RESUMEN
During the aging process our body becomes less well equipped to deal with cellular stress, resulting in an increase in unrepaired damage. This causes varying degrees of impaired functionality and an increased risk of mortality. One of the most effective anti-aging strategies involves interventions that combine simultaneous glucometabolic support with augmented DNA damage protection/repair. Thus, it seems prudent to develop therapeutic strategies that target this combinatorial approach. Studies have shown that the ADP-ribosylation factor (ARF) GTPase activating protein GIT2 (GIT2) acts as a keystone protein in the aging process. GIT2 can control both DNA repair and glucose metabolism. Through in vivo co-regulation analyses it was found that GIT2 forms a close coexpression-based relationship with the relaxin-3 receptor (RXFP3). Cellular RXFP3 expression is directly affected by DNA damage and oxidative stress. Overexpression or stimulation of this receptor, by its endogenous ligand relaxin 3 (RLN3), can regulate the DNA damage response and repair processes. Interestingly, RLN3 is an insulin-like peptide and has been shown to control multiple disease processes linked to aging mechanisms, e.g., anxiety, depression, memory dysfunction, appetite, and anti-apoptotic mechanisms. Here we discuss the molecular mechanisms underlying the various roles of RXFP3/RLN3 signaling in aging and age-related disorders.
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Relaxina , Ansiedad , Apetito , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Relaxina/genética , Relaxina/metabolismo , Transducción de Señal/fisiologíaRESUMEN
With the rapidly expanding catalogue of scientific publications, especially within the Biomedical Sciences field, it is becoming increasingly difficult for researchers to search for, read or even interpret emerging scientific findings. PubMed, just one of the current biomedical data repositories, comprises over 33 million citations for biomedical research, and over 2500 publications are added each day. To further strengthen the impact biomedical research, we suggest that there should be more synergy between publications and machines. By bringing machines into the realm of research and publication, we can greatly augment the assessment, investigation and cataloging of the biomedical literary corpus. The effective application of machine-based manuscript assessment and interpretation is now crucial, and potentially stands as the most effective way for researchers to comprehend and process the tsunami of biomedical data and literature. Many biomedical manuscripts are currently published online in poorly searchable document types, with figures and data presented in formats that are partially inaccessible to machine-based approaches. The structure and format of biomedical manuscripts should be adapted to facilitate machine-assisted interrogation of this important literary corpus. In this context, it is important to embrace the concept that biomedical scientists should also write manuscripts that can be read by machines. It is likely that an enhanced human-machine synergy in reading biomedical publications will greatly enhance biomedical data retrieval and reveal novel insights into complex datasets.
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Investigación Biomédica , Almacenamiento y Recuperación de la Información , Humanos , PublicacionesRESUMEN
Aging is a highly complex molecular process, affecting nearly all tissue systems in humans and is the highest risk factor in developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease, cardiovascular disease and Type 2 diabetes mellitus. The intense complexity of the aging process creates an incentive to develop more specific drugs that attenuate or even reverse some of the features of premature aging. As our current pharmacopeia is dominated by therapeutics that target members of the G protein-coupled receptor (GPCR) superfamily it may be prudent to search for effective anti-aging therapeutics in this fertile domain. Since the first demonstration of GPCR-based ß-arrestin signaling, it has become clear that an enhanced appreciation of GPCR signaling diversity may facilitate the creation of therapeutics with selective signaling activities. Such 'biased' ligand signaling profiles can be effectively investigated using both standard molecular biological techniques as well as high-dimensionality data analyses. Through a more nuanced appreciation of the quantitative nature across the multiple dimensions of signaling bias that drugs possess, researchers may be able to further refine the efficacy of GPCR modulators to impact the complex aberrations that constitute the aging process. Identifying novel effector profiles could expand the effective pharmacopeia and assist in the design of precision medicines. This review discusses potential non-G protein effectors, and specifically their potential therapeutic suitability in aging and age-related disorders.
