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1.
Analyst ; 149(10): 2956-2965, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38597984

RESUMO

Glioblastoma is the most fatal and insidious malignancy, due to the existence of the blood-brain barrier (BBB) and the high invasiveness of tumor cells. Abnormal mitochondrial viscosity has been identified as a key feature of malignancies. Therefore, this study reports on a novel fluorescent probe for mitochondrial viscosity, called ZVGQ, which is based on the twisted intramolecular charge transfer (TICT) effect. The probe uses 3-dicyanomethyl-1,5,5-trimethylcyclohexene as an electron donor moiety and molecular rotor, and triphenylphosphine (TPP) cation as an electron acceptor and mitochondrial targeting group. ZVGQ is highly selective, pH and time stable, and exhibits rapid viscosity responsiveness. In vitro experiments showed that ZVGQ could rapidly recognize to detect the changes in mitochondrial viscosity induced by nystatin and rotenone in U87MG cells and enable long-term imaging for up to 12 h in live U87MG cells. Additionally, in vitro 3D tumor spheres and in vivo orthotopic tumor-bearing models demonstrated that the probe ZVGQ exhibited exceptional tissue penetration depth and the ability to penetrate the BBB. The probe ZVGQ not only successfully visualizes abnormal mitochondrial viscosity changes, but also provides a practical and feasible tool for real-time imaging and clinical diagnosis of glioblastoma.


Assuntos
Corantes Fluorescentes , Glioblastoma , Mitocôndrias , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Mitocôndrias/metabolismo , Viscosidade , Linhagem Celular Tumoral , Animais , Camundongos , Camundongos Nus , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Imagem Óptica
2.
Molecules ; 29(19)2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39407530

RESUMO

As a traditional Chinese medicine (TCM), Allii Macrostemonis Bulbus (AMB) is a key herb for the treatment of thoracic paralytic cardiac pain, but its quality evaluation method has not yet been fully clarified. In this study, chromatographic fingerprints of AMB were developed using solid-phase extraction-high-performance liquid chromatography-evaporative light scattering detection (SPE-HPLC-ELSD) to evaluate the quality of AMB from various origins and processing methods. This was achieved by employing chemical pattern recognition techniques and verifying the feasibility and applicability of the quality evaluation of AMB through the quantitative analysis of multi-components via a single-marker (QAMS) method. Through the analysis of the fingerprints of 18 batches of AMB, 30 common peaks were screened, and 6 components (adenosine, syringin, macrostemonoside T, macrostemonoside A, macrostemonoside U, and macrostemonoside V) were identified. Moreover, three differential markers (macrostemonoside A, macrostemonoside T, and macrostemonoside U) were screened out using chemometrics techniques, including principal component analysis (PCA), hierarchical cluster analysis (HCA), and orthogonal partial least squares discriminant analysis (OPLS-DA). Subsequently, a QAMS method was established for macrostemonoside T and macrostemonoside U using macrostemonoside A as an internal reference. The results demonstrate the method's accuracy, reproducibility, and stability, rendering it suitable for the quality evaluation of AMB. This study provides a theoretical basis for drug quality control and the discovery of quality markers for AMB.


Assuntos
Medicamentos de Ervas Chinesas , Extração em Fase Sólida , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Extração em Fase Sólida/métodos , Quimiometria/métodos , Controle de Qualidade , Análise de Componente Principal , Luz
3.
Artif Organs ; 47(7): 1174-1183, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36906913

