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1.
Front Oncol ; 11: 760732, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712616

RESUMO

The high glycolytic activity of multiple myeloma (MM) cells is the rationale for use of Positron Emission Tomography (PET) with 18F-fluorodeoxyglucose ([18F]FDG) to detect both bone marrow (BM) and extramedullary disease. However, new tracers are actively searched because [18F]FDG-PET has some limitations and there is a portion of MM patients who are negative. Glutamine (Gln) addiction has been recently described as a typical metabolic feature of MM cells. Yet, the possible exploitation of Gln as a PET tracer in MM has never been assessed so far and is investigated in this study in preclinical models. Firstly, we have synthesized enantiopure (2S,4R)-4-fluoroglutamine (4-FGln) and validated it as a Gln transport analogue in human MM cell lines, comparing its uptake with that of 3H-labelled Gln. We then radiosynthesized [18F]4-FGln, tested its uptake in two different in vivo murine MM models, and checked the effect of Bortezomib, a proteasome inhibitor currently used in the treatment of MM. Both [18F]4-FGln and [18F]FDG clearly identified the spleen as site of MM cell colonization in C57BL/6 mice, challenged with syngeneic Vk12598 cells and assessed by PET. NOD.SCID mice, subcutaneously injected with human MM JJN3 cells, showed high values of both [18F]4-FGln and [18F]FDG uptake. Bortezomib significantly reduced the uptake of both radiopharmaceuticals in comparison with vehicle at post treatment PET. However, a reduction of glutaminolytic, but not of glycolytic, tumor volume was evident in mice showing the highest response to Bortezomib. Our data indicate that [18F](2S,4R)-4-FGln is a new PET tracer in preclinical MM models, yielding a rationale to design studies in MM patients.

2.
Blood Adv ; 5(23): 5164-5178, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34614505

RESUMO

Mechanisms underlying the resistance of acute lymphoblastic leukemia (ALL) blasts to l-asparaginase are still incompletely known. Here we demonstrate that human primary bone marrow mesenchymal stromal cells (MSCs) successfully adapt to l-asparaginase and markedly protect leukemic blasts from the enzyme-dependent cytotoxicity through an amino acid trade-off. ALL blasts synthesize and secrete glutamine, thus increasing extracellular glutamine availability for stromal cells. In turn, MSCs use glutamine, either synthesized through glutamine synthetase (GS) or imported, to produce asparagine, which is then extruded to sustain asparagine-auxotroph leukemic cells. GS inhibition prevents mesenchymal cells adaptation to l-asparaginase, lowers glutamine secretion by ALL blasts, and markedly hinders the protection exerted by MSCs on leukemic cells. The pro-survival amino acid exchange is hindered by the inhibition or silencing of the asparagine efflux transporter SNAT5, which is induced in mesenchymal cells by ALL blasts. Consistently, primary MSCs from ALL patients express higher levels of SNAT5 (P < .05), secrete more asparagine (P < .05), and protect leukemic blasts (P < .05) better than MSCs isolated from healthy donors. In conclusion, ALL blasts arrange a pro-leukemic amino acid trade-off with bone marrow mesenchymal cells, which depends on GS and SNAT5 and promotes leukemic cell survival during l-asparaginase treatment.

3.
Expert Rev Respir Med ; 15(11): 1473-1481, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34498989

RESUMO

OBJECTIVES: The potential of multi-walled carbon nanotubes (MWCNTs) in inducing airway hyperresponsiveness (AHR) was investigated in human airways. METHODS: Human isolated bronchi were exposed to MWCNTs and the contractility to electrical field stimulation (EFS) was measured. Neuronal acetylcholine (ACh) and cyclic adenosine monophosphate (cAMP) were quantified. Some tissues were desensitized by consecutive administrations of capsaicin. RESULTS: MWCNTs (100 ng/ml - 100 µg/ml) induced AHR (overall contractile tone vs. negative control: +83.43 ± 11.13%, P < 0.01). The potency was significantly (P < 0.05) greater when airways were stimulated at low frequency (EFS3Hz) then at medium-to-high frequencies (EFS10Hz and EFS25Hz) (delta potency: +2.13 ± 0.74 and +2.40 ± 0.65 logarithms, respectively). In capsaicin-desensitized airways, the AHR to MWCNTs 100 ng/ml was abolished. MWCNTs increased the release of ACh, an effect prevented by capsaicin-desensitization (-90.17 ± 18.59%, P < 0.05). MWCNTs did not alter the level of cAMP. CONCLUSION: MWCNTs administered at low concentrations elicit AHR in human airways by activating sensory C-fibers and, in turn, increasing the release of neuronal ACh. Our results suggest that work is required to understand the impact of MWCNTs in patients at risk of AHR, such as those suffering from chronic obstructive respiratory disorders.


