RESUMEN
Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that plays a role in many biological processes. Reversible carboxyl methylation of the PP2A catalytic subunit is an essential regulatory mechanism for its function. Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. However, the underlying mechanism of PME-1 function remains enigmatic. Here we report the crystal structures of PME-1 by itself and in complex with a PP2A heterodimeric core enzyme. The structures reveal that PME-1 directly binds to the active site of PP2A and that this interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. Strikingly, these interactions also lead to inactivation of PP2A by evicting the manganese ions that are required for the phosphatase activity of PP2A. These observations identify a dual role of PME-1 that regulates PP2A activation, methylation, and holoenzyme assembly in cells.
Asunto(s)
Proteína Fosfatasa 2/química , Proteína Fosfatasa 2/metabolismo , Secuencia de Aminoácidos , Animales , Hidrolasas de Éster Carboxílico/química , Cristalografía por Rayos X , Humanos , Metilación , Modelos Moleculares , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
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/etiologíaRESUMEN
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/metabolismoRESUMEN
Environmental stimuli attack the skin daily resulting in the generation of reactive oxygen species (ROS) and inflammation. One pathway that regulates oxidative stress in skin involves Protein Phosphatase 2A (PP2A), a phosphatase which has been previously linked to Alzheimer's Disease and aging. Oxidative stress decreases PP2A methylation in normal human dermal fibroblasts (NHDFs). Thus, we hypothesize agents that increase PP2A methylation and activity will promote skin health and combat aging. To discover novel inhibitors of PP2A demethylation activity, we screened a library of 32 natural botanical extracts. We discovered Grape Seed Extract (GSE), which has previously been reported to have several benefits for skin, to be the most potent PP2A demethylating extract. Via several fractionation and extraction steps we developed a novel grape seed extract called Activated Grape Seed Extract (AGSE), which is enriched for PP2A activating flavonoids that increase potency in preventing PP2A demethylation when compared to commercial GSE. We then determined that 1% AGSE and 1% commercial GSE exhibit distinct gene expression profiles when topically applied to a 3D human skin model. To begin to characterize AGSE's activity, we investigated its antioxidant potential and demonstrate it reduces ROS levels in NHDFs and cell-free assays equal to or better than Vitamin C and E. Moreover, AGSE shows anti-inflammatory properties, dose-dependently inhibiting UVA, UVB and chemical-induced inflammation. These results demonstrate AGSE is a novel, multi-functional extract that modulates methylation levels of PP2A and supports the hypothesis of PP2A as a master regulator for oxidative stress signaling and aging in skin.
Asunto(s)
Flavonoides/farmacología , Extracto de Semillas de Uva/farmacología , Estrés Oxidativo/efectos de los fármacos , Piel/efectos de los fármacos , Piel/metabolismo , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Fraccionamiento Químico , Cromatografía Líquida de Alta Presión , Citocinas/biosíntesis , Desmetilación/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Flavonoides/química , Flavonoides/aislamiento & purificación , Extracto de Semillas de Uva/química , Extracto de Semillas de Uva/aislamiento & purificación , Humanos , Proteína Fosfatasa 2/metabolismoRESUMEN
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 JovenRESUMEN
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/genéticaRESUMEN
Phosphorylation is a key post-translational modification necessary for normal cellular signaling and, therefore, lies at the heart of cellular function. In neurodegenerative disorders, abnormal hyperphosphorylation of pathogenic proteins is a common phenomenon that contributes in important ways to the disease process. A prototypical protein that is hyperphosphorylated in the brain is α-synuclein (α-syn) - found in Lewy bodies and Lewy neurites - the pathological hallmarks of Parkinson's disease (PD) and other α-synucleinopathies. The genetic linkage of α-syn to PD as well as its pathological association in both genetic and sporadic cases have made it the primary protein of interest. In understanding how α-syn dysfunction occurs, increasing focus is being placed on its abnormal aggregation and the contribution of phosphorylation to this process. Studies of both the kinases and phosphatases that regulate α-syn phosphorylation are beginning to reveal the roles of this post-translational modification in disease pathogenesis. Modulation of α-syn phosphorylation may ultimately prove to be a viable strategy for disease-modifying therapeutic interventions. In this review, we explore mechanisms related to α-syn phosphorylation, its biophysical and functional consequences, and its role in neurodegeneration.