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1.
Toxicol Appl Pharmacol ; : 114918, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32045588

RESUMO

Orlistat (Xenical™), a US Food and Drug Administration (FDA)-approved anti-obesity drug, shows efficacy against multiple tumor types, including hepatocellular carcinoma (HCC), due to its ability to inhibit fatty acid synthase (FASN) activity. However, whether orlistat affects hepatocellular malignant transformation during hepatocarcinogenesis in vivo is unknown. This study assessed the antisteatotic and antitumorigenic efficacy of orlistat in a rapid HCC FVB/N mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Human hepatoma cell lines were used for mechanical validation in vitro. Hematoxylin and eosin staining, immunohistochemistry, and immunoblotting were applied for the mechanistic investigation. The results revealed that when orlistat was administered in the early stage of AKT/c-Met-triggered hepatocarcinogenesis, it resulted in the elimination of hepatic tumor burden. Mechanistically, orlistat efficiently elevated PTEN expression and suppressed AKT/SREBP1/FASN signaling both in vivo and in vitro, impairing AKT/c-Met-driven de novo lipogenesis and aberrant proliferation. Altogether, this study demonstrates the antilipogenic and antiproliferative efficacy of orlistat in hepatocarcinogenesis, suggesting that orlistat may be beneficial for the treatment of HCC, especially in NAFLD-related HCCs featuring activated AKT/mTOR cascade and increased lipogenesis in livers.

2.
J Am Heart Assoc ; 9(3): e014899, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31973604

RESUMO

Background The trajectory of ischemic stroke patients attributable to large vessel occlusion is fundamentally altered by endovascular thrombectomy. This study aimed to develop a nomogram for predicting 3-month mortality risk in patients with ischemic stroke attributed to artery occlusion in anterior circulation who received successful endovascular thrombectomy treatment. Methods and Results Patients with successful endovascular thrombectomy (modified Thrombolysis in Cerebral Infarction IIb or III) were enrolled from a multicenter registry as the training cohort. Step-wise logistic regression with Akaike information criterion was utilized to establish the best-fit nomogram. The discriminative value of the nomogram was tested by concordance index. An additional 224 patients from 2 comprehensive stroke centers were prospectively recruited as the test cohort for validating the new nomogram. Altogether, 417 patients were enrolled in the training cohort. Age (odds ratio [OR], 1.07; 95% CI, 1.03-1.10), poor pretreatment collateral status (OR, 2.13; 95% CI, 1.18-3.85), baseline blood glucose level (OR, 1.12; 95% CI, 1.04-1.21), symptomatic intracranial hemorrhage (OR, 9.51; 95% CI, 4.54-19.92), and baseline National Institutes of Health Stroke Scale score (OR, 1.08; 95% CI, 1.03-1.12) were associated with mortality and were incorporated in the nomogram. The c-index of the nomogram was 0.835 (95% CI, 0.785-0.885) in the training cohort and 0.758 (95% CI, 0.667-0.849) in the test cohort. Conclusions The nomogram, composed of age, pretreatment collateral status, baseline blood glucose level, symptomatic intracranial hemorrhage, and baseline National Institutes of Health Stroke Scale score, may predict risk of mortality in patients with ischemic stroke and treated successfully with endovascular thrombectomy.

3.
Medicine (Baltimore) ; 99(4): e18683, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977858

RESUMO

Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of vicagrel in healthy Chinese subjects.This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive vicagrel or placebo. Platelet function was assessed using VerifyNow P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of vicagrel.Although the number of adverse events (AEs) increased with vicagrel dose, none were considered serious, suggesting that vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%-93.0%, mean ΔPRU 206.6-240.0) for doses of 40 to 75 mg of vicagrel. In contrast, for 5 mg vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study.The results suggest that vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that vicagrel may be a highly effective and well-tolerated antiplatelet agent.


