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1.
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
2.
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
3.
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
5.
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
6.
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
7.
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
8.
Food Funct ; 10(10): 6556-6567, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31549110

RESUMO

Postmenopausal osteoporosis (PMO) is a progressive disease occurring in elderly postmenopausal women that is characterized by low bone mass and impaired bone quality. Sclareol is a natural product (initially isolated from the leaves and flowers of Salvia Sclarea) that possesses immune-regulation and anti-inflammatory effects, but its role in osteoclastic formation and function as well as the PMO remains unknown. In the current study, we investigated the inhibitory effect of sclareol on osteoclastogenesis and progression of PMO. In vitro, sclareol not only inhibited osteoclast formation but also suppressed osteoclast function. The expression of the receptor activator of NF-κB ligand (RANKL)-induced osteoclast marker gene and protein was also reduced by sclareol treatment. Mechanistically, we found that sclareol inhibits RANKL-induced NF-κB and MAPK/ERK pathway activation. Furthermore, sclareol exerted a protective effect against bone loss in an ovariectomy-induced mouse model. Taken together, our findings suggest that sclareol has potential value as a therapeutic agent for PMO.


Assuntos
Diterpenos/administração & dosagem , NF-kappa B/metabolismo , Osteoporose Pós-Menopausa/prevenção & controle , Animais , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/fisiopatologia
10.
Drug Des Devel Ther ; 13: 2619-2632, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534311

RESUMO

Objective: The aim was to investigate the role and potential mechanism of geranylgeranylacetone (GGA) in the development of atherosclerosis, and to explore the role of heat shock protein 22 (HSP22) in mediating GGA effect. Methods: Human coronary artery endothelial cell (HCAEC) was used for in vitro study. RNA interference was applied to suppress HSP22 in the cells. Cellular apoptosis and intracellular level of reactive oxygen species (ROS) were detected by flow cytometer, and proteins of HSP22, NF-κB, eNOS, and ICAM-1 were assessed by immunoblotting. HSP22-/-//ApoE-/-, and HSP22+/+//ApoE-/- mice were used to investigate the effect of GGA in the animal model of atherosclerosis. Atherosclerotic lesion of the mice aortas was evaluated by Oil Red O staining and H&E staining. Results: GGA significantly inhibited HCAEC apoptosis in response to oxidized-LDL (ox-LDL), but stimulated HSP22 synthesis in the cells. Transfection of HSP22-siRNA in the cells resulted in complete blockage of the GGA effect on apoptosis. GGA also significantly inhibited ROS, NF-κB, and ICAM-1 in the cells transfected control siRNA, but not in the cells transfected with HSP22-siRNA. Atherosclerotic plaque in the aorta was significantly less in the wild type (WT) animals treated with GGA as stained either by Oil Red O or by H&E staining, but not in the HSP22-KO mice. GGA significantly inhibited expression of NF-κB and ICAM-1 in the WT mice, but not in the HSP22-KO mice. Conclusion: GGA-induced HSP22, and inhibited ox-LDL-induced apoptosis as well as expression of NF-κB and ICAM-1 in the HCAECs. GGA also attenuated formation of atherosclerotic plaques in mice aorta. Suppression of HSP22 by siRNA resulted in blockage of the GGA inhibition on apoptosis or stimulation on NF-κB and ICAM-1. These findings suggested that GGA protects endothelial cells from injury in response to ox-LDL and block atherosclerotic development in mice aorta through induction of HSP22.


Assuntos
Diterpenos/farmacologia , Proteínas de Choque Térmico/metabolismo , Lipoproteínas LDL/antagonistas & inibidores , Chaperonas Moleculares/metabolismo , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Diterpenos/administração & dosagem , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/administração & dosagem
11.
Phytomedicine ; 63: 153009, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301540

