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1.
J Pharm Pharmacol ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34289045

RESUMO

OBJECTIVES: Leishmaniasis is a zoonotic disease and several drugs have been used in the treatment, including meglumine antimoniate (AME). The chemotherapy reaches clinical cure but does not eliminate parasites, contributing to drug resistance. To improve AME efficacy we incorporated it in anionic liposomes. The antiparasitic activity and intracellular localization were investigated in canine macrophages infected with Leishmania infantum. METHODS: Liposomes (L-AME) is composed of egg phosphatidylcholine, cholesterol, palmitoyl oleoyl phosphatidyl serine and α-tocopherol (4 : 3 : 0.4 : 0.07 mol%) plus AME. L-AME size, polydispersity, zeta potential and morphology were analysed as well as antileishmanial activity and intracellular localization in DH82 macrophages. KEY FINDINGS: Liposomes (360 nm) zeta potential range from -40 to -65 mV, had 23% encapsulation efficiency and were stable for 180 days at 4°C. Free AME was cytotoxic towards L. infantum infected macrophages (ID50 = 0.012 M) while L-AME did not reduce cell viability. L-AME colocalized with parasites inside macrophages in a time-dependent manner, and reduced the percentage of infected cells and the number of intracellular parasites, decreasing the infection index (75-80%) twice as compared with AME treatment. CONCLUSIONS: Liposomal AME is a promising delivery system for treating visceral leishmaniasis, improving meglumine efficacy against L. infantum and minimizing its cytotoxicity towards canine macrophages.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34252542

RESUMO

Vertebrate skeletal muscle development and repair relies on the precise control of Wnt signaling. Dact1 (Dapper/Frodo) is an important modulator of Wnt signaling, interacting with key components of the various Wnt transduction pathways. Here, we characterized Dact1 mRNA and protein expression in chicken and mouse fetal muscles in vivo and during the differentiation of chick primary and mouse C2C12 myoblasts in vitro. We also performed in silico analysis to investigate Dact1 gene expression in human myopathies, and evaluated the Dact1 protein structure to seek an explanation for the accumulation of Dact1 protein aggregates in the nuclei of myogenic cells. Our results show for the first time that in both chicken and mouse, Dact1 is expressed during myogenesis, with a strong upregulation as cells engage in terminal differentiation, cell cycle withdrawal and cell fusion. In humans, Dact1 expression was found to be altered in specific muscle pathologies, including muscular dystrophies. Our bioinformatic analyses of Dact1 proteins revealed long intrinsically disordered regions, which may underpin the ability of Dact1 to interact with its many partners in the various Wnt pathways. In addition, we found that Dact1 has strong propensity for liquid-liquid phase separation, a feature that explains its ability to form nuclear aggregates and points to a possible role as a molecular 'on'-'off' switch. Taken together, our data suggest Dact1 as a candidate, multi-faceted regulator of amniote myogenesis with a possible pathophysiological role in human muscular diseases.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Mioblastos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Diferenciação Celular , Núcleo Celular/metabolismo , Proliferação de Células , Galinhas , Feminino , Humanos , Camundongos , Músculo Esquelético/citologia , Doenças Musculares/patologia , Mioblastos/citologia , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética
3.
Biomed Pharmacother ; 134: 110952, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33348307

