggested that Baeckea frutescens L. has effect on suppression of MALP-2-mediated inflammation in RAW264.7 cells. The secretion of NO and the expression of iNOS could be inhibited. The secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were also declined. Baeckea frutescens L. significantly decreased the expression of MyD88, therefore, inhibited the degradation of IκBα, reduced the level of nuclear translocation of p65. CONCLUSION: The results of this study indicated that Baeckea frutescens L. and its components could inhibit the anti-infectious inflammatory events and iNOS expression in MALP-2 stimulated RAW264.7 cells. Among them, BF-2 might play a role through the inhibition of the MyD88 and NF-κB pathway. Our study might provide a new strategy to design and develop this kind of drug towards mycoplasma-infected inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Myrtaceae/química , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Inflamação/patologia , Interleucina-6/metabolismo , Lipopeptídeos/administração & dosagem , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Infecções por Mycoplasma/tratamento farmacológico , Infecções por Mycoplasma/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
15.
Phytother Res ; 31(8): 1265-1272, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28639266

RESUMO

Psoralea corylifolia L. (Fructus Psoraleae) is widely used in Asia, but there are concerns about hepatotoxicity caused by constituents such as psoralens and bakukiol. Bakuchiol (BAK) has antiinflammatory, antipyretic, antibacterial antiviral, anticancer, and estrogenic activity but appears to be hepatotoxic in in vitro tests. This study investigated the hepatotoxicity in vivo in rats. Using intragastrically administered bakuchiol at doses of 52.5 and 262.5 mg/kg for 6 weeks. Bodyweight, relative liver weight, biochemical indicators, histopathology, mRNA expression of CYP7A1, HMG-CoA reductase, BSEP, PPARα, SREBP-2, and MRP3 were measured. Many abnormalities were observed in the bakuchiol-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, and increased weight of liver. The mRNA expression of CYP7A1, HMG-CoA reductase, PPARα, and SREBP-2 decreased in bakuchiol-treated group, the expression of BSEP increased in bakuchiol-treated low dosage, and the expression of BSEP decreased in bakuchiol-treated high dosage. In conclusion, we provide evidence for the first time that bakuchiol can induce cholestatic hepatotoxicity, suggesting potential hepatotoxicity. The mechanism may be related to effects on liver lipid metabolism, but further investigation is necessary. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Fenóis/toxicidade , Extratos Vegetais/toxicidade , Psoralea/toxicidade , Animais , Colestase/induzido quimicamente , Fabaceae/química , Frutas/química , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Estrutura Molecular , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley
16.
J Nutr Biochem ; 46: 57-67, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28458138

RESUMO

Injuries and diseases that occur in the nervous system are common and have few effective treatments. Previous studies have shown that quercetin has a therapeutic effect on nervous system injuries, but its potential effects on and mechanisms of action related to behavioral recovery and axonal regrowth have not been investigated. Here, we showed that quercetin administration promotes behavioral recovery following sciatic nerve-crush injury in mice. Long-term evaluation showed that mice administered 20 mg·kg-1·day-1 quercetin for 35 days had a greater sensorimotor recovery compared with all other treatment groups. The mechanisms behind these effects were further investigated, and quercetin was found to regulate the expression of genes involved in regeneration and trophic support. Moreover, quercetin increased cyclic adenosine monophosphate expression and downstream pathway activation, which directly leads to neuronal growth activation in peripheral axon regeneration. In addition, quercetin enhanced axon remyelination, motor nerve conduction velocity and plantar muscle function, indicating that the degree of distal portion hypotrophy during the peripheral axon regeneration process was reduced. These results suggest that quercetin accelerates functional recovery by up-regulating neuronal intrinsic growth capacity and postponing distal atrophy. Overall, quercetin triggered multiple effects to promote behavioral recovery following sciatic nerve-crush injury in mice.


Assuntos
Lesões por Esmagamento/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Quercetina/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Nervo Isquiático/lesões , Animais , Axônios/fisiologia , Lesões por Esmagamento/fisiopatologia , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/inervação
17.
Toxicology ; 378: 65-75, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28063906

RESUMO

Pyrazinamide (PZA)-induced serious liver injury, but the exact mechanism of PZA-induces hepatotoxicity remains controversial. Endoplasmic reticulum (ER) stress-caused cell apoptosis plays a critical role in the development of drug-induced liver injury (DILI). However, the direct connection between PZA toxicity and ER stress is unknown. In this study, we describe the role of ER stress in PZA induced hepatotoxicity in vivo and in vitro. We found that PZA induces apoptosis in HepG2 cells, and causes liver damage in rats, characterized by increased serum ALT, AST and TBA levels. PZA impairs antioxidant defenses, although this effect did not play an important role in resulting liver injury. The ER stress related proteins GRP78, p-PERK, p-eIF2α, ATF4, CHOP and caspase12 were activated after PZA exposure both in vivo and in vitro. Furthermore, as an ER stress inhibitor, sodium 4-phenylbutyrate (4-PBA) could ameliorate PZA toxicity in HepG2 cells and rat liver. These results have potential implications for the pathogenesis of PZA-induced hepatotoxicity in which ER stress especially PERK-eIF2α-ATF4-CHOP pathway participates in hepatocellular injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fenilbutiratos/farmacologia , Pirazinamida , Fator 4 Ativador da Transcrição/metabolismo , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Glutationa/metabolismo , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Malondialdeído/metabolismo , Fenilbutiratos/uso terapêutico , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/metabolismo
18.
Curr Cancer Drug Targets ; 17(2): 158-168, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27262320