RESUMO

BACKGROUND: The standard weekly treatment for end-stage renal disease patients is three 4-h-long hemodialysis sessions with each session c'onsuming over 120 L of clean dialysate, which prevents the development of portable or continuous ambulatory dialysis treatments. The regeneration of a small (~1 L) amount of dialysate would enable treatments that give conditions close to continuous hemostasis and improve patient quality of life through mobility. METHODS: Small-scale studies have shown that nanowires of TiO2 are highly efficient at photodecomposing urea into CO2 and N2 when using an applied bias and an air permeable cathode. To enable the demonstration of a dialysate regeneration system at therapeutically useful rates, a scalable microwave hydrothermal synthesis of single crystal TiO2 nanowires grown directly from conductive substrates was developed. These were incorporated into 1810 cm2 flow channel arrays. The regenerated dialysate samples were treated with activated carbon (2 min at 0.2 g/mL). RESULTS: The photodecomposition system achieved the therapeutic target of 14.2 g urea removal in 24 h. TiO2 electrode had a high urea removal photocurrent efficiency of 91%, with less than 1% of the decomposed urea generating NH4 + (1.04 µg/h/cm2 ), 3% generating NO3 - and 0.5% generating chlorine species. Activated carbon treatment could reduce total chlorine concentration from 0.15 to <0.02 mg/L. The regenerated dialysate showed significant cytotoxicity which could be removed by treatment with activated carbon. Additionally, a forward osmosis membrane with sufficient urea flux can cut off the mass transfer of the by-products back into the dialysate. CONCLUSION: Urea could be removed from spent dialysate at a therapeutic rate using a TiO2 based photooxidation unit, which can enable portable dialysis systems.


Assuntos
Nanofios , Ureia , Humanos , Carvão Vegetal , Cloro , Qualidade de Vida , Diálise Renal , Soluções para Diálise/química
4.
Phytother Res ; 37(2): 658-671, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36223243

RESUMO

Schisandrin B (Scheme B) is the most abundant and active lignan monomer isolated from Schisandra chinensis. At present, most reports focus on its cardioprotective and hepatoprotective effects, however, the related reports on gastrointestinal protective effects are still limited. The study aims to evaluate the protective effect of Scheme B on cisplatin-induced rat intestinal crypt epithelial (IEC-6) cell injury and the possible molecular mechanisms. The results showed that Scheme B at 2.5, 5 and 10 µM could inhibit dose-dependently the reduction of cell activity induced by cisplatin exposure at 1 µM, decrease the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) to alleviate oxidative stress injury in IEC-6 cell lines. Meanwhile, Scheme B could relieve cisplatin-induced apoptosis by regulating PI3K/AKT and the downstream caspase signaling pathway. The results from flow cytometry analysis and mitochondrial membrane potential (MMP) staining also demonstrated the anti-apoptosis effect of Scheme B. Furthermore, Scheme B was found to reduce the inflammation associated with cell damage by evaluating the protein expressions of the nuclear factor-kappa B (NF-κB) signaling pathway. Importantly, Wnt/ß-catenin, as a functional signaling pathway that drives intestinal self-recovery, was also in part regulated by Scheme B. In conclusion, Scheme B might alleviate cisplatin-induced IEC-6 cell damage by inhibiting oxidative stress, apoptosis, inflammation, and repairing intestinal barrier function. The present research provides a strong evidence that Scheme B may be a useful modulator in cisplatin-induced intestinal toxicity.


Assuntos
Lignanas , Schisandra , Ratos , Animais , Cisplatino/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Lignanas/farmacologia , Estresse Oxidativo , NF-kappa B/metabolismo , Glutationa/metabolismo , Inflamação
5.
Nanomedicine ; 37: 102440, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256062

RESUMO

Lately, chemotherapy and photodynamic therapy (PDT) synergistic therapy has become a promising anti-cancer treatment mean. However, the hypoxia in tumor leads to huge impediments to the oxygen-dependent PDT effects. In this work, a multifunctional nanoplatform (TUDMP) based on a multivariable porphyrin-nMOFs core and a manganese dioxide (MnO2) shell was prepared for relieving tumor hypoxia and enhancing chemo-photodynamic synergistic therapy performance. The obtained TUDMP nanoplatform could effectively catalyze the hydrolysis of hydrogen peroxide to generate oxygen and also lead to consumption of antioxidant GSH, thereby facilitating the production of cytotoxic reactive oxygen species (ROS) by photosensitizer under laser irradiation. More importantly, the decomposition of the MnO2 shell would further promote the release of the loaded doxorubicin (DOX), and thus an efficient chemo-PDT synergistic therapy was realized. Both in vitro and in vivo experimental results demonstrated the oxygen self-sufficient multifunctional nanoplatform could exhibit significantly enhanced anticancer efficiencies compared with chemotherapy or PDT alone.


