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1.
Biomed Pharmacother ; 155: 113759, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36271548

RESUMO

The inhibition of sustained angiogenesis is an attractive approach for the treatment of cancer, blindness and other angiogenesis-dependent diseases. Encouraged by our previous finding that toluquinol, a methyl hydroquinone isolated from a marine fungus, exhibited an interesting antiangiogenic activity, we further explored structural modifications of this natural compound in order to develop improved drug candidates. Our results indicate that although the methyl group plays a relevant role in the cytotoxic activity of toluquinol, some derivatives in which this methyl was replaced by another substituent, could keep the antiangiogenic activity, whereas exhibiting a lower cytotoxicity in vitro. This is the case of (E)- 2-(3-methoxyprop-1-en-1-yl) benzene-1,4-diol, which exhibits a decreased toxicity, whereas maintaining or even improving the antiangiogenic activity of toluquinol, as demonstrated by a number of in vitro (endothelial cells proliferation, migration and tube formation) and in vivo (chick embryo chrorioallantoic membrane vascularization and murine corneal neovascularization) experimental approaches. Our results point to a mechanism of action that could be related to an induction of apoptosis, as well as to an increase in the reactive oxygen species levels, a reduction of the redox capacity and the inhibition of the VEGFR2, Akt and ERK phosphorylation in VEGF-activated endothelial cells. The biological activity of this new angiogenesis inhibitor, along with its lower undesired toxicity, suggests that it is a promising drug candidate with improved potential for the treatment of angiogenesis-related diseases.


Assuntos
Inibidores da Angiogênese , Hidroquinonas , Embrião de Galinha , Animais , Camundongos , Humanos , Inibidores da Angiogênese/uso terapêutico , Hidroquinonas/farmacologia , Hidroquinonas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Endoteliais/metabolismo , Espécies Reativas de Oxigênio , Benzeno , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Neovascularização Patológica/tratamento farmacológico , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo
2.
J Chem Educ ; 99(6): 2270-2276, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35722632

RESUMO

Metabolism is a challenging subject for bioscience students due to the intrinsic complexity of the metabolic network, as well as that of the overlapping mechanisms of metabolic regulation. Collaborative learning based on a problem-based learning approach can help students to successfully learn and understand metabolism. In the present article, we propose a selection of exercises, problems, and cases aimed to focus students' attention on the scientific work made by Sir Hans Krebs and his collaborators to elucidate four main metabolic cycles, as well as on the study of these cycles, their regulation, and their metabolic integration. The objectives, the tools, and the implementation of this proposal are described, and the results obtained during its first implementation with volunteer students enrolled in two courses on metabolic regulation at our university are presented and discussed. These volunteer students signed a learning contract and were randomly distributed in small groups (3-4 students each). Application of this collaborative learning activity to our classrooms has been very satisfactory, as evidenced by an improvement in the volunteers' academic performance and a very positive perception by most of them, who declared to be "very satisfied" or "satisfied" with their experience and felt that they had learned more.

3.
Brief Bioinform ; 23(4)2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35731990

RESUMO

BACKGROUND: Angiogenesis is regulated by multiple genes whose variants can lead to different disorders. Among them, rare diseases are a heterogeneous group of pathologies, most of them genetic, whose information may be of interest to determine the still unknown genetic and molecular causes of other diseases. In this work, we use the information on rare diseases dependent on angiogenesis to investigate the genes that are associated with this biological process and to determine if there are interactions between the genes involved in its deregulation. RESULTS: We propose a systemic approach supported by the use of pathological phenotypes to group diseases by semantic similarity. We grouped 158 angiogenesis-related rare diseases in 18 clusters based on their phenotypes. Of them, 16 clusters had traceable gene connections in a high-quality interaction network. These disease clusters are associated with 130 different genes. We searched for genes associated with angiogenesis througth ClinVar pathogenic variants. Of the seven retrieved genes, our system confirms six of them. Furthermore, it allowed us to identify common affected functions among these disease clusters. AVAILABILITY: https://github.com/ElenaRojano/angio_cluster. CONTACT: seoanezonjic@uma.es and elenarojano@uma.es.


