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1.
Sci Rep ; 14(1): 13558, 2024 06 12.
Artículo en Inglés | MEDLINE | ID: mdl-38866809

RESUMEN

Longitudinal studies that continuously generate data enable the capture of temporal variations in experimentally observed parameters, facilitating the interpretation of results in a time-aware manner. We propose IL-VIS (incrementally learned visualizer), a new machine learning pipeline that incrementally learns and visualizes a progression trajectory representing the longitudinal changes in longitudinal studies. At each sampling time point in an experiment, IL-VIS generates a snapshot of the longitudinal process on the data observed thus far, a new feature that is beyond the reach of classical static models. We first verify the utility and correctness of IL-VIS using simulated data, for which the true progression trajectories are known. We find that it accurately captures and visualizes the trends and (dis)similarities between high-dimensional progression trajectories. We then apply IL-VIS to longitudinal multi-electrode array data from brain cortical organoids when exposed to different levels of quinolinic acid, a metabolite contributing to many neuroinflammatory diseases including Alzheimer's disease, and its blocking antibody. We uncover valuable insights into the organoids' electrophysiological maturation and response patterns over time under these conditions.


Asunto(s)
Aprendizaje Automático , Estudios Longitudinales , Humanos , Organoides , Enfermedad de Alzheimer/metabolismo , Encéfalo/fisiología
2.
Infection ; 52(5): 2043-2059, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38802702

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the highly contagious respiratory disease Corona Virus Disease 2019 (COVID-19) that may lead to various neurological and psychological disorders that can be acute, lasting days to weeks or months and possibly longer. The latter is known as long-COVID or more recently post-acute sequelae of COVID (PASC). During acute COVID-19 infection, a strong inflammatory response, known as the cytokine storm, occurs in some patients. The levels of interferon-γ (IFN-γ), interferon-ß (IFN-ß), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are particularly increased. These cytokines are known to activate the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), catalysing the first step of tryptophan (Trp) catabolism through the kynurenine pathway (KP) leading to the production of several neurotoxic and immunosuppressive metabolites. There is already data showing elevation in KP metabolites both acutely and in PASC, especially regarding cognitive impairment. Thus, it is likely that KP involvement is significant in SARS-CoV-2 pathogenesis especially neurologically.


Asunto(s)
COVID-19 , Quinurenina , SARS-CoV-2 , Quinurenina/metabolismo , Humanos , COVID-19/metabolismo , Citocinas/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Síndrome de Liberación de Citoquinas , Síndrome Post Agudo de COVID-19 , Triptófano/metabolismo
4.
Int J Tryptophan Res ; 16: 11786469231213521, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38106464

RESUMEN

The kynurenine pathway (KP) is the main pathway of tryptophan (TRP) metabolism that generates energy for multiple cellular processes. The activity of this pathway has been shown to be dysregulated in multiple human diseases. The resultant modulation of metabolites has been suggested to comprise biomarkers to track disease progression or could identify new therapeutic targets. While metabolite changes can be measured readily in blood, there is limited knowledge on the effect of blood matrices and sample processing time may have on the stability of KP metabolites. Understanding the stability of KP metabolites in blood is integral to obtaining accurate KP data to correlate with clinical pathology. Hence, the aim of this study was to assess the concentration of KP metabolites in matched whole blood, plasma and serum. The impact of pre-analytical sample processing time in the various blood matrices was also analysed. Serum and plasma had the higher concentration of KP metabolites compared to whole blood. Furthermore, concentrations of KP metabolites declined when the collected blood was processed after 24 hours storage at 4°C. Our study shows that that type of blood matrix and the time to processing have an impact on the stability of the KP metabolites. Serum or plasma are the preferred choice of matrix and the isolation of these matrices from whole blood is best performed immediately after collection for optimal analytical KP data.

5.
Artículo en Inglés | MEDLINE | ID: mdl-37910296

RESUMEN

Air pollutants are increasingly emitted into the atmosphere because of the high dependency of humans on fossil-derived fuels. Wind speed and direction assisted high dispersibility and uncontrolled nature of air pollution across geo-/demographical borders, making it one of the major global concerns. Besides climate change, air pollution has been found to be associated with various diseases, such as cancer. Lung cancer, which is the world's most common type of cancer, has been found to be associated with traffic-related air pollution. Research and political efforts have been taken to explore green/renewable energy sources. However, these efforts at the current intensity cannot cope with the increasing need for fossil fuels. More specifically, political tensions such as the Russian-Ukraine war, economic tension (e.g., China-USA economic tensions), and other issues (e.g., pandemic, higher inflation rate, and poverty) significantly hindered phasing out fossil fuels. In this context, an increasing global population will be exposed to traffic-related air pollution, which justifies the current uptrend in the number of lung cancer patients. To combat this health burden, novel treatments with higher efficiency and specificity must be designed. One of the potential "life changer" options is microRNA (miRNA)-based therapy to target the expression of oncogenic genes. That said, this review discusses the association of traffic-related air pollution with lung cancer, the changes in indigenous miRNAs in the body during lung cancer, and the current status of miRNA therapeutics for lung cancer treatment. We believe that the article will significantly appeal to a broad readership of oncologists, environmentalists, and those who work in the field of (bio)energy. It may also gain the policymakers' attention to establish better health policies and regulations about air pollution, for example, by promoting (bio)fuel exploration, production, and consumption.

