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1.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639096

RESUMO

Inorganic diatomite nanoparticles (DNPs) have gained increasing interest as drug delivery systems due to their porous structure, long half-life, thermal and chemical stability. Gold nanoparticles (AuNPs) provide DNPs with intriguing optical features that can be engineered and optimized for sensing and drug delivery applications. In this work, we combine DNPs with gelatin stabilized AuNPs for the development of an optical platform for Galunisertib delivery. To improve the DNP loading capacity, the hybrid platform is capped with gelatin shells of increasing thicknesses. Here, for the first time, full optical modeling of the hybrid system is proposed to monitor both the gelatin generation, degradation, and consequent Galunisertib release by simple spectroscopic measurements. Indeed, the shell thickness is optically estimated as a function of the polymer concentration by exploiting the localized surface plasmon resonance shifts of AuNPs. We simultaneously prove the enhancement of the drug loading capacity of DNPs and that the theoretical modeling represents an efficient predictive tool to design polymer-coated nanocarriers.


Assuntos
Terra de Diatomáceas/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Gelatina/química , Ouro/química , Nanopartículas Metálicas/química , Pirazóis/metabolismo , Quinolinas/metabolismo , Porosidade
2.
Arch Biochem Biophys ; 712: 109042, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34562470

RESUMO

RNAs have become a well-known target for chemotherapeutic agents in the recent years. The tails of most eukaryotic m-RNA are characterized by the presence of a long polyadenylate sequence which plays an important role in its growth and maturation. This lays emphasis on development of molecular probes that target the polyadenylate sequence. Cryptolepine (hereafter, CRP) is an indoloquinoline alkaloid well known for its anti-malarial activities. A series of spectroscopic experiments namely absorption studies, fluorimetric studies and circular dichroism studies show that cryptolepine binds with single-stranded polyriboadenylic acid (hereafter, ss-poly (rA)) with a binding constant of ∼5 × 103 M-1 at 25 °C. Moreover thermal denaturation experiments show that the bound form of polyriboadenylic acid shows a characteristic transition profile. Such a profile is indicative of the ability of cryptolepine to induce self-assembly in the polyriboadenylic acid sequence on binding to it. Such ability of CRP to modulate the structural conformation of poly (rA), which in turn may cause functional aspects of the RNA to change, may give us a chance to develop effective alkaloid based chemotherapeutic agents.


Assuntos
Alcaloides Indólicos/metabolismo , Poli A/metabolismo , Quinolinas/metabolismo , Polarização de Fluorescência , Alcaloides Indólicos/química , Conformação de Ácido Nucleico/efeitos dos fármacos , Transição de Fase , Poli A/química , Quinolinas/química , Espectrometria de Fluorescência , Termodinâmica , Temperatura de Transição
3.
J Med Chem ; 64(16): 12152-12162, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34355566

RESUMO

Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC50 = 3.7 µM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.


Assuntos
Leishmaniose Cutânea/tratamento farmacológico , Quinolinas/uso terapêutico , Tripanossomicidas/uso terapêutico , Animais , Feminino , Leishmania/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/metabolismo , Quinolinas/farmacocinética , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Tripanossomicidas/farmacocinética
4.
J Med Chem ; 64(16): 12200-12227, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34387088

RESUMO

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Imidazóis/uso terapêutico , Proteínas Nucleares/antagonistas & inibidores , Quinolinas/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Artrite/induzido quimicamente , Colágeno , Cristalografia por Raios X , Cães , Feminino , Imidazóis/síntese química , Imidazóis/metabolismo , Masculino , Camundongos , Estrutura Molecular , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Ligação Proteica , Domínios Proteicos , Quinolinas/síntese química , Quinolinas/metabolismo , Ratos Endogâmicos Lew , Ratos Wistar , Relação Estrutura-Atividade , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
5.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208368