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Cuerpos de Lewy/patología , Terapia Molecular Dirigida , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , alfa-Sinucleína/metabolismo , Animales , Quinasa de la Caseína I/metabolismo , Quinasa de la Caseína II/metabolismo , Drosophila , Quinasas de Receptores Acoplados a Proteína-G/metabolismo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Ratones , Ratones Transgénicos , Neuronas/patología , Fosforilación , Ratas , Serina/metabolismo , alfa-Sinucleína/genética , Quinasa Tipo Polo 1RESUMEN
The small t antigen (ST) of DNA tumor virus SV40 facilitates cellular transformation by disrupting the functions of protein phosphatase 2A (PP2A) through a poorly defined mechanism. The crystal structure of the core domain of SV40 ST bound to the scaffolding subunit of human PP2A reveals that the ST core domain has a novel zinc-binding fold and interacts with the conserved ridge of HEAT repeats 3-6, which overlaps with the binding site for the B' (also called PR61 or B56) regulatory subunit. ST has a lower binding affinity than B' for the PP2A core enzyme. Consequently, ST does not efficiently displace B' from PP2A holoenzymes in vitro. Notably, ST inhibits PP2A phosphatase activity through its N-terminal J domain. These findings suggest that ST may function mainly by inhibiting the phosphatase activity of the PP2A core enzyme, and to a lesser extent by modulating assembly of the PP2A holoenzymes.
Asunto(s)
Antígenos Virales de Tumores/metabolismo , Transformación Celular Viral/fisiología , Modelos Moleculares , Proteína Fosfatasa 2/metabolismo , Virus 40 de los Simios/inmunología , Secuencia de Aminoácidos , Antígenos Virales de Tumores/genética , Transformación Celular Viral/genética , Cristalización , Electroforesis en Gel de Poliacrilamida , Humanos , Datos de Secuencia Molecular , Proteína Fosfatasa 2/genética , Estructura Terciaria de Proteína , Subunidades de Proteína/genética , Virus 40 de los Simios/fisiologíaRESUMEN
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/metabolismoRESUMEN
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 farmacológicoRESUMEN
Signal transduction systems that mediate adaptive changes in gene expression to specific sensory inputs have been well characterized. Recent studies have focused on mechanisms that allow crosstalk between different information-processing modalities.
Asunto(s)
Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Escherichia coli/fisiología , Regulación Bacteriana de la Expresión Génica , Transducción de Señal , Escherichia coli/genética , Escherichia coli/metabolismo , Histidina Quinasa , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Members of the Ras superfamily of small GTPases and the heterotrimeric G protein gamma subunit are methylated on their carboxy-terminal cysteine residues by isoprenylcysteine methyltransferase. In Dictyostelium discoideum, small GTPase methylation occurs seconds after stimulation of starving cells by cAMP and returns quickly to basal levels, suggesting an important role in cAMP-dependent signaling. Deleting the isoprenylcysteine methyltransferase-encoding gene causes dramatic defects. Starving mutant cells do not propagate cAMP waves in a sustained manner, and they do not aggregate. Motility is rescued when cells are pulsed with exogenous cAMP, or coplated with wild-type cells, but the rescued cells exhibit altered polarity. cAMP-pulsed methyltransferase-deficient cells that have aggregated fail to differentiate, but mutant cells plated in a wild-type background are able to do so. Localization of and signaling by RasG is altered in the mutant. Localization of the heterotrimeric Ggamma protein subunit was normal, but signaling was altered in mutant cells. These data indicate that isoprenylcysteine methylation is required for intercellular signaling and development in Dictyostelium.
