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1.
Mol Cell ; 83(19): 3558-3573.e7, 2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37802028

RESUMO

Cellular senescence is a stress-response mechanism implicated in various physiological processes, diseases, and aging. Current detection approaches have partially addressed the issue of senescent cell identification in clinical specimens. Effective methodologies enabling precise isolation or live tracking of senescent cells are still lacking. In-depth analysis of truly senescent cells is, therefore, an extremely challenging task. We report (1) the synthesis and validation of a fluorophore-conjugated, Sudan Black-B analog (GLF16), suitable for in vivo and in vitro analysis of senescence by fluorescence microscopy and flow cytometry and (2) the development and application of a GLF16-carrying micelle vector facilitating GLF16 uptake by living senescent cells in vivo and in vitro. The compound and the applied methodology render isolation of senescent cells an easy, rapid, and precise process. Straightforward nanocarrier-mediated GLF16 delivery in live senescent cells comprises a unique tool for characterization of senescence at an unprecedented depth.


Assuntos
Senescência Celular , Indicadores e Reagentes , Citometria de Fluxo
2.
Mol Cell ; 81(23): 4907-4923.e8, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34793711

RESUMO

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that "escape" from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying "escape" from oncogene-induced senescence.


Assuntos
Senescência Celular , Inversão Cromossômica , Cromossomos/ultraestrutura , Transição Epitelial-Mesenquimal , Neoplasias/genética , Oncogenes , Recombinação Genética , Animais , Brônquios/metabolismo , Sistemas CRISPR-Cas , Ciclo Celular , Transformação Celular Neoplásica , Ritmo Circadiano , Biologia Computacional , Células Epiteliais/metabolismo , Citometria de Fluxo , Genômica , Humanos , Cariotipagem , Camundongos , Camundongos SCID , Neoplasias/metabolismo , Fenótipo , Ligação Proteica , Domínios Proteicos , Fenótipo Secretor Associado à Senescência
3.
EMBO Rep ; 23(2): e51287, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34897944

RESUMO

RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of γ-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors.


Assuntos
Receptores Notch , Transdução de Sinais , Fatores de Transcrição HES-1 , Proteínas Supressoras de Tumor , Humanos , Proteínas Nucleares/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
4.
Int J Mol Sci ; 25(2)2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38256239

RESUMO

Ropinirole is a non-ergolinic dopamine agonist used to manage Parkinson's disease and it is characterized by poor oral bioavailability. This study aimed to design and develop advanced drug delivery systems composed of poloxamer 407, a non-ionic surfactant (Tween 80), and cyclodextrins (methyl-ß-CD or hydroxy-propyl-ß-CD) for possible brain targeting of ropinirole after nasal administration for the treatment of Parkinson's disease. The hybrid systems were formed by the thin-film hydration method, followed by an extensive physicochemical and morphological characterization. The in vitro cytotoxicity of the systems on HEK293 cell lines was also tested. In vitro release and ex vivo mucosal permeation of ropinirole were assessed using Franz cells at 34 °C and with phosphate buffer solution at pH 5.6 in the donor compartment, simulating the conditions of the nasal cavity. The results indicated that the diffusion-controlled drug release exhibited a progressive increase throughout the experiment, while a proof-of-concept experiment on ex vivo permeation through rabbit nasal mucosa revealed a better performance of the prepared hybrid systems in comparison to ropinirole solution. The encouraging results in drug release and mucosal permeation indicate that these hybrid systems can serve as attractive platforms for effective and targeted nose-to-brain delivery of ropinirole with a possible application in Parkinson's disease. Further ex vivo and in vivo studies to support the results of the present work are ongoing.