RESUMO

pH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a desirable behavior in the treatment of cancer cells. Previously, we have shown that pH-sensitive liposomes accumulate in tumor tissues of mice, in which an acidic environment accelerates drug delivery. Ultimately, these formulations can be internalized by tumor cells and take the endosome-lysosomal route. However, the mechanism of doxorubicin release and intracellular traffic of pH-sensitive liposomes remains unclear. To investigate the molecular mechanisms underlying the intracellular release of doxorubicin from pH-sensitive liposomes, we followed HeLa cells viability, internalization, intracellular trafficking, and doxorubicin's intracellular delivery mechanisms from pH-sensitive (SpHL-DOX) and non-pH-sensitive (nSpHL-DOX) formulations. We found that SpHL-DOX has faster internalization kinetics and intracellular release of doxorubicin, followed by strong nuclear accumulation compared to nSpHL-DOX. The increased nuclear accumulation led to the activation of cleaved caspase-3, which efficiently induced apoptosis. Remarkably, we found that chloroquine and E64d enhanced the cytotoxicity of SpHL-DOX. This knowledge is paramount to improve the efficiency of pH-sensitive liposomes or to be used as a rational strategy for developing new formulations to be applied in vivo.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Composição de Medicamentos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Espaço Intracelular/metabolismo , Leucina/análogos & derivados , Leucina/farmacologia , Camundongos
5.
Cancers (Basel) ; 12(7)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668598

RESUMO

Background: Cancer-cachexia induces a variety of metabolic disorders, including skeletal muscle imbalance. Alternative therapy, as nutritional supplementation with leucine, shows a modulatory effect over tumour damage in vivo and in vitro. Method: Adult rats distributed into Control (C), Walker tumour-bearing (W), control fed a leucine-rich diet (L), and tumour-bearing fed a leucine-rich diet (WL) groups had the gastrocnemius muscle metabolomic and proteomic assays performed in parallel to in vitro assays. Results: W group presented an affected muscle metabolomic and proteomic profile mainly related to energy generation and carbohydrates catabolic processes, but leucine-supplemented group (WL) recovered the energy production. In vitro assay showed that cell proliferation, mitochondria number and oxygen consumption were higher under leucine effect than the tumour influence. Muscle proteomics results showed that the main affected cell component was mitochondria, leading to an impacted energy generation, including impairment in proteins of the tricarboxylic cycle and carbohydrates catabolic processes, which were modulated and improved by leucine treatment. Conclusion: In summary, we showed a beneficial effect of leucine upon mitochondria, providing information about the muscle glycolytic pathways used by this amino acid, where it can be associated with the preservation of morphometric parameters and consequent protection against the effects of cachexia.

6.
Eur J Pharm Biopharm ; 151: 162-170, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32311428

RESUMO

Bladder cancer is the fifth most common disease in the United States, and the treatment and alternatives for patients have not changed in the last decades. Silver nanoparticles (AgNP) have been used in the treatment of various cancer, mainly because of the antineoplastic activity; however, their use and the molecular mechanisms towards bladder cancer still unexplored. Therefore, this work aims to evaluate the in vitro and in vivo antitumoral mechanisms of biogenic silver nanoparticles synthesized from Fusarium sp. First, AgNP showed cytotoxicity in a dose- and time-response relationship and detailed analysis demonstrated the induction of cell death via apoptosis, also inhibiting cell migration and proliferation in bladder carcinoma cell line 5637. Next, it was evaluated the antitumoral activity of AgNP against non-muscle invasive bladder cancer (NMIBC). Bladder cancer was chemically induced with N-methyl-N-nitrosourea (MNU) on C57BL/6JUnib female mice and treated by intravesical route with AgNP concentrations of 0.5, 0.2, and 0.05 mg/mL. Finally, treatment with AgNP (0.05 mg/mL) led to 57.13% of tumor regression, with 14.28% of the animals showing normal urothelium, and 42.85% showing flat hyperplasia, considered to be a benign lesion. Overall, these findings demonstrated that AgNP might be a cost-effective alternative and promising candidate for the treatment of bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Nanopartículas Metálicas/administração & dosagem , Prata/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL
7.
Comput Methods Programs Biomed ; 193: 105476, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32302889

RESUMO

BACKGROUND AND OBJECTIVE: Image acquisition has greatly benefited from the automation of microscopes and has been followed by an increasing amount and complexity of data acquired. Here, we present the PyScratch, a new tool for processing spatial and temporal information from scratch assays. PyScratch is an open-source software implemented in Python that analyses the migration area in an automated fashion. METHODS: The software was developed in Python. Wound healing assays were used to validate its performance. The images were acquired using Cytation 5™ during 60 h. Data were analyzed using One-Way ANOVA. RESULTS: PyScratch performed a robust analysis of confluent cells, showing that high plating density affects cell migration. Additionally, PyScratch was approximately six times faster than a semi-automated analysis. CONCLUSIONS: PyScratch offers a user-friendly interface allowing researches with little or no programming skills to perform quantitative analysis of in vitro scratch assays.