Assuntos
Fenilacetatos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tiofenos/farmacologia , Adulto , Clopidogrel/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Fenilacetatos/administração & dosagem , Fenilacetatos/efeitos adversos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Testes de Função Plaquetária , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Adulto Jovem
4.
Adv Healthc Mater ; : e1901186, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31820852

RESUMO

The chronic inflammatory microenvironment is characterized by the elevated level of reactive oxygen species (ROS). Here, it is hypothesized that developing an ROS-scavenging scaffold loaded with rapamycin (Rapa@Gel) may offer a new strategy for modulating the local inflammatory microenvironment to improve intervertebral disk tissue regeneration. The therapeutic scaffold consisting of ROS-degradable hydrogel can be injected into the injured degeneration site of intervertebral disk (IVD) and can release therapeutics in a programmed manner. The ROS scavenged by scaffold reduces the inflammatory responses. It is found that when rats are treated with Rapa@Gel, this results in an increase in the percentage of M2-like macrophages and a decrease in M1-like macrophages in the inflammatory environment, respectively. Regeneration of IVD is achieved by Rapa@Gel local treatment, due to the increased M2 macrophages and reduced inflammation. This strategy may be extended to the treatment of many other inflammatory diseases.

5.
Am J Surg ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31818425

RESUMO

BACKGROUND: Optimal management for papillary thyroid microcarcinoma (PTMC) remains controversial. The purpose of this study was to explore risk factors predictive of cervical lymph node metastasis in conventional PTMCs. METHODS: Conventional PTMC patients (n = 2,404) undergoing surgery between 2010 and 2017 were grouped and analyzed according to the positivity of cervical lymph node. RESULTS: Central lymph node (CLN) metastases and lateral lymph node (LLN) metastases were observed in 915 (38.1%) and 184 (7.7%) cases, respectively. Multivariate analysis found that male (odds ratio [OR] = 1.974, p < 0.001), younger age (OR = 1.601, p < 0.001), tumor size (OR = 1.935, p < 0.001), extrathyroidal extension (ETE) (OR = 1.647, p < 0.001), multifocality (OR = 1.416, p < 0.001), and intrathyroidal spreading (OR = 3.355, p < 0.001) predicted increased CLN metastasis. In particular, younger age, multifocality, and intrathyroidal spreading were significantly associated with a high number of CLN metastases (n ≥ 5). The presence of CLN metastasis was strongly associated with LLN metastasis (OR = 5.426, p < 0.001). CONCLUSION: Male, younger age, tumor size, ETE, multifocality, and intrathyroidal spreading predict increased CLN metastasis in PTMCs. In patients with suspicious lateral lymphadenopathy, the presence of CLN metastasis is independently associated with LLN metastasis.

6.
Biomed Pharmacother ; 120: 109538, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629250

RESUMO

BACKGROUND/AIM: Danhong injection (DHI) is a Chinese drug used for relieving cardiovascular diseases. This study aimed to identify the effect and mechanism of action of DHI on post-infarct angiogenesis, especially the epigenetic regulation of angiogenesis. METHODS: A myocardial infarction (MI) mouse model was induced by ligating the left anterior descending coronary artery. A 4-week daily treatment with or without DHI via intraperitoneal injection was started immediately following MI. The changes in cardiac function, pathology, and angiogenesis following MI were measured by echocardiography and immunostaining. Matrigel tube formation and scratch wound assays were used to evaluate the effect of DHI on the proliferation and migration of hypoxic human umbilical vein endothelial cells (HUVECs). The expression of miR-126, Spred-1, and angiogenesis-related mRNAs was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of related proteins and the phosphorylated levels of extracellular signal-regulated kinase (ERK) and protein kinase B were detected by Western blot analysis. The loss-of-function study was performed using antagomir-126. RESULTS: The DHI-treated mice had significantly reduced infarct area, improved ejection fraction, and increased capillary density 4 weeks after MI. Also, DHI promoted the proliferation and migration of hypoxic HUVECs. The qRT-PCR and Western blot analysis revealed that DHI intervention upregulated miR-126, suppressed Spred-1 expression, and activated the ERK pathway, but not the Akt pathway. The loss-of-function study showed the blockade of the pro-angiogenic effect of DHI by antagomir-126 involving the ERK/vascular endothelial growth factor (VEGF) pathway. CONCLUSION: DHI enhanced post-infarct angiogenesis after MI by activating the miR-126/ERK/VEGF pathway.

