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Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFP+MCs were adoptively transferred to c-kit-/- MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.
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Liberación de Histamina , Accidente Cerebrovascular , Humanos , Ratones , Masculino , Animales , Mastocitos , Cromolin Sódico/farmacología , Cromolin Sódico/uso terapéutico , Histamina , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/etiología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , IsquemiaRESUMEN
BACKGROUND: After subarachnoid hemorrhage (SAH), early brain injury (EBI) and delayed cerebral ischemia (DCI) lead to poor outcomes. Discovery of biomarkers indicative of disease severity and predictive of DCI is important. We tested whether leucine-rich alpha-2-glycoprotein 1 (LRG1) is a marker of severity, DCI, and functional outcomes after SAH. METHODS: We performed untargeted proteomics using mass spectrometry in plasma samples collected at < 48 h of SAH in two independent discovery cohorts (n = 27 and n = 45) and identified LRG1 as a biomarker for DCI. To validate our findings, we used enzyme-linked immunosorbent assay and confirmed this finding in an internal validation cohort of plasma from 72 study participants with SAH (22 DCI and 50 non-DCI). Further, we investigated the relationship between LRG1 and markers of EBI, DCI, and poor functional outcomes (quantified by the modified Rankin Scale). We also measured cerebrospinal fluid (CSF) levels of LRG1 and investigated its relationship to EBI, DCI, and clinical outcomes. RESULTS: Untargeted proteomics revealed higher plasma LRG1 levels across EBI severity and DCI in both discovery cohorts. In the validation cohort, the levels of LRG1 were higher in the DCI group compared with the non-DCI group (mean (SD): 95 [44] vs. 72 [38] pg/ml, p < 0.05, Student's t-test) and in study participants who proceeded to have poor functional outcomes (84 [39.3] vs. 72 [43.2] pg/ml, p < 0.05). Elevated plasma LRG1 levels were also associated with markers of EBI. However, CSF levels of LRG1 were not associated with EBI severity or the occurrence of DCI. CONCLUSIONS: Plasma LRG1 is a biomarker for EBI, DCI, and functional outcomes after SAH. Further studies to elucidate the role of LRG1 in the pathophysiology of SAH are needed.
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Lesiones Encefálicas , Isquemia Encefálica , Hemorragia Subaracnoidea , Humanos , Biomarcadores , Lesiones Encefálicas/complicaciones , Infarto Cerebral/complicaciones , Glicoproteínas , LeucinaRESUMEN
INTRODUCTION: Approximately half of the people living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HANDs). However, the neuropathogenesis of HAND is complex, and identifying reliable biomarkers has been challenging. METHODS: This study included 132 participants aged 50 and older from greater San Diego County. The participants were divided into three groups: PLWH with HAND (n = 29), PLWH without HAND (n = 73), and seronegatives without cognitive impairment (n = 30). Peripheral blood was collected at the clinical assessment, and plasma levels of neurofilament light chain (NfL), phosphorylated Tau 181 (pTau181), and glial fibrillary acidic protein (GFAP) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma levels of NfL (but not pTau181 and GFAP) were significantly associated with HAND at a medium effect size (p = 0.039, Cohen's d = 0.45 for HAND + vs. HAND-). Notably, higher levels of NfL were significantly associated with HAND diagnosis even after adjusting for sex. DISCUSSION: Our data suggest that neuronal degeneration (as evidenced by increased levels of NfL), but not tau pathology or glial degeneration, is related to cognitive status in PLWH. Our results corroborate the view that blood NfL is a promising biomarker of cognitive impairment in PLWH.
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Disfunción Cognitiva , Infecciones por VIH , Humanos , Persona de Mediana Edad , Anciano , VIH , Neuronas , Biomarcadores , Proteínas tau , Disfunción Cognitiva/metabolismo , Infecciones por VIH/metabolismoRESUMEN
The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.
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Angiotensina I , Enzima Convertidora de Angiotensina 2 , Enfermedad de Huntington , Fragmentos de Péptidos , Receptor de Angiotensina Tipo 1 , Sistema Renina-Angiotensina , Angiotensina I/genética , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Animales , Modelos Animales de Enfermedad , Humanos , Enfermedad de Huntington/genética , Ratones , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologíaRESUMEN
OBJECTIVE: Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. METHODS: Plasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs-including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs-including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs. controls and (b) men vs. women. RESULTS: Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (p < 0.05) elevated in the COVID-19 cohort compared to controls. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p < 0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. CONCLUSION: The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.