Assuntos
Software , Cicatrização , Automação , Movimento Celular
8.
Sci Total Environ ; 715: 136797, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32014764

RESUMO

We previously demonstrated that N-acetylcysteine (NAC) could reduce the toxicity of silver (Ag) materials (nanoparticles (NPs) and Ag nitrate) to the soil invertebrate Enchytraeus crypticus (Oligochaeta). It remains however, unclear whether the antitoxic mechanism of NAC was caused by NAC-Ag binding in the soil or inside the organisms. This study aimed at determining the bioavailability of Ag in the soil in a 21-day toxicity test as well as the Ag uptake and elimination kinetics in E. crypticus exposed to AgNPs in LUFA 2.2 standard soil amended with low (100 mg/kg dry soil) and high (600 mg/kg dry soil) NAC concentrations. The addition of NAC to the soil alleviated the toxicity of AgNPs by decreasing the internal Ag concentration of E. crypticus in a dose-dependent manner. Indeed, NAC reduced the binding of Ag to the soil, which probably was due to the formation of soluble but biologically unavailable Ag-cysteine complexes. The reduced Ag uptake in the enchytraeids was explained from an increased elimination at high NAC levels. These findings reinforce the view that metal complexing-compounds like NAC play a key role in the modulation of AgNP toxicity and bioavailability in terrestrial environments. Further, it may inform on the potential of NAC as a remediation solution for Ag or other metal-contaminated soils.


Assuntos
Nanopartículas Metálicas , Oligoquetos , Acetilcisteína , Animais , Disponibilidade Biológica , Prata , Solo , Poluentes do Solo , Toxicocinética
9.
Bioprocess Biosyst Eng ; 43(6): 1105-1118, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32076836

RESUMO

Buriti oil is rich in monounsaturated fatty acids, carotenoids and tocopherols and it is used for the treatment of various diseases. One strategy to restructure the triglycerides is enzymatic interesterification and nanocarriers have been employed to improve the solubility, bioavailability and stability of active compounds. This work aims to investigate the in vitro cytotoxicity of this structured oil in nanoemulsions and nanostructured lipid carriers to expand the applicability of the crude oil. None of the samples had a cytotoxic effect on Caco-2 and HepG2 cell lines at the concentrations tested. Structured lipids acted protecting against oxidative stress and lipid peroxidation. Additionally, no consumption of glutathione has been observed in both cells, and the compounds present in buriti oil are possibly acting as antioxidants. Thus, nanoparticles prepared with interesterified buriti oil had low cytotoxicity and high oxidative stability, with great potential for future applications.


Assuntos
Carotenoides , Portadores de Fármacos , Nanoestruturas , Óleos Vegetais , Células CACO-2 , Carotenoides/química , Carotenoides/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Avaliação de Medicamentos , Células Hep G2 , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Óleos Vegetais/química , Óleos Vegetais/farmacologia
10.
J Control Release ; 321: 100-118, 2020 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-32035192

