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1.
Arch Pharm (Weinheim) ; 357(5): e2300693, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38332316

RESUMO

Aß1-42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aß1-42 and protect nerve cells, and it can also penetrate the blood-brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl3-induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Peptídeos beta-Amiloides , Inibidores da Colinesterase , Desenho de Fármacos , Peixe-Zebra , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Humanos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Donepezila/farmacologia , Donepezila/síntese química , Donepezila/química , Barreira Hematoencefálica/metabolismo , Estrutura Molecular , Flavanonas/farmacologia , Flavanonas/síntese química , Flavanonas/química , Relação Dose-Resposta a Droga , Comportamento Animal/efeitos dos fármacos
2.
Arch Pharm (Weinheim) ; 357(3): e2300524, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38036297

RESUMO

In the literature, daidzein has been reported to exhibit cardiovascular protective effects and hypoglycemic activity in mice. We sought to design and synthesize a novel compound, SJ-6, an analog of daidzein, with improved hypoglycemic properties. Although SJ-6 demonstrated favorable hypoglycemic effects, its pharmacokinetic limitations prompted us to design and synthesize prodrugs of SJ-6. We conducted a comprehensive evaluation of the prodrugs, including in vitro and in vivo studies, such as cytotoxicity, absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulation analysis, in vitro blood-brain barrier (BBB) permeability evaluation, compound effect on insulin resistance, oral glucose tolerance test (OGTT), in vivo plasma concentration testing, acute toxicity test in rats, and long-term gavage administration experiment. Furthermore, we examined the antidiabetic nephropathy activity of our lead compound, compound 10, which demonstrated superior efficacy compared with the positive control drug, metformin hydrochloride. Our findings suggest that compound 10 represents a promising lead compound for the prevention and treatment of diabetic nephropathy.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Pró-Fármacos , Animais , Camundongos , Ratos , Nefropatias Diabéticas/tratamento farmacológico , Relação Estrutura-Atividade , Hipoglicemiantes/farmacologia , Barreira Hematoencefálica
3.
J Enzyme Inhib Med Chem ; 38(1): 2199168, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37036026

RESUMO

Flavonoids are ubiquitous compounds in nature and are found in many Chinese herbal medicines. Due to their biological activity, flavonoids show potential for decreasing insulin resistance (IR), thereby delaying the progression of diabetes and accompanying metabolic syndromes. This review focuses on the mechanisms of flavonoids decreasing IR: (1) the interaction between flavonoids and target proteins of the insulin signalling pathway; (2) bioactivities of flavonoids, such as anti-inflammatory, lipid-lowering and antioxidant. Meanwhile, we summarise the structural characteristics, structure activity relationships and biological activity of flavonoids, providing evidence for their potential in the treatment of IR. Here, we also analyse the potential and limitations of their therapeutic use.


Assuntos
Diabetes Mellitus , Resistência à Insulina , Síndrome Metabólica , Humanos , Flavonoides/farmacologia , Flavonoides/química , Diabetes Mellitus/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Insulina
4.
Front Cell Dev Biol ; 10: 1079920, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36712965

RESUMO

Aging is the subject of many studies, facilitating the discovery of many interventions. Epigenetic influences numerous life processes by regulating gene expression and also plays a crucial role in aging regulation. Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging.

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