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1.
Carbohydr Polym ; 257: 117572, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33541631

RESUMO

Hyaluronic acid (HA)-coated liposomes were designed for the targeted delivery of 17-hydroxy-jolkinolide B (HA-Lip-HJB). HA-Lip-HJB had a particle size of 130.8 ± 1.9 nm, zeta potential of -52.36 ± 1.91 mV, and encapsulation efficiency of 89.2 ± 1.5 %. In vitro cell experiments indicated that modification of HA-Lip-HJB increased its cytotoxicity and cellular uptake via CD44 receptor-mediated endocytosis pathway. Of particular importance is that HA-Lip-HJB suppressed cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) process. Moreover, the HA-Lip-HJB displayed notable growth inhibition on tumor spheroids. Furthermore, in vivo tissue distribution and anti-tumor experiments carried on BALB/C mice bearing 4T1 tumor indicated that HA-Lip-HJB had strong tumor targeting and tumor suppression abilities. The results also demonstrated that HA-Lip-HJB inhibited tumor cells migration and colonization on the lung. Therefore, HA-Lip-HJB is a promising formulation for metastatic breast cancer therapy.


Assuntos
Diterpenos/administração & dosagem , Ácido Hialurônico/química , Lipossomos/química , Neoplasias Mamárias Animais/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Endocitose , Transição Epitelial-Mesenquimal , Feminino , Técnicas In Vitro , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Transplante de Neoplasias , Tamanho da Partícula , Solubilidade , Esferoides Celulares , Água/química
2.
Toxicol Lett ; 342: 85-94, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33600922

RESUMO

Triptolide (TP), an active component of Tripterygium wilfordii Hook. F, has been widely used in China for treating autoimmune and inflammatory diseases, and has also been validated by modern science and developed as a candidate anti-cancer treatment. However, liver toxicity of TP has seriously hindered its use and development, the clinical features and primary toxicological mechanism have been unclear. Considering the major target regulation mechanism of TP is the suppression of global transcription regulated by RNAPII, which is closed related with the detoxification of drugs. This paper tries to verify the synergistic liver injury and its mechanism of TP when co-administered with CYP3A4 substrate drug. The experiments showed that TP dose-dependently blocked transcriptional activation of CYP3A4 in both hPXR and hPXR-CYP3A4 reporter cell lines, lowered the mRNA and protein expression of PXR target genes such as CYP3A1, CYP2B1, and MDR1, and inhibited the functional activity of CYP3A in a time- and concentration-dependent manner in sandwich-cultured rat hepatocytes (SCRH) and female Sprague-Dawley (f-SD) rats. Furthermore, TP combined with atorvastatin (ATR), the substrate of CYP3A4, synergistically enhanced hepatotoxicity in cultured HepG2 and SCRH cells (CI is 0.38 and 0.29, respectively), as well as in f-SD rats, with higher exposure levels of both drugs. These results clearly indicate that TP inhibits PXR-mediated transcriptional activation of CYP3A4, leading to a blockade on the detoxification of itself and ATR, thereby greatly promoting liver injury. This study may implies the key cause of TP related liver injury and provides experimental data for the rational use of TP in a clinical scenario.


Assuntos
Atorvastatina/toxicidade , Citocromo P-450 CYP3A/metabolismo , Diterpenos/toxicidade , Hepatócitos/efeitos dos fármacos , Fenantrenos/toxicidade , Receptor de Pregnano X/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Atorvastatina/administração & dosagem , Atorvastatina/farmacocinética , Citocromo P-450 CYP3A/genética , Diterpenos/administração & dosagem , Diterpenos/farmacocinética , Sinergismo Farmacológico , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/toxicidade , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Fenantrenos/administração & dosagem , Fenantrenos/farmacocinética , Ratos , Ratos Sprague-Dawley
4.
J Ethnopharmacol ; 265: 113294, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32841693