RESUMO

Antimicrobial peptides (AMP) are molecules consisting of 12-100 amino acids synthesized by certain microbes and released extracellularly to inhibit the growth of other microbes. Among the AMP molecules, bacteriocins are produced by both gram-positive and gram-negative bacterial species and are used to kill or inhibit other prokaryotes in the environment. Due to their broad-spectrum antimicrobial activity, some bacteriocins have the potential of becoming the next generation of antibiotics for use in the crisis of multi antibiotic-resistant bacteria. Recently, bacteriocins have even been used to treat cancer. However, bacteriocins present a few drawbacks, such as sensitivity to proteases, immunogenicity issues, and the development of bacteriocin resistance by pathogenic bacteria. In this regard, nanoscale drug delivery systems (Nano-DDS) have led to the expectation that they will eventually improve the treatment of many diseases by addressing these limitations and improving bacteriocin pharmacokinetics and pharmacodynamics. Thus, combining bacteriocins with nano-DDS may be useful in overcoming these drawbacks and thereby reveal the full potential of bacteriocins. In this review article, we highlight the importance of tailoring nano-DDS to address bacteriocin limitations, the successes and failures of this technology thus far, the challenges that this technology still has to overcome before reaching the market, and future perspectives. Therefore, the purpose of this review is to highlight, categorize, compare and contrast the different nano-DDS described in the literature so far, and compare their effectiveness in order to improve the next generation of bacteriocin nano-sized drug delivery systems (Nano-DDS).


Assuntos
Bacteriocinas , Antibacterianos , Bactérias , Sistemas de Liberação de Medicamentos , Peptídeos
11.
Drug Deliv Transl Res ; 10(1): 34-42, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31240624

RESUMO

Cationic solid lipid nanoparticles (cSLNs) are considered as one of the most effective lipid nanocarriers for delivery of low water-solubility compounds and genetic materials. As the excipients used in the cSLN production are generally regarded as safe (GRAS), the formulations are granted as non-toxic. However, the toxicological profile of new SLN-based formulations should always be performed to confirm that the delivery systems themselves may not impose risks to the human health. Therefore, in this study, we delineate the toxicological profile of the cSLN formulation at 24 and 72 h after single intravenous injection to male Wistar rats. Hematological, biochemical, and histopathological evaluations of the spleen, lungs, liver, and kidneys indicated short-lived alterations including neutrophilia. We found increases in the population of macrophages in the lungs, liver, and spleen and also migration of circulating neutrophils into inflamed tissue and a decrease in blood urea nitrogen. We also observed the presence of cSLNs within the brain parenchyma without any sign of damage to the blood-brain barrier. These side effects appeared to be mild and transitory (< 72 h). These findings reinforce the importance of investigating the toxicity of SLN-based formulations before the incorporation of drugs/genetic material to the formulation and its translation to the clinic.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Lipídeos/química , Macrófagos/metabolismo , Nanopartículas/toxicidade , Administração Intravenosa , Animais , Nitrogênio da Ureia Sanguínea , Cátions , Rim/efeitos dos fármacos , Rim/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Nanopartículas/química , Tamanho da Partícula , Ratos , Ratos Wistar , Baço/efeitos dos fármacos , Baço/imunologia
12.
Cell Rep ; 27(3): 750-761.e7, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995474

RESUMO

Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.


Assuntos
Butiratos/administração & dosagem , Clostridioides difficile/patogenicidade , Colite/prevenção & controle , Fator 1 Induzível por Hipóxia/metabolismo , Administração Oral , Animais , Antibacterianos/farmacologia , Butiratos/farmacologia , Clostridioides difficile/metabolismo , Colite/etiologia , Colite/microbiologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Ácidos Graxos Voláteis/metabolismo , Humanos , Insulina/administração & dosagem , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Junções Íntimas/metabolismo , Toxinas Biológicas/toxicidade , Triglicerídeos/administração & dosagem
13.
J Agric Food Chem ; 67(16): 4453-4462, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30933503

RESUMO

Atrazine is one of the most used herbicides and has been associated with persistent surface and groundwater contamination, and novel formulations derived from nanotechnology can be a potential solution. We used poly(ε-caprolactone) nanoencapsulation of atrazine (NC+ATZ) to develop a highly effective herbicidal formulation. Detailed structural study of interaction between the formulation and Brassica juncea plants was carried out with evaluation of the foliar uptake of nanoatrazine and structural alterations induced in the leaves. Following postemergent treatment, NC+ATZ adhered to the leaf and penetrated mesophyll tissue mainly through the hydathode regions. NC+ATZ was transported directly through the vascular tissue of the leaves and into the cells where it degraded the chloroplasts resulting in herbicidal activity. Nanocarrier systems, such as the one used in this study, have great potential for agricultural applications in terms of maintenance of herbicidal activity at low concentrations and a substantial increase in the herbicidal efficacy.


