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1.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675149

RESUMO

Macromolecules containing acidic fragments in side-groups-polyacids-occupy a special place among synthetic polymers. Properties and applications of polyacids are directly related to the chemical structure of macromolecules: the nature of the acidic groups, polymer backbone, and spacers between the main chain and acidic groups. The chemical nature of the phosphorus results in the diversity of acidic >P(O)OH fragments in sidechain phosphorus-containing polyacids (PCPAs) that can be derivatives of phosphoric or phosphinic acids. Sidechain PCPAs have many similarities with other polyacids. However, due to the relatively high acidity of -P(O)(OH)2 fragment, bone and mineral affinity, and biocompatibility, sidechain PCPAs have immense potential for diverse applications. Synthetic approaches to sidechain PCPAs also have their own specifics. All these issues are discussed in the present review.


Assuntos
Fósforo , Polímeros , Polímeros/química , Ácidos , Substâncias Macromoleculares , Ácidos Fosfínicos/química
2.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293470

RESUMO

The adsorption properties of two coordination polymers, resulting from the reaction of divalent metal (Ca2+ or Co2+) salts with (2-carboxyethyl)(phenyl)phosphinic acid, are presented in this paper. The structural and textural characterization before and after adsorption experiments is presented. The adsorbent materials were prepared using the hydrothermal procedure. The compound Ca[O2P(CH2CH2COOH)(C6H5)]2 (CaCEPPA) has a layered topology, with the phenyl groups oriented into the interlayer space and crystallizes in the monoclinic system. Compound Co2[(O2P(CH2CH2COO)(C6H5)(H2O)]2·2H2O (CoCEPPA) has a 1D structure composed of zig-zag chains. The adsorption performances of CaCEPPA and CoCEPPA materials were tested in the removal of cadmium and lead from aqueous solutions. The optimum pH of ions adsorption was found to be five for both adsorbent materials. Pseudo-first and second-order kinetic models were used for fitting kinetic experimental data, and Langmuir and Freundlich isotherms were used for modeling the equilibrium experimental data. The pseudo-second-order kinetic model and Langmuir isotherm best described the adsorption of Cd and Pb ions onto the studied materials, judging from the results of the error function (correlation coefficient, sum of square error, chi-square test, and average relative error) analysis. The studied materials present a higher affinity for Cd ions compared with the adsorption capacity developed for the removal of Pb ions from aqueous solutions. CoCEPPA showed the highest adsorption performance in the removal process of metal ions from aqueous solutions compared with CaCEPPA (qm = 54.9 mg Cd2+/g of CoCEPPA, qm = 36.5 mg Cd2+/g of CaCEPPA).


Assuntos
Poluentes Ambientais , Poluentes Químicos da Água , /química , Cádmio/química , Poluentes Químicos da Água/química , Ácidos Fosfínicos , Sais , Dióxido de Carbono , Chumbo , Concentração de Íons de Hidrogênio , Adsorção , Íons , Cinética , Água , Polímeros
4.
Molecules ; 27(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35956755

RESUMO

The purpose of this study was to optimize the extraction conditions for separating Co2+ from Ni2+ using N-butylamine phosphinate ionic liquid of [C4H9NH3][Cyanex 272]. A Box-Behnken design of response surface methodology was used to analyze the effects of the initial pH, extraction time, and extraction temperature on the separation factor of Co2+ from sulfuric acid solution containing Ni2+. The concentrations of Co2+ and Ni2+ in an aqueous solution were determined using inductively coupled plasma-optical emission spectrometry. The optimized extraction conditions were as follows: an initial pH of 3.7, an extraction time of 55.8 min, and an extraction temperature of 330.4 K. The separation factor of Co2+ from Ni2+ under optimized extraction conditions was 66.1, which was very close to the predicted value of 67.2, and the error was 1.7%. The equation for single-stage extraction with high reliability can be used for optimizing the multi-stage extraction process of Co2+ from Ni2+. The stoichiometry of chemical reaction for ion-exchange extraction was also investigated using the slope method.


