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1.
Chem Biodivers ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32212241

RESUMO

Three new indole diketopiperazine alkaloids, 11-methylneoechinulin E ( 1 ) and variecolorin M ( 2 ), and (+)-Variecolorin G ( 3a ), along with 12 known analogues ( 3b - 14 ), were isolated from a soft coral-associated epiphytic fungus Aspergillus sp. EGF 15-0-3. The structures of the new compounds were unambiguously established by extensive spectroscopic analyses including HRESIMS, 1D and 2D NMR spectroscopy and optical rotation measurements. The absolute configurations of 3a and 3b were determined by experimental and quantum-chemical ECD investigations and single- crystal X-ray diffraction analysis. 3 is a pair of enantiomeric mixtures with a ratio of 1:2. Moreover, 9 is firstly reported as a natural product. The cytotoxic activities of all the isolated compounds against NCI-H1975 gefitinib resistance (NCI-H1975/GR) cell lines were preliminarily evaluated by MTT method.

2.
J Viral Hepat ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32048386

RESUMO

Not all treatment-naïve patients receiving entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy can achieve complete virological response, and many factors may be related with the outcome of partial virological response. This study aimed to determine whether the manner of drug administration affects the antiviral efficacy of ETV/TDF monotherapy. All eligible patients were divided into complete or partial response cohorts based on their virological response following 24-week therapy. Factors related with partial response were evaluated. Patients with partial response were further grouped depending on whether they later adjusted the manner of drug administration, and the antiviral efficacy was compared between the two groups during prolonged treatment. A total of 518 patients were enrolled. Suboptimal drug administration (OR 77.511, P = .000), positive-HBeAg (OR 3.191, P = .000) and ETV treatment (OR 2.537, P = .001) were identified as independent risk factors for partial response. Among patients with partial response, 213 were in the adjusted group and 76 were in the unadjusted group. The percentages of patients with undetectable serum HBV DNA (78.9% vs 31.6%, P < .001) and with normal alanine aminotransferase (ALT) (88.7% vs 68.4%, P < .001) were both higher in the adjusted group than that in unadjusted group following a further 6-month therapy. In conclusion, the manner of drug administration is an important factor influencing the efficacy of ETV/TDF therapy, and optimal drug administration manner can help to increase antiviral efficacy and rescue patients with partial response.

3.
J Med Virol ; 92(3): 302-308, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31609007

RESUMO

AIMS: The aim of this retrospective study was to compare the efficacy and safety of tenofovir disoproxil fumarate (TDF) monotherapy and TDF + entecavir (ETV) combination therapy for chronic hepatitis B (CHB) patients with the partial virological response (PVR) to ETV. METHODS: CHB patients with PVR to ETV were switched to TDF monotherapy or TDF + ETV combination therapy. The primary efficacy outcome was a virological response (VR), and the secondary efficacy outcomes were hepatitis B e antigen (HBeAg) seroconversion and alanine aminotransferase (ALT) normalization. The primary safety outcomes were changes in serum creatinine and serum phosphorus levels. RESULTS: A total of 143 patients were investigated, including 63 patients in the TDF monotherapy group and 80 patients in the TDF + ETV combination therapy group. Baseline demographics and clinical characteristics were comparable between groups. The median age of patients was 44.5 years, and 76.2% of them were male. The VR rate in TDF + ETV group was higher than that of the TDF group at 48 weeks (88.8% vs 71.4%; P = .009). At 48 weeks, the HBeAg seroconversion rate of TDF + ETV group was higher than that of the TDF group (30% vs 15.9%; P = .049). There was no significant difference in the proportion of patients with elevated ALT in the TDF group and TDF + ETV group at 48 weeks (9.5% vs 7.5%; P = .665). After adjusting the treatment regimen, serum creatinine levels increased slightly and serum phosphorus level decreased slightly in both groups. CONCLUSIONS: TDF + ETV combination therapy for 48 weeks had a higher VR rate than TDF monotherapy in CHB patients with PVR to ETV.