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Siegesbeckiae Herba (SiH) is a traditional anti-rheumatic herbal medicine in China. A SiH derived product, Phynova Joint and Muscle Relief Tablets™, has been granted the UK license in 2015. Although transdermal delivery provides better patient compliance and relative constant plasma drug concentration, the feasibility of transdermal delivery of SiH was not clear. AIM OF THE STUDY: The aim of the present study was to develop a novel transdermal patch containing SiH extract for alternative therapy of rheumatoid arthritis. MATERIALS AND METHODS: SiH extract containing 48.5% (w/w) of kirenol was prepared from Siegesbeckia pubescens Makino. Then transdermal patches containing SiH extract were prepared by the solvent evaporation technique. The formulation of the transdermal patch was optimized based on the in vitro skin permeation experiment. Finally, the anti-inflammatory and analgesic activity of the optimal patch were evaluated by chronic inflammation model induced by complete Freund's adjuvant (CFA) and writhing model induced by acetic acid, separately. RESULTS: Oleic acid (OA) showed the maximum permeation enhancement effect with the enhancement ratio (ER) values of 3.32. Therefore, OA was used as a permeation enhancer in the transdermal patch. The optimal formulation consisted of SiH extract (10% of the matrix, w/w), OA (10% of the matrix, w/w), DURO-TAK® 87-2287 (pressure sensitive adhesive matrix) and Scotchpak™ 9701 (backing layer). The optimal transdermal patch containing SiH extract significantly reduced the degree of paw swelling and number of writhing in inflammation model and writhing model, respectively. CONCLUSIONS: The developed transdermal patch containing Siegesbeckiae Herba extract showed good anti-inflammatory and analgesic effects, which demonstrated a great potential for alternative therapy of rheumatoid arthritis.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Extratos Vegetais/farmacologia , Analgésicos/administração & dosagem , Analgésicos/isolamento & purificação , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antirreumáticos/administração & dosagem , Antirreumáticos/isolamento & purificação , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Asteraceae/química , Diterpenos/administração & dosagem , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Adjuvante de Freund , Masculino , Camundongos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Adesivo Transdérmico
5.
Phytomedicine ; 80: 153377, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33126167

RESUMO

BACKGROUND: Osteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear. PURPOSE: We explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo. METHODS: The in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model. RESULTS: We found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2-10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression. CONCLUSIONS: Kir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis.


Assuntos
Caveolina 1/metabolismo , Diterpenos/farmacologia , Fatores de Transcrição NFATC/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/prevenção & controle , Administração Oral , Animais , Reabsorção Óssea/prevenção & controle , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diterpenos/administração & dosagem , Feminino , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoporose/etiologia , Ovariectomia/efeitos adversos , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Transdução de Sinais/efeitos dos fármacos
6.
J Pharmacol Sci ; 144(4): 189-196, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070837

RESUMO

Pneumonia is a common illness that continues to be the major killer of remaining to be a significant source of morbidity and mortality in the patient population. Many microorganisms cause pneumonia, and now concern is turning to the importance of the cause the new therapies for viral pneumonia. In the current study, we report the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on poly I: C-induced pneumonia. Andrographolide sulfonate was administrated through intraperitoneal injection to mice with poly I: C-induced pneumonia. Recruitment of airway inflammatory cells, alteration of lung histological induced by Poly I: C were significantly ameliorated by andrographolide sulfonate. The protein levels of pro-inflammatory cytokines in bronchoalveolar fluid (BALF) and serum were reduced by andrographolide sulfonate treatment. The levels of MUC5AC and MUC5B in lung tissue were also suppressed. These results reveal that andrographolide sulfate remarkably alleviated pneumonia induced by poly I:C in mice. Moreover, andrographolide sulfonate markedly inhibited the activation of nuclear factor-κB (NF-κB). Taken together, we demonstrated that andrographolide sulfonate ameliorated poly I: C-induced pneumonia in mice, suggesting the possible use of andrographolide sulfonate for virus-induced pneumonia in clinical.