Assuntos
Líquidos Iônicos , Concentração de Íons de Hidrogênio , Líquidos Iônicos/química , Ácidos Fosfínicos/química , Reprodutibilidade dos Testes
6.
Eur Urol ; 82(5): 501-509, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35690515

RESUMO

BACKGROUND: Fluorine-18 (18F)-labelled prostate-specific membrane antigen (PSMA) offers several advantages over gallium-68 (68Ga) in terms of costs, yield, transport/distribution, and image resolution. OBJECTIVE: This trial investigates the new radiotracer 18F-PSMA-11 via a prospective, intraindividual crossover design. The trial was powered for noninferiority of 18F-PSMA-11 over 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) in terms of the number of positive PET scans. Secondary endpoints were as follows: (1) superiority of 18F-PSMA-11 over 68Ga-PSMA-11 with respect to the number of positive PET scans, the total number of suspicious prostate cancer lesions, and the miPSMA expression score of corresponding lesions; (2) correlation of the PET/CT images with available follow-up data for 18F-PSMA-11 and 68Ga-PSMA-11; and (3) assessment of the interobserver variability. DESIGN, SETTING, AND PARTICIPANTS: Prostate cancer patients (primary or biochemical recurrence) were randomised in a double-blind crossover design whereby each patient received both 18F-PSMA-11 and 68Ga-PSMA-11 PET/CT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All scans were reviewed and scored by three independent experienced nuclear physicians following the proposed guideline for the interpretation of PSMA-ligand PET/CT, as described by Eiber et al. RESULTS AND LIMITATIONS: In total, 82 patients were included for scan analyses. The primary endpoint was met: per patient, the proportions of positive scans rated by the three readers were 67%/67%, 65%/65%, and 73%/70% for 18F-PSMA-11/68Ga-PSMA-11 PET/CT. The miPSMA expression score was higher for 18F-PSMA-11 than for 68Ga-PSMA-11 for the reference reader. Follow-up data showed identical estimated sensitivity for both the 18F-PSMA-11 and the 68Ga-PSMA-11 scan (0.92, 0.83, and 0.92 for the three readers). A fair to good agreement among readers (at patient level) was obtained, which was demonstrated by a Light's kappa value of 0.59 for both tracers. CONCLUSIONS: The tracer 18F-PSMA-11 is noninferior to68Ga-PSMA-11. Superiority of 18F-PSMA-11 was limited to the miPSMA expression score, given by the reference reader. Inter-rater agreement was fair to good, and equal for both radiotracers. PATIENT SUMMARY: In this study, we compared two radiotracers: 18F-PSMA-11 and 68Ga-PSMA-11. We proved that 18F-PSMA-11 is not inferior to 68Ga-PSMA-11 for detecting prostate cancer and thus can be used as an alternative. Possible superiority of this tracer should be further investigated in specific subpopulations.


Assuntos
Radioisótopos de Gálio , Neoplasias da Próstata , Estudos Cross-Over , Radioisótopos de Flúor , Isótopos de Gálio , Glutaratos , Humanos , Ligantes , Masculino , Ácidos Fosfínicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia
7.
Chem Commun (Camb) ; 58(45): 6530-6533, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35579270

RESUMO

Tubulin polyglycylation is a posttranslational modification that occurs primarily on the axonemes of flagella and cilia and has been shown to be essential for proper sperm motility. Inhibitors of both the initiase and elongase ligases (TTLL8 and TTLL10) are shown to inhibit tubulin glycylation in the low micromolar range.