RESUMO

BACKGROUND: Considering the limitations of conventional western treatment for community-acquired pneumonia (CAP) and the extensive exploration of Chinese herbal injections (CHIs), systematically and critically evaluating the efficacy of CHIs in the treatment of CAP is necessary. PURPOSE: This study constructed a network meta-analysis (NMA) to investigate the efficacy of CHIs (including the Reduning injection (RDN), Yanhuning injection (YHN), Xiyanping injection (XYP), and Tanreqing injection (TRQ)) combined with Western medicine (WM) and WM alone in CAP. METHODS: A literature review was conducted in several databases from inception to June 2018. The quality of the included studies was assessed by the Cochrane risk of bias tool and modified Jadad scale. Data were analyzed by STATA 13.0 and WinBUGS 14.0 software. Surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the examined treatments. Clustering analysis was utilized to compare the effect of CHIs between two different outcomes. RESULTS: A total of 47 eligible randomized controlled trials involving 4713 patients and 4 CHIs were included. The results of the NMA showed that RDN, YHN, XYP and TRQ combined with WM significantly improved treatment performance compared to WM alone. YHN+WM had obvious superiorities in the clinical effective rate, time for the disappearance of cough and the level of C-reactive protein. TRQ+WM was the most advantageous in shortening the time for defervescence and the average hospitalization time. XYP+WM was shown to reduce the time for the disappearance of lung rales best. Sixteen articles reported adverse drug reactions/adverse drug events (ADRs/ADEs) in detail, and 17 articles reported that there were no obvious ADRs/ADEs. CONCLUSION: This NMA showed that using CHIs in combination with WM improved treatment performance and could be beneficial for patients with CAP compared to using WM alone. Thereinto, YHN+WM showed a preferable improvement on patients with CAP when unified considering the clinical effective rate and other outcomes. As for safety, more evidence is needed to support this hypothesis.


Assuntos
Infecções Comunitárias Adquiridas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Pneumonia/tratamento farmacológico , Teorema de Bayes , Tosse/tratamento farmacológico , Diterpenos/administração & dosagem , Diterpenos/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Injeções , Tempo de Internação , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
12.
Biomed Chromatogr ; 33(11): e4649, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31301694

RESUMO

Rhodojaponin III is a bioactive diterpenoid isolated from the medicinal plant Rhododendron molle G. Don. Quantitative analysis of rhodojaponin III was challenging and the pharmacokinetics of oral rhodojaponin III remained to be investigated. Here, a rapid and sensitive liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated. The calibration curve was linear over the concentration range of 1-200 ng/mL (r = 0.992). The method was further validated following internationally approved guidelines and all the issues including intra- and inter-day precision, accuracy, carryover, extraction recovery, matrix effects and stability met the recommended limits. The method was then applied to study the pharmacokinetics of rhodojaponin III in mice after intravenous (0.06 mg/kg) or oral (0.24 mg/kg) administration. The results showed that rhodojaponin III had fast oral absorption (time to peak concentration, 0.08 h) and good oral bioavailability (73.6%). In addition, rhodojaponin III was quickly eliminated after it was intravenously or orally administered, with half-life values of 0.19 and 0.76 h, respectively. After oral administration, it was widely distributed in tissues including kidney, lung, heart, spleen and thymus, but had extremely low concentrations in liver and brain. The data presented in this study is beneficial for the further study of rhodojaponin III.


Assuntos
Diterpenos , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida/métodos , Diterpenos/administração & dosagem , Diterpenos/análise , Diterpenos/farmacocinética , Feminino , Injeções Intravenosas , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual
13.
Nutrients ; 11(6)2019 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-31234581

RESUMO

The bioaccessibility, metabolism, and excretion of lipids composing spent coffee grounds (SCGs) were investigated. An analysis of mycotoxins and an acute toxicity study in rats were performed for safety evaluation. Total fat, fatty acids, and diterpenes (cafestol and kahweol) were determined in SCGs and their digests obtained in vitro. A pilot repeated intake study was carried out in Wistar rats using a dose of 1 g SCGs/kg b.w. for 28 days. Fat metabolism was evaluated by analysis of total fat, cholesterol, and histology in liver. The dietary fiber effect of SCGs was measured radiographically. The absence of mycotoxins and toxicity was reported in SCGs. A total of 77% of unsaturated fatty acids and low amounts of kahweol (7.09 µg/g) and cafestol (414.39 µg/g) were bioaccessible after in vitro digestion. A significantly lower (p < 0.1) accumulation of lipids in the liver and a higher excretion of these in feces was found in rats treated with SCGs for 28 days. No lipid droplets or liver damage were observed by histology. SCGs acutely accelerated intestinal motility in rats. SCGs might be considered a sustainable, safe, and healthy food ingredient with potential for preventing hepatic steatosis due to their effect as dietary fiber with a high fat-holding capacity.