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Envejecimiento , Receptores Acoplados a Proteínas G , Transducción de Señal , Envejecimiento/fisiología , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/fisiologíaRESUMEN
It is widely accepted that molecular reductionist views of highly complex human physiologic activity, e.g., the aging process, as well as therapeutic drug efficacy are largely oversimplifications. Currently some of the most effective appreciation of biologic disease and drug response complexity is achieved using high-dimensionality (H-D) data streams from transcriptomic, proteomic, metabolomics, or epigenomic pipelines. Multiple H-D data sets are now common and freely accessible for complex diseases such as metabolic syndrome, cardiovascular disease, and neurodegenerative conditions such as Alzheimer's disease. Over the last decade our ability to interrogate these high-dimensionality data streams has been profoundly enhanced through the development and implementation of highly effective bioinformatic platforms. Employing these computational approaches to understand the complexity of age-related diseases provides a facile mechanism to then synergize this pathologic appreciation with a similar level of understanding of therapeutic-mediated signaling. For informative pathology and drug-based analytics that are able to generate meaningful therapeutic insight across diverse data streams, novel informatics processes such as latent semantic indexing and topological data analyses will likely be important. Elucidation of H-D molecular disease signatures from diverse data streams will likely generate and refine new therapeutic strategies that will be designed with a cognizance of a realistic appreciation of the complexity of human age-related disease and drug effects. We contend that informatic platforms should be synergistic with more advanced chemical/drug and phenotypic cellular/tissue-based analytical predictive models to assist in either de novo drug prioritization or effective repurposing for the intervention of aging-related diseases. SIGNIFICANCE STATEMENT: All diseases, as well as pharmacological mechanisms, are far more complex than previously thought a decade ago. With the advent of commonplace access to technologies that produce large volumes of high-dimensionality data (e.g., transcriptomics, proteomics, metabolomics), it is now imperative that effective tools to appreciate this highly nuanced data are developed. Being able to appreciate the subtleties of high-dimensionality data will allow molecular pharmacologists to develop the most effective multidimensional therapeutics with effectively engineered efficacy profiles.
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Enfermedades Cardiovasculares/tratamiento farmacológico , Interpretación Estadística de Datos , Síndrome Metabólico/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Farmacología/métodos , Animales , Biología Computacional , Humanos , Análisis de Componente PrincipalRESUMEN
DNA damage response (DDR) processes, often caused by oxidative stress, are important in aging and -related disorders. We recently showed that G protein-coupled receptor (GPCR) kinase interacting protein 2 (GIT2) plays a key role in both DNA damage and oxidative stress. Multiple tissue analyses in GIT2KO mice demonstrated that GIT2 expression affects the GPCR relaxin family peptide 3 receptor (RXFP3), and is thus a therapeutically-targetable system. RXFP3 and GIT2 play similar roles in metabolic aging processes. Gaining a detailed understanding of the RXFP3-GIT2 functional relationship could aid the development of novel anti-aging therapies. We determined the connection between RXFP3 and GIT2 by investigating the role of RXFP3 in oxidative stress and DDR. Analyzing the effects of oxidizing (H2O2) and DNA-damaging (camptothecin) stressors on the interacting partners of RXFP3 using Affinity Purification-Mass Spectrometry, we found multiple proteins linked to DDR and cell cycle control. RXFP3 expression increased in response to DNA damage, overexpression, and Relaxin 3-mediated stimulation of RXFP3 reduced phosphorylation of DNA damage marker H2AX, and repair protein BRCA1, moderating DNA damage. Our data suggests an RXFP3-GIT2 system that could regulate cellular degradation after DNA damage, and could be a novel mechanism for mitigating the rate of age-related damage accumulation.