Assuntos
Nanopartículas/química , Neoplasias/terapia , Fotoquimioterapia , Porfirinas/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Peróxido de Hidrogênio/química , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia , Óxidos/química , Óxidos/farmacologia , Oxigênio/metabolismo , Porfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Hipóxia Tumoral/genética
6.
Langmuir ; 35(23): 7560-7570, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30550289

RESUMO

The lack of an effective rewarming technique restricted the successful cryopreservation of organ or large tissues by vitrification. The conversion of electromagnetic (EM) energy into heat provides a possible solution for the rewarming process for the cryopreservation. In this work, an EM resonance rewarming system was set up with dynamic feedback control and power feeding optimization. In addition, we take advantage of magnetic nanoparticles (MNPs) to absorb magnetic field energy to further enhance the energy conversion efficiency. We achieved a >200 °C min-1 rewarming rate for tens of milliliters of cryopreserved samples. Besides, we also investigated the effect of nanoparticle size and concentration based on thermal properties by analyzing the contribution of nanoparticles and the utilization of field energy. The closed system reduced the possible concomitant side effects when increasing the number of nanoparticles or increasing the EM source power. With the remarkably low dosage of nanoparticles (0.1 mg mL-1 Fe) compared to that for other MNP-based rewarming applications, this study opens the door to new approaches for exploring novel techniques for tissue and organ preservation.

7.
Bioorg Med Chem ; 26(14): 4264-4275, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30031652

RESUMO

The overexpress of COX-2 was clearly associated with carcinogenesis and COX-2 as a possible target has long been exploited for cancer therapy. In this work, we described the design and synthesis of a series of diarylpyrazole derivatives integrating with chrysin. Among them, compound e9 exhibited the most potent inhibitory activity against COX-2 and antiproliferative activity against Hela cells with IC50 value of 1.12 µM. Further investigation revealed that e9 could induce apoptosis of Hela cells by mitochondrial depolarization and block the G1 phase of cell cycle in a dose-dependent manner. Besides, molecular docking simulation results was further confirmed that e9 could bind well with COX-2. In summary, compound e9 may be promising candidates for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Flavonoides/farmacologia , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/síntese química , Flavonoides/química , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
8.
Bioorg Med Chem ; 26(14): 4145-4152, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29983280

RESUMO

Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50 = 0.061 ±â€¯0.003 µM) and intact cell (IC50 = 0.89 ±â€¯0.05 µM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Urease/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Infecções por Helicobacter/metabolismo , Helicobacter pylori/citologia , Helicobacter pylori/enzimologia , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Cinética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Urease/isolamento & purificação , Urease/metabolismo
9.
Phytother Res ; 32(11): 2235-2246, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30039882

RESUMO

Acute liver injury (ALI) induced by acetaminophen (APAP) overdose is the most common cause of drug-induced liver injury. Saponins from Platycodon grandiflorum (PGSs) ameliorate alcohol-induced hepatotoxicity and enhance human lung carcinoma cell death via AMPK signaling pathway. However, whether PGS could protect from APAP-induced ALI through AMPK activation and its downstream signals is still poorly elucidated. This work investigated the protective effect and the underlying mechanisms of PGS against APAP-induced liver toxicity in mouse. PGS was administered at 15 or 30 mg/kg i.g./day for 1 week before a single injection of APAP (250 mg/kg, i.p.) 1 hr after last treatment of PGS. Serum alanine/aspartate aminotransferases, liver tumor necrosis factor-α and interleukin-1ß levels, liver malondialdehyde formation, liver glutathione depletion, cytochrome P450 E1, and 4-hydroxynonenal levels were measured to demonstrate the protective efficacy of PGS against APAP-induced ALI. Liver histological observation provided further evidence on PGS's protective effects. PGS treatment altered the phosphorylation of AMPK and PI3K/Akt, as well as the downstream signals including Bcl-2 family, caspase, and NF-κB in a dose-dependent manner. In conclusion, we demonstrate that PGS exhibits a significant liver protection against APAP-induced ALI, mainly through NF-κB and AMPK/PI3K/Akt signaling pathways.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Platycodon/química , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Aldeídos/metabolismo , Animais , Aspartato Aminotransferases/sangue , Sistema Enzimático do Citocromo P-450/metabolismo , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Fígado/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Raízes de Plantas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Int J Mol Sci ; 19(8)2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082659

