RESUMO
Per- and polyfluoroalkyl substances (PFAS) are a large group of synthetic surfactants of over 12,000 compounds that are incorporated into numerous products for their chemical and physical properties. Studies have associated PFAS with adverse health effects. Although there is a high potential for dermal exposure, these studies are lacking. The present study evaluated the systemic and immunotoxicity of subchronic 28- or 10-days of dermal exposure, respectively, to PFHpS (0.3125-2.5% or 7.82-62.5 mg/kg/dose) or PFOS (0.5% or 12.5 mg/kg/dose) in a murine model. Elevated levels of PFHpS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. PFHpS induced significantly increased relative liver weight, significantly decreased relative spleen and thymus weight, altered serum chemistries, and altered histopathology. Additionally, PFHpS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen of genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells and CD11b+ monocyte and/or macrophages in the spleen along with decreases in eosinophils and dendritic cells in the skin. These findings support PFHpS absorption through the skin leading to liver damage and immune suppression.
Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Animais , Fluorocarbonos/toxicidade , Fluorocarbonos/administração & dosagem , Camundongos , Ácidos Alcanossulfônicos/toxicidade , Ácidos Alcanossulfônicos/administração & dosagem , Feminino , Humanos , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Ácidos Sulfônicos/toxicidade , Ácidos Sulfônicos/administração & dosagem , Administração Tópica , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologiaRESUMO
Systemic hypertension is the leading cause of death and disability worldwide. The management of hypertension is challenging in the high-risk patient population with high salt-sensitivity and low serum renin levels. The renin-angiotensin system (RAS) plays a central role in blood pressure (BP) regulation. While we have effective medications to act on peripheral RAS, our understanding of brain RAS and its effect on BP regulation is still in an evolving stage. Brain RAS hyperactivity is associated with the development and maintenance of hypertension. In comparison to peripheral RAS, where angiotensin II is the most crucial component responsible for BP regulation, angiotensin III is likely the main active peptide in the brain RAS. Angiotensin II is metabolized by aminopeptidase A into angiotensin III in the brain. EC33 is a potent inhibitor of brain aminopeptidase A tested in animal models. The use of EC33 in conscious spontaneously hypertensive rats, hypertensive deoxycorticosterone acetate-salt rats, and conscious normotensive rat models leads to a reduction in BP. In order to facilitate the passage of EC33 through the blood-brain barrier, the 2 molecules of EC33 were linked by a disulfide bridge to form a prodrug called RB150. RB150, later renamed as QGC001 or firibastat, was found to be effective in animal models and well-tolerated when used in healthy participants. Firibastat was found to be safe and effective in phase 2 trials, and is now planned to undergo a phase 3 trial. Firibastat has the potential to be groundbreaking in the management of resistant hypertension.
Assuntos
Dissulfetos , Hipertensão , Ácidos Sulfônicos , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Encéfalo/metabolismo , Ensaios Clínicos Fase II como Assunto , Dissulfetos/administração & dosagem , Glutamil Aminopeptidase/antagonistas & inibidores , Humanos , Hipertensão/tratamento farmacológico , Ratos , Ácidos Sulfônicos/administração & dosagemRESUMO
Successful imaging of atherosclerosis, one of the leading global causes of death, is crucial for diagnosis and intervention. Near-infrared fluorescence (NIRF) imaging has been widely adopted along with multimodal/hybrid imaging systems for plaque detection. We evaluate two macrophage-targeting fluorescent tracers for NIRF imaging (TLR4-ZW800-1C and Feraheme-Alexa Fluor 750) in an atherosclerotic murine cohort, where the left carotid artery (LCA) is ligated to cause stenosis, and the right carotid artery (RCA) is used as a control. Imaging performed on dissected tissues revealed that both tracers had high uptake in the diseased vessel compared to the control, which was readily visible even at short exposure times. In addition, ZW800-1C's renal clearance ability and Feraheme's FDA approval puts these two tracers in line with other NIRF tracers such as ICG. Continued investigation with these tracers using intravascular NIRF imaging and larger animal models is warranted for clinical translation.