Assuntos
Indóis , Doença de Parkinson , Surfactantes Pulmonares , Humanos , Animais , Coelhos , Tensoativos , Polímeros , Células HEK293 , Doença de Parkinson/tratamento farmacológico , Encéfalo , Lipoproteínas , Mucosa Nasal
5.
Int J Mol Sci ; 25(5)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38473720

RESUMO

The currently available anti-cancer therapies, such as gamma-radiation and chemotherapeutic agents, induce cell death and cellular senescence not only in cancer cells but also in the adjacent normal tissue. New anti-tumor approaches focus on limiting the side effects on normal cells. In this frame, the potential anti-tumor properties of Pulsed Electromagnetic Fields (PEMFs) through the irradiation of breast cancer epithelial cells (MCF-7 and MDA-MB-231) and normal fibroblasts (FF95) were investigated. PEMFs had a frequency of 8 Hz, full-square wave type and magnetic flux density of 0.011 T and were applied twice daily for 5 days. The data collected showcase that PEMF application decreases the proliferation rate and viability of breast cancer cells while having the opposite effect on normal fibroblasts. Moreover, PEMF irradiation induces cell death and cellular senescence only in breast cancer cells without any effect in the non-cancerous cells. These findings suggest PEMF irradiation as a novel, non-invasive anti-cancer strategy that, when combined with senolytic drugs, may eliminate both cancer and the remaining senescent cells, while simultaneously avoiding the side effects of the current treatments.


Assuntos
Neoplasias da Mama , Campos Eletromagnéticos , Humanos , Feminino , Morte Celular , Senescência Celular , Fibroblastos
6.
J Liposome Res ; 33(3): 214-233, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36856671

RESUMO

Nanovaccines have shown to be effective, and this is the reason they are preferred than conventional vaccines. The scope of this review is to describe the role, mechanisms, and advantages of nano vaccines based on lipids, and present the most important types, their physicochemical characteristics, as well as their challenges. The most important categories of lipid nano-vaccines are liposomal nano vaccines and (virus-lipid nanoparticles (NPs)/virosomes. Examples of vaccine formulations from each category are presented and analyzed below, focusing on their structure and physicochemical characteristics. In all cases, a nanoscale platform is used, enriched with adjuvants, antigens, and other helping agents to trigger immune response process and achieve cell targeting, and eventually immunity against the desired disease. The exact mechanism of action of each vaccine is not always completely known or understood. Physicochemical characteristics, such as particle size, morphology/shape, and zeta potential are also mentioned as they seem to affect the properties and mechanism of action of the vaccine formulation.


Assuntos
Nanopartículas , Vacinas , Lipossomos/química , Vacinas/química , Nanopartículas/química , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Tamanho da Partícula , Lipídeos/química
7.
Int J Mol Sci ; 25(1)2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-38203467

RESUMO

Hyperthermia has the potential to damage cancerous tissue by increasing the body temperature. However, targeting cancer cells whilst protecting the surrounding tissues is often challenging, especially when implemented in clinical practice. In this direction, there are data showing that the combination of nanotechnology and hyperthermia offers more successful penetration of nanoparticles in the tumor environment, thus allowing targeted hyperthermia in the region of interest. At the same time, unlike radiotherapy, the use of non-ionizing radiation makes hyperthermia an attractive therapeutic option. This review summarizes the existing literature regarding the use of hyperthermia and nanoparticles in cancer, with a focus on nanoparticle-induced cytotoxicity mechanisms.


Assuntos
Hipertermia Induzida , Nanopartículas , Neoplasias , Humanos , Hipertermia , Neoplasias/terapia
8.
Eur Respir J ; 60(2)2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35086840

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP. METHODS: Autopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients. RESULTS: SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed angiotensin-converting enzyme 2 and exhibited increased senescence (p16INK4A and SenTraGor positivity) and interleukin (IL)-1ß and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), DNA damage (γ-H2AX) and increased cytokine (IL-1ß, IL-6, CXCL8) and apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extrapulmonary sites (kidney and liver) of a COVID-19 patient. CONCLUSIONS: We demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.