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Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/patología , COVID-19/complicaciones , Citocinas/sangre , Endotelio/patología , Inflamación/complicaciones , Inflamación/patología , Adulto , Anciano , Biomarcadores/sangre , Lesiones Encefálicas/sangre , Femenino , Hospitalización , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Caracteres Sexuales , Factores SexualesRESUMEN
Symptoms of depression are common among persons with HIV (PWH) and can have a significant impact on socioeconomic and personal well-being, but little is known about their neurobiological substrates in the context of HIV disease. This study examined the possible role of brain-derived neurotrophic factor (BDNF) in symptoms of depression and other aspects of mood in 109 PWH and 43 seronegative participants aged 50 and older. Participants completed the Profile of Mood States (POMS) which measured six dimensions of mood and was normatively adjusted for sex. A model controlling for medical comorbidities and substance use diagnoses among PWH showed a significant interaction between BDNF and POMS subscales. Planned post hoc analyses revealed that lower BDNF was only associated with higher scores on Depression-Dejection and Confusion-Bewilderment POMS subscales among PWH and at small-to-medium effect sizes. Lower levels of BDNF were associated with AIDS diagnoses and CD4 count, but not with viremia or duration of infection. BDNF levels did not differ between the PWH and HIV - samples, and there were no significant correlations between BDNF and any POMS variable in the HIV - group. Findings implicate BDNF in the neuropathophysiology of specific depressive symptoms in the context of HIV disease. Future studies may examine whether BDNF levels change over time, are sensitive to other aspects of mood disorders in HIV, and are associated with markers of HIV-associated neural injury.
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Factor Neurotrófico Derivado del Encéfalo/sangre , Depresión/etiología , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Anciano , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Major depressive disorder (MDD) is a heterogeneous condition with complex pathophysiology resulting from the interaction between genetic and environmental factors. Despite a reasonable array of therapeutic options, the management of MDD has been marked by an increasing number of treatment resistant cases. Identifying the multiple pathways involved in the pathogenesis of MDD is fundamental to move the field forward and to define novel and more effective therapeutic targets. The current disease models are not able to recapitulate the complexity of this condition. In the last years, induced pluripotent stem cells (iPSCs) have emerged as a unique tool to help the elucidation of the pathophysiology of psychiatric disorders through disease modeling. In addition, the iPSCs may play an important role in the validation of new therapeutic targets.
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Trastorno Depresivo Mayor , Células Madre Pluripotentes Inducidas , Depresión , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/terapia , HumanosRESUMEN
BACKGROUND: Inflammation is implicated in cocaine use and associated problems, including depression and cognitive impairment. OBJECTIVE: We assessed 18 cytokines, cocaine use, cognition, and depression in individuals with Cocaine Use Disorder. Our general hypothesis was that higher pro-inflammatory cytokines would relate to more cocaine use, poorer cognition, and more depression, while higher anti-inflammatory cytokines would relate to less cocaine use, better cognition, and less depression. METHODS: Data were collected from 85 individuals (76.5% male, 80% African American) aged 18-65. The ASI, Shipley-2, and BDI-II assessed frequency and duration of cocaine use, cognition, and depression. Cytokines were tested using Bio-Plex Pro™ assays. Elastic net regression identified which cytokines related to each measure, controlling for confounds. RESULTS: Lower IL-29 (B = -0.08, bootstrapped 95%CI = [-0.24,0.07]), scD163 (B = -0.11, bootstrapped 95%CI = [-0.27,0.04]), Eotaxin-1 CCL11 (B = -0.11, bootstrapped 95%CI = [-0.30,0.08]), and higher APRIL/TNFSF13 (B = 0.11, bootstrapped 95%CI = [-0.08,0.30]) related to more frequent cocaine use. Lower IL-29 (B = -0.24, bootstrapped 95% CI = [-2.26,1.79]) and IL-20 (B = -1.62, bootstrapped 95%CI = [-3.53,0.29]) related to longer duration of cocaine use. Higher Eotaxin-2 CCL24 (B = 2.79, bootstrapped 95%CI = [-0.59,6.17]) and TWEAK (B = 2.83, bootstrapped 95%CI = [-0.80,6.45]) related to better cognition. Finally, higher IL-20 (B = -1.83, bootstrapped 95%CI = [-3.70,0.04]) and Osteocalcin (B = -1.56, bootstrapped 95%CI = [-3.81,0.70]) related to lower depressive symptoms. However, none of these relationships survived bootstrapped analyses. CONCLUSION: Pro- and anti-inflammatory cytokines may relate to cocaine use, cognition, and depression, but inconsistent with our hypotheses, higher pro-inflammatory cytokines related to better functioning in several domains. Additionally, cytokines were selected at low frequencies and demonstrated weak relationships with outcomes. These preliminary findings suggest complex relationships between inflammation and cocaine use.
