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1.
Int J Mol Med ; 48(6)2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34643251

RESUMO

Multiple myeloma (MM) is an aggressive B cell malignancy. Substantial progress has been made in the therapeutic context for patients with MM, however it still represents an incurable disease due to drug resistance and recurrence. Development of more effective or synergistic therapeutic approaches undoubtedly represents an unmet clinical need. Tomentosin is a bioactive natural sesquiterpene lactone extracted by various plants with therapeutic properties, including anti­neoplastic effects. In the present study, the potential antitumor activity of tomentosin was evaluated on the human RPMI­8226 cell line, treated with increasing tomentosin concentration for cytotoxicity screening. The data suggested that both cell cycle arrest and cell apoptosis could explain the antiproliferative effects of tomentosin and may result in the inhibition of RPMI­8226 cell viability. To assess differentially expressed genes contributing to tomentosin activity and identify its mechanism of action, a microarray gene expression profile was performed, identifying 126 genes deregulated by tomentosin. To address the systems biology and identify how tomentosin deregulates gene expression in MM from a systems perspective, all deregulated genes were submitted to enrichment and molecular network analysis. The Protein­Protein Interaction (PPI) network analysis showed that tomentosin in human MM induced the downregulation of genes involved in several pathways known to lead immune­system processes, such as cytokine­cytokine receptor interaction, chemokine or NF­κB signaling pathway, as well as genes involved in pathways playing a central role in cellular neoplastic processes, such as growth, proliferation, migration, invasion and apoptosis. Tomentosin also induced endoplasmic reticulum stress via upregulation of cyclic AMP­dependent transcription factor ATF­4 and DNA damage­inducible transcript 3 protein genes, suggesting that in the presence of tomentosin the protective unfolded protein response signaling may induce cell apoptosis. The functional connections analysis executed using the Connectivity Map tool, suggested that the effects of tomentosin on RPMI­8226 cells might be similar to those exerted by heat shock proteins inhibitors. Taken together, these data suggested that tomentosin may be a potential drug candidate for the treatment of MM.

2.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445327

RESUMO

The fight against cancer is one of the main challenges for medical research. Recently, nanotechnology has made significant progress, providing possibilities for developing innovative nanomaterials to overcome the common limitations of current therapies. In this context, silver nanoparticles (AgNPs) represent a promising nano-tool able to offer interesting applications for cancer research. Following this path, we combined the silver proprieties with Artemisia arborescens characteristics, producing novel nanoparticles called Artemisia-AgNPs. A "green" synthesis method was performed to produce Artemisia-AgNPs, using Artemisia arborescens extracts. This kind of photosynthesis is an eco-friendly, inexpensive, and fast approach. Moreover, the bioorganic molecules of plant extracts improved the biocompatibility and efficacy of Artemisia-AgNPs. The Artemisia-AgNPs were fully characterized and tested to compare their effects on various cancer cell lines, in particular HeLa and MCF-7. Artemisia-AgNPs treatment showed dose-dependent growth inhibition of cancer cells. Moreover, we evaluated their impact on the cell cycle, observing a G1 arrest mediated by Artemisia-AgNPs treatment. Using a clonogenic assay after treatment, we observed a complete lack of cell colonies, which demonstrated cell reproducibility death. To have a broader overview on gene expression impact, we performed RNA-sequencing, which demonstrated the potential of Artemisia-AgNPs as a suitable candidate tool in cancer research.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Artemisia/química , Nanopartículas Metálicas , Prata , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/genética , Artemisia/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Química Verde , Células HeLa , Humanos , Células MCF-7 , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Células PC-3 , Extratos Vegetais/química , Prata/química , Prata/uso terapêutico
3.
Eur J Med Chem ; 222: 113590, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34139625

RESUMO

Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1-10 µM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 µM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, ß-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.


