Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
J Biochem Mol Toxicol ; : e22543, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32627270

RESUMO

The current work planned to assess the protecting properties of nimbolide against doxorubicin (DOX)-treated myocardial damage. Myocardial damage was produced with 2.5 mg/kg of DOX given on alternative days (14 days). Thiobarbituric acid reactive substances (TBARS) levels of a lipid peroxidative marker were elevated, whereas reduced body weight, heart weight, blood pressure indices and reduced levels of antioxidants like glutathione-S-transferase, superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione reductase were observed in the heart tissue of DOX-treated animals. DOX-treated animals showed augmented levels of cardiac markers likes monocyte chemotactic protein-1, interferon-gamma, aspartate transferase, creatine kinase, lactate dehydrogenase, creatine kinase-muscle/brain, heart-type fatty acid-binding protein, glycogen phosphorylase isoenzyme BB, transforming growth factor-ß, brain natriuretic peptide, myoglobin, and cTnI in serum. Histopathological assessment confirmed the DOX-induced cardiotoxicity. Furthermore, DOX-induced rats showed augmented inflammatory mediators (nuclear factor-κB [NF-kB], tumor necrosis factor-α [TNF-α], and interleukin-1ß [IL-1ß]) and increased PI3K/Akt signaling proteins (PI3K, p-Bad/Bad, caspase-3, and p-Akt), whereas decreased oxidative markers (HO-1 and NQO-1) and p-PTEN were observed. Nimbolide-supplemented rats showed reduced activity/levels of cardiac markers and TBARS levels in serum and heart tissue. Levels of enzymatic and nonenzymatic antioxidants were augmented in the heart tissue of nimbolide-supplemented rats. Nimbolide influence decreased apoptosis, inflammation, and enhanced antioxidant markers through the modulation of p-Bad/Bad, caspase-3, PI3K, p-Akt, TNF-α, NF-kB, IL-1ß, HO-1, NQO-1, and p-PTEN markers. The histopathological explanations were observed to be in line with biochemical analysis. Therefore, the finding of current work was that nimbolide has a defensive effect on the myocardium against DOX-induced cardiac tissue damage.

2.
Biochimie ; 175: 58-68, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32445654

RESUMO

Hepatocellular carcinoma (HCC) is a major malignancy that stands second in terms of global cancer-related mortality. STAT3 has been described as a latent transcription factor that promotes tumorigenesis. This study was designed to examine the effect of vitexin on STAT3 signaling and important hallmarks of cancer. HCC cells were employed to decipher the impact of vitexin on activation of STAT3 signaling using Western blotting, EMSA, immunocytochemistry, and reporter assay. The combinational apoptotic effects of vitexin with approved anti-cancer drugs was examined by live-dead assay, and its anti-invasive potential was studied using matrigel assay. The results obtained in cell-based assays were verified using in silico analysis. Vitexin effectively inhibited sustained activation of JAK1, JAK2, Src, and STAT3 in HCC cells. Vitexin downregulated DNA binding ability, reduced the nuclear pool of STAT3, and diminished epidermal growth factor (EGF)-driven STAT3 gene expression. Interestingly, treatment with tyrosine phosphatase inhibitor altered the vitexin-induced STAT3 phosphorylation, and the attenuation of STAT3 by vitexin was found to be driven through the upregulation of PTPεC. The combinational studies indicated that vitexin can exhibit substantial apoptotic effects with doxorubicin and sorafenib. It also suppressed the CXCL12-induced cell invasion. The results of cell-based assays are supported by in silico analysis as the vitexin displayed favorable interaction with kinase domain of JAK2 protein. Overall, this study demonstrated that vitexin can act as a potential blocker of the STAT3 signaling cascade and mitigate the survival as well as invasion of HCC cells.