Asunto(s)
Dictyostelium/crecimiento & desarrollo , Proteína Metiltransferasas/metabolismo , Animales , Sistema Libre de Células , Quimiotaxis , Clonación Molecular , AMP Cíclico/metabolismo , Dictyostelium/citología , Dictyostelium/enzimología , Dictyostelium/genética , Privación de Alimentos , Eliminación de Gen , Regulación de la Expresión Génica , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Metilación , Fenotipo , Transporte de Proteínas , Proteínas Protozoarias/metabolismo , Receptores de AMP Cíclico/metabolismo , Transducción de SeñalRESUMEN
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 , PielRESUMEN
Bacterial chemotaxis is mediated by two reversible protein modification chemistries: phosphorylation and carboxyl methylation. Attractants bind to membrane chemoreceptors that control the activity of a protein kinase which acts in turn to control flagellar motor activity. Coordinate changes in receptor carboxyl methylation provide a negative feedback mechanism that serves a memory function. Protein carboxyl methylation might play an analogous role in the nervous system. Two protein carboxyl methyltransferases serve to regulate signal transduction pathways in eukaryotic cells. One is highly expressed in the Purkinje layer of the cerebellum where it methyl esterifies prenylated cysteine residues at the carboxyl-termini of Ras-related and heterotrimeric G-proteins. The other is abundant throughout the brain where it methylates the carboxyl-terminus of protein phosphatase 2A. The phosphatase methyltransferase and the protein methylesterase that reverses phosphatase methylation are structurally related to the corresponding bacterial chemotaxis methylating and demethylating enzymes. Recent results indicate that deficiencies in phosphatase methylation play an important role in the etiology of Alzheimer's disease.
Asunto(s)
Ácidos Carboxílicos/metabolismo , Proteínas/química , Proteínas/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Bacterias/citología , Bacterias/metabolismo , Quimiotaxis , Células Eucariotas/citología , Células Eucariotas/metabolismo , Humanos , MetilaciónRESUMEN
Bacteria can detect and respond to a remarkably diverse set of environmental conditions. This ability enables motile species to integrate stimuli, to compare current surroundings with those of the recent past, and to adjust swimming behavior to move up gradients of attractants and avoid repellents. Many of the molecular details involved in the bacterial chemotaxis system have been elucidated. Several models have been proposed recently to explain how cells process external information through a patch of highly interactive transmembrane receptors and transduce this information to other components in the cytoplasm that, in turn, function to regulate motility.
Asunto(s)
Fenómenos Fisiológicos Bacterianos , Membrana Celular/metabolismo , Transducción de Señal , Proteínas Bacterianas/fisiología , Movimiento Celular , Quimiotaxis , Citoplasma/metabolismo , Escherichia coli/metabolismo , Flagelos/metabolismo , Modelos BiológicosRESUMEN
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.
RESUMEN
Motile bacteria regulate chemotaxis through a highly conserved chemosensory signal-transduction system. System-wide analyses and mathematical modeling are facilitated by extensive experimental observations regarding bacterial chemotaxis proteins, including biochemical parameters, protein structures and protein-protein interaction maps. Thousands of signaling and regulatory chemotaxis proteins within a bacteria cell form a highly interconnected network through distinct protein-protein interactions. A bacterial cell is able to respond to multiple stimuli through a collection of chemoreceptors with different sensory modalities, which interact to affect the cooperativity and sensitivity of the chemotaxis response. The robustness or insensitivity of the chemotaxis system to perturbations in biochemical parameters is a product of the system's hierarchical network architecture.
Asunto(s)
Bacterias/metabolismo , Proteínas Bacterianas/metabolismo , Quimiotaxis , Transducción de Señal , Adaptación Fisiológica , Fenómenos Fisiológicos Bacterianos , Receptores de Superficie Celular/metabolismoRESUMEN
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/metabolismoRESUMEN
Bacterial chemotaxis is mediated by transmembrane receptors that bind attractant and repellent chemicals and control an intracellular protein kinase. Each cell contains thousands of receptor subunits that form a tightly packed array at one pole. Recent studies of bacterial behavior have begun to reveal the molecular logic of this sensory architecture.