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Trastornos Relacionados con Cocaína/sangre , Cognición/fisiología , Citocinas/sangre , Depresión/sangre , Inflamación/sangre , Adolescente , Adulto , Anciano , Antiinflamatorios/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder encoding a mutant form of the huntingtin protein (HTT). HD is pathologically characterized by loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline and behavioral symptoms. Stem cell-based therapy has emerged as a feasible therapeutic approach for the treatment of neurodegenerative diseases and may be effective in alleviating and/or halting the pathophysiological mechanisms underlying HD. Several pre-clinical studies have used stem cells in animal models of HD. Here, we performed a systematic review of preclinical studies to estimate the treatment efficacy of stem cells in animal models of HD. Based on our systematic review, treatment with stem cells significantly improves neurological and behavioral outcomes in animal models of HD. Although promising results were found, the design of animal studies, the types of transplanted cells and the route of administration are poorly standardized and this greatly complicates comparative analysis.
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Enfermedad de Huntington/terapia , Trasplante de Células Madre/métodos , Animales , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Neurogénesis , Trasplante de Células Madre/efectos adversos , Células Madre/clasificación , Células Madre/citología , Células Madre/metabolismoRESUMEN
Huntington's disease (HD) is an inherited neurodegenerative disease. Besides the well-characterized motor symptoms, HD is marked by cognitive impairment and behavioral changes. In this study, we analyzed the blood of HD gene carries using RNA-sequencing techniques. We evaluated samples from HD gene carriers with (n = 8) and without clinically meaningful depressive symptoms (n = 8) compared with healthy controls (n = 8). Groups were age- and sex-matched. Preprocessing of data and between-group comparisons were calculated using DESeq2. The Wald test was used to generate p-values and log2 fold changes. We found 60 genes differently expressed in HD and healthy controls, of which 21 were upregulated and 39 downregulated. Within HD group, nineteen genes were differently expressed between patients with and without depression, being 6 upregulated and 13 downregulated. Several of the top differentially expressed genes are involved in nervous system development. Although preliminary, our findings corroborate the emerging view that in addition to neurodegenerative mechanisms, HD has a neurodevelopmental component. Importantly, the emergence of depression in HD might be related to these mechanisms.
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Depresión/genética , Enfermedad de Huntington/genética , Transcriptoma/genética , Adulto , Estudios de Casos y Controles , Comorbilidad , Progresión de la Enfermedad , Regulación hacia Abajo/genética , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/genética , Regulación hacia Arriba/genéticaRESUMEN
To date, there is no definitive treatment for Alzheimer's disease (AD). The realm of stem cells is very promising in regenerative medicine, particularly for neurodegenerative diseases. Various types of stem cells have been used in preclinical/clinical trials for AD aiming the development of an elusive disease modifying therapy. Over the last decade, much knowledge has been gained in this field regarding types of cells, routes and timing of administration, and outcomes of stem cells-based strategies for AD. In this chapter, we will trace the state of art and the challenges facing the use of stem cells in AD.
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Enfermedad de Alzheimer/terapia , Medicina Regenerativa , Células Madre/citología , HumanosRESUMEN
Mood disorders are heterogeneous conditions characterized by complex genetics, unclear pathophysiology, and variable symptomatology. Currently, there is no biomarker for the diagnosis or prognosis of mood disorders, and the treatments are of limited efficacy in a significant proportion of patients. Furthermore, the disease models are not able to recapitulate their complexity. In this scenario, stem cells may have different applications in mood disorders. Circulating stem cells may be regarded as potential biomarkers. Mesenchymal stem cells are a promising therapeutic strategy for mood disorders as they promote neurogenesis and increase the expression of neurotrophic factors that enhance the survival and differentiation of neurons. In addition, induced pluripotent stem cells, cells reprogrammed from somatic cells of healthy subjects or patients, offer a great opportunity to recapitulate both normal and pathological development of human brain tissues, thereby opening a new avenue for disease modeling and drug development in a more disease-relevant system.
