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1.
An Updated Evolutionary and Structural Study of TBK1 Reveals Highly Conserved Motifs as Potential Pharmacological Targets in Neurodegenerative Diseases.
Papageorgiou, L, Mangana, E, Papakonstantinou, E, Diakou, I, Pierouli, K, Dragoumani, K, Bacopoulou, F, Chrousos, GP, Exarchos, TP, Vlamos, P, et al
Advances in experimental medicine and biology. 2023;:41-57
Abstract
TANK-binding kinase 1 protein (TBK1) is a kinase that belongs to the IκB (IKK) family. TBK1, also known as T2K, FTDALS4, NAK, IIAE8, and NF-κB, is responsible for the phosphorylation of the amino acid residues, serine and threonine. This enzyme is involved in various key biological processes, including interferon activation and production, homeostasis, cell growth, autophagy, insulin production, and the regulation of TNF-α, IFN-β, and IL-6. Mutations in the TBK1 gene alter the protein's normal function and may lead to an array of pathological conditions, including disorders of the central nervous system. The present study sought to elucidate the role of the TBK1 protein in amyotrophic lateral sclerosis (ALS), a human neurodegenerative disorder. A broad evolutionary and phylogenetic analysis of TBK1 was performed across numerous organisms to distinguish conserved regions important for the protein's function. Subsequently, mutations and SNPs were explored, and their potential effect on the enzyme's function was investigated. These analytical steps, in combination with the study of the secondary, tertiary, and quaternary structure of TBK1, enabled the identification of conserved motifs, which can function as novel pharmacological targets and inform therapeutic strategies for amyotrophic lateral sclerosis.
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2.
Pythagorean Self-Awareness Intervention Promoted Healthy Dietary Patterns, Controlled Body Mass Index, and Reduced Self-Reported Stress Levels of Primary School Children: Α One-Arm Pilot Study.
Panagiotou, M, Velegraki, IM, Gerakini, O, Bacopoulou, F, Charalampopoulou, M, Louvardi, M, Tigani, X, Mantzou, A, Vlachakis, D, Kanaka-Gantenbein, C, et al
Advances in experimental medicine and biology. 2023;:13-22
Abstract
Stress is common in childhood and an important factor that affects behavior later in adulthood. The aim of this study was to assess the effects of the Pythagorean Self-Awareness Intervention (PSAI), a holistic "cognitive reconstruction" technique to assess primary school children's stress levels, adherence to the Mediterranean diet, and body mass index. Secondary outcome measures included relations with peers, sleep, and hair cortisol concentrations. This one-arm pilot study took place in a primary school, from February to June 2019. Participants were 32 pupils attending the second grade of primary school who received the 8-week PSAI to adopt healthy behaviors and lifestyle. Self-report measures were applied for the evaluation of various variables at the beginning and the end of the eight-week intervention. There were statistically significant reductions in stress levels (p = 0.00), nightmares' frequency (p = 0.00), body mass index (p = 0.03), and bully scale (p = 0.00), and improvement in Mediterranean diet quality (p = 0.00). Hair cortisol concentrations increased (p = 0.02). The social scale significantly increased. Bedtime remained the same after the intervention. This pilot trial showed that the PSAI promoted healthy dietary patterns, controlled children's body mass index, and reduced their self-reported stress levels. Further research on the implementation of this holistic program on children is suggested, in well-powered randomized controlled trials.
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3.
A randomized, observer-blind, vehicle-control, multi-center clinical investigation for assessing the efficacy and tolerability of a 1% ectoine and hyaluronic acid 0.1%-containing medical device in pediatric patients with mild-to-moderate atopic dermatitis.
Alexopoulos, A, Dakoutrou, M, Nasi, L, Thanopoulou, I, Kakourou, T, Kontara, L, Douladiris, N, Galani, M, Xepapadaki, P, Doxani, C, et al
Pediatric dermatology. 2023;(1):78-83
Abstract
BACKGROUND Ectoine is a widespread osmolyte enabling halophilic bacteria to withstand high osmotic stress that has many potential applications ranging from cosmetics to its use as a therapeutic agent. OBJECTIVE The aim of this study was to compare the efficacy and tolerability of ectoine 1% and hyaluronic acid 0.1% containing (EHA) cream with a vehicle cream in children with mild-to-moderate atopic dermatitis (AD). METHODS A randomized, controlled, observer-blind, multicenter clinical trial was conducted in children aged 2-18 years, diagnosed with mild-to-moderate AD (SCORAD ≤20). Patients were randomized to either receiving EHA cream or vehicle cream twice daily for 4 weeks. The primary outcome measure was the mean change in objective SCORAD from baseline to the final visit. The secondary outcome measures included the mean change in Investigator's Global Assessment score, patient's judgment of efficacy and patient's assessment of pruritus. Safety of EHA cream was also assessed. RESULTS A total of 70 patients (35 in each group) were randomized and 57 were included in the final analysis set. Based on SCORAD measurements, patients using EHA cream achieved superior clinical improvement compared to the control group at 28 days (p < .001). EHA cream was also superior to the vehicle cream regarding all secondary outcome measures. Eight (23.5%) patients receiving EHA cream and two (5.7%) patients receiving vehicle cream experienced mild cutaneous adverse events (AEs). CONCLUSIONS In children 2-18 years old with mild-to-moderate AD, EHA cream was superior to vehicle cream, with minor AEs.