4.
Oxid Med Cell Longev ; 2019: 1243215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871537

RESUMO

Excessive fructose consumption induces oxidative stress and myocardial fibrosis. Antioxidant compound pterostilbene has cardioprotective effect in experimental animals. This study is aimed at investigating how fructose drove fibrotic responses via oxidative stress in cardiomyocytes and explored the attenuation mechanisms of pterostilbene. We observed fructose-induced myocardial hypertrophy and fibrosis with ROS overproduction in rats. Paired-like homeodomain 2 (Pitx2c) increase, microRNA-15b (miR-15b) low expression, and p53 phosphorylation (p-p53) upregulation, as well as activation of transforming growth factor-ß1 (TGF-ß1)/drosophila mothers against DPP homolog (Smads) signaling and connective tissue growth factor (CTGF) induction, were also detected in fructose-fed rat hearts and fructose-exposed rat myocardial cell line H9c2 cells. The results from p53 siRNA or TGF-ß1 siRNA transfection showed that TGF-ß1-induced upregulation of CTGF expression and p-p53 activated TGF-ß1/Smads signaling in fructose-exposed H9c2 cells. Of note, Pitx2c negatively modulated miR-15b expression via binding to the upstream of the miR-15b genetic loci by chromatin immunoprecipitation and transfection analysis with pEX1-Pitx2c plasmid and Pitx2c siRNA, respectively. In H9c2 cells pretreated with ROS scavenger N-acetylcysteine, or transfected with miR-15b mimic and inhibitor, fructose-induced cardiac ROS overload could drive Pitx2c-mediated miR-15b low expression, then cause p-p53-activated TGF-ß1/Smads signaling and CTGF induction in myocardial fibrosis. We also found that pterostilbene significantly improved myocardial hypertrophy and fibrosis in fructose-fed rats and fructose-exposed H9c2 cells. Pterostilbene reduced cardiac ROS to block Pitx2c-mediated miR-15b low expression and p-p53-dependent TGF-ß1/Smads signaling activation and CTGF induction in high fructose-induced myocardial fibrosis. These results firstly demonstrated that the ROS-driven Pitx2c/miR-15b pathway was required for p-p53-dependent TGF-ß1/Smads signaling activation in fructose-induced myocardial fibrosis. Pterostilbene protected against high fructose-induced myocardial fibrosis through the inhibition of Pitx2c/miR-15b pathway to suppress p-p53-activated TGF-ß1/Smads signaling, warranting the consideration of Pitx2c/miR-15b pathway as a therapeutic target in myocardial fibrosis.

5.
Chin J Nat Med ; 17(12): 918-923, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31882046

RESUMO

Four new corynanthe-type alkaloids, meloslines C-F (1-4), together with four known ones (5-8) were isolated from the roots of Alstonia scholaris. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation. Compounds 1 and 2 exhibited potent vasorelaxant activity on endothelium-intact renal arteries precontracted with KCl.

6.
ACS Chem Biol ; 14(12): 2546-2552, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31742988

RESUMO

Affinity-based protein profiling has proven to be a powerful method in target identification of bioactive molecules. Here, this technology was applied in two photoreactive anticancer inhibitors, arenobufagin and HM30181. Using UV irradiation, these photoreactive reagents can covalently cross-link to target proteins, leading to a covalent binding with target proteins. Moreover, the cellular on/off targets of these two molecules, including ATP1A1, MDR1, PARP1, DDX5, NOP2, RAB6A, and ERGIC1 were first identified by affinity-based protein profiling and bioimaging approaches. The protein hit, PARP1, was further validated to be involved in the function of the anticancer effects.

7.
Diabetol Metab Syndr ; 11: 79, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572498

RESUMO

Background: Fibroblast growth factor 19 (FGF19) takes part in maintaining the balance of glycolipids and may be involved in regulating the secretory activity of islet beta cells in patients with type 2 diabetes. This study aimed to evaluate the relationship between the levels of serum FGF19 and endogenous islet beta cell function in type 2 diabetic patients. Methods: Samples were obtained from 271 subjects: 85 drug-naïve type 2 diabetes participants exclusively on lifestyle intervention (N-DM group), 122 type 2 diabetes subjects previously used medications (DM group) and 64 normal controls (NC group). Serum FGF19 concentrations were measured by ELISA. The insulin sensitivity (MI), insulin secretion (AUCins/AUCglu) and insulin secretion-sensitivity index-2 (ISSI-2) were also measured in the N-DM and DM. Results: Serum FGF19 levels decreased, in order, from the NC group [median (interquartile range), 245.03 (126.23-317.43) pg/mL] to the N-DM group [170.05 (89.01-244.70) pg/mL] and, finally, to the DM group [142.25 (55.55-187.58) pg/mL] (p for trend < 0.05). Among subjects in the DM group, there was a positive trend in the serum FGF19 concentration; plasma insulin levels at 60 min, 120 min (INS60, INS120, respectively); and area under the insulin curve (AUCins) at two points (r = 0.214, p = 0.025; r = 0.189, p = 0.048; r = 0.188, p = 0.049). However, the differences were no longer observed among the N-DM subjects. Simultaneously, the ISSI-2 was closely related to the serum FGF19 levels (r = 0.297, p = 0.002) among DM subjects. Furthermore, after adjusting for age, sex, duration, therapy and other clinical factors via multiple logistic regression analysis, ISSI-2 was a key independent factor in the levels of FGF19 (ß = 0.281, t = 2.557, p = 0.013). Conclusions: The serum FGF19 level has a close relation with endogenous beta cell function among DM subjects, as assessed by the ISSI-2. As ISSI-2 is higher in N-DM group, FGF19 may be a main protector in dysfunction of beta cell.