Assuntos
Ácidos Fosfínicos , Tubulina (Proteína) , Cílios/metabolismo , Humanos , Masculino , Microtúbulos/metabolismo , Processamento de Proteína Pós-Traducional , Motilidade Espermática , Tubulina (Proteína)/metabolismo
8.
Sci Rep ; 12(1): 6132, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35413967

RESUMO

Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for Cystic Fibrosis (CF). The most common CF-causing mutation is the deletion of the 508th amino-acid of CFTR (F508del), leading to dysregulation of the epithelial fluid transport in the airway's epithelium and the production of a thickened mucus favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure. c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftrtm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl-) conductance in F508del Cftrtm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue. Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Animais , Cloretos , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Transporte de Íons , Camundongos , Mutação , Ácidos Fosfínicos
9.
Int J Mol Sci ; 23(3)2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35163832

RESUMO

Recent studies have linked the activity of ER aminopeptidase 2 (ERAP2) to increased efficacy of immune-checkpoint inhibitor cancer immunotherapy, suggesting that pharmacological inhibition of ERAP2 could have important therapeutic implications. To explore the effects of ERAP2 inhibition on the immunopeptidome of cancer cells, we treated MOLT-4 T lymphoblast leukemia cells with a recently developed selective ERAP2 inhibitor, isolated Major Histocompatibility class I molecules (MHCI), and sequenced bound peptides by liquid chromatography tandem mass spectrometry. Inhibitor treatment induced significant shifts on the immunopeptidome so that more than 20% of detected peptides were either novel or significantly upregulated. Most of the inhibitor-induced peptides were 9mers and had sequence motifs and predicted affinity consistent with being optimal ligands for at least one of the MHCI alleles carried by MOLT-4 cells. Such inhibitor-induced peptides could serve as triggers for novel cytotoxic responses against cancer cells and synergize with the therapeutic effect of immune-checkpoint inhibitors.


Assuntos
Antígenos de Histocompatibilidade Classe I/química , Peptídeos/imunologia , Ácidos Fosfínicos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Aminopeptidases , Apresentação de Antígeno , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Humanos , Ácidos Fosfínicos/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Espectrometria de Massas em Tandem
10.
Molecules ; 27(4)2022 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-35209031

RESUMO

In this report, a synthetic protocol for the preparation of phosphinic dipeptides of type 5 is presented. These compounds serve as valuable building blocks for the development of highly potent phosphinopeptidic inhibitors of medicinally relevant Zn-metalloproteases and aspartyl proteases. The proposed method is based on the tandem esterification of α-aminophosphinic and acrylic acids under silylating conditions in order to subsequently participate in a P-Michael reaction. The scope of the transformation was investigated by using a diverse set of readily available acrylic acids and (R)-α-aminophosphinic acids, and high yields were achieved in all cases. In most examples reported herein, the isolation of biologically relevant (R,S)-diastereoisomers became possible by simple crystallization from the crude products, thus enhancing the operational simplicity of the proposed method. Finally, functional groups corresponding to acidic or basic natural amino acids are also compatible with the reaction conditions. Based on the above, we expect that the practicality of the proposed protocol will facilitate the discovery of pharmacologically useful bioactive phosphinic peptides.


Assuntos
Acrilatos/química , Dipeptídeos , Ácidos Fosfínicos/química , Dipeptídeos/síntese química , Dipeptídeos/química , Esterificação
11.
Clin Nucl Med ; 47(5): 441-443, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35020651

RESUMO

ABSTRACT: Primary mucinous tumors involving the prostate gland are rare. We describe MRI and 18F-PSMA-11 PET/MRI findings in a case of prostate adenocarcinoma with mucinous features. The prostate tumor showed inhomogeneous hyperintensity on T2-weighted images due to high extracellular mucin content and inhomogeneous 18F-PSMA-11 uptake with SUVmax of 12.5. This case indicates PSMA PET imaging may be helpful for detection of this uncommon variant of prostate adenocarcinoma.


