RESUMO
Hepatocellular carcinoma (HCC) has poor prognosis due to the advanced disease stages by the time it is diagnosed, high recurrence rates and metastasis. In the present study, we investigated the effects of metformin (a safe anti-diabetic drug) and curcumin (a turmeric polyphenol extracted from rhizome of Curcuma longa Linn.) on proliferation, apoptosis, invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. It was found that co-treatment of metformin and curcumin could not only induce tumor cells into apoptosis through activating the mitochondria pathways, but also suppress the invasion, metastasis of HCC cells and angiogenesis of HUVECs. These effects were associated with downregulation of the expression of MMP2/9, VEGF, and VEGFR-2, up-regulation of PTEN, P53 and suppression of PI3K/Akt/mTOR/NF-κB and EGFR/STAT3 signaling. Co-administration of metformin and curcumin significantly inhibited HCC tumor growth than administration with metformin or curcumin alone in a xenograft mouse model. Thus, metformin and curcumin in combination showed a better anti-tumor effects in hepatoma cells than either metformin or curcumin presence alone and might represent an effective therapeutic strategy for HCC treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Curcumina/administração & dosagem , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Metformina/administração & dosagem , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Sambutoxin, a representative derivative of 4-hydroxy-2-pyridone, was isolated from Hericium alpestre for the first time in this study. The possible correlation between the sambutoxin-induced suppression of tumor growth and its influence on cell-cycle arrest and apoptosis was investigated. The effects of sambutoxin on reactive oxygen species (ROS) production, DNA damage, mitochondrial transmembrane potential, cell apoptosis, and the expression of related proteins were evaluated. An in vitro cell viability study demonstrated that sambutoxin could inhibit the proliferation of various cancer cells. Treatment with sambutoxin induced the production of ROS, which caused DNA damage. Furthermore, the subsequent sambutoxin-induced activation of ATM and Chk2 resulted in G2/M arrest, accompanied by decreased expression of cdc25C, cdc2, and cyclin B1. Sambutoxin induced apoptosis by activating the mitochondrial apoptosis pathway through an increased Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (ΔΨm), cytochrome (Cyt) c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) degradation. The ROS elevation induced the sustained phosphorylation of c-Jun N-terminal kinase (JNK), while SP600125, a JNK inhibitor, nearly completely reversed sambutoxin-induced apoptosis. Accordingly, an in vivo study showed that sambutoxin exhibited potential antitumor activity in a BALB/c nude mouse xenograft model without significant systemic toxicity. Moreover, the expression changes in proteins related to the G2/M phase, DNA damage, and apoptosis in vivo were consistent with those in vitro. Importantly, sambutoxin has remarkable antiproliferative effects and is a promising anticarcinogen candidate for cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Micotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Basidiomycota/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micotoxinas/química , Micotoxinas/isolamento & purificação , Micotoxinas/uso terapêutico , Neoplasias/patologia , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The aim of the present study was to evaluate the antitumor effects of 2,2',4'-trihydroxychalcone (7a) on the A549 human lung cancer cell line. A549 cells were treated with different concentrations of 7a for different time periods. Cells without 7a were used as the negative control group. Cell proliferation, invasion, vasculogenic mimicry (VM) formation, heterogeneous adhesion and apoptosis were measured using Cell Counting Kit-8, Transwell invasion, VM, adhesion and flow cytometric assays, respectively. In addition, the expression of related proteins was determined using western blot analysis or ELISA. The present study found that 7a had a significant inhibitory effect on the survival rate of the A549 lung cancer cells but almost no effect on BEAS-2B human lung epithelial cells or human venous endothelial cells. The migration rate, VM length, invasion rate and heterogeneous adhesion number of cells treated with 7a significantly decreased as the concentration increased, while the apoptosis rate increased. Western blot analysis showed that 7a treatment significantly increased the expression levels of E-cadherin, cleaved poly (ADP-ribose) polymerase, Bax and caspase-3 and simultaneously decreased the expression levels of metalloproteinase-2/9, Bcl-2, phosphorylated (p)-PI3K, p-AKT, p-mTOR, vascular endothelial growth factor (VEGF), E-selectin and N-cadherin. At the same time, the ELISA results showed that the level of the pro-angiogenic factor VEGF in the culture media was reduced in the presence of 7a. In addition, 7a could also reduce the nuclear NF-κB protein expression, which could inhibit the gene transcription of tumor apoptosis and metastasis-related proteins. Therefore, 7a may exert inhibitory effects on A549 cells by inhibiting cell proliferation, migration, VM formation and heterogeneous adhesion, as well as by inducing apoptosis through the suppression of the PI3K/AKT/NF-κB signaling pathway; these findings suggested that 7a may be a promising agent for the treatment of lung cancer.