Assuntos
Diterpenos/administração & dosagem , Diterpenos/farmacologia , NF-kappa B/metabolismo , Fitoterapia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Poli I-C/efeitos adversos , Animais , Citocinas/sangue , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Mucina-5AC/metabolismo , Mucina-5B/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia Viral/tratamento farmacológico
7.
Medicine (Baltimore) ; 99(29): e21223, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702892

RESUMO

Lefamulin is a novel pleuromutilin antibiotic with potent in vitro activity against key community-acquired bacterial pneumonia (CABP) pathogens. However, the clinical efficacy and safety of lefamulin for treating CABP remains unclear.An integrated analysis of 2 phase III trials investigating the clinical efficacy and safety of lefamulin vs moxifloxacin in the treatment of CABP was conducted.A total of 1289 patients (lefamulin group: 646 and moxifloxacin group: 643) were included in this analysis. The early clinical response rate was 89.3% and 90.5% among lefamulin and moxifloxacin group, respectively. Lefamulin was noninferior to moxifloxacin (89.3% vs 90.5%, RR: 0.99, 95% CI: 0.95-1.02, I = 0%). In terms of clinical response at test of cure, no significant difference was observed between the lefamulin and moxifloxacin groups (for modified intention to treat population, RR: 0.98, 95% CI: 0.94-1.02, I = 0%; for clinically evaluable population, RR: 0.96, 95% CI: 0.93-1.00, I = 0%). In the subgroup analysis, the early clinical response rate at early clinical assessment and clinical response rate at test of cure of lefamulin was similar to that of moxifloxacin across different subgpopulations and all baseline CABP pathogens. Lefamulin was associated with a similar risk of adverse events as moxifloxacin.Clinical efficacy and tolerability for lefamulin in the treatment of CABP were similar to those for moxifloxacin.


Assuntos
Antibacterianos/uso terapêutico , Diterpenos/uso terapêutico , Moxifloxacina/uso terapêutico , Pneumonia Bacteriana/diagnóstico , Compostos Policíclicos/uso terapêutico , Tioglicolatos/uso terapêutico , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/mortalidade , Diterpenos/administração & dosagem , Diterpenos/farmacologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/isolamento & purificação , Taiwan , Tioglicolatos/administração & dosagem , Tioglicolatos/farmacologia , Resultado do Tratamento
8.
Life Sci ; 252: 117612, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32247004

RESUMO

AIMS: Intestinal mucositis is the most common side effect of 5-fluorouracil (5-Fu) treatment in cancer patients. Previous research suggested that andrographolide (Andro) attenuated the intestinal injury in colitis or diarrhea in mice. The present study was aimed at investigating the protective effect of Andro against 5-Fu induced intestinal mucositis and the underlying mechanism. MAIN METHODS: BALB/C mice were injected 5-Fu at a dose of 100 mg/kg for 5 days to induce intestinal mucositis. Andro at different doses (25, 50, 100 mg/kg/day) was administered. Weight loss, diarrhea score, cellular apoptosis and proliferation were evaluated. Apoptosis related proteins were detected by Western blotting. Then, NCM460 cells were used to explore the possible mechanism in vitro. The effect of Andro on the anti-tumor efficacy of 5-Fu was investigated in H22 tumor-bearing mice. KEY FINDINGS: Andro significantly ameliorated the 5-Fu induced weight loss and diarrhea. The apoptosis of intestinal cells was also attenuated by Andro treatment both in vivo and in vitro. Besides, Andro markedly down-regulated the 5-Fu-induced protein expression of caspase8/3, Bax and the phosphorylation of p38. Moreover, 5-Fu significantly reduced the viability of NCM460 cells, which was restored by the Andro pretreatment. Furthermore, asiatic acid, an agonist of p38 MAPK, reversed the anti-apoptotic effect of Andro in NCM460 cells. Andro did not weaken the anti-H22 tumor effect of 5-Fu in vivo. SIGNIFICANCE: We have demonstrated that p38 MAPK inhibition mediates anti-apoptotic effects of Andro against 5-Fu induced intestinal mucositis, suggesting that Andro may benefit the patients undergoing 5-Fu based chemotherapy.


Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Diterpenos/administração & dosagem , Fluoruracila/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosite/prevenção & controle , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Diarreia/induzido quimicamente , Diarreia/prevenção & controle , Modelos Animais de Doenças , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Fluoruracila/farmacologia , Humanos , Mucosa Intestinal/patologia , Neoplasias Hepáticas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucosite/induzido quimicamente , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Oncol Rep ; 43(6): 1863-1874, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32236588

RESUMO

Lung cancer has one of the highest mortalities of any cancer worldwide. Triptolide (TP) is a promising tumor suppressor extracted from the Chinese herb Tripterygium wilfordii. Our previous proteomics analysis revealed that TP significantly interfered with the ribosome biogenesis pathway; however, the underlying molecular mechanism remains poorly understood. The aim of the present study was to determine the molecular mechanism of TP's anticancer effect by investigating the association between ribosomal stress and p53 activation. It was found that TP induces nucleolar disintegration together with RNA polymerase I (Pol I) and upstream binding factor (UBF) translocation. TP interrupted ribosomal (r)RNA synthesis through inhibition of RNA Pol I and UBF transcriptional activation. TP treatment increased the binding of ribosomal protein L23 (RPL23) to mouse double minute 2 protein (MDM2), resulting in p53 being released from MDM2 and stabilized. Activation of p53 induced apoptosis and cell cycle arrest by enhancing the activation of p53 upregulated modulator of apoptosis, caspase 9 and caspase 3, and suppressing BCL2. In vivo experiments showed that TP significantly reduced xenograft tumor size and increased mouse body weight. Immunohistochemical assays confirmed that TP significantly increased the p53 level and induced nucleolus disintegration, during which nucleolin distribution moved from the nucleolus to the nucleoplasm, and RPL23 clustered at the edge of the cell membrane. Therefore, it was proposed that TP induces ribosomal stress, which leads to nucleolus disintegration, and inhibition of rRNA transcription and synthesis, resulting in increased binding of RPL23 with MDM2. Consequently, p53 is activated, which induces apoptosis and cell cycle arrest.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Diterpenos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Fenantrenos/administração & dosagem , RNA Ribossômico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos Alquilantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/farmacologia , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Ribossômicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Pharmacol Rep ; 72(2): 400-417, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32048269

RESUMO

BACKGROUND: Tanshinone IIA (Tan IIA) and andrographolide (Andro) are natural compounds that are reported to exhibit anticancer activities against various types of cancers. The aim of this study is to evaluate the synergistic anticancer effects of the combination of Tan IIA and Andro, and to investigate the mechanisms of pharmacological effect and their potential applications as an anticancer therapy in clinics. METHODS: The anticancer effects of the combination of Tan IIA and Andro on MCF7, SMMC7721, and BGC823 cells were explored. The apoptosis of the cancer cells was determined by MTT and AV-PI dual stain assays. The intracellular GSH level was measured by DTNB assay, and the intracellular levels of reactive oxygen species (ROS) were examined by flow cytometry. The expression of the proteins in the apoptosis pathway was determined by immunobloting. RESULTS: The combination of Tan IIA and Andro exhibited significant synergistic anticancer effects against cancer cells, especially at low concentrations. Andro reacted with the thiol group of intracellular GSH, thus disrupting the GSH redox cycle and eventually increasing the level of intracellular ROS. Tan IIA triggered p53 responses and apoptosis by binding to the DNA of cancer cells. The crosstalk between ROS and p53 exhibited a synergistic effect on the apoptosis of cancer cells. CONCLUSION: The combination of Tan IIA and Andro showed significant synergistic effects on cancer cell apoptosis by promoting crosstalk between ROS and p53, providing a novel and effective combination that has the potential to be applied in clinical anticancer therapy.


