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1.
Int J Mol Sci ; 23(15)2022 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-35955937

RESUMEN

Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.


Asunto(s)
Lipopolisacáridos , Degeneración Retiniana , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Electrorretinografía , Luz , Lipopolisacáridos/farmacología , Células Fotorreceptoras de Vertebrados , Ratas , Retina , Degeneración Retiniana/tratamiento farmacológico , Degeneración Retiniana/etiología
2.
Proc Natl Acad Sci U S A ; 115(51): E12053-E12062, 2018 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-30509990

RESUMEN

Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (SynTg) mice. Considering epidemiologic and experimental evidence suggesting protective effects of caffeine in PD, we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of α-synucleinopathy. Coadministration of these two compounds orally for 6 mo at doses that were individually ineffective in SynTg mice and in a striatal α-synuclein preformed fibril inoculation model resulted in reduced accumulation of phosphorylated α-synuclein, preserved neuronal integrity and function, diminished neuroinflammation, and improved behavioral performance. These indices were associated with increased levels of methylated PP2A in brain tissue. A similar profile of greater PP2A methylation and cytoprotection was found in SH-SY5Y cells cotreated with EHT and caffeine, but not with each compound alone. These findings suggest that these two components of coffee have synergistic effects in protecting the brain against α-synuclein-mediated toxicity through maintenance of PP2A in an active state.


Asunto(s)
Cafeína/farmacología , Café/química , Enfermedad por Cuerpos de Lewy/metabolismo , Neuroprotección/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Serotonina/análogos & derivados , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Enfermedad por Cuerpos de Lewy/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Fosforilación , Proteína Fosfatasa 2/metabolismo , Serotonina/farmacología , alfa-Sinucleína/metabolismo
3.
Exp Dermatol ; 27(9): 993-999, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29797368

RESUMEN

Cutibacterium (formerly Propionibacterium acnes) is a major contributor to the pathogenesis of acne. C. acnes initiates an innate immune response in keratinocytes via recognition and activation of toll-like receptor-2 (TLR2), a key step in comedogenesis. Tetramethyl-hexadecenyl-cysteine-formylprolinate (SIG1459), a novel anti-acne isoprenylcysteine (IPC) small molecule, is shown in this study to have direct antibacterial activity and inhibit TLR2 inflammatory signalling. In vitro antibacterial activity of SIG1459 against C. acnes was established demonstrating minimal inhibitory concentration (MIC = 8.5 µmol\L), minimal bactericidal concentration (MBC = 16.1 µmol\L) and minimal biofilm eradication concentration (MBEC = 12.5 µmol\L). To assess SIG1459's anti-inflammatory activity, human keratinocytes were exposed to C. acnes and different TLR2 ligands (peptidoglycan, FSL-1, Pam3CSK4) that induce pro-inflammatory cytokine IL-8 and IL-1α production. Results demonstrate SIG1459 inhibits TLR2-induced IL-8 release from TLR2/TLR2 (IC50  = 0.086 µmol\L), TLR2/6 (IC50  = 0.209 µmol\L) and IL-1α from TLR2/TLR2 (IC50  = 0.050 µmol\L). To assess the safety and in vivo anti-acne activity of SIG1459, a vehicle controlled clinical study was conducted applying 1% SIG1459 topically (n = 35 subjects) in a head-to-head comparison against 3% BPO (n = 15 subjects). Utilizing the Investigator Global Assessment scale for acne as primary endpoint, results demonstrate 1% SIG1459 significantly outperformed 3% BPO over 8 weeks, resulting in 79% improvement as compared to 56% for BPO. Additionally, 1% SIG1459 was well tolerated. Thus, SIG1459 and phytyl IPC compounds represent a novel anti-acne technology that provides a safe dual modulating benefit by killing C. acnes and reducing the inflammation it triggers via TLR2 signalling.