6.
Mol Neurobiol ; 2023 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-38015302

RESUMEN

Dysregulation of the kynurenine pathway (KP) is believed to play a significant role in neurodegenerative and cognitive disorders. While some evidence links the KP to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), further studies are needed to clarify the overall picture of how inflammation-driven KP disturbances may contribute to symptomology in ME/CFS. Here, we report that plasma levels of most bioactive KP metabolites differed significantly between ME/CFS patients and healthy controls in a manner consistent with their known contribution to symptomology in other neurological disorders. Importantly, we found that enhanced production of the first KP metabolite, kynurenine (KYN), correlated with symptom severity, highlighting the relationship between inflammation, KP dysregulation, and ME/CFS symptomology. Other significant changes in the KP included lower levels of the downstream KP metabolites 3-HK, 3-HAA, QUIN, and PIC that could negatively impact cellular energetics. We also rationalized KP dysregulation to changes in the expression of inflammatory cytokines and, for the first time, assessed levels of the iron (Fe)-regulating hormone hepcidin that is also inflammation-responsive. Levels of hepcidin in ME/CFS decreased nearly by half, which might reflect systemic low Fe levels or possibly ongoing hypoxia. We next performed a proteomics screen to survey for other significant differences in protein expression in ME/CFS. Interestingly, out of the seven most significantly modulated proteins in ME/CFS patient plasma, 5 proteins have roles in maintaining gut health, which considering the new appreciation of how gut microbiome and health modulates systemic KP could highlight a new explanation of symptomology in ME/CFS patients and potential new prognostic biomarker/s and/or treatment avenues.

7.
PLoS One ; 18(8): e0279612, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37549148

RESUMEN

BACKGROUND: Existing literature that examines the Hikikomori-like idiom of distress (HLID) initially labelled this phenomenon as a culture-bound syndrome. However, the increasing number of reports from other parts of the world suggest that HLID could instead be a culture-reactive idiom of distress, originating from biopsychosocial disequilibrium and cultural upheaval. The impact of imposed social withdrawal due to the Coronavirus 2 severe acute respiratory syndrome (SARS-CoV-2) pandemic on the growing prevalence of HLID has not yet been adequately explored. Aims: The first objective is to examine the factorial validity of the 25-item Hikikomori Questionnaire (HQ-25) in Oman. Second, we aimed to investigate the prevalence of HLID following the lifting of SARS-COV-2 restrictions in the Arabian Gulf country of Oman. The third related objective is to examine factors associated with the variation of HLID. METHODS: This cross-sectional online survey was widely distributed across the diverse socio-demographic population residing in Oman. After the validation of the questionnaire and the factorial validity, the Arabic version of HQ-25 was used to explore the prevalence and factors associated with HLID. RESULTS: A total of 1529 participants were included in the study (response rate = 76.5%), of whom 44% (n = 673) expressed HLID. We randomly split it into half, one for exploratory factor analysis (EFA) (n = 764) and the other half for confirmatory factor analysis (CFA) (n = 765). From the EFA results, a three-factor model was found for the Omani version of HQ-25, which represented 52.87% of the variance with good internal reliability (Overall Cronbach's: 0.92; Socialisation: 0.92; Isolation: 0.84; Emotional support: 0.73). The CFA results report acceptable goodness-of-fit indices (χ2/df = 17.92, p < .001; CFI = 0.90; TLI = 0.95; RMSEA = 0.04, 95% CI 0.02-0.07; SRMR = 0.05) of the three-factor model of the collected samples. All 1529 data were used in the respondents. The results of the logistic regression showed that married marital status (OR = 1.51, 95% CI: 1.12-2.03, p = 0.007), older age (OR = 0.97, 95% CI: 0.95-0.99, p = 0.008), living in an urban area (OR = 0.71, 95% CI: 0.56-0.91, p = 0.006), unemployed occupational status (OR = 1.72, 95% CI: 1.30-2.88, p < .001), screen time (7+ hours vs. <4 hours: OR = 4.50, 95% CI: 3.16-6.41, p < .001; 4-7 hours vs. <4 hours: OR = 2.10, 95% CI: 1.61-2.70, p < .001), history of mental illness (OR = 3.70, 95% CI: 2.29-5.91, p < .001), and adverse childhood experiences (OR = 2.60, 95% CI: 2.03-3.20, p < .001) were significant risk factors for HLID. CONCLUSION: The factorial validity of the HQ-25 performed in this study appears to mirror the previously reported 3-factor structures. Some of the associated factors appear to support and, conversely, dissent from the findings of previous studies. These are discussed in terms of the attributions of the SARS-COV-2 pandemic, demographic trends in Oman, and sociocultural factors specific to the region of interest.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Omán/epidemiología , Reproducibilidad de los Resultados , Estudios Transversales , Pandemias , Prevalencia , COVID-19/epidemiología , Encuestas y Cuestionarios , Psicometría
8.
Front Neurol ; 14: 1210453, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37360356

