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1.
Proc Natl Acad Sci U S A ; 120(52): e2308565120, 2023 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-38113255

RESUMEN

Coordination of cellular responses to stress is essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here, we identify how SKN-1 activation in two ciliated ASI neurons in Caenorhabditis elegans results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of noncoding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a unique regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, drh-1, in the intestine, can oppose the effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell nonautonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.


Asunto(s)
Proteínas de Caenorhabditis elegans , Factores de Transcripción , Animales , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Estrés Oxidativo/fisiología , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Longevidad/genética , Neuronas/metabolismo
2.
Can J Anaesth ; 69(9): 1099-1106, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35761062

RESUMEN

PURPOSE: Hypoalbuminemia has been described as a modifiable factor to optimize postoperative outcomes after major inpatient surgeries. Nevertheless, the role of hypoalbuminemia on outpatient procedures is not well defined. The purpose of this study was to examine the impact of hypoalbuminemia on postoperative outcomes of patients undergoing low-risk outpatient surgery. METHODS: Patients were extracted from the American College of Surgeons National Surgical Quality Improvement Program database who had outpatient surgery from 2018 and recorded preoperative albumin levels. The primary outcome was a composite of any major complications including: 1) unplanned intubation, 2) pulmonary embolism, 3) ventilator use > 48 hr, 4) progressive renal failure, 5) acute renal failure, 6) stroke/cerebrovascular accident, 7) cardiac arrest, 8) myocardial infarction, 9) sepsis, 10) septic shock, 11) deep venous thrombosis, and 12) transfusion. Death, any infection, and readmissions were secondary outcomes. RESULTS: A total of 65,192 (21%) surgical outpatients had albumin collected preoperatively and 3,704 (1.2%) patients had levels below 3.5 g⋅dL-1. In the albumin cohort, 394/65,192 (0.6%) patients had a major medical complication and 68/65,192 (0.1%) patients died within 30 days after surgery. Albumin values < 3.5 g⋅dL-1 were associated with major complications (adjusted odds ratio [aOR], 1.92; 95% confidence interval [CI], 1.44 to 2.57; P < 0.001; death-adjusted OR, 3.03; 95% CI, 1.72 to 5.34; P < 0.001); any infection (aOR, 1.49; 95% CI, 1.23 to 1.82; P < 0.001); and readmissions (aOR, 1.82; 95% CI, 1.56 to 2.14; P < 0.001). In addition, when evaluated as a continuous variable in a multivariate analysis, for each increase in albumin of 0.10 g⋅dL-1, there was an associated reduction of major complications (aOR, 0.94; 95% CI, 0.92 to 0.96; P < 0.001). CONCLUSIONS: Hypoalbuminemia is associated with major complications and death in outpatient surgery. Since hypoalbuminemia is a potential modifiable intervention, future clinical trials to evaluate the impact of optimizing preoperative albumin levels before outpatient surgery are warranted.


RéSUMé: OBJECTIF: L'hypoalbuminémie a été décrite comme un facteur modifiable pour optimiser les issues postopératoires après des chirurgies hospitalières majeures. Néanmoins, le rôle de l'hypoalbuminémie dans les interventions ambulatoires n'est pas bien défini. L'objectif de cette étude était d'examiner l'impact de l'hypoalbuminémie sur les issues postopératoires des patients bénéficiant d'une chirurgie ambulatoire à faible risque. MéTHODE: Les patients ayant bénéficié d'une chirurgie ambulatoire à partir de 2018 et pour lesquels les taux d'albumine préopératoire ont été enregistrés ont été extraits de la base de données américaine du programme national d'amélioration de la qualité chirurgicale (NSQIP) de l'American College of Surgeons. Le critère d'évaluation principal était un composite de toutes les complications majeures, y compris : 1) intubation non planifiée, 2) embolie pulmonaire, 3) utilisation d'un ventilateur > 48 h, 4) insuffisance rénale progressive, 5) insuffisance rénale aiguë, 6) accident vasculaire cérébral, 7) arrêt cardiaque, 8) infarctus du myocarde, 9) sepsis, 10) choc septique, 11) thrombose veineuse profonde, et 12) transfusion. Les décès, infections et réadmissions constituaient des critères d'évaluation secondaires. RéSULTATS: Au total, les taux d'albumine ont été prélevés chez 65 192 (21 %) patients chirurgicaux ambulatoires avant l'opération et 3704 (1,2 %) patients avaient des taux inférieurs à 3,5 g⋅dL-1. Dans la cohorte albumine, 394 / 65 192 (0,6 %) patients ont eu une complication médicale majeure et 68 / 65 192 (0,1%) patients sont décédés dans les 30 jours suivant la chirurgie. Des valeurs d'albumine < 3,5 g⋅dL-1 étaient associées à des complications majeures (rapport de cotes ajusté [RCA]), 1,92 ; intervalle de confiance [IC] à 95 %, 1,44 à 2,57; P < 0,001; RC ajusté en fonction du décès, 3,03; IC 95 %, 1,72 à 5,34; P < 0,001); infections (RCA, 1,49; IC 95 %, 1,23 à 1,82; P < 0,001); et réadmissions (RCA, 1,82; IC 95 %, 1,56 à 2,14; P < 0,001). De plus, lorsque le taux d'albumine était évalué comme variable continue dans une analyse multivariée, pour chaque augmentation de l'albumine de 0,10 g⋅dL-1, il y avait une réduction associée des complications majeures (RCA, 0,94; IC 95 %, 0,92 à 0,96; P < 0,001). CONCLUSION: L'hypoalbuminémie est associée à des complications majeures et au décès en chirurgie ambulatoire. Étant donné que l'hypoalbuminémie est une intervention potentiellement modifiable, de futures études cliniques visant à évaluer l'impact de l'optimisation des taux préopératoires d'albumine avant une chirurgie ambulatoire sont nécessaires.