Assuntos
Acrilonitrila/farmacologia , Antineoplásicos/farmacologia , Microtúbulos/efeitos dos fármacos , Triazóis/farmacologia , Acrilonitrila/química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Mitose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química
4.
J Cell Physiol ; 236(5): 3789-3799, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33089499

RESUMO

1,3,4-Oxadiazole derivatives are widely used in research on antineoplastic drugs. Recently, we discovered a novel unsymmetrical 1,3,4-oxadiazole compound with antiproliferative properties called 2j. To further investigate its possible targets and molecular mechanisms, RNA-seq was performed and the differentially expressed genes (DEGs) were obtained after treatment. Data were analyzed using functional (Gene Ontology term) and pathway (Kyoto Encyclopedia of Genes and Genomes) enrichment of the DEGs. The hub genes were determined by the analysis of protein-protein interaction networks. The connectivity map (CMap) information provided insight into the model action of antitumor small molecule drugs. Hub genes have been identified through function gene networks using STRING analysis. The small molecular targets obtained by CMap comparison showed that 2j is a tubulin inhibitor and it acts mainly affecting tumor cells through the cell cycle, FoxO signaling pathway, apoptotic, and p53 signaling pathways. The possible targets of 2j could be TUBA1A and TUBA4A. Molecular docking results indicated that 2j interacts at the colchicine-binding site on tubulin.

5.
Small ; 16(21): e2000123, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32338440

RESUMO

Considering the potential exposure to graphene, the most investigated nanomaterial, the assessment of the impact on human health has become an urgent need. The deep understanding of nanomaterial safety is today possible by high-throughput single-cell technologies. Single-cell mass cytometry (cytometry by time-of flight, CyTOF) shows an unparalleled ability to phenotypically and functionally profile complex cellular systems, in particular related to the immune system, as recently also proved for graphene impact. The next challenge is to track the graphene distribution at the single-cell level. Therefore, graphene oxide (GO) is functionalized with AgInS2 nanocrystals (GO-In), allowing to trace GO immune-cell interactions via the indium (115 In) channel. Indium is specifically chosen to avoid overlaps with the commercial panels (>30 immune markers). As a proof of concept, the GO-In CyTOF tracking is performed at the single-cell level on blood immune subpopulations, showing the GO interaction with monocytes and B cells, therefore guiding future immune studies. The proposed approach can be applied not only to the immune safety assessment of the multitude of graphene physical and chemical parameters, but also for graphene applications in neuroscience. Moreover, this approach can be translated to other 2D emerging materials and will likely advance the understanding of their toxicology.


Assuntos
Grafite , Leucócitos , Nanoestruturas , Análise de Célula Única , Citometria de Fluxo , Grafite/toxicidade , Humanos , Leucócitos/efeitos dos fármacos , Nanopartículas/toxicidade , Nanoestruturas/toxicidade
6.
J Hypertens ; 38(3): 546-552, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31584522

RESUMO

OBJECTIVE: Statin therapy was associated with lower blood pressure (BP) in some but not all studies. We evaluated the association between statin therapy and ambulatory BP in a large hypertensive population using 'propensity score matching'. METHODS: Retrospective observational study on 1827 consecutive essential hypertensive patients evaluated with 24-h ambulatory BP monitoring. Antihypertensive treatment intensity (ATI) was calculated to compare different drug associations. We used a propensity score matching to compare two equally-sized cohorts of patients with similar characteristics according to statin therapy. Matching was performed on log-transformed propensity score in a 1 : 1 fashion with a caliper of 0.1, in order to account for the different baseline characteristics between statin and no-statin group. RESULTS: Mean age: 58.1 ±â€Š13.8 years; male sex: 55%. Patients on statin therapy: 402 (22%). These patients showed lower 24-h BP (-2.8/-7.1 mmHg), daytime (-3.3/-7.6 mmHg) and night-time BP (-2.5/-6.0 mmHg, all P < 0.001). They also showed better ambulatory BP control, even after adjustment for confounding factors. The analyses on the groups derived from the 'propensity score matching' (369 patients in each group) confirmed these results (OR 1.8 for 24-h BP control; OR = 1.6 for daytime BP control; OR = 1.7 for night-time BP control, all P < 0.001). CONCLUSION: Statin therapy is associated with better ambulatory BP control in essential hypertensive patients. This result is not affected by the intensity of the antihypertensive treatment or by the several cofactors analyzed.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos
7.
Chem Biol Interact ; 312: 108813, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494105

