RESUMEN
Data from preclinical studies propose nicotinamide adenine dinucleotide (NAD+) as a neuroprotective and bioenergetics stimulant agent to treat Alzheimer's disease (AD); however, there seems to be inconsistency between behavioral and molecular outcomes. We performed this systematic review to provide a better understanding of the effects of NAD+ in rodent AD models and to summarize the literature.Studies were identified by searching PubMed, EMBASE, Scopus, Google Scholar, and the reference lists of relevant review articles published through December 2020. The search strategy was restricted to articles about NAD+, its derivatives, and their association with cognitive function in AD rodent models. The initial search yielded 320 articles, of which 11 publications were included in our systematic review.Based on the primary outcomes, it was revealed that NAD+ improves learning and memory. The secondary endpoints also showed neuroprotective effects of NAD+ on different AD models. The proposed neuroprotective mechanisms included, but were not limited to, the attenuation of the oxidative stress, inflammation, and apoptosis, while enhancing the mitochondrial function.The current systematic review summarizes the preclinical studies on NAD+ precursors and provides evidence favoring the pro-cognitive effects of such components in rodent models of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , NAD/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Metabolismo Energético , Ratones , Ratones Transgénicos , Mitocondrias/fisiología , NAD/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Niacina/farmacología , Niacinamida/farmacología , Niacinamida/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Agregación Patológica de Proteínas/prevención & control , Ratas , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Proteínas tau/metabolismoRESUMEN
Endoplasmic reticulum (ER) stress is a common threat to photoreceptors during the pathogenesis of chronic retinopathies and often results in irreversible visual impairment. 2,3,5,6-Tetramethylpyrazine (TMP), which possesses many beneficial pharmacological activities, is a potential drug that could be used to protect photoreceptors. In the present study, we found that the cellular growth rate of 661 W cells cultured under low glucose conditions was lower than that of control cells, while the G2/M phase of the cell cycle was longer. We further found that the mitochondrial membrane potential (ΔΨm) was lower and that ER stress factor expression was increased in 661 W cells cultured under low glucose conditions. TMP reversed these trends. Visual function and cell counts in the outer nuclear layer (ONL) were low and the TUNEL-positive rate in the ONL was high in a C3H mouse model of spontaneous retinal degeneration. Similarly, visual function was decreased, and the TUNEL-positive rate in the ONL was increased in fasted C57/BL6j mice compared with control mice. On the other hand, ER stress factor expression was found to be increased in the retinas of both mouse models, as shown by reverse transcription real-time PCR (RT-qPCR) and western blotting. TMP reversed the physiological and molecular biological variations observed in both mouse models, and ATF4 expression was enhanced again. Further investigation by using western blotting illustrated that the proportion of insoluble prion protein (PRP) versus soluble PRP was reduced both in vitro and in vivo. Taken together, these results suggest that TMP increased the functions of photoreceptors by alleviating ER stress in vitro and in vivo, and the intrinsic mechanism was the ATF4-mediated inhibition of PRP aggregation. TMP may potentially be used clinically as a therapeutic agent to attenuate the functional loss of photoreceptors during the pathogenesis of chronic retinopathies. KEY MESSAGES: ⢠Already known: TMP is a beneficial drug mainly used in clinic to enhance organ functions, and the intrinsic mechanism is still worthy of exploring. ⢠New in the study: We discovered that TMP ameliorated retinal photoreceptors function via ER stress alleviation, which was promoted by ATF4-mediated inhibition of PRP aggregation. ⢠Application prospect: In prospective clinical practices, TMP may potentially be used in the clinic as a therapeutic agent to attenuate the photoreceptors functional reduction in chronic retinopathies.