Asunto(s)
Hipoalbuminemia , Albúminas , Procedimientos Quirúrgicos Ambulatorios , Bases de Datos Factuales , Humanos , Hipoalbuminemia/complicaciones , Hipoalbuminemia/epidemiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Riesgo
3.
Proc Natl Acad Sci U S A ; 116(44): 22322-22330, 2019 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-31611372

RESUMEN

Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from pathogen response genes while restoring somatic lipid distribution. In addition, activating p38/MAPK signaling in the absence of pathogens, is sufficient to drive SKN-1-dependent loss of somatic fat. These data define a SKN-1- and p38-dependent axis for coordinating pathogen responses, lipid homeostasis, and survival and identify transcriptional redirection, rather than inactivation, as a mechanism for counteracting the pleiotropic consequences of aberrant transcriptional activity.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Metabolismo de los Lípidos , Infecciones por Pseudomonas/genética , Factores de Transcripción/metabolismo , Animales , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Unión al ADN/genética , Inmunidad Innata , Sistema de Señalización de MAP Quinasas , Estrés Oxidativo , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/patogenicidad , Factores de Transcripción/genética , Transcriptoma , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
4.
Br J Neurosurg ; 36(3): 372-376, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34994257

RESUMEN

Background: Neurosurgery is a surgical specialty that is felt to be under-represented in its teaching and education at an undergraduate level in Irish medical schools, particularly in those which are not attached to a specialist neurosurgical centre. We looked at exposure to neurosurgery among undergraduate students by organising two neurosurgical lecture days for the 2020/2021 final year medical class of National University of Ireland Galway (NUIG), an Irish medical school which is not associated with a neurosurgical centre. This study sought to ascertain students' engagement with and, respectively, desire for a greater emphasis on common subjects within neurosurgery as part of an undergraduate curriculum, specifically in a medical school without an associated neurosurgical centre.Methods: The lecture series was organised by a final year medical student in NUI Galway in conjunction with the National Neurosurgical Centre, Beaumont Hospital. The lectures took place over the course of two separate lecture days on Saturday October 10th and Saturday November 14th, respectively. Both lecture days were broadcast virtually, in compliance with COVID-19 guidelines, to the NUIG 2020/2021 final year medical class and the content covered therein composed part of the examinable syllabus for their final year medical exams. All class members were provided with an online pre-lecture survey prior to the initial lecture day and two post-lecture surveys, one at the end of each respective lecture day.Results: 194 final year medical students from a class of 205 attended over the course of the two given lecture days. Of the 148 students that completed the pre-lecture survey only 13 students had previously attended a neurosurgical lecture or conference. Of the 194 attendees, there were 116 students who completed the final post-lecture survey, 62% of whom agreed that they would like to receive further teaching and clinical exposure to neurosurgery as part of their undergraduate medical education.