Assuntos
Adenocarcinoma , Neoplasias da Próstata , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Radioisótopos de Gálio , Glutaratos , Humanos , Imageamento por Ressonância Magnética , Masculino , Ácidos Fosfínicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia
12.
Environ Technol ; 43(5): 737-750, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32727287

RESUMO

The objectives of this work were to develop polyacrylonitrile nanofibres modified with the commercial Cyanex 272 extractor and apply them for the recovery of gallium present in aqueous solution. The nanofibres were produced using the centrifugation technique, employing Forcespinning® equipment. The average nanofibre diameter ranged from 530 to 840 nm. The highest adsorption of gallium was achieved at pH 2.5, with a pseudo-second order kinetic model and the Freundlich equilibrium isotherm model providing the best fits of the experimental data. The thermodynamic parameters showed that the adsorption was spontaneous, favourable, and endothermic. The maximum capacity of the PAN/Cyanex 272 nanofibres for the recovery of gallium was 38.93 mg g-1. In successive reuse cycles, the nanofibres showed a small decrease of the adsorption capacity for the metal after the first cycle, while the efficiency remained constant in the subsequent cycles. The desorption efficiency remained constant throughout the cycles, with values in the range 80%-90%. The findings demonstrated that PAN/Cyanex 272 nanofibres have excellent potential for use as adsorbents, providing good capacity for the recovery of gallium and satisfactory stability during reuse in several cycles.


Assuntos
Gálio , Nanofibras , Poluentes Químicos da Água , Resinas Acrílicas , Adsorção , Cinética , Ácidos Fosfínicos , Termodinâmica , Poluentes Químicos da Água/análise
13.
Vet Med Sci ; 8(2): 781-791, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34904397

RESUMO

BACKGROUND: Management and control of metabolic disorders in sheep around parturition is important. and various researchers have suggested different managerial solutions. Butaphosphan and cyanocobalamin are widely used for curing metabolic disorders resulting from poor nutrition, inadequate management or diseases. OBJECTIVES: It was hypothesised that butaphosphan and cyanocobalamin could improve the metabolism of ewes around parturition. METHODS: Twenty-eight clinically healthy 3-year-old pregnant Afshari ewes from 21 days before parturition were enrolled into four equal groups: control (Ctrl), B+C1, B+C2 and B+C3. The Ctrl group only received intravenous normal saline and B+C1, B+C2 and B+C3 ewes, respectively, received an intravenous combination of 10% butaphosphan and 0.005% cyanocobalamin at 2, 4 and 6 ml/ewe, on Days 19-21, 10-12 and 1-3 before parturition. Blood samples were taken from all the ewes on Days 21, 12 and 3 before lambing at parturition day and on days 3, 12 and 21 after parturition. A body condition score of all the ewes was assessed at blood sampling days, and lambs born from the ewes were weighed at birth and every 2 weeks up to 3 months. Serum concentrations of glucose, cortisol, non-esterified fatty acids, beta-hydroxy butyric acid, triglyceride, cholesterol, high-, low- and very-low-density lipoproteins, aspartate aminotransferase and alanine aminotransferase were measured. RESULTS: This drug combination decreased circulating glucose, cortisol, lipid profile and hepatic enzymes via dose-dependent manner, 6 ml of this drug compound/ewe was more potent than 4 and 2 ml/ewe. The lambs' weight from mothers receiving 6 ml of this combination was significantly higher than those of the others. CONCLUSIONS: It may be suggested that the intravenous administration of 6 ml/ewe of this combination for 3 consecutive days in three states before parturition had prophylactic effects on metabolic disorders of ewes and enhanced the lambs weight gain after birth.


Assuntos
Hidrocortisona , Parto , Administração Intravenosa/veterinária , Animais , Butilaminas , Feminino , Glucose/farmacologia , Hidrocortisona/farmacologia , Ácidos Fosfínicos , Gravidez , Ovinos , Vitamina B 12/farmacologia , Aumento de Peso
14.
J Hazard Mater ; 424(Pt B): 127522, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34879517

