RESUMEN
The polarization of macrophages plays a critical role in the physiological and pathological progression of rheumatoid arthritis (RA). Activated M1 macrophages overexpress folate receptors in arthritic joints. Hence, we developed folic acid (FA)-modified liposomes (FA-Lips) to encapsulate triptolide (TP) (FA-Lips/TP) for the targeted therapy of RA. FA-Lips exhibited significantly higher internalization efficiency in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than liposomes (Lips) in the absence of folate. Next, an adjuvant-induced arthritis (AIA) rat model was established to explore the biodistribution profiles of FA-Lips which showed markedly selective accumulation in inflammatory paws. Moreover, FA-Lips/TP exhibited greatly improved therapeutic efficacy and low toxicity in AIA rats by targeting M1 macrophages and repolarizing macrophages from M1 to M2 subtypes. Overall, a safe FA-modified liposomal delivery system encapsulating TP was shown to achieve inflammation-targeted therapy against RA via macrophage repolarization.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Diterpenos/uso terapéutico , Ácido Fólico/uso terapéutico , Liposomas/química , Macrófagos/efectos de los fármacos , Fenantrenos/uso terapéutico , Animales , Artritis Reumatoide/patología , Química Farmacéutica , Citocinas/efectos de los fármacos , Diterpenos/administración & dosificación , Diterpenos/efectos adversos , Diterpenos/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/farmacología , Compuestos Epoxi/uso terapéutico , Ácido Fólico/administración & dosificación , Ácido Fólico/efectos adversos , Ácido Fólico/farmacología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Fenantrenos/administración & dosificación , Fenantrenos/efectos adversos , Fenantrenos/farmacología , Células RAW 264.7 , Ratas , Ratas Sprague-DawleyRESUMEN
Triptolide (TP), an active component of Tripterygium wilfordiiHook. f. (TWHF), has been widely used for centuries as a traditional Chinese medicine. However, the clinical application of TP has been restricted due to multitarget toxicity, such as hepatotoxicity. In this study, 28 days of oral TP administration (100, 200, or 400 µg·kg-1·d-1) induced the occurrence of cholestasis in female Wistar rats, as evidenced by increased serum levels of γ-glutamyl transpeptidase (γ-GGT), alkaline phosphatase (ALP) and hepatic total bile acids (TBAs). In addition, the heptocyte polarity associated with the strcture of tight junctions (TJs) was disrupted in both rats and sandwich-cultured primary hepatocytes. Immunoblotting revealed decreased expression of the TJ-associated proteins occludin, claudin-1, and zonula occludens protein (ZO-1), and downregulated mRNA levels of these TJs was also detected by real-time PCR. An immunofluorescence analysis showed abnormal subcellular localization of occludin, claudin-1 and ZO-1, which was also confirmed by transmission electron microscopy. Moreover, the concentration of FITC-dextran, a marker of paracellular penetration, was found to increase rapidly in bile increased rapidly (within 6 minutes) after treatment with TP, which indicated the functional impairment of TJs. Taken together, these results suggest that the administration of TP for 28 consecutive days to rats could induce cholestatic injury in the liver, and the increased paracellular permeability might play an important role in these pathological changes.