Asunto(s)
COVID-19 , Educación de Pregrado en Medicina , Neurocirugia , Estudiantes de Medicina , Curriculum , Humanos , Neurocirugia/educación , Facultades de Medicina , Encuestas y Cuestionarios
5.
PLoS Genet ; 14(7): e1007520, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30020921

RESUMEN

Across organisms, manipulation of biosynthetic capacity arrests development early in life, but can increase health- and lifespan post-developmentally. Here we demonstrate that this developmental arrest is not sickness but rather a regulated survival program responding to reduced cellular performance. We inhibited protein synthesis by reducing ribosome biogenesis (rps-11/RPS11 RNAi), translation initiation (ifg-1/EIF3G mutation and egl-45/EIF3A RNAi), or ribosome progression (cycloheximide treatment), all of which result in a specific arrest at larval stage 2 of C. elegans development. This quiescent state can last for weeks-beyond the normal C. elegans adult lifespan-and is reversible, as animals can resume reproduction and live a normal lifespan once released from the source of protein synthesis inhibition. The arrest state affords resistance to thermal, oxidative, and heavy metal stress exposure. In addition to cell-autonomous responses, reducing biosynthetic capacity only in the hypodermis was sufficient to drive organism-level developmental arrest and stress resistance phenotypes. Among the cell non-autonomous responses to protein synthesis inhibition is reduced pharyngeal pumping that is dependent upon AMPK-mediated signaling. The reduced pharyngeal pumping in response to protein synthesis inhibition is recapitulated by exposure to microbes that generate protein synthesis-inhibiting xenobiotics, which may mechanistically reduce ingestion of pathogen and toxin. These data define the existence of a transient arrest-survival state in response to protein synthesis inhibition and provide an evolutionary foundation for the conserved enhancement of healthy aging observed in post-developmental animals with reduced biosynthetic capacity.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Biosíntesis de Proteínas/fisiología , Proteínas Quinasas Activadas por AMP/genética , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Animales , Evolución Biológica , Proteínas de Caenorhabditis elegans/genética , Conducta Alimentaria/fisiología , Larva/fisiología , Longevidad/efectos de los fármacos , Longevidad/genética , Faringe/fisiología , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , Inhibidores de la Síntesis de la Proteína/farmacología , Interferencia de ARN , Ribosomas/efectos de los fármacos , Ribosomas/genética , Ribosomas/metabolismo , Transducción de Señal/genética , Tejido Subcutáneo/metabolismo
6.
Pain Pract ; 21(8): 907-911, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34352161

RESUMEN

BACKGROUND AND OBJECTIVE: Studies with nonsignificant results are less likely to be published or published in lower impact factor journals. To determine whether a similar phenomenon occurs in pain literature, we explored impact factor bias in peer-reviewed pain journals. METHODS: A PubMed search involving randomized controlled trials in pain journals during 2012 through 2018 was performed. The primary outcome was the publication impact factor. Exclusion criteria included commentaries, editorials, meta-analyses, reviews, and animal studies. The average impact factor for each journal was determined. The primary independent variable was a study with a positive outcome. RESULTS: Of the 9 journals evaluated, 1108 articles met our inclusion criteria and were included in our analysis. The quartiles for the impact factor for the journals included were 2.5, 2.9, and 3.6. A multivariate analysis identified sample size greater than 100, description of a sample size calculation, presence of a stated hypothesis, and presence of sponsorship funding as independent predictors of publication in a journal with greater impact factor. In contrast, positive results were not associated with publication in a greater impact factor journal, even when forced into the model, P = 0.49. CONCLUSIONS: After adjusting for study factors associated with publication, there is no evidence of impact factor bias within the pain literature. The lack of impact factor bias in the pain literature is a positive finding for the field and should benefit scientific development and the clinical care of patients.


Asunto(s)
Factor de Impacto de la Revista , Publicaciones Periódicas como Asunto , Humanos , Dolor
7.
PLoS Genet ; 13(4): e1006762, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28453520

RESUMEN

Cellular adaptation to stress is essential to ensure organismal survival. NRF2/NFE2L2 is a key determinant of xenobiotic stress responses, and loss of negative regulation by the KEAP1-CUL3 proteasome system is implicated in several chemo- and radiation-resistant cancers. Advantageously using C. elegans alongside human cell culture models, we establish a new WDR23-DDB1-CUL4 regulatory axis for NRF2 activity that operates independently of the canonical KEAP1-CUL3 system. WDR23 binds the DIDLID sequence within the Neh2 domain of NRF2 to regulate its stability; this regulation is not dependent on the KEAP1-binding DLG or ETGE motifs. The C-terminal domain of WDR23 is highly conserved and involved in regulation of NRF2 by the DDB1-CUL4 complex. The addition of WDR23 increases cellular sensitivity to cytotoxic chemotherapeutic drugs and suppresses NRF2 in KEAP1-negative cancer cell lines. Together, our results identify WDR23 as an alternative regulator of NRF2 proteostasis and uncover a cellular pathway that regulates NRF2 activity and capacity for cytoprotection independently of KEAP1.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Proteína 1 Asociada A ECH Tipo Kelch/genética , Factor 2 Relacionado con NF-E2/genética , Neoplasias/genética , Proteínas Represoras/genética , Secuencias de Aminoácidos/genética , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Línea Celular Tumoral , Proteínas Cullin/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias/patología , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica/genética , Proteínas Represoras/metabolismo , Transducción de Señal
8.
Proc Natl Acad Sci U S A ; 112(50): 15378-83, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26621724

