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1.
Front Immunol ; 12: 739130, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603323

RESUMO

Neuroinflammation play an important role in Alzheimer's disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer's disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer's disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer's disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

2.
Nat Commun ; 12(1): 5243, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475406

RESUMO

Peroxisome, a special cytoplasmic organelle, possesses one or more kinds of oxidases for hydrogen peroxide (H2O2) production and catalase for H2O2 degradation, which serves as an intracellular H2O2 regulator to degrade toxic peroxides to water. Inspired by this biochemical pathway, we demonstrate the reactive oxygen species (ROS) induced tumor therapy by integrating lactate oxidase (LOx) and catalase (CAT) into Fe3O4 nanoparticle/indocyanine green (ICG) co-loaded hybrid nanogels (designated as FIGs-LC). Based on the O2 redistribution and H2O2 activation by cascading LOx and CAT catalytic metabolic regulation, hydroxyl radical (·OH) and singlet oxygen (1O2) production can be modulated for glutathione (GSH)-activated chemodynamic therapy (CDT) and NIR-triggered photodynamic therapy (PDT), by manipulating the ratio of LOx and CAT to catalyze endogenous lactate to produce H2O2 and further cascade decomposing H2O2 into O2. The regulation reactions of FIGs-LC significantly elevate the intracellular ROS level and cause fatal damage to cancer cells inducing the effective inhibition of tumor growth. Such enzyme complex loaded hybrid nanogel present potential for biomedical ROS regulation, especially for the tumors with different redox state, size, and subcutaneous depth.


Assuntos
Antineoplásicos/farmacologia , Nanogéis/química , Peroxissomos/enzimologia , Fotoquimioterapia/métodos , Animais , Antineoplásicos/química , Catalase/química , Catalase/metabolismo , Catálise , Linhagem Celular Tumoral , Óxido Ferroso-Férrico/química , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Verde de Indocianina/química , Camundongos , Oxigenases de Função Mista/química , Oxigenases de Função Mista/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
3.
Biomaterials ; 271: 120763, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33780737

RESUMO

Nanomaterials have attracted increased attention because of their excellent drug-carrying capacity. However, these nanomaterials are rarely used in the treatment of metabolic diseases. Liraglutide, a glucagon-like peptide-1 receptor agonist, has been widely used in the treatment of type 2 diabetes mellitus (T2DM). Furthermore, fibroblast growth factor 21 (FGF-21) has been found to improve glucose metabolism and insulin resistance (IR). To investigate whether these two molecules have synergistic effects in vivo, we developed a novel drug delivery system using amino-functionalized and embedded dual-mesoporous silica nanoparticles (N-EDMSNs) to simultaneously carry liraglutide and FGF-21, and observed their biological effects. The resultant N-EDMSNs possessed unique hierarchical porous structures consisting of open large pores (>10 nm) and small mesopores (~2.5 nm) in the silica framework, highly positively charged surfaces and good disperisity in aqueous solution. We found that N-EDMSNs had a high loading capacity for exogenous genes and low toxicity to Hepa1-6 cells. Moreover, N-EDMSNs can simultaneously carry FGF-21 plasmids and liraglutide and successfully transfect them into Hepa1-6 cells. The transfection efficiency of N-EDMSNs was higher than that of Lipofectamine 2000 in vitro. In mice experiments, N-EDMSNs/pFGF21 treatment resulted in higher FGF-21 expression in the liver than pFGF21 treatment with hydrodynamic delivery. Compared with both pFGF21 and liraglutide, N-EDMSNs/pFGF21/Lira treatment significantly reduced the food intake, body weight, and blood glucose; increased the energy expenditure and improved hepatic IR in high-fat diet (HFD)-fed mice. Our results demonstrated that the biological effects of N-EDMSNs/pFGF21/Lira complexes were better than those of pFGF21 combined with liraglutide in vivo.