RESUMO

Plant specialized metabolites are widely used in the pharmaceutical industry, including the monoterpene indole alkaloids (MIAs) vinblastine and vincristine, which both display anticancer activity. Both compounds can be obtained through the chemical condensation of their precursors vindoline and catharanthine extracted from leaves of the Madagascar periwinkle. However, the extensive use of these molecules in chemotherapy increases precursor demand and results in recurrent shortages, explaining why the development of alternative production approaches, such microbial cell factories, is mandatory. In this context, the precursor-directed biosynthesis of vindoline from tabersonine in yeast-expressing heterologous biosynthetic genes is of particular interest but has not reached high production scales to date. To circumvent production bottlenecks, the metabolic flux was channeled towards the MIA of interest by modulating the copy number of the first two genes of the vindoline biosynthetic pathway, namely tabersonine 16-hydroxylase and tabersonine-16-O-methyltransferase. Increasing gene copies resulted in an optimized methoxylation of tabersonine and overcame the competition for tabersonine access with the third enzyme of the pathway, tabersonine 3-oxygenase, which exhibits a high substrate promiscuity. Through this approach, we successfully created a yeast strain that produces the fourth biosynthetic intermediate of vindoline without accumulation of other intermediates or undesired side-products. This optimization will probably pave the way towards the future development of yeast cell factories to produce vindoline at an industrial scale.


Assuntos
Alcaloides Indólicos/metabolismo , Oxigenases de Função Mista/metabolismo , Oxigenases/metabolismo , Quinolinas/metabolismo , Saccharomyces cerevisiae/metabolismo , Vimblastina/análogos & derivados , Vias Biossintéticas , Vimblastina/biossíntese , Vimblastina/química
6.
Biochem J ; 478(14): 2811-2823, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34190988

RESUMO

The human protein kinase ULK3 regulates the timing of membrane abscission, thus being involved in exosome budding and cytokinesis. Herein, we present the first high-resolution structures of the ULK3 kinase domain. Its unique features are explored against the background of other ULK kinases. An inhibitor fingerprint indicates that ULK3 is highly druggable and capable of adopting a wide range of conformations. In accordance with this, we describe a conformational switch between the active and an inactive ULK3 conformation, controlled by the properties of the attached small-molecule binder. Finally, we discuss a potential substrate-recognition mechanism of the full-length ULK3 protein.


Assuntos
Domínio Catalítico , Conformação Proteica , Domínios Proteicos , /química , Compostos de Anilina/metabolismo , Compostos de Anilina/farmacologia , Benzamidas/metabolismo , Benzamidas/farmacologia , Biocatálise/efeitos dos fármacos , Humanos , Modelos Moleculares , Nitrilas/metabolismo , Nitrilas/farmacologia , Proteínas Oncogênicas/química , Proteínas Oncogênicas/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , /metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Quinolinas/metabolismo , Quinolinas/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
7.
Mol Immunol ; 136: 45-54, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34082258

RESUMO

Toll-like receptor 8 (TLR8), as an important innate immune receptor, can recognize specific ligands, activate intracellular signaling and produce an inflammatory response to kill and eliminate pathogenic microorganisms. Recent studies have resolved the crystal structure of human TLR8 (hTLR8) and two types of ligand binding sites were identified. Among the conserved binding site 1 of hTLR8, the residues interacting with imidazoquinoline derivatives (IQDs) were determined. We previously showed that porcine TLR8 (pTLR8) exhibited species specificity for recognition of the hTLR7 agonist imiquimod (R837). Given the species specificity, the pTLR8 residues interacting with IQDs may be different from hTLR8 counterparts. The present study was aimed to identify the pTLR8 residues interacting with small molecular IQDs. Via molecular docking, the pTLR8 residues interacting with R837 and R848 were predicted. The corresponding mutants were tested for pTLR8 signaling in response to IQDs R837, R848 and CL075, and the results showed that five of nine predicted residues (Y336, K341, K342, F395 and G562) are critical for pTLR8 signaling and these residues are partially different from those reported in hTLR8. Further, we found that the pTLR8 GQKNG motif corresponding to hTLR8 RQSYA exhibited disparity to CL075 stimulation. Our study thus reveals fine TLR8 species specificity which deepens the understanding of TLR8 activation mechanism.