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Células Madre Pluripotentes Inducidas/citología , Células Madre Mesenquimatosas/citología , Trastornos del Humor/terapia , Encéfalo , Diferenciación Celular , Humanos , Factores de Crecimiento Nervioso , Neurogénesis , NeuronasRESUMEN
S100B is a calcium binding protein mainly produced by glial cells. Previous studies have shown elevated levels of S100B in patients with schizophrenia. We measured S100B levels in fasting plasma of 39 patients with schizophrenia and 19 adult healthy controls. We used linear regression to compare S100B between patients and controls. In patients only, we also investigated the relationship between S100B levels and psychotic symptoms (assessed by the Positive and Negative Syndrome Scale), and cognitive function (assessed by the NIH Toolbox Cognition Battery), respectively by calculating Pearson's correlation coefficients. Mean plasma S100B was significantly higher in the patient group than in the control group. There were no significant correlations between plasma S100B and psychotic symptoms or cognition.
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Disfunción Cognitiva/sangre , Trastornos Psicóticos/sangre , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Esquizofrenia/sangre , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate into all lineages of mesodermal origin, e.g., cartilage, bone, and adipocytes. MSCs have been identified at different stages of development, including adulthood, and in different tissues, such as bone marrow, adipose tissue and umbilical cord. Recent studies have shown that MSCs have the ability to migrate to injured sites. In this regard, an important characteristic of MSCs is their immunomodulatory and anti-inflammatory effects. For instance, there is evidence that MSCs can regulate the immune system by inhibiting proliferation of T and B cells. Clinical interest in the use of MSCs has increased considerably over the past few years, especially because of the ideal characteristics of these cells for regenerative medicine. Therapies with MSCs have shown promising results neurodegenerative diseases, in addition to regulating inflammation, they can promote other beneficial effects, such as neuronal growth, decrease free radicals, and reduce apoptosis. Notwithstanding, despite the vast amount of research into MSCs in neurodegenerative diseases, the mechanism of action of MSCs are still not completely clarified, hindering the development of effective treatments. Conversely, studies in models of psychiatric disorders are scarce, despite the promising results of MSCs therapies in this field as well.
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Trastornos Mentales/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Enfermedades Neurodegenerativas/terapia , Animales , Modelos Animales de EnfermedadRESUMEN
Bipolar disorder (BD) is a severe chronic psychiatric disorder that has been associated with cellular dysfunctions related to mitochondria, neurotrophin levels, and oxidative stress. Evidence has shown that endoplasmic reticulum (ER) stress may be a common pathway of the cellular changes described in BD. In the present study we assessed unfolded protein response (UPR) and the effects of this cellular process on lymphocytes from patients with BD. We also evaluated whether the stage of chronicity of BD was associated with changes in UPR parameters. Cultured lymphocytes from 30 patients with BD and 32 age- and sex-matched controls were treated with tunicamycin, an ER stressor, for 12 or 24 h to measure levels of UPR-related proteins (GRP78, eIF2α-P, and CHOP) using flow cytometry, and for 48 h to analyse ER stress-induced cell death. In healthy controls but not in patients we found an increase in levels of GRP78, eIF2α-P, and CHOP after ER stress induction. In addition, tunicamycin-induced cell death was significantly higher in patients compared to controls. More importantly, early-stage patients did not differ from controls while the late-stage patients showed an impaired ER stress response. Thus, dysfunction in ER-related stress response may be associated with decreased cellular resilience in BD and illness progression.