8.
Ying Yong Sheng Tai Xue Bao ; 30(9): 3137-3144, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31529889

RESUMO

The objective of this study was to evaluate the effects and underlying physiological mecha-nisms of partial root zone irrigation (PRI) and rational close planting, as well as their interaction on yield and water productivity (WP) of cotton and to explore new alternatives of water-saving irrigation in dry land areas. A factorial field experiment with irrigation mode (normal irrigation, partial root-zone irrigation and deficient irrigation) and plant population density (135000, 180000 and 225000 plants·hm-2) was conducted in the west of Inner Mongolia to examine their effects on cotton growth, yield, water productivity and related physiological characters. The results showed that the irrigation mode and plant density as well as their interaction significantly affected the biomass, yield, yield components and harvest index. Under normal irrigation, the biomass and the number of bolls per unit area increased with the increasing of plant density, but the harvest index and boll weight significantly reduced. The yield of high plant density was comparable to that of medium plant density, both of which were increased significantly compared with that of low plant density. The content of abscisic acid (ABA) significantly increased and that of auxin (IAA) significantly reduced in cotton leaves under partial root-zone irrigation, which significantly increased the harvest index by improving the partitioning of assimilates to reproductive organs under partial root-zone irrigation. The number of bolls per unit area increased and boll mass remained unchanged with the increasing of density under partial root-zone irrigation. The yield of high density increased by 6.7% and 11.5% compared with that of medium and low density under partial root zone irrigation. The pre-frost seed cotton increased by 22.5%, the amount of irrigation reduced by 30%, and water productivity increased by 49.3% under partial root zone irrigation compared with that under normal irrigation at high plant density. Plant density did not affect photosynthetic rate (Pn) of functional leaves, but irrigation mode significantly affected Pn. Deficient irrigation significantly reduced the Pn of the main-stem functional leaves, but the Pn under partial root-zone irrigation was comparable to that of normal irrigation. The jasmonate (JA) content and the expression level of plasma membrane intrinsic protein (PIP) gene were significantly increased in the hydrated root under partial root-zone irrigation compared with those under normal irrigation. The results suggested that the increased JA content, as a signal molecule, up-regulated the expression level of PIP gene in dehydrated root and increased water uptake capacity of roots and guaranteed water balance of leaves, and then contributed to a relatively high Pn. Partial root-zone irrigation combined with relatively high plant density (225000 plants·hm-2) is an important agronomic alternative for water saving in cotton plantation in the dry land areas.


Assuntos
Irrigação Agrícola/métodos , Gossypium/crescimento & desenvolvimento , Água , Biomassa , China , Fotossíntese
9.
Phytomedicine ; 58: 152769, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005714