RESUMO

Integrin αIIbß3 plays a pivotal role in platelet aggregation. Three αIIbß3 antagonists have been approved by the Food and Drug Administration (FDA) for the treatment of cardiovascular diseases. Unfortunately, all of these three drugs can cause the side effect of severe bleeding. Therefore, developing a new αIIbß3 antagonist with low bleeding was needed. In the present study, we screened compounds by using a fibrinogen/integrin αIIbß3 enzyme-linked immunosorbent assay (ELISA), and a novel αIIbß3 antagonist ANTP266 was attained. The antithrombotic effects of ANTP266 were estimated by using two animal models, the bleeding risk was estimated by using a mice tail cutting assay, and the plasma half-life time was tested by LC-MS/MS. The results showed that ANTP266 potently decreased thrombosis formation, while not prolonging bleeding time at its effective dosage. The bleeding of ANTP266 reduced rapidly as time went on from 5 to 60 min, but tirofiban produced high bleeding continuously. The plasma half-life of ANTP266 in rats was 10.8 min. Taken together, ANTP266 is an effective antithrombotic agent with a low bleeding risk. The shorter bleeding time benefits from its short plasma half-life. ANTP266 could be a candidate for developing the αIIbß3 antagonist of rapid elimination for a patient undergoing percutaneous coronary intervention.


Assuntos
Fibrinolíticos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Trombose/prevenção & controle , Animais , Plaquetas/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agregação Plaquetária/efeitos dos fármacos , Ratos
11.
Int J Mol Sci ; 19(5)2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29723988

RESUMO

Acetaminophen overdose-induced hepatotoxicity is the most common cause of acute liver failure in many countries. Previously, alpha-mangostin (α-MG) has been confirmed to exert protective effects on a variety of liver injuries, but the protective effect on acetaminophen-induced acute liver injury (ALI) remains largely unknown. This work investigated the regulatory effect and underlying cellular mechanisms of α-MG action to attenuate acetaminophen-induced hepatotoxicity in mice. The increased serum aminotransferase levels and glutathione (GSH) content and reduced malondialdehyde (MDA) demonstrated the protective effect of α-MG against acetaminophen-induced hepatotoxicity. In addition, α-MG pretreatment inhibited increases in tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) caused by exposure of mice to acetaminophen. In liver tissues, α-MG inhibited the protein expression of autophagy-related microtubule-associated protein light chain 3 (LC3) and BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3). Western blotting analysis of liver tissues also proved evidence that α-MG partially inhibited the activation of apoptotic signaling pathways via increasing the expression of Bcl-2 and decreasing Bax and cleaved caspase 3 proteins. In addition, α-MG could in part downregulate the increase in p62 level and upregulate the decrease in p-mTOR, p-AKT and LC3 II /LC3 I ratio in autophagy signaling pathways in the mouse liver. Taken together, our findings proved novel perspectives that detoxification effect of α-MG on acetaminophen-induced ALI might be due to the alterations in Akt/mTOR pathway in the liver.


Assuntos
Acetaminofen/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Xantonas/farmacologia , Animais , Medicamentos de Ervas Chinesas/uso terapêutico , Garcinia mangostana , Humanos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Xantonas/uso terapêutico
12.
Molecules ; 23(9)2018 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30142916