Assuntos
Doenças das Artérias Carótidas/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Compostos de Amônio Quaternário/administração & dosagem , Succinimidas/administração & dosagem , Ácidos Sulfônicos/administração & dosagem , Animais , Doenças das Artérias Carótidas/induzido quimicamente , Doenças das Artérias Carótidas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Óxido Ferroso-Férrico/química , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Imagem Molecular , Imagem Óptica , Placa Aterosclerótica/induzido quimicamente , Placa Aterosclerótica/metabolismo , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacocinética , Succinimidas/química , Succinimidas/farmacocinética , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacocinética , Receptor 4 Toll-Like/metabolismoRESUMO
Survival from pancreatic cancer remains extremely poor, in part because this malignancy is not diagnosed in the early stages, and precancerous pancreatic intraepithelial neoplasia (PanIN) lesions are not seen on routine radiographic imaging. Since the cholecystokinin-B receptor (CCK-BR) becomes over-expressed in PanIN lesions, it may serve as a target for early detection. We developed a biodegradable fluorescent polyplex nanoparticle (NP) that selectively targets the CCK-BR. The NP was complexed to a fluorescent oligonucleotide with Alexa Fluor 647 for far-red imaging and to an oligonucleotide conjugated to Alexa Fluor 488 for localization by immunohistochemistry. Fluorescence was detected over the pancreas of five- to ten-month-old LSL-KrasG12D/+; P48-Cre (KC) mice only after the injection of the receptor target-specific NP and not after injection of untargeted NP. Ex vivo tissue imaging and selective immunohistochemistry confirmed particle localization only to PanIN lesions in the pancreas and not in other organs, supporting the tissue specificity. A human pancreas tissue microarray demonstrated immunoreactivity for the CCK-BR only in the PanIN lesions and not in normal pancreas tissue. The long-term goal would be to develop this imaging tool for screening human subjects at high risk for pancreatic cancer to enable early cancer detection.
Assuntos
Fluoresceínas/administração & dosagem , Imagem Óptica/métodos , Neoplasias Pancreáticas/diagnóstico por imagem , Lesões Pré-Cancerosas/diagnóstico por imagem , Receptor de Colecistocinina B/metabolismo , Ácidos Sulfônicos/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Detecção Precoce de Câncer , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Nanopartículas , Especificidade de Órgãos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Análise Serial de Proteínas , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Introduction: Steroid sulfatase (STS) enzyme is responsible for transforming the inactive sulfate metabolites of steroid sex hormones into the active free steroids. Both the deficiency and the over-expression of STS are associated with the pathophysiology of certain diseases. This article provides the readership with a comprehensive review about STS enzyme and its recently reported inhibitors.Areas covered: In the present article, we reviewed the structure, location, and substrates of STS enzyme, physiological functions of STS, and disease states related to over-expression or deficiency of STS enzyme. STS inhibitors reported during the last five years (2016-present) have been reviewed as well.Expert opinion: Irosustat is the most successful STS inhibitor drug candidate so far. It is currently under investigation in clinical trials for treatment of estrogen-dependent breast cancer. Non-steroidal sulfamate is the most favorable scaffold for STS inhibitor design. They can be beneficial for the treatment of hormone-dependent cancers and neurodegenerative disorders without significant estrogenic side effects. Moreover, dual-acting molecules (inhibitors of STS + another synergistic mechanism) can be therapeutically efficient.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Esteril-Sulfatase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Patentes como Assunto , Esteril-Sulfatase/metabolismo , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/farmacologiaRESUMO
OBJECTIVE: Differentiating central nervous system (CNS) lymphoma from other intracranial malignancies remains a clinical challenge in surgical neuro-oncology. Advances in clinical fluorescence imaging contrast agents and devices may mitigate this challenge. Aptamers are a class of nanomolecules engineered to bind cellular targets with antibody-like specificity in a fraction of the staining time. Here, the authors determine if immediate ex vivo fluorescence imaging with a lymphoma-specific aptamer can rapidly and specifically diagnose xenografted orthotopic human CNS lymphoma at the time of biopsy. METHODS: The authors synthesized a fluorescent CNS lymphoma-specific aptamer by conjugating a lymphoma-specific aptamer with Alexa Fluor 488 (TD05-488). They modified human U251 glioma cells and Ramos lymphoma cells with a lentivirus for constitutive expression of red fluorescent protein and implanted them intracranially into athymic nude mice. Three to 4 