Assuntos
Diabetes Mellitus Tipo 2 , Nanopartículas , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fatores de Crescimento de Fibroblastos , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Camundongos , Plasmídeos , Dióxido de Silício
4.
AMB Express ; 10(1): 205, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33175252

RESUMO

This paper studied the inhibitory effects of dithiocyano-methane (DM) on the glucose decomposition pathway in the respiratory metabolism of Escherichia coli. We investigated the effects of DM on the activities of key enzymes (ATPase and glucose-6-phosphate dehydrogenase, G6PDH), the levels of key product (nicotinamide adenosine denucleotide hydro-phosphoric acid, NADPH), and gene expression in the hexose monophosphate pathway (HMP). The results showed that the minimum inhibitory concentration (MIC) and the minimum bactericide concentration (MBC) of DM against the tested strains were 5.86 mg/L and 11.72 mg/L, respectively. Bacteria exposed to DM at MIC demonstrated an increase in bacterial ATPase and G6PDH activities, NADPH levels, and gene expression in the HMP pathway compared to bacteria in the control group, which could be interpreted as a behavioral response to stress introduced by DM. However, DM at a lethal concentration of 10 × MIC affected glucose decomposition by inhibiting mainly the HMP pathway in E. coli.

5.
J Cell Mol Med ; 24(6): 3549-3559, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32052546

RESUMO

Lung cancer is the world's leading cause of cancer-related morbidity and mortality despite advances in surgery, chemotherapy and immunotherapy; thus, there is an urgent need to find new molecules to develop novel treatment strategies. Although ncRNAs were found to account for 98% transcripts, the number of lncRNAs with distinct function in lung cancer is extremely limited. We previously demonstrated that Plasmodium infection inhibits tumour growth and metastasis, but the exact mechanisms involved have not been fully understood. In this study, we carried out RNA sequencing (RNA-Seq) of tumour tissues isolated from LLC tumour-bearing mice treated with either Plasmodium yoelli (Py)-infected red blood cells or uninfected red blood cells. We found that F630028O10Rik (abbreviated as F63) is a novel lncRNA that was significantly up-regulated in tumours isolated from mice treated with Py-infected red blood cells compared to the control. By using gene silencing technique, F63 was found to inhibit both tumour Vascular Endothelial Growth Factor A (VEGFA) secretion and endothelial cells clone formation, migration, invasion and tube formation. Injection of cholesterol-modified siRNA-F63 into mice tumour tissues produced a significant increase in tumour volume, blood vessel formation and angiogenesis 17 days after injection. We further showed that inhibiting miR-223-3p results in the down-regulation of VEGFA and VEGFR2 which are vital molecules for angiogenesis. These results reveal that F63 inhibit tumour growth and progression by modulating tumour angiogenesis suggesting F63 can be a novel lncRNA with great potential as a candidate molecule for gene therapy in lung cancer.

6.
Cell Commun Signal ; 17(1): 32, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979375

RESUMO

BACKGROUND: A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown. METHODS: Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Differences between groups were analyzed for statistical significance using Student's t-test. RESULTS: Here we found that Plasmodium infection significantly reduced the proportions of MDSCs and Tregs in the lung tumor tissues of the treated mice by downregulating their recruiting molecules and blocking cellular activation pathways. Importantly, CD8+ T cells isolated from the tumors of Plasmodium-treated mice exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1. CONCLUSION: We reveal for the first time, the effects of Plasmodium infection on the expansion and activation of MDSCs and Tregs with a consequent elevation of CD8+T cell-mediated cytotoxicity within the tumor microenvironment and hold great promise for the development of effective immunotherapeutic strategies.


Assuntos
Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/terapia , Imunossupressão/métodos , Malária/imunologia , Células Supressoras Mieloides/imunologia , Plasmodium yoelii/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Feminino , Granzimas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Citotóxicas Formadoras de Poros/imunologia , Receptor de Morte Celular Programada 1/imunologia
7.
Int J Nanomedicine ; 14: 1519-1532, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880962