RESUMO

The purpose of this research was to evaluate whether maltol could protect from hepatic injury induced by carbon tetrachloride (CCl4) in vivo by inhibition of apoptosis and inflammatory responses. In this work, maltol was administered at a level of 100 mg/kg for 15 days prior to exposure to a single injection of CCl4 (0.25%, i.p.). The results clearly indicated that the intrapulmonary injection of CCl4 resulted in a sharp increase in serum aspartate transaminase (AST) and alanine transaminase (ALT) activities, tumor necrosis factor-α (TNF-α), irreducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB) and interleukin-1ß (IL-1ß) levels. Histopathological examination demonstrated severe hepatocyte necrosis and the destruction of architecture in liver lesions. Immunohistochemical staining and western blot analysis suggested an accumulation of iNOS, NF-κB, IL-1ß and TNF-α expression. Maltol, when administered to mice for 15 days, can significantly improve these deleterious changes. In addition, TUNEL and Hoechst 33258 staining showed that a liver cell nucleus of a model group diffused uniform fluorescence following CCl4 injection. Maltol pretreatment groups did not show significant cell nuclear condensation and fragmentation, indicating that maltol inhibited CCl4-induced cell apoptosis. By evaluating the liver catalase (CAT), glutathione (GSH), superoxide dismutase (SOD) activity, and further using a single agent to evaluate the oxidative stress in CCl4-induced hepatotoxicity by immunofluorescence staining, maltol dramatically attenuated the reduction levels of hepatic CAT, GSH and SOD, and the over-expression levels of CYP2E1 and HO-1. In the mouse model of CCl4-induced liver injury, we have demonstrated that the inflammatory responses were inhibited, the serum levels of ALT and AST were reduced, cell apoptosis was suppressed, and liver injury caused by CCl4 was alleviated by maltol, demonstrating that maltol may be an efficient hepatoprotective agent.


Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/lesões , Pironas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Aromatizantes/uso terapêutico , Glutationa/metabolismo , Imuno-Histoquímica , Inflamação/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
13.
Bioorg Med Chem Lett ; 27(16): 3653-3660, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28720504

RESUMO

In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50=0.23±0.16µM for COX-2, IC50=0.87±0.07µM for 5-LOX, IC50=4.48±0.57µM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50=0.41±0.28µM for COX-2, IC50=7.68±0.55µM against A549) and Zileuton (IC50=1.35±0.24µM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents.


Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Sítios de Ligação , Domínio Catalítico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 25(9): 2593-2600, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28363444

RESUMO

Focal adhesion kinase (FAK) is an important drug target that plays a fundamental role in mediating signal transduction system. We report herein the discovery of a novel class of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton with improved potency toward FAK. All of the 17 new synthesized compounds were assayed for the anticancer activities against four cancer cells, HepG2, Hela, SW116 and BGC823. Because of the combination of 1,4-benzodioxan, 1,3,4-oxadiazole and piperazine ring, most of them exhibited remarkable antitumor activities. Notably, compound 5m showed the most potent biological activities (IC50=5.78µM for HepG2, and IC50=47.15µM for SW1116), and its anti-FAK inhibitory activity (IC50=0.78µM) was also the best. Computational docking studies also showed that compound 5m has interaction with FAK key residues in the active site.


Assuntos
Dioxanos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Oxidiazóis/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Tionas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dioxanos/síntese química , Dioxanos/química , Ensaios Enzimáticos , Humanos , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/química
15.
Bioorg Med Chem Lett ; 26(15): 3491-8, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27349331

RESUMO

Cyclooxygenase-2 is frequently overexpression in malignant tumors and the product PGE2 promotes cancer cell progression and metastasis. We designed novel series of coumarin sulfonamides derivatives to improve biological activities of COX-2 inhibition and anticancer. Among them, compound 7t showed most powerful selective inhibitory and antiproliferative activity (IC50=0.09µM for COX-2, IC50=48.20µM for COX-1, IC50=0.36µM against HeLa cells), comparable to the control positive compound Celecoxib (0.31µM, 43.37µM, 7.79µM). Cancer cell apoptosis assay were performed and results indicated that compound 7t effectively fuels HeLa cells apoptosis in a dose and time-dependent manner. Moreover, 7t could significantly suppress cancer cell adhesion, migration and invasion which were essential process of cancer metastasis. Docking simulations results was further indicated that compound 7t could bind well to the COX-2 active site and guided a reasonable design of selective COX-2 inhibitor with anticancer activities in future.