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Daño del ADN , Proteínas Activadoras de GTPasa/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Estrés Oxidativo , Receptores Acoplados a Proteínas G/metabolismo , Camptotecina/toxicidad , Biología Computacional , Felodipino , Proteínas Activadoras de GTPasa/genética , Regulación de la Expresión Génica/fisiología , Redes Reguladoras de Genes , Células HEK293 , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/genética , Inhibidores de Topoisomerasa I/toxicidadRESUMEN
In most species, females live longer than males. An understanding of this female longevity advantage will likely uncover novel anti-aging therapeutic targets. Here we investigated the transcriptomic responses in the hypothalamus - a key organ for somatic aging control - to the introduction of a simple aging-related molecular perturbation, i.e. GIT2 heterozygosity. Our previous work has demonstrated that GIT2 acts as a network controller of aging. A similar number of both total (1079-female, 1006-male) and gender-unique (577-female, 527-male) transcripts were significantly altered in response to GIT2 heterozygosity in early life-stage (2 month-old) mice. Despite a similar volume of transcriptomic disruption in females and males, a considerably stronger dataset coherency and functional annotation representation was observed for females. It was also evident that female mice possessed a greater resilience to pro-aging signaling pathways compared to males. Using a highly data-dependent natural language processing informatics pipeline, we identified novel functional data clusters that were connected by a coherent group of multifunctional transcripts. From these it was clear that females prioritized metabolic activity preservation compared to males to mitigate this pro-aging perturbation. These findings were corroborated by somatic metabolism analyses of living animals, demonstrating the efficacy of our new informatics pipeline.
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Envejecimiento/genética , Envejecimiento/fisiología , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/fisiología , Hipotálamo/metabolismo , Animales , Análisis por Conglomerados , Biología Computacional , Femenino , Longevidad/genética , Longevidad/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , ARN/biosíntesis , ARN/genética , Caracteres Sexuales , Transducción de Señal/genética , Transducción de Señal/fisiología , TranscriptomaRESUMEN
The initial diagnosis, molecular investigation, treatment, and posttreatment care of major psychiatric disorders (schizophrenia and bipolar depression) are all still significantly hindered by the current inability to define these disorders in an explicit molecular signaling manner. High-dimensionality data analytics, using large datastreams from transcriptomic, proteomic, or metabolomic investigations, will likely advance both the appreciation of the molecular nature of major psychiatric disorders and simultaneously enhance our ability to more efficiently diagnose and treat these debilitating conditions. High-dimensionality data analysis in psychiatric research has been heterogeneous in aims and methods and limited by insufficient sample sizes, poorly defined case definitions, methodological inhomogeneity, and confounding results. All of these issues combine to constrain the conclusions that can be extracted from them. Here, we discuss possibilities for overcoming methodological challenges through the implementation of transcriptomic, proteomic, or metabolomics signatures in psychiatric diagnosis and offer an outlook for future investigations. To fulfill the promise of intelligent high-dimensionality data-based differential diagnosis in mental disease diagnosis and treatment, future research will need large, well-defined cohorts in combination with state-of-the-art technologies.
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Biomarcadores , Biología Computacional , Susceptibilidad a Enfermedades , Trastornos Mentales/etiología , Trastornos Mentales/metabolismo , Animales , Biología Computacional/métodos , Interpretación Estadística de Datos , Perfilación de la Expresión Génica , Humanos , Trastornos Mentales/diagnóstico , Trastornos Mentales/psicología , Metabolómica/métodos , Fenotipo , Proteoma , Proteómica/métodos , TranscriptomaRESUMEN
Aging is a complex biological process that is inevitable for nearly all organisms. Aging is the strongest risk factor for development of multiple neurodegenerative disorders, cancer and cardiovascular disorders. Age-related disease conditions are mainly caused by the progressive degradation of the integrity of communication systems within and between organs. This is in part mediated by, i) decreased efficiency of receptor signaling systems and ii) an increasing inability to cope with stress leading to apoptosis and cellular senescence. Cellular senescence is a natural process during embryonic development, more recently it has been shown to be also involved in the development of aging disorders and is now considered one of the major hallmarks of aging. G-protein-coupled receptors (GPCRs) comprise a superfamily of integral membrane receptors that are responsible for cell signaling events involved in nearly every physiological process. Recent advances in the molecular understanding of GPCR signaling complexity have expanded their therapeutic capacity tremendously. Emerging data now suggests the involvement of GPCRs and their associated proteins in the development of cellular senescence. With the proven efficacy of therapeutic GPCR targeting, it is reasonable to now consider GPCRs as potential platforms to control cellular senescence and the consequently, age-related disorders.
