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2.
Fitoterapia ; 158: 105174, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35296434

RESUMO

Five new cholestane glycosides, named parisfargosides A-E (1-5), were isolated from the rhizomes of Paris fargesii. Their structures were elucidated on the basis of UV, HR-ESI-MS, 1D and 2D NMR data as well as chemical methods. The structures of all compounds contained α, ß-unsaturated ketone unit. Compounds 3-5 possessed a 16,23-cyclocholest skeleton with 6/6/6/5/5 condensed ring, and the absolute configurations of C-16 and C-23 were confirmed according to ROESY spectra with pyridine­d5 and DMSO­d6 as solvents. In addition, the platelet aggregation activity and cytotoxic activity against five human cancer cell lines (HL-60, A549, SMMC-7721, MDA-MB-231, and SW480) of compounds 1-5 were evaluated.


Assuntos
Colestanos , Liliaceae , Colestanos/farmacologia , Glicosídeos/química , Humanos , Estrutura Molecular , Rizoma/química
3.
Int J Mol Sci ; 23(3)2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35162998

RESUMO

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.


Assuntos
Organismos Aquáticos/química , Esteroides/química , Esteroides/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Colestanos/química , Colestanóis/química , Humanos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Espermina/análogos & derivados , Espermina/química , Esteroides/síntese química , Triterpenos/síntese química
4.
J Asian Nat Prod Res ; 24(7): 663-672, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34292111

RESUMO

Ornithogalum caudatum Ait (OCA) is a natural product used in Chinese traditional medicine. The cholestane saponin OSW-1 is isolated from plant OCA and has recently been shown to have potent cytotoxic effects against different types of cancers. The therapeutic efficacy of OSW-1 on prostate cancer and its underlying mechanism are yet to be established. OSW-1 inhibited the growth of prostate cancer cells by interrupting the interaction between mTOR and Rictor/mTORC2. This mechanism showed a better therapeutic outcome than that of the conventional inhibition of mTOR and provided a basis for as sisting modern prostate cancer treatment strategies.


Assuntos
Colestanos , Ornithogalum , Neoplasias da Próstata , Saponinas , Colestenonas , Humanos , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Estrutura Molecular , Ornithogalum/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Saponinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo
5.
Nat Prod Rep ; 39(4): 742-753, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-34698757

RESUMO

Covering: 1993 to 2021 (mainly 2017-2021)Alzheimer's and Parkinson's diseases are neurodegenerative conditions affecting over 50 million people worldwide. Since these disorders are still largely intractable pharmacologically, discovering effective treatments is of great urgency and importance. These conditions are characteristically associated with the aberrant deposition of proteinaceous aggregates in the brain, and with the formation of metastable intermediates known as protein misfolded oligomers that play a central role in their aetiology. In this Highlight article, we review the evidence at the physicochemical, cellular, animal model and clinical levels on how the natural products squalamine and trodusquemine offer promising opportunities for chronic treatments for these progressive conditions by preventing both the formation of neurotoxic oligomers and their interaction with cell membranes.


Assuntos
Doença de Alzheimer , Produtos Biológicos , Doenças Neurodegenerativas , Doença de Alzheimer/tratamento farmacológico , Animais , Produtos Biológicos/farmacologia , Físico-Química , Colestanos , Colestanóis , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Espermina/análogos & derivados
7.
ACS Chem Neurosci ; 12(17): 3189-3202, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34382791

