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1.
J Biol Chem ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32241907

RESUMO

Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI-H520 squamous cells increased intracellular calcium levels and granulocyte macrophage-colony-stimulating factor (GM-CSF), tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) secretion. RPMI 2650 cells cultured at an air-liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, well-differentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyp and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases.

2.
Theranostics ; 10(7): 2918-2929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194844

RESUMO

Nanoparticle formulations have proven effective for cisplatin delivery. However, the development of a versatile nanoplatform for cisplatin-based combination cancer therapies still remains a great challenge. Methods: In this study, we developed a one-pot synthesis method for a microporous organosilica shell-coated cisplatin nanoplatform using a reverse microemulsion method, and explored its application in co-delivering acriflavine (ACF) for inhibiting hypoxia-inducible factor-1 (HIF-1). Results: The resulting nanoparticles were tunable, and they could be optimized to a monodisperse population of particles in the desired size range (40-50 nm). In addition, organic mPEG2000-silane and tetrasulfide bond-bridged organosilica were integrated into the surface and silica matrix of nanoparticles for prolonged blood circulation and tumor-selective glutathione-responsive degradation, respectively. After reaching the tumor sites, cisplatin induced cancer cell death and activated HIF-1 pathways, resulting in acquired drug resistance and tumor metastasis. To address this issue, ACF was co-loaded with cisplatin to prevent the formation of HIF-1α/ß dimers and suppress HIF-1 function. Hence, the efficacy of cisplatin was improved, and cancer metastasis was inhibited. Conclusion: Both in vitro and in vivo results suggested that this core-shell nanostructured cisplatin delivery system represented a highly efficacious and promising nanoplatform for the synergistic delivery of combination therapies involving cisplatin.

3.
Cell Mol Life Sci ; 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32172302

RESUMO

Bitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (M[Formula: see text]s) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis ~ threefold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance M[Formula: see text] phagocytosis. Together, these data define M[Formula: see text] T2R signal transduction and support an immune recognition role for T2Rs in M[Formula: see text] cell physiology.

4.
Eur Respir J ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029445

RESUMO

Airway submucosal gland serous cells are sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and are important for fluid secretion in conducting airways. To elucidate how neuropeptides regulate serous cells, we tested if human nasal turbinate serous cells secrete bicarbonate (HCO3 -), important for mucus polymerisation and antimicrobial peptide function, during stimulation with cAMP-elevating vasoactive intestinal peptide (VIP) and if this requires CFTR. Serous cells stimulated with VIP exhibited a ∼15-20% cAMP-dependent decrease in cell volume and a ∼0.15 unit decrease in intracellular pH (pHi), reflecting activation of Cl- and HCO3 - secretion, respectively. HCO3 - secretion was directly dependent on CFTR and was absent in cells from CF patients. In contrast, neuropeptide Y (NPY) reduced VIP-evoked cAMP increases, CFTR activation, and Cl-/HCO3 - secretion. Culture of primary serous cells in a model that maintained a serous phenotype confirmed the activating and inhibiting effects of VIP and NPY, respectively, on fluid and HCO3 - secretion. Moreover, VIP enhanced antimicrobial peptide secretion and antimicrobial efficacy of secretions while NPY reduced antimicrobial efficacy. In contrast, NPY enhanced cytokine release while VIP reduced cytokine release through a mechanism requiring CFTR. As levels of VIP and NPY are up-regulated in diseases like allergy, asthma, and chronic rhinosinusitis, the balance of these two peptides in the airway may control mucus rheology and inflammatory responses in serous cells. Furthermore, the loss of CFTR conductance in serous cells may contribute to CF pathophysiology by increasing serous cells inflammatory responses in addition to directly impairing Cl- and HCO3 - secretion.

5.
Molecules ; 25(2)2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947655

RESUMO

Proliposomes were used to improve the solubility and oral bioavailability of nifedipine. Nifedipine proliposomes were prepared by methanol injection-spray drying method. The response surface method was used to optimize formulation to enhance the encapsulation efficiency (EE%) of nifedipine. The particle size of nifedipine proliposomes after rehydration was 114 nm. Surface morphology of nifedipine proliposomes was observed by a scanning electron microscope (SEM) and interaction of formulation ingredients was assessed by differential scanning calorimetry (DSC). The solubility of nifedipine is improved 24.8 times after forming proliposomes. In vitro release experiment, nifedipine proliposomes had a control release effect, especially in simulated gastric fluid. In vivo, nifedipine proliposomes significantly improved the bioavailability of nifedipine. The area under the concentration-time curve (AUC0-∞) of nifedipine proliposomes was about 10 times than nifedipine after oral administration. The elimination half-life (T1/2ß) of nifedipine was increased from 1.6 h to 6.6 h. In conclusion, proliposomes was a promising system to deliver nifedipine through oral route and warranted further investigation.