Assuntos
Coffea/metabolismo , Diterpenos/metabolismo , Ácidos Graxos/metabolismo , Sementes/metabolismo , Animais , Disponibilidade Biológica , Biotransformação , Coffea/toxicidade , Diterpenos/administração & dosagem , Ácidos Graxos/administração & dosagem , Fezes/química , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Eliminação Intestinal , Fígado/metabolismo , Masculino , Projetos Piloto , Ratos Wistar , Sementes/toxicidade , Fatores de Tempo
14.
Neurourol Urodyn ; 38(6): 1540-1550, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31180583

RESUMO

OBJECTIVES: To investigate if intravesical administration during spinal shock of resiniferatoxin (RTX), an ultrapotent desensitizing agonist of transient receptor potential vanilloid-1 (TRPV1), would silence TRPV1-expressing bladder afferents at an early stage of disease progression and modulate neurogenic detrusor overactivity (NDO) emergence. MATERIALS AND METHODS: Rats submitted to largely incomplete spinal cord transection at T8/9 spinal segment were treated with intravesical RTX (50 nM) or its vehicle during spinal shock. Four weeks after spinal lesion, bladder-reflex activity was evaluated by cystometry under urethane anesthesia, after which the bladder, spinal cord, and dorsal root ganglia were collected and processed. RESULTS: We found improvements on bladder function several weeks after early intravesical RTX administration, including a marked decrease of intravesical pressures and amplitude of bladder contractions. Such strong long-lasting urodynamic effects resulted from the very potent desensitizing activity of RTX on peripheral terminals of sensory afferents, an effect restricted to the bladder. CONCLUSION: Our results support that an early intervention with RTX could potentially attenuate NDO development and ensuing urinary incontinence, with a dramatic impact on the quality of life of spinal cord injury patients.


Assuntos
Diterpenos/uso terapêutico , Traumatismos da Medula Espinal/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologia , Administração Intravesical , Animais , Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Diterpenos/administração & dosagem , Feminino , Proteína GAP-43/biossíntese , Gânglios Espinais/diagnóstico por imagem , Neurônios Aferentes , Ratos , Ratos Wistar , Reflexo , Traumatismos da Medula Espinal/fisiopatologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/biossíntese , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Urodinâmica/efeitos dos fármacos
15.
Biomed Pharmacother ; 115: 108899, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31063955

RESUMO

BACKGROUND: Hydroxycamptothecin (HCPT) is used as a clinical chemotherapy regimen to treat bladder cancer, but more efficacious novel combination treatments are needed. METHODS: Cultured bladder cancer cell lines EJ and UMUC3 were treated with triptolide (TPL) and/or HCPT. A flow cytometry approach was used to detect cell cycle phase, apoptosis and reactive oxygen species. Western blotting was used to measure CDK4, CDK6, CyclinD1, catalase, Caspase8 and Bcl-xl protein levels in control, TPL treatment, HCPT treatment and TPL plus HCPT treatment bladder cancer cells. AKT pathway proteins, including AKT and p-AKT, were also detected by western blotting. UMUC3 cells treated with DMSO, HCPT, TPL and HCPT plus TPL were injected subcutaneously into mice (n = 3 per group). RESULTS: The flow cytometry and western blot results indicated that compared to TPL or HCPT treatment alone, combination treatment of HCPT and TPL significantly induced cell cycle arrest at the G1 phase via suppressing CDK4, CDK6 and CyclinD1 in the EJ and UMUC3 bladder cancer cell lines. HCPT and TPL combination treatment also significantly increased the apoptosis rate and apoptosis-related protein levels (Caspase8 and Bcl-xl). Levels of the AKT pathway-related proteins AKT/p-AKT were significantly lower in EJ and UMUC3 cells treated with TPL and UMUC3 than in those cells treated with TPL or HCPT alone. TPL plus HCPT treatment significantly reduced bladder tumour sizes in vivo on the seventh and tenth days. CONCLUSIONS: Compared to TPL or HCPT treatment alone, TPL plus HCPT combination treatment had significantly better anticancer effects.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Fenantrenos/farmacologia , Neoplasias da Bexiga Urinária/patologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/administração & dosagem , Sinergismo Farmacológico , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Fenantrenos/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Vet Pharmacol Ther ; 42(4): 447-451, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102285