7.
Chin J Integr Med ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31630361

RESUMO

OBJECTIVE: To analyze the effective components of Chinese medicine (CM) contained in Chaihu Shugan Powder (, CSP) in the treatment of depressive disorders and to predict its anti-depressant mechanism by network pharmacology. METHODS: Absorption, distribution, metabolism, excretion, and toxicity calculation method was used to screen the active components of CSP. Traditional Chinese Medicine System Pharmacological Database Analysis Platform and text mining tool (GoPuMed database) were used to predict and screen the active ingredients of CSP and anti-depressive targets. Through Genetic Association Database, Therapeutic Target Database, and PharmGkb database targets for depression were obtained. Cytoscape3.2.1 software was used to establish a network map of the active ingredients-targets of CSP, and to analyze gene function and metabolic pathways through Database for Annotation, Visualization and Integrated Discovery and the Omicshare database. RESULTS: The 121 active ingredients and 15 depression-related targets which were screened from the database can exert antidepressant effects by improving the neural plasticity, growth, transfer condition and gene expression of neuronal cell, and the raise of the expression of gap junction protein. The 15 targets passed 14 metabolic pathways, mainly involved in the regulation of neurotransmitters (5-hydroxytryptamine, dopamine and epinephrine), inflammatory mediator regulation of TRP channels, calcium signaling pathway, cyclic adenosine monophosphate signaling pathway and neuroactive ligand-receptor interaction and other signal channels to exert anti-depressant effects. CONCLUSION: This article reveals the possible mechanism of CSP in the treatment of depression through network pharmacology research, and lays a foundation for further target studies.

8.
J Cancer ; 10(21): 5212-5222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602272

RESUMO

Amplified in breast cancer 1 (AIB1) gene, has been reported to be associated with biological malignancy in several cancers. However, the molecular status of the AIB1 gene in cervical cancer and the clinicopathological/prognostic significance of AIB1 expression in chemoradiotherapy (CRT) sensitivity have not been determined. In our present study, we found that the high expression of AIB1 was frequent detected in specimens of cervical cancer patients, and this was significantly correlated with CRT response (P = 0.014), clinical stage (P = 0.003), T status (P = 0.027), N status (P = 0.021), M status (P = 0.015) and progression-free survival (P < 0.001). Moreover, the clonogenic survival fraction and cell apoptosis experiments showed that knockdown of AIB1 substantially increased cervical cancer cells sensitivity to ionizing radiation (IR) or cisplatin/5-fluorouracil. Collectively, our results demonstrated that the high expression of AIB1 in cervical cancer cells contributes to the resistance to CRT, which provides the evidence that AIB1 may be a promising predictor of aggressive cervical cancer patients with poor response to CRT.

9.
Aging (Albany NY) ; 11(17): 6839-6850, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479421

RESUMO

Data regarding the association between subclinical thyroid dysfunction and clinical outcomes in ischemic stroke patients with intravenous thrombolysis (IVT) are limited. We aimed to investigate the predictive value of subclinical thyroid dysfunction in END, functional outcome and mortality at 3 months among IVT patients. We prospectively recruited 563 IVT patients from 5 stroke centers in China. Thyroid function status was classified as subclinical hypothyroidism, subclinical hyperthyroidism (SHyper) and euthyroidism. The primary outcome was END, defined as ≥ 4 point in the NIHSS score within 24 h after IVT. Secondary outcomes included 3-month functional outcome and mortality. Of the 563 participants, END occurred in 14.7%, poor outcome in 50.8%, and mortality in 9.4%. SHyper was an independent predictor of END [odd ratio (OR), 4.35; 95% confidence interval [CI], 1.86-9.68, P = 0.003], 3-month poor outcome (OR, 3.24; 95% CI, 1.43-7.33, P = 0.005) and mortality [hazard ratio, 2.78; 95% CI, 1.55-5.36, P = 0.003]. Subgroup analysis showed that there was no significant relationship between SHyper and clinical outcomes in IVT patients with endovascular therapy. In summary, SHyper is associated with increased risk of END, and poor outcome and mortality at 3 months in IVT patients without endovascular therapy.