Assuntos
Nanotubos de Carbono , Hipersensibilidade Respiratória , Acetilcolina/farmacologia , Brônquios , Capsaicina/farmacologia , Humanos , Nanotubos de Carbono/toxicidade
4.
Front Cell Dev Biol ; 9: 714755, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34277645

RESUMO

Within the bone marrow hematopoietic cells are in close connection with mesenchymal stromal cells (MSCs), which influence the behavior and differentiation of normal or malignant lymphoid and myeloid cells. Altered cell metabolism is a hallmark of cancer, and changes in nutrient pools and fluxes are important components of the bidirectional communication between MSCs and hematological cancer cells. Among nutrients, amino acids play a significant role in cancer progression and chemo-resistance. Moreover, selected types of cancer cells are extremely greedy for glutamine, and significantly deplete the extracellular pool of the amino acid. As a consequence, this influences the behavior of MSCs in terms of either cytokine/chemokine secretion or differentiation potential. Additionally, a direct nutritional interaction exists between MSCs and immune cells. In particular, selected subpopulations of lymphocytes are dependent upon selected amino acids, such as arginine and tryptophan, for full differentiation and competence. This review describes and discusses the nutritional interactions existing in the neoplastic bone marrow niche between MSCs and other cell types, with a particular emphasis on cancer cells and immune cells. These relationships are discussed in the perspective of potential novel therapeutic strategies based on the interference on amino acid metabolism or intercellular fluxes.

5.
J Cancer Res Clin Oncol ; 147(11): 3169-3181, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34235580

RESUMO

PURPOSE: Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival. METHODS: We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations. RESULTS: High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival. CONCLUSION: Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.


Assuntos
Glutamato-Amônia Ligase/biossíntese , Glutamina/metabolismo , Hepatoblastoma/metabolismo , Neoplasias Hepáticas/metabolismo , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/biossíntese , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Éxons , Expressão Gênica , Glutamato-Amônia Ligase/genética , Glutamina/deficiência , Hepatoblastoma/genética , Hepatoblastoma/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mutação , beta Catenina/genética
6.
Anthropol Anz ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34165489

RESUMO

Objective. To report the results of dental morphological analysis performed on the remains of two European nobles (Duke Alessandro Farnese and his wife Maria D'Aviz) who lived in the 16th century, together with hypotheses on their nutrition and oral hygiene habits. Design and results. The remains of Alessandro Farnese (1545-1592) and Princess Maria D'Aviz (1538-1577) were exhumed in Parma, Italy, in the context of an historical investigation into their possible causes of death. The skulls were examined and analysed through direct inspection, high-detailed photographs and radiographs. Ante mortem tooth loss (AMTL), postmortem tooth loss (PMTL), Scott and Smith dental wear indexes and the Kerr periodontal index were used to assess the dental and periodontal status of the couple. Alessandro Farnese suffered from severe dental wear while it was presumed that Maria D'Aviz was affected by periodontal disease and tooth decay. Conclusions. Based on the findings of the present analysis, we hypothesise that Alessandro Farnese's diet was mainly based on hard and unrefined foods, also suggested by limited historical reports. It is likely that Maria D'Aviz's nutrition was based on sugar-enriched foods.