RESUMO

The bioavailability and pharmacokinetic disposition of tiamulin in broiler chicken were investigated after administration through the crop, drinking water, and feed at 40 mg/kg body weight. Residues of tiamulin in tissues of broiler chicken were also assessed. Plasma and tissue concentrations of tiamulin were analyzed by reverse-phase high-performance liquid chromatography (HPLC) method. Plasma concentration-time data were described by the non-compartmental model for all three routes, and pharmacokinetic parameters were calculated. There were no significant differences (p > 0.05) in pharmacokinetic parameters and mean plasma concentrations of tiamulin between three routes tested (crop, water, and feed), indicating equal efficacy. Tiamulin residues in edible tissues (muscles, skin, and fat) were lower than the advocated maximum residue limit (MRL of 0.1 µg/g and that of liver was 1 µg/g) on the 3rd day. No traces were found on the 5th day after drug administration. This indicated that the withdrawal period (less than 5 days) is very short, which makes it safer. This study shows that tiamulin can be used with equal efficacy through all routes of administration in broiler chicken (crop, water, and feed).


Assuntos
Antibacterianos/farmacocinética , Galinhas/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Disponibilidade Biológica , Galinhas/sangue , Diterpenos/administração & dosagem , Diterpenos/sangue , Diterpenos/farmacocinética , Vias de Administração de Medicamentos , Resíduos de Drogas , Farmacorresistência Bacteriana , Meia-Vida , Mycoplasma gallisepticum/efeitos dos fármacos
17.
J Med Food ; 22(5): 469-478, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084539

RESUMO

Aging and lifestyle factors, including high-sugar and high-fat diets, promote a systemic metabolic imbalance that promotes neurodegeneration. Hericium erinaceus has long been used in traditional Chinese medicine. Recently, its functional activities, such as antimetabolic dysfunction, antineuroinflammatory activities, and stimulation of nerve growth factor (NGF) synthesis, have been revealed. This study demonstrated that Hericium erinaceus mycelium (HEM) and an isolated diterpenoid derivative, erinacine A (EA), may reverse spatial learning disabilities in aging mice (15 months old) fed with a high-fat and high-sucrose diet (HFSD). Aging mice were randomly assigned to one of four treatment groups: (1) a chow diet (control), (2) an HFSD, and an HFSD supplemented with either (3) HEM or (4) EA for 18 weeks. The Morris water maze (MWM) and Y-maze were used for behavioral assessments. Both HEM- and EA-treated mice had shorter mean daily escape latencies than HFSD-treated mice in the MWM. In addition, HEM-treated mice had a slightly increased exploratory time and frequency in the novel arm in the Y-maze. Quantitative PCR revealed that both HEM- and EA-treated mice exhibited reduced messenger RNA (mRNA) expression of tumor necrosis factor-α, interleukin-1ß, and HEM-treated mice exhibited increased mRNA expression of NGF and NeuN in the hippocampus. Moreover, HEM and EA also decreased body weight, abdominal fat, plasma glucose, serum and liver total cholesterol, and liver triacylglycerol. Thus, HEM may be a potential health-promoting supplement for minimizing the progression of aging and obesity-induced neurodegeneration by reducing metabolic abnormalities and neuroinflammatory cytokines and increasing neurogenesis factors.


