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1.
Acta Pharmacol Sin ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911638

RESUMO

Geissoschizine methyl ether (GM) is an indole alkaloid isolated from Uncaria rhynchophyll (UR) that has been used for the treatment of epilepsy in traditional Chinese medicine. An early study in a glutamate-induced mouse seizure model demonstrated that GM was one of the active ingredients of UR. In this study, electrophysiological technique was used to explore the mechanism underlying the antiepileptic activity of GM. We first showed that GM (1-30 µmol/L) dose-dependently suppressed the spontaneous firing and prolonged the action potential duration in cultured mouse and rat hippocampal neurons. Given the pivotal roles of ion channels in regulating neuronal excitability, we then examined the effects of GM on both voltage-gated and ligand-gated channels in rat hippocampal neurons. We found that GM is an inhibitor of multiple neuronal channels: GM potently inhibited the voltage-gated sodium (NaV), calcium (CaV), and delayed rectifier potassium (IK) currents, and the ligand-gated nicotinic acetylcholine (nACh) currents with IC50 values in the range of 1.3-13.3 µmol/L. In contrast, GM had little effect on the voltage-gated transient outward potassium currents (IA) and four types of ligand-gated channels (γ-amino butyric acid (GABA), N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainite (AMPA/KA receptors)). The in vivo antiepileptic activity of GM was validated in two electricity-induced seizure models. In the maximal electroshock (MES)-induced mouse seizure model, oral administration of GM (50-100 mg/kg) dose-dependently suppressed generalized tonic-clonic seizures. In 6-Hz-induced mouse seizure model, oral administration of GM (100 mg/kg) reduced treatment-resistant seizures. Thus, we conclude that GM is a promising antiepileptic candidate that inhibits multiple neuronal channels.

2.
Cancer Biomark ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31958078

RESUMO

BACKGROUNDS: Anaplastic thyroid cancer/ATC is highly lethal malignancy without reliable chemotherapeutic drug. Resveratrol possesses anti-ATC activities but encounters resistance in some cases due to certain unknown reason(s). OBJECTIVE: Because signal transducer and activator of transcription/STAT3 signaling is critical for ATC cell survival and the main molecular target of resveratrol, its roles in determining the fates of resveratrol-treated ATC cells were investigated here. METHODS: Human THJ-11T, THJ-16 and THJ-21T ATC cell lines were treated by 100 µM resveratrol and their growth, statuses of STAT3 signaling and STAT3-related gene expression were examined. The relevance of STAT3 activation with resveratrol resistance was elucidated using STAT selective inhibitor AG490. Leukemia inhibitory factor/LIF expression and phosphorylated-STAT3/p-STAT3 nuclear translocation in ATC tissues were immunohistochemically analyzed. RESULTS: Resveratrol inhibited proliferation, p-STAT3 nuclear translocation as well as LIF and STAT3 expression of THJ-16T and THJ-21T but not THJ-21T cells which showed LIF upregulation and more frequent p-STAT3 nuclear translocation. AG490 significantly prevent p-STAT3 nuclear translocation, and reversed the resveratrol tolerance of THJ-11T cells. Immonohistochemical staining revealed 14.3% (4/28) of LIF and 3.6% (1/28) of p-STAT3 detection in noncancerous ATC-surrounding tissues, which increased to 89.5% (17/19) and 52.6% (10/19) respectively among ATC specimens. The correlative analysis indicated the relevance of LIF expression and STAT3 activation (r= 0.825; P< 0.01). CONCLUSIONS: The status of STAT3 activation and LIF expression are closely correlated with the therapeutic effect of resveratrol on ATCs. Frequent LIF upregulation and STAT3 activation are the unfavorable factors of ATCs and the potential targets of anti-ATC therapy.