Asunto(s)
Colestasis , Diterpenos/efectos adversos , Hígado/efectos de los fármacos , Fenantrenos/efectos adversos , Uniones Estrechas , Animales , Colestasis/inducido químicamente , Claudina-1 , Compuestos Epoxi/efectos adversos , Femenino , Hepatocitos/efectos de los fármacos , Ocludina , Ratas , Ratas Wistar , Uniones Estrechas/patología , Proteína de la Zonula Occludens-1RESUMEN
Triptolide (TP) is the most effective ingredient found in the traditional Chinese herbal Tripterygium wilfordii Hook F, and it is widely used in therapies of autoimmune and inflammatory disorders. However, the hepatotoxicity induced by TP has restricted its use in clinical trials. Arctiin is known as a protective agent against oxidative stress, and it exerts liver-protecting effect. This study was aimed at investigating the protective role of arctiin against TP-induced hepatotoxicity using in vitro and in vivo models. The results indicated that TP not only obviously induced liver injury in mice but also significantly inhibited the growth of HepG2 cells and increased the level of intracellular reactive oxygen. Furthermore, TP obviously decreased the expressions of proteins of Nrf2 pathway including HO-1, NQO1, and Nrf2 associated with oxidative stress pathway. However, the above experimental indexes were reversed by the treatment of arctiin. Our results suggested that arctiin could alleviate TP-induced hepatotoxicity, and the molecular mechanism is likely related to its capacity against oxidative stress.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Diterpenos/efectos adversos , Furanos/farmacología , Glucósidos/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fenantrenos/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Compuestos Epoxi/efectos adversos , Células Hep G2 , Humanos , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Triptolide (TP), one of the main bioactive diterpenes of the herbal medicine Tripterygium wilfordii Hook F, is used for the treatment of autoimmune diseases in the clinic and is accompanied by severe hepatotoxicity. CYP3A4 has been reported to be responsible for TP metabolism, but the mechanism remains unclear. The present study applied a UPLC-QTOF-MS-based metabolomics analysis to characterize the effect of CYP3A4 on TP-induced hepatotoxicity. The metabolites carnitines, lysophosphatidylcholines (LPCs) and a serious of amino acids were found to be closely related to liver damage indexes in TP-treated female mice. Metabolomics analysis further revealed that the CYP3A4 inducer dexamethasone improved the level of LPCs and amino acids, and defended against oxidative stress. On the contrary, pretreatment with the CYP3A4 inhibitor ketoconazole increased liver damage with most metabolites being markedly altered, especially carnitines. Among these metabolites, except for LPC18:2, LPC20:1 and arginine, dexamethasone and ketoconazole both affected oxidative stress induced by TP. The current study provides new mechanistic insights into the metabolic alterations, leading to understanding of the role of CYP3A4 in hepatotoxicity induced by TP.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Citocromo P-450 CYP3A , Diterpenos/efectos adversos , Metabolómica/métodos , Fenantrenos/efectos adversos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cromatografía Líquida de Alta Presión/métodos , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Dexametasona/farmacología , Compuestos Epoxi/efectos adversos , Femenino , Cetoconazol/farmacología , Hígado/metabolismo , Hígado/patología , Espectrometría de Masas/métodos , Metaboloma/efectos de los fármacos , Ratones , Ratones Endogámicos C57BLRESUMEN
Tripterygium wilfordii Hook. F. (TwHF), a traditional Chinese Medicine, is effective in treating rheumatoid arthritis (RA), but its severe nephrotoxicity limits its extensive application. The nephrotoxic mechanism of Triptolide (TP), the main pharmacological and toxic component of TwHF, has not been fully revealed. This study was designed to explore the nephrotoxicity of TP in the RA state and the potential molecular mechanism. A rat collagen-induced arthritis (CIA) model was constructed and administered with TP for 28â¯days in vivo. Results showed that the kidney injury induced by TP was aggravated in the CIA state, the concentration of TP in the renal cortex was higher than that of the medulla after TP administration in the CIA rats, and the expression of organic cation transporter 2 (Oct2) in kidney was up-regulated under CIA condition. Besides, rat kidney slice study demonstrated that TP was transported by Oct2 and this was confirmed by transient silencing and overexpression of OCT2 in HEK-293T cells. Furthermore, cytoinflammatory models on HK-2 and HEK-293T cell lines were constructed by exposure of TNF-α or IL-1ß to further explore the TP's renal toxicity. Results suggested that TNF-α exposure aggravated TP's toxicity and up-regulated the protein expression of OCT2 in both cell lines. TNF-α treatment also increased the function of OCT2 and finally OCT2 silencing confirmed OCT2 mediated nephrotoxicity of TP in HEK-293T cells. In summary, the exposure of TNF-α in RA state induced the expression of OCT2, which transported more TP into kidney cortex, subsequently exacerbated the kidney injury.