10.
ACS Omega ; 4(1): 2311-2319, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459473

RESUMO

Most of the existing robots would find it difficult to stretch and transform all parts of their body together due to rigid components and complex actuation mechanisms inside. Here, we presented a highly transformable liquid-metal composite (LMC) that is easy to change shape in large magnitude and resume its original state again according to need. When subject to heating, part of the ethanol droplets embedded in the composite would change phase and then actuate. We demonstrate the flexible transformation of LMC-made octopus from a two-dimensional shape into several predictable three-dimensional shapes freely on a large scale (even up to 11 times its initial height) through remote wireless heating, which needs no sophisticated operating system at all. Further, several designed behaviors, such as movement of octopus and entangling objects of soft robots, are also realized. Theoretical analysis of the heating-induced liquid-vapor transition of the embedded ethanol droplet interprets the mechanisms involved. The present findings open a new way to fabricate functional transformable composites that would find significant applications in developing future generation soft robots.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31440476

RESUMO

The presence of carbapenem-producing Klebsiella pneumoniae (CP-Kp) is a serious threat to the control of nosocomial infections. Plasmid-mediated horizontal transfer of the resistance gene makes it difficult to control hospital-acquired CP- Kp infections. Nine CP- Kp strains were isolated during an outbreak in the intensive care unit of Shanghai Huashan hospital in east China. We conducted a retrospective study to identify the origin and route of transmission of this CP-Kp outbreak. Whole-genome sequencing (WGS) analysis was performed on 9 clinical isolates obtained from 8 patients, and the results were compared to clinical and epidemiological records. All isolates were ST11 CP-Kp. Single-nucleotide polymorphisms and the presence and structure of plasmids indicated that this CP-Kp outbreak had different origins. These 9 isolates were partitioned into two clades according to genetic distance. Four plasmids, CP002474.1, CP006799.1, CP018455.1, and CP025459.1, were detected among the 9 isolates. The plasmid phylogeny and antibiotic resistance (AR) gene profile results were consistent with the sequencing results. We found that two clades of CP-Kp were responsible for this nosocomial outbreak and demonstrated the transmission route from two index patients. Plasmid carriage and phylogeny are a useful tool for identifying clades involved in disease transmission.

12.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1869-1875, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342715

RESUMO

To study the effects of ellagic acid(EA)on inflammation and oxidative stress in mice with fatty liver disease induced by AKT gene transfection,the 20 female FVB mice were randomly divided into normal control group,model group and ellagic acid administration group(150,300 mg·kg~(-1)·d~(-1))(n=5).EA experimental groups and model group were using a high pressure into the tail vein transfection plasmid AKT.The next day,EA was started to administered continuously for 5 weeks after the AKT gene transfection,while the model group and the normal control group were given the same amount of saline.After the administration,the liver tissue and serum of mice were taken.HE and oil red O staining were using to observe the histopathological changes in liver;liver function to detect the serum and liver tissue as well as MDA and SOD levels;real-time quantitative PCR(RT-qPCR)was used to measure the mR-NA expression of NF-κB and TNF-α;Western blot and immunohistochemistry were used to measure the expression of NF-κB,TNF-αand COX-2 in liver tissue.RESULTS:: show that after AKT gene transfection,the model group had significant increase in the serum levels of AST,ALT,elevated the levels of MDA and decreased the levels of SOD in serum and liver tissue,aggravated histopathology degeneration and Liver inflammation,and significantly higher expression of NF-κB,TNF-α,IL-6,COX-2 and other inflammatory-related factors in liver tissue.EA administration group significant reductions in the serum levels of AST,ALT,and improved in hepatocyte fatty degeneration and liver inflammation,lower the levels of MDA and increased the levels of SOD in serum and liver tissue,and significant reductions in the expression of NF-κB,TNF-α,IL-6 and COX-2 in liver tissue.These results suggest that EA has obvious anti-inflammatory effect and inhibits oxidative stress and EA has a significant therapeutic effecton AKT gene inducing fatty liver,and the mechanism possibly by inhibiting inflammatory factors of NF-κB,TNF-α,IL-6,COX-2 and anti-oxidative stress-related.


Assuntos
Ácido Elágico/farmacologia , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Fígado Gorduroso/genética , Feminino , Camundongos , Distribuição Aleatória , Transfecção
13.
Food Funct ; 10(6): 3410-3420, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31123744