3.
J Cardiovasc Transl Res ; 13(1): 85-96, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31637585

RESUMO

There are significant differences in clinical presentation and treatment of atrial fibrillation (AF) between women and men. The primary goal of AF management is to restore sinus rhythm and to prevent various complications, including stroke and heart failure. In many areas of AF, such as prevalence, clinical manifestations, morbidity, risk factors, pathophysiology, treatment strategies, and complications, gender-specific variability is observed and needs to be further addressed by large-scale population researches or randomized clinical trials, which help to promote the customization of AF treatment programs, hence to maximize the success rate of AF therapy in both sexes. This review highlights our current understanding of these gender differences in AF and how these differences affect treatment decisions on AF.

4.
Vascul Pharmacol ; 117: 35-44, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30610955

RESUMO

High mobility group box 1 (HMGB1), a critical nonclassical inflammatory cytokine, has been found up-regulated in patients with idiopathic pulmonary arterial hypertension (IPAH), but its role in vascular remodeling of pulmonary hypertension (PH) is still unknown. In present study, we demonstrated that the plasma level of inflammatory cytokine including HMGB1, interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were elevated in hypoxia-induced pulmonary hypertension rats model. Moreover, expressions of HMGB1 and Toll like receptor-4 (TLR4) in pulmonary arteries were obviously up-regulated accompanied with down-regulation of bone morphogenetic protein receptor 2 (BMPR2) signaling, characterized by decline of phosphorylated Smad1/5/8 (p-Smsd1/5/8) and inhibitor of differention 1 (Id1) expression. In cultured primary pulmonary arterial smooth muscle cells (PASMCs), we found that HMGB1 incubation significantly promoted proliferation and migration of PASMCs, down-regulated p-Smsd1/5/8 and Id1 expression, which can be abrogated by HMGB1 inhibitors saquinavir, glycyrrhizn and TLR4 inhibitors TAK-242. Furthermore, saquinavir, glycyrrhizn and TAK-242 treatment significantly attenuated the development of PH in rats by recovering homodynamic parameters, pulmonary vascular remodeling and BMPR2 signaling pathway. In summary, our results suggest that HMGB1/TLR4 signaling promotes hypoxia-induced pulmonary hypertension via suppressing BMPR2 signaling.

5.
Acta Pharmacol Sin ; 40(1): 133-142, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30442987

RESUMO

Berberine, berberrubine, thalifendine, demethyleneberberine, jatrorrhizine, and columbamine are six natural protoberberine alkaloid (PA) compounds that display extensive pharmacological properties and share the same protoberberine molecular skeleton with only slight substitution differences. The oral delivery of most PAs is hindered by their poor bioavailability, which is largely caused by P-glycoprotein (P-gp)-mediated drug efflux. Meanwhile, P-gp undergoes large-scale conformational changes (from an inward-facing to an outward-facing state) when transporting substrates, and these changes might strongly affect the P-gp-binding specificity. To confirm whether these six compounds are substrates of P-gp, to investigate the differences in efflux capacity caused by their trivial structural differences and to reveal the key to increasing their binding affinity to P-gp, we conducted a series of in vivo, in vitro, and in silico assays. Here, we first confirmed that all six compounds were substrates of P-gp by comparing the drug concentrations in wild-type and P-gp-knockout mice in vivo. The efflux capacity (net efflux) ranked as berberrubine > berberine > columbamine ~ jatrorrhizine > thalifendine > demethyleneberberine based on in vitro transport studies in Caco-2 monolayers. Using molecular dynamics simulation and molecular docking techniques, we determined the transport pathways of the six compounds and their binding affinities to P-gp. The results suggested that at the early binding stage, different hydrophobic and electrostatic interactions collectively differentiate the binding affinities of the compounds to P-gp, whereas electrostatic interactions are the main determinant at the late release stage. In addition to hydrophobic interactions, hydrogen bonds play an important role in discriminating the binding affinities.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Berberina/análogos & derivados , Berberina/metabolismo , Animais , Berberina/sangue , Células CACO-2 , Humanos , Ligações de Hidrogênio , Fígado/química , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica
6.
Oxid Med Cell Longev ; 2018: 6235417, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30116486