weeks postimplantation, acute slices (biopsies, n = 28) from the xenografts were collected, placed in aptamer solution, and imaged with a Zeiss fluorescence microscope. Three aptamer staining concentrations (0.3, 1.0, and 3.0 µM) and three staining times (5, 10, and 20 minutes) followed by a 1-minute wash were tested. A file of randomly selected images was distributed to neurosurgeons and neuropathologists, and their ability to distinguish CNS lymphoma from negative controls was assessed. RESULTS: The three staining times and concentrations of TD05-488 were tested to determine the diagnostic accuracy of CNS lymphoma within a frozen section time frame. An 11-minute staining protocol with 1.0-µM TD05-488 was most efficient, labeling 77% of positive control lymphoma cells and less than 1% of negative control glioma cells (p < 0.001). This protocol permitted clinicians to positively identify all positive control lymphoma images without misdiagnosing negative control images from astrocytoma and normal brain. CONCLUSIONS: Ex vivo fluorescence imaging is an emerging technique for generating rapid histopathological diagnoses. Ex vivo imaging with a novel aptamer-based fluorescent nanomolecule could provide an intraoperative tumor-specific diagnosis of CNS lymphoma within 11 minutes of biopsy. Neurosurgeons and neuropathologists interpreted images generated with this molecular probe with high sensitivity and specificity. Clinical application of TD05-488 may permit specific intraoperative diagnosis of CNS lymphoma in a fraction of the time required for antibody staining.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Fluoresceínas/administração & dosagem , Corantes Fluorescentes/administração & dosagem , Linfoma/patologia , Ácidos Sulfônicos/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Biópsia/métodos , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/diagnóstico , Fluoresceínas/análise , Corantes Fluorescentes/análise , Humanos , Linfoma/diagnóstico , Camundongos , Camundongos Nus , Técnicas de Cultura de Órgãos , Ácidos Sulfônicos/análise , Fatores de TempoRESUMO
The present study exposed adult zebrafish to 0, 10, and 100 µg/L perfluorobutanesulfonate (PFBS) with or without dietary supplement of probiotic Lactobacillus rhamnosus. Interaction between probiotic and PFBS on sex endocrine and reproduction was investigated. It was striking to find that PFBS and probiotic coexposures almost ceased the fecundity, which was accompanied by disturbances in sex hormones and oocyte maturation in females. In contrast, probiotic additive efficiently antagonized the estrogenic activity of PFBS in males. For the first time, this study reported that probiotic heavily depended on sex to modulate the endocrine disruption and reproductive toxicity of aquatic pollutants.
Assuntos
Disruptores Endócrinos/toxicidade , Fluorocarbonos/toxicidade , Probióticos/toxicidade , Reprodução/efeitos dos fármacos , Ácidos Sulfônicos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Suplementos Nutricionais , Disruptores Endócrinos/administração & dosagem , Estrogênios/metabolismo , Feminino , Fluorocarbonos/administração & dosagem , Hormônios Esteroides Gonadais/antagonistas & inibidores , Lacticaseibacillus rhamnosus/química , Masculino , Oócitos/efeitos dos fármacos , Probióticos/administração & dosagem , Ácidos Sulfônicos/administração & dosagem , Poluentes Químicos da Água/administração & dosagem , Peixe-ZebraRESUMO
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) are the major risk factor for developing colitis associated cancer (CAC). Previously, we have reported that Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was overexpressed in colorectal cancer (CRC), but we don't know the role of PIK3R3 in IBD. METHODS: We investigated the differential expression of PIK3R3 and ZO-1 in IBD patients by using Immunohistochemical (IHC) and Gene Expression Omnibus (GEO) database analysis. Caco-2 cells were exposed to different conditions to assess protein level changes of PIK3R3 and ZO-1. Caco-2 cell monolayers were transfected with PIK3R3/siPIK3R3 to assess transepithelial electrical resistance. Tight junction protein integrity was assessed by immunoblot and immunofluorescence. For further, intestinal permeability and tight junction protein integrity were assessed in animal study to assess the treatment role of PIK3R3 specific inhibitor TAT-N 15 (N15). RESULTS: PIK3R3 was increased in IBD patients, and negatively controlled the expression of ZO-1. In vitro, PIK3R3 regulates ZO-1 by activating NF-kB pathway. Overexpression of PIK3R3 in Caco-2 cells decreased transepithelial electrical resistance (TEER), an opposite result was observed in siPIK3R3 cells. In animal study, inhibition of PIK3R3 by N15 contributed to amelioration of DSS-induced intestinal permeability. Mice treated with N15 exhibited less disruption of TJs in colon tissues. CONCLUSIONS: PIK3R3 was increased in clinical IBD patients with accompanying disruption of ZO-1 expression. Inhibition of PIK3R3 attenuated DSS-induced IBD symptoms in a mouse model. These findings indicated that PIK3R3 could be a therapeutic target for IBD.