RESUMEN
G protein coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of ß-arrestin functionality. ß-Arrestins were first thought to only regulate receptor desensitization and internalization - exemplified by the action of visual arrestin with respect to rhodopsin desensitization. Nearly 20 years ago, it was found that rather than controlling GPCR signal termination, productive ß-arrestin dependent GPCR signaling paradigms were highly dependent on multi-protein complex formation and generated long-lasting cellular effects, in contrast to G protein signaling which is transient and functions through soluble second messenger systems. ß-Arrestin signaling was then first shown to activate mitogen activated protein kinase signaling in a G protein-independent manner and eventually initiate protein transcription - thus controlling expression patterns of downstream proteins. While the possibility of developing ß-arrestin biased or functionally selective ligands is now being investigated, no additional research has been performed on its possible contextual specificity in treating age-related disorders. The ability of ß-arrestin-dependent signaling to control complex and multidimensional protein expression patterns makes this therapeutic strategy feasible, as treating complex age-related disorders will likely require therapeutics that can exert network-level efficacy profiles. It is our understanding that therapeutically targeting G protein-independent effectors such as ß-arrestin will aid in the development of precision medicines with tailored efficacy profiles for disease/age-specific contextualities.
RESUMEN
G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and physiological resilience. This is in part mediated by age-related aberrations in energy metabolism, mitochondrial function, protein folding and sorting, inflammatory activity and genomic stability. Indeed, an increased rate of unrepaired DNA damage is considered to be one of the 'hallmarks' of aging. Over the last two decades our appreciation of the complexity of GPCR signaling systems has expanded their functional signaling repertoire. One such example of this is the incipient role of GPCRs and GPCR-interacting proteins in DNA damage and repair mechanisms. Emerging data now suggest that GPCRs could function as stress sensors for intracellular damage, e.g., oxidative stress. Given this role of GPCRs in the DNA damage response process, coupled to the effective history of drug targeting of these receptors, this suggests that one important future activity of GPCR therapeutics is the rational control of DNA damage repair systems.
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Daño del ADN , Reparación del ADN , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/fisiología , Envejecimiento/fisiología , Animales , Metabolismo Energético/fisiología , Humanos , Mapas de Interacción de Proteínas/fisiologíaRESUMEN
Biomedical data sets are becoming increasingly larger and a plethora of high-dimensionality data sets ("Big Data") are now freely accessible for neurodegenerative diseases, such as Alzheimer's disease. It is thus important that new informatic analysis platforms are developed that allow the organization and interrogation of Big Data resources into a rational and actionable mechanism for advanced therapeutic development. This will entail the generation of systems and tools that allow the cross-platform correlation between data sets of distinct types, for example, transcriptomic, proteomic, and metabolomic. Here, we provide a comprehensive overview of the latest strategies, including latent semantic analytics, topological data investigation, and deep learning techniques that will drive the future development of diagnostic and therapeutic applications for Alzheimer's disease. We contend that diverse informatic "Big Data" platforms should be synergistically designed with more advanced chemical/drug and cellular/tissue-based phenotypic analytical predictive models to assist in either de novo drug design or effective drug repurposing.