RESUMO

Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid malignancy without a reliable therapeutic agent. Resveratrol possesses cancer-suppressive effects, while its effect(s) on ATC cells remains unknown. Because oxidative damage caused by increased reactive oxygen species (ROS) is one of the therapeutic effects of anticancer drugs and oxidative stress-caused mitochondria swelling is observed in resveratrol-treated cancer cells, the oxidative statuses and their relevance with resveratrol sensitivities are elucidated using THJ-16T and THJ-11T ATC cells established from two human anaplastic thyroid carcinoma cases. The results revealed that resveratrol-treated THJ-16T rather than THJ-11T cells showed remarkable growth arrest and extensive apoptosis accompanied with the elevated ROS generation and the attenuated superoxide dismutase 2 (SOD2) and catalase (CAT) levels. Mitochondrial impairment and the enhanced caspase-9/caspase-3 activation are found only in resveratrol-sensitive THJ-16T cells. Treatment with the antioxidant N-acetylcysteine (NAC) partly attenuated resveratrol-induced ROS generation and apoptosis of THJ-16T cells. The levels of resveratrol metabolic enzymes (SULT1A1 and SULT1C2) in THJ-16T cells were lower than those in THJ-11T cells and therefore reversely related with resveratrol sensitivities of ATC cells. Our findings demonstrate the ability of resveratrol to increase ROS generation and oxidative-related cellular lesions in resveratrol-sensitive THJ-16T cells presumably through activating the ROS-mitochondrial signal pathway. The levels of SULTs and ROS may reflect the response manners of ATC cells to resveratrol.


Assuntos
Antioxidantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/uso terapêutico , Carcinoma Anaplásico da Tireoide/diagnóstico , Antioxidantes/farmacologia , Humanos , Resveratrol/farmacologia
7.
Zhen Ci Yan Jiu ; 43(6): 388-93, 2018 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-30091547

RESUMO

OBJECTIVE: To analyze the regularity of acupoint selection, main acupoints and theoretical basis in acupuncture treatment of urticaria. METHODS: Papers collected from the time of establishment of each database to September of 2017 were retrieved from databases CNKI, CBM, VIP and WF by using keywords of "acupuncture" "moxibustion" "blood-letting therapy" "autohemotherapy" "cupping" "acupoint catgut embedding" "auricular points" "acupoint injection" "fire-needle" (or red-hot needle), "dermal needle" "needle-embedding" "urticaria" in both Chinese and English. The collected papers were brought into analysis according to the inclusion and exclusion criteria, from which the prescriptions for acupuncture treatment of urticaria were subjected into descriptive statistical analysis, association rule analysis, and cluster analysis by using Access 2010, Clementine 18.0 and Stata software. RESULTS: Outcomes of analysis indicated that the treatment methods of urticaria with acupuncture and moxibustion, with different emphases, may be classified into eight categories. For treating the exterior syndrome of urticaria, acupoints of the Bladder Meridian, Governor Vessel and Conception Vessel were often employed to harmonize Ying and Wei and to dispel the pathogenic wind, while for treating the interior syndrome, acupoints of the Large Intestine Meridian, Spleen Meridian, and Stomach Meridian were usually used to invigorate the spleen to dispel dampness and to regulate blood circulation. The top five frequently used acupoints were Quchi (LI 11), Xuehai (SP 10), Zusanli (ST 36), Sanyinjiao (SP 6) and Geshu (BL 17). It was crucial to make use of the specific acupoints with adequate meridian-qi, such as He-Sea points, Back-Shu points, and Yuan-Primary points. There were some fixed forms in the combination of acupoints, including LI 11, SP 10, Dazhui (GV 14) and auricular Lung, Shenmen, Fengxi, Adrenal gland, which had the highest confidence coefficient for the meridian points and ear acu-points, respectively. The outcomes of cluster analysis about the acupoint prescriptions showed that 12 acupoint groups as the SP 6-Hegu (LI 4)-LI 11-SP 10-ST 36, etc. were frequently used. CONCLUSION: The regularity of acupuncture treatment of urticaria can be discovered using data mining technology, resulting in an in-depth understanding and having a solid theoretical basis.