7.
Acta Biomed ; 92(2): e2021167, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33988137

RESUMO

BACKGROUND AND AIM: Reports about the teaching of the History of Medicine in universities worldwide can be found easily in medical literature. They are often comparative studies in which the opinions provided by the professors are collected and the teaching programs are compared. Our study focuses instead on the relationship between the students and the discipline, what they look for from it, and how their interest changes with the progress of the course of study. METHODS: The final tests of the students of two Italian universities, Parma and Bologna, were analyzed, in which the candidate had the ability to choose the topic of discussion and to outline his personal analysis. The course year in which the final examination was faced is different: in the first year in Bologna, in the fourth year in Parma. RESULTS: This survey show that in both universities most students have carried out autonomous research regardless of the educational material made available to them. This attitude can be interpreted as a real interest in the history of medicine, widening their search throughout all the fields of the discipline. CONCLUSIONS: These results seem to suggest to teachers of History of Medicine to convey to their students the methodology of historical and epistemological research, giving the student to the pupils the opportunity to become passionate about history in the way he/she prefers. (www.actabiomedica.it).


Assuntos
Estudantes de Medicina , Estudantes , Atitude , História da Medicina , Humanos , Itália , Inquéritos e Questionários , Universidades
8.
Cancers (Basel) ; 12(11)2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33167336

RESUMO

Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.

9.
Mater Sci Eng C Mater Biol Appl ; 117: 111307, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32919668

RESUMO

In vitro studies have consistently shown that titanium surface wettability affects the response of osteoprogenitors, leading to important advances in the clinical osseointegration of dental implants. However, the underlying molecular mechanisms remain unknown. Since surface conditioning by blood components initiates within milliseconds after insertion, it is reasonable to hypothesize that the amount and the type of blood proteins adsorbed influences the interaction between the implant surface and osteoprogenitors. To test this hypothesis, titanium implant surfaces with different characteristics, in terms of topography and wettability, have been conditioned with selected plasma proteins. Pure fibronectin (HFN) and albumin (HSA) solutions, or their mixture at the relative plasma concentrations were allowed to adsorb on titanium surfaces for 60 min. Protein adsorption was monitored by Bradford assay, while the contribution of HSA and HFN in forming the microfilm layer at the interface was studied by Western Blot. Subsequently, the same protein-conditioned surfaces were used to culture C2C12 cells, thus studying their capacity to adhere and to spread after 3 h. Cell viability was evaluated up to 7 days, while the expression of osteogenic genes was assessed after 3 days. Under competitive adsorption conditions, hydrophilicity promotes the selectivity of titanium for HFN regardless of the surface microtopography. As a consequence of selective HFN adsorption, cells on hydrophilic surfaces displayed enhanced adhesion and spreading, as well as increased proliferation. On the other hand, selective HFN adsorption did not appreciably affect cell differentiation. These data suggest that implant surface hydrophilicity plays a key role in guiding the selective adsorption of specific proteins from blood plasma. Moreover, the selective adsorption of HFN, as a consequence of surface hydrophilicity, was found to account for early cell responses amelioration. Thus, titanium surface hydrophilicity contributes to the clinical success of dental implant by selectively controlling protein adsorption at the interface.


Assuntos
Implantes Dentários , Titânio , Adsorção , Albuminas , Fibronectinas , Interações Hidrofóbicas e Hidrofílicas , Propriedades de Superfície
10.
Nanomaterials (Basel) ; 10(7)2020 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-32708373

RESUMO

Previous work has demonstrated that precipitated (NM-200) and pyrogenic (NM-203) Amorphous Silica Nanoparticles (ASNPs) elicit the inflammatory activation of murine macrophages, with more pronounced effects observed with NM-203. Here, we compare the effects of low doses of NM-200 and NM-203 on human macrophage-like THP-1 cells, assessing how the pre-exposure to these nanomaterials affects the cell response to lipopolysaccharide (LPS). Cell viability was affected by NM-203, but not by NM-200, and only in the presence of LPS. While NM-203 stimulated mTORC1, neither ASNPs activated NFκB or the transcription of its target genes PTGS2 and IL1B. NM-200 and NM-203 caused a block of the autophagic flux and inhibited the LPS-dependent increase of Glutamine Synthetase (GS) expression. Both ASNPs suppressed the activation of caspase-1, delaying the LPS-dependent secretion of IL-1ß. Thus, ASNPs modulate several important pathways in human macrophages, altering their response to LPS. NM-203 had larger effects on autophagy, mTORC1 activity and GS expression than NM-200, confirming the higher biological activity of pyrogenic ASNPs when compared with precipitated ASNPs.

