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Metallic nanowire-based transparent conductors (MNTCs) are essential to various technologies, including displays, heat-regulating windows, and photo-communication. Hybrid configurations are primarily adopted to design stable, high-functioning MNTCs. Although hybrid MNTCs enhance electrical performance, they often suffer from optical degradation due to losses associated with the hybrid layers. Highly conductive hybrid MNTCs with minimal reduction in transparency are achieved with AgNWs/Ag(O)/Al-doped ZnO (AZO) design. The design provides a high visible light transmittance of 95.1%, representing a minimized optical loss of 3% compared to pristine AgNWs by optimizing optical interference between the AZO and Ag(O) layers. Furthermore, it allows for enhanced mobility of metallic nanowires by controlling the selective formation of conductive layers in the voids of the nanowire networks. The oxygen additive enables a continuous Ag ultrathin film of 6 nm in the macro-voids of AgNWs system, corresponding to 25 times higher mobility for AgNWs/Ag(O)/AZO than that of sole AgNWs. The significant enhancement in the mobility of AgNWs/Ag(O)/AZO induces a reduction of sheet resistance of MNTCs by 73%. The AgNWs/Ag(O)/AZO, with an optimized sheet resistance of 24 Ω sq-1, is explored for transparent heater applications, demonstrating a fast thermal response with reliable stability, as evidenced by consistent high-temperature profiles during prolonged operation.
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Despite recent advances in diagnostic and therapeutic methods in antifungal research, aspergillosis still remains a leading cause of morbidity and mortality. One strategy to address this problem is to enhance the activity spectrum of known antifungals, and we now report the first successful application of Candida antarctica lipase (CAL) for the preparation of optically enriched fluconazole analogues. Anti-Aspergillus activity was observed for an optically enriched derivative, (-)-S-2-(2',4'-difluorophenyl)-1-hexyl-amino-3-(1â´,2â´,4â´)triazol-1â´-yl-propan-2-ol, which exhibits MIC values of 15.6 µg/ml and 7.8 µg/disc in broth microdilution and disc diffusion assays, respectively. This compound is tolerated by mammalian erythrocytes and cell lines (A549 and U87) at concentrations of up to 1,000 µg/ml. When incorporated into dextran nanoparticles, the novel, optically enriched fluconazole analogue exhibited improved antifungal activity against Aspergillus fumigatus (MIC, 1.63 µg/ml). These results not only demonstrate the ability of biocatalytic approaches to yield novel, optically enriched fluconazole derivatives but also suggest that enantiomerically pure fluconazole derivatives, and their nanotized counterparts, exhibiting anti-Aspergillus activity may have reduced toxicity.
Assuntos
Antifúngicos/farmacologia , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/efeitos dos fármacos , Fluconazol/análogos & derivados , Fluconazol/farmacologia , Células A549 , Linhagem Celular , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Fluconazol/efeitos adversos , Proteínas Fúngicas/metabolismo , Humanos , Lipase/metabolismo , Nanopartículas/químicaRESUMO
Omnidirectional photosensing is crucial in optoelectronic devices, enabling a wide field of view (wFoV) and leveraging potential applications for the Internet of Things in sensors, light fidelity, and photocommunication. The wFoV helps overcome the limitations of line-of-sight communication, and transparent photodetection becomes highly desirable as it enables the capture of optical information from various angles. Therefore, developing a photoelectric device with a 360° wFoV, ultra sensitivity to photons, power generation, and transparency is of utmost importance. This study utilizes a heterojunction of van der Waals SnS with Ga2 O3 to fabricate a transparent photovoltaic (TPV) device showing a 360° wFoV with bifacial onsite power production. SnS/Ga2 O3 heterojunction preparation consists of magnetron sputtering and is free from nanopatterning/nanostructuring to achieve the desired wFoV window device. The device exhibits a high average visible transmittance of 56%, generates identical power from bifacial illumination, and broadband fast photoresponse. Careful analysis of the device shows an ultra-sensitive photoinduced defect-modulated heterojunction and photocapacitance, revealed by the impedance spectroscopy, suggesting photon-flux driven charge diffusion. Leveraging the wFoV operation, the TPV embedded visual and speech photocommunication prototype demonstrated, aiming to help visually and auditory impaired individuals, promising an environmental-friendly sustainable future.