RESUMEN

Up to 10 million people per annum experience traumatic brain injury (TBI), 80-90% of which are categorized as mild. A hit to the brain can cause TBI, which can lead to secondary brain injuries within minutes to weeks after the initial injury through unknown mechanisms. However, it is assumed that neurochemical changes due to inflammation, excitotoxicity, reactive oxygen species, etc., that are triggered by TBI are associated with the emergence of secondary brain injuries. The kynurenine pathway (KP) is an important pathway that gets significantly overactivated during inflammation. Some KP metabolites such as QUIN have neurotoxic effects suggesting a possible mechanism through which TBI can cause secondary brain injury. That said, this review scrutinizes the potential association between KP and TBI. A more detailed understanding of the changes in KP metabolites during TBI is essential to prevent the onset or at least attenuate the severity of secondary brain injuries. Moreover, this information is crucial for the development of biomarker/s to probe the severity of TBI and predict the risk of secondary brain injuries. Overall, this review tries to fill the knowledge gap about the role of the KP in TBI and highlights the areas that need to be studied.

10.
Ann Clin Transl Neurol ; 10(8): 1338-1352, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37318955

RESUMEN

OBJECTIVE: To determine the prevalence and natural history of post-acute COVID-19 objective cognitive impairment and function, and their relationship to demographic, clinical factors, post-acute sequelae of COVID-19 (PASC), and biomarkers. METHODS: A total of 128 post-acute COVID-19 patients (age = 46 ± 15; 42% women, acute disease severity: not hospitalized: 38.6% mild: 0-1 symptoms, 52% 2+ symptoms; 9.4% hospitalized) completed standard cognition, olfaction, and mental health examinations 2-, 4-, and 12-month post diagnosis. Over the same time frame, WHO-defined PASC was determined. Blood cytokines, peripheral neurobiomarkers, and kynurenine pathway (KP) metabolites were measured. Objective cognitive function was demographically/practice corrected, and impairment prevalence was determined using the evidence-based Global Deficit Score method to detect at least mild cognitive impairment (GDS > 0.5). Linear mixed effect regression models with time effect (month post diagnosis) evaluated the relationships to cognition. RESULTS: Across the 12-month study period, mild to moderate cognitive impairment ranged from 16% to 26%, and 46.5% were impaired at least once. Impairment associated with poorer work capacity (p < 0.05), and 2-month objectively tested anosmia (p < 0.05). PASC with (p = 0.01) and without disability (p < 0.03) associated with acute COVID-19 severity. KP measures showed prolonged activation (2 to 8 months) (p < 0.0001) linked to IFN-beta in those with PASC. Of the blood analytes, only the KP metabolites (elevated quinolinic acid, 3-hydroxyanthranilic acid, kynurenine, the kynurenine/tryptophan ratio) associated (p < 0.001) with poorer cognitive performance and greater likelihood of impairment. PASC, independent of disability associated with abnormal kynurenine/tryptophan (p < 0.03). INTERPRETATION: The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC, thereby enabling biomarker and therapeutic possibilities.