Assuntos
Cumarínicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
16.
J Nanobiotechnology ; 13: 42, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-26084491

RESUMO

BACKGROUND: Amphiphilic poly(N-isopropylacrylamide)-block-poly(ε-caprolactone) (PNiPAAm-b-PCL) copolymers were synthesized by ring-opening polymerization to form thermosensitive micelles as nanocarriers for bioimaging and carboplatin delivery. RESULTS: The critical micelle concentration increased from 1.8 to 3.5 mg/l following the decrease of the PNiPAAm chain length. The copolymers revealed a lower critical solution temperature (LCST) between 33 and 40°C. The copolymers self-assembled to form spherical particles of 146-199 nm in diameter. Carboplatin in micelles exhibited a slower release at 37°C relative to that at 25°C due to the gel layer formation on the micellar shell above the LCST. The micelles containing dye or carboplatin were intravenously injected into the rats for in vivo bioimaging and drug biodistribution. The bioimaging profiles showed a significant accumulation of micelles in the lungs. The micelles could minimize the reticuloendothelial system (RES) recognition of the dye. In vivo biodistribution demonstrated an improved pulmonary accumulation of carboplatin from 2.5 to 3.4 µg/mg by the micelles as compared to the control solution. Carboplatin accumulation in the heart and kidneys was reduced after encapsulation by the micelles. CONCLUSION: This study supports the potential of PNiPAAm-b-PCL micelles to passively target the lungs and attenuate RES uptake and possible side effects.


Assuntos
Resinas Acrílicas/administração & dosagem , Resinas Acrílicas/química , Carboplatina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Poliésteres/administração & dosagem , Poliésteres/química , Adulto , Animais , Caproatos/química , Carboplatina/química , Carboplatina/farmacocinética , Portadores de Fármacos/farmacocinética , Células HEK293/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Lactonas/química , Pulmão/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Micelas , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Distribuição Tecidual
17.
Pak J Pharm Sci ; 27(6 Suppl): 2007-12, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25410064

RESUMO

Naturally existing -α -glucosidase inhibitors from traditional herbal medicines have attracted considerable interest to treat type 2 diabetes mellitus (T2DM). Hundreds of herbs have been reported to have the potential to inhibit -α -glucosidase. However, most common methods to examine the inhibitors of -α -glucosidase are usually time-consuming. In the current study, the screening of -α -glucosidase ligands from Coptis chinensis Franch extract was undertaken by ultrafiltration liquid chromatography coupled to electrospray ionization tandem mass spectrometry (ultrafiltration LC-ESI-MS(n)). Resultantly, the enzyme inhibition studies showed that Coptis chinensis Franch extract carries the strongest -α -glucosidase inhibitory activity among the five kinds of Chinese herbal extracts. Subsequently, five compounds that could bind to -α -glucosidase in the Coptis chinensis Franch extract were found using ultrafiltration liquid chromatography, and their structures were identified by ESI-MS(n) to be coptisine, epiberberine, jatrorrhizine, berberine, palmatine. Cumulatively, these results were anticipated to be encouraging for applying the Coptis chinensis Franch extracts as efficient anti-diabetic drug candidates.


Assuntos
Coptis/química , Inibidores de Glicosídeo Hidrolases/análise , Extratos Vegetais/análise , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas por Ionização por Electrospray , Ultrafiltração
18.
Food Chem X ; 21: 101144, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38304049

RESUMO

Allii Macrostemonis Bulbus (AMB), a traditional Chinese edible and medicinal plant, is considered beneficial to health. In this study, we isolated and purified nine steroidal saponins (compounds 1-9) from AMB. Their structures were characterized using physicochemical properties, HR-ESI-MS, 1D and 2D NMR spectroscopy. Among these compounds, compounds 1-5 were newly discovered named macrostemonoside U-Y, respectively. We assessed the in vitro antioxidant properties of the nine steroidal saponins through free radical scavenging and reducing power assays. This provides options for developing natural antioxidants. Additionally, an HPLC-ELSD quantitative analysis method was developed for the nine saponins in 12 batches of AMB from different origins and processing methods. The results showed that the contents of the nine steroidal saponins in AMB varied greatly among different growing environments and processing methods.

