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1.
Angew Chem Int Ed Engl ; 63(6): e202314468, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-37955419

RESUMO

Molecularly generated light, referred to here as "molecular light", mainly includes bioluminescence, chemiluminescence, and Cerenkov luminescence. Molecular light possesses unique dual features of being both a molecule and a source of light. Its molecular nature enables it to be delivered as molecules to regions deep within the body, overcoming the limitations of natural sunlight and physically generated light sources like lasers and LEDs. Simultaneously, its light properties make it valuable for applications such as imaging, photodynamic therapy, photo-oxidative therapy, and photobiomodulation. In this review article, we provide an updated overview of the diverse applications of molecular light and discuss the strengths and weaknesses of molecular light across various domains. Lastly, we present forward-looking perspectives on the potential of molecular light in the realms of molecular imaging, photobiological mechanisms, therapeutic applications, and photobiomodulation. While some of these perspectives may be considered bold and contentious, our intent is to inspire further innovations in the field of molecular light applications.


Assuntos
Fotoquimioterapia , Fotoquimioterapia/métodos , Imagem Molecular
2.
Angew Chem Int Ed Engl ; 62(45): e202312519, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37721455

RESUMO

The development of Alzheimer's disease (AD) drugs has recently witnessed substantial achievement. To further enhance the pool of drug candidates, it is crucial to explore non-traditional therapeutic avenues. In this study, we present the use of a photolabile curcumin-diazirine analogue, CRANAD-147, to induce changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aß) species both in cells and in vivo. This manipulation was achieved through irradiation with LED light or molecularly generated light, dubbed as "molecular light", emitted by the chemiluminescence probe ADLumin-4. Next, aided by molecular chemiluminescence imaging, we demonstrated that the combination of CRANAD-147/LED or CRANAD-147/ADLumin-4 (molecular light) could effectively slow down the accumulation of Aßs in transgenic 5xFAD mice in vivo. Leveraging the remarkable tissue penetration capacity of molecular light, phototherapy employing the synergistic effect of a photolabile Aß ligand and molecular light emerges as a promising alternative to conventional AD treatment interventions.


Assuntos
Doença de Alzheimer , Curcumina , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Curcumina/farmacologia , Curcumina/uso terapêutico , Diazometano , Camundongos Transgênicos , Fototerapia , Modelos Animais de Doenças
3.
Phytomedicine ; 104: 154158, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35728383

RESUMO

BACKGROUND: Based on the complex pathology of AD, a single chemical approach may not be sufficient to deal simultaneously with multiple pathways of amyloid-tau neuroinflammation. A polydrug approach which contains multiple bioactive components targeting multiple pathways in AD would be more appropriate. Here we focused on a Chinese medicine (HLXL), which contains 56 bioactive natural products identified in 11 medicinal plants and displays potent anti-inflammatory and immuno-modulatory activity. HYPOTHESIS/PURPOSE: We investigated the neuroimmune and neuroinflammation mechanisms by which HLXL may attenuate AD neuropathology. Specifically, we investigated the effects of HLXL on the neuropathology of AD using both transgenic mouse models as well as microglial cell-based models. STUDY DESIGN: The 5XFAD transgenic animals and microglial cell models were respectively treated with HLXL and Aß42, and/or lipopolysaccharide (LPS), and then analyzed focusing on microglia mediated Aß uptake and clearance, as well as pathway changes. METHODS: We showed that HLXL significantly reduced amyloid neuropathology by upregulation of microglia-mediated phagocytosis of Aß both in vivo and in vitro. HLXL displayed multi-modal mechanisms regulating pathways of phagocytosis and energy metabolism. RESULTS: Our results may not only open a new avenue to support pharmacologic modulation of neuroinflammation and the neuroimmune system for AD intervention, but also identify HLXL as a promising natural medicine for AD. CONCLUSION: It is conceivable that the traditional wisdom of natural medicine in combination with modern science and technology would be the best strategy in developing effective therapeutics for AD.