Assuntos
Imidazóis/metabolismo , Quinolinas/metabolismo , Receptor 8 Toll-Like/metabolismo , Sequência de Aminoácidos/genética , Animais , Sítios de Ligação/fisiologia , Linhagem Celular , Células HEK293 , Humanos , Imiquimode/farmacologia , Imunidade Inata/imunologia , Conformação Molecular , Simulação de Acoplamento Molecular , Domínios Proteicos/imunologia , Transdução de Sinais/genética , Especificidade da Espécie , Suínos , Receptor 8 Toll-Like/genética
8.
Molecules ; 26(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070798

RESUMO

A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).


Assuntos
Alcaloides Indólicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Anti-Infecciosos/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Alcaloides Indólicos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/metabolismo , Relação Estrutura-Atividade
9.
Food Chem Toxicol ; 153: 112256, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33974948

RESUMO

The aim of this study was to investigate the mechanism of action of cyanidin-3-O-glucoside (C3G) and its metabolite protocatechuic acid (PCA) mediated protection against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced cytotoxicity in HepG2 cells. The effects of C3G and PCA on cell viability, LDH release and apoptosis in IQ-induced HepG2 cells were evaluated using CCK-8, LDH release and flow cytometry assays, respectively. TMT-based proteomics was utilized to characterize the proteins and pathways associated with the improvement after C3G and PCA treatment. Results showed that exposure to IQ significantly increased cytotoxicity and apoptosis in HepG2 cells, which were alleviated by C3G and PCA. C3G was more effective than PCA in protecting HepG2 cells against IQ-induced cytotoxicity and regulating the related signaling pathways. Proteomics and bioinformatics analyses and Western blot validation revealed that apoptosis-related signaling pathways played pivotal roles in protecting against the cytotoxicity of IQ by C3G, and XIAP was identified as the target protein. Molecular docking proved that C3G had strong binding affinity to XIAP and hindered the binding of IQ to the BIR3 domain of XIAP, resulting in the inhibition of apoptosis. Our findings suggested that C3G has potential as a preventive food ingredient to prevent carcinogenic risk of heterocyclic aromatic amines.


Assuntos
Antocianinas/farmacologia , Apoptose/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Substâncias Protetoras/farmacologia , Quinolinas/toxicidade , Antocianinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteoma/metabolismo , Proteômica , Quinolinas/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
10.
J Med Chem ; 64(10): 6856-6876, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33973470

RESUMO

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aß deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aß1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/química , Peptídeos beta-Amiloides/farmacologia , Animais , Sítios de Ligação , Butirilcolinesterase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Grelina/metabolismo , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
11.
J Ind Microbiol Biotechnol ; 48(3-4)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33982054

RESUMO

The ammosamides (AMMs) are a family of pyrroloquinoline alkaloids that exhibits a wide variety of bioactivities. A biosynthetic gene cluster (BGC) that is highly homologous in both gene content and genetic organization to the amm BGC was identified by mining the Streptomyces uncialis DCA2648 genome, leading to the discovery of a sub-family of new AMM congeners, named ammosesters (AMEs). The AMEs feature a C-4a methyl ester, differing from the C-4a amide functional group characteristic to AMMs, and exhibit modest cytotoxicity against a broad spectrum of human cancer cell lines, expanding the structure-activity relationship for the pyrroloquinoline family of natural products. Comparative analysis of the ame and amm BGCs supports the use of a scaffold peptide as an emerging paradigm for the biosynthesis of the pyrroloquinoline family of natural products. AME and AMM biosynthesis diverges from a common intermediate by evolving the pathway-specific Ame24 O-methyltransferase and Amm20 amide synthetase, respectively. These findings will surely inspire future efforts to mimic Nature's combinatorial biosynthetic strategies for natural product structural diversity.


Assuntos
Genoma Bacteriano , Pirróis/metabolismo , Quinolinas/metabolismo , Streptomyces/metabolismo , Amidas/química , Amidas/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Humanos , Família Multigênica , Pirróis/química , Quinolinas/química , Streptomyces/química , Streptomyces/genética
12.
Chem Commun (Camb) ; 57(48): 5941-5944, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34018521

RESUMO

This work describes a single-stranded degradable modular grafting probe for analyzing microRNA-21. In the system, the exonuclease activity of phi29 polymerase restrains the SYBR Green I/ssDNA induced background. The palindrome activation caused remarkable target fluorescence. The detection limit was achieved as 0.26 fM, showing potential in biochemical analysis.