RESUMO

Many neurodegenerative diseases are associated with the self-assembly of peptides and proteins into fibrillar aggregates. Soluble misfolded oligomers formed during the aggregation process, or released by mature fibrils, play a relevant role in neurodegenerative processes through their interactions with neuronal membranes. However, the determinants of the cytotoxicity of these oligomers are still unclear. Here we used liposomes and toxic and nontoxic oligomers formed by the same protein to measure quantitatively the affinity of the two oligomeric species for lipid membranes. To this aim, we quantified the perturbation to the lipid membranes caused by the two oligomers by using the fluorescence quenching of two probes embedded in the polar and apolar regions of the lipid membranes and a well-defined protein-oligomer binding assay using fluorescently labeled oligomers to determine the Stern-Volmer and dissociation constants, respectively. With both approaches, we found that the toxic oligomers have a membrane affinity 20-25 times higher than that of nontoxic oligomers. Circular dichroism, intrinsic fluorescence, and FRET indicated that neither oligomer type changes its structure upon membrane interaction. Using liposomes enriched with trodusquemine, a potential small molecule drug known to penetrate lipid membranes and make them refractory to toxic oligomers, we found that the membrane affinity of the oligomers was remarkably lower. At protective concentrations of the small molecule, the binding of the oligomers to the lipid membranes was fully prevented. Furthermore, the affinity of the toxic oligomers for the lipid membranes was found to increase and slightly decrease with GM1 ganglioside and cholesterol content, respectively, indicating that physicochemical properties of lipid membranes modulate their affinity for misfolded oligomeric species.


Assuntos
Colestanos , Bicamadas Lipídicas , Peptídeos beta-Amiloides , Gangliosídeo G(M1) , Espermina/análogos & derivados
8.
J Phys Chem B ; 125(33): 9557-9563, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34387998

RESUMO

Plasma membranes are assumed to be highly compartmentalized, which is believed to be important for the membrane protein functionality. The liquid ordered-disordered phase segregation in the membranes results in nanoscale liquid-ordered assemblies-lipid rafts. Double electron-electron resonance spectroscopy (DEER, also known as PELDOR) is sensitive to spin-spin dipolar interactions between spin labels at the nanoscale range of distances. Here, DEER is applied to spin-labeled cholestane, 3ß-doxyl-5α-cholestane (DChl), diluted in bilayers composed of an equimolar mixture of dioleoyl-glycero-phosphocholine (DOPC) and dipalmitoyl-glycero-phosphocholine (DPPC) phospholipids, with cholesterol (Chol) added. The DEER data allowed us to detect clustering of the DChl molecules. Their lateral distribution in the clusters in the absence of Chol was found to be random, while in the presence of Chol it became quasi-regular. DEER time traces are fairly well simulated within a simple square superlattice model. For the 20 mol % Chol content, for which at physiological temperatures, the lipid rafts are formed, the found superlattice parameter was 3.7 nm. Assuming that lipid rafts are captioned upon shock freezing at the temperature of investigation (80 K), the found regularity of DChl lateral distribution was interpreted by raft substructuring, with the DChl molecules embedded between the substructures.


Assuntos
Colestanos , Bicamadas Lipídicas , Espectroscopia de Ressonância de Spin Eletrônica , Elétrons , Microdomínios da Membrana , Fosfatidilcolinas , Marcadores de Spin
9.
Am J Physiol Cell Physiol ; 321(3): C569-C584, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288720

RESUMO

Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on the expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice, treatment with a small molecule-specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pretreatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule-specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Colestanos/farmacologia , Células Supressoras Mieloides/imunologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Comunicação Celular , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Expressão Gênica , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/transplante , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/antagonistas & inibidores , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/imunologia , Índice de Gravidade de Doença , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia
10.
Neurobiol Dis ; 155: 105397, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34015491