7.
Int J Pharm ; 572: 118769, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31669557

RESUMO

Bmi-1 is a gene related to malignant transformation in hepatocellular carcinoma (HCC). The liver cancer cells developed the ability to tolerate CDDP treatment with the elevation of Bmi-1. Bmi-1 is also an oncogene promoting malignance of tumor and an anti-cancer target in many studies. Herein, a biocompatible nanocarrier was designed in the study to deliver a chemotherapeutical agent CDDP and Bmi-1 siRNA to kill cancer cells and silence drug resistance related gene simultaneously. Calciumphosphate (CaP) was applied to coat both nanoplatin cores and siRNA as a shell for the purpose of delivering cargos to the cytosol of the tumor cells. Nanoplatin and siRNA co-loaded CaP nanoparticles (NPSC) enhanced cell uptake of CDDP and showed elevated drug accumulation in tumor. NPSC achieved considerable anti-cancer efficacy and counter-regulated drug tolerance, therefore, warranted a further investigation as a novel therapeutic nanosystem to improve cancer therapy.

8.
Nat Commun ; 10(1): 5351, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767858

RESUMO

Long non-coding RNAs (lncRNAs) are important regulatory molecules that are implicated in cellular physiology and pathology. In this work, we dissect the functional role of the HOXB-AS3 lncRNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 is shown to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.

9.
Am J Orthod Dentofacial Orthop ; 156(4): 566-573, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31582128

RESUMO

INTRODUCTION: Accurate root position is imperative for successful orthodontic treatment that is stable and functional. Current methods to monitor root position are either inaccurate or use relatively high levels of radiation. A method to generate an expected root position (ERP) setup has been reported to have the potential to accurately evaluate root position with minimal radiation. The purpose of this study was to determine the accuracy and reliability of the clinical decisions made on root position using the ERP setup. METHODS: This retrospective study included 10 subjects who had pretreatment and midtreatment cone-beam computed tomography (CBCT) scans and study models. An ERP setup was generated for all patients at midtreatment. Four examiners assessed both the CBCT scan and ERP setup and made clinical decisions regarding the root position with each method. Cohen's kappa was determined to assess intraoperator and intermethod reliability. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated to determine the accuracy of the ERP setup. RESULTS: The kappa values for intraoperator reliability for both the CBCT scan and ERP setup fell within the 0.61-0.80 range. The kappa values for intermethod reliability between the CBCT scan and ERP setup fell within the 0.61-0.80 range for all tooth groups. The sensitivity of the ERP setup ranged from 0.72 to 0.90, specificity ranged from 0.89 to 0.97, positive predictive value ranged from 0.57 to 0.85, and negative predictive value ranged from 0.93 to 0.99. CONCLUSIONS: This study demonstrated that the ERP setup, when compared with the gold standard CBCT scan, was accurate and reliable in making clinical decisions regarding root position at midtreatment.


Assuntos
Tomada de Decisão Clínica , Tomografia Computadorizada de Feixe Cônico/métodos , Imagem Tridimensional/métodos , Técnicas de Movimentação Dentária , Raiz Dentária/anatomia & histologia , Raiz Dentária/diagnóstico por imagem , Modelos Dentários , Humanos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
10.
Molecules ; 24(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31574945