Assuntos
Benzotiazóis/química , DNA de Cadeia Simples/química , Diaminas/química , Exodesoxirribonucleases/química , MicroRNAs/análise , Quinolinas/química , Benzotiazóis/metabolismo , DNA de Cadeia Simples/metabolismo , Diaminas/metabolismo , Exodesoxirribonucleases/metabolismo , Fluorescência , Humanos , MicroRNAs/metabolismo , Técnicas de Amplificação de Ácido Nucleico , Quinolinas/metabolismo
13.
J Med Chem ; 64(8): 4810-4840, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33830764

RESUMO

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.


Assuntos
Doença de Charcot-Marie-Tooth/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Quinolinas/química , Acetilação , Animais , Benzamidas/química , Benzamidas/metabolismo , Sítios de Ligação , Doença de Charcot-Marie-Tooth/metabolismo , Doença de Charcot-Marie-Tooth/patologia , Cristalografia por Raios X , Modelos Animais de Doenças , Meia-Vida , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fenótipo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Quinolinas/metabolismo , Quinolinas/uso terapêutico , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo
14.
Clin Nucl Med ; 46(8): 694-696, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826568

RESUMO

ABSTRACT: A 59-year-old woman with newly diagnosed pulmonary nodules underwent both 18F-FDG and 68Ga-FAPI PET/CT. Both studies showed similarly increased uptake in pneumonia. However, only 68Ga-FAPI PET/CT showed increased uptake in splenic hemangioma, whereas FDG uptake in the splenic lesion is low. Our case illustrates that splenic hemangioma can also reveal increased FAPI activity.


Assuntos
Hemangioma/metabolismo , Pneumonia/metabolismo , Quinolinas/metabolismo , Neoplasias Esplênicas/metabolismo , Feminino , Fluordesoxiglucose F18/metabolismo , Hemangioma/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Pneumonia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Esplênicas/diagnóstico por imagem
15.
Clin Nucl Med ; 46(8): 683-685, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826569

RESUMO

ABSTRACT: 68Ga-fibroblast activation protein-specific inhibitor (FAPI)-04 PET/CT was performed in a 49-year-old woman diagnosed with breast cancer. In PET/CT imaging, intense 68Ga-FAPI uptake was observed in the primary tumor, axillary lymph nodes, and also in the thyroid gland, whereas pathological 18F-FDG uptake was not observed in the thyroid gland. On thyroid ultrasonography, parenchyma was heterogeneous, and an area of focal thyroiditis was observed in the superior part of the right lobe. Biochemical parameters were found to be consistent with thyroiditis. This case shows that FAPI uptake in the thyroid gland may be associated with thyroiditis and should be evaluated clinically.


Assuntos
Neoplasias da Mama/complicações , Quinolinas/metabolismo , Tireoidite/complicações , Tireoidite/metabolismo , Transporte Biológico , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tireoidite/diagnóstico por imagem
16.
Clin Nucl Med ; 46(8): 700-702, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826575

RESUMO

ABSTRACT: A 78-year-old man with a newly diagnosed gastric adenocarcinoma underwent 18F-FDG and 68Ga-FAPI-04 PET/CT before treatment. Both 18F-FDG and 68Ga-FAPI-04 PET/CT demonstrated intense radioactivity in the gastric cancer. However, the benign Schmorl node in the inferior endplate of the T5 vertebrae showed increased uptake of 68Ga-FAPI-04, which was not FDG avid. Two months after radical gastrectomy of the gastric cancer (pT1aN0M0, IA), a follow-up CT showed that the Schmorl node in T5 vertebrae remained unchanged.