3.
Molecules ; 25(6)2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183146

RESUMO

Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted that EVO showed cytotoxicity and anti-proliferation activities in PC-3 and DU145 cells. Next, we found that EVO markedly inhibited HGF-induced c-Met/Src/STAT3 phosphorylation and impaired the nuclear translocation of STAT3 protein. Then, we noted that EVO arrested the cell cycle, caused apoptosis, and downregulated the expression of various carcinogenic markers such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cyclin D1, cyclooxygenase 2 (COX-2), survivin, vascular endothelial growth factor (VEGF), and matrix metallopeptidases 9 (MMP-9). Moreover, it was observed that in cPC-3 and DU145 cells transfected with c-Met small interfering RNA (siRNA), Src/STAT3 activation was also mitigated and led to a decrease in EVO-induced apoptotic cell death. According to our results, EVO can abrogate the activation of the c-Met/Src/STAT3 signaling axis and thus plays a role as a robust suppressor of tumor cell survival, proliferation, and angiogenesis.

4.
Int J Mol Sci ; 21(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041250

RESUMO

The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1ß, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury.

5.
J Photochem Photobiol B ; 203: 111773, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31931385

RESUMO

Glioma is the prime cause of cancer allied mortality in adolescent people and it accounts about 80% of all malignant tumours. Eugenol is a major bioactive constituent present in the essential oils with numerous pharmacological benefits including nueroprotective activity. The major drawback of eugenol is its extreme volatile property and oxygen sensitivity therefore we increased the efficacy of drug; eugenol by encapsulating with chitosan polymer. Eugenol loaded chitosan polymer (EuCs) was characterized using FTIR, XRD, SEM, HR-TEM analysis and the encapsulation, drug release efficacy was assessed at in vitro condition. The induction of autophagy and anticancer efficacy of EuCs on glioma cells was evaluated with rat C6 glioma cells using MTT assay, acridine orange staining, immunocytochemical analysis of NFκß protein expression and FLOW cytometric analysis. The anti-metastatic property of Eu-CS was assessed by immunoblotting and RT-PCR analysis of epithelial mesenchymal transition protein expression in EuCs treated rat C6 glioma cells. Our characterization analysis proves that EuCs possess essential physical and functional properties of copolymer to be utilized as a drug. Further the MTT analysis and AO staining confirms even in the presence of oncogenic inducer and autophagic inhibitors, EuCs exhibits apoptotic potency on rat C6 glioma cells. The result of immunocytochemical studies depicts the inhibition of NFκß protein expression and flow cytometry studies confirm apoptosis induction by EuCs. The inhibition of metastasis by EuCs was proven by the decrease in epithelial mesenchymal transition protein expression in Eu-Cs treated rat C6 glioma cells. Over all our results authentically confirms eugenol loaded chitosan nanopolymer persuasively induces apoptosis and inhibits metastasis in rat C6 glioma cells.


Assuntos
Antineoplásicos/química , Apoptose/efeitos dos fármacos , Quitosana/química , Eugenol/química , Metaloproteinase 9 da Matriz/metabolismo , Nanoestruturas/química , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Eugenol/farmacologia , Glioma/metabolismo , Glioma/patologia , NF-kappa B/metabolismo , Ratos , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
6.
J Photochem Photobiol B ; 203: 111749, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31884347

RESUMO

Gastric cancer (GC) is mainly widespread gastrointestinal malignancy,which reports for 8% of overallcases in carcinogenesis and 10% of yearly fatality, is 4thprimary cause of cancer associated death global. The plan of the present research was to develop ethanolic extract of Vitex negundo-loaded gold nanoparticles (VN-AuNPs) and to appraise the various characteristic methods likes UV-vis spectroscopy, SAED, FTIR, XRD and HR-TEM. Additionally, the anticancer effect of VN-AuNPs on AGS cells were analysed by cell viability, apoptotic morphological changes by TUNEL, AO/EtBr and Hoechst staining, alterations of mitochondrial membrane potential (MMP) and production reactive oxygen species (ROS). Moreover, the status of apoptosis gene such as caspase-3, Bcl-2, Bcl-XL, Bax and caspase-9 expressions was analysed by using western and RT-PCR techniques. Synthesized AuNPs established by UV absorption peak of the highest at 538 and crystal nature of AuNPs was additionallyverifiedwith SAED and XRD. TEM images were illustrates size and morphological division of NPs. FTIR examinationscompletedalkene, carbodiimide and aliphatic primary amines of biomolecules werepresent in synthesized VN-AuNPs. Additionally, AuNPs were stimulatedapoptosis throughthe cytotoxicity effect,changes of MMP, generation of ROS, nuclear and apoptotic morphological alterationsvia TUNEL, AO/EtBr and Hoechst assay. Furthermore, molecular mechanisms also provoked apoptosis through modulating pro (caspase-3, Bax, Bid, caspase-9) and anti-apoptotic (Bcl-2 and Bcl-XL) mediators by western blotting and gene expression in AGS cells. This production of AuNPs from VN was eco-friendly, large-scaled up and easy.