Assuntos
Atrazina/química , Herbicidas/química , Mostardeira/efeitos dos fármacos , Nanopartículas/química , Atrazina/metabolismo , Atrazina/farmacologia , Composição de Medicamentos , Herbicidas/metabolismo , Herbicidas/farmacologia , Mostardeira/metabolismo , Nanopartículas/metabolismo , Nanotecnologia , Tamanho da Partícula , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento
14.
Nanotoxicology ; 13(3): 326-338, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30477371

RESUMO

The increasing use of silver nanoparticles (AgNPs) in consumer products raises the risk of human toxicity. Currently, there are no therapeutic options or established treatment protocols in cases of AgNPs intoxication. We demonstrated previously that thiol antioxidants compounds can reverse the cytotoxicity induced by AgNPs in Huh-7 hepatocarcinoma cells. Here, we investigated the use of N-acetylcysteine (NAC) against the systemic toxic effects of AgNPs (79.3 nm) in rats. Biochemical, histopathological, hematological, and oxidative parameters showed that a single intravenous injection of AgNPs (5 mg/kg b.w.) induced deleterious effects such as hepatotoxicity, potentially as a result of AgNPs accumulation in the liver. Treatment with a single intraperitoneal injection of NAC (1 g/kg b.w.) one hour after AgNPs exposure significantly attenuated all toxic effects evaluated and altered the bioaccumulation and release patterns of AgNPs in rats. The findings show that NAC may be a promising candidate for clinical management of AgNPs intoxication.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Animais , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Nanopartículas Metálicas/química , Ratos , Prata/química
15.
J Infect ; 77(2): 137-144, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29746940

RESUMO

OBJECTIVES: To investigate the involvement of NLRP3 in the effector functions of human dendritic cells (DCs) in response to Paracoccidioides brasiliensis yeast cells (Pb) and to evaluate its role in the modulation of the adaptive immune response. METHODS: DCs were differentiated from purified peripheral blood monocytes and analyzed in relation to the participation of TLR-2, dectin-1, and Syk in Pb recognition, as well as, the indirect mechanisms (Reactive Oxygen Species production, endosome acidification, or K+ efflux) involved in NLRP3 inflammasome activation after the stimulus with Pb. Additionally, we analyzed the role of NLRP3 in the activation of T cells. RESULTS: Our results demonstrated that the NLRP3 inflammasome activation and cytokines production by DCs are dependent on ROS generation, endosome acidification, and K+ efflux and involve the Pb recognition by dectin-1 and Syk phosphorylation. Our data also demonstrate that the NLRP3 inflammasome is essential for the activation/expansion of Th1/Th17 cells and its inhibition leads to an increased frequency of Th2 and Treg cells. CONCLUSION: Altogether our data indicated that activation of NLRP3 presents an important role in both the induction of the initial inflammatory response and in the development of the acquired immune response associated with resistance to infection.


Assuntos
Células Dendríticas/fisiologia , Inflamassomos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Paracoccidioides/imunologia , Células Th17/fisiologia , Anticorpos , Diferenciação Celular , Citocinas/genética , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/imunologia , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Fosforilação , Quinase Syk/efeitos dos fármacos , Quinase Syk/genética , Quinase Syk/metabolismo
16.
Biochem Mol Biol Educ ; 46(1): 66-75, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29131491