Asunto(s)
Acné Vulgar/tratamiento farmacológico , Cisteína/análogos & derivados , Fármacos Dermatológicos/uso terapéutico , Inflamación/metabolismo , Queratinocitos/metabolismo , Prolina/análogos & derivados , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 2/antagonistas & inhibidores , Adolescente , Adulto , Peróxido de Benzoílo/uso terapéutico , Células Cultivadas , Cisteína/farmacología , Cisteína/uso terapéutico , Fármacos Dermatológicos/farmacología , Diglicéridos/farmacología , Femenino , Humanos , Interleucina-1alfa/metabolismo , Interleucina-8/metabolismo , Queratinocitos/efectos de los fármacos , Lipopéptidos/farmacología , Masculino , Oligopéptidos/farmacología , Peptidoglicano/farmacología , Prolina/farmacología , Prolina/uso terapéutico , Propionibacterium acnes/efectos de los fármacos , Índice de Severidad de la Enfermedad , Método Simple Ciego , Adulto Joven
4.
Ann Neurol ; 77(6): 930-41, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25820831

RESUMEN

OBJECTIVE: Effective medical management of levodopa-induced dyskinesia (LID) remains an unmet need for patients with Parkinson disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed agonist/antagonist analgesic nalbuphine in reducing LID and its molecular markers in the nonhuman primate model. METHODS: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline subcutaneously as: (1) monotherapy, (2) acute coadministration with levodopa, and (3) chronic coadministration for 1 month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma levodopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses. RESULTS: Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine coadministered with levodopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine cotherapy blocks several molecular correlates of LID, including overexpression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5, and increased phosphorylation of DARPP-32 at threonine-34. INTERPRETATION: Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.


Asunto(s)
Analgésicos Opioides/farmacología , Antiparkinsonianos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa , Nalbufina/farmacología , Neostriado/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Receptores Opioides kappa/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Analgésicos Opioides/administración & dosificación , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/sangre , Antiparkinsonianos/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Levodopa/administración & dosificación , Levodopa/efectos adversos , Levodopa/sangre , Levodopa/farmacología , Macaca , Masculino , Nalbufina/administración & dosificación
5.
J Neurosci ; 31(19): 6963-71, 2011 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-21562258

RESUMEN

α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129 and that this activity is greatly enhanced by carboxyl methylation of the catalytic C subunit of PP2A. α-Syn-transgenic mice raised on a diet supplemented with eicosanoyl-5-hydroxytryptamide, an agent that enhances PP2A methylation, dramatically reduced both α-Syn phosphorylation at Serine 129 and α-Syn aggregation in the brain. These biochemical changes were associated with enhanced neuronal activity, increased dendritic arborizations, and reduced astroglial and microglial activation, as well as improved motor performance. These findings support the notion that serine 129 phosphorylation of α-Syn is of pathogenetic significance and that promoting PP2A activity is a viable disease-modifying therapeutic strategy for α-synucleinopathies such as PD.


Asunto(s)
Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Serotonina/análogos & derivados , alfa-Sinucleína/metabolismo , Animales , Astrocitos/metabolismo , Astrocitos/patología , Western Blotting , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Células Cultivadas , Dendritas/genética , Dendritas/metabolismo , Dendritas/patología , Modelos Animales de Enfermedad , Inmunohistoquímica , Metilación , Ratones , Ratones Transgénicos , Microglía/metabolismo , Microglía/patología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Neuronas/patología , Fosforilación/fisiología , Serotonina/metabolismo , alfa-Sinucleína/genética
6.
Int J Pharm ; 611: 121326, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-34848365

RESUMEN

Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanyl-induced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally. In NX-90 treated rats RR over the time of observation (RR AUC) was significantly higher at all respective doses with no re-narcotization observed. Apart from the enhanced pharmacodynamics profile, NX-90 was found to have lower circulating levels of naloxone, clean profile in in vitro selectivity panels, as well as Ames and CYP450 counter screens. Finally, we demonstrated a robust release of the parent naloxone in brain matrix, as well as lower peripheral naloxone levels after NX-90 iv administration. With the demonstrated pharmacological profile superior yet congruent to naloxone we nominated NX-90 for preclinical development as an effective intranasal fentanyl antidote.