11.
Data Brief ; 30: 105636, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32426426

RESUMO

The data included in this paper are associated with a research article entitled 'Differences in toxicity, mitochondrial function and miRNome in human cells exposed in vitro to Cd as CdS quantum dots or ionic Cd' [1]. The article concerns the use of miRNAs as biomarkers for engineered nanomaterials (ENMs) risk assessment. Two different type of human cells, HepG2 and THP-1, were exposed to different forms of Cadmium: nanoscale, as CdS quantum dots (CdS QDs), and ionic, as CdSO4 8/3 -hydrate (Cd(II)). The cells were treated with sub-toxic doses of CdS QDs; 3 µg ml-1 in HepG2 and 6.4 µg ml-1 and 50 µg ml-1 in THP-1, as well as equivalent cadmium doses as Cd(II). In this dataset, changes in expression levels of miRNAs are reported. In addition, GO enrichment analyses of target genes of miRNAs modulated by Cd stress, network analysis of the microRNome and an in silico pathway analysis are also reported. These data enhance and also summarize much of the data independently presented in the research article and therefore, must be considered as supplementary.

12.
J Hazard Mater ; 393: 122430, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32155524

RESUMO

Cadmium is toxic to humans, although Cd-based quantum dots exerts less toxicity. Human hepatocellular carcinoma cells (HepG2) and macrophages (THP-1) were exposed to ionic Cd, Cd(II), and cadmium sulfide quantum dots (CdS QDs), and cell viability, cell integrity, Cd accumulation, mitochondrial function and miRNome profile were evaluated. Cell-type and Cd form-specific responses were found: CdS QDs affected cell viability more in HepG2 than in THP-1; respective IC20 values were ∼3 and ∼50 µg ml-1. In both cell types, Cd(II) exerted greater effects on viability. Mitochondrial membrane function in HepG2 cells was reduced 70 % with 40 µg ml-1 CdS QDs but was totally inhibited by Cd(II) at corresponding amounts. In THP-1 cells, CdS QDs has less effect on mitochondrial function; 50 µg ml-1 CdS QDs or equivalent Cd(II) caused 30 % reduction or total inhibition, respectively. The different in vitro effects of CdS QDs were unrelated to Cd uptake, which was greater in THP-1 cells. For both cell types, changes in the expression of miRNAs (miR-222, miR-181a, miR-142-3p, miR-15) were found with CdS QDs, which may be used as biomarkers of hazard nanomaterial exposure. The cell-specific miRNome profiles were indicative of a more conservative autophagic response in THP-1 and as apoptosis as in HepG2.


Assuntos
Compostos de Cádmio/toxicidade , Cádmio/toxicidade , Mitocôndrias/efeitos dos fármacos , Pontos Quânticos/toxicidade , Sulfetos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , MicroRNAs/metabolismo , Mitocôndrias/fisiologia , Células THP-1
13.
Elife ; 92020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32175843

RESUMO

The inability of cells to adapt to increased environmental tonicity can lead to inflammatory gene expression and pathogenesis. The Rel family of transcription factors TonEBP and NF-κB p65 play critical roles in the switch from osmoadaptive homeostasis to inflammation, respectively. Here we identified PACT-mediated PKR kinase activation as a marker of the termination of adaptation and initiation of inflammation in Mus musculus embryonic fibroblasts. We found that high stress-induced PACT-PKR activation inhibits the interaction between NF-κB c-Rel and TonEBP essential for the increased expression of TonEBP-dependent osmoprotective genes. This resulted in enhanced formation of TonEBP/NF-κB p65 complexes and enhanced proinflammatory gene expression. These data demonstrate a novel role of c-Rel in the adaptive response to hyperosmotic stress, which is inhibited via a PACT/PKR-dependent dimer redistribution of the Rel family transcription factors. Our results suggest that inhibiting PACT-PKR signaling may prove a novel target for alleviating stress-induced inflammatory diseases.