Assuntos
Envelhecimento/efeitos dos fármacos , Basidiomycota/química , Dieta Hiperlipídica/efeitos adversos , Diterpenos/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Sacarose/efeitos adversos , Envelhecimento/metabolismo , Envelhecimento/psicologia , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Aprendizagem em Labirinto , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Micélio/química , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Aprendizagem Espacial/efeitos dos fármacos
18.
Eur J Med Chem ; 176: 21-40, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091478

RESUMO

Male late-onset hypogonadism (LOH) is reported as one of the most common age-related diseases occurred in middle-aging men. Testosterone replacement therapy (TRT) is currently the main clinical treatment for LOH, however it has obvious side effects. A 2-methylpyrimidine-fused tricyclic diterpene analog 7 was afforded as anti-LOH hit, which was screened out from our small synthetic library. Then a series of derivates were designed and synthesized based on the hit and their effects in promoting testosterone production and cytotoxicities were evaluated in mouse TM3 Leydig cells. The most potent and safe compound 29 (SH379) was obtained, which significantly promoted the expression of the key testosterone synthesis-related enzymes StAR and 3ß-HSD. Further studies discovered that 29 could stimulate autophagy through regulating AMPK/mTOR signaling pathway. More importantly, 29 increased the testosterone levels and the sperm viability and motility in PADAM (partial androgen deficiency in aging males) rats obviously and displayed almost no side effects. Furthermore, Preliminary pharmacokinetics evaluation also indicated an excellent oral bioavailability of 29. Therefore, these methylpyrimidine-fused tricyclic diterpene analogs could be used as leads for the development of a new type of potential anti-LOH agent.


Assuntos
Diterpenos/uso terapêutico , Hipogonadismo/tratamento farmacológico , Pirimidinas/uso terapêutico , Testosterona/metabolismo , 3-Hidroxiesteroide Desidrogenases/metabolismo , Administração Oral , Animais , Linhagem Celular , Diterpenos/administração & dosagem , Diterpenos/síntese química , Diterpenos/toxicidade , Humanos , Masculino , Camundongos , Estrutura Molecular , Fosfoproteínas/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/toxicidade , Ratos Sprague-Dawley , Glândulas Seminais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Testículo/efeitos dos fármacos , Testículo/patologia
20.
Photodiagnosis Photodyn Ther ; 27: 34-38, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31141728

RESUMO

BACKGROUND: Field-directed therapy, such as daylight-photodynamic therapy (DL-PDT) or ingenol mebutate (IM), is indicated for multiple actinic keratosis (AK) lesions located on contiguous areas of skin with significant sun damage. OBJECTIVE: To compare the efficacy of sequential DL-PDT and IM treatment with that of 2 sessions of DL-PDT in AK patients. MATERIAL AND METHODS: For this observational, multicenter, prospective study we recruited patients for whom DL-PDT was indicated for the treatment of AK lesions (grades I and II) located on the head. After 1 month of follow-up those who did not achieve a satisfactory clinical response received either a second session of DL-PDT or were treated with IM. Epidemiological and clinical data were collected and analyzed. RESULTS: Forty-three patients were enrolled (39 male, 4 female). The mean (standard deviation, SD) age was 78 (7.84) years, and the mean (SD) number of AK lesions per patient was 9.58 (1.16). After the first session of DL-PDT, 27 patients (62.8%) required further treatment: 13 (48.1%) received a second session of DL-PDT and 14 (51.9%) were treated with IM. After 1 year of follow-up, lesion clearance rates were higher in patients who received 2 sessions of DL-PDT than those treated with sequential DL-PDT plus IM (75.2%vs 54.6%, p = 0.0013). Local skin reactions were more frequent in the DL-PDT plus IM group than the group treated with 2 sessions of DL-PDT (p = 0.0245). CONCLUSIONS: The combination of DL-PDT plus IM appears to have no synergistic effect in the treatment of field cancerization, and offers no benefits over 2 sessions of DL-PDT monotherapy, although both combinations produced high lesion clearance rates, a good safety profile, excellent cosmetic outcome, and good patient satisfaction.


Assuntos
Ácido Aminolevulínico/análogos & derivados , Diterpenos/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Luz Solar , Idoso , Idoso de 80 Anos ou mais , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/uso terapêutico , Diterpenos/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Masculino , Satisfação do Paciente , Fármacos Fotossensibilizantes/administração & dosagem , Projetos Piloto , Estudos Prospectivos
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