Assuntos
Abietanos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Abietanos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/administração & dosagem , Sinergismo Farmacológico , Humanos , Células MCF-7
11.
Hum Exp Toxicol ; 39(3): 374-383, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31773988

RESUMO

The purpose of this study is to histologically and immunohistochemically determine the changes created by grayanotoxin-III (GTX-III), which is a sodium channel neurotoxin, on heart tissues in different dosages. Rats were randomly divided into 10 groups to determine the acute and chronic effects of GTX-III. While the rats in groups 1 and 6 were control rats, the rats in groups 2-5 (1, 2, 4, and 8 µg/kg bw GTX-III) received a single dose of intraperitoneal GTX-III, and the rats in groups 7-10 received GTX-III every day for 3 weeks. As a result of the trial, in the heart tissues, histopathological changes were determined by hematoxylin-eosin staining, interleukin-1 (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and brain natriuretic peptide (BNP) were determined by the avidin-biotin peroxidase method, and apoptosis was examined by immunohistochemistry (IHC) analysis and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining method. In the immunohistochemistry sense, while the BNP level in the AGTX-III groups did not vary significantly, an increase in dosage significantly increased the IL-6, IL-1ß, and TNF-α levels in comparison to the control groups. In their comparison to the control groups, the BNP levels increase and the IL-6 and IL-1ß levels decreased in the CGTX-III groups. TUNEL analysis revealed that apoptosis increased in both the acute and chronic groups.


Assuntos
Diterpenos/toxicidade , Cardiopatias/induzido quimicamente , Coração/efeitos dos fármacos , Animais , Diterpenos/administração & dosagem , Esquema de Medicação , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
12.
Eur J Pharmacol ; 867: 172836, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811858

RESUMO

Excessive sympathetic activity is associated with heart failure and ventricular arrhythmias, which regulated by enhanced cardiac sympathetic afferent reflex, which can be blunted by resiniferatoxin, a selective receptor agonist of transient vanilloid potential 1 (TRPV1) + primary sensory afferents. The present study is aimed to determine whether intrathecal resiniferatoxin application affect cardiac sympathetic tone and electrophysiology, furtherly create a new effective strategy to prevent lethal arrhythmias in chronic heart failure. Four weeks after coronary artery occlusion to induce heart failure in rats, RTX (2µg/10 µl) or vehicle was injected intrathecally into the T2/T3 interspace. Cardiac sympathetic nerve activities (CSNA) and cardiac electrophysiology were evaluated two weeks later. Intrathecal resiniferatoxin significantly and selectively abolished the afferent markers expression (TRPV1 and calcitonin gene-related peptide) in dorsal horn and reduced overactivated CSNA. Electrophysiological studies revealed that resiniferatoxin administration intrathecally significantly reversed the prolongation of action potential duration (APD) and APD alternan, reduced the inducibilities of ventricular arrhythmias. Moreover, the over-activated calcium handling related protein CaMKII and RyR2 in heart failure was reversed by resiniferatoxin administration. In conclusion, these results firstly demonstrate that central chemo-ablation of the TRPV1+ afferents in spinal cord prevent heart from ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord, which suggest a novel promising therapeutic method for anti-arrhythmia in heart failure.


Assuntos
Arritmias Cardíacas/prevenção & controle , Bloqueio Nervoso Autônomo/métodos , Diterpenos/administração & dosagem , Gânglios Simpáticos/efeitos dos fármacos , Insuficiência Cardíaca/terapia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Modelos Animais de Doenças , Gânglios Simpáticos/fisiopatologia , Coração/efeitos dos fármacos , Coração/inervação , Coração/fisiopatologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Injeções Espinhais , Masculino , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo
13.
Drug Deliv Transl Res ; 10(1): 93-107, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31418132