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Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by loss of the neurons, excessive accumulation of misfolded Aß and Tau proteins, and degeneration of neural synapses, primarily occurring in the neocortex and the hippocampus regions of the brain. AD Progression is marked by cognitive deterioration, memory decline, disorientation, and loss of problem-solving skills, as well as language. Due to limited comprehension of the factors contributing to AD and its severity due to neuronal loss, even today, the medications approved by the U.S. Food and Drug Administration (FDA) are not precisely efficient and curative. Stem cells possess great potential in aiding AD due to their self-renewal, proliferation, and differentiation properties. Stem cell therapy can aid by replacing the lost neurons, enhancing neurogenesis, and providing an enriched environment to the pre-existing neural cells. Stem cell therapy has provided us with promising results in regard to the animal AD models, and even pre-clinical studies have shown rather positive results. Cell replacement therapies are potential curative means to treat AD, and there are a number of undergoing human clinical trials to make Stem Cell therapy accessible for AD patients. In this review, we aim to discuss the AD pathophysiology and varied stem cell types and their application.
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Thermal losses in photoelectric devices limit their energy conversion efficiency, and cyclic input of energy coupled with pyroelectricity can overcome this limit. Here, incorporating a pyroelectric absorber into a photovoltaic heterostructure device enables efficient electricity generation by leveraging spontaneous polarization based on pulsed light-induced thermal changes. The proposed pyroelectric-photovoltaic device outperforms traditional photovoltaic devices by 2.5 times due to the long-range electric field that occurs under pulse illumination. Optimization of parameters such as pulse frequency, scan speed, and illumination wavelength enhances power harvesting, as demonstrated by a power conversion efficiency of 11.9% and an incident-photon-to-current conversion efficiency of 200% under optimized conditions. This breakthrough enables reconfigurable electrostatic devices and presents an opportunity to accelerate technology that surpasses conventional limits in energy generation.
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Skin cancer is a significant health burden being the fourth most common cancer globally and accounts for 6.2% of the total combined cancer cases. However, mortality rates due to skin cancer are less when compared with other cancers, but it is significantly high in the Asian population (43%). DNA mutations and environmental and genetic factors are linked with skin cancer prognosis; however, long-term exposure to ultraviolet (UV) radiation remains one of the leading factors worldwide. Sun exposure is a major environmental risk factor for skin cancers but is also an essential source of vitamin D. On the other hand, studies exploring the relationship between skin cancer risk and vitamin D show mixed, somewhat conflicting results. This study investigates the role of vitamin D and skin carcinogenesis to clarify the associations. Moreover, in addition to suppressing cancer stem cells, it has been observed that vitamin D also regulates tumor initiation and metastasis. In conclusion, the incorporation of well-designed studies on the metabolism of vitamin D from a genotypic and phenotypic perspective is required to understand the intricate mechanisms linking the role of vitamin D in skin carcinogenesis. These new findings will open up new pathways in targeting the disease and lead to novel opportunities for its treatment and cure.
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If we can transparently produce energy, we may apply invisible power generators to residential architectures to supply energy without losing visibility. Transparent photovoltaic cells (TPVs) are a transparent solar technology that transmits visible light while absorbing the invisible short wavelengths, such as ultraviolet. Installing TPVs in buildings provides an on-site energy supply platform as a window-embedded power generator or color-matched solar cell installation on a building surface. The record-high power generation (10.82 mW) and photocurrent value (68.25 mA) were achieved from large-scale TPVs (25 cm2). The metal oxide heterojunction is the fundamental TPV structure. The high-performance TPVs were achieved by adopting a thin Si film between ZnO and NiO as a functional light-absorbing layer. Based on the large energy band gap of metal oxides, TPVs have a clear transmittance (43%) and good color coordinates, which ensure degrees of freedom to adopt TPV power generators in various colored structures or transparent power windows. The bidirectional feature of TPVs is ultimately desirable to maximize light utilization. TPVs can generate electric power from sunlight during the day and can also work from artificial light sources at night. In the near future, humans will acquire electric power without losing visibility with on-site energy supply platforms.