RESUMEN

Animals in nature are continually challenged by periods of feast and famine as resources inevitably fluctuate, and must allocate somatic reserves for reproduction to abate evolutionary pressures. We identify an age-dependent lipid homeostasis pathway in Caenorhabditis elegans that regulates the mobilization of lipids from the soma to the germline, which supports fecundity but at the cost of survival in nutrient-poor and oxidative stress environments. This trade-off is responsive to the levels of dietary carbohydrates and organismal oleic acid and is coupled to activation of the cytoprotective transcription factor SKN-1 in both laboratory-derived and natural isolates of C. elegans. The homeostatic balance of lipid stores between the somatic and germ cells is mediated by arachidonic acid (omega-6) and eicosapentaenoic acid (omega-3) precursors of eicosanoid signaling molecules. Our results describe a mechanism for resource reallocation within intact animals that influences reproductive fitness at the cost of somatic resilience.


Asunto(s)
Caenorhabditis elegans/metabolismo , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/farmacología , Alimentos , Células Germinativas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Animales , Caenorhabditis elegans/efectos de los fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Células Germinativas/efectos de los fármacos , Ácido Oléico/deficiencia , Reproducción/efectos de los fármacos , Análisis de Supervivencia , Vitelogénesis/efectos de los fármacos
9.
Nature ; 459(7250): 1079-84, 2009 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-19506556

RESUMEN

Unlike the soma, which ages during the lifespan of multicellular organisms, the germ line traces an essentially immortal lineage. Genomic instability in somatic cells increases with age, and this decline in somatic maintenance might be regulated to facilitate resource reallocation towards reproduction at the expense of cellular senescence. Here we show that Caenorhabditis elegans mutants with increased longevity exhibit a soma-to-germline transformation of gene expression programs normally limited to the germ line. Decreased insulin-like signalling causes the somatic misexpression of the germline-limited pie-1 and pgl family of genes in intestinal and ectodermal tissues. The forkhead boxO1A (FOXO) transcription factor DAF-16, the major transcriptional effector of insulin-like signalling, regulates pie-1 expression by directly binding to the pie-1 promoter. The somatic tissues of insulin-like mutants are more germline-like and protected from genotoxic stress. Gene inactivation of components of the cytosolic chaperonin complex that induce increased longevity also causes somatic misexpression of PGL-1. These results indicate that the acquisition of germline characteristics by the somatic cells of C. elegans mutants with increased longevity contributes to their increased health and survival.


Asunto(s)
Caenorhabditis elegans/citología , Caenorhabditis elegans/genética , Longevidad/genética , Transformación Genética , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Supervivencia Celular , Factores de Transcripción Forkhead , Regulación de la Expresión Génica , Células Germinativas/citología , Células Germinativas/metabolismo , Insulina/fisiología , Factor I del Crecimiento Similar a la Insulina/fisiología , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Transformación Genética/genética
10.
Bioessays ; 34(8): 652-4, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22674543

RESUMEN

A recent study reported that longevity in Caenorhabditits elegans can be inherited over several generations. This is probably achieved through the following epigenetic mechanism: inherited demethylated histones at some central loci, such as miRNA, transcription factors or signaling regulators affect the expression of certain genes leading to the longevity phenotype.