RESUMO

Glioma is one of the most aggressive and common malignant brain tumors. Due to the presence of the blood-brain barrier (BBB), the effectiveness of therapeutics is greatly affected. In this work, to develop an efficient anti-glioma drug with targeting and which was able to cross the BBB, cell-penetrating peptides (R8) and transferrin co-modified doxorubicin (DOX)-loaded liposomes (Tf-LPs) were prepared. Tf-LPs possessed a spherical shape and uniform size with 128.64 nm and their ξ-potential was 6.81 mV. Tf-LPs were found to be stable in serum within 48 h. Uptake of Tf-LPs in both U87 and GL261 cells was analyzed by confocal laser scanning microscopy and by flow cytometry. Tf-LPs were efficiently taken up by both U87 and GL261 cells. Moreover, Tf-LPs exhibited sustained-release. The cumulative release of DOX from Tf-LPs reached ~50.0% and showed excellent anti-glioma efficacy. Histology of major organs, including brain, heart, liver, spleen, lungs and kidney, and the bodyweight of mice, all indicated low toxicity of Tf-LPs. In conclusion, Tf-LPs showed great promise as an anti-glioma therapeutic agent.


Assuntos
Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Transferrina/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Humanos , Lipossomos , Camundongos , Polietilenoglicóis/administração & dosagem , Transferrina/química , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancers (Basel) ; 11(10)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623082

RESUMO

Microfluidic technology (MF) has improved the formulation of nanoparticles (NPs) by achieving uniform particle size distribution, controllable particle size, and consistency. Moreover, because liquid mixing can be precisely controlled in the pores of the microfluidic chip, maintaining high mixing efficiency, MF exerts higher of NP encapsulation efficiency (EE) than conventional methods. MF-NPs-cabazitaxel (CTX) particles (MF-NPs-CTX) were first prepared by encapsulating CTX according to MF. Folate (FA)- Polyethylene glycol (PEG)-NPs-CTX particles (FA-PEG-NPs-CTX) were formulated by connecting FA to MF-NPs-CTX to endow NPs with targeted delivery capability. Accordingly, the mean particle size of FA-PEG-NPs-CTX increased by approximately 25 nm, as compared with MF-NPs-CTX. Upon morphological observation of FA-PEG-NPs-CTX and MF-NPs-CTX by transmission electron microscopy (TEM), all NPs were spherical and particle size distribution was uniform. Moreover, the increased delivery efficiency of CTX in vitro and its strong tumor inhibition in vivo indicated that FA-PEG-NPs-CTX had a powerful tumor-suppressive effect both in vitro and in vivo. In vivo imaging and pharmacokinetic data confirmed that FA-PEG-NPs-CTX had good drug delivery efficiency. Taken together, FA-PEG-NPs-CTX particles prepared using MF showed high efficient and targeted drug delivery and may have a considerable driving effect on the clinical application of targeting albumin NPs.

12.
Dose Response ; 17(3): 1559325819872583, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523204

RESUMO

Docetaxel (DTX) is commonly used for breast cancer treatment. Tween 80 used for DTX dissolution in its clinical formulation causes severe hypersensitivity and other adverse reactions. In this study, trastuzumab (Tmab)-coated lipid-polymer hybrid nanoparticles (PLNs) were prepared, composed of poly (d, l-lactide-co-glycolide), PLGA; polyethylenimine (PEI); and lipids. The PLGA/PEI/lipid formed a hydrophobic core, while Tmab was electrostatically adsorbed on the surface of the PLNs as a ligand that targets human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells. The resulting PLNs, electrostatically adsorbed Tmab-bearing PLGA/PEI/lipid nanoparticles (eTmab-PPLNs), had a mean particle size of 217.4 ± 13.36 nm, a ζ potential of 0.056 ± 0.315 mV, and good stability. In vitro, the eTmab-PPLNs showed increased cytotoxicity in HER2-postive BT474 cells but not in HER2-negative MCF7 cells. Studies of the ability of eTmab-PPLNs to target HER2 were performed. The uptake of eTmab-PPLNs was shown to be dependent on HER2 expression level. Therefore, eTmab-PPLNs provide a promising therapeutic for the treatment of breast cancer.

13.
Biochem Biophys Res Commun ; 519(2): 385-390, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31519326

RESUMO

Solid lipid nanoparticles (SLNs) were prepared by biocompatible and biodegradable solid-phase lipids. ß-elemene is a safe natural essential oil with broad-spectrum anti-tumor activity. However, its clinical application has been adversely affected by its poor water solubility and limited bioavailability. SLN incorporation is a potential strategy to bypass the blood-brain barrier, the most important factor limiting the bioactivity of neurotherapeutics. The SLNs-ß has the same efficacy as commercially available elemene in vitro and an enhanced brain drug accumulation in vivo. The survival rate data was promising and acute toxicity experiment proved its safety. All these data suggested that SLN-ß is a safe and effective drug delivery system, especially for brain tumor therapy, and warrants further development.