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Trastorno Bipolar/patología , Estrés del Retículo Endoplásmico/fisiología , Linfocitos/fisiología , Adulto , Trastorno Bipolar/tratamiento farmacológico , Estudios de Casos y Controles , Supervivencia Celular , Progresión de la Enfermedad , Chaperón BiP del Retículo Endoplásmico , Femenino , Citometría de Flujo , Proteínas de Choque Térmico/metabolismo , Humanos , Linfocitos/ultraestructura , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Factor de Transcripción CHOP/metabolismo , Factores de Transcripción/metabolismo , Tunicamicina , Respuesta de Proteína Desplegada/fisiologíaRESUMEN
The prevalence of older persons with HIV (PWH) disease has increased considerably in the last 20 years, but our understanding of biological factors of aging and their clinical correlates among PWH remains limited. Study participants were 149 persons aged 50 and older, including 107 PWH and 42 seronegatives. All participants completed a blood draw, research medical evaluation, structured psychiatric interview, neurocognitive assessment, questionnaires, and measures of health literacy. Four epigenetic clocks were generated from stored blood samples using standardized laboratory methods. In regression models adjusting for sex and smoking status, PWH had significantly higher epigenetic aging acceleration values than seronegatives on all four indicators. Within the PWH sample, higher levels of epigenetic aging acceleration were moderately associated with lower current CD4 count, AIDS diagnoses, higher scores on the Veterans Aging Cohort Study Index, and lower telomere values. Higher epigenetic aging acceleration indices were also associated with lower health literacy among PWH. PWH experience accelerated aging as measured by a series of epigenetic clocks, which may be linked to immune compromise and risk of all-cause mortality. Health literacy may be a modifiable target for mitigating the risk of accelerated aging among older PWH.
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Infecciones por VIH , Alfabetización en Salud , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Infecciones por VIH/epidemiología , Infecciones por VIH/genética , Infecciones por VIH/complicaciones , Envejecimiento/genética , Epigénesis GenéticaRESUMEN
Background: Stroke is a major cause of morbidity and mortality, and its incidence increases with age. While acute therapies for stroke are currently limited to intravenous thrombolytics and endovascular thrombectomy, recent studies have implicated an important role for the gut microbiome in post-stroke neuroinflammation. After stroke, several immuno-regulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, become activated. AHR is a master regulatory pathway that mediates neuroinflammation. Among various cell types, microglia (MG), as the resident immune cells of the brain, play a vital role in regulating post-stroke neuroinflammation and antigen presentation. Activation of AHR is dependent on a dynamic balance between host-derived and microbiota-derived ligands. While previous studies have shown that activation of MG AHR by host-derived ligands, such as kynurenine, is detrimental after stroke, the effects of post-stroke changes in microbiota-derived ligands of AHR, such as indoles, is unknown. Our study builds on the concept that differential activation of MG AHR by host-derived versus microbiome-derived metabolites affects outcomes after ischemic stroke. We examined the link between stroke-induced dysbiosis and loss of essential microbiota-derived AHR ligands. We hypothesize that restoring the balance between host-derived (kynurenine) and microbiota-derived (indoles) ligands of AHR is beneficial after stroke, offering a new potential avenue for therapeutic intervention in post-stroke neuroinflammation. Method: We performed immunohistochemical analysis of brain samples from stroke patients to assess MG AHR expression after stroke. We used metabolomics analysis of plasma samples from stroke and non-stroke control patients with matched comorbidities to determine the levels of indole-based AHR ligands after stroke. We performed transient middle cerebral artery occlusion (MCAO) in aged (18 months) wild-type (WT) and germ-free (GF) mice to investigate the effects of post-stroke treatment with microbiota-derived indoles on outcome. To generate our results, we employed a range of methodologies, including flow cytometry, metabolomics, and 16S microbiome sequencing. Results: We found that MG AHR expression is increased in human brain after stroke and after ex vivo oxygen-glucose deprivation and reperfusion (OGD/R). Microbiota-derived ligands of AHR are decreased in the human plasma at 24 hours after ischemic stroke. Kynurenine and indoles exhibited differential effects on aged WT MG survival after ex vivoOGD/R. We found that specific indole-based ligands of AHR (indole-3-propionic acid and indole-3-aldehyde) were absent in GF mice, thus their production depends on the presence of a functional gut microbiota. Additionally, a time-dependent decrease in the concentration of these indole-based AHR ligands occurred in the brain within the first 24 hours after stroke in aged WT mice. Post-stroke treatment of GF mice with a cocktail of microbiota-derived indole-based ligands of AHR regulated MG-mediated neuroinflammation and molecules involved in antigen presentation (increased CD80, MHC-II, and CD11b). Post-stroke treatment of aged WT mice with microbiota-derived indole-based ligands of AHR reduced both infarct volume and neurological deficits at 24 hours. Conclusion: Our novel findings provide compelling evidence that the restoration of a well-balanced pool of host-derived kynurenine-based and microbiota-derived indole-based ligands of AHR holds considerable therapeutic potential for the treatment of ischemic stroke.