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Diterpenos/efectos adversos , Diterpenos/farmacología , Riñón/efectos de los fármacos , Transportador 2 de Cátion Orgánico/metabolismo , Fenantrenos/efectos adversos , Fenantrenos/farmacología , Insuficiencia Renal/inducido químicamente , Tripterygium/efectos adversos , Animales , Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Línea Celular , Citocinas/metabolismo , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/farmacología , Femenino , Células HEK293 , Humanos , Riñón/metabolismo , Medicina Tradicional China/efectos adversos , Ratas , Ratas Wistar , Insuficiencia Renal/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Eucommia ulmoides has been used for many years as a successful strategy to treat male infertility. Aucubin (AU) is the active ingredient extracted from Eucommia ulmoides. However, its protective action and exact mechanism on testicular injury is not yet known. PURPOSE: Here, the protective effect and the mechanism of action of AU on testis damage under oxidative stress was investigated in vivo and in vitro. METHODS: As regard the in vivo experiment, male mice were divided into five groups and testicular injury model was established by Triptolide (TP) (120⯵g/kg) intraperitoneal injection for two weeks. Animals in the treatment group were pretreated with an intraperitoneal injection of AU at different doses (5, 10 and 20â¯mg/kg) for 1â¯h and subsequently treated with TP (120⯵g/kg). At the end of the experimental period, the testis was collected for biochemical and histological examination. As regard the in vitro experiment, Sertoli cells (SCs) were used to investigate the protective effect and mechanism of action of AU against disruption of the blood-testis-barrier (BTB) and apoptosis induced by TP via apoptosis detection, western blot, immunofluorescence analysis, and siRNA transient transfection. RESULTS: TP-treated animals showed testicular atrophy, BTB disruption, increased ROS levels and spermatogenic dysfunction. Pre-administration of AU resulted in a significant protection on keeping a normal testicular weight, sperm morphology, BTB integrity, and a normal level of oxidative stress markers and antioxidants. Furthermore, AU prevented apoptosis through an effective inhibition of PERK/CHOP and JNK dependent apoptosis pathway, as well as protected the integrity of BTB by up-regulating the expression of tight junction proteins (ZO-1, Occludin, Claudin-11) and gap junction protein (Cx43). The mechanistic study revealed that AU significantly triggered Nrf2 translocation, thus increasing nuclear Nrf2 accumulation and then induced antioxidant enzymes expression in the testis and SCs. Furthermore, Nrf2 silencing unsuccessfully reversed the increased CHOP and p-JNK expression induced by TP, abolishing the protective effect of AU. CONCLUSION: These results indicate that AU might be considered as a potential protective agent against testicular injury.
Asunto(s)
Eucommiaceae/química , Infertilidad Masculina/tratamiento farmacológico , Glucósidos Iridoides/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Barrera Hematotesticular/efectos de los fármacos , Línea Celular , Diterpenos/efectos adversos , Compuestos Epoxi/efectos adversos , Humanos , Inyecciones Intraperitoneales , Masculino , Ratones , Factor 2 Relacionado con NF-E2/genética , Fenantrenos/efectos adversos , Células de Sertoli/efectos de los fármacos , Testículo/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
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.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Diterpenos/efectos adversos , Medicamentos Herbarios Chinos/efectos adversos , Neutrófilos/inmunología , Fenantrenos/efectos adversos , Tripterygium/efectos adversos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Compuestos Epoxi/efectos adversos , Femenino , Humanos , Interleucina-6/genética , Interleucina-6/inmunología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/inmunología , Hígado/efectos de los fármacos , Hígado/inmunología , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Tripterygium/química , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Triptolide (TP), a major extract of the herb Tripterygium wilfordii Hook F (TWHF), has been shown to exert potent pharmacological effects, especially an immunosuppressive effect in the treatment of rheumatoid arthritis (RA). However, its multiorgan toxicity prevents it from being widely used in clinical practice. Recently, several attempts are being performed to reduce TP toxicity. In this review, recent progress in the use of TP for RA, including its pharmacological effects and toxicity, is summarized. Meanwhile, strategies relying on chemical structural modifications, innovative delivery systems, and drug combinations to alleviate the disadvantages of TP are also reviewed. Furthermore, we also discuss the challenges and perspectives in their clinical translation.