14.
Theranostics ; 9(18): 5282-5297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410215

RESUMO

Purpose: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy. However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration. microRNA-124 (miR-124) has shown direct bone protection activity against RA. A co-delivery system for MTX and microRNA combination may provide therapeutic synergy. Methods: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional amphiphilic polymers (MTX-PEI-LA and mPEG-LA) at an optimized weight ratio. Incorporation of microRNA was achieved through electrostatic interactions between microRNA and cationic polymer MTX-PEI-LA. Cellular uptake, endosome escape, biodistribution, and therapeutic efficacy of M-PHMs/miR-124 complexes were investigated and evaluated in RAW264.7 cells and a rat adjuvant-induced arthritis (AIA) model. Results: M-PHMs/miR-124 complexes exhibited folate receptor-mediated uptake in activated RAW264.7 cells. miR-124 was able to escape from the endosome and down-regulate nuclear factor of activated T cells cytoplasmic1 (NFATc1). M-PHMs/miR-124 complexes accumulated in inflamed joints of AIA rats and showed superior therapeutic efficacy through both anti-inflammatory effect and direct bone protective effect. Combination of miR-124 and MTX in these micelles induced disease remission. Conclusions: M-PHMs/miR-124 was highly effective against RA through therapeutic synergy. Additional studies are warranted to further investigate its therapeutic potential and delineate its mechanisms of action.

15.
Biomater Sci ; 7(10): 4260-4272, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31402373

RESUMO

Hypoxia, acidosis and high level of glutathione (GSH) are characteristic abnormalities of the tumor microenvironment (TME), which promote tumor progression, metastasis, and resistance to therapies. Previous attempts to improve therapeutic efficacy were limited to modifying individual TME elements. In this study, we proposed a comprehensive TME modulation strategy that modifies multiple elements of the TME in order to enhance cisplatin anticancer efficacy. To do so, we prepared biocompatible lipid-coated CaO2/cisplatin nanoparticles (LipoCaO2/DDP) by the reverse microemulsion method. We imbued CaO2 with the following reverse-TME properties: O2 generation, increased pH value in tumor cells, and oxidation of intracellular glutathione. In vitro experiments showed that LipoCaO2/DDP could deplete GSH for preventing the binding of GSH to cisplatin. Simultaneously, CaO2 could significantly downregulate multidrug resistance-associated protein 2 (MRP2) by O2-dependent hypoxia-inducible factor 1 (HIF-1) inactivation. Hence, the complete drug-efflux pathway was blocked, and the anticancer effect of cisplatin was enhanced both in vitro and in vivo. Herein, we not only demonstrated the GSH depletion capacity of CaO2 for the first time, but also provided a new comprehensive therapeutic strategy to overcome therapeutic resistance caused by multiple factors in the TME.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Peróxidos/administração & dosagem , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lipídeos/administração & dosagem , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
16.
Int J Pharm ; 570: 118638, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31449842

RESUMO

Osteosarcoma is the bone tumor that most commonly affects children and teenagers with low survival rate because of metastatic relapse or recurrence. Cisplatin is a first-line chemotherapy for osteosarcoma. However, severe side effects limit its use in clinic. Selenium (Se) is an anticarcinogen that can protect normal tissues from side effects of chemotherapy. In this study, nanoparticles were used to co-deliver cisplatin and Se in a synergistic combination. Se-doped and lipid-coated calcium carbonate nanoparticles loaded with cisplatin (Pt/Se@CaCO3 NPs) were prepared by a reverse microemulsion method. The NPs delivered cisplatin and Se to tumour cells at an optimal synergistic ratio of 1:1 (mol/mol) both in vitro and in an osteosarcoma xenograft model. These results demonstrate that Pt/Se@CaCO3 NPs have great prospects for the osteosarcoma therapy.