RESUMO

BACKGROUND: Melanoma is a high fatality skin cancer which lacks effective drugs. Sasanquasaponin, an important sort of constituents in theaceae, has been demonstrated to have potent anti-tumor effect in breast cancer and hepatocellular carcinoma. As a sasanquasaponin, we speculate that Sasanquasaponin III (SQS III) isolated from Schima crenata Korth may also have anti-tumor activity. PURPOSE: This study aims to investigate whether SQS III has anti-melanoma activity and examine the underlying mechanisms of SQS III against melanoma. METHODS/STUDY DESIGNS: The anti-proliferative effect of SQS III was assessed by cells viability assay. Annexin V-FITC/PI double staining assay was utilized for detection of apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) production were detected using JC-1 and DCFH-DA assay, respectively. Autophagy was monitored using transmission electron microscopy (TEM) and GFP-LC3 transfection fluorescence analysis. Autophagosome-lysosome fusion and lysosomal degradation were determined using a GFP-LC3 & LAMP1 co-localization assay and DQ-BSA staining. Proteins related to apoptosis and autophagy were analyzed by Western blotting. RESULTS: Our results demonstrated that the SQS III exhibited potent anti-cancer activity in A375 cells by inducing both apoptosis and autophagy. In melanoma cells treated with SQS III, caspases were activated and PARP was cleaved, proving the occurrence of apoptosis. Mechanistic studies indicated that the pro-apoptosis activity of SQS III was mediated by death receptor pathway and mitochondrial dysfunction which was induced by ROS accumulation and reversed by the ROS inhibitor N-acetyl-cysteine (NAC). In addition to triggering apoptosis, SQS III may also cause autophagy in melanoma cells. Our results demonstrated that SQS III induced up-regulated expression of GFP-LC3, autophagosome-lysosomal fusion and lysosomal degradation. Additionally, the ROS accumulation was also involved in the activation of autophagy. Meanwhile, it was also found that after SQS III treatment, the expression of LC3-II was up-regulated and the AKT/mTOR signaling pathway was inhibited. The autophagy inhibitor 3-MA converted cytotoxicity and apoptosis of SQS III in A375 cells, which indicated that autophagy promoted the SQS III-induced apoptosis. CONCLUSION: SQS III showed potent anti-cancer activity by inducing apoptosis and autophagy, which provides insights into its possible use as a therapy for melanoma.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Melanoma/tratamento farmacológico , Saponinas/farmacologia , Theaceae/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Saponinas/química , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
10.
Chem Biodivers ; 16(6): e1900052, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30946516

RESUMO

One new racemic mixture, penicilliode A (1) and four pairs of enantiomeric polyketides, penicilliode B and C (2 and 3) and coniochaetone B and C (4 and 5), were obtained from the starfish-derived symbiotic fungus Penicillium sp. GGF16-1-2. Interestingly, the strain GGF16-1-2 can produce enantiomers. The absolute configuration of 1 was determined by X-ray diffraction (XRD) analysis, and the absolute configurations of 2-4 were determined by the optical rotation (OR) values and electronic circular dichroism (ECD) calculations. Compounds 1-5 were firstly isolated from the marine-derived fungus Penicillium as racemates, and 2-5 were separated by HPLC with a chiral stationary phase. All the compounds were evaluated for their antibacterial, cytotoxic and inhibitory activities against PDE4D2.


Assuntos
Penicillium/metabolismo , Policetídeos/química , Estrelas-do-Mar/microbiologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Conformação Molecular , Penicillium/química , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Estereoisomerismo , Simbiose
11.
Fitoterapia ; 134: 362-371, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30872126

RESUMO

Toad venom (venenum bufonis, also called Chan'su) has been widely used for centuries in China to treat different diseases, especially for cancer. Bufadienolides are mainly responsible for the anti-cancer effects of toad venom. However, systematic chemical composition and cytotoxicity as well as key pharmacophores of these bufadienolides from toad venom have not yet been defined clearly. To enrich the understanding of the diversity of bufadienolides and to find bufadienolides with better activities from toad venom. This study was carried out to isolate chemical constituents, research their anti-tumor effects and mechanisms by MTT assay, flow cytometry and Western blotting, and develop a CoMFA and CoMSIA quantitative structure-activity relationship (QSAR) model for illustrating the vital relationship between the chemical structures and cytotoxicities. Among 47 natural bufadienolides, most of bufadienolides (21 compounds isolated in this study and 26 compounds isolated previously) could significantly inhibit the proliferation of cancer cells, and compounds 1, 8, 12, 18 and 19 showed the most potent inhibitory activity against four types of human tumor cells. Compound 18 induced G2/M cell cycle arrest and apoptosis. Moreover, 3D contour maps generated from CoMFA and CoMSIA identified several pharmacophores of bufadienolides responsible for the anti-tumor activities. Our study might provide reliable information for future structure modification and rational drug design of bufadienolides with anticancer activities in medical chemistry.