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Macrodatos , Minería de Datos/métodos , Enfermedades Neurodegenerativas/terapia , Genómica , Humanos , Metabolómica , ProteómicaRESUMEN
Since its discovery, G protein-coupled receptor kinase-interacting protein 2, GIT2, and its family member, GIT1, have received considerable interest concerning their potential key roles in regulating multiple inter-connected physiological and pathophysiological processes. GIT2 was first identified as a multifunctional protein that is recruited to G protein-coupled receptors (GPCRs) during the process of receptor internalization. Recent findings have demonstrated that perhaps one of the most important effects of GIT2 in physiology concerns its role in controlling multiple aspects of the complex ageing process. Ageing can be considered the most prevalent pathophysiological condition in humans, affecting all tissue systems and acting as a driving force for many common and intractable disorders. The ageing process involves a complex interplay among various deleterious activities that profoundly disrupt the body's ability to cope with damage, thus increasing susceptibility to pathophysiologies such as neurodegeneration, central obesity, osteoporosis, type 2 diabetes mellitus and atherosclerosis. The biological systems that control ageing appear to function as a series of interconnected complex networks. The inter-communication among multiple lower-complexity signaling systems within the global ageing networks is likely coordinated internally by keystones or hubs, which regulate responses to dynamic molecular events through protein-protein interactions with multiple distinct partners. Multiple lines of research have suggested that GIT2 may act as one of these network coordinators in the ageing process. Identifying and targeting keystones, such as GIT2, is thus an important approach in our understanding of, and eventual ability to, medically ameliorate or interdict age-related progressive cellular and tissue damage.
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Envejecimiento/genética , Envejecimiento/metabolismo , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Envejecimiento/patología , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Fosfoproteínas/genética , Fosfoproteínas/metabolismoRESUMEN
Complex aging-triggered disorders are multifactorial programs that comprise a myriad of alterations in interconnected protein networks over a broad range of tissues. It is evident that rather than being randomly organized events, pathophysiologies that possess a strong aging component such as cardiovascular diseases (hypertensions, atherosclerosis, and vascular stiffening) and neurodegenerative conditions (dementia, Alzheimer's disease, mild cognitive impairment, Parkinson's disease), in essence represent a subtly modified version of the intricate molecular programs already in place for normal aging. To control such multidimensional activities there are layers of trophic protein control across these networks mediated by so-called "keystone" proteins. We propose that these "keystones" coordinate and interconnect multiple signaling pathways to control whole somatic activities such as aging-related disease etiology. Given its ability to control multiple receptor sensitivities and its broad protein-protein interactomic nature, we propose that G protein coupled receptor kinase 5 (GRK5) represents one of these key network controllers. Considerable data has emerged, suggesting that GRK5 acts as a bridging factor, allowing signaling regulation in pathophysiological settings to control the connectivity between both the cardiovascular and neurophysiological complications of aging.
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The type 1 taste receptor member 3 (T1R3) is a G protein-coupled receptor involved in sweet-taste perception. Besides the tongue, the T1R3 receptor is highly expressed in brain areas implicated in cognition, including the hippocampus and cortex. As cognitive decline is often preceded by significant metabolic or endocrinological dysfunctions regulated by the sweet-taste perception system, we hypothesized that a disruption of the sweet-taste perception in the brain could have a key role in the development of cognitive dysfunction. To assess the importance of the sweet-taste receptors in the brain, we conducted transcriptomic and proteomic analyses of cortical and hippocampal tissues isolated from T1R3 knock-out (T1R3KO) mice. The effect of an impaired sweet-taste perception system on cognition functions were examined by analyzing synaptic integrity and performing animal behavior on T1R3KO mice. Although T1R3KO mice did not present a metabolically disrupted phenotype, bioinformatic interpretation of the high-dimensionality data indicated a strong neurodegenerative signature associated with significant alterations in pathways involved in neuritogenesis, dendritic growth, and synaptogenesis. Furthermore, a significantly reduced dendritic spine density was observed in T1R3KO mice together with alterations in learning and memory functions as well as sociability deficits. Taken together our data suggest that the sweet-taste receptor system plays an important neurotrophic role in the extralingual central nervous tissue that underpins synaptic function, memory acquisition, and social behavior.
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Conducta Animal , Espinas Dendríticas/metabolismo , Aprendizaje , Memoria , Neuritas/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Conducta Social , Animales , Espinas Dendríticas/patología , Ratones , Ratones Noqueados , Neuritas/patologíaRESUMEN
Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of 'neurometabolic' integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2-/- mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2-/- (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical 'organ', i.e. 'parathymic lobes'. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe - suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature 'aging' phenotype of GIT2KO mice.