RESUMO

As an emerging alternative legacy perfluoroalkyl substance, C6/C6 PFPiA (perfluoroalkyl phosphinic acids) has been detected in aquatic environments and causes potential risks to human health. The degradation mechanisms of C6/C6 PFPiA in a dielectric barrier discharge (DBD) plasma system were explored using validated experimental data and density functional theory (DFT) calculations. Approximately 94.5% of C6/C6 PFPiA was degraded by plasma treatment within 15 min at 18 kV. A relatively higher discharge voltage and alkaline conditions favored its degradation. C6/C6 PFPiA degradation was attributed to attacks of •OH, •O2-, and 1O2. Besides PFHxPA and C2 -C6 shorter-chain perfluorocarboxylic acids, several other major intermediates including C4/C6 PFPiA, C4/C4 PFPiA, and C3/C3 PFPiA were identified. According to DFT calculations, the potential energy surface was proposed for possible reactions during C6/C6 PFPiA degradation in the discharge plasma system. Integrating the identified intermediates and DFT results, C6/C6 PFPiA degradation was deduced to occur by stepwise losing CF2, free radical polymerization, and C-C bond cleavage. Furthermore, the DBD plasma treatment process decreased the toxicity of C6/C6 PFPiA to some extent. This study provides a comprehensive understanding of C6/C6 PFPiA degradation by plasma advanced oxidation.


Assuntos
Poluentes Químicos da Água , Humanos , Ácidos Fosfínicos
15.
Int J Mol Sci ; 22(22)2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34830051

RESUMO

Epileptic activity leads to rapid insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) into the synapses of cortical and hippocampal glutamatergic neurons, which generally do not express them. The physiological significance of this process is not yet fully understood; however, it is usually assumed to be a pathological process that augments epileptic activity. Using whole-cell patch-clamp recordings in rat entorhinal cortex slices, we demonstrate that the timing of epileptiform discharges, induced by 4-aminopyridine and gabazine, is determined by the shunting effect of Ca2+-dependent slow conductance, mediated predominantly by K+-channels. The blockade of CP-AMPARs by IEM-1460 eliminates this extra conductance and consequently increases the rate of discharge generation. The blockade of NMDARs reduced the additional conductance to a lesser extent than the blockade of CP-AMPARs, indicating that CP-AMPARs are a more significant source of intracellular Ca2+. The study's main findings were implemented in a mathematical model, which reproduces the shunting effect of activity-dependent conductance on the generation of discharges. The obtained results suggest that the expression of CP-AMPARs in principal neurons reduces the discharge generation rate and may be considered as a protective mechanism.


Assuntos
Córtex Entorrinal/metabolismo , Epilepsia/metabolismo , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Cálcio/metabolismo , Simulação por Computador , Maleato de Dizocilpina/farmacologia , Epilepsia/induzido quimicamente , Antagonistas de Receptores de GABA-B/farmacologia , Técnicas In Vitro , Masculino , Membranas/efeitos dos fármacos , Modelos Teóricos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ácidos Fosfínicos/farmacologia , Propanolaminas/farmacologia , Ratos Wistar , Receptores de AMPA/antagonistas & inibidores , Receptores de GABA-B/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
16.
Sci Rep ; 11(1): 22623, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799653

RESUMO

This two-part preclinical study aims to evaluate prostate specific membrane antigen (PSMA) as a valuable target for expression-based imaging applications and to determine changes in target binding in function of varying apparent molar activities (MAapp) of [18F]AlF-PSMA-11. For the evaluation of PSMA expression levels, male NOD/SCID mice bearing prostate cancer (PCa) xenografts of C4-2 (PSMA+++), 22Rv1 (PSMA+) and PC-3 (PSMA-) were administered [18F]AlF-PSMA-11 with a medium MAapp (20.24 ± 3.22 MBq/nmol). SUVmean and SUVmax values were respectively 3.22 and 3.17 times higher for the high versus low PSMA expressing tumors (p < 0.0001). To evaluate the effect of varying MAapp, C4-2 and 22Rv1 xenograft bearing mice underwent additional [18F]AlF-PSMA-11 imaging with a high (211.2 ± 38.9 MBq/nmol) and/or low MAapp (1.92 ± 0.27 MBq/nmol). SUV values showed a significantly increasing trend with higher MAapp. Significant changes were found for SUVmean and SUVmax between the high versus low MAapp and medium versus low MAapp (both p < 0.05), but not between the high versus medium MAapp (p = 0.055 and 0.25, respectively). The effect of varying MAapp was more pronounced in low expressing tumors and PSMA expressing tissues (e.g. salivary glands and kidneys). Overall, administration of a high MAapp increases the detection of low expression tumors while also increasing uptake in PSMA expressing tissues, possibly leading to false positive findings. In radioligand therapy, a medium MAapp could reduce radiation exposure to dose-limiting organs with only limited effect on radionuclide accumulation in the tumor.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glutamato Carboxipeptidase II/biossíntese , Glutaratos/farmacocinética , Glicoproteínas de Membrana/biossíntese , Ácidos Fosfínicos/farmacocinética , Neoplasias da Próstata/metabolismo , Complexo de Endopeptidases do Proteassoma/biossíntese , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/patologia , Ligação Proteica , Compostos Radiofarmacêuticos , Distribuição Tecidual
17.
Sci Rep ; 11(1): 20827, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675338