Assuntos
Apoptose/efeitos dos fármacos , Ouro/química , Nanopartículas Metálicas/toxicidade , Vitex/química , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Química Verde , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/química , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Vitex/metabolismo
7.
Biomolecules ; 9(12)2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847229

RESUMO

STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

8.
Biomolecules ; 10(1)2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878046

RESUMO

Daidzin (DDZ) extracted from Pueraria lobate (Fabaceae) is a widely known phytoestrogen. DDZ can display anti-cancer activities against breast and prostate cancers, but its anti-oncogenic actions in multiple myeloma (MM) cells have not been studied. The signal transducer and activator of transcription 3 (STAT3) can control key processes including proliferation, differentiation, and survival in MM cells. Here, we noted that DDZ abrogated STAT3 activation (both constitutive as well as inducible) at Tyr705 and Ser727 in MM cells. Additionally, DDZ mitigated the phosphorylation of STAT3 upstream Janus-activated kinases (JAK1/2) and c-Src kinases. Pervanadate (tyrosine phosphatase blocker) exposure altered the DDZ-induced inhibition of STAT3 activation, thus affecting the action of this phytoestrogen on apoptosis. Moreover, DDZ impeded proliferation and augmented the apoptotic effects of bortezomib (Bor) in MM cells. Overall, the data indicate that DDZ may act as a potent suppressor of STAT3 signaling cascade, and the co-treatment of DDZ and Bor could be a promising therapeutic strategy, specifically in MM.

9.
Pharmacol Res ; 150: 104504, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31678208

RESUMO

Epithelial mesenchymal transition (EMT) refers to a phenomenon through which epithelial cells develop the metastatic and invasive potential, which are closely related to carcinogenesis. Farnesol (FOH) obtained from the oils of diverse plants can exhibit significant therapeutic actions against obesity, diabetes, inflammatory conditions and cancers. Here, we evaluated the potential effects of FOH on growth and metastasis and it was observed that FOH significantly abrogated cell proliferation in lung cancer cells. Moreover, FOH inhibited cell repair movement by wound healing assay and reduced cell adhesion. It suppressed the expression of mesenchymal genes such as fibronectin, vimentin, N-cadherin, twist, and snail, and increased expression of epithelial genes such as occludin and E-cadherin. It also attenuated the migration and invasion through the inhibition of the PI3K/Akt/mTOR signaling pathway. Furthermore, FOH inhibited the tumor growth of xenograft mouse lung cancer model, and modulated the expression of mesenchymal and epithelial markers. The results suggest that FOH may block the PI3K/Akt/mTOR signaling pathway and thus exhibit anti-proliferative and anti-metastatic activity against lung cancer cells.

10.
Molecules ; 24(17)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466313

RESUMO

Fangchinoline (FCN) derived from Stephaniae tetrandrine S. Moore can be employed to treat fever, inflammation, rheumatism arthralgia, edema, dysuria, athlete's foot, and swollen wet sores. FCN can exhibit a plethora of anti-neoplastic effects although its precise mode of action still remains to be deciphered. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) can closely regulate carcinogenesis and thus we analyzed the possible action of FCN may have on these two signaling cascades in tumor cells. The effect of FCN on NF-κB and AP-1 signaling cascades and its downstream functions was deciphered using diverse assays in both human chronic myeloid leukemia (KBM5) and multiple myeloma (U266). FCN attenuated growth of both leukemic and multiple myeloma cells and repressed NF-κB, and AP-1 activation through diverse mechanisms, including attenuation of phosphorylation of IκB kinase (IKK) and p65. Furthermore, FCN could also cause significant enhancement in TNFα-driven apoptosis as studied by various molecular techniques. Thus, FCN may exhibit potent anti-neoplastic effects by affecting diverse oncogenic pathways and may be employed as pro-apoptotic agent against various malignancies.