Asunto(s)
Fentanilo , Naloxona , Animales , Frecuencia Cardíaca , Ratas
7.
Neurochem Int ; 143: 104936, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33309980

RESUMEN

Long term consequence of non-fatal overdose in people who use opioids are not well understood. The intermittent exposure to non-fatal overdose leads to a tauopathy that is often accompanied by abrogated neuroprotective response, abnormal amyloid processing and other pathologies. The scope and limitations of available literature are discussed including neuropathologies associated with opioid and overdose exposures, contributing comorbidities and proteinopathies. Contrasting postmortem data of overdose victims with animal models of opioid neuropathologies and hypoxic injury paints a picture distinct from other proteinopathies as well as effects of moderate opioid exposure. Furthermore the reported biochemical changes and potential targets for therapeutic intervention were mapped pointing to underlying imbalance between tau kinases and phosphatases that is characteristic of Alzheimer Disease.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Analgésicos Opioides/efectos adversos , Sobredosis de Droga/metabolismo , Trastornos Relacionados con Opioides/metabolismo , Enfermedad de Alzheimer/patología , Animales , Sobredosis de Droga/patología , Humanos , Trastornos Relacionados con Opioides/patología , Proteínas tau/metabolismo
8.
Eur J Pharm Sci ; 159: 105734, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33515698

RESUMEN

Developing non-addictive and safer opioids for pain management is unmet medical need. Among a number of bioreversible derivatives of Nalbuphine - an equipotent to morphine opioid without serious side effects - NB-33 was identified in silico and confirmed in vivo as a superior analgesic agent. Apart from enhanced pharmacodynamics profile, NB-33 outperformed the parent compound on equimolar bases in cold ethanol tail-flick and mechanical models of pain in rats. With no ß-arrestin engagement liability, good stability in simulated gastro-intestinal fluid and slow release of Nalbuphine by plasma NB-33 is being developed as an oral and safer alternative of its parent drug.


Asunto(s)
Nalbufina , Analgésicos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Animales , Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Ratas
9.
Int J Drug Policy ; 97: 103362, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34314956

RESUMEN

In the midst of an escalating U.S. opioid crisis, the immediate focus of public health interventions is on fatal overdose prevention. Few studies, however, have sought to examine the long-term health consequences of exposure to repeated nonfatal opioid overdose. We reviewed recent literature to examine three corresponding downstream health outcomes of repeated overdose: a) neurodegenerative processes; b) cognition and memory; and c) overdose risk behaviours. We found a remarkable congruency among available biochemical and cognitive data on how nonfatal overdose precipitates various pathological feedforward and feedback loops that affect people who use opioids for years to come. We found however that downstream behavioural implications of neurodegenerative and cognitive sequelae are less studied despite being most proximal to an overdose. Findings point to a vicious cycle of nonfatal overdose leading to neurodegeneration - closely resembling Alzheimer Disease - that results in cognitive decline that in turn leads to potentially reduced adherence to safe drug use behaviours. The collected evidence not only brings into the focus the long-term health consequences of nonfatal overdose from the perspectives of biology, neuroscience, and public health, but also creates new cross-disciplinary context and awareness in the research and public health community that should benefit people at risk.


Asunto(s)
Sobredosis de Droga , Sobredosis de Opiáceos , Trastornos Relacionados con Sustancias , Analgésicos Opioides/uso terapéutico , Cognición , Sobredosis de Droga/tratamiento farmacológico , Sobredosis de Droga/epidemiología , Humanos , Trastornos Relacionados con Sustancias/tratamiento farmacológico
10.
J Cosmet Dermatol ; 19(9): 2386-2393, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32378329

RESUMEN

BACKGROUND: Chia seeds have gained importance as it is the highest known plant source of omega-3 (ω3) polyunsaturated fatty acids. Specifically, chia seeds possess ω3 α-linolenic acid (ALA) and ω6 linoleic acid (LA), together known as Vitamin F, which play an important role in maintaining skin function. Protein phosphatase 2A (PP2A) is a master regulatory protein that plays a critical role in skin barrier function and its activity is modulated by natural lipids. AIMS: Obtain a chia seed extract (HYVIA™) with significant higher levels of Vitamin F, determine in vitro PP2A activity and skin hydration markers compared to other commercial chia seed extracts (CCSEs), and evaluate the potential skin hydration benefits clinically in human subjects. METHODS: A PP2A demethylation assay was utilized to assess PP2A activity. In vitro studies utilizing normal human epidermal keratinocytes (NHEKs) were treated with HYVIA™ and gene expression of hydration markers (AQP3, HAS2) were measured by quantitative PCR (qPCR). A 16-subject clinical trial was performed with 0.1% HYVIA™ formulated in a cream and applied topically to assess its skin moisturizing potential. RESULTS: We demonstrate here that HYVIA™, ALA, and LA inhibit PP2A demethylation, boosting PP2A activity, while most other CCSEs do not. Unlike other CCSEs, HYVIA™ increases keratinocyte hydration factors aquaporin-3 and hyaluronic acid synthase-2 in vitro. Clinical assessment of 0.1% HYVIA™ cream shows that HYVIA™ improves skin hydration. CONCLUSIONS: HYVIA™ is a novel chia seed extract, enriched for Vitamin F, that modulates PP2A activity and clinically improves skin hydration and barrier function.