RESUMO

Previous studies in humans have indicated that de novo lipogenesis contributes considerably to redundant lipid storage and steatosis in the liver of patients with nonalcoholic fatty liver disease (NAFLD), and then more severe complications occur. Recently, ellagic acid (EA) has drawn attention mainly due to its biological functionalities and a series of molecular targets. However, the molecular mechanism by which EA attenuates hepatic steatosis in individuals with undesirable hepatic genetic alterations remains rarely studied. Here, we evaluate the therapeutic efficacy of EA in a hepatic steatosis mouse model featuring elevated expression of sterol regulatory element-binding protein-1 (SREBP-1) and its downstream modulators of lipogenesis by hydrodynamic injection of v-akt murine thymoma viral oncogene homolog (AKT). Hematoxylin and eosin staining, oil red O staining, immunohistochemistry, immunoblotting, and quantitative polymerase chain reaction (qPCR) were performed for mechanistic investigations. Human hepatoma cell lines were used for mechanical validation in vitro. The results suggest that EA lightens the accumulation of lipids in hepatocytes of AKT-injected mice and an oleic acid-induced in vitro hepatic steatosis model. Mechanistically, EA administration decreases the expression of phospho-AKT (Thr308) and suppresses two effectors lying downstream of the AKT/mTORC1 pathway, ribosomal protein S6 (RPS6) and SREBP-1, in the AKT-injected mice. The consequence of the EA-mediated decrease of SREBP-1 is found to be a transcriptional and translational inhibition of fatty acid synthase (FASN), accompanied by the downregulation of acetyl-CoA carboxylase (ACC). Consistent with in vivo findings, EA efficiently represses the SREBP-1/FASN axis in vitro. Collectively, our study provides a novel mechanism whereby EA alleviates AKT-triggered hepatic de novo lipogenesis, indicating that EA might serve as a potential agent in the therapy of hepatic steatosis in patients with NAFLD and/or steatosis-associated complications, especially in that characterized by activation of AKT/mTORC1 signaling in the liver.


Assuntos
Ácido Elágico/administração & dosagem , Ácido Graxo Sintases/metabolismo , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Ácido Graxo Sintases/genética , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
14.
Zhongguo Zhong Yao Za Zhi ; 44(8): 1517-1523, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090313

RESUMO

The present study was conducted to explore the effect of endophytic fungi fraction on growth and anti-oxidative activity of Eleutherococcus senticosus. The growth,yield,contents of MDA,and antioxidant activities were assessed in E. senticosus under five fungi fractions,namely BZ,MH,DT,JS,and XFZ. The results showed that fungi fractions and component significantly affected the growth,low concentration of DT fungi fraction significantly increased the biomass of E. senticosus,reduced the MDA content in cells,and the antioxidant activities of the aqueous extracts were superior to the others. The results indicated that low concentration of DT fungi fraction was the optimum fraction to achieve high yield and quality of E. senticosus.


Assuntos
Antioxidantes/metabolismo , Eleutherococcus/crescimento & desenvolvimento , Fungos/química , Eleutherococcus/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo
15.
Colloids Surf B Biointerfaces ; 178: 269-275, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30878801

RESUMO

CZ48, a prodrug of camptothecin (CPT) with derivative resistant to lactone hydrolysis, suffers from limited application for cancer treatment due to poor water-solubility, thus causing its low bioavailability and absorption in vivo. To echo this problem, CZ48 was incorporated into poly (lactic acid) (PLA) microbubbles via a double emulsion technique (W/O/W), and the successful loading was confirmed by X-ray diffraction (XRD) patterns and confocal laser scanning microscope (CLSM). The obtained CZ48-loaded microbubbles had a diameter ranging from 0.5 to 6.7 µm, and the encapsulation efficiency and drug-loading content were as high as 85.73 ± 2.41% and 26.07 ± 0.76%, respectively. The in vitro drug release demonstrated that only about 55% of CZ48 was released for CZ48-loaded PLA microbubbles in 48 h. In contrast, over 90% of CZ48 was released for free CZ48 crystals sample in only 5 h. Besides, in vivo pharmacokinetic studies further revealed that the availability of both CZ48 and its metabolite CPT were obviously enhanced after the incorporation of CZ48 into PLA microbubbles. To be noted, the value of AUC0-∞ of the CZ48-loaded microbubbles was about 5-fold higher than that of free CZ48 suspension, implying a much higher anticancer effect of the CZ48-loaded microbubbles. The half-life time (T1/2) of both CZ48 and CPT of the CZ48-loaded microbubbles were also significantly longer than that of the free CZ48, indicating a delayed release time for the microbubbles. Hence, this work promotes a promising drug carrier system for the controlled release of CZ48 as well as other drugs with poor water-solubility.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Microbolhas , Poliésteres/química , Camptotecina/química , Camptotecina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos
16.
Food Chem Toxicol ; 126: 192-198, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30802477