Assuntos
Meridianos , Urticária , Pontos de Acupuntura , Mineração de Dados , Humanos
8.
Acta Pharmacol Sin ; 39(12): 1923-1934, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29795136

RESUMO

Timosaponin A3, a saponin in Zhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication of Zhimu has been historically regarded as safe, probably associated with the antioxidants it contains. However, the related information on the in vivo levels of timosaponin A3 and antioxidants remained unclear on Zhimu treatments. Therefore, a combination of the in vitro metabolism, including microbiota-mediated and liver-mediated metabolism, and in vivo pharmacokinetics and hepatic disposition, was conducted for three xanthones (neomangiferin, mangiferin, and norathyriol) and three saponins (timosaponin B2, timosaponin B3, and timosaponin A3) on Zhimu treatments. Consequently, following oral administration of Zhimu decoction to rats, those saponins and xanthones were all observed in the plasma with severe liver first-pass effect, where mangiferin was of the maximum exposure. Despite the ignorable content in the herb, timosaponin A3 elicited sizable hepatic exposure as the microbiota-mediated metabolite of saponins in Zhimu. The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes in Zhimu were of limited hepatic exposure. We deduced the hepatic collection of norathyriol, maximum circulating levels of mangiferin, and timosaponin B2 and mangiferin interaction may directly or indirectly contribute to the whole anti-oxidation of Zhimu, and then resisted the timosaponin A3-induced hepatotoxicity. Thus, our study exploratively interpreted the discrepancy between herbal safety and timosaponin A3-induced hepatotoxicity. However, given the considerable levels and slow eliminated rate of timosaponin A3 in the liver, more attention should be paid to the safety on the continuous clinical medication of Zhimu in the future.


Assuntos
Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/efeitos adversos , Saponinas/metabolismo , Esteroides/efeitos adversos , Xantonas/metabolismo , Administração Oral , Animais , Antioxidantes/farmacocinética , Asparagaceae/química , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Saponinas/efeitos adversos , Saponinas/farmacocinética , Esteroides/metabolismo , Esteroides/farmacocinética , Espectrometria de Massas em Tandem/métodos , Xantonas/farmacocinética
9.
Int J Mol Sci ; 19(4)2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29596381

RESUMO

Anaplastic thyroid cancer (ATC) is a highly lethal undifferentiated malignancy without reliable therapies. Retinoic acid (RA) has been employed to promote redifferentiation of thyroid cancers by increasing their I131 uptake and radio-sensitivity, but its effect(s) on ATCs has not yet been ascertained. Likewise, resveratrol induces cancer redifferentiation but, also in this case, its effects on ATCs remain unknown. These issues have been addresses in the current study using three human ATC cell lines (THJ-11T, THJ-16T, and THJ-21T) through multiple experimental approaches. The results reveal that RA exerts a small inhibitory effect on these cell lines. In comparison with normally cultured cells, the total cell number in resveratrol-treated THJ-16T and THJ-21T cultures significantly decreased (p < 0.05), and this effect was accompanied by reduced Cyclin D1 immuno-labeling, increased apoptotic fractions, and distinct caspase-3 activation. Resveratrol failed to inhibit growth but enhanced RA sensitivity of THJ-11T cells, suppressed peroxisome proliferator-activated receptor-ß/δ (PPAR-ß/δ), and upregulated cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor beta (RAR-ß) expression. Increased thyroglobulin (Tg) and E-cadherin levels and appearance of membranous E-cadherin were evidenced in resveratrol-treated THJ-11T cells. Our results demonstrate for the first time: (1) the therapeutic value of resveratrol by itself or in combination with RA in the management of ATCs, (2) the capacity of resveratrol to overcome RA resistance in ATC cells by reprogramming CRABP2/RAR- and fatty acid-binding protein 5 (FABP5)/PPAR-ß/δ-mediated RA signaling, and (3) the redifferentiating potential of resveratrol in ATC cells.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estilbenos/farmacologia , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Tretinoína/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/biossíntese , Resveratrol , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima/efeitos dos fármacos
10.
Histol Histopathol ; 28(3): 337-44, 2013 03.
Artigo em Inglês | MEDLINE | ID: mdl-23348387