Asunto(s)
Epigénesis Genética , Genoma Humano , Patrón de Herencia , Longevidad , Envejecimiento , Animales , Metilación de ADN , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Sitios Genéticos , Genotipo , Histonas/metabolismo , Humanos , Fenotipo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
11.
bioRxiv ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-39026841

RESUMEN

In the presence of stressful environments, the SKN-1 cytoprotective transcription factor is activated to induce the expression of gene targets that can restore homeostasis. However, chronic activation of SKN-1 results in diminished health and a reduction of lifespan. Here we demonstrate the necessity of modulating SKN-1 activity to maintain the longevity-promoting effects associated with genetic mutations that impair daf-2/insulin receptor signaling, the eat-2 model of caloric restriction, and glp-1-dependent loss of germ cell proliferation. A hallmark of animals with constitutive SKN-1 activation is the age-dependent loss of somatic lipids and this phenotype is linked to a general reduction in survival in animals harboring the skn-1gf allele, but surprisingly, daf-2lf; skn-1gf double mutant animals do not redistribute somatic lipids which suggests the insulin signaling pathway functions downstream of SKN-1 in the maintenance of lipid distribution. As expected, the eat-2lf allele, which independently activates SKN-1, continues to display somatic lipid depletion in older ages with and without the skn-1gf activating mutation. In contrast, the presence of the skn-1gf allele does not lead to somatic lipid redistribution in glp-1lf animals that lack a proliferating germline. Taken together, these studies support a genetic model where SKN-1 activity is an important regulator of lipid mobilization in response to nutrient availability that fuels the developing germline by engaging the daf-2/insulin receptor pathway.

12.
Cell Signal ; 116: 111061, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38242270

RESUMEN

Mitochondrial adaptation is important for stress resistance throughout life. Here we show that WDR23 loss results in an enrichment for genes regulated by nuclear respiratory factor 1 (NRF1), which coordinates mitochondrial biogenesis and respiratory functions, and an increased steady state level of several nuclear coded mitochondrial resident proteins in the brain. Wdr23KO also increases the endogenous levels of insulin degrading enzyme (IDE) and the relaxin-3 peptide (RLN3), both of which have established roles in mediating mitochondrial metabolic and oxidative stress responses. Taken together, these studies reveal an important role for WDR23 as a component of the mitochondrial homeostat in the murine brain.


Asunto(s)
Encéfalo , Proteostasis , Animales , Ratones , Homeostasis , Mitocondrias , Proteínas Mitocondriales , Proteínas Nucleares
13.
Front Aging ; 5: 1369740, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38501033

RESUMEN

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

14.
Geroscience ; 46(5): 4461-4478, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38767782

RESUMEN

Maintaining insulin homeostasis is critical for cellular and organismal metabolism. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here, we establish a hepatic regulatory axis for IDE through WDR23-proteostasis. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults, supporting the use of WDR23 as a new molecular determinant of metabolic health in humans.


Asunto(s)
Homeostasis , Insulina , Insulisina , Hígado , Ratones Noqueados , Proteostasis , Humanos , Homeostasis/fisiología , Animales , Insulina/metabolismo , Ratones , Insulisina/metabolismo , Insulisina/genética , Hígado/metabolismo , Masculino , Femenino , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Transducción de Señal , Hemoglobina Glucada/metabolismo , Anciano , Persona de Mediana Edad
15.
Mech Ageing Dev ; 218: 111914, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38301772

RESUMEN

Pathogenic brain aging and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are characterized by chronic neuroinflammation and the accumulation of dysfunctional or misfolded proteins that lead to progressive neuronal cell death. Here we demonstrate that a murine model with global loss of the CUL4-DDB1 substrate receptor WDR23 (Wdr23KO) results in changes in multiple age-related hippocampal-dependent behaviors. The behavioral differences observed in Wdr23KO animals accompany the stabilization of the NRF2/NFE2L2 protein, an increase in RNA transcripts regulated by this cytoprotective transcription factor, and an increase in the steady state level of antioxidant defense proteins. Taken together, these findings reveal a role for WDR23-proteostasis in mediating cytoprotective capacity in the hippocampus and reveal the potential for targeting WDR23-NRF2 signaling interactions for development of therapies for neurodegenerative disorders.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Ratones , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Proteostasis , Enfermedad de Parkinson/metabolismo , Hipocampo/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Estrés Oxidativo/fisiología
16.
bioRxiv ; 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38464186

RESUMEN

Alzheimer's disease (AD) is a common debilitating neurodegenerative disease with limited treatment options. Amyloid-ß (Aß) and tau fibrils are well-established hallmarks of AD, which can induce oxidative stress, neuronal cell death, and are linked to disease pathology. Here, we describe the effects of Oolonghomobisflavan A (OFA) and Oolonghomobisflavan B (OFB) on tau fibril disaggregation and prionogenic seeding. Transcriptomic analysis of OF-treated animals reveals the induction of a proteostasis-enhancing and health-promoting signature. OFA treatment reduced the burden of Tau protein aggregation in a C. elegans model expressing pathogenic human tau ("hTau-expressing") and promoted Tau disaggregation and inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer's disease brain donors. Correspondingly, treatment with OF improved multiple fitness and aging-related health parameters in the hTau-expressing C. elegans model, including reproductive output, muscle function, and importantly, reversed the shortened lifespan stemming from pathogenic Tau expression. Collectively, this study provides new evidence supporting the neuroprotective effects of OFs and reveal a new therapeutic strategy for targeting AD and other neurodegenerative diseases characterized by tauopathy.