Assuntos
Doença de Alzheimer , Amiloidose , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Microglia , Doenças Neuroinflamatórias , Fagocitose
4.
Anal Chim Acta ; 1097: 144-152, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-31910954

RESUMO

Disruption of copper homeostasis is associated with a number of severe diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Wilson's disease, and Menkes syndrome. Given this association, the detection and capture of Cu2+ in biological fluids and tissues may provide a new direction for the diagnosis and treatment of related disorders. The current analytical approaches, however, are challenging due to the high cost, complexity, and long time required to prepare and analyze samples. Here, we report a novel salen ligand, namely N,N'-(1,2-phenylene)bis(1-(1H-imidazol-4-yl)methanimine) (pimi), which can readily detect and concurrently capture Cu2+ from aqueous as well as biological mediums. Pimi can selectively and specifically detect Cu2+ from biofluid and cellular samples with rapid ccresponse time (<3 s) and an ultra-sensitive detecting limit (2.7 nM). More importantly, pimi showed excellent environmental tolerance and had a very wide pH range for detecting Cu2+ in a variety of biological samples. Attributed to the strong binding affinity and selectivity towards Cu2+, pimi was found to capture Cu2+ ions from Cu-Aß complexes, thus inhibiting copper-induced aggregation of Aß and protecting neuronal cells from the toxicity of aggregated Aß. These results provide a compelling starting point for further fine-tuning of salen-based chemosensor for the diagnosis and treatment of diseases associated with the hyperaccumulation of copper.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Cobre/análise , Cobre/toxicidade , Avaliação Pré-Clínica de Medicamentos , Etilenodiaminas/química , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Concentração de Íons de Hidrogênio , Íons/análise , Íons/farmacologia
5.
Mol Pharm ; 15(2): 695-702, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29298483

RESUMO

Dyshomeostasis or abnormal accumulation of metal ions such as copper, zinc, and iron have been linked to the pathogenesis of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Huntington's disease (HD). 5,7-Dichloro-2-((dimethylamino)methyl)quinolin-8-ol, PBT2, is a second generation metal protein-attenuating compound that has recently advanced in Phase II clinical trials for the treatment of AD and HD based on promising preclinical efficacy data. Herein, we report the first radiosynthesis and preclinical positron emission tomography (PET) neuroimaging evaluation of [11C]PBT2 in rodents and nonhuman primates. Carbon-11 labeled PBT2 was synthesized in 4.8 ± 0.5% (nondecay corrected) radiochemical yield (RCY) at end-of-synthesis, based upon [11C]CH3I (n = 6), with >99% radiochemical purity and 80-90 GBq/µmol molar activity (Am) from the corresponding normethyl precursor. In the nonhuman primate brain, [11C]PBT2 uptake was extensive with peak concentration SUVpeak of 3.2-5.2 within 2.5-4.5 min postinjection in all cortical and subcortical gray matter regions (putamen > caudate > cortex ≫ white matter) followed by rapid washout from normal brain tissues. Furthermore, it is shown that [11C]PBT2 binds specifically in AD human brain tissue in vitro. The results presented here, combined with the clinical data available for PBT2, warrant the evaluation of [11C]PBT2 as an exploratory PET radiotracer in humans.


Assuntos
Radioisótopos de Carbono , Clioquinol/análogos & derivados , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Doença de Alzheimer/patologia , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Clioquinol/administração & dosagem , Clioquinol/síntese química , Clioquinol/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Papio anubis , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética
6.
Proc Natl Acad Sci U S A ; 112(31): 9734-9, 2015 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-26199414

RESUMO

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aß) species of AD have been reported, none of these probes has been used to monitor changes of Aßs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aß species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aß-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aßs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aß cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aß plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Monitoramento de Medicamentos , Imagem Molecular/métodos , Espectroscopia de Luz Próxima ao Infravermelho , Animais , Benzotiazóis , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Modelos Animais de Doenças , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Camundongos Transgênicos , Fótons , Presenilina-1/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Fluorescência , Tiazóis/metabolismo , Extratos de Tecidos , Titulometria
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