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric tumor, which arises from muscle precursor cells. Recently, it has been demonstrated that Hippo Pathway (Hpo), a pathway that regulates several physiological and biological features, is involved in RMS tumorigenesis. For instance, an upregulation of the Hpo downstream effector Yes-Associated Protein 1 (YAP) leads to the development of embryonal rhabdomyosarcoma (eRMS) in murine activated muscle satellite cells. On the other hand, the YAP paralog transcriptional co-activator with PDZ-binding motif (TAZ) is overexpressed in alveolar rhabdomyosarcoma (aRMS) patients with poor survival. YAP and TAZ exhibit both cytoplasmic and nuclear functions. In the nucleus, YAP binds TEADs (TEA domain family members) factors and together they constitute a complex that is able either to activate the transcription of several genes such as MYC, Tbx5 and PAX8 or to maintain the stability of others like p73. Due to the key role of YAP and TAZ in cancer, the identification and/or development of new compounds able to block their activity might be an effective antineoplastic strategy. Verteporfin (VP) is a molecule able to stop the formation of YAP/TEAD complex in the nucleus. The aim of this study is to evaluate the action of VP on RMS cell lines. This work shows that VP has an anti-proliferative activity on all RMS cell lines analyzed. Depending on RMS cell lines, VP affects cell cycle differently. Moreover, VP is able to decrease YAP protein levels, and to induce the activation of apoptosis mechanism through the cleavage of PARP-1. In addition, Annexin V assay showed the activation of apoptosis and necrosis after VP treatment. In summary, the ability of VP to disrupt RMS cell proliferation could be a novel and valuable strategy to improve the therapeutic approaches in treating rhabdomyosarcoma.


Assuntos
Proliferação de Células/efeitos dos fármacos , Verteporfina/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Fatores de Transcrição/metabolismo
8.
Nanoscale ; 11(41): 19408-19421, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31386739

RESUMO

Nanosystems are able to enhance bone regeneration, a complex process requiring the mutual interplay between immune and skeletal cells. Activated monocytes can communicate pro-osteogenic signals to mesenchymal stem cells and promote osteogenesis. Thus, the activation of monocytes is a promising strategy to improve bone regeneration. Nanomaterials specifically selected to provoke immune-mediated bone formation are still missing. As a proof of concept, we apply here the intrinsic immune-characteristics of graphene oxide (GO) with the well-recognized osteoinductive capacity of calcium phosphate (CaP) in a biocompatible nanomaterial called maGO-CaP (monocytes activator GO complexed with CaP). In the presence of monocytes, the alkaline phosphatase activity and the expression of osteogenic markers increased. Studying the mechanisms of action, we detected an up-regulation of Wnt and BMP signaling, two key osteogenic pathways. The role of the immune activation was evidenced by the over-production of oncostatin M, a pro-osteogenic factor produced by monocytes. Finally, we tested the pro-osteogenic effects of maGO-CaP in vivo. maGO-CaP injected into the tibia of mice enhanced local bone mass and the bone formation rate. Our study suggests that maGO-CaP can activate monocytes to enhance osteogenesis ex vivo and in vivo.


Assuntos
Materiais Biocompatíveis/química , Grafite/química , Animais , Materiais Biocompatíveis/farmacologia , Proteína Morfogenética Óssea 2/metabolismo , Fosfatos de Cálcio/química , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oncostatina M/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tíbia/efeitos dos fármacos , Tíbia/metabolismo , Proteínas Wnt/metabolismo
9.
Biomacromolecules ; 19(8): 3560-3571, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30008208

RESUMO

Alginate (ALG) and chitosan (CS) have been extensively used for biomedical applications; however, data relative to immune responses exerted by them are scarce. We synthesized a submicron vesicle system (SV) displaying a CS shell over an ALG core. Intravenous injection of these promising carriers could be a possible route of delivery; therefore, we evaluated their impact on human peripheral blood mononuclear cells (PBMCs). By this ex vivo approach, we established how SV chemical-physical characteristics affected the immune cells in terms of cellular uptake, viability, and state of activation. By flow cytometry, we demonstrated that SVs were internalized by PBMCs with differential trends. No substantial necrotic and apoptotic signals were recorded, and SVs weakly affected activation status of PBMCs (concerning the markers CD69, CD25, CD80, and the cytokines TNF-α and IL-6), showing high immune biocompatibility and low immunomodulating properties. Our findings gain particular value toward the biomedical applications of SVs and make these polymer-based structures more attractive for translation into clinical uses.