Assuntos
Doenças Inflamatórias Intestinais/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo , Animais , Células CACO-2 , Colite/sangue , Colite/induzido quimicamente , Colite/imunologia , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery. EXPERIMENTAL DESIGN: We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer. RESULTS: cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio. CONCLUSIONS: cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.
Assuntos
Carcinoma/diagnóstico , Colo/diagnóstico por imagem , Neoplasias do Colo/diagnóstico , Corantes Fluorescentes/administração & dosagem , Imagem Óptica/métodos , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma/patologia , Carcinoma/terapia , Quimiorradioterapia Adjuvante , Colectomia/métodos , Colo/patologia , Colo/cirurgia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Estudos de Viabilidade , Feminino , Corantes Fluorescentes/efeitos adversos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Voluntários Saudáveis , Humanos , Integrinas/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Imagem Óptica/efeitos adversos , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/efeitos adversos , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacocinética , Ratos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/efeitos adversos , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacocinética , Testes de Toxicidade AgudaRESUMO
AIM: Development of a preactivated thiomer as sprayable excipient for mucoadhesive formulations. METHODS: CG4500 (acrylic acid/acrylamide-methyl propane sulfonic acid copolymer) was thiolated by conjugation with L-cysteine and preactivated by further modification with 2-mercaptonicotinic acid (MNA) in a two-step synthesis and characterized regarding degree of modification and cytotoxicity on Caco-2 cells. The mucoadhesive properties of this novel thiomer were evaluated via rheological synergism, tensile and mucosal residence time studies. Furthermore, the sprayability of the thiomer was evaluated. RESULTS: The newly synthesized derivatives CG4500-SH and CG4500-S-S-MNA showed mean coupling rates of 651 µmol thiol groups and 264 µmol MNA per gram polymer, respectively. Even for the unmodified polymer a rheological synergism was observed with isolated porcine intestinal mucus, which was 2.81-fold higher in case of the preactivated thiomer. Mucoadhesion studies on freshly excised porcine intestinal mucosa confirmed these results via a 2.43-fold higher total work of adhesion and a 2.31-fold higher mucosal residence time of the preactivated thiomer. In sprayability tests it was shown that solutions of the preactivated thiomer could be sprayed in concentrations up to 12% (m/V). CONCLUSION: The novel polymer CG4500-S-S-MNA is a promising sprayable excipient for mucoadhesive formulations.
Assuntos
Acrilamida , Acrilatos , Cisteína , Ácidos Nicotínicos , Polímeros , Compostos de Sulfidrila , Ácidos Sulfônicos , Acrilamida/administração & dosagem , Acrilamida/química , Acrilatos/administração & dosagem , Acrilatos/química , Adesividade , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Cisteína/administração & dosagem , Cisteína/química , Humanos , Mucosa Intestinal/química , Muco/química , Ácidos Nicotínicos/administração & dosagem , Ácidos Nicotínicos/química , Polímeros/administração & dosagem , Polímeros/química , Reologia , Compostos de Sulfidrila/administração & dosagem , Compostos de Sulfidrila/química , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/química , SuínosRESUMO
Monodispersed hollow Fe3O4 nanoparticles with the diameters of 7 and 10 nm were prepared via a high-temperature pyrolysis method and the Kirkendall effect by regulating the ratio of oleylamine to oleic acid. The water solubility was studied by zwitterionic dopamine sulfonate (ZDS) to obtain ZDS-conjugated Fe3O4 nanoparticles (Fe3O4@ZDS NPs). The 7 nm Fe3O4@ZDS NPs exhibited a good T1 positive contrast with a longitudinal relaxivity (r1) of 0.23 mM-1 s-1 and a small ratio of r1 to transversal relaxivity (r2) of 4.00. In the 4T1 xenograft mouse model, the tumor signal from T1-weighted MRI was positively enhanced by â¼23% after the intravenous injection of 7-Fe3O4@ZDS NPs (40 mg kg-1). More importantly, 7-Fe3O4@ZDS NPs can be partially metabolized by the kidney, which is an important step for the use of MRI contrast agents in clinic.