RESUMO

Introduction: In this work, we have developed a novel "confined-growth" strategy to synthesize PEGylated multiple gold nanorices-encapsulated dual-mesoporous silica nanospheres (designated as PEGylated MGNRs@DMSSs) containing both small mesopores (2.5 nm) in the shell and large mesopores (21.7 nm) in the core based on a well-established, seed-mediated growth method. The photothermal effect and CT imaging ability were also studied. Methods: The nanoparticles were characterized by Fourier transform infrared (FT-IR) spectra, N2 absorption isotherms, Field-emission scanning electron microscopy (FE-SEM), Transmission electron microscopy (TEM), Inductively coupled plasma atomic emission spectroscopy (ICP-AES) and Confocal microscopy. Results: The longitudinally-localized surface (LSPR) absorption properties of MGNRs@DMSSs can be easily tuned by altering the amount of HAuCl4 in the gold growth solution. Additionally, the resultant PEGylated MGNRs@DMSSs have monodispersed, spherical morphology and good colloidal stability in an aqueous solution. More importantly, when exposed to NIR irradiation, the PEGylated MGNRs@DMSSs exhibit both higher temperature increments and better photothermal effects than that of single PEGylated gold nanorods at nearly an equivalent LSPR absorption. In addition, as CT contrast agents, the PEGylated MGNRs@DMSSs display a better CT imaging performance, in comparison with single PEGylated gold nanorods at the same Au concentration. Conclusion: Taken together, results indicate the potential for MGNRs@DMSSs used in CT imaging-guided photothermal therapy. Such a simple "confined-growth" strategy within a porous matrix offers a promising platform to design and prepare novel metal(s) oxide@silica nanocomposites for use in further cancer bio-imaging and therapy.


Assuntos
Carcinoma Hepatocelular/terapia , Ouro/química , Neoplasias Hepáticas/terapia , Nanocompostos/administração & dosagem , Fototerapia , Dióxido de Silício/química , Tomografia Computadorizada por Raios X/métodos , Animais , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Nanocompostos/química , Células Tumorais Cultivadas
8.
J Med Chem ; 62(7): 3503-3512, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30856324

RESUMO

Identification of novel chemotypes with antimalarial efficacy is imperative to combat the rise of Plasmodium species resistant to current antimalarial drugs. We have used a hybrid target-phenotype approach to identify and evaluate novel chemotypes for malaria. In our search for drug-like aspartic protease inhibitors in publicly available phenotypic antimalarial databases, we identified GNF-Pf-4691, a 4-aryl- N-benzylpyrrolidine-3-carboxamide, as having a structure reminiscent of known inhibitors of aspartic proteases. Extensive profiling of the two terminal aryl rings revealed a structure-activity relationship in which relatively few substituents are tolerated at the benzylic position, but the 3-aryl position tolerates a range of hydrophobic groups and some heterocycles. Out of this effort, we identified (+)-54b (CWHM-1008) as a lead compound. 54b has EC50 values of 46 and 21 nM against drug-sensitive Plasmodium falciparum 3D7 and drug-resistant Dd2 strains, respectively. Furthermore, 54b has a long half-life in mice (4.4 h) and is orally efficacious in a mouse model of malaria (qd; ED99 ∼ 30 mg/kg/day). Thus, the 4-aryl- N-benzylpyrrolidine-3-carboxamide chemotype is a promising novel chemotype for malaria drug discovery.


Assuntos
Antimaláricos/farmacologia , Pirrolidinas/farmacologia , Administração Oral , Animais , Antimaláricos/administração & dosagem , Antimaláricos/química , Disponibilidade Biológica , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Malária/tratamento farmacológico , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Relação Estrutura-Atividade
9.
J Ultrasound Med ; 38(1): 191-202, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29781183

RESUMO

OBJECTIVES: Low-intensity pulsed ultrasound (LIPUS) combined with porous scaffolds can be used as a new therapy to treat bone defect repair. The aim of this study was to evaluate the effects of 1 and 3.2 MHz LIPUS on osteogenesis on porous Ti64 alloy scaffolds for both in vitro and in vivo studies. METHODS: Scaffolds were randomly divided into the high-frequency ultrasound group, low-frequency ultrasound group, and control group. Mouse pre-osteoblast cells were cultured with porous Ti-6Al-4V scaffolds in vitro to evaluate cell proliferation and differentiation. In addition, scaffolds were implanted into rabbit mandibular defects in vivo. The effects of LIPUS on bone regeneration were evaluated by observing the micro-computed tomography (micro-CT), toluidine blue staining, and von Kossa staining. RESULTS: The results revealed no significant difference in the cell counting kit-8 values between the ultrasound groups and control groups (P > .05). Compared with the control group, ultrasound promoted alkaline phosphatase activity and osteocalcin levels of the cells on the scaffolds (P < .05), but there was no significant difference between the two frequencies. In addition, histomorphologic analyses revealed that the volume and amount of new bone formation increased and that bone maturity improved in the ultrasound groups compared with the control group, but no significant difference was noted between the two frequencies. CONCLUSIONS: Under the present experimental conditions, LIPUS promoted osteoblast differentiation and promoted bone maturity on porous Ti64 scaffolds. No significant differences were noted between the two frequencies.