RESUMO

The metronomic administration of a low-dose cytotoxic agent with no prolonged drug-free breaks is an anti-angiogenic cancer treatment method. The use of nano-formulations in this manner enhances anti-tumor efficacy and reduces toxicity by inhibiting angiogenic activity, reduces adverse effects, and changes the biodistribution of TP in the body, steering TP away from potentially endangering healthy tissues. The present study uses liposomes and Asn-Gly-Arg (NGR) peptide conjugated aminopeptidase N(APN)-targeted liposomes for triptolide (TP), as a model for the investigation of targeted metronomic administration and subsequent effects on the toxicity profile and efficacy of the chemotherapeutic agent. Metronomic NGR-PEG-TP-LPs have been found to have enhanced anti-tumor activity, a phenomenon that is attributed to an increase in angiogenic inhibition properties. In vitro experiments demonstrate that the viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) are obviously suppressed in comparison with that of other treatment groups. In vivo experiments also demonstrate that the anti-tumor efficacy of targeted metronomic administration is superior to that of liposome-administered treatments given at maximum tolerated dose (MTD) schemes, as is evidenced by markedly decreased tumor volume, vessel density, and the volume of circulating endothelial progenitor cells (CEPCs) in serum. Moreover, we observed that the metronomic administration of NGR-PEG-TP-LPs could elevate thrombospondin-1 (TSP-1) expression in tumors, a finding that is consistent with the promotion of TSP-1 secretion specifically from HUVECs. Additionally, metronomic NGR-PEG-TP-LPs have minimal drug-associated toxicity (weight loss, hepatotoxicity and nephrotoxicity in mice). Our research demonstrates the significance of targeted metronomic administration using liposomes for anti-angiogenic cancer therapy.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Diterpenos/administração & dosagem , Fenantrenos/administração & dosagem , Administração Metronômica , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/química , Diterpenos/farmacocinética , Composição de Medicamentos , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Células HCT116 , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipossomos , Camundongos , Oligopeptídeos , Fenantrenos/química , Fenantrenos/farmacocinética , Distribuição Tecidual , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 20(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795079

RESUMO

This article summarizes the histories of six patients with different solid tumors treated with a new strategy based on tumor burden reduction and immune evasion as potential targets. All six patients were at a high risk of relapse and were likely to have a minimal residual disease following conventional therapy: biochemical recurrence (BCR) following radical prostatectomy (RP) (two prostate cancers patients), removal of distant metastases (one colorectal and one breast cancer), and complete response (CR) of distant metastases to conventional therapy (one breast cancer and one esophageal-gastric junction cancer). Four of the patients, two after RP and BCR, one after removal of a single pulmonary metastasis from breast cancer, and one after CR to chemotherapy of peritoneal metastases and ascites from an esophageal-gastric junction primary cancer, regularly received cycles of a new drug schedule with the aim of inhibiting immune suppression (IT). In these four patients, preliminary laboratory tests of peripheral blood suggested an interleukin (IL)-2/IL-12 mediated stimulation of cellular immune response with a concomitant decrease in vascular endothelial growth factor (VEGF) immune suppression. The fifth case was a breast cancer patient with distant metastases in CR, while receiving beta-interferon and interleukin-2 in addition to conventional hormone therapy. To date, all five patients are alive and doing well and they have been unexpectedly disease-free for 201 and 78 months following BCR, 28 months following the removal of a single pulmonary metastases, 32 months following CR to chemotherapy of peritoneal metastases and ascites, and 140 months following diagnosis of multiple bone metastases, respectively. The sixth patient, who had colorectal cancer and multiple synchronous liver metastases and underwent nine surgical interventions for metastatic disease, although not disease-free, is doing well 98 months after primary surgery. Our six cases reports can be interpreted with the hypothesis that immune manipulation and/or a concomitant low tumor burden favored their clinical outcome.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Imunossupressores/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Celecoxib/administração & dosagem , Celecoxib/uso terapêutico , Neoplasias do Colo/patologia , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Diterpenos/administração & dosagem , Diterpenos/uso terapêutico , Feminino , Humanos , Imunossupressores/administração & dosagem , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias da Próstata/patologia , Carga Tumoral , Evasão Tumoral , Vitamina A/administração & dosagem , Vitamina A/análogos & derivados , Vitamina A/uso terapêutico , Vitaminas/administração & dosagem , Vitaminas/uso terapêutico , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/uso terapêutico
15.
Drug Des Devel Ther ; 13: 3963-3975, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819370