Asunto(s)
Factor de Transcripción Activador 4/fisiología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas Priónicas/efectos de los fármacos , Agregado de Proteínas/efectos de los fármacos , Agregación Patológica de Proteínas/prevención & control , Pirazinas/farmacología , Células Fotorreceptoras Retinianas Conos/efectos de los fármacos , Degeneración Retiniana/prevención & control , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Electrorretinografía , Proteínas del Ojo/biosíntesis , Proteínas del Ojo/genética , Ayuno , Femenino , Glucosa/farmacología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Proteínas Priónicas/química , Agregación Patológica de Proteínas/metabolismo , Retina/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Degeneración Retiniana/fisiopatología , Método Simple Ciego , Solubilidad , Organismos Libres de Patógenos Específicos , Transcripción Genética/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia chebula Retz. (T.chebula) is an important medicinal plant in Tibetan medicine and Ayurveda. T.chebula is known as the "King of Tibetan Medicine", due to its widespread clinical pharmacological activity such as anti-inflammatory, antioxidative, antidiabetic as well as anticancer in lots of in vivo and in vitro models. In this study, we use transgenic and/or RNAi Caenorhabditis elegans (C.elegans) model to simulation the AD pathological features induced by Aß, to detect the effect of TWE on improving Aß-induced toxicity and the corresponding molecular mechanism. AIM OF STUDY: The study aimed to tested the activities and its possible mechanism of T.chebula to against Aß1-42 induced toxicity and Aß1-42 aggregation. MATERIALS AND METHODS: Using transgenic C.elegans strain CL2006 and CL4176 as models respond to paralytic induced by Aß toxicity. The transcription factors DAF-16 and SKN-1 were analyzed used a fluorescence microscope in transgenic strains (DAF-16:GFP, SKN-1:GFP). The function of DAF-16 and SKN-1 was further investigated using loss-of-function strains by feeding RNA interference (RNAi) bacteria. To evaluate the aggregation level of Aß in the transgenic C.elegans, Thioflavin S (ThS) staining and WB visualized the levels of Aß monomers and oligomers. RESULTS: TWE treatment can significantly improve the paralysis of transgenic C.elegans caused by Aß aggregation (up to 14%). The Aß aggregates in transgenic C.elegans are significantly inhibited under TWE exposure (up to 70%). TWE increases the nuclear localization of the key transcription factor DAF-16 and HSF-1, which in turn leads to the expression of downstream Hsp-16.2 protein and exerts its inhibitory effect on Aß aggregation. Meanwhile, paralysis improved has not observed in SKN-1 mutation and/or RNAi C.elegans. CONCLUSION: Our results indicate that TWE can protect C.elegans against the Aß1-42-induced toxicity, inhibition Aß1-42 aggregation and delaying Aß-induced paralysis. The neuroprotective effect of TWE involves the activation of DAF-16/HSF-1/Hsp-16.2 pathway.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Fragmentos de Péptidos/toxicidad , Extractos Vegetales/uso terapéutico , Agregación Patológica de Proteínas/inducido químicamente , Agregación Patológica de Proteínas/prevención & control , Terminalia , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans , Relación Dosis-Respuesta a Droga , Humanos , Fragmentos de Péptidos/antagonistas & inhibidores , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Agregación Patológica de Proteínas/patologíaRESUMEN
Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Fármacos Neuroprotectores/química , Proteínas tau/metabolismo , Animales , Benzodioxoles/farmacología , Inhibidores de la Colinesterasa/farmacología , Colinesterasas/metabolismo , Curcumina/farmacología , Humanos , Terapia Molecular Dirigida , Ovillos Neurofibrilares/metabolismo , Fármacos Neuroprotectores/farmacología , Fosforilación , Placa Amiloide/metabolismo , Agregación Patológica de Proteínas/prevención & control , Procesamiento Proteico-Postraduccional , Quinazolinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tiadiazoles/farmacologíaRESUMEN
It has been thought that caloric restriction favors longevity and healthy aging where autophagy plays a vital role. However, autophagy decreases during aging and that can lead to the development of aging-associated diseases such as cancer, diabetes, neurodegeneration, etc. It was shown that autophagy can be induced by mechanical or chemical stress. In this regard, various pharmacological compounds were proposed, including natural polyphenols. Apart from the ability to induce autophagy, polyphenols, such as resveratrol, are capable of modulating the expression of pro- and anti-apoptotic factors, neutralizing free radical species, affecting mitochondrial functions, chelating redox-active transition metal ions, and preventing protein aggregation. Moreover, polyphenols have advantages compared to chemical inducers of autophagy due to their intrinsic natural bio-compatibility and safety. In this context, polyphenols can be considered as a potential therapeutic tool for healthy aging either as a part of a diet or as separate compounds (supplements). This review discusses the epigenetic aspect and the underlying molecular mechanism of polyphenols as an anti-aging remedy. In addition, the recent advances of studies on NAD-dependent deacetylase sirtuin-1 (SIRT1) regulation of autophagy, the role of senescence-associated secretory phenotype (SASP) in cells senescence and their regulation by polyphenols have been highlighted as well. Apart from that, the review also revised the latest information on how polyphenols can help to improve mitochondrial function and modulate apoptosis (programmed cell death).