Asunto(s)
Ácidos Grasos Omega-3 , Salvia , Humanos , Extractos Vegetales/farmacología , Semillas , Piel
11.
J Cosmet Dermatol ; 18(5): 1366-1371, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30456862

RESUMEN

BACKGROUND: SIG-1273 is a novel cosmetic active that provides a broad spectrum of benefits to the skin. Considering the chronic skin exposure to pollution in urban areas, we sought to determine if SIG-1273 could provide additional protection against skin aging by inhibiting pollutant-induced cytotoxicity and inflammation. OBJECTIVE: Determine if SIG-1273 possesses antipollution properties in vitro and evaluate the potential anti-aging benefits of Age IQ™ Night Cream clinically in human subjects. METHODS: In vitro studies utilizing normal human epidermal keratinocytes (NHEKs), were co-treated with urban dust (SRM 1649b) and SIG-1273 (toxicity protection measured by MTS assay). A water-soluble fraction of urban dust (UD-WS) induces pro-inflammatory cytokine release (IL-8) from NHEKs (measured via ELISA). An 8-week, 37-subject clinical trial was performed with 0.05% SIG-1273 formulated in Age IQ™ Night Cream and applied topically to assess its potential to reduce the appearance of aging. RESULTS: In vitro studies using NHEKs demonstrate SIG-1273 protects against urban dust-induced cell toxicity, reducing cell death by 66% and concentration dependently inhibits UD-WS-induced IL-8 production (IC50  = 20 nmol/L), outperforming niacinamide, ascorbic acid, and α-tocopherol, commonly used actives in antipollution skin-care products. Clinical assessment of Age IQ™ Night Cream shows it is effective in improving the appearance of facial skin aging including fine lines and wrinkles, skin texture, skin clarity/brightness, and firmness/elasticity. CONCLUSIONS: SIG-1273, is demonstrated here for the first time to possess antipollution properties. Included as a key active ingredient in Age IQ™ Night Cream, this novel topical formulation provides benefits to individuals with aging skin.

13.
J Neuropathol Exp Neurol ; 77(2): 139-148, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29281045

RESUMEN

Hyperphosphorylated tau aggregates are characteristic of tauopathies including progressive supranuclear palsy (PSP) and Alzheimer disease (AD), but factors contributing to pathologic tau phosphorylation are not well understood. Here, we studied the regulation of the major tau phosphatase, the heterotrimeric AB55αC protein phosphatase 2 A (PP2A), in PSP and AD. The assembly and activity of this PP2A isoform are regulated by reversible carboxyl methylation of its catalytic C subunit, while the B subunit confers substrate specificity. We sought to address whether the decreases in PP2A methylation and its methylating enzyme, leucine carboxyl methyltransferase (LCMT-1), which are reported in AD, relate to tau pathology or to concomitant amyloid pathology by comparing them in the relatively pure tauopathy PSP. Immunohistochemical analysis of frontal cortices showed that methyl-PP2A is reduced while demethyl-PP2A is increased, with no changes in total PP2A or B55α subunit, resulting in a reduction in the methyl/demethyl PP2A ratio of 63% in PSP and 75% in AD compared to controls. Similarly, Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains. This was associated with a decrease in LCMT-1 and an increase in the demethylating enzyme, protein phosphatase methylesterase (PME-1), in both diseases. These findings suggest that PP2A dysregulation in tauopathies may contribute to the accumulation of hyperphosphorylated tau and to neurodegeneration.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Proteína Fosfatasa 2/metabolismo , Parálisis Supranuclear Progresiva/metabolismo , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Metilación , Fosforilación , Proteína O-Metiltransferasa/metabolismo
14.
PLoS One ; 12(12): e0189413, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29253878