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AIM: The aim of this study was to evaluate the efficacy of solid lipid nanoparticles of berberine against doxorubicin-induced cardiotoxicity. BACKGROUND: Berberine (Ber) is cardioprotective, but its oral bioavailability is low, and its effect on chemotherapy-induced cardiotoxicity has not been studied. OBJECTIVE: Solid lipid nanoparticles (SLNs) of berberine chloride were prepared, characterized and evaluated in vitro against doxorubicin-induced cardiomyocyte injury. METHODS: Berberine-loaded SLNs (Ber-SLNs) were synthesized using the water-in-oil microemulsion technique with tripalmitin, Tween 80 and poloxamer 407. Ber-SLNs were evaluated for preventive effect against toxicity of doxorubicin in H9c2 cells. The culture was pre-treated (24 h) with Ber (10 µM) and Ber-SLNs (1 and 10 µM), and 1 µM of doxorubicin (Dox) was added for 3 h. The cell viability assay (MTT (3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) and LDH (Lactate dehydrogenase)), levels of Creatine kinase-MB (CK-MB), Nitrite, MDA (Malondialdehyde), ROS (Reactive oxygen species) generation, and apoptotic DNA (Deoxyribonucleic acid) content were assessed. RESULTS: Ber-SLNs had a mean particle size of 13.12±1.188 nm, the zeta potential of -1.05 ± 0.08 mV, poly-dispersity index (PDI) of 0.317 ± 0.05 and entrapment efficiency of 50 ± 4.8%. Cell viability was 81 ± 0.17% for Ber-SLNs (10 µM) and 73.22 ± 0.83% for Ber (10 µM) treated cells in the MTT assay. Percentage cytotoxicity calculated from LDH release was 58.91 ± 0.54% after Dox, 40.3 ± 1.3% with Ber (10 µM) and 40.7 ± 1.3% with Ber-SLNs (1 µM) (p<0.001). Inflammation and oxidative stress markers were lower with Ber and Ber-SLNs. Attenuation of ROS generation and apoptosis of cardiomyocytes were noted on fluorescence microscopy. CONCLUSION: Ber SLNs effectively prevented doxorubicin-induced inflammation and oxidative stress in rat cardiomyocytes. The results demonstrate that microemulsion is a simple and costeffective technique to prepare Ber-SLNs, and may be considered as a drug delivery vehicle for berberine.
Assuntos
Berberina , Animais , Apoptose , Berberina/farmacologia , Berberina/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipídeos , Lipossomos , Miócitos Cardíacos , Nanopartículas , Ratos , Espécies Reativas de OxigênioRESUMO
Inspired by the brain, future computation depends on creating a neuromorphic device that is energy-efficient for information processing and capable of sensing and learning. The current computation-chip platform is not capable of self-power and neuromorphic functionality; therefore, a need exists for a new platform that provides both. This Perspective illustrates potential transparent photovoltaics as a platform to achieve scalable, multimodal sensory, self-sustainable neural systems (e.g., visual cortex, nociception, and electronic skin). We present herein a strategy to harvest solar power using a transparent photovoltaic device that provides neuromorphic functionality to implement versatile, sustainable, integrative, and practical applications. The proposed solid-inorganic heterostructure platform is indispensable for achieving a variety of biosensors, sensory systems, neuromorphic computing, and machine learning.
Assuntos
Técnicas Biossensoriais , Fontes de Energia Elétrica , Aprendizado de Máquina , Redes Neurais de Computação , HumanosRESUMO
Bio-inspired electronic devices have significant potential for use in memory devices of the future, including in the context of neuromorphic computing and architecture. This study proposes a transparent heterojunction device for the artificial human visual cortex. Owing to their high transparency, such devices directly react to incoming light to mimic neurological and biological processes in the nervous system. Metal-oxide materials are applied to form a transparent heterojunction (n-type ZnO/p-type NiO) in the proposed device that also provides the photovoltaic function to realize the optic nerve system. The device also exhibits nociceptive features. Its transparent photovoltaic feature endows it with self-powered operation that ensures long-term reliability without needing to replace the power system. This self-powered and highly transparent visual electronic device can provide a route for sustainable applications of neuromorphic computing, including artificial eyes.