Asunto(s)
Envejecimiento/efectos de los fármacos , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Autofagia/fisiología , Restricción Calórica , Suplementos Dietéticos , Envejecimiento Saludable/fisiología , Polifenoles/farmacología , Envejecimiento/fisiología , Animales , Senescencia Celular/efectos de los fármacos , Diabetes Mellitus/etiología , Humanos , Longevidad , Mitocondrias/metabolismo , Neoplasias/etiología , Enfermedades Neurodegenerativas/etiología , Agregación Patológica de Proteínas/prevención & control , Resveratrol/farmacología , Sirtuina 1/metabolismoRESUMEN
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease of the elderly. Current therapies are only symptomatic, and have no disease-modifying effect. Therefore, disease progresses continuously over time, presenting with both motor and non-motor features. The precise molecular basis for PD is still elusive, but the aggregation of the protein alpha-synuclein (α-syn) is a key pathological hallmark of the disease and is, therefore, a major focus of current research. Considering the intrinsic properties of cell-penetrating peptides (CPPs) for mediating drug delivery of neurotherapeutics across the blood brain barrier (BBB), these might open novel opportunities for the development of new solutions for the treatment of brain-related aspects of PD and other neurodegenerative disorders. METHODS: Here, we synthesized solid-phase CPPs using an amphipathic model peptide (MAP) conjugated with the drug Rasagiline (RAS), which we named RAS-MAP, and evaluated its effect on α-syn inclusion formation in a human cell-based model of synucleinopathy. RESULTS: We found that treatment with RAS-MAP at low concentrations (1-3 µM) reduced α-syn aggregation in cells. CONCLUSIONS: For the first time, we report that conjugation of a current drug used in the therapy of PD with CPP reduces α-syn aggregation, which might prove beneficial in PD and other synucleinopathies.
Asunto(s)
Péptidos de Penetración Celular/química , Portadores de Fármacos/química , Indanos/farmacología , Fármacos Neuroprotectores/farmacología , Agregación Patológica de Proteínas/prevención & control , alfa-Sinucleína/metabolismo , Barrera Hematoencefálica/metabolismo , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Indanos/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Técnicas de Síntesis en Fase SólidaRESUMEN
The inherited polyglutamine (polyQ) expansion diseases are characterized by progressive accumulation of aggregation-prone polyQ proteins, which may provoke proteostasis imbalance and result in significant neurotoxicity. Using polyQ transgenic Caenorhabditis elegans models, we find that Kai-Xin-San (KXS), a well-known herbal formula traditionally used to treat mental disorders in China, can alleviate polyQ-mediated neuronal death and associated chemosensory deficiency. Intriguingly, KXS does not reduce polyQ aggregation in vitro as demonstrated by Thioflavin-T test, but does inhibit polyQ aggregation in C. elegans models, indicating an indirect aggregation-inhibitory mechanism. Further investigation reveals that KXS can modulate two key arms of the protein quality control system, that is, heat shock response and autophagy, to clear polyQ aggregates, but has little effect on proteasome activity. In addition, KXS is able to reduce oxidative stress, which is involved in proteostasis and neurodegeneration, but has no effect on life span or dietary restriction response. To examine potential interaction of the four component herbs of KXS, a dissection strategy was used to study the effects of differential herbal combinations in C. elegans polyQ models. While the four herbs do contribute additively to KXS function, Panax ginseng is found to be the most effective constituent. Taken together, these findings not only demonstrate the neuroprotective ability of KXS but also suggest its potential as a proteostasis regulator in protein aggregation disorders and provide an insight into the mechanism studies of traditionally used complex prescriptions and their rationality.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Síndromes de Neurotoxicidad/prevención & control , Péptidos/toxicidad , Proteostasis/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Conducta Animal/efectos de los fármacos , Caenorhabditis elegans , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/uso terapéutico , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/prevención & control , Proteoma/efectos de los fármacos , Proteoma/metabolismoRESUMEN
The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of ß2-microglobulin (D76N ß2-m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N ß2-m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N ß2-m expressing worms. We also demonstrated the specificity of the ß2-m variant in determining the pathological phenotype by rescuing the wild type phenotype when ß2-m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates.
Asunto(s)
Amiloidosis/genética , Evaluación Preclínica de Medicamentos/métodos , Microglobulina beta-2/genética , Amiloide/química , Amiloide/genética , Amiloide/metabolismo , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Mutación Missense , Fenotipo , Agregación Patológica de Proteínas/prevención & control , Pliegue de Proteína , Microglobulina beta-2/metabolismoRESUMEN
Grape seed extract (GSE) displays strong antioxidant activity, but its instability creates barriers to its applications. Herein, three HP-ß-CD/GSE inclusion complexes with host-guest ratios of 1:0.5, 1:1, and 1:2 were successfully prepared by co-precipitation method to improve stability. Successful embedding of GSE in the HP-ß-CD cavity was confirmed by fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) analyses. The Autodock Tools 1.5.6 was used to simulate the three-dimensional supramolecular structure of the inclusion complex of 2-hydroxypropyl-ß-cyclodextrin and grape seed extract (HP-ß-CD/GSE) by molecular docking. The MALDI-TOF-MS technology and chemical database Pubchem, and structural database PDB were combined to reconstitute the three-dimensional structure of target protein. The binding mode of the HP-ß-CD/GSE inclusion complex to target protein was studied at the molecular level, and the antioxidant ability of the resulting HP-ß-CD/GSE inclusion complexes was investigated by measuring 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging. The effects of HP-ß-CD/GSE on myofibrillar protein from lamb tripe were also investigated under oxidative conditions. The positions and interactions of the binding sites of HP-ß-CD/GSE inclusion complexes and target protein receptors were simulated by molecular docking. The results showed that HP-ß-CD/GSE inclusion complexes were successfully prepared, optimally at a molar ratio of 1:2. At low (5 µmol/g) to medium (105 µmol/g) concentrations, HP-ß-CD/GSE inclusion complexes decreased the carbonyl content, hydrophobicity, and protein aggregation of myofibrillar protein from lamb tripe, and increased the sulphydryl content. Furthermore, high concentration (155 µmol/g) of HP-ß-CD/GSE inclusion complexes promoted protein oxidation.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/farmacología , Antioxidantes/farmacología , Extracto de Semillas de Uva/farmacología , Estrés Oxidativo/efectos de los fármacos , 2-Hidroxipropil-beta-Ciclodextrina/química , Animales , Antioxidantes/química , Compuestos de Bifenilo/farmacología , Rastreo Diferencial de Calorimetría , Extracto de Semillas de Uva/química , Microscopía Electrónica de Rastreo , Miofibrillas/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/genética , Picratos/farmacología , Polifenoles/química , Polifenoles/farmacología , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/prevención & control , Ovinos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Five pairs of enantiomeric compounds (1a/1b-5a/5b) including seven undescribed compounds (1a/1b-3a/3b, 4b) along with two known ones (. and .) have been isolated from corn silk (Stigma maydis). Racemic mixtures of these enantiomers were separated by HPLC with different types of chiral columns. Their structures were elucidated based on comprehensive spectroscopic analyses together with quantum chemical calculations of 13C NMR data and electronic circular dichroism (ECD) curves. All the isolates were evaluated for their inhibition ability of self-induced Aß1-42 aggregation. Among them, compounds 4a (88.36%), 4b (74.66%) and . (85.65%) showed stronger inhibitory activity than the positive control curcumin (61.90%). The different inhibition profiles of enantiomers 4a and 4b were explained by docking simulation studies.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Flores/química , Fragmentos de Péptidos/antagonistas & inhibidores , Fitoquímicos/farmacología , Agregación Patológica de Proteínas/prevención & control , Zea mays/química , China , Simulación del Acoplamiento Molecular , Estructura Molecular , Fitoquímicos/aislamiento & purificaciónRESUMEN
Protein aggregation has been implicated in many medical disorders, including Alzheimer's and Parkinson's diseases. Potential therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process. However, viable treatment protocols require balancing the efficacy of the drug with its toxicity, while accounting for the underlying events of aggregation and inhibition at the molecular level. To address this key problem, we combine here protein aggregation kinetics and control theory to determine optimal protocols that prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for the aggregation of the amyloid-ß(1-42) peptide of Alzheimer's disease in the model organism Caenorhabditis elegans Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up avenues for the design of rational therapies to control pathological protein aggregation.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/antagonistas & inhibidores , Bexaroteno/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Fragmentos de Péptidos/antagonistas & inhibidores , Agregación Patológica de Proteínas/prevención & control , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Caenorhabditis elegans , Modelos Animales de Enfermedad , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Humanos , Cinética , Fragmentos de Péptidos/metabolismo , Agregado de Proteínas/efectos de los fármacos , Agregación Patológica de Proteínas/patología , Factores de TiempoRESUMEN
The inhibition of amyloid-ß (Aß) aggregation by photo-oxygenation has become an effective way of treating Alzheimer's disease (AD). New near-infrared (NIR) activated treatment agents, which not only possess high photo-oxygenation efficiency, but also show low biotoxicity, are urgently needed. Herein, for the first time, it is demonstrated that NIR activated black phosphorus (BP) could serve as an effective nontoxic photo-oxidant for amyloid-ß peptide in vitro and in vivo. The nanoplatform BP@BTA (BTA: one of thioflavin-T derivatives) possesses high affinity to the Aß peptide due to specific amyloid selectivity of BTA. Importantly, under NIR light, BP@BTA can significantly generate a high quantum yield of singlet oxygen (1 O2 ) to oxygenate Aß, thereby resulting in inhibiting the aggregation and attenuating Aß-induced cytotoxicity. In addition, BP could finally degrade into nontoxic phosphate, which guarantees the biosafety. Using transgenic Caenorhabditis elegans CL2006 as AD model, the results demonstrate that the 1 O2 -generation system could dramatically promote life-span extension of CL2006 strain by decreasing the neurotoxicity of Aß.
Asunto(s)
Péptidos beta-Amiloides/efectos de la radiación , Oxígeno/metabolismo , Fósforo/uso terapéutico , Fototerapia/métodos , Agregación Patológica de Proteínas/prevención & control , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de la radiación , Modelos Animales de Enfermedad , Humanos , Rayos Infrarrojos/uso terapéutico , Oxidación-Reducción/efectos de la radiación , Fósforo/química , Agregación Patológica de Proteínas/metabolismoRESUMEN
Nine autosomal dominant spinocerebellar ataxias (SCAs) are caused by an abnormal expansion of CAG trinucleotide repeats that encodes a polyglutamine (polyQ) tract within different genes. Accumulation of aggregated mutant proteins is a common feature of polyQ diseases, leading to progressive neuronal dysfunction and degeneration. SCA type 3 (SCA3), the most common form of SCA worldwide, is characterized by a CAG triplet expansion in chromosome 14q32.1 ATXN3 gene. As accumulation of the mutated polyQ protein is a possible initial event in the pathogenic cascade, clearance of aggregated protein by ubiquitin proteasome system (UPS) has been proposed to inhibit downstream detrimental events and suppress neuronal cell death. In this study, Chinese herbal medicine (CHM) extracts were studied for their proteasome-activating, polyQ aggregation-inhibitory and neuroprotective effects in GFPu and ATXN3/Q 75 -GFP 293/SH-SY5Y cells. Among the 14 tested extracts, 8 displayed increased proteasome activity, which was confirmed by 20S proteasome activity assay and analysis of ubiquitinated and fused GFP proteins in GFPu cells. All the eight extracts displayed good aggregation-inhibitory potential when tested in ATXN3/Q 75 -GFP 293 cells. Among them, neuroprotective effects of five selected extracts were shown by analyses of polyQ aggregation, neurite outgrowth, caspase 3 and proteasome activities, and ATXN3-GFP, ubiquitin, BCL2 and BAX protein levels in neuronal differentiated ATXN3/Q 75 -GFP SH-SY5Y cells. Finally, enhanced proteasome function, anti-oxidative activity and neuroprotection of catalpol, puerarin and daidzein (active constituents of Rehmannia glutinosa and Pueraria lobata) were demonstrated in GFPu and/or ATXN3/Q 75 -GFP 293/SH-SY5Y cells. This study may have therapeutic implication in polyQ-mediated disorders.
Asunto(s)
Antioxidantes , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Enfermedad de Machado-Joseph/tratamiento farmacológico , Enfermedad de Machado-Joseph/genética , Fármacos Neuroprotectores , Péptidos/genética , Péptidos/metabolismo , Fitoterapia , Complejo de la Endopetidasa Proteasomal/metabolismo , Agregación Patológica de Proteínas/metabolismo , Ubiquitina/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Glucósidos Iridoides/farmacología , Glucósidos Iridoides/uso terapéutico , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Terapia Molecular Dirigida , Mutación , Agregación Patológica de Proteínas/prevención & control , Pueraria/química , Rehmannia/química , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
The main factors of Alzheimer's disease (AD) are the cerebral accumulation and the formation of extracellular amyloid plaques. The Aß peptides are highly able to accumulative and produce fibrils that are placed to form these plaques in the AD. The biological action and drug delivery properties of curcumin (Cur) nanoformulation in the Alzheimer's disease therapeutics can be developed by the altering surface of the Poly-lactide-co-glycolide (PLGA) polymer and encapsulation of selenium nanoparticles (Se NPs). The morphological structure, size distributions of nanospheres, chemical interactions between the polymer and nanoformulations of synthesized curcumin and Se NPs loaded PLGA nanospheres have been studied by using the techniques of analytical instruments. The microscopic and nano observation results of synthesized Cur loaded nanospheres are exhibited that the mono-dispersed distributions of particles with spherical shaped structure. The present drug delivery system of Cur loaded Se-PLGA nanospheres could be decreases the amyloid-ß load in the brains samples of AD mice, and greatly cured the memory deficiency of the model mice. The specific binding of Cur loaded Se-PLGA nanospheres with Aß plaques were visualized by fluorescence microscopic technique. Se-PLGA targeting delivery system to amyloid plaques might be providing the enhanced therapeutic efficacy in AD lesions, which was studied by using transgenic mice (5XFAD). In conclusion, Cur loaded Se-PLGA nanoformulation has been demonstrated that valued delivery system for the targeted delivery and effective way to treat AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Curcumina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Placa Amiloide/tratamiento farmacológico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Selenio/química , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Ratones , Nanopartículas/química , Nanosferas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/farmacocinética , Agregación Patológica de Proteínas/prevención & controlRESUMEN
Deposition of amyloid-ß (Aß) aggregates and formation of neurotoxic reactive oxygen species (ROS) are significant pathological signatures of Alzheimer's disease (AD). Resveratrol (Res) is an antioxidant with the potential to treat AD. However, the bioavailability and solubility of Res is very low and it cannot entirely inhibit Cu2+ -induced Aß42 aggregation at low concentration. Herein, we combine the unique Aß absorption property of selenium nanoparticles with the natural antioxidant agent Res to form Res@SeNPs. Our in vitro biological evaluation revealed that modification of Res with SeNPs provides a synergistic effect on Cu2+ -induced Aß42 aggregation, ROS generation and, more importantly, protects PC12 cells from Aß42-Cu2+ complexes-induced cell death. It is believed that SeNPs can improve the application of Res in AD treatment as Res@SeNPs is more efficient than Res in reducing Aß42 toxicity in long-term use. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3034-3041, 2018.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Antioxidantes/farmacología , Nanopartículas/química , Especies Reactivas de Oxígeno/metabolismo , Resveratrol/farmacología , Selenio/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Antioxidantes/química , Humanos , Células PC12 , Agregado de Proteínas/efectos de los fármacos , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/prevención & control , Ratas , Resveratrol/química , Selenio/químicaRESUMEN
Protein misfolding and aggregation are associated with amyloidosis. The toxic aggregation of amyloid-ß 1-42 (Aß42) may disrupt cell membranes and lead to cell death and is thus regarded as a contributing factor in Alzheimer's disease (AD). 1,4-naphthoquinone (NQ) has been shown to exhibit strong anti-aggregation effects on amyloidogenic proteins such as insulin and α-synuclein; however, its high toxicity and poor solubility limit its clinical application. Menadione sodium bisulfite (MSB, also known as vitamin K3), is used clinically in China to treat hemorrhagic diseases caused by vitamin K deficiency and globally as a vitamin K supplement. We hypothesized that MSB could inhibit amyloid formation since its backbone structure is similar to NQ. To test our hypothesis, we first investigated the effects of MSB on Aß42 amyloid formation in vitro. We found that MSB inhibited Aß42 amyloid formation in a dose dependent manner, delayed the secondary structural conversion of Aß42 from random coil to ordered ß-sheet, and attenuated the ability of Aß42 aggregates to disrupt membranes; moreover, the quinone backbone rather than lipophilicity is esstial for the inhibitory effects of MSB. Next, in cells expressing a pathogenic APP mutation (Osaka mutation) that results in the formation of intraneuronal Aß oligomers, MSB inhibited the intracellular aggregation of Aß. Moreover, MSB treatment significantly extended the life span of Caenorhabditis elegans CL2120, a strain that expresses human Aß42. Together, these results suggest that MSB and its derivatives may be further explored as potential therapeutic agents for the prevention or treatment of AD.
Asunto(s)
Péptidos beta-Amiloides/química , Animales Modificados Genéticamente/crecimiento & desarrollo , Caenorhabditis elegans/crecimiento & desarrollo , Fragmentos de Péptidos/química , Agregación Patológica de Proteínas/prevención & control , Vitamina K 3/farmacología , Vitaminas/farmacología , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Animales Modificados Genéticamente/genética , Animales Modificados Genéticamente/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Humanos , Longevidad , Fragmentos de Péptidos/efectos de los fármacosRESUMEN
Cadmium is a highly toxic environmental pollutant that can cause many adverse effects including cancer, neurological disease and kidney damage. Aquatic amphibians are particularly susceptible to this toxicant as it was shown to cause developmental abnormalities and genotoxic effects. In mammalian cells, the accumulation of heme oxygenase-1 (HO-1), which catalyzes the breakdown of heme into CO, free iron and biliverdin, was reported to protect cells against potentially lethal concentrations of CdCl2. In the present study, CdCl2 treatment of A6 kidney epithelial cells, derived from the frog, Xenopus laevis, induced the accumulation of HO-1, heat shock protein 70 (HSP70) and HSP30 as well as an increase in the production of aggregated protein and aggresome-like structures. Treatment of cells with inhibitors of HO-1 enzyme activity, tin protoporphyrin (SnPP) and zinc protoporphyrin (ZnPP), enhanced CdCl2-induced actin cytoskeletal disorganization and the accumulation of HO-1, HSP70, aggregated protein and aggresome-like structures. Treatment of cells with hemin and baicalein, which were previously shown to provide cytoprotection against various stresses, induced HO-1 accumulation in a concentration-dependent manner. Also, treatment of cells with hemin and baicalein suppressed CdCl2-induced actin dysregulation and the accumulation of aggregated protein and aggresome-like structures. This cytoprotective effect was inhibited by SnPP. These results suggest that HO-1-mediated protection against CdCl2 toxicity includes the maintenance of actin cytoskeletal and microtubular structure and the suppression of aggregated protein and aggresome-like structures.