RESUMO
Galectin-3 (gal-3), a member of the galectin family, is a glycoprotein with high affinity for ß-galactoside. Gal-3 is a cytoplasmically synthesized protein that can shuttle between the cytoplasm and nucleus and can even be transported to the membrane and secreted into the extracellular environment. Cardio/cerebrovascular diseases generally refer to ischemic or hemorrhagic diseases occurring in the heart, brain and systemic tissues, which are characterized by high morbidity, high disability rates and high mortality rates. To date, considerable research has demonstrated that gal-3 expression is aberrantly increased and plays important roles in cardio/cerebrovascular diseases, such as acute ischemic stroke (AIS), myocardial fibrosis, acute coronary syndrome (ACS), and heart failure (HF). Hence, understanding the biological roles of gal-3 in these diseases may be essential for cardio/cerebrovascular disease treatment and diagnosis to improve patient quality of life. In this review, we summarize current research on the roles of gal-3 in human cardiovascular diseases and potential inhibitors of gal-3, which may provide new strategies for disease therapies.
Assuntos
Proteínas Sanguíneas/metabolismo , Doenças Cardiovasculares/metabolismo , Transtornos Cerebrovasculares/metabolismo , Galectinas/metabolismo , Transdução de Sinais , Animais , Proteínas Sanguíneas/antagonistas & inibidores , Proteínas Sanguíneas/genética , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/genética , Galectinas/antagonistas & inibidores , Galectinas/genética , Humanos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
Hepatic diseases include all diseases that occur in the liver, including hepatitis, cirrhosis, hepatocellular carcinoma, etc. Hepatic diseases worldwide are characterized by high incidences of digestive system diseases, which present with subtle symptoms, are difficult to treat and have high mortality. Galectins are ß-galactoside-binding proteins that have been found to be aberrantly expressed during hepatic disease progression. An increasing number of studies have shown that abnormal expression of galectins is extensively involved in hepatic diseases, such as hepatocellular carcinoma (HCC), liver cirrhosis, hepatitis and liver fibrosis. Galectins function as intracellular and extracellular hepatic disease regulators mainly through the binding of their carbohydrate recognition domain to glycoconjugates expressed in hepatocytes. In this review, we summarize current research on the various roles of galectins in cirrhosis, hepatitis, liver fibrosis and HCC, which may provide a preliminary theoretical basis for the exploration of new targets for the treatment of hepatic diseases.
Assuntos
Suscetibilidade a Doenças , Galectinas/genética , Galectinas/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Animais , Regulação da Expressão Gênica , Humanos , Imunomodulação , Hepatopatias/diagnóstico , Família Multigênica , Transdução de SinaisRESUMO
Neural (N)-cadherin is a calcium-dependent single-chain transmembrane glycoprotein that mediates homotypic and heterotypic cell-cell adhesion. As an important member of the cadherin family, N-cadherin plays an important role in the developmental and functional regulation of the nervous system, brain, heart, skeletal muscles, blood vessels and hematopoietic microenvironment. However, aberrant expression of N-cadherin has been found in many cancers, such as lung cancer, breast cancer, prostate cancer and squamous cell carcinoma. It is increasingly recognized that aberrant expression of N-cadherin is closely related to aspects of malignant tumor progression in humans, such as transformation, adhesion, apoptosis, angiogenesis, invasion and metastasis, suggesting that N-cadherin can be a therapeutic target for tumor invasion and metastasis. This minireview summarizes the diverse roles of N-cadherin in cancer progression and the regulatory factors that affect the expression of N-cadherin in cancer, findings that increase our awareness of the importance of developing new therapeutic agents targeting N-cadherin.
Assuntos
Caderinas/metabolismo , Neoplasias/metabolismo , Animais , Caderinas/genética , Adesão Celular , Movimento Celular , Sobrevivência Celular , Humanos , Modelos Biológicos , Neoplasias/irrigação sanguínea , Neoplasias/genética , Neoplasias/patologiaRESUMO
An acid/base responsive amphiphilic [2]rotaxane switch containing a hydrophilic macrocycle component and a hydrophobic terminal bulky group was prepared and characterized. The morphology of the supramolecular assemblies formed by the rotaxanes could be switched between spherical vesicles and worm-like micelles using acid/base stimuli, as confirmed by transmission electron microscopy (TEM).
