RESUMO
Alzheimer's Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership-AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Pironas/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroproteção , Estudo de Prova de Conceito , Pironas/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Omega-3 polyunsaturated fatty acids (n3-PUFA) are well recognized for their potent triglyceride-lowering effects, but the potential influence of these bioactive lipids on other biological processes, particularly in the context of healthy aging, remains unknown. With the goal of gaining new insight into some less well-characterized biological effects of n3-PUFAs in healthy older adults, we performed metabolomics of fasting peripheral blood plasma collected from 12 young adults and 12 older adults before and after an open-label intervention of n3-PUFA (3.9 g/day, 2.7 g eicosapentaenoic [EPA], 1.2 g docosahexaenoic [DHA]). Proton nuclear magnetic resonance (1H-NMR) based lipoprotein subclass analysis revealed the expected reduction in total triglyceride (TG), but also demonstrated that n3-PUFA supplementation reduced very low-density lipoprotein (VLDL) particle number, modestly increased high-density lipoprotein (HDL) cholesterol, and shifted the composition of HDL subclasses. Further metabolite profiling by 1H-NMR and mass spectrometry revealed pronounced changes in phospholipids, cholesterol esters, diglycerides, and triglycerides following n3-PUFA supplementation. Furthermore, significant changes in hydroxyproline, kynurenine, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) following n3-PUFA supplementation provide further insight into some less well-recognized biological effects of n3-PUFA supplementation, including possible effects on protein metabolism, the kynurenine pathway, and glucose metabolism.
Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Metaboloma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Cinurenina/metabolismo , Lipídeos/sangue , Lipoproteínas/sangue , Masculino , Adulto JovemRESUMO
Protein folding can introduce strain in peptide covalent geometry, including deviations from planarity that are difficult to detect, especially for a protein in solution. We have found dependencies in protein backbone (2)J(NC') couplings on the planarity and the relative orientation of the sequential peptide planes. These dependences were observed in experimental (2)J(NC') couplings from seven proteins, and also were supported by DFT calculations for a model tripeptide. Findings indicate that elevated (2)J(NC') couplings may serve as reporters of structural strain in the protein backbone imposed by protein folds. Such information, supplemented with the H-bond strengths derived from (h3)J(NC') couplings, provides useful insight into the overall energy profile of the protein backbone in solution.
Assuntos
Dobramento de Proteína , Proteínas/química , Proteínas de Bactérias/química , Calmodulina/química , Isótopos de Carbono , Proteínas de Ligação a Ácido Graxo/química , Humanos , Ligação de Hidrogênio , Conformação Molecular , Isótopos de Nitrogênio , Oligopeptídeos/química , Parvalbuminas/química , Proteínas de Plantas/química , Conformação Proteica , Ubiquitina/químicaRESUMO
A new tetrahydrofuranoid lignan named seselinone was isolated from the aerial parts of Seseli annuum, together with three known lignans (eudesmin, magnone A and hernone) and prenylated coumarin umbelliprenin. Seselinone and eudesmin showed cytotoxic activity against C6 rat glioma cell cultures.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/toxicidade , Apiaceae/química , Glioma/patologia , Lignanas/toxicidade , Animais , Linhagem Celular Tumoral , Lignanas/química , Componentes Aéreos da Planta/química , RatosRESUMO
Examination of the aerial parts of Achillea clavennae afforded eight guaianolides (1-8), three bisabolenes (9-11), four flavonols (12-15), sesamin (lignan) and isofraxidin (coumarin). The structures of the new compounds (2, 4, 5, 7 and 10) were determined by spectroscopic methods. The antiproliferative action of 2, 8, 9 and 12 were tested to HeLa, K562 and Fem-X human cancer cell lines. Guaianolides 2 (9alpha-acetoxyartecanin) and 8 (apressin) showed significant cytotoxic effects to all tested lines and inducumenone (9) exhibited a moderate activity. The most active was flavonol centaureidin (12), already known as cytotoxic compound.
Assuntos
Achillea/química , Proliferação de Células/efeitos dos fármacos , Componentes Aéreos da Planta/química , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Células Cultivadas , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Flavonóis/química , Flavonóis/isolamento & purificação , Flavonóis/farmacologia , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/isolamento & purificação , Sesquiterpenos de Guaiano/farmacologia , IugosláviaRESUMO
Quantitative (1)H NMR measurements revealed delta(11(13)) sesquiterpene gamma-lactones as the main constituents ( >or= 1% per weight of dried plant material) in the crude extracts of the aerial parts of Amphoricarpos neumayeri ssp. neumayeri and ssp. murbeckii from mountains Orjen and Visitor (Montenegro), respectively. Preparative silica gel chromatography afforded thirteen guai-11(13)-en-12,6alpha-olides, named amphoricarpolides (1-13), with the same relative (1alphaH,4betaH,5alphaH,7betaH) configuration of the basic skeleton. The common structural feature of lactones 2-13 was 3beta,15-dioxygenation pattern. The only exception was 1 (3-deoxyamphoricarpolide), containing a single oxygen substituent (15-OH). Eight of them exhibited an additional oxygen substituent, 9beta-OH (5 and 6), 2alpha-OH (8-12), or 2alpha-OAc (13). Compound 7 was epoxydated at 10alpha(14)-position, whereas the remaining lactones contained a 10(14) double bond.
Assuntos
Antifúngicos/isolamento & purificação , Asteraceae/química , Plantas Medicinais/química , Sesquiterpenos de Guaiano/isolamento & purificação , Antifúngicos/química , Antifúngicos/farmacologia , Asteraceae/classificação , Cromatografia em Gel , Lactonas/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Oxigênio , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , IugosláviaRESUMO
As shown by quantitative (1)H NMR measurements, a lipophilic extract of the aerial parts of Hypericum atomarium ssp. degenii contained a high percentage (3.1% per weight of dried plant material) of a prenylated phloroglucinol (1). Compound 1, named hyperatomarin, occurring in two tautomeric forms (1a <==> 1b), was isolated by bioactivity-guided preparative TLC and was identified on the basis of spectral data interpretation. This isolated phloroglucinol exhibited activity against Gram-positive (Staphyloccocus aureus and Microccocus luteus) and Gram-positive spore-forming bacteria (Bacillus subtilis and B. IP 5832).