Assuntos
Regeneração Óssea/fisiologia , Doenças Mandibulares/terapia , Osteogênese/fisiologia , Titânio , Terapia por Ultrassom/métodos , Ondas Ultrassônicas , Ligas , Animais , Técnicas de Cultura de Células , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Técnicas In Vitro , Masculino , Mandíbula/diagnóstico por imagem , Doenças Mandibulares/diagnóstico por imagem , Camundongos , Osteoblastos/fisiologia , Coelhos , Microtomografia por Raio-X/métodos
10.
Mater Sci Eng C Mater Biol Appl ; 88: 53-60, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29636138

RESUMO

Calcium sulfate or plaster of Paris (POP) is considered as a bone cement with a fast degradation rate, which frequently makes it resorb before the bone defect area is completely filled by new bone. The incorporation of tricalcium silicate (C3S) into POP cement has been proven as a feasible approach to reduce the in vitro degradation rate and improve the in vitro bioactivity of the material. However, the in vivo performance of the POP/C3S composite cement is still unclear. Therefore, the aim of the present study is to assess the biodegradability and osteogenesis of POP/C3S composite cement in comparison with those of POP bone cement. To carry out the in vivo evaluation, POP and POP/C3S cements were implanted into a femoral condyle defect model in rabbits (5 mm diameter × 10 mm length) for 4, 8, and 12 weeks duration. The area of the remaining cement and new bone regeneration in bone defect were investigated and quantitatively measured using radiography, micro-computed tomography, and histological staining. For both cements, no sign of inflammation was observed. POP cement was completely degraded at the 8th week of post-implantation. By contrast, only approximately 50% by volume of POP/C3S composite cement degraded at the 12th week, which allowed a long-term framework for new bone formation. The osteogenic ability of POP/C3S composite cement was significantly superior to that of POP as indicated by the higher mineralization rate and maturity of the newly formed bone around the composite cement. In summary, our findings demonstrated that the in vivo degradation behaviors and osteogenic ability of POP cement could be improved by incorporating C3S in vivo, suggesting that POP/C3S composite cement has potential as a biodegradable cement for bone repair.


Assuntos
Cimentos Ósseos , Compostos de Cálcio , Sulfato de Cálcio , Fêmur , Osteogênese/efeitos dos fármacos , Silicatos , Animais , Cimentos Ósseos/química , Cimentos Ósseos/farmacologia , Compostos de Cálcio/química , Compostos de Cálcio/farmacologia , Sulfato de Cálcio/química , Sulfato de Cálcio/farmacologia , Fêmur/lesões , Fêmur/metabolismo , Fêmur/patologia , Coelhos , Silicatos/química , Silicatos/farmacologia
11.
Oncotarget ; 8(15): 24785-24796, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28445973

RESUMO

We have previously demonstrated that malaria parasite infection has an anti-tumor effect in a mouse model. This research aimed to investigate the possibility of using Plasmodium parasite as a novel vaccine vector for hepatocellular carcinoma (HCC) immunotherapy. We constructed a Plasmodium yoelii 17XNL strain (P.y) expressing murine glypican-3 (GPC3) protein (P.y-GPC3), and examined its therapeutic potency in a murine Hepa1-6-induced hepatoma model that highly expressed GPC3 protein. The prerequisites for invoking a CD8+ T cell response were assessed after P.y-based immunization, which included obviously increased concentrations of T helper cell type 1 (Th1)-associated cytokines, such as IL-2, IFN-γ and TNF-α, in serum and preferential expansion of the CD8α+ dendritic cell (DC) subset with higher expression of CD80 and CD86 molecules. Compared with uninfected and wild-type P.y-infected mice, a significant GPC3-specific cytotoxic T lymphocyte (CTL) response was detected in P.y-GPC3 vaccinated mice. Furthermore, P.y-GPC3-based vaccination dramatically inhibited Hepa1-6-induced tumor growth in the implanted HCC and prolonged the survival of tumor-bearing mice. We concluded that a Plasmodium-based vector is highly efficient in inducing tumor antigen-specific T cell-mediated immunity and protection against tumor cells. More broadly, this strategy supported our hypothesis that Plasmodium parasites, as novel therapeutic antigen vectors, may be applicable to tumor immunotherapy for patients with HCC.