Assuntos
Biologia Computacional , Doenças Raras , Algoritmos , Análise por Conglomerados , Humanos , Fenótipo , Doenças Raras/genética , Semântica
4.
Antioxidants (Basel) ; 11(2)2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35204185

RESUMO

Despite the extensive knowledge on cancer nature acquired over the last years, the high incidence of this disease evidences a need for new approaches that complement the clinical intervention of tumors. Interestingly, many types of cancer are closely related to dietary habits associated with the Western lifestyle, such as low fruit and vegetable intake. Recent advances around the old-conceived term of chemoprevention highlight the important role of phytochemicals as good candidates for the prevention or treatment of cancer. The potential to inhibit angiogenesis exhibited by many natural compounds constituent of plant foods makes them especially interesting for their use as chemopreventive agents. Here, we review the antitumoral potential, with a focus on the antiangiogenic effects, of phenolic and polyphenolic compounds, such as quercetin or myricetin; terpenoids, such as ursolic acid or kahweol; and anthraquinones from Aloe vera, in different in vitro and in vivo assays, and the available clinical data. Although clinical trials have failed to assess the preventive role of many of these compounds, encouraging preclinical data support the efficacy of phytochemicals constituent of diet in the prevention and treatment of cancer, but a deeper understanding of their mechanisms of action and better designed clinical trials are urgently needed.

5.
Pharmaceutics ; 14(2)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35213989

RESUMO

The number of cancer cases worldwide keeps growing unstoppably, despite the undeniable advances achieved by basic research and clinical practice. Urologic tumors, including some as prevalent as prostate, bladder or kidney tumors, are no exceptions to this rule. Moreover, the fact that many of these tumors are detected in early stages lengthens the duration of their treatment, with a significant increase in health care costs. In this scenario, prevention offers the most cost-effective long-term strategy for the global control of these diseases. Although specialized diets are not the only way to decrease the chances to develop cancer, epidemiological evidence support the role of certain plant-derived foods in the prevention of urologic cancer. In many cases, these plants are rich in antiangiogenic phytochemicals, which could be responsible for their protective or angiopreventive properties. Angiogenesis inhibition may contribute to slow down the progression of the tumor at very different stages and, for this reason, angiopreventive strategies could be implemented at different levels of chemoprevention, depending on the targeted population. In this review, epidemiological evidence supporting the role of certain plant-derived foods in urologic cancer prevention are presented, with particular emphasis on their content in bioactive phytochemicals that could be used in the angioprevention of cancer.

6.
Biomed Pharmacother ; 144: 112263, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34626933

RESUMO

The tropical plant Annona muricata has been widely used for traditional ethnobotanic and pharmacologic applications. Extracts from different parts of this plant have been shown to have a wide range of biological activities. In the present study, we carry out a metabolomic study of both aqueous and DMSO extracts from Annona muricata leaves that has allowed us to identify 33 bioactive compounds. Furthermore, we have shown that aqueous extracts are able to inhibit endothelial cell migration and both aqueous and DMSO extracts inhibit the formation of tubule-like structures by endothelial cells cultured on Matrigel. We conclude that extracts of Annona muricata leaves have great potential as anti-angiogenic natural combinations of bioactive compounds.


Assuntos
Inibidores da Angiogênese/farmacologia , Annona , Células Endoteliais/efeitos dos fármacos , Metabolômica , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Angiogênese/isolamento & purificação , Animais , Annona/metabolismo , Bovinos , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Metaboloma , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Espectrometria de Massas por Ionização por Electrospray
7.
Biochem Mol Biol Educ ; 49(2): 236-241, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32897596

RESUMO

Metabolism and its regulation is one of the most complex and difficult topics for students learning biochemistry. A problem-/case-based learning (PBL) approach can be useful to help biochemistry students to fulfill the goal of acquiring an integrated view of metabolism and its regulation. The present article describes our experience enrolling volunteer students to learn glycogen metabolism making use of a design-based research methodology to develop teaching learning sequences focused on a PBL approach. Enrolled undergraduate students had better final scores than those students that did not participates. Furthermore, enrolled students were satisfied with the experience, finding it interesting, formative, and challenging.