RESUMO
SCOPE: Although the previous trials of inflammation have indicated that morin hydrate (MO) hold considerable promise, understanding the distinct mechanism of MO against inflammation remains a challenge. METHODS AND RESULTS: This study investigated the effect of MO in atherosclerosis in ApoE-/- mice and underlying cell signaling of MO effect in inflammation in human umbilical vein endothelial cells (HUVECs). Administration of MO significantly reduced serum lipid level, inflammatory cytokines (TNF-α and ICAM-1), and atherosclerotic plaque formation in vivo. MO presence attenuated the expression of TNF-α-induced inflammatory cytokines (ICAM-1, COX-2, and MMP-9), and remarkably enhanced microtubule associated protein 1 light chain 3 beta 2 (MAP1LC3B2) expression and sequestosome 1 (SQSTM1/p62) degradation in HUVECs. These MO effects were significantly prevented by the presence of autophagic inhibitors, 3-methyladenine (3-MA), or chloroquine (CQ), as well as siRNA suppression of ATG5 and BECN1. MO increased intracellular cAMP levels and activated cAMP-PKA-AMPK-SIRT1 signaling in vivo and in vitro. These changes resulted in increased expression of autophagy-related protein MAP1LC3B2 and decreased secretion of inflammatory cytokines (ICAM-1, COX-2, and MMP-9). CONCLUSION: Our results suggest that anti-AS and anti-inflammatory effects of MO are largely associated with its induction of autophagy through stimulation of cAMP-PKA-AMPK-SIRT1 signaling pathway.
Assuntos
Anti-Inflamatórios/farmacologia , Aterosclerose/tratamento farmacológico , AMP Cíclico/fisiologia , Flavonoides/farmacologia , Transdução de Sinais/fisiologia , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Flavonoides/uso terapêutico , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Galectin-4, a tandem repeat member of the ß-galactoside-binding proteins, possesses two carbohydrate-recognition domains (CRD) in a single peptide chain. This lectin is mostly expressed in epithelial cells of the intestinal tract and secreted to the extracellular. The two domains have 40% similarity in amino acid sequence, but distinctly binding to various ligands. Just because the two domains bind to different ligands simultaneously, galectin-4 can be a crosslinker and crucial regulator in a large number of biological processes. Recent evidence shows that galectin-4 plays an important role in lipid raft stabilization, protein apical trafficking, cell adhesion, wound healing, intestinal inflammation, tumor progression, etc. This article reviews the physiological and pathological features of galectin-4 and its important role in such processes.
Assuntos
Galectina 4/metabolismo , Neoplasias/patologia , Animais , Axônios/metabolismo , Endocitose , Galectina 4/sangue , Galectina 4/genética , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Microdomínios da Membrana/metabolismo , Neoplasias/metabolismo , Neurônios/metabolismo , CicatrizaçãoRESUMO
A novel photo-responsive nano-container was successfully constructed based on well-defined vesicles formed by an amphiphilic overcrowded alkene switch. The nano-container could adjust its inner volume in reversible photo/heat controlled mode, which could show potential in remote drug delivery systems.
RESUMO
A fluorescent bistable [2]rotaxane terminated with an alkyne functional group was constructed and immobilized onto the surface of SiO2 nanoparticles through click reaction. The shuttling motion of the macrocycle component between two different stations was driven by external acid-base stimuli both in solution and on SiO2 nanoparticles, accompanied by visual fluorescence changes.
RESUMO
A multifunctional bis-branched [1]rotaxane containing a perylene bisimide (PBI) core and two identical bistable[1]rotaxane arms terminated with ferrocene units was prepared and characterized by (1)H NMR, (13)C NMR, and 2D ROESY NMR spectroscopies and by HR-ESI spectrometry. The system is shown to possess several key features: (1) In acetone solution, external acid-base stimuli can result in relative mechanical movements of its ring and thread, which can induce extension and contraction movements of the whole system accompanied by a rotational movement of the ferrocene units, thus realizing dual-mode molecular motions, and the optimized conformations at different states are obtained through molecular dynamics simulations employing the general Amber force field. (2) The introduction of PBI enables the system fluorescence encoding through distance-dependent photoinduced electron transfer process from the ferrocene units to the PBI fluorophore. (3) The addition of Zn(2+) can increase the degree of aggregation of the system, while adding base hinders aggregation because of the movement of the macrocycle. The tunable aggregated nanostructural morphologies of [1]rotaxane were examined by scanning electron microscopy. These results can pave the way to achieve precise control of integrated and coupling nanomechanical motions at a single-molecule level and provide more insight into controlling the aggregate behavior of switchable mechanically interlocked molecules.