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To promote the specific targeting and elimination of CD44-positive cancer cells, berberine chloride (BRB)-encapsulated hyaluronic acid-grafted poly(lactic-co-glycolic acid) copolymer (BRB-d(HA)-g-PLGA) nanoparticles (NPs) were prepared. The targeted action of these NPs was compared to non-targeted BRB-loaded PLGA NPs and bulk BRB. The in vitro studies demonstrated faster release of BRB and increased cytotoxicity of BRB-d(HA)-g-PLGA NPs in Hela and MCF-7 cells in comparison to BRB-PLGA NPs and bulk BRB. The uptake of BRB-d(HA)-g-PLGA NPs was increased in case of MCF-7 cells as compared to HeLa cells owing to the higher expression of CD44 receptors on MCF-7 cells. The CD44 receptor-mediated uptake of these NPs was confirmed through competitive inhibition experiments. The in vitro results were further validated in vivo in Ehrlich Ascites Carcinoma (EAC)-bearing mice. EAC-bearing mice were injected intravenously with these NPs and the results obtained were compared with that of BRB-PLGA NPs and bulk BRB. BRB-d(HA)-g-PLGA NPs were found to significantly enhance apoptosis, sub-G1 content, life span, mean survival time, and ROS levels in EAC cells with subsequent decrease in mitochondrial membrane potential and tumor burden ion tumor-bearing mice. Taking into account the findings of in vitro and in vivo studies, the enhanced and targeted anti-tumor activity of HA-grafted PLGA copolymer-encapsulated NPs of BRB cannot be negated. Therefore, HA-grafted nanoparticle-based delivery of BRB may offer a promising and improved alternative for anti-tumor therapy.
Assuntos
Antineoplásicos/administração & dosagem , Berberina/administração & dosagem , Carcinoma de Ehrlich/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Ácido Láctico/administração & dosagem , Nanopartículas/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Berberina/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Endocitose , Células HeLa , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Ácido Láctico/química , Células MCF-7 , Masculino , Camundongos , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Rapidly increasing malignant neoplastic disease demands immediate attention. Several dietary compounds have recently emerged as strong anti-cancerous agents. Among, Bromelain (BL), a protease from pineapple plant, was used to enhance its anti-cancerous efficacy using nanotechnology. In lieu of this, hyaluronic acid (HA) grafted PLGA copolymer, having tumor targeting ability, was developed. BL was encapsulated in copolymer to obtain BL-copolymer nanoparticles (NPs) that ranged between 140 to 281nm in size. NPs exhibited higher cellular uptake and cytotoxicity in cells with high CD44 expression as compared with non-targeted NPs. In vivo results on tumor bearing mice showed that NPs were efficient in suppressing the tumor growth. Hence, the formulation could be used as a self-targeting drug delivery cargo for the remission of cancer.
Assuntos
Bromelaínas/administração & dosagem , Carcinoma de Ehrlich/patologia , Portadores de Fármacos , Ácido Hialurônico/química , Ácido Láctico/química , Nanopartículas/química , Ácido Poliglicólico/química , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The clinical success of the applicability of tea polyphenols awaits efficient systemic delivery and bioavailability. Herein, following the concept of nanochemoprevention, which uses nanotechnology for enhancing the efficacy of chemotherapeutic drugs, we employed tea polyphenols, namely theaflavin (TF) and epigallocatechin-3-gallate (EGCG) encapsulated in a biodegradable nanoparticulate formulation based on poly(lactide-co-glycolide) (PLGA) with approximately 26% and 18% encapsulation efficiency, respectively. It was observed that TF/EGCG encapsulated PLGA nanoparticles (NPs) offered an up to ~7-fold dose advantage when compared with bulk TF/EGCG in terms of exerting its antiproliferative effects and also enhanced the anticancer potential of cisplatin (CDDP) in A549 (lung carcinoma), HeLa (cervical carcinoma), and THP-1 (acute monocytic leukemia) cells. Cell cycle analysis revealed that TF/EGCG-NPs were more efficient than bulk TF/EGCG in sensitizing A549 cells to CDDP-induced apoptosis, with a dose advantage of up to 20-fold. Further, TF/EGCG-NPs, alone or in combination with CDDP, were more effective in inhibiting NF-κB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase-9, and vascular endothelial growth factor, involved in cell proliferation, metastasis, and angiogenesis, respectively. EGCG and TF-NPs were also found to be more effective than bulk TF/EGCG in inducing the cleavage of caspase-3 and caspase-9 and Bax/Bcl2 ratio in favor of apoptosis. Further, in vivo evaluation of these NPs in combination with CDDP showed an increase in life span (P<0.05) in mice bearing Ehrlich's ascites carcinoma cells, with apparent regression of tumor volume in comparison with mice treated with bulk doses with CDDP. These results indicate that EGCG and TF-NPs have superior cancer chemosensitization activity when compared with bulk TF/EGCG.