Assuntos
Vacinas Anticâncer/administração & dosagem , Carcinoma Hepatocelular/terapia , Glipicanas/administração & dosagem , Neoplasias Hepáticas/terapia , Plasmodium/genética , Animais , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/parasitologia , Carcinoma Hepatocelular/patologia , Feminino , Glipicanas/genética , Glipicanas/imunologia , Xenoenxertos , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/parasitologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium/imunologia , Distribuição Aleatória , Análise de Sobrevida , Linfócitos T Citotóxicos/imunologia
12.
Biochim Biophys Acta Mol Basis Dis ; 1863(5): 1037-1045, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27156888

RESUMO

Cognitive decline in chronic diabetic patients is a less investigated topic. Diabetes and obesity are among the modifiable risk factors for Alzheimer's disease (AD), the most common form of dementia. Studies have identified several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, and inflammation that are observed in these disorders. Advanced glycation end products generated by chronic hyperglycemia and their receptor RAGE provide critical links between diabetes and AD. Peripheral inflammation observed in obesity leads to insulin resistance and type 2 diabetes. Although the brain is an immune-privileged organ, cross-talks between peripheral and central inflammation have been reported. Damage to the blood brain barrier (BBB) as seen with aging can lead to infiltration of immune cells into the brain, leading to the exacerbation of central inflammation. Neuroinflammation, which has emerged as an important cause of cognitive dysfunction, could provide a central mechanism for aging-associated ailments. To further add to these injuries, adult neurogenesis that provides neuronal plasticity is also impaired in the diabetic brain. This review discusses these molecular mechanisms that link obesity, diabetes and AD. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Complicações do Diabetes/etiologia , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Complicações do Diabetes/patologia , Diabetes Mellitus/patologia , Humanos , Inflamação/complicações , Inflamação/metabolismo , Inflamação/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Obesidade/patologia , Estresse Oxidativo , Receptor para Produtos Finais de Glicação Avançada/metabolismo
13.
Pharmacol Res ; 110: 25-34, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27157248

RESUMO

Despite advances in chemotherapy and immunotherapy, advanced lung cancer remains an incurable disease. Novel trends in anticancer therapeutics focus on harnessing the therapeutically-targeted tumor-related immune suppression. In this respect, myeloid-derived suppressor cells (MDSCs) have captured considerable attention in the last few years, as they are vividly implicated in tumor immune escape mechanisms. In this review, we specifically discuss the multifaceted roles of MDSCs in lung tumor microenvironment, encompassing lung tumor growth and progression via suppression of anti-tumor immunity, association with worse prognosis, and hampering the efficacy of lung cancer chemotherapy and immunotherapy. In addition, we also discuss that therapeutic manipulation of MDSCs-targeting, either alone or in combination with chemo- and/or immune-therapeutic regimens, may not only have tumor growth inhibition, anti-angiogenesis and anti-metastasis effects, but may also have the potential to enhance the efficacy of lung cancer chemotherapy and immunotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Células Supressoras Mieloides/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
14.
Curr Alzheimer Res ; 13(12): 1346-1355, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27033055

RESUMO

Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.


Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/imunologia , Citocinas/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Peptídeo 1 Semelhante ao Glucagon/genética , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos Zucker , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Uracila/análogos & derivados , Uracila/farmacologia , Uracila/uso terapêutico
15.
J Neurochem ; 136(5): 918-30, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26677139

RESUMO

Communications between neurons and glial cells play an important role in regulating homeostasis in the central nervous system. cAMP response element-binding protein (CREB), a transcription factor, is down-regulated by neurotoxins, which are known to be released by activated glial cells. To determine the role of CREB signaling in neuroglial interactions, we used three neuroglial coculture models consisting of human neuroprogenitor cell (NPC)-derived neurons and human microglia. Conditioned medium from the Abeta (Aß)-activated microglia decreased CREB phosphorylation and brain-derived neurotrophic factor promoter activity (47%), whereas the same medium induced (p < 0.01) the promoter of CXCL10, a chemokine, in NPC-derived neuron-rich cultures. These effects were reversed when microglia were exposed to Aß in the presence of minocycline, an anti-inflammatory agent. The expression of CREB targets, including brain-derived neurotrophic factor, synapsin-1, and BIRC3 decreased by 50-65% (p < 0.01) in neurons isolated by laser capture microdissection in close proximity of microglia in neuroglial mixed cultures. Neuronal survival actively modulated microglial behavior when neurons and microglia were cocultured side-by-side on semicircles of ACLAR membrane. Neuronal injury, caused by the over-expression of dominant negative form of CREB, exacerbated Aß-mediated microglial activation, whereas CREB over-expression resulted in decreased microglial activation. Decreases in the levels of neuronal markers were observed when NPCs were differentiated in the presence of proinflammatory cytokines IL-1ß, tumor necrosis factor α, or IL-6. Instead, the NPCs differentiated into a glial phenotype, and these effects were more pronounced in the presence of tumor necrosis factor α. Our findings suggest that CREB down-regulation is an important component of defective neuroglial communications in the brain during neuroinflammation. Neuroglial interactions were examined using coculture models of human neuroprogenitor cell-derived neurons and microglia isolated from human fetal brain. A novel coculture model of neurons and microglia cultured on ACLAR membranes in the same dish was also included. In this model, over-expression of the dominant negative mutant form of the transcription factor CREB in neurons induced neuronal apoptosis and microglial activation whereas expression of the wild type form of CREB resulted in protection of neurons and suppressed microglial activity, thereby suggesting that neurons play an active role in neuroglial interactions.


Assuntos
Apoptose/fisiologia , Diferenciação Celular/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Microglia/citologia , Neurônios/citologia , Animais , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Regulação para Baixo , Feminino , Camundongos , Microglia/efeitos dos fármacos , Transdução de Sinais/fisiologia
16.
Tumour Biol ; 37(4): 5551-60, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26572153

RESUMO

Lung cancer is the leading cause of cancer deaths worldwide; the study of microRNAs gives new hope for lung cancer treatment. miR-411 has been demonstrated to be an independent prognostic factor for lung adenocarcinoma, but the role and regulatory mechanism are largely unknown. In the present study, we found miR-411 was overexpressed in the lung cancer cells; overexpression of miR-411 promoted anchorage-dependent and anchorage-independent growths of lung cancer, while miR-411 knockdown reduced this effect. Further study showed forkhead box O1 (FOXO1) was a target of miR-411. Overexpression of miR-411 suppressed the expression of FOXO1; the effect of suppression was abrogated when the mutation occurred in the 3'UTR of FOXO1. Knockdown of FOXO1 in cells which miR-411 was inhibited recapitulated the phenotype of miR-411 overexpression. Taken together, our study revealed miR-411 promoted cell proliferation of lung cancer by targeting tumor suppressor gene FOXO1 and miR-411 might be a potential target for lung cancer therapy.


Assuntos
Proteína Forkhead Box O1/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteína Forkhead Box O1/biossíntese , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/biossíntese
17.
Bioorg Med Chem ; 23(16): 5144-50, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25797165

RESUMO

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease ß-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 µM and 0.099 µM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Hidantoínas/química , Hidantoínas/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Descoberta de Drogas , Humanos , Hidantoínas/metabolismo , Hidantoínas/farmacocinética , Malária Falciparum/parasitologia , Camundongos , Microssomos Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/farmacologia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/metabolismo , Ratos , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia
18.
Bioorg Med Chem Lett ; 25(7): 1538-40, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25704890

RESUMO

The inhibitive activities of the human immunodeficiency virus protease inhibitors ritonavir (RTV) boosted indinavir (IDV) and RTV boosted lopinavir (LPV) for erythrocytic stage malaria were evaluated in rhesus macaques. The IDV/RTV regimen effectively inhibits the replication of Plasmodium knowlesi with clinically relevant doses, whereas the LPV/RTV regimen did not show activity against plasmodium infection.