RESUMO

Metabolism involves numerous reactions and organic compounds that the student must master to understand adequately the processes involved. Part of biochemical learning should include some knowledge of the structure of biomolecules, although the acquisition of such knowledge can be time-consuming and may require significant effort from the student. In this report, we describe the "polygonal model" as a new means of graphically representing biomolecules. This model is based on the use of geometric figures such as open triangles, squares, and circles to represent hydroxyl, carbonyl, and carboxyl groups, respectively. The usefulness of the polygonal model was assessed by undergraduate students in a classroom activity that consisted of "transforming" molecules from Fischer models to polygonal models and vice and versa. The survey was applied to 135 undergraduate Biology and Nursing students. Students found the model easy to use and we noted that it allowed identification of students' misconceptions in basic concepts of organic chemistry, such as in stereochemistry and organic groups that could then be corrected. The students considered the polygonal model easier and faster for representing molecules than Fischer representations, without loss of information. These findings indicate that the polygonal model can facilitate the teaching of metabolism when the structures of biomolecules are discussed. Overall, the polygonal model promoted contact with chemical structures, e.g. through drawing activities, and encouraged student-student dialog, thereby facilitating biochemical learning. © 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):66-75, 2018.


Assuntos
Bioquímica/educação , Modelos Químicos , Compostos Orgânicos/química , Compostos Orgânicos/metabolismo , Humanos , Estudantes , Ensino
17.
Curr Pharm Des ; 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29173149

RESUMO

BACKGROUND: Topical drug administration offers an attractive route with minimal invasiveness. It also avoids limitations of intravenous administration such as the first pass metabolism and presystemic elimination within the gastrointestinal tract. Furthermore, topical drug administration is safe, have few side effects, is easy to apply, and offers a fast onset of action. However, the development of effective topical formulations still represents a challenge for the desired effect to be reached, locally or systemically. Solid lipid nanoparticles and nanostructured lipid carriers are particular candidates to overcome the problem of topical drug administration. The nanometric particle size of lipid nanoparticles favors the physical adhesion to the skin or mucosal, what can also be attained with the formation of hybrid (nanoparticles/polymer) systems. METHODS: In this review, we discuss the major challenges for lipid nanoparticles formulations for topical application to oral mucosa, skin, and eye, highlighting the strategies to improve the performance of lipid nanoparticles for topical applications. Next, we critically analyzed the in vitro and in vivo approaches used to evaluate lipid nanoparticles performance and toxicity. CONCLUSION: We addressed some major drawbacks related to lipid nanoparticle topical formulations and concluded the key points that have to be overcome to help them to reach the market in topical formulations to oral mucosa, skin and eye.

18.
Mol Pharm ; 13(11): 3913-3924, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27712077

RESUMO

Polyethylene glycol (PEG) coating has been frequently used to improve the pharmacokinetic behavior of nanoparticles. Studies that contribute to better unravel the effects of PEGylation on the toxicity of nanoparticle formulation are therefore highly relevant. In the present study, reduced graphene oxide (rGO) was functionalized with PEG, and its effects on key components of the blood-brain barrier, such as astrocytes and endothelial cells, were analyzed in culture and in an in vivo rat model. The in vitro studies demonstrated concentration-dependent toxicity. The highest concentration (100 µg/mL) of non-PEGylated rGO had a lower toxic influence on cell viability in primary cultures of astrocytes and rat brain endothelial cells, while PEGylated rGO induced deleterious effects and cell death. We assessed hippocampal BBB integrity in vivo by evaluating astrocyte activation and the expression of the endothelial tight and adherens junctions proteins. From 1 h to 7 days post-rGO-PEG systemic injection, a notable and progressive down-regulation of protein markers of astrocytes (GFAP, connexin-43), the endothelial tight (occludin), and adherens (ß-catenin) junctions and basal lamina (laminin) were observed. The formation of intracellular reactive oxygen species demonstrated by increases in the enzymatic antioxidant system in the PEGylated rGO samples was indicative of oxidative stress-mediated damage. Under the experimental conditions and design of the present study the PEGylation of rGO did not improve interaction with components of the blood-brain barrier. In contrast, the attachment of PEG to rGO induced deleterious effects in comparison with the effects caused by non-PEGylated rGO.