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Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/tratamento farmacológico , Cisplatino/uso terapêutico , Ácido Láctico/química , Ácido Poliglicólico/química , Polifenóis/uso terapêutico , Chá/química , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Carcinoma de Ehrlich/patologia , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/uso terapêutico , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Feminino , Citometria de Fluxo , Humanos , Cinética , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nanopartículas/química , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polifenóis/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Conventional cancer chemotherapy leads to severe side effects, which limits its use. Nanoparticles (NPs) based delivery systems offer an effective alternative. Several evidences highlight the importance of Bromelain (BL), a proteolytic enzyme, as an anti-tumor agent which however has been limited due to the requirement of high doses at the tumor site. Therefore, we illustrate the development of BL loaded poly (lactic-co-glycolic acid) NPs that show enhanced anti-tumor effects compared to free BL. The formulated NPs with a mean particle size of 130.4 ± 8.81 nm exhibited sustained release of BL. Subsequent investigation revealed enhanced anti-tumor ability of NPs in 2-stage skin tumorigenesis mice model. Reduction in average number of tumors (â¼ 2.3 folds), delay in tumorigenesis (â¼ 2 weeks), percent tumorigenesis (â¼ 4 folds), and percent mortality rate as well as a reduction in the average tumor volume (â¼ 2.5 folds) in mice as compared to free BL were observed. The NPs were found to be superior in exerting chemopreventive effects over chemotherapeutic effects at 10 fold reduced dose than free BL, validated by the enhanced ability of NPs (â¼ 1.8 folds) to protect the DNA from induced damage. The effects were also supported by histopathological evaluations. NPs were also capable of modulating the expression of pro-apoptotic (P53, Bax) and anti-apoptotic (Bcl2) proteins. Therefore, our findings demonstrate that developed NPs formulation could be used to improve the efficacy of chemotherapy by exerting chemo-preventive effects against induced carcinogenesis at lower dosages.
Assuntos
Anticarcinógenos/administração & dosagem , Bromelaínas/administração & dosagem , Carcinogênese/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Nanopartículas/química , Proteínas de Plantas/administração & dosagem , Neoplasias Cutâneas/prevenção & controle , Administração Cutânea , Ananas/química , Animais , Anticarcinógenos/química , Anticarcinógenos/uso terapêutico , Bromelaínas/química , Bromelaínas/uso terapêutico , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Estabilidade Enzimática , Ácido Láctico/química , Masculino , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Proteínas de Plantas/química , Proteínas de Plantas/uso terapêutico , Caules de Planta/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Distribuição Aleatória , Pele/efeitos dos fármacos , Pele/patologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacosRESUMO
The study aimed to measure the neuroprotective efficacy of caffeine-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles over bulk and to delineate the mechanism of improvement in efficacy both in vitro and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinsonism. Caffeine-encapsulated PLGA nanoparticles exhibited more pronounced increase in the endurance of dopaminergic neurons, fibre outgrowth and expression of tyrosine hydroxylase (TH) and growth-associated protein-43 (GAP-43) against 1-methyl-4-phenylpyridinium (MPP+)-induced alterations in vitro. Caffeine-encapsulated PLGA nanoparticles also inhibited MPP(+)-mediated nuclear translocation of nuclear factor-kappa B (NF-κB) and augmented protein kinase B phosphorylation more potentially than bulk counterpart. Conversely, MPTP reduced the striatal dopamine and its metabolites and nigral TH immunoreactivity whereas augmented the nigral microglial activation and nigrostriatal lipid peroxidation and nitrite content, which were shifted towards normalcy by caffeine. The modulations were more evident in caffeine-encapsulated PLGA nanoparticles treated animals as compared with bulk. Moreover, the striatal caffeine and its metabolites were found to be significantly higher in caffeine-encapsulated PLGA nanoparticles-treated mice as compared with bulk. The results thus suggest that nanotization improves the protective efficacy of caffeine against MPTP-induced Parkinsonism owing to enhanced bioavailability, inhibition of the nuclear translocation of NF-κB and activation of protein kinase B phosphorylation.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Cafeína/química , Cafeína/farmacologia , Portadores de Fármacos/química , Nanopartículas/química , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/prevenção & controle , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Transporte Biológico , Cafeína/metabolismo , Contagem de Células , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Liberação Controlada de Fármacos , Fluoresceína-5-Isotiocianato/química , Proteína GAP-43/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Láctico/química , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Nitritos/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Fosfoproteínas/metabolismo , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson's disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats.