RESUMO

Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (Lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355's potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, αSMA and TNF-α mRNAs as well as secreted collagen1α1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development, which was comparable to activity of obeticholic acid in a robust mouse model of NASH, but awaits further testing to determine its relative efficacy in patients. These data identify a well-tolerated clinical stage asset as a novel candidate therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.


Assuntos
Reposicionamento de Medicamentos , Agonistas dos Receptores de GABA-B/uso terapêutico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácidos Fosfínicos/uso terapêutico , Propilaminas/uso terapêutico , Adulto , Idoso , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Agonistas dos Receptores de GABA-B/farmacologia , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ácidos Fosfínicos/farmacologia , Propilaminas/farmacologia
18.
FASEB J ; 35(9): e21846, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34405458

RESUMO

Myopia (short-sightedness), usually caused by excessive elongation of the eye during development, has reached epidemic proportions worldwide. In animal systems including the chicken model, several treatments have been shown to inhibit ocular elongation and experimental myopia. Although diverse in their apparent mechanism of action, each one leads to a reduction in the rate of ocular growth. We hypothesize that a defined set of retinal molecular changes may underlie growth inhibition, irrespective of the treatment agent used. Accordingly, across five well-established but diverse methods of inhibiting myopia, significant overlap is seen in the retinal transcriptome profile (transcript levels and alternative splicing events) in chicks when analyzed by RNA-seq. Within the two major pathway networks enriched during growth inhibition, that of cell signaling and circadian entrainment, transcription factors form the largest functional grouping. Importantly, a large percentage of those genes forming the defined retinal response are downstream targets of the transcription factor EGR1 which itself shows a universal response to all five growth-inhibitory treatments. This supports EGR1's previously implicated role in ocular growth regulation. Finally, by contrasting our data with human linkage and GWAS studies on refractive error, we confirm the applicability of our study to the human condition. Together, these findings suggest that a universal set of transcriptome changes, which sit within a well-defined retinal network that cannot be bypassed, is fundamental to growth regulation, thus paving a way for designing novel targets for myopia therapies.


Assuntos
Olho/crescimento & desenvolvimento , Olho/metabolismo , Redes Reguladoras de Genes , Miopia/genética , Miopia/prevenção & controle , Transcriptoma , Processamento Alternativo/efeitos dos fármacos , Animais , Atropina/farmacologia , Galinhas , Ritmo Circadiano/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Olho/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Janus Quinases/metabolismo , Masculino , Modelos Biológicos , Ácidos Fosfínicos/farmacologia , Pirenzepina/farmacologia , Piridinas/farmacologia , Reprodutibilidade dos Testes , Retina/efeitos dos fármacos , Retina/crescimento & desenvolvimento , Retina/metabolismo , Fatores de Transcrição STAT/metabolismo , Tetra-Hidronaftalenos/farmacologia , Fatores de Tempo , Transcriptoma/efeitos dos fármacos
19.
Artigo em Inglês | MEDLINE | ID: mdl-34379946