Assuntos
Benzilisoquinolinas/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Mieloma Múltiplo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Quinase I-kappa B/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Biomolecules ; 9(7)2019 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-31284669

RESUMO

Here, we determined the anti-neoplastic actions of formononetin (FT) against multiple myeloma (MM) and elucidated its possible mode of action. It was observed that FT enhanced the apoptosis caused by bortezomib (Bor) and mitigated proliferation in MM cells, and these events are regulated by nuclear factor-κB (NF-κB), phosphatidylinositol 3-kinase (PI3K)/AKT, and activator protein-1 (AP-1) activation. We further noted that FT treatment reduced the levels of diverse tumorigenic proteins involved in myeloma progression and survival. Interestingly, we observed that FT also blocked persistent NF-κB, PI3K/AKT, and AP-1 activation in myeloma cells. FT suppressed the activation of these oncogenic cascades by affecting a number of signaling molecules involved in their cellular regulation. In addition, FT augmented tumor growth-inhibitory potential of Bor in MM preclinical mouse model. Thus, FT can be employed with proteasomal inhibitors for myeloma therapy by regulating the activation of diverse oncogenic transcription factors involved in myeloma growth.


Assuntos
Antineoplásicos/farmacologia , Bortezomib/farmacologia , Isoflavonas/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Knockout , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo
12.
Phytomedicine ; 59: 152907, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981183

RESUMO

BACKGROUND: Cycloastragenol (CAG), a triterpene aglycone is commonly prescribed for treating hypertension, cardiovascular disease, diabetic nephropathy, viral hepatitis, and various inflammatory-linked diseases. HYPOTHESIS: We investigated CAG for its action on signal transducer and activator of transcription 3 (STAT3) activation cascades, and its potential to sensitize gastric cancer cells to paclitaxel-induced apoptosis. METHODS: The effect of CAG on STAT3 phosphorylation and other hallmarks of cancer was deciphered using diverse assays in both SNU-1 and SNU-16 cells. RESULTS: We observed that CAG exhibited cytotoxic activity against SNU-1 and SNU-16 cells to a greater extent as compared to normal GES-1 cells. CAG predominantly caused negative regulation of STAT3 phosphorylation at tyrosine 705 through the abrogation of Src and Janus-activated kinases (JAK1/2) activation. We noted that CAG impaired translocation of STAT3 protein as well as its DNA binding activity. It further decreased cellular proliferation and mediated its anticancer effects predominantly by causing substantial apoptosis rather than autophagy. In addition, CAG potentiated paclitaxel-induced anti-oncogenic effects in gastric tumor cells. CONCLUSIONS: Our results indicate that CAG can function to impede STAT3 activation in human gastric tumor cells and therefore it may be a suitable candidate agent for therapy of gastric cancer.


Assuntos
Apoptose/efeitos dos fármacos , Paclitaxel/farmacologia , Fator de Transcrição STAT3/metabolismo , Sapogeninas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinase 1 , Janus Quinase 2/metabolismo , Paclitaxel/administração & dosagem , Fosforilação/efeitos dos fármacos , Fitoterapia , Fator de Transcrição STAT3/genética , Sapogeninas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos
13.
J Cell Biochem ; 120(3): 4504-4513, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30260018

RESUMO

Oleuropein is one of the most abundant phenolic compounds found in olives. Epidemiological studies have indicated that an increasing intake of olive oil can significantly reduce the risk of breast cancer. However, the potential effect(s) of oleuropein on estrogen receptor (ER)-negative breast cancer is not fully understood. This study aims to understand the anticancer effects and underlying mechanism(s) of oleuropein on ER-negative breast cancer cells in vitro. The effect of oleuropein on the viability of breast cancer cell lines was examined by mitochondrial dye-uptake assay, apoptosis by flow cytometric analysis, nuclear factor-κB (NF-κB) activation by DNA binding/reporter assays and protein expression by Western blot analysis. In the present report, thiazolyl blue tetrazolium bromide assay results indicated that oleuropein inhibited the viability of breast cancer cells, and its effects were more pronounced on MDA-MB-231 as compared with MCF-7 cells. It was further found that oleuropein increased the level of reactive oxygen species and also significantly inhibited cellular migration and invasion. In addition, the activation of NF-κB was abrogated as demonstrated by Western blot analysis, NF-κB-DNA binding, and luciferase assays. Overall, the data indicates that oleuropein can induce substantial apoptosis via modulating NF-κB activation cascade in breast cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama , Iridoides/farmacologia , NF-kappa B/metabolismo , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7
14.
Langmuir ; 35(5): 1727-1739, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29925240