Assuntos
Antimaláricos/farmacologia , Eritrócitos/efeitos dos fármacos , Indinavir/farmacologia , Malária/tratamento farmacológico , Plasmodium knowlesi/efeitos dos fármacos , Ritonavir/farmacologia , Animais , Relação Dose-Resposta a Droga , Eritrócitos/parasitologia , Macaca mulatta , Malária/parasitologia , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
19.
Eur J Pharmacol ; 755: 42-9, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25720341

RESUMO

Incretin therapies are effective in controlling blood glucose levels in type 2 diabetic patients by improving the survival and function of ß-cells. They include dipeptidyl peptidase-4 (DPP-4) inhibitors and long-acting glucagon-like peptide-1 (GLP-1) analogs. We have previously reported that GLP-1 enhances the survival of cultured human islets by activation of the transcription factor CREB. To test the in vivo relevance of these findings, we examined the effects of alogliptin, a DPP-4 inhibitor, in Zucker Diabetic rats, a model for type 2 diabetes. The plasma levels of GLP-1 increased in alogliptin-treated diabetic rats leading to normoglycemia. Pancreatic islets of untreated diabetic rats were characterized by decreased immunostaining for insulin and PDX-1. Elevation of GLP-1 in treated diabetic rats resulted in the improved survival of ß-cells. Dual immunofluorescent staining showed phosphorylation/activation of CREB in insulin-positive ß-cells of islets. This led to increases in the levels of CREB targets including Bcl-2, an antiapoptotic mitochondrial protein, BIRC3, a caspase inhibitor and IRS-2, an adapter protein needed for insulin signaling. Findings from this study suggest potential activation of cytoprotective CREB by GLP-1 in pancreatic ß-cells of diabetic patients undergoing incretin-based therapies.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Piperidinas/farmacologia , Uracila/análogos & derivados , Animais , Proteína 3 com Repetições IAP de Baculovírus , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Zucker , Triglicerídeos/sangue , Uracila/farmacologia
20.
Shanghai Kou Qiang Yi Xue ; 24(6): 696-701, 2015 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-27063121

RESUMO

PURPOSE: To investigate the changes of retentive force of cobalt-chromium alloy, pure titanium and vitallium cast clasps in the simulated 3-year clinical use. METHODS: Fifteen metal abutment crowns made of No.QT800-2 nodular cast iron were used in the test. Five clasps from each of the following alloys: cobalt-chromium alloy, pure titanium and vitallium were fabricated. The undercut depth was 0.25 mm. A masticatory simulator was used to cycle the clasp on and off the metal abutment crown 5000 times, simulating 3-year clinical use. Retentive force was measured 11 times during this process. SPSS13.0 software package was used to analyze the results. Casting defects were observed using X-ray non destructive testing (X-ray NDT) before cyclic test. Surface characteristics were qualitatively evaluated using scanning electron microscope (SEM) before and after cyclic test. RESULTS: The results indicated that there were significant differences (P=0.000) in the retentive force of the 3 groups before and after the cyclic test. The highest retentive force was recorded in the vitallium clasps, and the lowest retentive force was measured in the pure titanium clasps. The results of X-ray NDT depicted the typical casting defect seen at the end of the connector. SEM examination revealed that no evidence of pores and cracks in the inner surfaces of the 3 groups was found before cyclic test. Wear was evident in the inner surfaces of the 3 groups but none of the clasps exhibited any evidence of cracks after cyclic test through SEM examination. CONCLUSIONS: In this in vitro test, vitallium clasps show the best retentive force in the 3 groups before and after 5000 cycles at 0.25 mm undercut depth. Cobalt-chromium alloy and vitallium clasps can maintain ideal retentive force at 0.25mm undercut depth in the long-term use. Wear may be one of the reasons for the loss of retentive force of clasps in the cyclic test.


Assuntos
Ligas de Cromo , Grampos Dentários , Análise do Estresse Dentário , Titânio , Vitálio , Retenção de Dentadura , Humanos
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