Assuntos
COVID-19 , SARS-CoV-2 , Senescência Celular , Citocinas/metabolismo , Humanos , Inflamação , Interleucina-6 , Pulmão/metabolismo , Mutagênese , Fenótipo
9.
Sensors (Basel) ; 22(3)2022 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-35161984

RESUMO

Early-stage disease diagnosis is of particular importance for effective patient identification as well as their treatment. Lack of patient compliance for the existing diagnostic methods, however, limits prompt diagnosis, rendering the development of non-invasive diagnostic tools mandatory. One of the most promising non-invasive diagnostic methods that has also attracted great research interest during the last years is breath analysis; the method detects gas-analytes such as exhaled volatile organic compounds (VOCs) and inorganic gases that are considered to be important biomarkers for various disease-types. The diagnostic ability of gas-pattern detection using analytical techniques and especially sensors has been widely discussed in the literature; however, the incorporation of novel nanomaterials in sensor-development has also proved to enhance sensor performance, for both selective and cross-reactive applications. The aim of the first part of this review is to provide an up-to-date overview of the main categories of sensors studied for disease diagnosis applications via the detection of exhaled gas-analytes and to highlight the role of nanomaterials. The second and most novel part of this review concentrates on the remarkable applicability of breath analysis in differential diagnosis, phenotyping, and the staging of several disease-types, which are currently amongst the most pressing challenges in the field.


Assuntos
Líquidos Corporais , Compostos Orgânicos Voláteis , Testes Respiratórios , Expiração , Gases , Humanos
10.
Biomimetics (Basel) ; 9(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38534838

RESUMO

The rehabilitation of alveolar bone defects of moderate to severe size is often challenging. Currently, the therapeutic approaches used include, among others, the guided bone regeneration technique combined with various bone grafts. Although these techniques are widely applied, several limitations and complications have been reported such as morbidity, suboptimal graft/membrane resorption rate, low structural integrity, and dimensional stability. Thus, the development of biomimetic scaffolds with tailor-made characteristics that can modulate cell and tissue interaction may be a promising tool. This article presents a critical consideration in scaffold's design and development while also providing information on various fabrication methods of these nanosystems. Their utilization as delivery systems will also be mentioned.

11.
Nanomaterials (Basel) ; 14(7)2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38607176

RESUMO

Polyaniline (PANI) constitutes a very propitious conductive polymer utilized in several biomedical, as well as environmental applications, including tissue engineering, catalysis, and photocatalysis, due to its unique properties. In this study, nano-PANI/N-TiO2 and nano-PANI/Ag-TiO2 photocatalytic composites were fabricated via aniline's oxidative polymerization, while the Ag-and N-chemically modified TiO2 nanopowders were synthesized through the sol-gel approach. All produced materials were fully characterized. Through micro-Raman and FT-IR analysis, the co-existence of PANI and chemically modified TiO2 particles was confirmed, while via XRD analysis the composites' average crystallite size was determined as ≈20 nm. The semi-crystal structure of polyaniline exhibits higher photocatalytic efficiency compared to that of other less crystalline forms. The spherical-shaped developed materials are innovative, stable (zeta potential in the range from -26 to -37 mV), and cost-effective, characterized by enhanced photocatalytic efficiency under visible light (energy band gaps ≈ 2 eV), and synthesized with relatively simple methods, with the possibility of recycling and reusing them in potential future applications in industry, in wastewater treatment as well as in biomedicine. Thus, the PANI-encapsulated Ag and N chemically modified TiO2 nanocomposites exhibit high degradation efficiency towards Rhodamine B dye upon visible-light irradiation, presenting simultaneously high biocompatibility in different normal cell lines.