RESUMEN

Soluble forms of oligomeric beta-amyloid (Aß) are thought to play a central role in Alzheimer's disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aß. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson's disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aß. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aß-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aß-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aß-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/química , Trastornos del Conocimiento/prevención & control , Serotonina/análogos & derivados , Enfermedad de Alzheimer/patología , Animales , Café , Cognición/efectos de los fármacos , Condicionamiento Psicológico , Modelos Animales de Enfermedad , Electrofisiología , Miedo , Femenino , Potenciación a Largo Plazo , Masculino , Aprendizaje por Laberinto , Metilación , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/patología , Plasticidad Neuronal , Fosforilación , Serotonina/farmacología , Solubilidad
15.
Arch Dermatol Res ; 309(2): 103-110, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27988893

RESUMEN

Isoprenylcysteine (IPC) small molecules were discovered as signal transduction modulating compounds ~25 years ago. More recently, IPC molecules have demonstrated antioxidant and anti-inflammatory properties in a variety of dermal cells as well as antimicrobial activity, representing a novel class of compounds to ameliorate skin conditions and disease. Here, we demonstrate a new IPC compound, N-acetylglutaminoyl-S-farnesyl-L-cysteine (SIG-1191), which inhibits UVB-induced inflammation blocking pro-inflammatory cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) production. To investigate further the previously reported hydrating potential of IPC compounds, SIG-1191 was tested for its ability to modulate aquaporin expression. Specifically, aquaporin 3 (AQP3) the most abundant aquaporin found in skin has been reported to play a key role in skin hydration, elasticity and barrier repair. Results show here for the first time that SIG-1191 increases AQP3 expression in both cultured normal human epidermal keratinocytes as well as when applied topically in a three-dimensional (3D) reconstructed human skin equivalent. Additionally, SIG-1191 dose dependently increased AQP3 protein levels, as determined by specific antibody staining, in the epidermis of the 3D skin equivalents. To begin to elucidate which signaling pathways SIG-1191 may be modulating to increase AQP3 levels, we used several pharmacological pathway inhibitors and determined that AQP3 expression is mediated by the Mitogen-activated protein kinase/Extracellular signal-regulated kinase kinase (MEK) pathway. Altogether, these data suggest SIG-1191 represents a new IPC derivative with anti-inflammatory activity that may also promote increased skin hydration based on its ability to increase AQP3 levels.


Asunto(s)
Antiinflamatorios/farmacología , Acuaporina 3/metabolismo , Dipéptidos/farmacología , Interleucina-6/biosíntesis , Queratinocitos/metabolismo , Lipopéptidos/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Rayos Ultravioleta/efectos adversos , Acuaporina 3/biosíntesis , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Hipodermoclisis/métodos , Inflamación/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Piel/citología , Piel/efectos de los fármacos
16.
J Cosmet Dermatol ; 15(2): 150-7, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26754448

RESUMEN

BACKGROUND: Isoprenylcysteine (IPC) small molecules were identified as a new class of anti-inflammatory compounds over 20 years ago. Since then, they have been developed as novel cosmetic functional ingredients (CFI) and topical drug candidates. SIG1273 is a second generation CFI that has previously been shown to provide a broad spectrum of benefits for the skin through its anti-inflammatory and antimicrobial properties. OBJECTIVE: To determine whether SIG1273 possesses anti-aging properties in vitro and evaluate the tolerability and activity of SIG1273 when applied topically to human subjects. METHODS: To model photoaging in vitro, human dermal fibroblasts (HDFs) were exposed in culture to UVA to induce collagenase (MMP-1) production. An in vitro wound-healing model was based on the activation of HDF migration into cell-free tissue culture surface. Hydrogen peroxide-induced oxidative stress was performed using HDFs to measure intracellular ROS activity. Radical scavenging capacity was determined using a colorimetric antioxidant assay kit (ABTS method). Lastly, a 4-week, 29-subject study was performed in which SIG1273 was applied topically as a cream to assess its tolerance and activity in reducing the appearance of aging. RESULTS: In vitro studies demonstrate SIG1273 inhibits UVA-induced MMP-1 production, hydrogen peroxide-induced oxidative stress and promotes wound healing. Moreover, SIG1273 was shown to be a radical scavenging antioxidant. Clinical assessment of SIG1273 cream (0.25%) showed it was well tolerated with significant improvement in the appearance of fine lines, coarse wrinkles, radiance/luminosity, pore size, texture/smoothness, hydration and increased firmness. CONCLUSIONS: SIG1273 represents a novel CFI with antioxidant, anti-aging, and anti-inflammatory properties that when applied topically is well tolerated and provides benefits to individuals with aging skin.