Assuntos
Bioquímica/educação , Educação de Graduação em Medicina , Glicogênio/metabolismo , Motivação , Aprendizagem Baseada em Problemas , Humanos
8.
Biomed Pharmacother ; 131: 110716, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32920516

RESUMO

The traditional ethnobotanic and pharmacologic use of Spondias mombin L. samples includes a wide range of applications. In the present study, new antiangiogenic and antitumor effects of two types of extracts from Spondias mombin L. leaves have been demonstrated by using a number of in vitro assays in both endothelial and human cancer and non cancer cells.


Assuntos
Anacardiaceae , Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Anacardiaceae/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Humanos , Folhas de Planta/química
9.
Sci Rep ; 10(1): 6132, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273578

RESUMO

The synthetic compound fasentin has been described as a modulator of GLUT-1 and GLUT-4 transporters, thus inhibiting glucose uptake in some cancer cells. Endothelial glucose metabolism has been recently connected to angiogenesis and it is now an emerging topic in scientific research. Indeed, certain compounds with a known effect on glucose metabolism have also been shown to inhibit angiogenesis. In this work we tested the capability of fasentin to modulate angiogenesis in vitro and in vivo. We show that fasentin inhibited tube formation in endothelial cells by a mechanism that involves a negative effect on endothelial cell proliferation and invasion, without affecting other steps related to the angiogenic process. However, fasentin barely decreased glucose uptake in human dermal microvascular endothelial cells and the GLUT-1 inhibitor STF-31 failed to inhibit tube formation in these cells. Therefore, this modulatory capacity on endothelial cells function exerted by fasentin is most likely independent of a modulation of glucose metabolism. Taken together, our results show a novel biological activity of fasentin, which could be evaluated for its utility in cancer and other angiogenesis-dependent diseases.


Assuntos
Anilidas/farmacologia , Diferenciação Celular , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Animais , Bovinos , Células Cultivadas , Embrião de Galinha , Glucose/metabolismo , Células HeLa , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Células MCF-7 , Neovascularização Fisiológica , Piridinas/farmacologia
10.
Biology (Basel) ; 9(1)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936882

RESUMO

Metabolic reprogramming in tumor cells is considered one of the hallmarks of cancer. Many studies have been carried out in order to elucidate the effects of tumor cell metabolism on invasion and tumor progression. However, little is known about the immediate substrate preference in tumor cells. In this work, we wanted to study this short-time preference using the highly invasive, hormone independent breast cancer cell line MDA-MB-231. By means of Seahorse and uptake experiments, our results point to a preference for glucose. However, although both glucose and glutamine are required for tumor cell proliferation, MDA-MB-231 cells can survive two days in the absence of glucose, but not in the absence of glutamine. On the other hand, the presence of glucose increased palmitate uptake in this cell line, which accumulates in the cytosol instead of going to the plasma membrane. In order to exert this effect, glucose needs to be converted to glycerol-3 phosphate, leading to palmitate metabolism through lipid synthesis, most likely to the synthesis of triacylglycerides. The effect of glucose on the palmitate uptake was also found in other triple-negative, invasive breast cancer cell lines, but not in the non-invasive ones. The results presented in this work suggest an important and specific role of glucose in lipid biosynthesis in triple-negative breast cancer.