Assuntos
Venenos de Anfíbios/farmacologia , Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade
12.
Int Immunopharmacol ; 70: 187-200, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30807932

RESUMO

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a member of the scavenger receptor family, recognizes multiple ligands and participates in several inflammatory responses, but its function within the central nervous system (CNS) remains unclear. In this study, we discovered an increased LOX-1 expression in activated microglia in vivo and in vitro. Employing the specific inhibitors, we found that conditioned medium of necrotic neurons (Necrotic-CM) induced microglial LOX-1 expression through the MAPKs/NF-κB pathway. Silencing LOX-1 inhibited MAPK phosphorylation, NF-κB-p65 nuclear transportation, and pro-inflammatory factor production in microglia exposed to Necrotic-CM. Furthermore, utilizing the conditioned medium of activated microglia (MG-CM), we discovered microglial LOX-1 aggravated the neuroinflammation-induced neuronal apoptosis. Collectively, a LOX-1/MPAKs/NF-κB positive loop might promote microglia activation and drive the vicious cycle of neuroinflammation and neuronal injury.


Assuntos
Sistema Nervoso Central/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Microglia/fisiologia , NF-kappa B/metabolismo , Inflamação Neurogênica/metabolismo , Neurônios/patologia , Receptores Depuradores Classe E/metabolismo , Animais , Apoptose , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose , RNA Interferente Pequeno/genética , Receptores Depuradores Classe E/genética , Transdução de Sinais , Regulação para Cima
13.
Neural Regen Res ; 14(5): 913-920, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30688278

RESUMO

Many studies have shown that (5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether (5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM (5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation model with 1.0 µg/mL lipopolysaccharide for 24 hours. The generation of nitric oxide was detected by Griess reagents. Astrocyte marker glial fibrillary acidic protein was measured by immunohistochemical staining. The levels of tumor necrosis factor-α and interleukin-1ß in the culture supernatant were assayed by enzyme linked immunosorbent assay. Nuclear factor-κB/p65 expression was examined by immunofluorescence staining. The phosphorylation of inhibitor of nuclear factor IκB-α and the location of nuclear factor-κB/P65 were determined using western blot assay. Our data revealed that (5R)-5-hydroxytriptolide inhibited the generation of nitric oxide, tumor necrosis factor-α and interleukin-1ß from primary astrocytes activated by lipopolysaccharide, decreased the positive reaction intensity of glial fibrillary acidic protein, reduced the expression of tumor necrosis factor alpha and interleukin-1ß in culture supernatant, inhibited the phosphorylation of IκB-α and the translocation of nuclear factor-κB/P65 to the nucleus. These results have confirmed that (5R)-5-hydroxytriptolide inhibits lipopolysaccharide-induced glial inflammatory response and provides cytological experimental data for (5R)-5-hydroxytriptolide in the treatment of neurodegenerative diseases.

14.
J Plant Res ; 132(1): 69-80, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30610496

RESUMO

Clonal propagation is the main strategy for clonal plants to adapt to wind-sand habitat, and underground bud bank could reflect the potential ability of clonal propagation. However, the effects of population density on belowground bud bank are unknown, hindering efforts in the process of dune stabilization. We investigated the horizontal density and vertical distribution of belowground bud bank of a typical rhizomatous grass Leymus secalinus, and soil water content in four dune types with different population density (dune type I: 11.2 ± 1.7 no. m-2, type II: 24.2 ± 2.6 no. m-2, type III: 40.0 ± 4.0 no. m-2, and type IV: 53.5 ± 7.2 no. m-2) in Mu Us sandy land. Our results showed that (1) total bud density of population increased markedly with increasing population density, but it did not exhibit significant difference between dune types III and IV, where density was about 130 buds m-2; and tiller bud density of population first increased, then decreased, and reached a maximum in dune type III. (2) Total bud density per individual in dune type III was significantly larger than that in other dune types (P < 0.05), whereas rhizome and tiller bud density per individual did not show significant differences in dune types II, III and IV (P > 0.05). (3) Buds tended to be concentrated at 10-30 cm soil layer in all dune types, and be buried deeper in dune types III and IV than that in dune types I and II. (4) No pronounced relationship was shown between bud density and soil water content in 10-30 cm soil layer with increasing population density. Our results suggest that moderate population density (40.0 ± 4.0 no. m-2) significantly increase the bud bank density of L. secalinus population and individual. Soil water content was not the main factor responsible for the density of L. secalinus bud bank. These results can provide important information for implementation of effective sand fixation measures and species selection for desertification control in semiarid sandy land ecosystems.