RESUMO

The evolution of genomic research enabled the genetic and molecular profiling of breast cancer and revealed the profound complexity and heterogeneity of this disease. Subtypes of breast cancer characterized by mutations and/or amplifications of some proto-oncogenes are associated with an increased rate of recurrence and poor prognosis. They represent a challenge in the clinic with limited arsenal to attack them. Nowadays, metabolic reprogramming is firmly established as a hallmark of cancer. An increased rate of lipid and protein syntheses in cancerous tissues, a direct consequence of alterations in key metabolic enzymes involved in these pathways, is now recognized as an important aspect of the rewired metabolism of neoplastic cells. Over the past several years, accumulating evidence has revealed that mutations or amplifications of some proto-oncogenes are primarily involved in this metabolic dysregulation. It is thus critically important to dissect the molecular mechanisms tumors use to link metabolic reprogramming with upstream altered signaling. In this article, we review the recent findings that support the importance of lipid and protein biosyntheses in breast tumorigenesis, discuss the crosstalk between growth factor signal transduction and key metabolic enzymes involved in these processes, and point out the potentials of developing new strategies and therapeutics to target these key parameters in order to help breast cancer patients by providing new therapeutic opportunities.


Assuntos
Neoplasias da Mama/metabolismo , Enzimas/metabolismo , Metabolismo dos Lipídeos , Proteínas/metabolismo , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Biossíntese de Proteínas , Receptor ErbB-2/metabolismo
19.
Acta Pharmacol Sin ; 38(1): 29-40, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27840407

RESUMO

Recent studies focus on promoting neurite outgrowth to remodel the central nervous network after brain injury. Currently, however, there are few drugs treating brain diseases in the clinic by enhancing neurite outgrowth. In this study, we established an NGF-induced PC12 differentiation model to screen novel compounds that have the potential to induce neuronal differentiation, and further characterized 4,10-Aromadendranediol (ARDD) isolated from the dried twigs of the Baccharis gaudichaudiana plant, which exhibited the capability of promoting neurite outgrowth in neuronal cells in vitro. ARDD (1, 10 µmol/L) significantly enhanced neurite outgrowth in NGF-treated PC12 cells and N1E115 cells in a time-dependent manner. In cultured primary cortical neurons, ARDD (5, 10 µmol/L) not only significantly increased neurite outgrowth but also increased the number of neurites on the soma and the number of bifurcations. Further analyses showed that ARDD (10 µmol/L) significantly increased the phosphorylation of ERK1/2 and the downstream GSK-3ß, subsequently induced ß-catenin expression and up-regulated the gene expression of the Wnt ligands Fzd1 and Wnt3a in neuronal cells. The neurite outgrowth-promoting effect of ARDD in neuronal cells was abolished by pretreatment with the specific ERK1/2 inhibitor PD98059, but was partially reversed by XAV939, an inhibitor of the Wnt/ß-catenin pathway. ARDD also increased the expression of BDNF, CREB and GAP-43 in N1E115 cells, which was reversed by pretreatment with PD98059. In N1E115 cells subjected to oxygen and glucose deprivation (OGD), pretreatment with ARDD (1-10 µmol/L) significantly enhanced the phosphorylation of ERK1/2 and induced neurite outgrowth. These results demonstrated that the natural product ARDD exhibits neurite outgrowth-inducing activity in neurons via activation of the ERK signaling pathway, which may be beneficial to the treatment of brain diseases.


Assuntos
Proteína GAP-43/biossíntese , Proteína GAP-43/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Flavonoides/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Camundongos , Fator de Crescimento Neural/farmacologia , Neuritos/metabolismo , Neuritos/ultraestrutura , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Ratos , Sesquiterpenos/antagonistas & inibidores
20.
Curr Cancer Drug Targets ; 17(2): 100-108, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26758533

RESUMO

Pristimerin, a natural triterpenoid isolated form Celastrus and Maytenus spp, has been shown to possess a variety of biological and pharmacological effects. Recently, pristimerin has attracted more attention, especially for its potential anticancer activities. The anticancer activities of pristimerin have been illustrated in various cancer cell lines and animal models. It has been found to inhibit in vitro and in vivo proliferation, survival, angiogenesis and metastasis of tumor cells. These activities have been attributed to its modulation of various molecular targets such as cyclins, apoptosis- related proteins, proteasome activity, reactive oxygen species, as well as NF-kB, AKT/mTOR and MAPK/ERK pathways. This mini-review discussed the cellular impact and animal studies of pristimerin treatment, with more attention on the various molecular targets of pristimerin.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Triterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
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