RESUMO

Subanesthetic doses of ketamine induce schizophrenia-like behaviors in mice including hyperlocomotion and deficits in working memory and sensorimotor gating. Here, we examined the effect of in vivo ketamine administration on neuronal properties and endocannabinoid (eCB)-dependent modulation of synaptic transmission onto layer 2/3 pyramidal neurons in brain slices of the prefrontal cortex, a region tied to the schizophrenia-like behavioral phenotypes of ketamine. Since deficits in working memory and sensorimotor gating are tied to activation of the tyrosine phosphatase PTP1B in glutamatergic neurons, we asked whether PTP1B contributes to these effects of ketamine. Ketamine increased membrane resistance and excitability of pyramidal neurons. Systemic pharmacological inhibition of PTP1B by Trodusquemine restored these neuronal properties and prevented each of the three main ketamine-induced behavior deficits. Ketamine also reduced mobilization of eCB by pyramidal neurons, while unexpectedly reducing their inhibitory inputs, and these effects of ketamine were blocked or occluded by PTP1B ablation in glutamatergic neurons. While ablation of PTP1B in glutamatergic neurons prevented ketamine-induced deficits in memory and sensorimotor gating, it failed to prevent hyperlocomotion (a psychosis-like phenotype). Taken together, these results suggest that PTP1B in glutamatergic neurons mediates ketamine-induced deficits in eCB mobilization, memory and sensorimotor gating whereas PTP1B in other cell types contributes to hyperlocomotion. Our study suggests that the PTP1B inhibitor Trodusquemine may represent a new class of fast-acting antipsychotic drugs to treat schizophrenia-like symptoms.


Assuntos
Colestanos/farmacologia , Ketamina/toxicidade , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Esquizofrenia/induzido quimicamente , Esquizofrenia/prevenção & controle , Espermina/análogos & derivados , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Anestésicos Dissociativos/toxicidade , Animais , Colestanos/uso terapêutico , Relação Dose-Resposta a Droga , Proteínas com Domínio LIM/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Esquizofrenia/metabolismo , Espermina/farmacologia , Espermina/uso terapêutico
11.
J Biol Chem ; 297(1): 100818, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029592

RESUMO

The cleavage of the insulin receptor by ß-secretase 1 (BACE1) in the liver increases during diabetes, which contributes to reduce insulin receptor levels and impair insulin signaling. However, the precise signaling events that lead to this increased cleavage are unclear. We showed that BACE1 cleaves the insulin receptor in the early secretory pathway. Indeed, coimmunoprecipitation experiments reveal the interaction of the proforms of the two proteins. Moreover, fragments of insulin receptor are detected in the early secretory pathway and a mutated form of BACE1 that retains its prodomain cleaves an early secretory pathway-resident form of the insulin receptor. We showed that BACE1 proform levels are regulated by proteasome and/or lysosome-dependent degradation systems whose efficiencies are dependent on the O-GlcNacylation process. Our results showed that enhanced O-GlcNacylation reduces the efficiency of intracellular protein degradation systems, leading to the accumulation of the proform of BACE1 in the early secretory pathway where it cleaves the precursor of the insulin receptor. All these dysregulations are found in the livers of diabetic mice. In addition, we performed a screen of molecules according to their ability to increase levels of the insulin receptor at the surface of BACE1-overexpressing cells. This approach identified the aminosterol Claramine, which accelerated intracellular trafficking of the proform of BACE1 and increased autophagy. Both of these effects likely contribute to the reduced amount of the proform of BACE1 in the early secretory pathway, thereby reducing insulin receptor cleavage. These newly described properties of Claramine are consistent with its insulin sensitizing effect.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Colestanos/farmacologia , Receptor de Insulina/metabolismo , Espermina/análogos & derivados , Animais , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Fígado/patologia , Modelos Biológicos , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Proteostase/efeitos dos fármacos , Via Secretória/efeitos dos fármacos , Espermina/farmacologia , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos
12.
Neurobiol Dis ; 156: 105402, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34044147