17.
bioRxiv ; 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38405962

RESUMEN

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defense capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals new insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival. KEY POINTS: Identify an apathy-like behavioral response for pathogens resulting from the constitutive activation of the cytoprotective transcription factor SKN-1.Uncover the obligate role for serotonin synthesis in both neuronal and non-neuronal cells for the apathy-like state and ability of serotonin treatment to restore normal behaviors.Characterize the timing and tissue specificity of SKN-1 nuclear localization in neurons and intestinal cells in response to pathogen exposure.Define the unique and context-specific transcriptional signatures of animals with constitutive SKN-1 activation when exposed to pathogenic environments.Reveal necessity for both neuronal and non-neuronal serotonin signaling in host survival from pathogen infection.

18.
Nat Commun ; 15(1): 8129, 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39285192

RESUMEN

When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.


Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Unión al ADN , Pseudomonas aeruginosa , Serotonina , Factores de Transcripción , Animales , Caenorhabditis elegans/microbiología , Caenorhabditis elegans/inmunología , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Pseudomonas aeruginosa/fisiología , Pseudomonas aeruginosa/patogenicidad , Serotonina/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Neuronas/metabolismo , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Inmunidad Innata , Transducción de Señal , Apatía/fisiología , Interacciones Huésped-Patógeno/inmunología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología
19.
MicroPubl Biol ; 20242024.
Artículo en Inglés | MEDLINE | ID: mdl-39027732

RESUMEN

The transcription factor SKN-1 in Caenorhabditis elegans is a critical regulator of various biological processes, impacting development, diet and immune responses, cellular detoxification, and lipid metabolism; thereby playing a pivotal role in regulating the health and lifespan of the organism. The primary isoforms of SKN-1 ( SKN-1 a, SKN-1 b, and SKN-1 c) exhibit distinct functions resembling mammalian Nrf transcription factors. This study investigates the specific role of the SKN-1 c isoform in development by generating mutants with targeted missense mutations in the skn-1 c and skn-1 a isoforms. The skn-1 c Met1Ala mutants, which replaces a start methionine with alanine, renders SKN-1 c non-functional while preserving other isoforms, produced inviable embryos, requiring a balancer chromosome for proper embryonic development. In contrast, skn-1 a Met1Ala mutants, which replaces the start methionine with alanine for this isoform, displayed normal embryonic development and hatching. Moreover, the data suggest that SKN-1 c plays a crucial role in embryonic development, as strains without maternally deposited SKN-1 c lead to embryos that are developmentally arrested. Together, these findings contribute to our understanding of SKN-1 c's specific role in influencing embryogenesis and development in C. elegans.

20.
BMJ Open Qual ; 13(1)2024 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-38267215

RESUMEN

BACKGROUND: The Medicare Annual Wellness Visit (AWV) allows providers to acquire critical information about patients' health through a review of vitals, environmental risks, and medical and family history. These visits are free to those enrolled in Medicare and prioritize patient-provider relationship building and preventative care. Despite this, AWV completion rates are suboptimal. METHODS: A quality improvement project was aimed to increase the percentage of AWVs among Medicare patients in a primary care internal medicine practice from a baseline of 1.7% completion to 2.7% in 3 months from January to April 2023. INTERVENTION: With eligible patients identified, a standardized approach was created where an AWV appointment was ordered, and a patient message explaining the benefit of the appointment was sent by the patient portal. RESULTS: Our AWV intervention resulted in 72 patients being seen for an AWV, which increased the percentage of completed AWVs in the division by 2.1% from 1.7% to 3.8% in 3 months. CONCLUSION: This intervention will continue to improve AWV rates and improve patient care for Medicare patients in internal medicine. It could be applied to other areas of primary care and within other health systems.


Asunto(s)
Medicare , Portales del Paciente , Anciano , Estados Unidos , Humanos , Medicina Interna , Pacientes , Relaciones Profesional-Paciente
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