19.
Curr Med Chem ; 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38204228

RESUMO

BACKGROUND: Based on the Maillard reaction principle of red ginseng, this study innovatively synthesized a new amino acid derivative by combining arginine with lactose through simulated synthesis and was separated and purified through repeated silica gel and polyacrylamide gel (Bio-gel P-II) column chromatography. PURPOSE: The work was aimed at elucidating the synthesis of a novel amino acid derivative and investigating the intestinal protective activity of the novel amino acid derivative and possible molecular mechanism by establishing the intestinal injury model induced by cisplatin in mice. METHODS: The purity and molecular weight of the amino acid derivatives were determined to be by electrospray ionization mass spectrometry (ESI-MS). Subsequently, by establishing cisplatin (20 mg/kg)-induced intestinal injury in vivo for 10 days and IEC-6 cell model. The biochemical indexes and histopathological analysis were used to evaluate the oxidative stress and inflammatory and pathological changes of intestinal tissue in mice. The protein expression levels of p-Nuclear transcription factor-κB (p-NF-κB), cleaved caspase 3/caspase 3, cleaved caspase 9/caspase-9, Bcl-2, Bax, cytochrome C, phosphatidylinositol 3-kinase (PI3K), Protein Kinase B (Akt), p-PI3K, p-Akt were quantified through immunofluorescence staining and western blot analysis. RESULTS: The new amino acid derivatives of chemical structure were identified to be 1- (arginine-Nαgroup)-1-deoxy-4-O-(ß-D-galactopyranosyl)-D-fructose, named Argininylfructosyl- galactose (AFGA, C18H34N4O12). The results showed that pretreatment with a single AFGA dose remarkably alleviated cisplatin-evoked intestinal oxidative stress injury, and the levels of reactive oxygen species (ROS) were lessening in IEC-6 cells (p<0.05, p<0.01) and could effectively reduce the secretion of TNF-α and IL-1ß in serum and the expression level of NF-κB protein in intestinal tissues (p<0.01). Meantime, AFGA also significantly suppressed the caspase 3, caspase 9, cytochrome C and Bax protein expression in intestinal tissue in mice (p<0.01), and regulated the PI3K/Akt pathway (p<0.05, p<0.01). Importantly, the molecular docking results of AFGA also suggested a better binding ability with the above-mentioned related target proteins. CONCLUSION: The results clearly revealed AFGA as a potential multifunctional therapeutic agent with a clear protective effect against cisplatin-induced intestinal injury may be related to the PI3K/Akt signaling pathway.

20.
Phytomedicine ; 135: 156063, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39305744

RESUMO

BACKGROUND: Damage to the blood-brain barrier (BBB) is vital for the development of Alzheimer's disease (AD). Ginsenoside Rg2 (G-Rg2) has been shown to improve a variety of brain injuries, but whether G-Rg2 can improve the BBB leakage related to AD is still unclear. PURPOSE: Illuminate the effect and mechanism of G-Rg2 on AD-related BBB damage. To clarify the role of G-Rg2 in Toll-like receptor pathway and oxidative stress pathway and its effect on tight junction proteins (TJs) expression in vivo and in vitro experiments. METHODS AND RESULTS: In our research, the tightness of the BBB was improved and the inflammatory pathway was suppressed after 4 weeks of treatment with G-Rg2 (10 mg kg-1 and 20 mg kg-1) in aluminum trichloride (AlCl3) plus d-galactose (D-gal) caused AD mice (p < 0.05; p < 0.01). Concurrently, the stability of TJs in mouse brain endothelial cells (bEnd3) was improved after okadaic acid (OA) -induced AD model cells were pretreated with G-Rg2 (5 µM, 10 µM, and 20 µM) for 24 h (p < 0.05; p < 0.01). The oxidative stress pathway and Toll-like receptor pathway in mouse astrocyte-cerebellum (MA-c) were inhibited (p < 0.05; p < 0.01). Meanwhile, in vitro interaction model results showed that G-Rg2 reduced the activation of MA-c, thereby alleviating the degradation of TJs in bEnd3 (p < 0.05; p < 0.01). The co-culture system of MA-c and bEnd3 further clearly demonstrated that G-Rg2 (20 µM) could improve their interaction and enhance BBB tightness. CONCLUSION: This study suggests that G-Rg2 can inhibit the TLR4/MyD88/MMP9 inflammatory pathway by reducing the activation of MA-c and the binding of TLR4 to MyD88, thereby decreasing the secretion of inflammatory factors and matrix metalloproteinases (MMPs), hence maintaining the stability of TJs in bEnd3, which may be one of the mechanisms of G-Rg2 in reducing AD-related BBB damage.

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