12.
In Vivo ; 38(4): 1665-1670, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38936909

RESUMO

BACKGROUND/AIM: Hyperthermia represents an adjuvant local anticancer strategy which relies on the increase of temperature beyond the physiological level. In this study, we investigated the anticancer potential of Fe3O4 and Fe3O4core Aushell nanoparticles as hyperthermic agents in terms of cytotoxicity and studied the expression of cellular markers of proliferation (changes in mRNA levels via real-time polymerase chain reaction). MATERIALS AND METHODS: The human breast cancer cell line SK-BR-1 was incubated with either Fe3O4 or Fe3O4core Aushell nanoparticles stabilized with tryptophan, prior to hyperthermia treatment. The normal HEK293 cell line was used as a control. Toxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay to estimate possible toxic effects of the tested nanoparticles. After RNA extraction and cDNA synthesis, mRNA expression of three indicators of proliferation, namely marker of proliferation Ki-67, DNA topoisomerase II alpha (TOP2A) and TPX2 microtubule nucleation factor (TPX2), was investigated. RESULTS: At each concentration tested, Fe3O4core Aushell nanoparticles showed greater toxicity compared to Fe3O4, while SK-BR-3 cells were more susceptible to their cytotoxic effects compared to the HEK293 cell line. The expression of Ki-67, TOP2A and TPX2 was reduced in SK-BR-3 cells by both Fe3O4 or Fe3O4core Aushell nanoparticles compared to untreated cells, while the only observed change in HEK293 cells was the up-regulation of TOP2A. CONCLUSION: Both Fe3O4core Aushell and Fe3O4 NPs exhibit increased cytotoxicity to the cancer cell line tested (SK-BR-3) compared to HEK293 cells. The down-regulation in SK-BR-3 cells of the three proliferative markers studied, Ki-67, TOP2A and TPX2, after incubation with NPs suggests that cells that survived thermal destruction were not actively proliferating.


Assuntos
Neoplasias da Mama , Proteínas de Ciclo Celular , Proliferação de Células , DNA Topoisomerases Tipo II , Hipertermia Induzida , Antígeno Ki-67 , Proteínas Associadas aos Microtúbulos , Proteínas de Ligação a Poli-ADP-Ribose , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo II/genética , Proliferação de Células/efeitos dos fármacos , Hipertermia Induzida/métodos , Antígeno Ki-67/metabolismo , Antígeno Ki-67/genética , Linhagem Celular Tumoral , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Feminino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Células HEK293 , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética
13.
Nanomaterials (Basel) ; 14(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38470728

RESUMO

The wide array of structures and characteristics found in ZnO-based nanostructures offers them a versatile range of uses. Over the past decade, significant attention has been drawn to the possible applications of these materials in the biomedical field, owing to their distinctive electronic, optical, catalytic, and antimicrobial attributes, alongside their exceptional biocompatibility and surface chemistry. With environmental degradation and an aging population contributing to escalating healthcare needs and costs, particularly in developing nations, there's a growing demand for more effective and affordable biomedical devices with innovative functionalities. This review delves into particular essential facets of different synthetic approaches (chemical and green) that contribute to the production of effective multifunctional nano-ZnO particles for biomedical applications. Outlining the conjugation of ZnO nanoparticles highlights the enhancement of biomedical capacity while lowering toxicity. Additionally, recent progress in the study of ZnO-based nano-biomaterials tailored for biomedical purposes is explored, including biosensing, bioimaging, tissue regeneration, drug delivery, as well as vaccines and immunotherapy. The final section focuses on nano-ZnO particles' toxicity mechanism with special emphasis to their neurotoxic potential, as well as the primary toxicity pathways, providing an overall review of the up-to-date development and future perspectives of nano-ZnO particles in the biomedicine field.

14.
J Mater Chem B ; 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38804576

RESUMO

In this study, we designed and developed systems composed of poly(ethylene-oxide)-b-poly(ε-caprolactone) block copolymers of different molecular weights and compositions, non-ionic surfactant, and cyclodextrins. The innovation of this study lies in the combination of these diverse biomaterials to create biomimetic and bioinspired drug delivery supramolecular structures. The systems were formed by the thin-film hydration method. Extensive physicochemical and morphological characterization was conducted using differential scanning calorimetry, light scattering techniques, microcalorimetry analysis, high-resolution ultrasound spectroscopy, surface tension measurements, fluorescence spectroscopy, cryogenic transmission electron microscopy images, and in vitro cytotoxicity evaluation. These innovative hybrid nanoparticles were found to be attractive candidates as drug delivery systems with unique properties by encompassing the physicochemical and thermotropic properties of both classes of materials. Subsequently, Ropinirole hydrochloride was used as a model drug for the purpose of this study. These systems showed a high RH content (%), and in vitro diffusion experiments revealed that more than 90% of the loading dose was released under pH and temperature conditions that simulate the conditions of the nasal cavity. Promising drug release performance was observed with all tested formulations, worth further investigation to explore both ex vivo permeation through the nasal mucosa and in vivo performance in an experimental animal model.