Assuntos
Proteínas de Transporte/metabolismo , Pressão Osmótica , Proteínas de Ligação a RNA/metabolismo , eIF-2 Quinase/metabolismo , Adaptação Fisiológica , Animais , Proteínas de Transporte/genética , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-rel/genética , Proteínas Proto-Oncogênicas c-rel/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA/genética , Transdução de Sinais , eIF-2 Quinase/genética
14.
Int J Mol Sci ; 21(5)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32164327

RESUMO

In cultured human fibroblasts, SNAT transporters (System A) account for the accumulation of non-essential neutral amino acids, are adaptively up-regulated upon amino acid deprivation and play a major role in cell volume recovery upon hypertonic stress. No information is instead available on the expression and activity of SNAT transporters in human bone marrow mesenchymal stromal cells (MSC), although they are increasingly investigated for their staminal and immunomodulatory properties and used for several therapeutic applications. The uptake of glutamine and proline, two substrates of SNAT1 and SNAT2 transporters, was measured in primary human MSC and an MSC line. The amino acid analogue MeAIB, a specific substrate of these carriers, has been used to selectively inhibit SNAT-dependent transport of glutamine and, through its sodium-dependent transport, as an indicator of SNAT1/2 activity. SNAT1/2 expression and localization were assessed with RT-PCR and confocal microscopy, respectively. Cell volume was assessed from urea distribution space. In all these experiments, primary human fibroblasts were used as the positive control for SNAT expression and activity. Compared with fibroblasts, MSC have a lower SNAT1 expression and hardly detectable membrane localization of both SNAT1 and SNAT2. Moreover, they exhibit no sodium-dependent MeAIB uptake or MeAIB-inhibitable glutamine transport, and exhibit a lower ability to accumulate glutamine and proline than fibroblasts. MSC exhibited an only marginal increase in MeAIB transport upon amino acid starvation and did not recover cell volume after hypertonic stress. In conclusion, the activity of SNAT transporters is low in human MSC. MSC adaptation to amino acid shortage is expected to rely on intracellular synthesis, given the absence of an effective up-regulation of the SNAT transporters.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Aminoácidos Neutros/metabolismo , Células-Tronco Mesenquimais/citologia , Sistema A de Transporte de Aminoácidos/genética , Técnicas de Cultura de Células/métodos , Membrana Celular/metabolismo , Células Cultivadas , Meios de Cultura/química , Fibroblastos/citologia , Fibroblastos/metabolismo , Glutamina/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Prolina/metabolismo , Transporte Proteico , beta-Alanina/análogos & derivados , beta-Alanina/metabolismo
15.
Eur J Pharm Biopharm ; 150: 1-13, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32113915

RESUMO

This work here presented provides insights over a novel biodegradable polymeric nanosystem made of hyaluronic acid and polyarginine for diaminocyclohexane-platinum (DACHPt) encapsulation. Using mild conditions based on ionic gelation technique, monodispersed blank and DACHPt-loaded nanoparticles (NP) with a size of around 200 nm and negative ζ potential (-35 mV) were obtained. The freeze-drying process was optimized to improve the stability and shelf-life of the developed nanoparticles. After reconstitution, nanoparticles maintained their size showing an association efficiency of around 70% and a high drug loading (8%). In vitro cytotoxicity studies revealed that DACHPt-loaded nanoparticles had a superior anticancer activity compared with oxaliplatin solution. The IC50 was reduced by a factor of two in HT-29 cells (IC50 39 µM vs 74 µM, respectively), and resulted almost 1.3 fold lower in B6KPC3 cells (18 µM vs 23 µM respectively). Whereas toxic effects of both drug and DACHPt-loaded nanoparticles were comparable in the A549 cell line (IC50 11 µM vs 12 µM). DACHPt-loaded nanoparticles were also able to modulate immunogenic cell death (ICD) in vitro. After incubation with B6KPC3 cells, an increase in HMGB1 (high-mobility group box 1) production associated with ATP release occurred. Then, in vivo pharmacokinetic studies were performed after intravenous injection (IV) of DACHPt-loaded nanoparticles and oxaliplatin solution in healthy mice (35.9 µg of platinum equivalent/mouse). An AUC six times higher (24 h * mg/L) than the value obtained following the administration of oxaliplatin solution (3.76 h * mg/L) was found. Cmax was almost five times higher than the control (11.4 mg/L for NP vs 2.48 mg/L). Moreover, the reduction in volume of distribution and clearance clearly indicated a more limited tissue distribution. A simulated repeated IV regimen was performed in silico and showed no accumulation of platinum from the nanoparticles. Overall, the proposed approach discloses a novel nano-oncological treatment based on platinum derivative with improved antitumor activity in vitro and in vivo stability as compared to the free drug.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos , Ácido Hialurônico/química , Nanopartículas , Oxaliplatina/administração & dosagem , Peptídeos/química , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Composição de Medicamentos , Estabilidade de Medicamentos , Feminino , Células HT29 , Humanos , Injeções Intravenosas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Oxaliplatina/química , Oxaliplatina/farmacocinética , Distribuição Tecidual
16.
Nanomaterials (Basel) ; 10(2)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013138