RESUMO

Poly(ethylene terephtalate) (PET)-based materials face general biofouling issues that we addressed by grafting a copolymer of glycidyl methacrylate and sulfobetaine methacrylate, poly(GMA- r-SBMA). The grafting procedure involved a dip-coating step followed by UV-exposure and led to successful grafting of the copolymer as evidenced by X-ray photoelectron spectroscopy and zeta potential measurements. It did not modify the pore size nor the porosity of the PET membranes. In addition, their surface hydrophilicity was considerably improved, with a water contact angle falling to 30° in less than 20 s and 0° in less than 1 min. The effect of copolymer concentration in the coating bath (dip-coating procedure) and UV exposure time (UV step) were scrutinized during biofouling studies involving several bacteria such as Escherichia coli and Stenotrophomonas maltophilia, but also whole blood and HT1080 fibroblasts cells. The results indicate that if all conditions led to improved biofouling mitigation, due to the efficiency of the zwitterionic copolymer and grafting procedure, a higher concentration (15 mg/mL) and longer UV exposure time (at least 10 min) enhanced the grafting density which reflected on the biofouling results and permitted a better general biofouling control regardless of the nature of the biofoulant (bacteria, blood cells, fibroblasts).


Assuntos
Polietilenotereftalatos/química , Aderência Bacteriana/efeitos dos fármacos , Betaína/análogos & derivados , Betaína/síntese química , Betaína/química , Incrustação Biológica/prevenção & controle , Células Sanguíneas/efeitos dos fármacos , Linhagem Celular Tumoral , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Escherichia coli/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Metacrilatos/síntese química , Metacrilatos/química , Polietilenotereftalatos/síntese química , Stenotrophomonas maltophilia/efeitos dos fármacos
15.
J Cell Biochem ; 120(6): 9787-9798, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30520154

RESUMO

Casticin (CTC), one of the major components of Vitex rotundifolia L., has been reported to exert significant beneficial pharmacological activities and can function as an antiprolactin, anticancer, anti-inflammatory, neuroprotective, analgesic, and immunomodulatory agent. This study aimed at investigating whether the proapoptotic effects of CTC may be mediated through the abrogation of signal transducers and activators of transcription-3 (STAT3) signaling pathway in a variety of human tumor cells. We found that CTC significantly decreased cell viability in a concentration-dependent manner and suppressed cell proliferation in 786-O, YD-8, and HN-9 cells. CTC also induced programmed cell death that was found to be mediated via caspase-3 activation and induction of poly(ADP-ribose) polymerase cleavage. Interestingly, CTC repressed both constitutive and interleukin-6-induced STAT3 activation in 786-O and YD-8 cells but only affected constitutive STAT3 phosphorylation in HN-9 cells. Moreover, CTC could potentiate ionizing radiation-induced apoptotic effects leading to the downregulation of STAT3 activation and thus may be used in combination with radiation against diverse malignancies.