RESUMO

Purpose: The aim of this study was to investigate the effects of triptolide on the tooth movement and root resorption in rats during orthodontic treatment. Material and methods: A total of 48 male Wistar rats were divided into three groups of 16 each. The right maxillary first molars of rats were drawn mesially by closed coil nickel-titanium spring with a force of 50 g. The two experimental groups received intraperitoneal injections of triptolide for 14 days at a dose of 15 µg/kg/day and 30 µg/kg/day, respectively. The control group received vehicle injections. After 14 days, the rats were humanely killed. The amount of tooth movement was measured. Eight rats from each group were randomly chosen for analysis of the percentage of root resorption area by scanning electron microscopy. For the remaining eight rats in each group, the H&E staining, tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry analysis were performed. Results: The amount of tooth movement and the ratio of root resorption area were significantly decreased in the triptolide-treated rats. The number of TRAP-positive cells was significantly lower in triptolide-treated groups. Moreover, the expression of nuclear factor kappa B ligand (RANKL) was reduced. In contrast, the expression of osteoprotegerin was significantly up-regulated. In the tension side, the expressions of runt-related transcription factor 2 and osteocalcin were significantly enhanced by triptolide injection. Conclusion: Triptolide injection could arrest orthodontic tooth movement and reduce root resorption in rats via inhibition of osteoclastogenesis. In addition, triptolide may exert a positive effect on osteoblastogenesis.


Assuntos
Diterpenos/uso terapêutico , Aparelhos Ortodônticos Removíveis , Fenantrenos/uso terapêutico , Reabsorção da Raiz/tratamento farmacológico , Técnicas de Movimentação Dentária , Administração Oral , Animais , Modelos Animais de Doenças , Diterpenos/administração & dosagem , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/uso terapêutico , Masculino , Fenantrenos/administração & dosagem , Ratos , Ratos Wistar
16.
EBioMedicine ; 50: 433-441, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810818

RESUMO

BACKGROUND: Tigilanol tiglate, a short-chain diterpene ester, is being developed as intratumoral treatment of a broad range of cancers. We conducted the first-in-human study of intratumoral tigilanol tiglate in patients with solid tumors. METHODS: Tigilanol tiglate was administered in a multicentre, non randomized, single-arm study, with escalating doses beginning with 0·06 mg/m2 in tumors estimated to be at least twice the volume of injection (dose-escalation cohorts). Patients with smaller tumors were assigned to the local effects cohort and received the appropriate dose for tumor size. FINDINGS: Twenty-two patients were enrolled. The maximum dose was 3·6 mg/m2 and the maximum tolerated dose was not reached. There was one report of dose-limiting toxicity (upper airway obstruction), two serious adverse events (upper airway obstruction and septicemia), 160 treatment-emergent adverse events, and no deaths. Injection site reactions in all tumors and tumor types occurred even at the lowest dose. Six of the 22 patients experienced a treatment response, with four of the six patients achieving complete response. INTERPRETATION: Intratumoral tigilanol tiglate was generally well tolerated, the maximum tolerated dose was not reached, and clinical activity was observed in 9 tumor types including complete response in four patients. These results support the continued development of tigilanol tiglate for intratumoral administration. FUNDING: QBiotics Group Limited Brisbane, Queensland, Australia was the sponsor of the study.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Diterpenos/administração & dosagem , Diterpenos/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Diterpenos/efeitos adversos , Monitoramento de Medicamentos , Feminino , Humanos , Injeções Intralesionais , Masculino , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Resultado do Tratamento
18.
Int J Pharm ; 572: 118721, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31626922