Assuntos
Meios de Contraste/química , Dopamina/química , Rim/diagnóstico por imagem , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/química , Ácidos Sulfônicos/química , Animais , Meios de Contraste/administração & dosagem , Meios de Contraste/metabolismo , Dopamina/administração & dosagem , Dopamina/metabolismo , Injeções Intravenosas , Rim/química , Rim/metabolismo , Nanopartículas de Magnetita/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Porosidade , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/metabolismo , Propriedades de SuperfícieRESUMO
We report, the one-pot synthesis of water-soluble and biocompatible 3-mercaptopropylsulfonate (MPS) protected novel copper nanoclusters (CuNCs). Interestingly, the TEM image of MPS protected CuNCs exhibits an ultrasmall nanoclusters of particle size <2-nm, similar to its Au and Ag analogue. The hydrophilic and biocompability property of thiolate protected CuNCs. i.e., MPS stabilized CuNCs and its luminescent nature gave rise to maximum quantum yield of 1.5%. Further, as achieved CuNCs was investigated for haemocompatibility, cell viability and fluorescent microscopic analysis with A549 lung cancer cell line. Haemolytic study was examined using human RBCs in the concentration range of 4 to 22 µg/mL for which 7.5% of haemolysis was obtained for an optimum concentration of 22 µg/mL of CuNCs. The cell viability analysis was carried out by MTT assay using A549 lung cancer cells for the minimum (10 µg/mL) and maximum (45 µg/mL) concentration of CuNCs which reports 93.1% and 38.2% cell viability respectively. The inverted light microscopic images from the control and CuNCs treated (20 µg/mL) cells exhibited an excellent biocompatibility with a normal morphology. Upon increasing the concentration of CuNCs upto 45 µg/mL, the cell viability trends to decrease and the cell morphology also denature gradually. Further, the bio-imaging application of CuNCs was analyzed with A549 lung cancer cells. The efficient imaging with CuNCs treated (20 µg/mL) A549 cells resulted in a green colour emission using FITC filter (460- 490 nm). Thereby the obtained results confirm the applicability of CuNCs for the biomedical and cancer diagnosis applications.
Assuntos
Materiais Biocompatíveis , Cobre , Neoplasias Pulmonares/diagnóstico por imagem , Nanoestruturas , Compostos de Sulfidrila , Ácidos Sulfônicos , Células A549 , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Sobrevivência Celular/efeitos dos fármacos , Cobre/administração & dosagem , Cobre/química , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Compostos de Sulfidrila/administração & dosagem , Compostos de Sulfidrila/química , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/químicaRESUMO
BACKGROUND: A new approach targeting aeroallergen sensing in the early events of mucosal immunity could have greater benefit. The CSF1-CSF1R pathway has a critical role in trafficking allergens to regional lymph nodes through activating dendritic cells. Intervention in this pathway could prevent allergen sensitization and subsequent Th2 allergic inflammation. OBJECTIVE: To examine the therapeutic effectiveness of CSF1 and CSF1R inhibition for blocking the dendritic cell function of sensing aeroallergens. METHODS: We adopted a model of chronic asthma induced by a panel of three naturally occurring allergens and novel delivery system of CSF1R inhibitor encapsulated nanoprobe. RESULTS: Selective depletion of CSF1 in airway epithelial cells abolished the production of allergen-reactive IgE, resulting in prevention of new asthma development as well as reversal of established allergic lung inflammation. CDPL-GW nanoprobe containing GW2580, a selective CSF1R inhibitor, showed favorable pharmacokinetics for inhalational treatment and intranasal insufflation delivery of CDPL-GW nanoprobe ameliorated asthma pathologies including allergen-specific serum IgE production, allergic lung and airway inflammation and airway hyper-responsiveness (AHR) with minimal pulmonary adverse reaction. CONCLUSION: The inhibition of the CSF1-CSF1R signaling pathway effectively suppresses sensitization to aeroallergens and consequent allergic lung inflammation in a murine model of chronic asthma. CSF1R inhibition is a promising new target for the treatment of allergic asthma.