RESUMO

Mutations in the beta-amyloid protein (APP) cause familial Alzheimer's disease. In hAPP-J20 mice expressing mutant APP, pharmacological inhibition or genetic ablation of the tyrosine phosphatase PTP1B prevents CA3 hippocampus neuron loss and cognitive decline. However, how targeting PTP1B affects the cellular mechanisms underlying these cognitive deficits remains unknown. Changes in synaptic strength at the hippocampus can affect information processing for learning and memory. While prior studies have focused on post-synaptic mechanisms to account for synaptic deficits in Alzheimer's disease models, presynaptic mechanisms may also be affected. Here, using whole cell patch-clamp recording, coefficient of variation (CV) analysis suggested a profound presynaptic deficit in long-term potentiation (LTP) of CA3:CA1 synapses in hAPP-J20 mice. While the membrane-impermeable ionotropic NMDA receptor (NMDAR) blocker norketamine in the post-synaptic recording electrode had no effect on LTP, additional bath application of the ionotropic NMDAR blockers MK801 could replicate the deficit in LTP in wild type mice. In contrast to LTP, the paired-pulse ratio and short-term facilitation (STF) were aberrantly increased in hAPP-J20 mice. These synaptic deficits in hAPP-J20 mice were associated with reduced phosphorylation of NMDAR GluN2B and the synaptic vesicle recycling protein NSF (N-ethylmaleimide sensitive factor). Phosphorylation of both proteins, together with synaptic plasticity and cognitive function, were restored by PTP1B ablation or inhibition by the PTP1B-selective inhibitor Trodusquemine. Taken together, our results indicate that PTP1B impairs presynaptic NMDAR-mediated synaptic plasticity required for spatial learning in a mouse model of Alzheimer's disease. Since Trodusquemine has undergone phase 1/2 clinical trials to treat obesity, it could be repurposed to treat Alzheimer's disease.


Assuntos
Doença de Alzheimer/metabolismo , Plasticidade Neuronal/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Pré-Sinápticos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Colestanos/farmacologia , Colestanos/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores Pré-Sinápticos/genética , Espermina/análogos & derivados , Espermina/farmacologia , Espermina/uso terapêutico
13.
J Asian Nat Prod Res ; 23(11): 1107-1114, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33225748

RESUMO

A new homo-aro-cholestane glycoside parispolyside H, along with nine known compounds, were isolated from 75% ethanolic extract of the rhizome of Paris polyphylla var. chinensis. Their chemical structures were elucidated on the basic of analysis of detailed spectroscopic and physicochemical properties. In addition, the isolated compounds (1, 6-9) were evaluated for their cytotoxic activity against HepG2 human liver cancer cell lines. Among them, four known compounds (6-9) showed cytotoxicity with IC50 values ranging from 0.41 to 3.6 µM.


Assuntos
Colestanos , Liliaceae , Saponinas , Glicosídeos/farmacologia , Estrutura Molecular , Rizoma
14.
Sci Rep ; 10(1): 20590, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239727

RESUMO

Vitamin D plays a critical role in calcium homeostasis and in the maintenance and development of skeletal health. Vitamin D status has increasingly been linked to non-skeletal health outcomes such as all-cause mortality, infectious diseases and reproductive outcomes in both humans and veterinary species. We have previously demonstrated a relationship between vitamin D status, assessed by the measurement of serum concentrations of the major vitamin D metabolite 25 hydroxyvitamin D (25(OH)D), and a wide range of non-skeletal health outcomes in companion and wild animals. The aims of this study were to define the host and environmental factors associated with vitamin D status in a cohort of 527 calves from Western Kenya which were part of the Infectious Disease of East African Livestock (IDEAL) cohort. A secondary aim was to explore the relationship between serum 25(OH)D concentrations measured in 7-day old calves and subsequent health outcomes over the following 12 months. A genome wide association study demonstrated that both dietary and endogenously produced vitamin D metabolites were under polygenic control in African calves. In addition, we found that neonatal vitamin D status was not predictive of the subsequent development of an infectious disease event or mortality over the 12 month follow up period.