15.
STAR Protoc ; 5(1): 102929, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38460134

RESUMO

Identification and isolation of senescent cells is challenging, rendering their detailed analysis an unmet need. We describe a precise one-step protocol to fluorescently label senescent cells, for flow cytometry and fluorescence microscopy, implementing a fluorophore-conjugated Sudan Black-B analog, GLF16. Also, a micelle-based approach allows identification of senescent cells in vivo and in vitro, enabling live-cell sorting for downstream analyses and live in vivo tracking. Our protocols are applicable to cellular systems, tissues, or animal models where senescence is present. For complete details on the use and execution of this protocol, please refer to Magkouta et al.1.


Assuntos
Senescência Celular , Corantes Fluorescentes , Animais , Separação Celular , Citometria de Fluxo , Modelos Animais
16.
FEBS J ; 290(5): 1384-1392, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-34653312

RESUMO

In-depth analysis of SARS-CoV-2 biology and pathogenesis is rapidly unraveling the mechanisms through which the virus induces all aspects of COVID-19 pathology. Emergence of hundreds of variants and several important variants of concern has focused research on the mechanistic elucidation of virus mutagenesis. RNA viruses evolve quickly either through the error-prone polymerase or the RNA-editing machinery of the cell. In this review, we are discussing the links between cellular senescence, a natural aging process that has been recently linked to SARS-CoV-2 infection, and virus mutagenesis through the RNA-editing enzymes APOBEC. The action of APOBEC, enhanced by cellular senescence, is hypothesized to assist the emergence of novel variants, called quasispecies, within a cell or organism. These variants when introduced to the community may lead to the generation of a variant of concern, depending on fitness and transmissibility of the new genome. Such a mechanism of virus evolution may highlight the importance of inhibitors of cellular senescence during SARS-CoV-2 clinical treatment.


Assuntos
COVID-19 , Vírus , Humanos , SARS-CoV-2/genética , COVID-19/genética , Quase-Espécies , Vírus/genética , Senescência Celular/genética , RNA
17.
Pharmaceutics ; 15(2)2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36839826

RESUMO

The medical application of nanotechnology in the field of drug delivery has so far exhibited many efforts in treating simple to extremely complicated and life-threatening human conditions, with multiple products already existing in the market. A plethora of innovative drug delivery carriers, using polymers, surfactants and the combination of the above, have been developed and tested pre-clinically, offering great advantages in terms of targeted drug delivery, low toxicity and immune system activation, cellular biomimicry and enhanced pharmacokinetic properties. Furthermore, such artificial systems can be tailor-made with respect to each therapeutic protocol and disease type falling under the scope of personalized medicine. The simultaneous delivery of multiple therapeutic entities of different nature, such as genes and drugs, can be achieved, while novel technologies can offer systems with multiple modalities often combining therapy with diagnosis. In this review, we present prominent, innovative and state-of-the-art scientific efforts on the applications of surfactant-based, polymer-based, and mixed surfactant-polymer nanoparticle drug formulations intended for use in the medical field and in drug delivery. The materials used, formulation steps, nature, properties, physicochemical characteristics, characterization techniques and pharmacokinetic behavior of those systems, are presented extensively in the length of this work. The material presented is focused on research projects that are currently in the developmental, pre-clinical stage.

18.
Gels ; 9(11)2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37998946

RESUMO

The generation of 3D structures comprises three interlinked phases: material development, the printing process, and post-printing treatment. Numerous factors control all three phases, making the optimization of the entire process a challenging task. Until now, the state of the art has mainly focused on optimizing material processability and calibration of the printing process. However, after the successful Direct Ink Writing (DIW) of a hydrogel scaffold, the post-printing stage holds equal importance, as this allows for the treatment of the structure to ensure the preservation of its structural integrity for a duration that is sufficient to enable successful cell attachment and proliferation before undergoing degradation. Despite this stage's pivotal role, there is a lack of extensive literature covering its optimization. By studying the crosslinking factors and leveling the post-treatment settings of alginate-gelatin hydrogel, this study proposes a method to enhance scaffolds' degradation without compromising the targeted swelling behavior. It introduces an experimental design implementing the Response Surface Methodology (RSM) Design of Experiments (DoE), which elucidated the key parameters influencing scaffold degradation and swelling, and established an alginate ratio of 8% and being immersed for 15 min in 0.248 M CaCl2 as the optimal level configuration that generates a solution of 0.964 desirability, reaching a degradation time of 19.654 days and the swelling ratio of 50.00%.