Asunto(s)
COVID-19 , Disfunción Cognitiva , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Quinurenina , Triptófano , COVID-19/complicaciones , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Biomarcadores , Síndrome Post Agudo de COVID-19
11.
Antioxidants (Basel) ; 12(5)2023 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-37237903

RESUMEN

Tetrahydrobiopterin (BH4) is an endogenous cofactor for some enzymatic conversions of essential biomolecules, including nitric oxide, and monoamine neurotransmitters, and for the metabolism of phenylalanine and lipid esters. Over the last decade, BH4 metabolism has emerged as a promising metabolic target for negatively modulating toxic pathways that may result in cell death. Strong preclinical evidence has shown that BH4 metabolism has multiple biological roles beyond its traditional cofactor activity. We have shown that BH4 supports essential pathways, e.g., to generate energy, to enhance the antioxidant resistance of cells against stressful conditions, and to protect from sustained inflammation, among others. Therefore, BH4 should not be understood solely as an enzyme cofactor, but should instead be depicted as a cytoprotective pathway that is finely regulated by the interaction of three different metabolic pathways, thus assuring specific intracellular concentrations. Here, we bring state-of-the-art information about the dependency of mitochondrial activity upon the availability of BH4, as well as the cytoprotective pathways that are enhanced after BH4 exposure. We also bring evidence about the potential use of BH4 as a new pharmacological option for diseases in which mitochondrial disfunction has been implicated, including chronic metabolic disorders, neurodegenerative diseases, and primary mitochondriopathies.

12.
Biotechnol Adv ; 66: 108172, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37169103

RESUMEN

Chitin, as the main component of the exoskeleton of Arthropoda, is a highly available natural polymer that can be processed into various value-added products. Its most important derivative, i.e., chitosan, comprising ß-1,4-linked 2-amino-2-deoxy-ß-d-glucose (deacetylated d-glucosamine) and N-acetyl-d-glucosamine units, can be prepared via alkaline deacetylation process. Chitosan has been used as a biodegradable, biocompatible, non-antigenic, and nontoxic polymer in some in-vitro applications, but the recently found potentials of chitosan for in-vivo applications based on its biological activities, especially antimicrobial, antioxidant, and anticancer activities, have upgraded the chitosan roles in biomaterials. Chitosan approval, generally recognized as a safe compound by the United States Food and Drug Administration, has attracted much attention toward its possible applications in diverse fields, especially biomedicine and agriculture. Despite some favorable characteristics, the chitosan's structure should be customized for advanced applications, especially due to its drawbacks, such as low drug-load capacity, low solubility, high viscosity, lack of elastic properties, and pH sensitivity. In this context, derivatization with relatively inexpensive and highly available mono- and di-saccharides to soluble branched chitosan has been considered a "game changer". This review critically scrutinizes the emerging technologies based on the synthesis and application of lactose- and galactose-modified chitosan as two important chitosan derivatives. Some characteristics of chitosan derivatives and biological activities have been detailed first to understand the value of these natural polymers. Second, the saccharide modification of chitosan has been discussed briefly. Finally, the applications of lactose- and galactose-modified chitosan have been scrutinized and compared to native chitosan to provide an insight into the current state-of-the research for stimulating new ideas with the potential of filling research gaps.


Asunto(s)
Antiinfecciosos , Quitosano , Quitosano/química , Lactosa , Galactosa , Materiales Biocompatibles/química , Antiinfecciosos/química
13.
Br J Cancer ; 129(2): 185-203, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37041200

RESUMEN

Breast cancer (BrCa) is the leading cause of cancer incidence and mortality in women worldwide. While BrCa treatment has been shown to be highly successful if detected at an early stage, there are few effective strategies to treat metastatic tumours. Hence, metastasis remains the main cause in most of BrCa deaths, highlighting the need for new approaches in this group of patients. Immunotherapy has been gaining attention as a new treatment for BrCa metastasis and the kynurenine pathway (KP) has been suggested as one of the potential targets. The KP is the major biochemical pathway in tryptophan (TRP) metabolism, catabolising TRP to nicotinamide adenine dinucleotide (NAD+). The KP has been reported to be elevated under inflammatory conditions such as cancers and that its activity suppresses immune surveillance. Dysregulation of the KP has previously been reported implicated in BrCa. This review aims to discuss and provide an update on the current mechanisms involved in KP-mediated immune suppression and cancer growth. Furthermore, we also provide a summary on 58 studies about the involvement of the KP and BrCa and five clinical trials targeting KP enzymes and their outcome.


Asunto(s)
Neoplasias de la Mama , Quinurenina , Humanos , Femenino , Quinurenina/metabolismo , Triptófano/metabolismo , Neoplasias de la Mama/terapia
14.
EBioMedicine ; 91: 104589, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37119734

RESUMEN

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University.