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4.
The Impact of Genetic Variability of TGF-Beta Signaling Biomarkers in Major Craniofacial Syndromes.
Yapijakis, C, Davaria, S, Gintoni, I, Chrousos, GP
Advances in experimental medicine and biology. 2023;:187-191
Abstract
Craniofacial development is a complex process involving several signaling pathways, including the one regulated by the TGF-beta (TGF-β) superfamily of growth factors. Isoforms of TGF-β play a vital part in embryonic development, notably in craniofacial patterning. Consequently, pathogenic variants in their coding genes may result in a variety of orofacial and craniofacial malformations. Here, we review the impact of genetic variability of TGF-β signaling biomarkers in major disorders, including palatal and lip clefts, dental anomalies, and craniofacial syndromes, such as the Loeys-Dietz syndrome (LDS) and Camurati-Engelmann disease. Cleft lip and cleft palate are associated with missense mutations in the TGFB1 and TGFB3 genes, while mutations in the LTBP3 gene encoding TGF-β binding protein 3 may cause selective tooth agenesis. Oligodontia may also be caused by TGFB1-inactivating mutations and/or by variations in the GREM2 gene, which disrupt the activity of gremlin 2, a TGF-β/bone morphogenetic protein (BMP4) signaling antagonist. CED may be caused by mutations in the TGFB1 gene, while the TGF-β-related genetic background of LDS consists mostly of TGFBR1 and TGFBR2 mutations, which may also impact the above syndromes' vascular manifestations. The potential utility of the TGF-β signaling pathway factors as biomarkers that correlate genetics with clinical outcome of craniofacial malformations is discussed.
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5.
Effects of Three Different Family-Based Interventions in Overweight and Obese Children: The "4 Your Family" Randomized Controlled Trial.
Varagiannis, P, Magriplis, E, Risvas, G, Vamvouka, K, Nisianaki, A, Papageorgiou, A, Pervanidou, P, Chrousos, GP, Zampelas, A
Nutrients. 2021;(2)
Abstract
Childhood overweight and obesity prevalence has risen dramatically in the past decades, and family-based interventions may be an effective method to improve children's eating behaviors. This study aimed to evaluate the effectiveness of three different family-based interventions: group-based, individual-based, or by website approach. Parents and school aged overweight or obese children, 8-12 years of age, were eligible for the study. A total of 115 children were randomly allocated in one of the three interventions, and 91 completed the study (79% compliance); Group 1 (n = 36) received group-based interventions by various experts; Group 2 (n = 30) had interpersonal family meetings with a dietitian; and Group 3 (n = 25) received training through a specifically developed website. Anthropometric, dietary, physical activity, and screen time outcomes were measured at baseline and at the end of the study. Within-group comparisons indicated significant improvement in body weight, body mass index (BMI)-z-score, physical activity, and screen time from baseline in all three study groups (p < 0.05). Furthermore, total body fat percentage (%TBF) was also decreased in Groups 2 and 3. Between-group differences varied with body weight and %TBF change, being larger in Group 3 compared to Groups 1 and 2, in contrast to BMI-z-score, screen time, and health behaviors, which were significantly larger in Group 2 than the other two groups. In conclusion, personalized family-based interventions are recommended to successfully improve children's lifestyle and body weight status.
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6.
Genotypic and Clinical Analysis of a Thalassemia Major Cohort: An Observational Study.
A, T, Lambrou, GI, Samartzi, A, Vlachou, E, Papassotiriou, I, Geronikolou, SA, Kanaka-Gantenbein, C, Chrousos, GP, Kattamis, A
Advances in experimental medicine and biology. 2021;:65-76
Abstract
Thalassemia major (TM) is a hereditary disease caused by defective globin synthesis. Because of the significant increase in life expectancy, these patients are suffering from various health conditions, including endocrinopathies and low bone mineral density. The aim of the present study was to investigate the correlation between clinical and biochemical parameters as well as to identify possible relations in a genotype to phenotype pattern. Sixty-four patients with TM (32 men and 32 women) participated in a cross-sectional study design. The patients were recruited from "Aghia Sofia" Children's Hospital. Clinical and biochemical parameters were evaluated as well as specific mutations were identified. We have found significant correlations between biochemical parameters and iron chelation, hormone replacement treatment as well as TM genotype and hematocrit and T-score. To conclude, the current study showed that clinical parameters of TM patients correlate significantly with both biochemical factors and genotypical patient parameters. Our present study showed that there is a connection between genotype and phenotype as, for example, the identified relation between hematocrit and T-scores and TM-specific mutations. This connection indicates that there is still much more to learn about the role of mutations not only in the disease itself but also in the underlying comorbidities.