11.
Nutrients ; 11(9)2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31480406

RESUMO

Diet-based chemoprevention of cancer has emerged as an interesting approach to evade the disease or even target its early phases, reducing its incidence or slowing down tumor progression. In its basis in the essential role of angiogenesis for tumor growth and metastasis, angioprevention proposes the use of inhibitors of angiogenesis in cancer prevention. The anti-angiogenic potential exhibited by many natural compounds contained in many Mediterranean diet constituents makes this dietary pattern especially interesting as a source of chemopreventive agents, defined within the angioprevention strategy. In this review, we focus on natural bioactive compounds derived from the main foods included in the Mediterranean diet that display anti-angiogenic activity, as well as their possible use as angiopreventive agents.


Assuntos
Dieta Mediterrânea , Neoplasias/prevenção & controle , Inibidores da Angiogênese/análise , Quimioprevenção/métodos , Humanos , Neovascularização Patológica/prevenção & controle
12.
Biomolecules ; 9(8)2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374952

RESUMO

Endothelial cells form the inner lining of blood vessels, in a process known as angiogenesis. Excessive angiogenesis is a hallmark of several diseases, including cancer. The number of studies in endothelial cell metabolism has increased in recent years, and new metabolic targets for pharmacological treatment of pathological angiogenesis are being proposed. In this work, we wanted to address experimental evidence of substrate (namely glucose, glutamine and palmitate) dependence in immortalized dermal microvascular endothelial cells in comparison to primary endothelial cells. In addition, due to the lack of information about lactate metabolism in this specific type of endothelial cells, we also checked their capability of utilizing extracellular lactate. For fulfilling these aims, proliferation, migration, Seahorse, substrate uptake/utilization, and mRNA/protein expression experiments were performed. Our results show a high glycolytic capacity of immortalized dermal microvascular endothelial cells, but an early independence of glucose for cell growth, whereas a total dependence of glutamine to proliferate was found. Additionally, in contrast with reported data in other endothelial cell lines, these cells lack monocarboxylate transporter 1 for extracellular lactate incorporation. Therefore, our results point to the change of certain metabolic features depending on the endothelial cell line.


Assuntos
Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Glucose/farmacologia , Glicólise/efeitos dos fármacos , Microvasos/citologia , Pele/irrigação sanguínea , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Espaço Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamina/farmacologia , Humanos , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Simportadores/metabolismo
13.
Mar Drugs ; 17(9)2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31450731

RESUMO

Encouraged by the promising antitumoral, antiangiogenic, and antilymphangiogenic properties of toluquinol, a set of analogues of this natural product of marine origin was synthesized to explore and evaluate the effects of structural modifications on their cytotoxic activity. We decided to investigate the effects of the substitution of the methyl group by other groups, the introduction of a second substituent, the relative position of the substituents, and the oxidation state. A set of analogues of 2-substituted, 2,3-disubstituted, and 2,6-disubstituted derived from hydroquinone were synthesized. The results revealed that the cytotoxic activity of this family of compounds could rely on the hydroquinone/benzoquinone part of the molecule, whereas the substituents might modulate the interaction of the molecule with their targets, changing either its activity or its selectivity. The methyl group is relevant for the cytotoxicity of toluquinol, since its replacement by other groups resulted in a significant loss of activity, and in general the introduction of a second substituent, preferentially in the para position with respect to the methyl group, was well tolerated. These findings provide guidance for the design of new toluquinol analogues with potentially better pharmacological properties.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Hidroquinonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroquinonas/química , Estrutura Molecular , Relação Estrutura-Atividade
14.
Biochem Pharmacol ; 168: 366-383, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31351052