RESUMO

The purpose of present HUVE cells and mice study was to investigate the combined effects of carnosine and asiatic acid (AA) against diabetic progression. In HUVE cells, high glucose decreased cell viability, reduced Bcl-2 mRNA expression and increased Bax mRNA expression. The co-treatment of 0.5 µM carnosine plus 0.5 µM AA led to greater cell viability and Bcl-2 mRNA expression than 1 µM carnosine or 1 µM AA treatment alone. This combination more significantly decreased the production of DNA fragmentation, tumor necrosis factor (TNF)-alpha, reactive oxygen species (ROS), and nuclear factor kappa B binding activity than carnosine or AA treatment alone. In diabetic mice, the combination of 0.25% carnosine plus 0.25% AA in diet resulted in higher final body weight, and lower levels of plasma glucose and triglyceride than 0.5% carnosine or 0.5% AA treatment alone. Carnosine and AA combination caused more reduction in renal levels of leukin-6, TNF-alpha and ROS than carnosine or AA treatment alone. This combination also more significantly limited renal cyclooxygenase-2 activity and p-p38 phosphorylation than carnosine or AA treatment alone. These novel findings support that this combination is a more powerful remedy for diabetic control.


Assuntos
Anti-Inflamatórios/administração & dosagem , Carnosina/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Triterpenos Pentacíclicos/administração & dosagem , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Sinergismo Farmacológico , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , NF-kappa B/imunologia , Espécies Reativas de Oxigênio/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
17.
J Cell Physiol ; 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30680718

RESUMO

Hypoxia is a common biological hallmark of solid cancers, which has been proposed to be associated with oncogenesis and chemotherapy resistance. The purpose of the present study was to investigate the role and underlying mechanisms of olfactomedin 4 (OLFM4) in the hypoxia-induced invasion, epithelial-mesenchymal transition (EMT), and chemotherapy resistance of non-small-cell lung cancer (NSCLC). We observed dramatically upregulated expression of OLFM4 in several NSCLC cell lines, and this effect was more pronounced in A549 and H1299 cells. In addition, our data revealed that OLFM4 expression was remarkably increased in both A549 and H1299 cells under hypoxic microenvironment, accompanied by enhanced levels of hypoxia-inducible factor (HIF)-1α protein. The HIF-1α level was elevated in response to hypoxia, resulting in the regulation of OLFM4. Interestingly, OLFM4 was a positive regulator of hypoxia-driven HIF-1α production. Moreover, depletion of OLFM4 modulated multiple EMT-associated proteins, as evidenced by the enhanced E-cadherin levels along with the diminished expression of N-cadherin and vimentin in response to hypoxia, and thus blocked invasion ability of A549 and H1299 cells following exposure to hypoxia. Furthermore, ablation of OLFM4 accelerated the sensitivity of A549 cells to cisplatin under hypoxic conditions, implying that OLFM4 serves as a key regulator in chemotherapeutic resistance under hypoxia. In conclusion, OLFM4/HIF-1α axis might be a potential therapeutic strategy for NSCLC.

18.
J Steroid Biochem Mol Biol ; 189: 240-247, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30654105

RESUMO

Active vitamin D (1,25(OH)2D) has been shown to regulate numerous cell processes in mammary cells. Degradation of 1,25(OH)2D is initiated by the mitochondrial enzyme, 25-hydroxyvitamin D 24-hydroxylase (CYP24 A1), and provides local control of 1,25(OH)2D bioactivity. Several reports of the association between elevated CYP24 A1 activity and breast cancer incidence, suggest that CYP24 A1 may be a target for therapeutic intervention. Whether CYP24 A1 activity within the mammary epithelium regulates 1,25(OH)2D levels and mammary gland development is yet to shown. We have used a conditional knockout of the Cyp24a1 gene specifically in the mammary epithelium to demonstrate reduced terminal end bud number, ductal outgrowth and branching during puberty and alveologenesis at early pregnancy, by inhibiting proliferation but not apoptosis in both basal and luminal MECs. In vitro study showed increased sensitivity of luminal MECs to lower levels of 1,25(OH)2D with the ablation of Cyp24a1 activity. In summary, Cyp24a1 within MECs plays an important role in modulating postnatal and pregnancy-associated mammary gland development which provides support for inhibiting CYP24 A1 as a potential approach to activating the vitamin D pathway in breast cancer prevention and therapy.