Assuntos
Alginatos/química , Quitosana/análogos & derivados , Monócitos/efeitos dos fármacos , Nanopartículas/efeitos adversos , Adulto , Antígenos CD/imunologia , Apoptose , Células Cultivadas , Quitosana/imunologia , Humanos , Interleucina-6/imunologia , Pessoa de Meia-Idade , Monócitos/imunologia , Nanopartículas/química , Fator de Necrose Tumoral alfa/imunologia
10.
Respiration ; 95 Suppl 1: 22-29, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29705783

RESUMO

Cardiovascular (CV) comorbidities in patients with chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality, especially in old and very old subjects. The question if long-acting beta-agonist and long-acting muscarinic antagonist could be associated with the increased prevalence of CV-related adverse effects has puzzled, particularly in the past, specialists involved in the management of respiratory diseases. The safety of these compounds has scarcely been tested in patients aged ≥ 65 years with CV comorbidities, since randomized controlled trials rarely include this subpopulation. However, the fixed combination indacaterol/glycopyrronium has shown a favorable CV safety profile in both healthy volunteers and COPD patients. Thus, we aimed to assess the CV safety pro-- file of the fixed combination indacaterol/glycopyrronium 110/50 µg in a series of COPD patients aged ≥ 80 years with several comorbidities. Our results indicate that this combination is safe in the comorbid elderly, since no significant electrocardiographic abnormalities were recorded after the administration of the inhaled therapy. Only rare and nonclinically significant changes in heart rate and corrected QT interval duration were evident, mainly in females and in patients with concomitant impaired kidney function.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Glicopirrolato/efeitos adversos , Indanos/efeitos adversos , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/efeitos adversos , Administração por Inalação , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Eletrocardiografia , Feminino , Humanos , Masculino
11.
J Am Med Dir Assoc ; 19(4): 342-347, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29128438

RESUMO

OBJECTIVES: Cardiovascular diseases are mainly related to hypertension and dyslipidemia and increase with aging because of the larger time span for these risk factors to damage arterial blood vessels. The impact of cardiovascular drug therapy on outcomes in the very elderly hospitalized is still not well established. The aim of our study was to evaluate the associations between cardiovascular therapy and in-hospital mortality in very elderly hypertensives. DESIGN: Prospective observational study. SETTING: Hospital assessment. PARTICIPANTS: 310 very elderly hypertensive patients admitted to our Internal Medicine and Geriatrics Department for medical conditions. MEASUREMENTS: Main comorbidities, laboratory parameters, and cardiovascular drug therapy taken before admission were considered for the analyses. RESULTS: The mean age was 88.1 ±â€¯5.1 years, with female prevalence of 57.4%. Among cardiovascular drugs taken before admission, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and statins were those associated with lower in-hospital mortality, even after adjusting for covariates (age, hemoglobin, albumin, acute kidney injury, ADL Hierarchy Scale, NT-proBNP levels) [odds ratio (OR) = 0.46, P = .045, and OR = 0.21, P = .008, respectively]. No difference regarding in-hospital mortality was found between ACE inhibitors and angiotensin receptor blockers (P = .414). CONCLUSION: ACE inhibitors/angiotensin receptor blockers and statins, through their beneficial effects on the cardiovascular system, have a positive impact on survival in very elderly hospitalized patients. Our data confirm the important role of such drugs even in this particular population with a mean age higher than 88 years, where scientific evidence is still scanty.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Doenças Cardiovasculares/tratamento farmacológico , Mortalidade Hospitalar/tendências , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipertensão/tratamento farmacológico , Hipertensão/mortalidade , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/administração & dosagem , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Quimioterapia Combinada , Feminino , Idoso Fragilizado , Hospitalização/estatística & dados numéricos , Humanos , Hipertensão/diagnóstico , Itália , Masculino , Prognóstico , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
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