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Systemic toxicity is a relevant dimension of pathophysiology in bipolar disorder, and oxidative damage is one potential link between central and peripheral pathology. Although there is mounting evidence that chronic bipolar disorder is associated with oxidative stress, studies in the early stages of bipolar disorder are scarce, and heavily reliant on clinical in lieu of population studies. The objective of this study was to confirm leading hypotheses about the role of oxidative damage in bipolar disorder. To that end, we nested a case-control study in a population-based study of young adults aged 18-24 yr. After an initial psychopathology screen, all people with a lifetime history of (hypo)mania and matched controls underwent a structured diagnostic interview. This yielded a sample of 231 participants, in whom we measured serum protein carbonyl content (PCC) and thiobarbituric acid reactive substances (TBARS). People with bipolar disorder had higher PCC levels than healthy subjects. Those with major depression were not different from control subjects in either PCC or TBARS levels. Both bipolar disorder and major depression were associated with higher PCC levels in the a priori regression model controlling for possible confounders. These findings indicate that protein oxidative damage is present from early stages and can be seen as a sign of early illness activity in mood disorders.
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Trastornos del Humor/metabolismo , Trastornos del Humor/fisiopatología , Estrés Oxidativo/fisiología , Adolescente , Adulto , Estudios de Casos y Controles , Planificación en Salud Comunitaria , Femenino , Humanos , Masculino , Carbonilación Proteica/fisiología , Escalas de Valoración Psiquiátrica , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Adulto JovenRESUMEN
INTRODUCTION: The ultimate cause of neuronal death in Huntington's disease (HD) is still uncertain. Apart from impairment in systems handling abnormal proteins, other mechanisms might contribute to neurodegeneration and progression of HD. Decreased cerebral blood flow (CBF) has been described in other neurodegenerative disorders and may play a role in HD. OBJECTIVES: To investigate CBF changes in HD gene carriers. METHODS: A group of 39 HD gene carriers (18 premanifest and 21 manifest HD) and 16 controls underwent a comprehensive clinical evaluation and a brain magnetic resonance imaging protocol that included pseudo-continuous arterial spin labeling to quantify CBF. Regions of interest (ROI) analyses were performed to compare CBF in controls vs premanifest HD vs manifest HD. Correlation analyses were performed to ascertain the relationship between CBF and clinical and biomarkers data. RESULTS: We found a decrease in CBF in bilateral caudate and putamen of patients with manifest HD in comparison with controls. CBF of premanifest HD carriers in the same ROIs was midway between controls and the HD patients, with differences not reaching statistical significance. Lower CBF in caudate and putamen was associated with worse motor symptoms, functionality, and cognitive performance. CBF was also associated with markers of neurodegeneration: higher CBF in caudate and putamen significantly correlated to higher volumes in the same ROI and to lower levels of neurofilament light chain. CONCLUSION: As CBF changes in caudate and putamen nuclei were associated with markers of neurodegeneration and with clinical outcomes, decreased CBF and oxygen supply could emerge as a relevant mechanism contributing to degeneration in HD.
Asunto(s)
Enfermedad de Huntington , Biomarcadores , Circulación Cerebrovascular , Humanos , Enfermedad de Huntington/genética , Imagen por Resonancia Magnética/métodos , OxígenoRESUMEN
Coronavirus disease (COVID-19), caused by SARS-CoV-2, leads to symptoms ranging from asymptomatic disease to death. Although males are more susceptible to severe symptoms and higher mortality due to COVID-19, patient sex has rarely been examined. Sex-associated metabolic changes may implicate novel biomarkers and therapeutic targets to treat COVID-19. Here, using serum samples, we performed global metabolomic analyses of uninfected and SARS-CoV-2-positive male and female patients with severe COVID-19. Key metabolic pathways that demonstrated robust sex differences in COVID-19 groups, but not in controls, involved lipid metabolism, pentose pathway, bile acid metabolism, and microbiome-related metabolism of aromatic amino acids, including tryptophan and tyrosine. Unsupervised statistical analysis showed a profound sexual dimorphism in correlations between patient-specific clinical parameters and their global metabolic profiles. Identification of sex-specific metabolic changes in severe COVID-19 patients is an important knowledge source for researchers striving for development of potential sex-associated biomarkers and druggable targets for COVID-19 patients.