Assuntos
Carbonato de Cálcio/química , Cisplatino/química , Nanopartículas/química , Selênio/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Emulsões/química , Humanos , Lipídeos/química , Camundongos , Camundongos Nus , Osteossarcoma/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
ACS Omega ; 4(5): 8874-8880, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459975

RESUMO

A series of thiophene derivatives were synthesized by functionalization of 2,3-fused thiophene scaffolds. Their cytotoxicity was assessed against HeLa and Hep G2 cells. Compound 480 was identified as a promising candidate because of its low IC50 in HeLa (12.61 µg/mL) and Hep G2 (33.42 µg/mL) cells. The drug was loaded into folic acid (FA)-coated nanoparticles (NPs) to address its poor water solubility and to improve its selectivity for cancer cells. Compound 480 was shown to induce apoptosis by changes in mitochondrial membrane potential (ΔΨm) and the reactive oxygen species level. Furthermore, FA-modified NPs enhanced uptake capacity compared to unmodified controls by flow cytometry. This drug delivered in folate nanocarriers is promising for the treatment of cancers.

18.
Nutrients ; 11(9)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466230

RESUMO

Taste receptors, first identified on the tongue, are best known for their role in guiding our dietary preferences. The expression of taste receptors for umami, sweet, and bitter have been demonstrated in tissues outside of the oral cavity, including in the airway, brain, gastrointestinal tract, and reproductive organs. The extra-oral taste receptor chemosensory pathways and the endogenous taste receptor ligands are generally unknown, but there is increasing data suggesting that taste receptors are involved in regulating some aspects of innate immunity, and may potentially control the composition of the nasal microbiome in healthy individuals or patients with upper respiratory diseases like chronic rhinosinusitis (CRS). For this reason, taste receptors may serve as potential therapeutic targets, providing alternatives to conventional antibiotics. This review focuses on the physiology of sweet (T1R) and bitter (T2R) taste receptors in the airway and their activation by secreted bacterial products. There is particular focus on T2R38 in sinonasal ciliated cells, as well as the sweet and bitter receptors found on specialized sinonasal solitary chemosensory cells. Additionally, this review explores the impact of genetic variations in these receptors on the differential susceptibility of patients to upper airway infections, such as CRS.


Assuntos
Imunidade Inata , Imunidade nas Mucosas , Receptores Acoplados a Proteínas-G/metabolismo , Mucosa Respiratória/metabolismo , Sistema Respiratório/metabolismo , Infecções Respiratórias/metabolismo , Paladar , Animais , Antibacterianos/uso terapêutico , Bactérias/imunologia , Bactérias/metabolismo , Cílios/imunologia , Cílios/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/microbiologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Transdução de Sinais , Paladar/efeitos dos fármacos
19.
Colloids Surf B Biointerfaces ; 181: 872-878, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382335

RESUMO

Fluorescence imaging is widely used to determine biodistribution of drugs in mice. However, the dye distribution may not be able to exactly reflect the true distribution of drug molecules. We synthesized PTX-Cy5.5 and mPEG-PLA-Cy5.5, and then prepared dye-loaded nanoparticles (NPs) (Cy5.5, DiR, PTX-Cy5.5, and mPEG-PLA-Cy5.5), dye and PTX co-loaded NPs, and PTX-loaded NPs, respectively. The particle sizes of resulting NPs were between 42.7 nm and 68.8 nm, and Zeta potential was between -0.86 mV and -8.49 mV. The biodistribution of fluorescent NPs (dye-loaded NPs and dye and PTX co-loaded NPs) on Bel-7402 tumor-bearing mice was studied via in vivo fluorescence imaging assays, results of which suggested that Cy5.5 loaded NPs and Cy5.5 conjugates (PTX-Cy5.5 and mPEG-PLA-Cy5.5) formulated NPs can reflect the tissue distribution of PTX whether it was incorporated or not. However, DiR failed to reflect true tissue distribution of PTX unless it was co-loaded with PTX. Based on these results, a guidance for the selection of dyes in drug distribution investigations and disease-targeted treatment was presented.


Assuntos
Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacocinética , Corantes Fluorescentes/química , Imagem Óptica , Paclitaxel/análise , Paclitaxel/farmacocinética , Células A549 , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Corantes Fluorescentes/análise , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Conformação Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/patologia , Paclitaxel/química , Distribuição Tecidual
20.
Artigo em Inglês | MEDLINE | ID: mdl-31422134

RESUMO

OBJECTIVES: The goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque. BACKGROUND: High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. METHODS: In a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. RESULTS: In total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33). CONCLUSIONS: Dual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303).

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