Assuntos
Anisóis/administração & dosagem , Anisóis/farmacologia , Asma/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Macrófagos/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Alérgenos/imunologia , Alérgenos/farmacologia , Animais , Asma/induzido quimicamente , Modelos Animais de Doenças , Feminino , Imunoglobulina E/biossíntese , Fator Estimulador de Colônias de Macrófagos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nanoestruturas/administração & dosagem , Compostos de Amônio Quaternário/administração & dosagem , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Ácidos Sulfônicos/administração & dosagem , Resultado do TratamentoRESUMO
Sulfated polysaccharides have received much attention in recent years due to their special biological activities, especially the regulation of the biological activity of growth factors such as the representative inductive growth factor recombinant human bone morphogenetic protein-2 (rhBMP-2). However, the regulatory mechanisms from the aspect of the molecular chain structure have rarely been reported. In this article, we selected three kinds of sulfonates containing different backbone structures and functional groups, 2-N,6-O-sulfated chitosan (26 SCS), sulfated dextran (DSS) and poly(sodium-p-styrenesulfonate) (PSS), to explore the interaction between them and rhBMP-2. From in vivo and in vitro osteogenesis-related experiments, 26 SCS showed the best promoting effect on rhBMP-2 induced osteogenic differentiation and the sulfated amino group in 26 SCS could specifically bind to rhBMP-2. These findings indicated that the polysaccharide chain structure was a prerequisite for the synergy effect between 26 SCS and rhBMP-2; the effective combination of -SO3- and rhBMP-2 was an important factor in protecting the bioactivity of rhBMP-2. In addition, the presence of the sulfated amino group was the key factor in the specific binding between 26 SCS and rhBMP-2 and provided the possibility of capturing factors in vivo.
Assuntos
Proteína Morfogenética Óssea 2/administração & dosagem , Quitosana/administração & dosagem , Sulfato de Dextrana/administração & dosagem , Osteogênese/efeitos dos fármacos , Polímeros/administração & dosagem , Ácidos Sulfônicos/administração & dosagem , Fator de Crescimento Transformador beta/administração & dosagem , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Regeneração Óssea/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Masculino , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagemRESUMO
Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands.
Assuntos
Complicações Intraoperatórias/prevenção & controle , Laparoscopia/efeitos adversos , Compostos de Amônio Quaternário/administração & dosagem , Ácidos Sulfônicos/administração & dosagem , Ureter/diagnóstico por imagem , Adolescente , Adulto , Idoso , Feminino , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/efeitos adversos , Corantes Fluorescentes/farmacocinética , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Complicações Intraoperatórias/etiologia , Ionóforos/administração & dosagem , Ionóforos/efeitos adversos , Ionóforos/farmacocinética , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Imagem Óptica/métodos , Compostos de Amônio Quaternário/efeitos adversos , Compostos de Amônio Quaternário/farmacocinética , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Ácidos Sulfônicos/efeitos adversos , Ácidos Sulfônicos/farmacocinética , Ureter/lesões , Adulto JovemRESUMO
AIMS: Inhibition of brain angiotensin III by central infusion of aminopeptidase A (APA) inhibitor firibastat (RB150) inhibits sympathetic hyperactivity and heart failure in rats after myocardial infarction (MI). This study evaluated effectiveness of systemic treatment with firibastat compared with AT1R blocker, losartan. METHODS AND RESULTS: MI was induced by ligation of left coronary artery in male Wistar rats. Rats were treated from 1 to 5 weeks after MI in protocol 1 with vehicle, or firibastat at 50 mg/kg/d subcutaneously (s.c.) or 150 mg/kg/d oral, once daily, and in protocol 2, with vehicle, firibastat 150 mg/kg or losartan 50 mg/kg oral twice daily. At 5 weeks, left ventricle function was evaluated by echocardiography and Millar catheter. After MI, rats developed moderate severe heart failure. Both s.c. and oral firibastat inhibited brain APA and attenuated left ventricle dysfunction. Oral firibastat and losartan similarly improved left ventricular end diastolic pressure. However, whereas firibastat improved dP/dtmax, losartan lowered dP/dtmax and left ventricular peak systolic pressure, and increased plasma creatinine by ~50%. On the other hand, losartan more effectively inhibited cardiac fibrosis. CONCLUSION: Inhibition of the brain renin-angiotensin system by oral APA inhibitor is at least as effective as oral AT1R blocker to inhibit cardiac dysfunction after MI but without hypotension or renal dysfunction.