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Diterpenos/uso terapéutico , Fenantrenos/uso terapéutico , Animales , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Diterpenos/administración & dosificación , Diterpenos/efectos adversos , Evaluación Preclínica de Medicamentos , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/uso terapéutico , Humanos , Fenantrenos/administración & dosificación , Fenantrenos/efectos adversosRESUMEN
OBJECTIVE: To systematically evaluate the effectiveness and safety of Sodium Tanshinone II A Sulfonate Injection (STS) as one adjuvant therapy for treating unstable angina pectoris (UAP). METHODS: Randomized controlled trials (RCTs) of UAP treated by STS were searched in the China National Knowledge Infrastructure Database (CNKI), VIP Database for Chinese Technical Periodicals (VIP), Wanfang Database, the Chinese Biomedical Literature Database (CBM), Web of Science, the Cochrane Library, Embase, and PubMed, which from inception to January, 2016. The Cochrane Risk Assessment Tool was used to evaluate the methodological quality of the RCTs. The Review Manager 5.3 software was used to conduct the metaanalysis. RESULTS: The results showed that 17 RCTs involving 1,372 patients were included. The meta-analysis indicated that the combined use of STS and Western medicine (WM) in the treatment of UAP can obviously improve the total effective rate [risk ratio (RR)=1.31, 95% confidence interval (CI) (1.24,1.39), P<0.0001], and the total effective rate of electrocardiogram [RR=1.43, 95% CI (1.30,1.56), P<0.0001], decrease the level of CRP [mean difference (MD)=-3.06, 95%CI (-3.85,-2.27), P<0.00001], fibrinogen [MD=-1.03, 95% CI (-1.16,-0.89), P<0.00001], and whole blood high shear viscosity [MD=-0.70, 95% CI (-0.92,-0.49), P<0.00001]. Additionally, the occurrence of adverse drug reaction of the experimental group was significantly higher than that of the control group [RR=3.57, 95% CI (1.28, 9.94), P<0.05]. CONCLUSIONS: Compared with WM, the combined use of STS was more effective.
Asunto(s)
Adyuvantes Farmacéuticos/administración & dosificación , Adyuvantes Farmacéuticos/uso terapéutico , Angina Inestable/tratamiento farmacológico , Inyecciones , Fenantrenos/administración & dosificación , Fenantrenos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Angina Inestable/sangre , Angina Inestable/diagnóstico por imagen , Electrocardiografía , Hemorreología , Humanos , Fenantrenos/efectos adversos , Sesgo de PublicaciónRESUMEN
Drug-induced liver injury (DILI) is the most common cause of acute liver failure. Disruption of the Th17/Treg balance can lead to hepatic inflammation, which causes the main symptoms of DILI. Here we investigate the protective mechanisms of (-)-Epigallocatechin-3-gallate (EGCG) on triptolide (TP)-induced DILI that shows the Th17/Treg imbalance. Pretreatment with EGCG (5[Formula: see text]mg/kg) for 10 days before TP (0.5[Formula: see text]mg/kg) administration in mice significantly reduced the increased alanine aminotransferase (ALT) level ([Formula: see text]) induced by TP treatment. The hepatic histology analysis further proved that EGCG protected mice from TP-induced liver injury. The imbalance of Th17/Treg was induced by TP treatment, as shown by the upregulation of TLR4 and downregulation of Tim3 expression. EGCG pretreatment can maintain the expression of TLR4 and Tim3 at normal levels to restore the Th17/Treg imbalance. In addition, EGCG can block the TP-induced expression of the downstream targets of TLR4, including MyD88, NF[Formula: see text]B, and retinoid related orphan receptor (ROR-[Formula: see text]t), while EGCG can restore the TP inhibition of forkhead/winged-helix family transcriptional repressor p3 (FoxP3) that is the downstream target of Tim3. Consequently, EGCG pretreatment can effectively inhibit the Th17-related pro-inflammatory cytokine (e.g. IL-17 and IL-6) upregulation induced by TP treatment. However, TP inhibition of Treg-related anti-inflammatory cytokine IL-10 production was restored by EGCG pretreatment. Taken together, these results suggest that EGCG possesses significant protective properties against TP-induced hepatic inflammatory injury, and that these properties are carried out via the restoration of the Th17/Treg imbalance by the inhibition of the TLR4 signaling pathway and the enhanced activation of the Tim3 signaling pathway.