19.
Nanomaterials (Basel) ; 13(15)2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37570542

RESUMO

Over the last ten years, there has been a growing interest in metal-organic frameworks (MOFs), which are a unique category of porous materials that combine organic and inorganic components. MOFs have garnered significant attention due to their highly favorable characteristics, such as environmentally friendly nature, enhanced surface area and pore volume, hierarchical arrangements, and adjustable properties, as well as their versatile applications in fields such as chemical engineering, materials science, and the environmental and biomedical sectors. This article centers on examining the advancements in using MOFs for environmental remediation purposes. Additionally, it discusses the latest developments in employing MOFs as potential tools for disease diagnosis and drug delivery across various ailments, including cancer, diabetes, neurological disorders, and ocular diseases. Firstly, a concise overview of MOF evolution and the synthetic techniques employed for creating MOFs are provided, presenting their advantages and limitations. Subsequently, the challenges, potential avenues, and perspectives for future advancements in the utilization of MOFs in the respective application domains are addressed. Lastly, a comprehensive comparison of the materials presently employed in these applications is conducted.

20.
J Exp Clin Cancer Res ; 42(1): 187, 2023 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-37507762

RESUMO

BACKGROUND: Prostate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage androgen-sensitive disease, but prostate cancer gradually develops into an androgen-resistant metastatic state in the vast majority of patients. According to our oncogene-induced model for cancer development, senescence is a major tumor progression barrier. However, whether senescence is implicated in the progression of early-stage androgen-sensitive to highly aggressive castration-resistant prostate cancer (CRPC) remains poorly addressed. METHODS: Androgen-dependent (LNCaP) and -independent (C4-2B and PC-3) cells were treated or not with enzalutamide, an Androgen Receptor (AR) inhibitor. RNA sequencing and pathway analyses were carried out in LNCaP cells to identify potential senescence regulators upon treatment. Assessment of the invasive potential of cells and senescence status following enzalutamide treatment and/or RNAi-mediated silencing of selected targets was performed in all cell lines, complemented by bioinformatics analyses on a wide range of in vitro and in vivo datasets. Key observations were validated in LNCaP and C4-2B mouse xenografts. Senescence induction was assessed by state-of-the-art GL13 staining by immunocytochemistry and confocal microscopy. RESULTS: We demonstrate that enzalutamide treatment induces senescence in androgen-sensitive cells via reduction of the replication licensing factor CDC6. Mechanistically, we show that CDC6 downregulation is mediated through endogenous activation of the GATA2 transcription factor functioning as a CDC6 repressor. Intriguingly, GATA2 levels decrease in enzalutamide-resistant cells, leading to CDC6 stabilization accompanied by activation of Epithelial-To-Mesenchymal Transition (EMT) markers and absence of senescence. We show that CDC6 loss is sufficient to reverse oncogenic features and induce senescence regardless of treatment responsiveness, thereby identifying CDC6 as a critical determinant of prostate cancer progression. CONCLUSIONS: We identify a key GATA2-CDC6 signaling axis which is reciprocally regulated in enzalutamide-sensitive and -resistant prostate cancer environments. Upon acquired resistance, GATA2 repression leads to CDC6 stabilization, with detrimental effects in disease progression through exacerbation of EMT and abrogation of senescence. However, bypassing the GATA2-CDC6 axis by direct inhibition of CDC6 reverses oncogenic features and establishes senescence, thereby offering a therapeutic window even after acquiring resistance to therapy.


Assuntos
Neoplasias da Próstata , Receptores Androgênicos , Masculino , Humanos , Animais , Camundongos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Neoplasias da Próstata/patologia , Androgênios/farmacologia , Antagonistas de Androgênios , Fator de Transcrição GATA2/genética , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proteínas Nucleares/metabolismo
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