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Angiotensina III/metabolismo , Encéfalo/efeitos dos fármacos , Dissulfetos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Glutamil Aminopeptidase/antagonistas & inibidores , Insuficiência Cardíaca/prevenção & controle , Losartan/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Ácidos Sulfônicos/administração & dosagem , Administração Oral , Animais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Fibrose , Glutamil Aminopeptidase/metabolismo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Injeções Subcutâneas , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/fisiopatologia , Ratos Wistar , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Perfluorohexanesulfonate (PFHxS), which belongs to the group of perfluoroalkyl and polyfluoroalkyl substances (PFASs), has been extensively used in industry and subsequently detected in the environment. Its use may be problematic, as PFHxS is known to induce neuronal cell death, and has been associated with early onset menopause in women and with attention deficit/hyperactivity disorder. Due to these impending issues, the aim of this study is to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for PFHxS in male and female rats, and apply this to a human health risk assessment. We conducted this study in vivo after the oral or intravenous administration of PFHxS in male (dose of 10 mg/kg) and female rats (dose of 0.5-10 mg/kg). The biological samples consisted of plasma, nine tissues, urine, and feces. We analyzed the sample using ultra-liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS). Our findings showed the tissue-plasma partition coefficients for PFHxS were highest in the liver. The predicted rat plasma and tissue concentrations using a simulation fitted well with the observed values. We extrapolated the PBPK model in male and female rats to a human PBPK model of PFHxS based on human physiological parameters. The reference doses of 0.711 µg/kg/day (male) and 0.159 µg/kg/day (female) and external doses of 0.007 µg/kg/day (male) and 0.006 µg/kg/day (female) for human risk assessment were estimated using Korean biomonitoring values. This study provides valuable insight into human health risk assessment regarding PFHxS exposure.
Assuntos
Medição de Risco/métodos , Ácidos Sulfônicos/farmacocinética , Ácidos Sulfônicos/toxicidade , Administração Oral , Animais , Proteínas Sanguíneas/metabolismo , Feminino , Fluorocarbonos , Humanos , Injeções Intravenosas , Masculino , Modelos Biológicos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Fatores Sexuais , Ácidos Sulfônicos/administração & dosagem , Distribuição TecidualRESUMO
Background: Since it is known that serum albumin-bound dyes can cross the blood-brain barrier (BBB) after ischemia, Evans Blue dye is commonly used to assess BBB disruption because of its rapid binding to serum albumin. In addition, indocyanine green (ICG), a clinically available dye, binds to serum proteins that could also be used for assessment of BBB impairment. Unlike these near-infrared (NIR) dyes, zwitterionic NIR fluorophore (ZW800-1) shows no serum binding, ultralow non-specific tissue uptake, and rapid elimination from the body via renal filtration. In this study, we report the use of ZW800-1 as a NIR fluorescence imaging agent for detecting BBB disruption in rat stroke models. Methods: Three types of NIR fluorophores, Evans Blue, ICG, and ZW800-1, were administered intraperitoneally into rat photothrombotic stroke models by using 4% concentration of each NIR dye. The NIR fluorescence signals in the infarcted brain tissue and biodistribution were observed in real-time using the Mini-FLARE® imaging system up to 24 h post-injection. Results: ZW800-1 provided successful visualization of the ischemic injury site in the brain tissue, while the remaining injected dye was clearly excreted from the body within a certain period of time. Although Evans Blue and ICG provided mapping of the infarcted brain lesions, they exhibited high non-specific uptake in most of the tissues and organs and persisted in the body over 24 h post-injection. Conclusion: Our results suggest the promising application of ZW800-1 as a new strategy in BBB experiments and future therapeutic development.