RESUMO

Over the last decades, cerium oxide nanoparticles (CeO2 NPs) have gained great interest due to their potential applications, mainly in the fields of agriculture and biomedicine. Promising effects of CeO2 NPs are recently shown in some neurodegenerative diseases, but the mechanism of action of these NPs in Parkinson's disease (PD) remains to be investigated. This issue is addressed in the present study by using a yeast model based on the heterologous expression of the human α-synuclein (α-syn), the major component of Lewy bodies, which represent a neuropathological hallmark of PD. We observed that CeO2 NPs strongly reduce α-syn-induced toxicity in a dose-dependent manner. This effect is associated with the inhibition of cytoplasmic α-syn foci accumulation, resulting in plasma membrane localization of α-syn after NP treatment. Moreover, CeO2 NPs counteract the α-syn-induced mitochondrial dysfunction and decrease reactive oxygen species (ROS) production in yeast cells. In vitro binding assay using cell lysates showed that α-syn is adsorbed on the surface of CeO2 NPs, suggesting that these NPs may act as a strong inhibitor of α-syn toxicity not only acting as a radical scavenger, but through a direct interaction with α-syn in vivo.

17.
Mater Sci Eng C Mater Biol Appl ; 107: 110250, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761226

RESUMO

OBJECTIVES: To investigate how a thermal treatment to increase titanium wettability influences proteins adsorption from blood serum and osteoblasts responses. METHODS: Titanium discs with machined or micro-rough profiles were thermally treated to obtain hydrophilic surfaces. The adsorption kinetics of two representative serum proteins were determined by Bradford assay, while the stable protein adsorption pattern from blood serum was investigated by SDS-PAGE and Western Blot analysis. Subsequently, MC3T3-E1 cells were cultured on titanium for 24h and assayed for adhesion and morphology. RESULTS: Thermally-induced hydrophilicity dramatically improved the capacity of titanium to selectively adsorb fibronectin and fibrinogen from blood serum, without evident influence on other representative serum proteins. The selective adsorption of fibronectin was linked to the improved capacity of MC3T3-E1 cells to adhere and spread on hydrophilic surfaces. SIGNIFICANCE: We identified a potential method to improve selective protein adsorption on titanium by enhancing implant surface wettability through a thermal treatment. Selective fibronectin adsorption was further indicated as the responsible for improved osteoblasts adhesion. Targeting specific cell response by selective protein adsorption appears to be crucial to conceive even more performant therapies.


Assuntos
Adesão Celular , Titânio/química , Actinas/química , Actinas/metabolismo , Adsorção , Animais , Linhagem Celular , Fibrinogênio/química , Fibronectinas/química , Camundongos , Microscopia de Fluorescência , Osteoblastos/citologia , Osteoblastos/metabolismo , Propriedades de Superfície , Molhabilidade
18.
Nanotoxicology ; 14(4): 433-452, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726913