16.
Front Pharmacol ; 9: 1294, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30564115

RESUMO

Overexpression of chemokine receptor type 4 (CXCR4) has been found to be associated with increased cell proliferation, metastasis and also act as an indicator of poor prognosis in patients with breast cancer. Therefore, new agents that can abrogate CXCR4 expression have potential against breast cancer metastasis. In this study, we examined the potential effect of thymoquinone (TQ), derived from the seeds of Nigella sativa, on the expression and regulation of CXCR4 in breast cancer cells. TQ was found to inhibit the expression of CXCR4 in MDA-MB-231 triple negative breast cancer (TNBC) cells in a dose- and time-dependent manner. It was noted that suppression of CXCR4 by TQ was possibly transcriptionally regulated, as treatment with this drug caused down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and suppression of NF-κB binding to the CXCR4 promoter. Pretreatment with a proteasome inhibitor and/or lysosomal stabilization did not affect TQ induced suppression of CXCR4. Down-regulation of CXCR4 was further correlated with the inhibition of CXCL12-mediated migration and invasion of MDA-MB-231 cells. Interestingly, it was observed that the deletion of p65 could reverse the observed anti-invasive/anti-migratory effects of TQ in breast cancer cells. TQ also dose-dependently inhibited MDA-MB-231 tumor growth and tumor vascularity in a chick chorioallantoic membrane assay model. We also observed TQ (2 and 4 mg/kg) treatment significantly suppressed multiple lung, brain, and bone metastases in a dose-dependent manner in a metastasis breast cancer mouse model. Interestingly, H&E and immunohistochemical analysis of bone isolated from TQ treated mice indicated a reduction in number of osteolytic lesions and the expression of metastatic biomarkers. In conclusion, the results indicate that TQ primarily exerts its anti-metastatic effects by down-regulation of NF-κB regulated CXCR4 expression and thus has potential for the treatment of breast cancer.

17.
Front Pharmacol ; 9: 1125, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455641

RESUMO

Hepatocellular carcinoma (HCC) is a fatal disease and ranked fifth in cancer related mortality. Persistent activation of NF-κB is responsible for the oncogenesis, metastasis, tumor evasion, anti-apoptosis, angiogenesis and proliferation in HCC. Therefore, designing of chemically novel, biologically potent small molecules that target NF-κB signaling cascade have gained prominent clinical interest. Herein we synthesized a novel class of 4-(substituted)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one by reacting 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one with various alkyl halides by using combustion derived bismuth oxide. We evaluated the antiproliferative efficacy of newly synthesized compounds against HCC cells and identified 4-(4-nitrobenzyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (NPO) as lead anticancer agent. In addition, we investigated the effect of NPO on the DNA binding ability of NF-κB and NF-κB regulated luciferase expression in HCC cells. The results demonstrated that NPO can induce significant growth inhibitory effects in HepG2, HCCLM3 and Huh-7 cells in dose and time-dependent manner. Interestingly, NPO induced significant downregulation in p65 DNA binding ability, p65 phosphorylation and subsequent expression of NF-κB dependent luciferase gene expression in diverse HCC cell lines. Further, in silico docking analysis suggested that NPO can show direct physical interaction with NF-κB. Finally, NPO was found to significantly abrogate tumor growth at a dose of 50 mg/kg in an orthotopic mouse model. Thus, we report the potential anticancer effects of NPO as a novel inhibitor of NF-κB signaling pathway in HCC.

18.
Cancers (Basel) ; 10(7)2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29996471

RESUMO

Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study, we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer in comparison to normal tissues. The downregulation of NGAL was strongly correlated with both degree of differentiation and stage (I⁻IV); it can also serve as a prognostic biomarker for oral cancer. Additionally, tobacco carcinogens were found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration; it also induced resistance against cisplatin. Silencing of NGAL activated mammalian target of rapamycin (mTOR)signaling and reduced autophagy by the liver kinase B1 (LKB1)-activated protein kinase (AMPK)-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and matrix metalloproteinase-9 (MMP-9) were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study, it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer.

20.
Front Oncol ; 8: 42, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29616186

RESUMO

Aberrant activation of NF-κB is linked with the progression of human malignancies including hepatocellular carcinoma (HCC), and blockade of NF-κB signaling could be a potential target in the treatment of several cancers. Therefore, designing of novel small molecule inhibitors that target NF-κB activation is of prime importance in the treatment of several cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells, and identified 2-(3-chlorobenzo[b]thiophen-2-yl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (CMO) as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry), apoptosis (annexin V-propidium iodide-FITC staining), and phosphorylation of NF-κB signaling pathway proteins (IκB and p65) in HCC cells. We found that CMO induced antiproliferative effect in dose- and time-dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IκB (Ser 32) in the cytoplasmic extract and p65 (Ser 536) in the nuclear extract of HCC cells. It also abrogated the DNA binding ability and transcriptional activity of NF-κB. CMO induced the cleavage of PARP and caspase-3 in a time-dependent manner. In addition, transfection with p65 small interfering RNA blocks CMO-induced caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with the hydrophobic region of p65 protein. Thus, we are reporting CMO as an inhibitor of NF-κB signaling pathway.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA