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1.
Nat Commun ; 12(1): 49, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397961

RESUMO

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer's disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/fisiologia , Longevidade , Esteril-Sulfatase/metabolismo , Sulfatases/metabolismo , Animais , Modelos Animais de Doenças , Epistasia Genética , Gônadas/metabolismo , Camundongos , Fenótipo , Células Receptoras Sensoriais/metabolismo , Esteroides/metabolismo
2.
Biomolecules ; 10(8)2020 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784855

RESUMO

Zinc therapy is normally utilized for treatment of Wilson disease (WD), an inherited condition that is characterized by increased levels of non-ceruloplasmin bound ('free') copper in serum and urine. A subset of patients with Alzheimer's disease (AD) or its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper metabolic balance and exhibit higher than normal values of non-ceruloplasmin copper. Zinc's action mechanism involves the induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract, thus restoring physiological levels of non-ceruloplasmin copper in the body. On this basis, it is employed in WD. Zinc therapy has shown potential beneficial effects in preliminary AD clinical trials, even though the studies have missed their primary endpoints, since they have study design and other important weaknesses. Nevertheless, in the studied AD patients, zinc effectively decreased non-ceruloplasmin copper levels and showed potential for improved cognitive performances with no major side effects. This review discusses zinc therapy safety and the potential therapeutic effects that might be expected on a subset of individuals showing both cognitive complaints and signs of copper imbalance.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Cobre/metabolismo , Zinco/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Ceruloplasmina/metabolismo , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Humanos , Zinco/administração & dosagem , Zinco/efeitos adversos , Zinco/metabolismo
3.
BMC Complement Med Ther ; 20(1): 129, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345272

RESUMO

BACKGROUND: Evolvulus alsinoides (Linn.) Linn. (Convolvulaceae) is a therapeutic herb alleviating brain patterns associated with three categories of regulatory principles of the body, mind, and behaviour. In the current research, enzyme inhibition and cytotoxic potentials of E. alsinoides (L.) L. leaf extract has been studied validating its potential application. METHODS: The plant phenolics in the leaf extracts obtained via cold-maceration with solvents viz.: n-hexane, chloroform, ethyl acetate, methanol, and water were quantitatively analyzed. The antioxidant potency was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric Reducing Ability of Plasma (FRAP) assays at five concentrations (100-500 µg). The enzyme inhibition potential was performed with α-amylase, α-glucosidase, and acetylcholinesterase at seven concentrations (25-500 µg). The experiments were done in triplicates and statistically validated using Minitab-17 and SPSS 22. RESULTS: Water extract contain 45.08 ± 0.02 mg GAE/g, 49.30 ± 0.07 mg GAE/g, 211.21 ± 0.02 mg QE/g tannins, phenolics, flavonoids respectively. Its antioxidant activity was supported by IC50 52.43 ± 0.2 µg/mL (DPPH assay) and 41.58 ± 0.03 (FRAP assay). Methanolic extract inhibits α-amylase with IC50 1.33 ± 0.05 µg/mL. Water extract inhibits α-glucosidase and acetylcholinesterase with IC50 3.58 ± 0.02 µg/mL and 4.46 ± 0.03 µg/mL. Cytotoxicity studies with SH-SY5Y cell-line substantiate the inhibition potential of water extract with IC50 103.0035 µg/mL. DISCUSSION AND CONCLUSIONS: The extracts with potent antioxidant and enzyme-inhibiting activity were determined. The findings of the research are the first report about the inhibition effects of Evolvulus alsinoides (Linn.) Linn extracts against α-amylase, α-glucosidase and acetylcholinesterase. The extracts shall be examined in future studies to evaluate its pharmaceutical potential.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Diabetes Mellitus/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , alfa-Amilases/antagonistas & inibidores , Acetilcolinesterase , Doença de Alzheimer/enzimologia , Linhagem Celular Tumoral , Convolvulaceae/química , Diabetes Mellitus/enzimologia , Humanos , Índia , Medicina Ayurvédica , Extratos Vegetais/química , Folhas de Planta/química , alfa-Glucosidases
4.
Biochim Biophys Acta Proteins Proteom ; 1868(8): 140428, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32305689

RESUMO

Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, and related brain disorders. The results together indicate the role of cathepsin B in the behavioral deficits and neuropathology of these disorders. Lysosomal leakage occurs in AD and TBI, and related neurodegeneration, which leads to the hypothesis that cathepsin B is redistributed from the lysosome to the cytosol where it initiates cell death and inflammation processes associated with neurodegeneration. These results together implicate cathepsin B as a major contributor to these neuropathological changes and behavioral deficits. These findings support the investigation of cathepsin B as a potential drug target for therapeutic discovery and treatment of AD, TBI, and TBI-related brain disorders.


Assuntos
Doença de Alzheimer/enzimologia , Lesões Encefálicas Traumáticas/enzimologia , Encéfalo/enzimologia , Catepsina B/genética , Transtornos Neurocognitivos/enzimologia , Neurônios/enzimologia , Adulto , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Catepsina B/antagonistas & inibidores , Catepsina B/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Criança , Citosol/efeitos dos fármacos , Citosol/enzimologia , Modelos Animais de Doenças , Feto , Regulação da Expressão Gênica , Humanos , Lactente , Lisossomos/efeitos dos fármacos , Lisossomos/enzimologia , Terapia de Alvo Molecular , Transtornos Neurocognitivos/tratamento farmacológico , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais
5.
Adv Exp Med Biol ; 1221: 631-645, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274729

RESUMO

Amyloidosis refers to a group of diseases characterized by abnormal deposition of denatured endogenous proteins, termed amyloid, in the affected organs. Analysis of biopsy and autopsy tissues from patients revealed the presence of heparan sulfate proteoglycans (HSPGs) along with amyloid proteins in the deposits. For a long time, HSPGs were believed to occur in the deposits as an innocent bystander. Yet, the consistent presence of HSPGs in various deposits, regardless of the amyloid species, led to the hypothesis that these macromolecular glycoconjugates might play functional roles in the pathological process of amyloidosis. In vitro studies have revealed that HSPGs, or more precisely, the heparan sulfate (HS) side chains interact with amyloid peptides, thus promoting amyloid fibrillization. Although information on the mechanisms of HS participation in amyloid deposition is limited, recent studies involving a transgenic mouse model of Alzheimer's disease point to an active role of HS in amyloid formation. Heparanase cleavage alters the molecular structure of HS, and thus modulates the functional roles of HS in homeostasis, as well as in diseases, including amyloidosis. The heparanase transgenic mice have provided models for unveiling the effects of heparanase, through cleavage of HS, in various amyloidosis conditions.


Assuntos
Amiloidose/metabolismo , Glucuronidase/metabolismo , Heparitina Sulfato/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Amiloidose/enzimologia , Animais , Proteoglicanas de Heparan Sulfato , Heparitina Sulfato/química , Humanos
6.
Adv Exp Med Biol ; 1233: 195-221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274758

RESUMO

Alzheimer's disease (AD) is the most common form of dementia, most prevalent in the elderly population and has a significant impact on individuals and their family as well as the health care system and the economy. While the number of patients affected by various forms of dementia including AD is on the increase, there is currently no cure. Although genome-wide association studies have identified genetic markers for familial AD, the molecular mechanisms underlying the initiation and development of both familial and sporadic AD remain poorly understood. Most neurodegenerative diseases and in particular those associated with dementia have been defined as proteinopathies due to the presence of intra- and/or extracellular protein aggregates in the brain of affected individuals. Although loss of proteostasis in AD has been known for decades, it is only in recent years that we have come to appreciate the role of ubiquitin-dependent mechanisms in brain homeostasis and in brain diseases. Ubiquitin is a highly versatile post-translational modification which regulates many aspects of protein fate and function, including protein degradation by the Ubiquitin-Proteasome System (UPS), autophagy-mediated removal of damaged organelles and proteins, lysosomal turnover of membrane proteins and of extracellular molecules brought inside the cell through endocytosis. Amyloid-ß (Aß) fragments as well as hyperphosphorylation of Tau are hallmarks of AD, and these are found in extracellular plaques and intracellular fibrils in the brain of individuals with AD, respectively. Yet, whether it is the oligomeric or the soluble species of Aß and Tau that mediate toxicity is still unclear. These proteins impact on mitochondrial energy metabolism, inflammation, as well as a number of housekeeping processes including protein degradation through the UPS and autophagy. In this chapter, we will discuss the role of ubiquitin in neuronal homeostasis as well as in AD; summarise crosstalks between the enzymes that regulate protein ubiquitination and the toxic proteins Tau and Aß; highlight emerging molecular mechanisms in AD as well as future strategies which aim to exploit the ubiquitin system as a source for next-generation therapeutics.


Assuntos
Doença de Alzheimer/metabolismo , Ubiquitina/metabolismo , Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Lisossomos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo
7.
Am J Physiol Cell Physiol ; 318(6): C1123-C1135, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267716

RESUMO

Praja2 (Pja2), a member of the growing family of mammalian RING E3 ubiquitin ligases, is reportedly involved in not only several types of cancer but also neurological diseases and disorders, but the genetic mechanism underlying the regulation of Pja2 in the nervous system remains unclear. To study the cellular and molecular functions of Pja2 in mouse hippocampal neuronal cells (MHNCs), we used gain- and loss-of-function manipulations of Pja2 in HT-22 cells and tested their regulatory effects on three Alzheimer's disease (AD) genes and cell proliferation. The results revealed that the expression of AD markers, including amyloid beta precursor protein (App), microtubule-associated protein tau (Mapt), and gamma-secretase activating protein (Gsap), could be inhibited by Pja2 overexpression and activated by Pja2 knockdown. In addition, HT-22 cell proliferation was enhanced by Pja2 upregulation and suppressed by its downregulation. We also evaluated and quantified the targets that responded to the enforced expression of Pja2 by RNA-Seq, and the results showed that purinergic receptor P2X, ligand-gated ion channel 3 and 7 (P2rx3 and P2rx7), which show different expression patterns in the critical calcium signaling pathway, mediated the regulatory effect of Pja2 in HT-22 cells. Functional studies indicated that Pja2 regulated HT-22 cells development and AD marker genes by inhibiting P2rx3 but promoting P2rx7, a gene downstream of P2rx3. In conclusion, our results provide new insights into the regulatory function of the Pja2 gene in MHNCs and thus underscore the potential relevance of this molecule to the pathophysiology of AD.


Assuntos
Doença de Alzheimer/enzimologia , Proliferação de Células , Hipocampo/enzimologia , Neurônios/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Hipocampo/patologia , Humanos , Camundongos , Neurônios/patologia , Proteínas/genética , Proteínas/metabolismo , Receptores Purinérgicos P2X3/genética , Receptores Purinérgicos P2X7/genética , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Proteínas tau/genética , Proteínas tau/metabolismo
8.
J Mol Model ; 26(4): 68, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32130533

RESUMO

Pro-inflammatory activation of caspase-1 in the neurodegenerative pathway has been associated with age-dependent cognitive impairment and Alzheimer's disease (AD) in humans. A recent report highlighted 2,4-diaminopyrimidine ring as an essential fragment in the inhibition of human caspase-1. However, the role of the ring and its enzyme inhibitory mechanism is not thoroughly investigated at the molecular level. The purpose of this study is therefore in twofold: (1) to understand the enzyme binding mechanism of the 2,4-diaminopyrimidine ring and (2) to search for more potent caspase-1 inhibitors that contain the ring, using integrative per-residue energy decomposition (PRED) pharmacophore modeling. Ligand interaction profile of a reference compound revealed a peculiar hydrogen formation of the amino group of 2,4-diaminopyrimidine with active site residue Arg341, possibly forming the bases for its inhibitory prowess against caspase-1. A generated pharmacophore model for structure-based virtual screening identified compounds, ZINC724667, ZINC09908119, and ZINC09933770, as potential caspase-1 inhibitors that possessed desirable pharmacokinetic and physiochemical properties. Further analyses revealed active site residues, Arg179, Ser236, Cys285, Gln283, Ser339, and Arg341, as crucial to inhibitor binding by stabilizing and forming hydrogen bonds, hydrophobic, and pi-pi interactions with the 2,4-diaminopyrimidine rings. Common interaction patterns of the hits could have accounted for their selective and high-affinity ligand binding, which was characterized by notable disruptions in caspase-1 structural architecture. These compounds could further be explored as potential leads in the development of novel caspase-1 inhibitors.


Assuntos
Doença de Alzheimer , Caspase 1/química , Inibidores de Caspase/química , Pirimidinas/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Inibidores de Caspase/uso terapêutico , Humanos , Pirimidinas/uso terapêutico
9.
Mol Cell Biochem ; 468(1-2): 1-11, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32144518

RESUMO

Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases and is characterized by progressive cognitive impairment and multiple neurological changes. To date, there are no effective drugs to delay or cure AD. Breviscapine (Bre) is an active ingredient of flavonoids extracted from breviscapus. Previous research suggests that Bre is an effective medicine for the prevention and treatment of AD. In the present study, we sought to explore the molecular mechanisms responsible for short-term beneficial effects of Breviscapine on Aß burden, neuronal and synaptic, cognitive function in APP/PS1 transgenic mice at 6 months age. Our results showed that 3 months of intraperitoneal treatment with Bre rescued learning deficits, relieved memory retention, improved the ability to explore the outside world, markedly decreased Aß burden, attenuated function of neocortical and hippocampal neuron, and increased the synaptic proteins levels in the brain of APP/PS1 mice by decreasing BACE1, promoting Aß-degrading enzyme IDE expression, suppressing RAGE expression, and regulating p38/p53/NT4 pathway. This finding provides more evidence of neuroprotective effects and action mechanisms of Bre antagonist AD, suggesting that Bre may have potential as anti-AD agent.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Flavonoides/uso terapêutico , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Flavonoides/farmacologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Insulisina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Receptor para Produtos Finais de Glicação Avançada/metabolismo
10.
Int J Mol Sci ; 21(3)2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32046281

RESUMO

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer's disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Arginase/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/genética , Neurogênese , Valina/análogos & derivados , Doença de Alzheimer/enzimologia , Doença de Alzheimer/fisiopatologia , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/enzimologia , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Valina/farmacologia , Valina/uso terapêutico
11.
Mol Med Rep ; 21(1): 115-122, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31939621

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder causing progressive memory loss and cognitive impairment. The aberrant accumulation of amyloid­ß (Aß) and neuroinflammation are two major events in AD. Aß­induced neurotoxicity and oxidative stress are also involved in the pathogenesis of AD. The purpose of the current study was to investigate the effect of compound porcine cerebroside and ganglioside injection (CPCGI) on the progression of AD, and to explore the molecular mechanism. In vivo and in vitro models of AD were established and treated with CPCGI. Aß40 and Aß42 protein levels were detected using western blotting. Production of pro­inflammatory factors [tumor necrosis factor (TNF)­α and interleukin (IL)­1ß] and oxidative stress markers [malondialdehyde (MDA), superoxide dismutase (SOD)] and reactive oxygen species (ROS) production were determined. Cell viability and apoptosis were detected using 3­(4,5­dimethyl­2­thiazolyl)­2,5­â€‹diphenyl­2­H­tetrazolium bromide assay and flow cytometry analysis respectively. Results demonstrated that CPCGI administration reduced Aß40 and Aß42 accumulation, and inhibited inflammatory response and oxidative stress in the in vivo rat model of AD, evidenced by decreased Aß40 and Aß42 protein expression, reduced levels of TNF­α and IL­1ß, reduced MDA content, enhanced SOD activity, and reduced ROS level. It was found that CPCGI enhanced cell viability and reduced cell apoptosis of Aß25­35 induced PC12 cells. In addition, the mitogen­activated protein kinase/NF­κB pathway was involved in the protective effect of CPCGI on AD. Taken together, the data demonstrated that CPCGI exerted a protective effect on AD by reducing Aß accumulation, inhibiting inflammatory response and oxidative stress, In addition to preventing neuronal apoptosis.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Animais , Apoptose/efeitos dos fármacos , Escala de Avaliação Comportamental , Sobrevivência Celular/efeitos dos fármacos , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/metabolismo , Suínos , Fator de Necrose Tumoral alfa/metabolismo
12.
Amino Acids ; 52(3): 387-396, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31902008

RESUMO

Alzheimer's disease (AD), the most common form of dementia, is a growing problem worldwide, with 10 million incident cases registered every year. The complex etiology of AD has not been clarified yet and represents an active research topic. In this work, we studied the inhibitory properties of Hp-1935, a natural peptide extracted from the skin secretions of an Argentinian frog (Boana pulchella). It was initially isolated as an antimicrobial peptide by our group, but we later discovered its anti-AChE action. Since not many peptides with this activity have been reported, we focused on defining the basis of its inhibitory mechanism against acetylcholinesterase (AChE) and on finding the primary portion for the inhibitory activity in its sequence, through the combination of an experimental strategy of design and synthesis with molecular dynamics simulations. We also tested its cytotoxicity. We found that Hp-1935 is an interesting sequence for the development of new AChE inhibitors. This peptide is a peripheral anionic site inhibitor with an inhibitory activity that collocates it between the most potent natural amino acids peptides against AChE reported. We also demonstrate that its inhibitory activity is concentrated on the central part of the sequence.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Inibidores da Colinesterase/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Anuros , Células CHO , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cricetulus , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Relação Estrutura-Atividade
13.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979317

RESUMO

A series of novel compounds 6a-h, 8i-1, 10s-v, and 16a-d were synthesized and evaluated, together with the known analogs 11a-f, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated in vitro by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound 8i showed the strongest inhibitory effect on both AChE (eeAChE IC50 = 0.39 µM) and BChE (eqBChE IC50 = 0.28 µM). Enzyme inhibition kinetics and molecular modeling studies have shown that compound 8i bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound 8i is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer's disease (anti-AD) agents. In summary, these data suggest that compound 8i is a promising multipotent agent for the treatment of AD.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/enzimologia , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Sítios de Ligação , Butirilcolinesterase/metabolismo , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Donepezila/farmacologia , Cinética , Simulação de Acoplamento Molecular , Células PC12 , Ratos , Relação Estrutura-Atividade , Tacrina/farmacologia
14.
Biochem Pharmacol ; 176: 113818, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31978378

RESUMO

Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer's disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models. In addition to NO donors, several other pharmacological agents, such as phosphodiesterase 5 (PDE5) inhibitors have been used to activate the pathway and rescue memory disorders. PDE5 inhibitors, including sildenafil, tadalafil and vardenafil, are marketed for the treatment of erectile dysfunction and arterial pulmonary hypertension due to their vasodilatory properties. The ability of PDE5 inhibitors to interfere with the NO/cGMP/PKG/CREB signaling pathway by increasing the levels of cGMP has prompted the hypothesis that PDE5 inhibition might be used as an effective therapeutic strategy for the treatment of AD. To this end, newly designed PDE5 inhibitors belonging to different chemical classes with improved pharmacologic profile (e.g. higher potency, improved selectivity, and blood-brain barrier penetration) have been synthesized and evaluated in several animal models of AD. In addition, recent medicinal chemistry effort has led to the development of agents concurrently acting on the PDE5 enzyme and a second target involved in AD. Both marketed and investigational PDE5 inhibitors have shown to reverse cognitive defects in young and aged wild type mice as well as transgenic mouse models of AD and tauopathy using a variety of behavioral tasks. These studies confirmed the therapeutic potential of PDE5 inhibitors as cognitive enhancers. However, clinical studies assessing cognitive functions using marketed PDE5 inhibitors have not been conclusive. Drug discovery efforts by our group and others are currently directed towards the development of novel PDE5 inhibitors tailored to AD with improved pharmacodynamic and pharmacokinetic properties. In summary, the present perspective reports an overview of the correlation between the NO signaling and AD, as well as an outline of the PDE5 inhibitors used as an alternative approach in altering the NO pathway leading to an improvement of learning and memory. The last two sections describe the preclinical and clinical evaluation of PDE5 inhibitors for the treatment of AD, providing a comprehensive analysis of the current status of the AD drug discovery efforts involving PDE5 as a new therapeutic target.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Inibidores da Fosfodiesterase 5/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Humanos , Óxido Nítrico/metabolismo
15.
Adv Clin Exp Med ; 29(1): 71-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31967744

RESUMO

BACKGROUND: Paraoxonase 1 (PON1) is an enzyme with the capability to protect against lipid oxidation and atherosclerotic lesions formation. Impaired antioxidative capacity and enhanced lipid peroxidation (reflected by malondialdehyde rise) accompany dementias. OBJECTIVES: The aim of this study was to discern the possible differences in the activity and phenotype distribution of PON1, and lipid peroxidation level in dementias of neurodegenerative and vascular pathology, to assess whether they reflect structural changes in the brain, and to evaluate their potential as dementia markers. MATERIAL AND METHODS: Paraoxonase 1 arylesterase activity and polymorphisms (dual-substrate method), and malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS) levels were determined spectrophotometrically in 257 serum samples derived from 136 dementive patients (with Alzheimer's disease (AD; n = 63), vascular dementia (VaD; n = 40) and mixed-type dementia (MD; n = 33), as well as from 121 non-dementive individuals. The results were analyzed with reference to dementia type and severity (assessed with Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales), structural brain changes (estimated with magnetic resonance imaging (MRI) - Global Cortical Atrophy (GCA), Medial Temporal lobe Atrophy (MTA) and Fazekas scales)) and brain ischemia (Hachinski Ischemic Scale (HIS) index), and evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Malondialdehyde/thiobarbituric acid reactive substances were increased in dementia (more in VaD than AD). In patients with vascular involvement, MDA/TBARS elevation reflected a degree of global cortical atrophy. Paraoxonase 1 activity was decreased in patients with dementia, especially in patients with severe cognitive deficits. In VaD, a drop in PON1 reflected a degree of MTA and brain ischemia. MDA/TBARS displayed 75% accuracy as a general dementia marker, but, similarly to PON1, were a poor differential marker. CONCLUSIONS: Both indices were more associated with vascular involvement and the severity of brain atrophy or ischemia rather than with degree of cognitive decline.


Assuntos
Doença de Alzheimer , Arildialquilfosfatase , Encéfalo , Disfunção Cognitiva , Demência Vascular , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Arildialquilfosfatase/metabolismo , Atrofia , Encéfalo/patologia , Demência Vascular/enzimologia , Demência Vascular/patologia , Feminino , Humanos , Peroxidação de Lipídeos , Imagem por Ressonância Magnética , Masculino
16.
Curr Issues Mol Biol ; 35: 195-230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31422940

RESUMO

Post-translational modifications (PTMs) play important roles in altering the structure and function of proteins. In this article, we focus on ubiquitination and SUMOylation of amyloidogenic proteins. We discuss the functional contributions of PTMs on proteins involved in amyloid-related diseases as well as the aberrant PTM signatures of the disease agents. In addition, we extend our discussion to the nascent field of functional amyloids, a subclass of amyloids that perform physiological functions. Here, we present examples from mammals and yeast to gain insight into physiological regulation of amyloid-like proteins.


Assuntos
Doença de Alzheimer/metabolismo , Proteínas Amiloidogênicas/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Sumoilação , Sinucleinopatias/metabolismo , Ubiquitinação , Doença de Alzheimer/enzimologia , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/toxicidade , Esclerose Amiotrófica Lateral/enzimologia , Animais , Humanos , Peptídeos/metabolismo , Príons/química , Príons/metabolismo , Processamento de Proteína Pós-Traducional , Superóxido Dismutase-1/química , Superóxido Dismutase-1/metabolismo , Sinucleinopatias/enzimologia , Leveduras/genética , Leveduras/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo
17.
Appl Radiat Isot ; 155: 108915, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31590101

RESUMO

To develop PET radiotracers for imaging of Alzheimer's disease, a new carbon-11 labeled potent and selective γ-secretase modulator (GSM) has been synthesized. The reference standard tetrahydrobenzisoxazole derivative 8 and its desmethylated precursor 9 were synthesized from cyclohex-2-en-1-one and 3-hydroxy-4-nitrobenzaldehyde in eight and nine steps with 11% and 5% overall chemical yield, respectively. The radiotracer [11C]8 was prepared from its corresponding precursor 9 with [11C]CH3OTf through O-11C-methylation and isolated by RP-HPLC combined with SPE in 45-50% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was 555-740 GBq/µmol.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Secretases da Proteína Precursora do Amiloide/metabolismo , Radioisótopos de Carbono/química , Oxazóis/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Doença de Alzheimer/enzimologia , Cromatografia de Fase Reversa , Humanos , Extração em Fase Sólida
18.
Curr Comput Aided Drug Des ; 16(1): 54-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30827255

RESUMO

BACKGROUND: There are over 44 million persons who suffer with Alzheimer's disease (AD) worldwide, no existence of cure and only symptomatic treatments are available for it. The aim of this study is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy. Among all AChEIs donepezil possesses lowest adverse effects, it can treat mildmoderate- severe AD and only once-daily dosing is required. Therefore, donepezil is recognized as a significant prototype for design and development of new drug molecule. METHODS: In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. RESULTS: As a result 26 compounds have been indicates better inhibitory activity on AChE enzyme and all the screening parameters have also been satisfied by all 26 compounds. From these 26 compounds, six compounds 17, 18, 24, 30, 36 and 56 are found to be the most potent inhibitors of this series by insilico study through INVENTUS v 1.1 software, having highest bio-affinities i.e. - 8.51, - 7.67, - 8.30, - 7.59, - 8.71 and -7.62 kcal/mol respectively, while the standard or reference drug donepezil had binding affinity of - 6.32 kcal/mol. CONCLUSION: Computer aided drug design approach has been playing an important role in the design and development of novel anti- AD drugs. With the help of structure based drug design some novel analogues of donepezil have been designed and the molecular docking studies with structure based ADME properties prediction studies is performed for prediction of AChE inhibitory activity. The binding mode of proposed compounds with target protein i.e. AChE has been evaluated and the resulting data from docking studies explains that all of the newly designed analogues had significantly high affinity towards target protein compared to donepezil as a reference ligand.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/enzimologia , Sítios de Ligação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Simulação por Computador , Desenho Assistido por Computador , Donepezila/farmacologia , Humanos
19.
Eur Arch Psychiatry Clin Neurosci ; 270(4): 495-496, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30806771

RESUMO

We shortly discuss a possible contribution of insulin-degrading enzyme to Alzheimer´s disease pathology by binding varicella zoster virus glycoprotein E, which increases the infectivity and cell-cell spread of the virus.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/etiologia , Herpesvirus Humano 3/patogenicidade , Insulisina/metabolismo , Proteínas do Envelope Viral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Humanos
20.
Curr Top Med Chem ; 20(1): 4-36, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31797761

RESUMO

Alzheimer's disease (AD) is a chronic neurodegenerative disease that 4 widespread in the elderly. The etiology of AD is complicated, and its pathogenesis is still unclear. Although there are many researches on anti-AD drugs, they are limited to reverse relief symptoms and cannot treat diseases. Therefore, the development of high-efficiency anti-AD drugs with no side effects has become an urgent need. Based on the published literature, this paper summarizes the main targets of AD and their drugs, and focuses on the research and development progress of these drugs in recent years.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Humanos
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