Assuntos
Bovinos/metabolismo , Vitamina D/análogos & derivados , Vitamina D/análise , Animais , Animais Recém-Nascidos/sangue , Animais Recém-Nascidos/metabolismo , Animais Lactentes/sangue , Animais Lactentes/metabolismo , Calcifediol , Bovinos/sangue , Colestanos , Estudos de Coortes , Dieta , Suplementos Nutricionais , Feminino , Estudo de Associação Genômica Ampla , Quênia , Masculino , Vitamina D/sangue , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/veterinária , Vitaminas
15.
Nanoscale ; 12(44): 22596-22614, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33150350

RESUMO

Trodusquemine is an aminosterol known to prevent the binding of misfolded protein oligomers to cell membranes and to reduce their toxicity in a wide range of neurodegenerative diseases. Its precise mechanism of action, however, remains unclear. To investigate this mechanism, we performed confocal microscopy, fluorescence resonance energy transfer (FRET) and nuclear magnetic resonance (NMR) measurements, which revealed a strong binding of trodusquemine to large unilamellar vesicles (LUVs) and neuroblastoma cell membranes. Then, by combining quartz crystal microbalance (QCM), fluorescence quenching and anisotropy, and molecular dynamics (MD) simulations, we found that trodusquemine localises within, and penetrates, the polar region of lipid bilayer. This binding behaviour causes a decrease of the negative charge of the bilayer, as observed through ζ potential measurements, an increment in the mechanical resistance of the bilayer, as revealed by measurements of the breakthrough force applied with AFM and ζ potential measurements at high temperature, and a rearrangement of the spatial distances between ganglioside and cholesterol molecules in the LUVs, as determined by FRET measurements. These physicochemical changes are all known to impair the interaction of misfolded oligomers with cell membranes, protecting them from their toxicity. Taken together, our results illustrate how the incorporation in cell membranes of sterol molecules modified by the addition of polyamine tails leads to the modulation of physicochemical properties of the cell membranes themselves, making them more resistant to protein aggregates associated with neurodegeneration. More generally, they suggest that therapeutic strategies can be developed to reinforce cell membranes against protein misfolded assemblies.


Assuntos
Bicamadas Lipídicas , Lipossomas Unilamelares , Membrana Celular , Colestanos , Espermina/análogos & derivados
16.
Molecules ; 25(19)2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998410

RESUMO

Previously, various steroidal glycosides were reported from plants of Cestrum species. However, phytochemical investigation has not been conducted on Cestrum newellii. A systematic phytochemical investigation of the leaves of C. newellii resulted in the isolation of eight novel steroidal glycosides (1-8), which were classified into three spirostanol glycosides (1-3), two furostanol glycosides (4 and 5), two pseudofurostanol glycosides (6 and 7), and one cholestane glycoside (8). In addition, three known cholestane glycosides (9-11) were isolated and identified. The structures of the new compounds were determined based on spectroscopic data and chemical transformations. Compounds 1 and 2 are spirostanol glycosides having hydroxy groups at C-2, C-3, C-12, and C-24 of the aglycone moiety. Although C. newellii is known to be a poisonous plant, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay exhibited that none of the isolated compounds were cytotoxic to HL-60 human promyelocytic leukemia cells.


Assuntos
Cestrum/química , Colestanos/análise , Glicosídeos/análise , Fitosteróis/análise , Espirostanos/análise , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Colestanos/química , Glicosídeos/química , Fitosteróis/química , Espectroscopia de Prótons por Ressonância Magnética , Espirostanos/química
17.
Commun Biol ; 3(1): 435, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792544

RESUMO

The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-ß (Aß) in Alzheimer's disease and α-synuclein (αS) in Parkinson's disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aß and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.