RESUMO

Phytohormones have shown great potential as natural anticancer compounds, being interesting in cancer prevention and therapy. Strigolactones are a class of plant hormones involved in the inhibition of root branching and sprouting. The antiproliferative capacity of the synthetic strigolactone analog GR-24 has been described against breast cancer cell lines in vitro. In this study, we show for the first time that GR-24 is a potent antiangiogenic compound in vivo and in vitro. In the in vivo tests, GR-24 shows a great inhibitory effect on vasculature formation in the chicken chorioallantoic membrane and in two different zebrafish models. Our in vitro results show that GR-24 inhibits the growth of endothelial cells and different cancer cell lines with a micromolar range of half inhibitory concentration (IC50) values. In addition, GR-24 inhibits key steps of the angiogenic process in vitro, such as tubulogenesis, invasion, extracellular matrix remodeling capacity, migration and adhesion of endothelial cells at non-cytotoxic concentrations. Our data point to an effect of GR-24 on cytoskeleton organization in endothelial cells, in addition to a decrease in focal adhesion kinase (FAK) presence in these cells. All these data, together with the observed increase in surface expression of vascular endothelial-cadherin (VE-cadherin) and platelet and endothelial cell adhesion molecule 1 (PECAM-1), suggest that GR-24 prevents angiogenesis by maintaining the quiescent phenotype in endothelial cells. The proposed mechanism of action underlying the antiangiogenic activity of GR-24 involves the inhibition of VEGFR2 phosphorylation, and the downstream reduction in activation of FAK, a key regulator protein implicated in angiogenesis. Our results suggest that GR-24 may be a promising new compound for antiangiogenic therapy of cancer and other angiogenesis-dependent diseases.


Assuntos
Inibidores da Angiogênese/farmacologia , Citoesqueleto/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Lactonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Animais Geneticamente Modificados , Bovinos , Embrião de Galinha , Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Transdução de Sinais/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra
15.
Mar Drugs ; 17(4)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991727

RESUMO

Marine sponges are a prolific source of bioactive compounds. In this work, the putative antiangiogenic potential of a series of synthetic precursors of Solomonamide A, a cyclic peptide isolated from a marine sponge, was evaluated. By means of an in vitro screening, based on the inhibitory activity of endothelial tube formation, the compound Solo F-OH was selected for a deeper characterization of its antiangiogenic potential. Our results indicate that Solo F-OH is able to inhibit some key steps of the angiogenic process, including the proliferation, migration, and invasion of endothelial cells, as well as diminish their capability to degrade the extracellular matrix proteins. The antiangiogenic potential of Solo F-OH was confirmed by means of two different in vivo models: the chorioallantoic membrane (CAM) and the zebrafish yolk membrane (ZFYM) assays. The reduction in ERK1/2 and Akt phosphorylation in endothelial cells treated with Solo F-OH denotes that this compound could target the upstream components that are common to both pathways. Taken together, our results show a new and interesting biological activity of Solo F-OH as an inhibitor of the persistent and deregulated angiogenesis that characterizes cancer and other pathologies.


Assuntos
Inibidores da Angiogênese/farmacologia , Peptídeos Cíclicos/farmacologia , Inibidores da Angiogênese/química , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Membrana Corioalantoide , Células Endoteliais/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Estrutura Molecular , Proteína Oncogênica v-akt/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos Cíclicos/química , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra
16.
Biochem Mol Biol Educ ; 47(3): 341-347, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30735292

RESUMO

The enzymatic determination of glucose in soft drinks, based on the glucose concentration measurement by means of the coupled reactions of glucose oxidase and peroxidase, has been implemented at the University of Malaga and optimized according to the Biochemistry and Chemistry undergraduate students' results and feedback throughout the last few years. This traditional and robust laboratory practical has been reformed, in the light of inquiry-based and interdisciplinary learning approaches, in order to optimize the students' formative achievements that now are not restricted to the learning of enzymology, but also integrates cross-curricular knowledge from chemistry and mathematics. In this experiment, inexpensive and feasible to be carried out in a single laboratory session, students have to make the decision of what method is the most suitable for a given analytical problem, anticipating situations that they will probably face throughout their professional careers. It not only illustrates basic issues related to the use of enzymes as reagents for enzymatic analyses and its application to food chemistry, but it is also used to put into practice some principles of statistical analysis and analytical methods evaluation. This can be achieved because students get results from two different enzymatic analysis protocols (kinetic and end-point methods) using a single reaction mixture. The measurement of glucose concentration in four carbonated soft-drinks, regular or sugar-free colas and tonic waters makes students deal with the presence of color interferences that should be either avoided or eliminated. Undergraduate students, having performed this experiment, have found it formative, interesting, and challenging. © 2019 International Union of Biochemistry and Molecular Biology, 47(3):341-347, 2019.