Asunto(s)
Catequina/análogos & derivados , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Diterpenos/efectos adversos , Inmunosupresores/efectos adversos , Fenantrenos/efectos adversos , Fitoterapia , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Catequina/administración & dosificación , Catequina/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Compuestos Epoxi/efectos adversos , Femenino , Receptor 2 Celular del Virus de la Hepatitis A , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4 , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: The natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer. METHODS: Mice injected subcutaneously with H460 lung cancer cells were treated with MRx102 or carboplatin to determine the effect of MRx102 on tumor formation in comparison to standard treatment. Patient-derived xenografts (PDX) with different WIF1 expression levels were treated with MRx102 or cisplatin. We tested the effects of MRx102 treatment on migration and invasion of lung cancer cells using Transwell filters coated with fibronectin and Matrigel, respectively. Tail vein injections using H460 and A549 cells were performed. RESULTS: Here we report that the triptolide derivative MRx102 significantly decreases NSCLC proliferation and stimulates apoptosis. Further, MRx102 potently inhibits NSCLC haptotactic migration and invasion through Matrigel. In vivo, NSCLC tumor formation and metastasis were greatly decreased by MRx102 treatment. The decrease in tumor formation by MRx102 in the patient-derived xenograft model was WIF1-dependent, demonstrating that MRx102 is a potent inhibitor of the Wnt pathway in low WIF1 expressing NSCLC patient tumors. CONCLUSIONS: These results indicate that MRx102 has potent antitumor effects both in vitro and in vivo, and is a potential novel therapy for the treatment of NSCLC.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Fenantrenos/uso terapéutico , Vía de Señalización Wnt/efectos de los fármacos , Células A549 , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diterpenos/efectos adversos , Diterpenos/uso terapéutico , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/uso terapéutico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Invasividad Neoplásica , Fenantrenos/administración & dosificación , Fenantrenos/efectos adversos , Proteínas Represoras/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Triptolide (TPL) is a diterpene triepoxide with potent immunosuppressive and anti-inflammatory properties. It is the main effective component of the traditional Chinese herb Tripterygium wilfordii Hook F and has been used in China for centuries to treat immune-related disorders. The present study was conducted to investigate the effects of TPL on cardiac remodeling in rats. Age matched male Wistar rats were used in this study. Cardiac remodeling rat model was established by hypodermic injection of isoprenaline for ten days. The rats were treated with TPL (20 or 100 µg/kg/d) for six consecutive weeks. At the end of the study, the cardiac function, collagen volume fraction, perivascular collagen area and hydroxyproline concentration were studied. Echocardiography, Masson staining, immunohistochemistry, western blot and real-time polymerase chain reaction were performed. The protein and mRNA expression of transforming growth factor-ß1 (TGF-ß1), drosophila mothers against decapentaplegic protein 3 (Smad3) and p38 mitogen activated protein kinase (p38 MAPK) were analyzed. The results indicated that TPL treatment significantly reduced the collagen volume fraction, perivascular collagen area, ventricular weight/body weight ratio and hydroxyproline concentration in myocardial tissue compared with the model group. In addition, it also improved the cardiac function. TPL attenuated cardiac remodeling in rats by down-regulating the p38 MAPK and TGF-ß1/Smad3 signaling pathways. TPL treatment significantly attenuated cardiac fibrosis and improved cardiac function through suppressing the p38 MAPK and TGF-ß1/Smad3 signaling pathway in isoprenaline-induced cardiac remodeling rats. Our findings suggested that TPL might be a novel complementary medicine in the treatment of chronic heart failure.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Cardiotónicos/antagonistas & inhibidores , Diterpenos/farmacología , Isoproterenol/antagonistas & inhibidores , Fenantrenos/farmacología , Proteína smad3/fisiología , Factor de Crecimiento Transformador beta1/fisiología , Remodelación Ventricular/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Diterpenos/efectos adversos , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/farmacología , Fibrosis/prevención & control , Hidroxiprolina/metabolismo , Masculino , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Fenantrenos/efectos adversos , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii Hook. f. (Tripterygium wilfordii), also known as Huangteng and gelsemium elegan, is a traditional Chinese medicine that has been marketed in China as Tripterygium wilfordii glycoside tablets. Triptolide (TP), an active component in Tripterygium wilfordii extracts, has been used to treat various diseases, including lupus, cancer, rheumatoid arthritis and nephritic syndrome. This review summarizes recent developments in the research on the pharmacodynamics, pharmacokinetics, pharmacy and toxicology of TP, with a focus on its novel mechanism of reducing toxicity. This review provides insight for future studies on traditional Chinese medicine, a field that is both historically and currently important. MATERIALS AND METHODS: We included studies published primarily within the last five years that were available in online academic databases (e.g., PubMed, Google Scholar, CNKI, SciFinder and Web of Science). RESULTS: TP has a long history of use in China because it displays multiple pharmacological activities, including anti-rheumatism, anti-inflammatory, anti-tumor and neuroprotective properties. It has been widely used for the treatment of various diseases, such as rheumatoid arthritis, nephritic syndrome, lupus, Behcet׳s disease and central nervous system diseases. Recently, numerous breakthroughs have been made in our understanding of the pharmacological efficacy of TP. Although TP has been marketed as a traditional Chinese medicine, its multi-organ toxicity prevents it from being widely used in clinical practice. CONCLUSIONS: Triptolide, a biologically active natural product extracted from the root of Tripterygium wilfordii, has shown promising pharmacological effects, particularly as an anti-tumor agent. Currently, in anti-cancer research, more effort should be devoted to investigating effective anti-tumor targets and confirming the anti-tumor spectrum and clinical indications of novel anti-tumor pro-drugs. To apply TP appropriately, with high efficacy and low toxicity, the safety and non-toxic dose range for specific target organs and diseases should be determined, the altered pathways and mechanisms of exposure need to be clarified, and an early warning system for toxicity needs to be established. With further in-depth study of the efficacy and toxicity of TP, we believe that TP will become a promising multi-use drug with improved clinical efficacy and safety in the future.
Asunto(s)
Diterpenos/farmacología , Medicamentos Herbarios Chinos/farmacología , Fenantrenos/farmacología , Tripterygium/química , Animales , Diterpenos/efectos adversos , Diterpenos/aislamiento & purificación , Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/uso terapéutico , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/aislamiento & purificación , Compuestos Epoxi/farmacología , Etnofarmacología , Humanos , Medicina Tradicional China/métodos , Fenantrenos/efectos adversos , Fenantrenos/aislamiento & purificaciónRESUMEN
The study was designed to investigate the immune-modulatory effects of triptolide (TP) on CD4(+) T cell responses during liver injury. Previous studies have suggested that TP plays a critical role in modulating both innate and adaptive immune reactions, but its effects on the Th17/Treg balance during TP-induced liver injury remain unknown. In this study, female C57BL/6 mice were administered by oral gavage with TP at a dose of 250 or 500 µg/kg per mouse. We examined the plasma biochemical parameters, histopathological changes, hepatic frequencies of Th17 cells and Treg cells, hepatic expression of transcriptional factors and cytokine genes and hepatic interleukin (IL)-17 and IL-10 levels in TP-administered mice. Mice treated with TP displayed liver injury with markedly increased plasma transaminase as well as hepatic mRNA expression of retinoid related orphan receptor (ROR)-γt and hepatic IL-17 level at 24h. However, hepatic frequencies of Tregs and hepatic expression of forkhead/winged-helix family transcriptional repressor p3 (FoxP3) decreased at 24h after TP administration. Furthermore, we found that elevated serum biochemical parameters positively correlated with the Th17/Treg ratios. Taken together, these results revealed a novel and interesting phenomenon of TP in the enhancement of the expansion of Th17 cells and suppression of the production of Tregs during liver injury, which may represent a new pathogenesis of TP-induced liver injury.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Diterpenos/efectos adversos , Inmunosupresores/efectos adversos , Fenantrenos/efectos adversos , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Relación Dosis-Respuesta a Droga , Compuestos Epoxi/efectos adversos , Femenino , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: To explore clinical features the adverse reactions of Tanshinone II(A) Sodium Sulfonate Injection (T II(A) SSI) and their reasons, thus providing reference for rational medication. METHODS: The literatures on adverse reactions and incompatibilities of T II(A) SSI were retrieved (domestic medical journals from January 2000 to December 2011) and statistically analyzed. RESULTS: In the 18 cases of adverse drug reaction (ADR), the clinical manifestations of T II(A) SSI induced adverse reactions were various, involving reactions of appendages and the neuromuscular system (each accounting for 50%). The elderly and women were mainly involved. Many organs and systems were involved. There existed more incompatibilities. CONCLUSION: The medical workers should pay special attention to T II(A) SSI induced adverse reactions, thus avoiding recurrence of ADR, evading risks, and ensuring safe and rational medication.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Fenantrenos/efectos adversos , Adulto , Anciano , Femenino , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Fenantrenos/administración & dosificaciónRESUMEN
Angiogenesis is essential for the survival and growth of most tumors. As such, targeting the tumor neovasculature is an attractive strategy for effective cancer therapy. Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. The functional domain within amino acid residues 120-180 of vasostatin (VAS) has been confirmed to be effective in inhibiting the proliferation, migration, and invasiveness of cancer cells by its suppressive capacity against angiogenesis. Triptolide (TPL) is an active component extracted from the traditional Chinese herbal medicine Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic antitumor activity of TPL and VAS in solid tumor cells. Our results showed that the sensitivity of combined therapy using TPL and VAS was higher than that of monotherapy using TPL or VAS. Apoptosis induced by the combined treatment was accompanied by activation of caspase-9, caspase-8, and caspase-3. Upregulation of proapoptotic protein (Bax, Bak, and Bad) expression and suppression of NF-κB transcriptional activity and its targeting antiapoptotic genes (c-FLIP, cIAP, Bcl-2, Bcl-xl, and Mcl-1) may contribute to the synergistic effects of this combination therapy. Further, using a mouse xenograft model, we demonstrated that combined treatment completely suppressed tumor growth as compared with treatment with TPL or VAS alone. These results suggest that the combination of TPL and VAS at lower concentrations may produce a synergistic antitumor effect that warrants further investigation for its potential clinical applications.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Calreticulina/uso terapéutico , Diterpenos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Fragmentos de Péptidos/uso terapéutico , Fenantrenos/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/genética , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Calreticulina/administración & dosificación , Calreticulina/genética , Calreticulina/farmacología , Línea Celular , Línea Celular Tumoral , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Diterpenos/administración & dosificación , Diterpenos/efectos adversos , Diterpenos/farmacología , Sinergismo Farmacológico , Medicamentos Herbarios Chinos/química , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/farmacología , Compuestos Epoxi/uso terapéutico , Etnofarmacología , Células HCT116 , Humanos , Ratones , Ratones Desnudos , Neoplasias/irrigación sanguínea , Neoplasias/patología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/farmacología , Fenantrenos/administración & dosificación , Fenantrenos/efectos adversos , Fenantrenos/farmacología , Distribución Aleatoria , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Tripterygium/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: To date, Kaposi sarcoma has not been mentioned among the adverse effects of triptolide/tripdiolide, ethyl acetate extracts or polyglycosides of the Chinese herbal remedy Tripterygium wilfordii Hook F. CASE REPORT: A patient was diagnosed with rheumatoid arthritis at the age of 29 years. She underwent treatment with corticosteroids, methotrexate and gold sodium thiosulfate, and was chronically taking ketoprofen. At the age of 59 years she started to take a powder (≈2 g/day) from a Chinese physician for treatment of rheumatoid arthritis. This powder was supplied to her regularly for 10 years. At the age of 69 years, multiple soft, violaceous to dark-red patches, plaques, nodules and blisters of varying sizes appeared on a background of severely edematous skin on her legs, and later on her arms. Biopsy specimens of the leg lesions were diagnostic for human herpesvirus 8-associated Kaposi sarcoma. Triptolide (235 µg/1 g) and tripdiolide were found in the Chinese powder by the use of Liquid Chromatography Electrospray Ionization Mass Spectrometry. Administration of the powder was stopped and medication with paclitaxel was introduced. General condition of the patient improved and skin lesions diminished significantly. CONCLUSIONS: This case indicates a possible association between triptolide/tripdiolide chronic intake and development of human herpesvirus 8-associated Kaposi sarcoma. Triptolide/tripdiolide could contribute to development of Kaposi sarcoma by reactivation of latent human herpesvirus 8, permitted by immunosuppression induced by triptolide.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Diterpenos/efectos adversos , Diterpenos/uso terapéutico , Fenantrenos/efectos adversos , Fenantrenos/uso terapéutico , Sarcoma de Kaposi/inducido químicamente , Neoplasias Cutáneas/inducido químicamente , Adulto , Anciano , Edema/patología , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/uso terapéutico , Femenino , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Pierna/patología , Persona de Mediana Edad , Polvos , Sarcoma de Kaposi/patología , Neoplasias Cutáneas/patologíaRESUMEN
Triptolide, a diterpenoid epoxide, is one of the major active ingredients of Tripterygium wilfordii Hook F, a woody vine plant called lei gong teng in China, which is used in traditional Chinese Medicine (TCM) for treating many diseases. In this paper, we investigate the relation between inhibition of mitochondrial respiratory chain and liver injury induced by triptolide. Results indicate that the secondary ß-oxidation impairment caused by inhibition of mitochondrial respiratory chain is involved in triptolide-induced liver injury, which featured by microvesicular steatosis, hyperlactacidemia and enhanced oxidant stress, although other mechanisms of triptolide-induced liver injury may also exist.
Asunto(s)
Respiración de la Célula/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Diterpenos/efectos adversos , Hígado/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Fenantrenos/efectos adversos , Extractos Vegetales/efectos adversos , Tripterygium/efectos adversos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Compuestos Epoxi/efectos adversos , Hígado Graso/inducido químicamente , Femenino , Ácido Láctico/sangre , Hígado/metabolismo , Membranas Mitocondriales/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Ratas , Ratas Sprague-Dawley , Tripterygium/químicaRESUMEN
Ischemia and reperfusion have been identified as a complex cascade of inflammatory mediators that are involved in the pathogenesis of hepatic injury. Triptolide (diterpenoid triepoxide), was extracted from a purified component of a traditional Chinese Medicine, Tripterygium wilfondii Hook F. Currently, triptolide has been shown to have anti-inflammatory, immunosuppressive, and antineoplastic activity. Accumulated data have shown that Th17 cells might contribute to the pathogenesis of liver diseases. Triptolide has been shown to reduce interleukin (IL)-17 expression in inflammatory bowel disease and arthritis. However, the role of triptolide in liver ischemia/reperfusion (I/R) and whether it can attenuate injury and the potential mechanism have not been investigated. Mice were treated with triptolide (0.1mg/kg) for 1 week or IL-17 antibody (50 µg/mouse) 2 days before ischemic insult. Partial warm ischemia was produced in the hepatic lobes of C57BL/6 mice for 90 min, followed by various periods of reperfusion. We demonstrated that IL-17 was involved in the inflammatory response to hepatic I/R injury, and that triptolide inhibited IL-17 generation and suppressed neutrophil migration after liver I/R injury through downregulation of signal transducer and activator of transcription 3 (STAT3) transcription. Also, triptolide pretreatment protected the liver from warm I/R injury, at least in part, mediated by the upregulation of Foxp3 expression. These results could pave the way for the use of triptolide as a novel agent to attenuate I/R injury.
Asunto(s)
Diterpenos/administración & dosificación , Interleucina-17/metabolismo , Hepatopatías/tratamiento farmacológico , Hígado/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Fenantrenos/administración & dosificación , Fitoterapia , Tripterygium , Animales , Anticuerpos Monoclonales/administración & dosificación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Diterpenos/efectos adversos , Diterpenos/aislamiento & purificación , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/aislamiento & purificación , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Hígado/inmunología , Hígado/metabolismo , Hígado/cirugía , Hepatopatías/inmunología , Hepatopatías/fisiopatología , Ratones , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Fenantrenos/efectos adversos , Fenantrenos/aislamiento & purificación , Daño por Reperfusión/prevención & control , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Tripterygium/inmunologíaRESUMEN
OBJECTIVE: To study the effects of cryptotanshinone on androgen synthesis for the prenatally androgenized male rats. METHODS: On days 16-18 of pregnancy, rats were injected s. c. with testosterone propionas continuously for 3 days; male offspring were studied as subject. Serum concentrations of testosterone (T), 17a-hydroxy progesterone (17-OHP), blood glucose, and insulin were measured by radioimmunoassay. Then, the rats were treated with cryptotanshinone by gavage for 14 days, and the levels of serum T, 17-OHP and insulin were detected and the 17a-hydroxylase protein expression in interstitial cell was measured using the method of immunohistochemistry. RESULTS: There was no difference between the male groups who were prenatally androgenized in serum levels of T, but the 17-OHP, fasting insulin levels and homeostatic model assessment for insulin resistance (HOMA-IR) elevated significantly (P < 0.05). Cryptotanshinone could lower the levels of 17-OHP (P < 0.05) but had no effect on 17a-hydroxylase. CONCLUSION: Prenatally androgenized male rats exhibit elevated 17-OHP and diminished insulin sensitivity. Cryptotanshinone could decrease 17-OHP, but has no effect on insulin, indicating it may reduce androgen synthesis.