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Barreira Hematoencefálica/metabolismo , Dopamina/química , Dopamina/metabolismo , Nanopartículas/química , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Animais , Linhagem Celular Tumoral , Dopamina/efeitos adversos , Neurônios Dopaminérgicos/metabolismo , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Humanos , Ácido Láctico/química , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Oxirredução , Oxidopamina/química , Oxidopamina/farmacologia , Oxidopamina/uso terapêutico , Doença de Parkinson/metabolismo , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Wistar , Receptores Dopaminérgicos/metabolismo , Segurança , Regulação para Cima/efeitos dos fármacosRESUMO
Nanotized phytochemicals are being explored by researchers for promoting their uptake and effectiveness at lower concentrations. In this study, O-hexadecyl-dextran entrapped berberine chloride nanoparticles (BC-HDD NPs) were prepared, and evaluated for their cytoprotective efficacy in high glucose stressed primary hepatocytes and the results obtained compared with bulk berberine chloride (BBR) treatment. The nanotized formulation treated primary hepatocytes that were exposed to high glucose (40 mM), showed increased viability compared to the bulk BBR treated cells. BC-HDD NPs reduced the ROS generation by â¼ 3.5 fold during co-treatment, prevented GSH depletion by â¼ 1.6 fold, reduced NO formation by â¼ 5 fold and significantly prevented decline in SOD activity in stressed cells. Lipid peroxidation was also prevented by â¼ 1.9 fold in the presence of these NPs confirming the antioxidant capacity of the formulation. High glucose stress increased Bax/Bcl2 ratio followed by mitochondrial depolarization and activation of caspase-9/-3 confirming involvement of mitochondrial pathway of apoptosis in the exposed cells. Co- and post-treatment of BC-HDD NPs prevented depolarization of mitochondrial membrane, reduced Bax/Bcl2 ratio and prevented externalization of phosphatidyl-serine confirming their anti-apoptotic capacity in those cells. Sub-G1 phase apparent in high glucose stressed cells was not seen in BC-HDD NPs treated cells. The present study reveals that BC-HDD NPs at â¼ 20 fold lower concentration are as effective as BBR in preventing high glucose induced oxidative stress, mitochondrial depolarization and downstream events of apoptotic cell death.
Assuntos
Apoptose/efeitos dos fármacos , Berberina/química , Berberina/farmacologia , Dextranos/química , Glucose/efeitos adversos , Nanopartículas , Estresse Oxidativo/efeitos dos fármacos , Animais , Berberina/metabolismo , Transporte Biológico , Citoproteção/efeitos dos fármacos , DNA/metabolismo , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico/metabolismo , Tamanho da Partícula , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Oral administration of anti-cancer drugs is an effective alternative to improve their efficacy and reduce undesired toxicity. Bromelain (BL) is known as an effective anti-cancer phyto-therapeutic agent, however, its activity is reduced upon oral administration. In addressing the issue, BL was encapsulated in Poly(lactic-co-glycolic acid) (PLGA) to formulate nanoparticles (NPs). Further, the NPs were coated with Eudragit L30D polymer to introduce stability against the gastric acidic conditions. The resultant coated NPs were characterized for BL entrapment, proteolytic activity and mean particle size. The stability and release pattern of NPs were evaluated under simulated gastrointestinal tract (GIT) pH conditions. Cytotoxicity studies carried out in human cell lines of diverse origin have shown significant dose advantage (-7-10 folds) with NPs in reducing the IC50 values compared with free BL. The cellular uptake of NPs in MCF-7, HeLa and Caco-2 cells monolayer was significantly enhanced several folds as compared to free BL. Altered expression of marker proteins associated with apoptosis and cell death (P53, P21, Bcl2, Bax) also confirmed the enhanced anti-carcinogenic potential of formulated NPs. Oral administration of NPs reduced the tumor burden of Ehrlich ascites carcinoma (EAC) in Swiss albino mice and also increased their life-span (160.0 ± 5.8%) when compared with free BL (24 ± 3.2%). The generation of reactive oxygen species, induction of apoptosis and impaired mitochondrial membrane potential in EAC cells treated with NPs confirmed the suitability of Eudragit coated BL-NPs as a promising candidate for oral chemotherapy.