Assuntos
Glucose Oxidase/metabolismo , Laboratórios , Peroxidase/metabolismo , Ensino/educação , Universidades , Humanos , Estudantes
17.
Med Res Rev ; 39(1): 70-113, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29785785

RESUMO

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages, and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment (TME). Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the TME and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that TME is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including antitumor agents with those targeting stromal cell metabolism, antiangiogenic drugs, and/or immunotherapy are being developed as promising therapeutics.


Assuntos
Progressão da Doença , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral , Glicólise , Humanos , Modelos Biológicos
18.
Mar Drugs ; 16(9)2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30200585

RESUMO

The bioactive natural compound from marine origin, (+)-aeroplysinin-1, has been shown to exhibit potent anti-inflammatory and anti-angiogenic effects. The aim of the present study was to identify new targets for (+)-aeroplysinin-1 in endothelial cells. The sequential use of 2D-electrophoresis and MALDI-TOF-TOF/MS allowed us to identify several differentially expressed proteins. Four of these proteins were involved in redox processes and were validated by Western blot. The effects of (+)-aeroplysinin-1 were further studied by testing the effects of the treatment with this compound on the activity of several anti- and pro-oxidant enzymes, as well as on transcription factors involved in redox homeostasis. Finally, changes in the levels of total reactive oxygen species and mitochondrial membrane potential induced by endothelial cell treatments with (+)-aeroplysinin-1 were also determined. Taken altogether, these findings show that (+)-aeroplysinin-1 has multiple targets involved in endothelial cell redox regulation.


Assuntos
Acetonitrilas/farmacologia , Antioxidantes/farmacologia , Cicloexenos/farmacologia , Células Endoteliais/efeitos dos fármacos , Poríferos , Animais , Linhagem Celular , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estereoisomerismo
19.
Food Funct ; 9(8): 4310-4316, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30040093

RESUMO

Hydroxytyrosol is a phenolic compound present in extra virgin olive oil, either in free form or as derivatives, and related to some of the health benefits described for olive oil intake. We have demonstrated previously that hydroxytyrosol inhibits angiogenesis both in vitro and in vivo. In the present study, we evaluate the anti-angiogenic potential of five hydroxytyrosol derivatives. Three of these derivatives contain a nitro group and they exhibit a much weaker effect than hydroxytyrosol in the tubule formation assay on Matrigel and therefore were not studied further. In contrast, both hydroxytyrosyl acetate and ethyl hydroxytyrosyl ether show more potent inhibitory effects than hydroxytyrosol in both the in vitro tubule formation assay on Matrigel and the in vivo chorioallantoic membrane assay. Additionally, these three compounds had slight pro-apoptotic effects and decreased matrix metalloproteinase-2 levels in cell extracts.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Álcool Feniletílico/análogos & derivados , Animais , Bovinos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Relação Estrutura-Atividade
20.
J Org Chem ; 83(10): 5365-5383, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29676156

RESUMO

New synthetic strategies directed toward the novel cyclopeptides solomonamides have been explored utilizing an olefin metathesis as the key reaction. In the various strategies investigated, we worked on minimally oxidized systems, and the olefin metathesis reaction demonstrated efficiency and validity for the construction of the macrocyclic core. The described synthetic strategies toward the solomonamides are well suited for the subsequent access to the natural products and represent flexible and diversity-oriented routes that allow for the generation of a variety of analogues via oxidative transformations. In addition, preliminary biological evaluations of the generated solomonamide precursors revealed antitumor activity against various tumor cell lines.


Assuntos
Antineoplásicos/farmacologia , Peptídeos Cíclicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade
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