Asunto(s)
Cisteína/análogos & derivados , Oxidación-Reducción/efectos de los fármacos , Satisfacción del Paciente/estadística & datos numéricos , Envejecimiento de la Piel/efectos de los fármacos , Administración Cutánea , Adulto , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Cisteína/uso terapéutico , Estética , Fibroblastos/efectos de los fármacos , Estudios de Seguimiento , Humanos , Técnicas In Vitro , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento
17.
Ann Clin Transl Neurol ; 3(10): 769-780, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27752512

RESUMEN

OBJECTIVE: Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α-Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho-Ser129 phosphatase. The objective of this study was to investigate PP2A in α-synucleinopathies. METHODS: We compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT-1), and demethylating enzyme, protein phosphatase methylesterase (PME-1), in postmortem brains from PD and DLB cases as well as age-matched Controls. Immunohistochemical studies and quantitative image analysis were employed. RESULTS: LCMT-1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME-1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected. INTERPRETATION: These findings support the hypothesis that PP2A dysregulation in α-synucleinopathies may contribute to the accumulation of hyperphosphorylated α-synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease-modifying therapeutic approach.

18.
Neurobiol Aging ; 35(12): 2701-2712, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25034344

RESUMEN

A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimer's disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2(PP2A), or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic amyloid-ß protein. Dietary supplementation with EHT for 6-12 months resulted in substantial amelioration of all these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiologic studies indicating that coffee drinkers have substantially lowered risk of developing AD.


Asunto(s)
Enfermedad de Alzheimer/prevención & control , Café/química , Modelos Animales de Enfermedad , Fármacos Neuroprotectores , Serotonina/análogos & derivados , Animales , Femenino , Metilación/efectos de los fármacos , Proteína Fosfatasa 2/metabolismo , Ratas , Ratas Transgénicas , Serotonina/farmacología , Serotonina/uso terapéutico
19.
Neurotherapeutics ; 10(1): 143-53, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23296837

RESUMEN

Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD.


Asunto(s)
Antiinflamatorios/farmacología , Café/química , Intoxicación por MPTP/prevención & control , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Intoxicación por MPTP/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL
20.
Neurochem Int ; 61(6): 899-906, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22342821

RESUMEN

Phosphorylation is a key post-translational modification for cellular signaling, and abnormalities in this process are observed in several neurodegenerative disorders. Among these disorders, Parkinson's disease (PD) is particularly intriguing as there are both genetic causes of disease that involve phosphorylation, and pathological hallmarks of disease composed of a hyperphosphorylated protein. Two of the major genes linked to PD are themselves kinases - leucine rich repeat kinase 2 (LRRK2) and phosphatase and tensin induced homolog kinase 1 (PINK1). Mutations in LRRK2 lead to its increased kinase activity and dominantly inherited PD, while mutations in PINK1 lead to loss of function and recessive PD. A third genetic linkage to disease is α-synuclein, a protein that is heavily phosphorylated in Lewy bodies and Lewy neurites, the pathological hallmarks of PD. The phosphorylation of α-synuclein at various residues influences its aggregation, either positively or negatively, thereby impacting its central role in disease pathogenesis. Given these associations of phosphorylation with PD, modulation of this modification is an attractive therapeutic strategy. The kinases that act in these disease relevant pathways have been the primary target for such approaches. But, the development of kinase inhibitors has been complicated by the necessary specificity to retain safety, the redundancy of kinases leading to lack of efficacy, and the difficulties in overcoming the blood-brain barrier. The field of modulating phosphatases has the potential to overcome some of these issues and provide the next generation of therapeutic targets for PD. In this review, we address the phosphorylation pathways involved in PD, the kinases and issues related to their inhibition, and the evolving field of the phosphatases relevant in PD and how they may be targeted pharmacologically.


Asunto(s)
Enfermedad de Parkinson/tratamiento farmacológico , Monoéster Fosfórico Hidrolasas/metabolismo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Mutación , Monoéster Fosfórico Hidrolasas/uso terapéutico , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo
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