Assuntos
Grafite/química , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Barreira Hematoencefálica/química , Barreira Hematoencefálica/efeitos dos fármacos , Western Blotting , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Grafite/toxicidade , Imuno-Histoquímica , Masculino , Nanoestruturas/química , Estresse Oxidativo/fisiologia , Ratos
19.
J Nanobiotechnology ; 14(1): 53, 2016 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-27342277

RESUMO

BACKGROUND: We have previously demonstrated that reduced graphene oxide (rGO) administered intravenously in rats was detected inside the hippocampus after downregulation of the tight and adherens junction proteins of the blood-brain barrier. While down-regulators of junctional proteins could be useful tools for drug delivery through the paracellular pathway, concerns over toxicity must be investigated before clinical application. Herein, our purpose was to trace whether the rGO inside the hippocampus triggered toxic alterations in this brain region and in target organs (blood, liver and kidney) of rats at various time points (15 min, 1, 3 h and 7 days). RESULTS: The assessed rGO-treated rats (7 mg/kg) were clinically indistinguishable from controls at all the time points. Hematological, histopathological (neurons and astrocytes markers), biochemical (nephrotoxicity and hepatotoxicity assessment) and genotoxicological based tests showed that systemic rGO single injection seemed to produce minimal toxicological effects at the time points assessed. Relative to control, the only change was a decrease in the blood urea nitrogen level 3 h post-treatment and increases in superoxide dismutase activity 1 h and 7 days post-treatment. While no alteration in leukocyte parameters was detected between control and rGO-treated animals, time-dependent leukocytosis (rGO-1 h versus rGO-3 h) and leukopenia (rGO-3 h versus rGO-7 days) was observed intra-treated groups. Nevertheless, no inflammatory response was induced in serum and hippocampus at any time. CONCLUSIONS: The toxic effects seemed to be peripheral and transitory in the short-term analysis after systemic administration of rGO. The effects were self-limited and non-significant even at 7 days post-rGO administration.


Assuntos
Grafite/farmacologia , Hipocampo/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/ultraestrutura , Nitrogênio da Ureia Sanguínea , Esquema de Medicação , Índices de Eritrócitos , Grafite/química , Grafite/farmacocinética , Hipocampo/ultraestrutura , Injeções Intravenosas , Rim/ultraestrutura , Contagem de Leucócitos , Fígado/ultraestrutura , Masculino , Nanopartículas/química , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Óxidos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Testes de Toxicidade
20.
Nanomedicine ; 12(3): 789-799, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26724539

RESUMO

UNLABELLED: Silver nanoparticles are well known potent antimicrobial agents. Although significant progresses have been achieved on the elucidation of antimicrobial mechanism of silver nanoparticles, the exact mechanism of action is still not completely known. This overview incorporates a retrospective of previous reviews published and recent original contributions on the progress of research on antimicrobial mechanisms of silver nanoparticles. The main topics discussed include release of silver nanoparticles and silver ions, cell membrane damage, DNA interaction, free radical generation, bacterial resistance and the relationship of resistance to silver ions versus resistance to silver nanoparticles. The focus of the overview is to summarize the current knowledge in the field of antibacterial activity of silver nanoparticles. The possibility that pathogenic microbes may develop resistance to silver nanoparticles is also discussed. FROM THE CLINICAL EDITOR: Antibacterial effect of nanoscopic silver generated a lot of interest both in research projects and in practical applications. However, the exact mechanism is still will have to be elucidated. This overview incorporates a retrospective of previous reviews published from 2007 to 2013 and recent original contributions on the progress of research on antimicrobial mechanisms to summarize our current knowledge in the field of antibacterial activity of silver nanoparticles.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Nanopartículas Metálicas/química , Prata/química , Prata/farmacologia , Animais , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Proteínas de Bactérias/metabolismo , Dano ao DNA/efeitos dos fármacos , DNA Bacteriano/genética , Farmacorresistência Bacteriana , Radicais Livres/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos
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