Asunto(s)
Enfermedades del Sistema Nervioso , Triptófano , Masculino , Humanos , Niño , Lactante , Preescolar , Adolescente , Triptófano/metabolismo , Quinurenina , Neopterin/metabolismo , Ácido Quinolínico/líquido cefalorraquídeo , Enfermedades Neuroinflamatorias , Leucocitosis , Inflamación/diagnóstico , Inflamación/metabolismo , Biomarcadores/metabolismo
16.
Brain Sci ; 13(3)2023 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-36979315

RESUMEN

Suicide, a global health burden, represents the 17th leading cause of death worldwide (1.3%), but the 4th among young people aged between 15 and 29 years of age, according to World Health Organization (WHO), 2019. Suicidal behaviour is a complex, multi-factorial, polygenic and independent mental health problem caused by a combination of alterations and dysfunctions of several biological pathways and disruption of normal mechanisms in brain regions that remain poorly understood and need further investigation to be deciphered. Suicide complexity and unpredictability gained international interest as a field of research. Several studies have been conducted at the neuropathological, inflammatory, genetic, and molecular levels to uncover the triggers behind suicidal behaviour and develop convenient and effective therapeutic or at least preventive procedures. This review aims to summarise and focus on current knowledge of diverse biological pathways involved in the neurobiology of suicidal behaviour, and briefly highlights future potential therapeutic pathways to prevent or even treat this significant public health problem.

17.
Eur Arch Psychiatry Clin Neurosci ; 273(6): 1317-1328, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36460745

RESUMEN

Schizophrenia is a chronic psychotic disease burdened by cognitive deficits which hamper daily functioning causing disability and costs for society. Biological determinants underlying cognitive impairment are only partially understood and there are no convincing pharmacological targets able to improve cognitive outcome. Mounting evidence has shown the involvement of the kynurenine pathway in the pathophysiology of schizophrenia, also concerning cognitive symptoms. Therefore, the action of specific metabolites of kynurenine could affects cognition in schizophrenia. To evaluate the impact of the metabolites of kynurenine pathway on cognitive functions in schizophrenia spectrum disorders, with a focus on the modulating role of gender, to identify predictors of cognitive functioning and hypothetical pharmacological targets able to resize disability by improving cognition, thus functioning and quality of life. A systematic review was performed in PubMed/MEDLINE and Embase according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. All studies measuring the direct impact of kynurenine metabolites on cognitive performances in living individuals with schizophrenia spectrum disorders were included in the review. Six studies were included. The activation of the kynurenine pathway resulted associated with greater cognitive deficits in patients with schizophrenia and both elevations and reduction of metabolites seemed able to affect cognitive outcome. No modulating role of sex emerged. This systematic review provides evidence that the activation of the kynurenine pathway affects cognition in patients with schizophrenia and highlights this pathway as a possible future target for developing novel drugs toward this still unmet clinical need. However, evidence is still limited and future studies are needed to further clarify the relationship between kynurenine pathway and cognition in schizophrenia.


Asunto(s)
Trastornos Psicóticos , Esquizofrenia , Humanos , Quinurenina/metabolismo , Calidad de Vida , Trastornos Psicóticos/metabolismo , Cognición , Ácido Quinurénico/metabolismo
18.
Brain Res ; 1799: 148180, 2023 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-36463954

RESUMEN

Sonic Hedgehog (Shh) signaling plays a critical role during central nervous system (CNS) development, and its dysregulation leads to neurological disorders. Nevertheless, little is known about Shh signaling regulation in the adult brain. Here, we investigated the contribution of DNA methylation on the transcriptional control of Shh signaling pathway members and its basal distribution impact on the brain, as well as its modulation by inflammation. The methylation status of the promoter regions of these members and the transcriptional profile of DNA-modifying enzymes (DNA Methyltransferases - DNMTs and Tet Methylcytosine Dioxygenase - TETs) were investigated in a murine model of neuroinflammation by qPCR. We showed that, in the adult brain, methylation in the CpG promoter regions of the Shh signaling pathway members was critical to determine the endogenous differential transcriptional pattern observed between distinct brain regions. We also found that neuroinflammation differentially modulates gene expression of DNA-modifying enzymes. This study reveals the basal transcriptional profile of DNMTs and TETs enzymes in the CNS and demonstrates the effect of neuroinflammation on the transcriptional control of members of the Shh Signaling pathway in the adult brain.


Asunto(s)
Proteínas Hedgehog , Enfermedades Neuroinflamatorias , Ratones , Animales , Proteínas Hedgehog/metabolismo , Regulación de la Expresión Génica , Sistema Nervioso Central/metabolismo , Epigénesis Genética
19.
Int J Tryptophan Res ; 15: 11786469221126063, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36329761

RESUMEN

Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls (P ⩽ .05). LPK kidneys also showed an age effect (P ⩽ .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls (P ⩽ .05). Plasma XA and 3-HK also showed an age effect (P ⩽ .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P ⩽ .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect (P ⩽ .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD.

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