Assuntos
Ecossistema , Poaceae/fisiologia , Rizoma/crescimento & desenvolvimento , China , Poaceae/crescimento & desenvolvimento , Densidade Demográfica , Rizoma/fisiologia , Solo/química , Água/análise
15.
Eur J Pharmacol ; 842: 70-78, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30336139

RESUMO

High dietary fructose is a key causative factor in the development of renal fibrosis. Pterostilbene has anti-fibrotic effect. Understanding the action mechanism of pterostilbene in fructose-induced renal fibrosis remains as a challenge. Here, fructose feeding was found to promote the progress of epithelial-to-mesenchymal transition (EMT) of proximal tubule epithelial cells (PTECs) and collagen deposition in renal cortex of rats with tubulointerstitial fibrosis. Simultaneously, it impaired insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/protein kinase B (Akt) pathway, and increased transforming growth factor-beta 1 (TGF-ß1) and TGF-ß type I receptor to enhance phosphorylation of drosophila mothers against decapentaplegic homolog 2 (Smad2) and Smad3, and Smad4 expression in rat kidney cortex. These changes were also observed in cultured PTECs HK-2 cells exposed to 5 mM fructose. The data from fructose-exposed HK-2 cells co-incubated with TGF-ß type I receptor inhibitor further demonstrated that the activation of TGF-ß1/TGF-ß type I receptor/Smads signaling promoted renal tubular EMT and collagen accumulation. Pterostilbene was found to ameliorate fructose-induced renal fibrosis in rats. Importantly, pterostilbene improved IR/IRS-1/Akt pathway impairment and suppressed TGF-ß1/TGF-ß type I receptor/Smads signaling activation in vivo and in vitro, being consistent with its reduction of EMT and collagen deposition. Upregulation of IR/Akt signaling by pterostilbene was also confirmed in Akt inhibitor (MK-2206 2HCl) or IR inhibitor (GSK1904529A)-treated HK-2 cells. Taken together, pterostilbene may be a promising therapeutic agent for the treatment of fructose-induced kidney fibrosis with insulin signaling impairment.


Assuntos
Células Epiteliais/patologia , Frutose/efeitos adversos , Túbulos Renais Proximais/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Proteínas Smad/metabolismo , Estilbenos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular , Colágeno/metabolismo , Citoproteção/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Insulina/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
16.
Eur J Gastroenterol Hepatol ; 31(3): 382-388, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30383554

RESUMO

BACKGROUND: A combination of sofosbuvir (SOF)+NS5A inhibitor therapies is the main treatment for patients with hepatitis C virus (HCV) genotype-2 (GT-2) chronic infection, but the data are rarely reported in China. This study aimed to investigate the virological response and liver fibrosis improvement among GT-2 patients receiving SOF+NS5A inhibitors. PATIENTS AND METHODS: In this retrospective study, patients who received SOF+NS5A inhibitors between March 2016 and July 2017 were recruited. The treatment duration was 12 weeks and the treatment strategies included SOF+daclatasvir, SOF/ledipasvir, and SOF/velpatasvir. The primary endpoint was a sustained virologic response (serum HCV RNA undetectable) at week 12 after the end of therapy and the secondary endpoint was the improvement in liver stiffness and scores of apartate aminotransferase to platelet ratio index and fibrosis-4. RESULTS: A total of 30 GT-2 patients were enrolled, with 13 (43.3%) patients in SOF+daclatasvir, 13 (43.3%) patients in SOF/ledipasvir, and four (13.3%) patients in SOF/velpatasvir. All patients [30/30 (100%)] achieved SVR, irrespective of treatment regimens and degree of liver fibrosis. After the treatment, liver fibrosis scores of apartate aminotransferase to platelet ratio index (2.27±2.14 vs. 0.89±0.77, P=0.003) and fibrosis-4 (1.17±1.22 vs. 0.42±0.25, P=0.013) were both significantly lower than those before treatment. CONCLUSION: SOF+NS5A inhibitor therapies may induce an excellent virological response and fibrosis improvement in HCV GT-2-infected patients.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Imidazóis/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Sofosbuvir/uso terapêutico , Uridina Monofosfato/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Adulto , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Imidazóis/efeitos adversos , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/genética , Estudos Retrospectivos , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêutico , Carga Viral , Proteínas não Estruturais Virais/metabolismo
17.
Cancer Cell Int ; 18: 209, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30574018