RESUMO

Nasal chondromesenchymal hamartoma (NCMH) is an extremely rare benign tumor arising in the sinonasal tract, predominantly involving infants and children. To date, only 27 cases are reported in the international literature and there have been no reported cases of malignant transformation. We present a 40-year-old female patient with nasal obstruction and bloody rhinorrhea. Computed tomography (CT) of the nose and paranasal sinuses confirmed a heterogeneous polypoid soft-tissue mass filling the nasal cavity and extending into the maxillary and ethmoid sinus. The patient underwent a complete radical resection. Histological and immunohistochemical analyses showed a portion of the mass was consistent with typical NCMH. However, some areas of mass exhibited cytological atypia, marked mitotic activity and foci of necrosis. The atypical mesenchymal spindle cells were immunoreactive for vimentin, CD99 and smooth muscle actin (SMA) diffusely. The cartilaginous cells were immunopositive for S-100 protein. Ki-67 index was high in atypical areas, accounting for 50%. A rapid mass recurrence was observed at the original site only 3 months after surgery. The final diagnosis of NCMH with malignant transformation was made. To our knowledge, this is the first report of malignant transformation occurring in an adult with NCMH. Although NCMH commonly develops in the neonate or young infants and exhibits benign histological appearance and favorable prognosis, there is a possibility of malignant transformation in adult patients. Thoroughly histological inspections are suggested to be necessary to accurately diagnose this tumor when it is encountered in adults.


Assuntos
Doenças das Cartilagens/diagnóstico , Transformação Celular Neoplásica/patologia , Hamartoma/diagnóstico , Doenças Nasais/diagnóstico , Adulto , Doenças das Cartilagens/genética , Doenças das Cartilagens/metabolismo , Doenças das Cartilagens/cirurgia , Condrossarcoma Mesenquimal/diagnóstico , Diagnóstico Diferencial , Feminino , Hamartoma/genética , Hamartoma/metabolismo , Hamartoma/cirurgia , Humanos , Hibridização in Situ Fluorescente , Cavidade Nasal/patologia , Cavidade Nasal/cirurgia , Doenças Nasais/genética , Doenças Nasais/metabolismo , Doenças Nasais/cirurgia , Neoplasias Nasais/diagnóstico , Sarcoma/diagnóstico
11.
Virol J ; 8: 494, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22044910

RESUMO

BACKGROUND: Rabbit haemorrhagic disease virus (RHDV), as the pathogeny of Rabbit haemorrhagic disease, can cause a highly infectious and often fatal disease only affecting wild and domestic rabbits. Recent researches revealed that it, as one number of the Caliciviridae, has some specialties in its genome, its reproduction and so on. RESULTS: In this report, we firstly analyzed its genome and two open reading frameworks (ORFs) from this aspect of codon usage bias. Our researches indicated that mutation pressure rather than natural is the most important determinant in RHDV with high codon bias, and the codon usage bias is nearly contrary between ORF1 and ORF2, which is maybe one of factors regulating the expression of VP60 (encoding by ORF1) and VP10 (encoding by ORF2). Furthermore, negative selective constraints on the RHDV whole genome implied that VP10 played an important role in RHDV lifecycle. CONCLUSIONS: We conjectured that VP10 might be beneficial for the replication, release or both of virus by inducing infected cell apoptosis initiate by RHDV. According to the results of the principal component analysis for ORF2 of RSCU, we firstly separated 30 RHDV into two genotypes, and the ENC values indicated ORF1 and ORF2 were independent among the evolution of RHDV.


Assuntos
Biologia Computacional/métodos , Genoma Viral , Vírus da Doença Hemorrágica de Coelhos/genética , RNA Viral/genética , Animais , Códon , Fases de Leitura Aberta , Coelhos , Proteínas Virais/genética
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