Assuntos
Barreira Hematoencefálica/diagnóstico por imagem , Isquemia Encefálica/diagnóstico por imagem , Compostos de Amônio Quaternário/administração & dosagem , Acidente Vascular Cerebral/diagnóstico por imagem , Ácidos Sulfônicos/administração & dosagem , Animais , Barreira Hematoencefálica/fisiopatologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Azul Evans/administração & dosagem , Humanos , Verde de Indocianina/administração & dosagem , Ratos , Espectrometria de Fluorescência , Espectroscopia de Luz Próxima ao Infravermelho , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologiaRESUMO
BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally. The primary endpoint was changed in FLT uptake; secondary endpoints included safety and tolerability of irosustat, changes in tumoral Ki67 and steroidogenic enzymes expression and circulating steroid hormone levels. RESULTS: Thirteen women were recruited, and ten started irosustat for 2 weeks, followed by repeat FLT-PET scans in eight. Defining response as decreases of ≥20% in standardized uptake value (SUV) or ≥30% in Ki, 1 (12.5% (95% CI 2-47%, p = 0.001)) and 3 (43% (95% CI 16-75%, p = <0.001) patients, respectively, responded. 6 out of 7 patients had a Ki67 reduction (range = -19.3 to 76.4%), and median percentage difference in Ki67 was 52.3% (p = 0.028). In one patient with a low baseline STS expression, a 19.7% increase in Ki67 was recorded. STS decreases were seen in tumours with high basal STS expression, significant decreases were also noted in aromatase, and 17ß-hydroxysteroid dehydrogenase type 1 and 2. Irosustat was generally well tolerated with all adverse event CTCAE Grade ≤2. CONCLUSIONS: Irosustat resulted in a significant reduction in FLT uptake and Ki67, and is well tolerated. These data are the first demonstrating clinical activity of irosustat in early breast cancer. Baseline expression of STS may be a biomarker of sensitivity to irosustat.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Ácidos Sulfônicos/administração & dosagem , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Pós-Menopausa , Compostos Radiofarmacêuticos/administração & dosagem , Receptores de Estrogênio/metabolismo , Esteril-Sulfatase/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Resultado do TratamentoRESUMO
Propane-2-sulfonic acid octadec-9-enyl-amide (N15), an analogue of oleoylethanolamide (OEA), is a novel PPARα/γ dual agonist. Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischemia. However, it is not clear whether N15 is effective against ischemic cerebral injury. In the present study, male Kunming mice were subjected to middle cerebral artery occlusion (MCAO). To evaluate its preventive effects, N15 (50, 100 or 200mg/kg, ip) was administered for 3days before ischemia. To evaluate its therapeutic effects, N15 (200mg/kg, ip) was administered 1h before reperfusion or 0, 1, 2 or 4h after reperfusion. Neurological deficit scores, infarct volume and the degree of brain oedema were determined at 24h after reperfusion. Blood brain barrier (BBB) disruption was evaluated by Evans blue (EB) and FITC-dextran leakages at 6h after reperfusion. The activation/inflammatory responses of microglia/macrophages were detected using immunohistochemistry and western blot. N15 pretreatment improved neurological dysfunction, reduced infarct volume and alleviated brain oedema in a dose-dependent manner; the most effective dose was 200mg/kg. The therapeutic time window was within 2h after reperfusion. N15 treatment preserved the BBB integrity and suppressed the activation of microglia/macrophages. N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Additionally, N15 markedly decreased the phosphorylation levels of NF-κBp65, STAT3, and ERK1/2 both in vivo and in vitro. Furthermore, the PPARα antagonist MK886 or PPARγ antagonist T0070907 respectively partly abolished the anti-inflammatory effects of N15 in vitro. Our findings demonstrated that N15 can exert neuroprotective effects against cerebral ischemic insult. Moreover, the neuroprotective effects of N15 on cerebral ischemia may be attributed to its anti-inflammatory properties, at least in part, by enhancing PPARα/γ dual signaling and inhibiting the activation of the NF-κB, STAT3, and ERK1/2 signaling pathways. These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischemic stroke.