RESUMO

Background: It has been demonstrated that bufadienolides exert potent anti-cancer activity in various tumor types. However, the mechanisms that underlie their anti-cancer properties remain unclear. Yes-associated protein, a key effector of Hippo signaling, functions as a transcription coactivator, plays oncogenic and tumor suppressor roles under different conditions. Here, we report that arenobufagin (ABF), a representative bufadienolide, induced breast cancer MCF-7 cells to undergo apoptosis, which occurred through the JNK-mediated multisite phosphorylation of YAP. Methods: Cytotoxicity was examined using an MTT assay. ABF-induced apoptosis was measured with a TUNEL assay and Annexin V-FITC/PI double staining assay. Western blotting, immunofluorescence, qRT-PCR and coimmunoprecipitation were employed to assess the expression levels of the indicated molecules. Lose-of-function experiments were carried out with siRNA transfection and pharmacological inhibitors. ABF-induced phosphopeptides were enriched with Ti4+-IMAC chromatography and further subjected to reverse-phase nano-LC-MS/MS analysis. Results: ABF significantly reduced the viability of MCF-7 cells and increased the percentage of early and late apoptotic cells in a concentration- and time-dependent manner. Following ABF treatment, YAP accumulated in the nucleus and bound to p73, which enhanced the transcription of the pro-apoptotic genes Bax and p53AIP1. YAP knock-down significantly attenuated ABF-induced apoptotic cell death. Importantly, we found that the mobility shift of YAP was derived from its phosphorylation at multiple sites, including Tyr357. Moreover, mass spectrometry analysis identified 19 potential phosphorylation sites in YAP, with a distribution of 14 phosphoserine and 5 phosphothreonine residues. Furthermore, we found that the JNK inhibitor SP600125 completely diminished the mobility shift of YAP and its phosphorylation at Tyr357, the binding of YAP and p73, the transcription of Bax and p53AIP1 as well as the apoptosis induced by ABF. These data indicate that ABF induced YAP multisite phosphorylation, which was associated with p73 binding, and that apoptosis was mediated by the JNK signaling pathway. Conclusions: Our data demonstrate that ABF suppresses MCF-7 breast cancer proliferation by triggering the pro-apoptotic activity of YAP, which is mediated by JNK signaling-induced YAP multisite phosphorylation as well as its association with p73. The present work not only provides additional information on the use of ABF as an anti-breast cancer drug, but also offers evidence that the induction of the tumor suppressor role of YAP may be a therapeutic strategy.

18.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 40(5): 617-624, 2018 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-30404692

RESUMO

Objective To evaluate the prevalence and clinical characteristics of obstructive sleep apnea (OSA) in bariatric surgery population.Methods Consecutive patients undergoing preoperative evaluation for bariatric surgery and referred for sleep monitoring in Peking Union Medical College Hospital from January 2009 to December 2015 were retrospectively analyzed. Age,gender,symptoms of snoring,fatigue,apnea and somnolence,apnea hyponea index (AHI),arterial blood gas,pulmonary function,sleep respiratory monitoring,positive airway therapy of OSA,and postoperative complications were recorded. The clinical characteristics of OSA groups at different severity were compared using AHI≥5 events/hour and AHI≥15 events/hour as cut-off values. Correlation analysis was applied to identify the clinical factors associated with AHI.Results Of 42 patients with complete sleeping monitoring data before bariatric surgery,30(71.4%) were diagnosed as OSA,14 (33.3%) were moderate or severe and 11 (26.2%) were severe. Also,OSA was not detected before the bariatric surgery in 25 cases (83.3%). Compared with patients with AHI<5 events/hour,patients with AHI≥5 events/hour had significantly older age (t=2.869,P=0.007),higher proportion of observed apnea (P=0.035),higher AHI (z=-4.592,P=0.000),higher proportion of night pulse oxygen saturation(SpO2) below 90% (z=-2.746,P=0.006),lower mean SpO2 (t=-2.071,P=0.046) and lower lowest SpO2 (t=-3.914,P=0.000). Compared with AHI<15 events/hour group,the AHI≥15 events/hour group had significantly higher BMI (t=2.281,P=0.043),male ratio (P=0.005),incidence of hypertension (P=0.011),proportion of observed apnea (P=0.001),percentage of smoking history (P=0.017),partial pressure of carbon dioxide(PaCO2)(t=3.478,P=0.002),AHI (z=-4.592,P=0.000),and proportion of night SpO2 below 90% (z=-4.530,P=0.000); in addition,the forced expiratory volume in one second(FEV1)% predicted (t=-3.377,P=0.002),forced vital capacity(FVC)% predicted (t=-2.342,P=0.026),night time mean SpO2 (t=-3.392,P=0.007),lowest SpO2 (t=-5.535,P=0.000) were significantly decreased. Correlation analysis showed that,in populations with normal PaCO2 (n=36),AHI was positively correlated with age (r=0.450,P=0.006) and BMI (r=0.384,P=0.021) and negatively correlated with FEV1% predicted (r=-0.457,P=0.008) and FVC% predicted (r=-0.432,P=0.013). Partial correlation analysis showed that,after age and BMI were adjusted,AHI was not correlated with FEV1% predicted(r=-0.287,P=0.125)and FVC%predicted(r=-0.241,P=0.200).Conclusion The incidence and underdiagnosis rate of OSA are high in bariatric surgery population. OSA should be routinely screened in bariatric population to reduce the postoperative complication.