Assuntos
Núcleo Pulposo/metabolismo , Quinolinas/metabolismo , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/metabolismo , Idoso , Transporte Biológico , Fluordesoxiglucose F18/metabolismo , Gastrectomia , Humanos , Masculino , Núcleo Pulposo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Gástricas/cirurgia
17.
Clin Nucl Med ; 46(6): 520-522, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33661208

RESUMO

ABSTRACT: A left pulmonary nodule was identified by CT scan in a 53-year-old woman who had a car accident 10 days earlier. 18F-FDG PET/CT showed multiple FDG-avid lesions located at the left lung nodule, mediastinal lymph nodules, and L4 vertebral body. 68Ga-FAPI PET/CT was performed for further evaluation. However, 68Ga-FAPI demonstrated intense FAPI uptake in the accident-related fracture of the L4 vertebral body. This case documents that the fracture of the vertebral body may cause FAPI uptake, and nuclear clinicians evaluating 68Ga-FAPI imaging should be aware of this potential pitfall.


Assuntos
Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/metabolismo , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Quinolinas/metabolismo , Corpo Vertebral/lesões , Artefatos , Transporte Biológico , Feminino , Fraturas Ósseas/complicações , Humanos , Pessoa de Meia-Idade
18.
Clin Nucl Med ; 46(8): e433-e435, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33782295

RESUMO

ABSTRACT: 68Ga-fibroblast activation protein-specific inhibitor (FAPI)-04 PET/CT was performed in a patient with left lower outer quadrant breast cancer who had 18F-FDG PET/CT imaging. 68Ga-FAPI-04 PET/CT showed higher accumulation of radiotracer in primary tumor and axillary lymph nodes than 18F-FDG PET/CT. In addition, focal increased FAPI uptake was observed in another nodular lesion in the lower inner quadrant in the same breast, which was considered malignant. However, Tru-Cut biopsy of this lesion was reported as benign lymphoid tissue. This case showed that all FAPI accumulation in breast tissue should not be interpreted in favor of malignancy; histopathological confirmation is required.


Assuntos
Neoplasias da Mama/metabolismo , Linfócitos/metabolismo , Quinolinas/metabolismo , Transporte Biológico , Neoplasias da Mama/diagnóstico por imagem , Reações Falso-Positivas , Feminino , Humanos , Linfócitos/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
19.
Clin Nucl Med ; 46(7): 601-602, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33782317

RESUMO

ABSTRACT: 68Ga-FAPI PET/CT has been used in the evaluation of a variety of malignancies. An increasing number of case studies on FAPI uptake in nonmalignant diseases is also gaining support and enthusiasm. We present a case of asymptomatic chronic cholecystitis and degenerative osteophyte detected incidentally by 68Ga-FAPI PET/CT.


Assuntos
Colecistite/metabolismo , Osteófito/metabolismo , Osteófito/patologia , Quinolinas/metabolismo , Transporte Biológico , Colecistite/diagnóstico por imagem , Doença Crônica , Humanos , Osteófito/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
20.
J Biol Chem ; 296: 100363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539919

RESUMO

During the integration step, human immunodeficiency virus type 1 integrase (IN) interacts with viral DNA and the cellular cofactor LEDGF/p75 to effectively integrate the reverse transcript into the host chromatin. Allosteric human immunodeficiency virus type 1 integrase inhibitors (ALLINIs) are a new class of antiviral agents that bind at the dimer interface of the IN catalytic core domain and occupy the binding site of LEDGF/p75. While originally designed to block IN-LEDGF/p75 interactions during viral integration, several of these compounds have been shown to also severely impact viral maturation through an IN multimerization mechanism. In this study, we tested the hypothesis that these dual properties of ALLINIs could be decoupled toward late stage viral replication effects by generating additional contact points between the bound ALLINI and a third subunit of IN. By sequential derivatization at position 7 of a quinoline-based ALLINI scaffold, we show that IN multimerization properties are enhanced by optimizing hydrophobic interactions between the compound and the C-terminal domain of the third IN subunit. These features not only improve the overall antiviral potencies of these compounds but also significantly shift the ALLINIs selectivity toward the viral maturation stage. Thus, we demonstrate that to fully maximize the potency of ALLINIs, the interactions between the inhibitor and all three IN subunits need to be simultaneously optimized.


Assuntos
Integrase de HIV/metabolismo , HIV-1/metabolismo , Quinolinas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Antivirais/farmacologia , Células HEK293 , Integrase de HIV/fisiologia , Inibidores de Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Quinolinas/química , Quinolinas/metabolismo , Integração Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
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