RESUMO

Length and aspect ratio represent important toxicity determinants of fibrous nanomaterials. We have previously shown that anatase TiO2 nanofibers (TiO2 NF) cause a dose-dependent decrease of cell viability as well as the loss of epithelial barrier integrity in polarized airway cell monolayers. Herein we have investigated the impact of fiber shortening, obtained by ball-milling, on the biological effects of TiO2 NF of industrial origin. Long TiO2 NF (L-TiO2 NF) were more cytotoxic than their shortened counterparts (S-TiO2 NF) toward alveolar A549 cells and bronchial 16HBE cells. Moreover, L-TiO2 NF increased the permeability of 16HBE monolayers and perturbed the distribution of tight-junction proteins, an effect also mitigated by fiber shortening. Raw264.7 macrophages efficiently internalized shortened but not long NF, which caused cell stretching and deformation. Compared with L-TiO2 NF, S-TiO2 NF triggered a more evident macrophage activation, an effect suppressed by the phagocytosis inhibitor cytochalasin B. Conversely, a significant increase of inflammatory markers was detected in either the lungs or the peritoneal cavity of mice exposed to L-TiO2 NF but not to S-TiO2 NF, suggesting that short-term macrophage activation in vitro may not be always a reliable indicator of persistent inflammation in vivo. It is concluded that fiber shortening mitigates NF detrimental effects on cell viability and epithelial barrier competence in vitro as well as inflammation development in vivo. These data suggest that fiber shortening may represent an effective safe-by-design strategy for mitigating TiO2 NF toxic effects.


Assuntos
Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanofibras/química , Nanofibras/toxicidade , Titânio/química , Titânio/toxicidade , Células A549 , Animais , Biomarcadores/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Humanos , Inflamação , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Tamanho da Partícula , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , Propriedades de Superfície
19.
Nanomaterials (Basel) ; 9(10)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581730

RESUMO

The host-material interface is a crucial relationship dictating the possibility of successful osseointegration in implant dentistry. The aim of the present study was to characterize the effects of plasma proteins pre-adsorption on the adhesion capacity of osteoblasts, which occurs immediately after implant insertion in vivo. After having pre-adsorbed human plasma proteins on a machined and microrough titanium surface, MC3T3-E1 osteoblasts adhesion was evaluated through crystal violet cell adhesion assay, immunofluorescence staining for cytoskeleton, focal adhesions and cell nuclei, and scanning electron microscopy. The pre-adsorbed protein layer markedly affected the adhesion rate of cells, as well as their morphology and the expression of focal contacts. Moreover, protein adsorption to the underlying titanium surface was found to be correlated to surface pre-wetting. Thus, the early adsorption of serum proteins to the interface of dental implants impacts cell adhesion in terms of strength and of focal adhesions expression.

20.
Nutrients ; 11(10)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546671

RESUMO

The possibility of counteracting inflammation-related barrier defects with dietary compounds such as (poly)phenols has raised much interest, but information is still scarce. We have investigated here if (+)-catechin (CAT) and procyanidin B2 (PB2), two main dietary polyphenols, protect the barrier function of intestinal cells undergoing inflammatory stress. The cell model adopted consisted of co-cultured Caco-2 and HT29-MTX cells, while inflammatory conditions were mimicked through the incubation of epithelial cells with the conditioned medium of activated macrophages (MCM). The epithelial barrier function was monitored through trans-epithelial electrical resistance (TEER), and ROS production was assessed with dichlorofluorescein, while the expression of tight-junctional proteins and signal transduction pathways were evaluated with Western blot. The results indicated that MCM produced significant oxidative stress, the activation of NF-κB and MAPK pathways, a decrease in occludin and ZO-1 expression, and an increase in claudin-7 (CL-7) expression, while TEER was markedly lowered. Neither CAT nor PB2 prevented oxidative stress, transduction pathways activation, ZO-1 suppression, or TEER decrease. However, PB2 prevented the decrease in occludin expression and both polyphenols produced a huge increase in CL-7 abundance. It is concluded that, under the conditions adopted, CAT and PB2 do not prevent inflammation-dependent impairment of the epithelial barrier function of intestinal cell monolayers. However, the two compounds modify the expression of tight-junctional proteins and, in particular, markedly increase the expression of CL-7. These insights add to a better understanding of the potential biological activity of these major dietary flavan-3-ols at intestinal level.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , Permeabilidade/efeitos dos fármacos , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Proteínas de Junções Íntimas/metabolismo , Células CACO-2 , Técnicas de Cultura de Células , Células Epiteliais , Células HT29 , Humanos , Intestinos/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Ocludina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
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