Asunto(s)
Cadmio/toxicidad , Contaminantes Ambientales/toxicidad , Proteínas del Choque Térmico HSP30/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Hemo-Oxigenasa 1/metabolismo , Riñón/efectos de los fármacos , Agregación Patológica de Proteínas/inducido químicamente , Animales , Antioxidantes/química , Antioxidantes/metabolismo , Línea Celular , Suplementos Dietéticos , Inhibidores Enzimáticos/farmacología , Flavanonas/antagonistas & inhibidores , Flavanonas/metabolismo , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/química , Hemina/antagonistas & inhibidores , Hemina/metabolismo , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/metabolismo , Riñón/citología , Riñón/metabolismo , Riñón/patología , Metaloporfirinas/farmacología , Microscopía Confocal , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/prevención & control , Protoporfirinas/farmacología , Proteínas de Xenopus/agonistas , Proteínas de Xenopus/antagonistas & inhibidores , Proteínas de Xenopus/química , Proteínas de Xenopus/metabolismo , Xenopus laevisRESUMEN
Huntington's disease (HD) is a monogenic disorder, caused by mutations in the HTT gene which result in expansion of CAG triplets. The product of the mutated gene is misfolded huntingtin protein that forms aggregates leading to impairment of neuronal function, neurodegeneration, motor abnormalities and cognitive deficits. No effective cure is currently available for HD. Here we studied effects of genistein (trihydroxyisoflavone) on a HD cellular model consisting of HEK-293 cells transfected with a plasmid bearing mutated HTT gene. Both level of mutated huntingtin and number of aggregates were significantly decreased in genistein-treated HD cell model. This led to increased viability of the cells. Autophagy was up-regulated while inhibition of lysosomal functions by chloroquine impaired the genistein-mediated degradation of the mutated huntingtin aggregates. Hence, we conclude that through stimulating autophagy, genistein removes the major pathogenic factor of HD. Prolonged induction of autophagy was suspected previously to be risky for patients due to putative adverse effects; however, genistein has been demonstrated recently to be safe and suitable for long-term therapies even at doses as high as 150 mg/kg/day. Therefore, results presented in this report provide a basis for the use of genistein in further studies on development of the potential treatment of HD.
Asunto(s)
Autofagia/efectos de los fármacos , Genisteína/farmacología , Enfermedad de Huntington/tratamiento farmacológico , Autofagia/fisiología , Cloroquina/toxicidad , Evaluación Preclínica de Medicamentos , Genes Reporteros , Células HEK293 , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/patología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/prevención & control , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
The amyloid aggregation process of amyloid ß1-42 peptide is responsible for Alzheimer's disease, affecting millions of elderly people worldwide. Although there has been a great deal of attention directed toward tackling this disease, still no medicine has been found for this fatal disorder. To address this challenge, it is vital to thoroughly understand the molecular mechanism underlying the amyloid peptide aggregation process, as well as seek substances that could hamper this aggregation. In order to shed light on mechanisms leading to amyloidogenesis, we employed a microfluidic system to determine the possible influence of in vivo-like flow in the microchip channel itself on feline Aß1-42 peptide amyloidogenesis. We have shown that shear forces occurring during such flow immensely accelerated peptide aggregation. We also tested the inhibitory influence of 3,3'-[1,6-(2,5-dioxahexane)]bis(1-dodecylimidazolium) dichloride gemini surfactant on peptide amyloidogenesis. Our results suggest that this surfactant may inhibit amyloid ß1-42 fibril formation.
Asunto(s)
Péptidos beta-Amiloides/química , Amiloide/química , Dispositivos Laboratorio en un Chip , Fragmentos de Péptidos/química , Agregado de Proteínas , Amiloide/efectos de los fármacos , Amiloide/ultraestructura , Animales , Benzotiazoles , Gatos , Dicroismo Circular , Evaluación Preclínica de Medicamentos , Fluorometría , Microscopía de Fuerza Atómica , Microscopía Electrónica de Transmisión , Agregación Patológica de Proteínas/prevención & control , Pliegue de Proteína/efectos de los fármacos , Reología , Dispersión del Ángulo Pequeño , Resistencia al Corte , Tensoactivos/farmacología , Tiazoles/análisis , Difracción de Rayos XRESUMEN
Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.