RESUMO

Triptolide (TP), a diterpenoid triepoxide that is extracted from the plant Tripterygium wilfordii, has been found to be quite effective for treating many malignant tumors. Although TP was initially considered to be a promising chemotherapeutic agent, its poor solubility and high toxicity limited its potential clinical application. Consequently, we synthesized nanoformulated TP coated with hyaluronic acid (HA) for application in treating breast cancer. Our results showed that TP can prevent tumor progression, but at the cost of significant toxicity. By contrast, using the nanoformulated TP, uptake of drugs into the tumor can be facilitated, which leads to a further increase in efficacy while decreasing systemic toxicity.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Diterpenos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas/administração & dosagem , Fenantrenos/administração & dosagem , Animais , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/química , Diterpenos/toxicidade , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/química , Compostos de Epóxi/toxicidade , Feminino , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/toxicidade , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/toxicidade , Fenantrenos/química , Fenantrenos/toxicidade
19.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614480

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetric polyarthritis with swelling and pain at synovial joints. In RA patients, delayed neutrophil apoptosis amplifies the inflammatory response and massively released neutrophil extracellular traps (NETs) induce tissue damage and provide self-antigens. Andrographolide (AD) is the major active labdane diterpenoid derived from Andrographis paniculata, which has multiple pharmacological effects, including hepatoprotection, anti-angiogenesis, anti-thrombosis, and anti-inflammation. In the present study, we investigated the effect of AD on an adjuvant-induced arthritis (AA) murine model of RA and found that AD alleviated murine arthritis by reducing neutrophil infiltration and NETosis in the ankle joints and relieved the systematic inflammation. In vitro experiments showed that AD accelerated the apoptosis of lipopolysaccharide-activated neutrophils and inhibited autophagy-dependent extracellular traps formation of neutrophils. These findings suggest that AD has considerable potential for RA therapy.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Diterpenos/administração & dosagem , Neutrófilos/citologia , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/imunologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Células Cultivadas , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Diterpenos/farmacologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia
20.
Biomater Sci ; 7(12): 5312-5323, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31617509

RESUMO

Bad water solubility and undesired toxicity of triptolide (TP) still restrict its clinical applications in renal diseases. In this work, well-defined, monodispersed, and uniform-sized TP-encapsulated mesoscale nanoparticles (TP-MNPs) were fabricated through a nanoprecipitation method, which possesses special kidney-targeting capacity, slow-release property, and high-efficiency treatment for renal ischaemia-reperfusion injury (IRI). The TP-MNPs had good cytocompatibility in wide TP concentration (0-500 ng ml-1) and time ranges (6-24 h). Ex vivo organ fluorescence imaging and pharmacokinetic analysis suggested that TP-MNPs possessed excellent kidney-targeting capability with long retention time (7 days). The TP-MNPs with a very low dose of TP (0.01 mg kg-1) could effectively protect the kidney against IRI, while 0.01 mg kg-1 TP was completely ineffective. After treatment with TP-MNPs, the serum creatine, blood urea nitrogen, expression of C3 complement, and phospho-extracellular signal-regulated kinase of renal IRI mice were estimated to be 5.9-, 2.0-, 5.4-, and 2.8-fold lower than those of the mice treated with TP, respectively. Compared with TP, the TP-MNPs exhibited ignorable hepatotoxicity, reproductive toxicity, and immunotoxicity, such as lower alanine aminotransferase (0.5 fold) and aspartate aminotransferase (0.2 fold), and a higher ratio of CD4+/CD8+ (2.2 fold). Thus, the monodispersed and uniform-sized TP-MNPs with special kidney-targeting and slow-release property may pave an avenue for designing a new therapeutic strategy for renal diseases.


Assuntos
Diterpenos/administração & dosagem , Nefropatias/tratamento farmacológico , Rim/química , Fenantrenos/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Complemento C3/metabolismo , Creatinina/sangue , Preparações de Ação Retardada , Modelos Animais de Doenças , Diterpenos/química , Diterpenos/farmacocinética , Relação Dose-Resposta a Droga , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Injeções Intravenosas , Rim/efeitos dos fármacos , Nefropatias/sangue , Masculino , Camundongos , Nanopartículas/química , Fenantrenos/química , Fenantrenos/farmacocinética , Traumatismo por Reperfusão/sangue
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