RESUMO

BACKGROUND: Melasma is the commonest cause of facial hypermelanosis in skin type IV-VI. First-line treatment includes a triple combination containing topical corticosteroid and hydroquinone which have side effects on prolonged use. Chemical peels are a second-line management option with the laser being used in refractory cases, but the worsening of hyperpigmentation in darker skin types can occur following laser therapy. Sunscreen is a must to prevent relapses. AIMS AND OBJECTIVES: (i) To compare the effects of treatment with a proprietary combination (phenyl ethyl resorcinol, nonapeptide-1, aminoethyl phosphinic acid, antioxidants and sunscreen) versus sunscreen alone in limiting or reducing, melasma and preventing recurrence as a maintenance regimen after the initial use of triple combination,(ii) to evaluate the safety of the formulation studied, and (iii) to study the improvement of the quality of life of the patients after using the study formulation versus placebo. METHODS: It was a prospective double-blinded parallel-group randomized controlled pilot study. A total of 46 subjects were recruited by consecutive sampling methods and randomized to 23 each in case and control groups. The study period was eight months with three phases. Phase 1 constituted the application of triple combination for eight weeks by both groups followed by phase 2 with the case group applying proprietary medicine and the control group applying sunscreen. Phase 3 was a follow-up period to see the sustenance of results in both groups as well as any evidence of relapses. Sunscreen was applied in all three phases. RESULTS: Case group in the study showed improvement in the melasma severity score and mean melanin index as measured by mexameter but it did not attain statistical significance as compared to the control group. The melasma area and severity index score showed a consistent reduction in the case group, whereas it increased in the control group from baseline. LIMITATIONS: Small sample size and a short follow-up period of our study were major limitations. CONCLUSION: The proprietary combination, which has sunscreen as one of its constituents, is more effective in maintaining remission after triple combination without any added inconvenience of application of two separate preparations as compared to sunscreen alone.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Melanose/tratamento farmacológico , Protetores Solares/administração & dosagem , Adulto , Antioxidantes/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Éteres Fenílicos/administração & dosagem , Ácidos Fosfínicos/administração & dosagem , Projetos Piloto , Estudos Prospectivos , Resorcinóis/administração & dosagem , Índice de Gravidade de Doença
20.
Neuropharmacology ; 196: 108705, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34246684

RESUMO

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not known how blockade of GABAB receptors in the region affects anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to hyperactivity of LHb neurons and decreased the level of extracellular dopamine (DA) in the basolateral amygdala (BLA) compared to sham-lesioned rats. Intra-LHb injection of pre-synaptic GABAB receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABAB receptor antagonist CGP35348 induced anxiety-like responses in both groups. Further, intra-LHb injection of CGP36216 decreased the firing rate of the neurons, and increased the GABA/glutamate ratio in the LHb and release of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 increased the firing rate of the neurons and decreased the GABA/glutamate ratio and release of DA and 5-HT in sham-lesioned and the lesioned rats. However, the doses of the antagonists producing these behavioral effects in the lesioned rats were lower than those in sham-lesioned rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in the lesioned rats. Collectively, these findings suggest that pre-synaptic and post-synaptic GABAB receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway up-regulates function and/or expression of these receptors.


Assuntos
Ansiedade/metabolismo , Complexo Nuclear Basolateral da Amígdala/metabolismo , Antagonistas de Receptores de GABA-B/farmacologia , Habenula/metabolismo , Transtornos Parkinsonianos/metabolismo , Receptores de GABA-B/metabolismo , Receptores Pré-Sinápticos/metabolismo , Animais , Ansiedade/fisiopatologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Habenula/efeitos dos fármacos , Habenula/fisiopatologia , Compostos Organofosforados/farmacologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/psicologia , Parte Compacta da Substância Negra , Ácidos Fosfínicos/farmacologia , Ratos , Receptores Pré-Sinápticos/antagonistas & inibidores , Serotonina/metabolismo , Regulação para Cima
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