Assuntos
Membrana Celular/metabolismo , Colestanos/farmacologia , Dobramento de Proteína , Multimerização Proteica , Espermina/análogos & derivados , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Fenômenos Biofísicos/efeitos dos fármacos , Carboxil e Carbamoil Transferases/química , Carboxil e Carbamoil Transferases/toxicidade , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/toxicidade , Humanos , Dobramento de Proteína/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Espermina/farmacologia , alfa-Sinucleína/química , alfa-Sinucleína/toxicidade
18.
NMR Biomed ; 33(9): e4356, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32575161

RESUMO

Chemical exchange saturation transfer (CEST) can provide metabolite-weighted images in the clinical setting; therefore, understanding the origin of each CEST signal is essential to revealing the changes in diseases at the molecular level, which would provide further insight for diagnoses and treatments. The CEST signal at -1.6 ppm is attributed to the choline methyl group of phosphatidylcholines. The methyl groups have no exchangeable protons, so the corresponding CEST signals must result from the relayed nuclear Overhauser effect (rNOE); however, the detailed mechanism remains unclear. Cholesterol is a major component of biological membranes, and its content is closely related to the dynamics and phases of these lipids. However, cholesterol has a hydroxyl group, which could participate in proton exchange to complete the rNOE process. In this study, we used liposomes containing cholesterol and its analogs (5α-cholestane and progesterone), which presumably have similar capabilities of influencing lipid bilayers, and found that the steroid hydroxyl group is the key to inducing the rNOE at -1.6 ppm. Our results suggest that the origin of the rNOE at -1.6 ppm likely requires an intermolecular NOE between the proton of the choline methyl group and that of the cholesterol hydroxyl group, and a chemical exchange between the cholesterol hydroxyl group and bulk water. However, the phenomenon in which the rNOE at -1.6 ppm appears when the cholesterol concentration is high seems to contradict the in vivo results, suggesting a more complicated mechanism associated with the rNOE at -1.6 ppm in biological membranes.


Assuntos
Colesterol/química , Imageamento por Ressonância Magnética , 1,2-Dipalmitoilfosfatidilcolina/química , Colestanos/química , Lipossomos , Ácido Palmítico/química
19.
J Nat Prod ; 83(4): 1043-1050, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32227943

RESUMO

An extract of Galtonia regalis from the Natural Products Discovery Institute showed moderate antiplasmodial activity, with an IC50 value less than 1.25 µg/mL. The two known cholestane glycosides 1 and 2 and the five new cholestane glycosides galtonosides A-E (3-7) were isolated after bioassay-directed fractionation. The structures of the new compounds were determined by interpretation of their NMR and mass spectra. Among these compounds, galtonoside B (4) displayed the most potent antiplasmodial activity, with an IC50 value of 0.214 µM against the drug-resistant Dd2 strain of Plasmodium falciparum.


Assuntos
Antimaláricos/química , Colestanos/farmacologia , Glicosídeos/farmacologia , Asparagales/química , Colestanos/química , Colestanos/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plasmodium falciparum/química
20.
J Neurosci ; 40(7): 1581-1593, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31915254

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid ß (Aß) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3ß (GSK3ß) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aß pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3ß inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aß plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.SIGNIFICANCE STATEMENT Familial forms of Alzheimer's disease (AD) are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Here, we used a mouse model expressing human amyloid precursor protein bearing two familial mutations and asked whether activation of a phosphatase PTP1B participates in the disease process. Systemic inhibition of this phosphatase using a selective inhibitor prevented cognitive decline, neuron loss in the hippocampus, and attenuated inflammation. Importantly, neuron-targeted ablation of PTP1B also prevented cognitive decline and neuron loss but did not reduce inflammation. Therefore, neuronal loss rather than inflammation was critical for AD progression in this mouse model, and that disease progression could be ameliorated by inhibition of PTP1B.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , Memória Espacial/fisiologia , Peptídeos beta-Amiloides/análise , Animais , Colestanos/farmacologia , Modelos Animais de Doenças , Feminino , Glicogênio Sintase Quinase 3 beta/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Inflamação , Resistência à Insulina , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fragmentos de Peptídeos/análise , Placa Amiloide/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Memória Espacial/efeitos dos fármacos , Espermina/análogos & derivados , Espermina/farmacologia
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