Assuntos
Deleção de Genes , Glândulas Mamárias Animais/metabolismo , Vitamina D3 24-Hidroxilase/genética , Vitamina D/metabolismo , Animais , Proliferação de Células , Feminino , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Maturidade Sexual , Vitamina D/análogos & derivados , Vitamina D3 24-Hidroxilase/metabolismo
19.
Toxicol Appl Pharmacol ; 365: 51-60, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30625338

RESUMO

Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. Metformin, a first-line oral agent used in the treatment of type 2 diabetes, exhibits efficacy in metabolic reprogramming fueling changes in cell growth and proliferation for multiple cancer types, including HCC. However, the molecular mechanism by which metformin delays hepatocarcinogenesis in individuals with hepatic steatosis remains rare. Here, we investigate the preventive efficacy of metformin in a rapid AKT/c-Met-triggered HCC mouse model featuring excessive levels of steatosis. Hematoxylin and eosin staining, Oil Red O staining and immunoblotting were applied for mechanistic investigations. Pharmacological and biochemical strategies were employed to illuminate molecular evidence for HCC cell lines. The results show that metformin obstructs the malignant transformation of hepatocytes in AKT/c-Met mice. Mechanistically, metformin reduces the expression of phospho-ERK (Thr202/Tyr204) and two forms of proto-oncogenes, Cyclin D1 and c-Myc, in AKT/c-Met mice. Moreover, metformin ameliorates FASN-mediated aberrant lipogenesis and HK2/PKM2-driven ATP generation in vivo. Furthermore, metformin represses the expression of FASN and HK-2 by targeting c-Myc in an AMPK-dependent manner in vitro. In addition, metformin is effective at inhibiting PKM2 expression in the presence of an AMPK inhibitor compound C, suggesting that its functioning in PKM2 is AMPK-independent. Our study experimentally validates a novel molecular mechanism by which metformin alleviates enhanced lipogenesis and high energy metabolism during hepatocarcinogenesis, indicating that metformin may serve as an agent for the prevention of HCC in patients with nonalcoholic fatty liver diseases.


Assuntos
Trifosfato de Adenosina/metabolismo , Anticarcinógenos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Transformação Celular Neoplásica/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Metformina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Hexoquinase/metabolismo , Humanos , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Piruvato Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Bioorg Chem ; 84: 239-253, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30503850

RESUMO

Drug resistance and cancer cells metastasis have been the leading causes of chemotherapy failure and cancer-associated death in breast cancer patients. In present, various active molecules either exhibiting novel mechanism of action such as inducing autophagy or inhibiting metastasis have been developed to address these problems. However, the compounds exhibiting such dual functions have rarely been described. Previous work in our group showed that TSA, as a synthetic analog of asperphenamate, induced autophagic cell death in breast cancer cells instead of apoptosis. Furthermore, the target enzyme of TSA was predicted to be cathepin L (Cat L) by natural product consensus pharmacophore strategy. Accumulated evidences have shown that cathepsins are closely associated with migration and invasion of breast cancer cells. It seemed likely that TSA-like molecules may possess the dual functions of inducing autophagy and inhibiting metastasis. Therefore, sixty optically active derivatives were firstly designed and synthesized by replacing the A-ring moiety of TSA with other substituted-phenyl sulfonyl groups. Further cathepsin inhibitory activity assay showed that (S, S) and (S, R) isomers displayed no activity against four kinds of cathepsins (L, S, K, B), while all derivatives tested were inactive toward K and B subtypes. Compound 6a with meta-bromo substituent displayed the greatest inhibitory activity, and its inhibitory capability against Cat L and S was 3.9 and 11.5-fold more potent than that of TSA, respectively. Molecular docking also exhibited that 6a formed more hydrogen bonds or π-π contacts with Cat L or S than TSA. In order to determine whether 6a could play dual roles, its anti-cancer mechanism was further investigated. On the one hand, MDC staining experiment and western blotting analysis validated that 6a can induce autophagy in MDA-MB-231 cells. On the other hand, its metastatic inhibitory ability was also confirmed by wound healing and transwell chamber experiment.


Assuntos
Autofagia/efeitos dos fármacos , Catepsinas/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Catepsinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Fenilalanina/análogos & derivados , Fenilalanina/química , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Estrutura Terciária de Proteína , Estereoisomerismo , Relação Estrutura-Atividade
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