Assuntos
Cirurgia Bariátrica , Apneia Obstrutiva do Sono/diagnóstico , Feminino , Humanos , Masculino , Polissonografia , Cuidados Pré-Operatórios , Estudos Retrospectivos
19.
Bioorg Med Chem Lett ; 28(20): 3391-3394, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30181060

RESUMO

Arenobufagin is a naturally occurring bufadienolide showing promising antitumor activity accompanied however with apparent cardiac toxicity. Following the recent discovery that oxidative damage possibly be an important cause of the cardiac toxicity of cardenolides, a strategy fusing the antitumor agent arenobufagin with a benzoisoselenazol fragment, a reactive oxygen species (ROS) scavenger, has been developed. Six novel hybrids were synthesized and their ROS scavenging activities as well as their in vitro cytotoxicity against the human hepatocellular carcinoma cell line HepG2, an adriamycin-resistant subline HepG2/ADM, and the human myocardial cell line AC16 were evaluated. The results indicate that the hybrids exhibit various degrees of in vitro ROS scavenging activities, and weaker cytotoxicity than that of arenobufagin against the myocardial cell line AC16. These findings suggest the feasibility of a strategy in which the cardiotoxicity of the potential antitumor agent arenobufagin is reduced.


Assuntos
Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Cardiotoxicidade/prevenção & controle , Depuradores de Radicais Livres/farmacologia , Compostos Organosselênicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Bufanolídeos/síntese química , Bufanolídeos/química , Bufanolídeos/toxicidade , Linhagem Celular Tumoral , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/toxicidade , Humanos , Estrutura Molecular , Miócitos Cardíacos/patologia , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Compostos Organosselênicos/toxicidade , Espécies Reativas de Oxigênio/metabolismo
20.
Biomed Res Int ; 2018: 3410135, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30151379

RESUMO

Objectives: Obstructive sleep apnea (OSA) is closely associated with obesity, insulin resistance, and inflammation. Adiponectin, omentin, ghrelin, and visfatin are adipokines involved in insulin sensitivity or regulation of inflammatory disease. This study aims to clarify the relationship between OSA and associated adipokines. Patients and Methods: Thirty overweight male patients with severe OSA and twenty controls underwent standard diagnostic polysomnography (PSG), and 10 patients underwent overnight continuous positive airway pressure (CPAP) treatment. Blood samples were collected in the morning after PSG or CPAP procedures. Results: Among the investigated adipokines, only plasma omentin levels of patients with OSA were significantly lower than those of control subjects (442.94 ± 191.89 ng/ml versus 573.52±228.67 ng/ml, p=0.034) and levels did not change after CPAP treatment. In patients with OSA, omentin levels were positively correlated with high-density lipoprotein cholesterol (HDL) levels (r=0.378, p=0.007), adiponectin levels (r=0.709, p<0.001), percentage of sleep at the rapid eye movement (REM) stage (r=0.307, p=0.003), and average and minimum SpO2 (p=0.041, 0.046, respectively) and negatively with hypersensitive C-reactive protein (hsCRP, r=-0.379, p=0.007) and apnea-hypopnea index (AHI, r=-0.315, p=0.026). However, plasma concentrations of adiponectin, ghrelin, and visfatin in patients with OSA did not significantly differ from those of the control or correlate with sleep parameters and CPAP treatment. Conclusions: Patients with OSA have decreased omentin levels, which are associated with sleep parameters, including AHI, SpO2, percentage of REM sleep, hsCRP, HDL, and adiponectin levels.


Assuntos
Citocinas/sangue , Lectinas/sangue , Obesidade/metabolismo , Apneia Obstrutiva do Sono/metabolismo , Adiponectina/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , China , Pressão Positiva Contínua nas Vias Aéreas , Proteínas Ligadas por GPI/sangue , Grelina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/sangue , Obesidade/complicações , Apneia Obstrutiva do Sono/complicações , Adulto Jovem
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