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Envejecimiento Prematuro/genética , Envejecimiento/genética , Proteínas de Ciclo Celular/genética , Senescencia Celular/genética , Sistema Inmunológico/fisiopatología , Fosfoproteínas/genética , Timo/fisiopatología , Envejecimiento/inmunología , Envejecimiento/fisiología , Envejecimiento Prematuro/inmunología , Envejecimiento Prematuro/fisiopatología , Animales , Proteínas Activadoras de GTPasa , Péptidos y Proteínas de Señalización Intercelular , Queratina-8/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/genética , Timo/inmunología , TranscriptomaRESUMEN
OBJECTIVE: To evaluate the safety and tolerability of alternate-day fasting (ADF) and to compare changes in weight, body composition, lipids, and insulin sensitivity index (Si) with those produced by a standard weight loss diet, moderate daily caloric restriction (CR). METHODS: Adults with obesity (BMI ≥30 kg/m(2) , age 18-55) were randomized to either zero-calorie ADF (n = 14) or CR (-400 kcal/day, n = 12) for 8 weeks. Outcomes were measured at the end of the 8-week intervention and after 24 weeks of unsupervised follow-up. RESULTS: No adverse effects were attributed to ADF, and 93% completed the 8-week ADF protocol. At 8 weeks, ADF achieved a 376 kcal/day greater energy deficit; however, there were no significant between-group differences in change in weight (mean ± SE; ADF -8.2 ± 0.9 kg, CR -7.1 ± 1.0 kg), body composition, lipids, or Si. After 24 weeks of unsupervised follow-up, there were no significant differences in weight regain; however, changes from baseline in % fat mass and lean mass were more favorable in ADF. CONCLUSIONS: ADF is a safe and tolerable approach to weight loss. ADF produced similar changes in weight, body composition, lipids, and Si at 8 weeks and did not appear to increase risk for weight regain 24 weeks after completing the intervention.
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Restricción Calórica , Ayuno , Obesidad/dietoterapia , Adulto , Composición Corporal , Peso Corporal , Dieta Reductora/métodos , Ingestión de Energía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Resultado del Tratamiento , Pérdida de PesoRESUMEN
Ligands possessing different physico-chemical structures productively interact with G protein-coupled receptors generating distinct downstream signaling events due to their abilities to activate/select idiosyncratic receptor entities ('receptorsomes') from the full spectrum of potential receptor partners. We have employed multiple novel informatic approaches to identify and characterize the in vivo transcriptomic signature of an arrestin-signaling biased ligand, [D-Trp(12),Tyr(34)]-bPTH(7-34), acting at the parathyroid hormone type 1 receptor (PTH1R), across six different murine tissues after chronic drug exposure. We are able to demonstrate that [D-Trp(12),Tyr(34)]-bPTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated, in an arrestin signaling-dependent manner, across more tissues than that of the pluripotent endogenous PTH1R ligand, hPTH(1-34). This arrestin-focused response signature is strongly linked with the transcriptional regulation of cell growth and development. Our informatic deconvolution of a conserved arrestin-dependent transcriptomic signature from wild type mice demonstrates a conceptual framework within which the in vivo outcomes of biased receptor signaling may be further investigated or predicted.
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Redes Reguladoras de Genes/fisiología , Informática/métodos , Hormona Paratiroidea/farmacología , Receptores Acoplados a Proteínas G/fisiología , Transducción de Señal/fisiología , Animales , Bovinos , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Hormona Paratiroidea/metabolismo , Receptor de Hormona Paratiroídea Tipo 1/agonistas , Receptor de Hormona Paratiroídea Tipo 1/fisiología , Receptores Acoplados a Proteínas G/agonistas , Transducción de Señal/efectos de los fármacosRESUMEN
Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.
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Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.