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7.
Amyotrophic lateral sclerosis (ALS) and the endocrine system: Are there any further ties to be explored?
Mentis, AA, Bougea, AM, Chrousos, GP
Aging brain. 2021;:100024
Abstract
Amyotrophic Lateral Sclerosis (ALS) belongs to the family of neurodegenerative disorders and is classified as fronto-temporal dementia (FTD), progressive muscular atrophy, primary lateral sclerosis, and pseudobulbar palsy. Even though endocrine dysfunction independently impacts the ALS-related survival rate, the complex connection between ALS and the endocrine system has not been studied in depth. Here we review earlier and recent findings on how ALS interacts with hormones a) of the hypothalamus and pituitary gland, b) the thyroid gland, c) the pancreas, d) the adipose tissue, e) the parathyroid glands, f) the bones, g) the adrenal glands, and h) the gonads (ovaries and testes). Of note, endocrine issues should always be explored in patients with ALS, especially those with low skeletal muscle and bone mass, vitamin D deficiency, and decreased insulin sensitivity (diabetes mellitus). Because ALS is a progressively deteriorating disease, addressing any potential endocrine co-morbidities in patients with this malady is quite important for decreasing the overall ALS-associated disease burden. Importantly, as this burden is estimated to increase globally in the decades to follow, in part because of an increasingly aging population, it is high time for future multi-center, multi-ethnic studies to assess the link between ALS and the endocrine system in significantly larger patient populations. Last, the psychosocial stress experienced by patients with ALS and its psycho-neuro-endocrinological sequelae, including hypothalamic-pituitaryadrenal dysregulation, should become an area of intensive study in the future.
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8.
Non-genetic risk and protective factors and biomarkers for neurological disorders: a meta-umbrella systematic review of umbrella reviews.
Mentis, AA, Dardiotis, E, Efthymiou, V, Chrousos, GP
BMC medicine. 2021;(1):6
Abstract
BACKGROUND The etiologies of chronic neurological diseases, which heavily contribute to global disease burden, remain far from elucidated. Despite available umbrella reviews on single contributing factors or diseases, no study has systematically captured non-purely genetic risk and/or protective factors for chronic neurological diseases. METHODS We performed a systematic analysis of umbrella reviews (meta-umbrella) published until September 20th, 2018, using broad search terms in MEDLINE, SCOPUS, Web of Science, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature, ProQuest Dissertations & Theses, JBI Database of Systematic Reviews and Implementation Reports, DARE, and PROSPERO. The PRISMA guidelines were followed for this study. Reference lists of the identified umbrella reviews were also screened, and the methodological details were assessed using the AMSTAR tool. For each non-purely genetic factor association, random effects summary effect size, 95% confidence and prediction intervals, and significance and heterogeneity levels facilitated the assessment of the credibility of the epidemiological evidence identified. RESULTS We identified 2797 potentially relevant reviews, and 14 umbrella reviews (203 unique meta-analyses) were eligible. The median number of primary studies per meta-analysis was 7 (interquartile range (IQR) 7) and that of participants was 8873 (IQR 36,394). The search yielded 115 distinctly named non-genetic risk and protective factors with a significant association, with various strengths of evidence. Mediterranean diet was associated with lower risk of dementia, Alzheimer disease (AD), cognitive impairment, stroke, and neurodegenerative diseases in general. In Parkinson disease (PD) and AD/dementia, coffee consumption, and physical activity were protective factors. Low serum uric acid levels were associated with increased risk of PD. Smoking was associated with elevated risk of multiple sclerosis and dementia but lower risk of PD, while hypertension was associated with lower risk of PD but higher risk of dementia. Chronic occupational exposure to lead was associated with higher risk of amyotrophic lateral sclerosis. Late-life depression was associated with higher risk of AD and any form of dementia. CONCLUSIONS We identified several non-genetic risk and protective factors for various neurological diseases relevant to preventive clinical neurology, health policy, and lifestyle counseling. Our findings could offer new perspectives in secondary research (meta-research).
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9.
Stress System Activation Analysis in Greek Female Adolescents: A Bioimpedance Study.
S, G, Bacopoulou, F, Boschiero, D, Chrousos, GP
Advances in experimental medicine and biology. 2021;:105-110
Abstract
Adolescence is a developmental stage characterized by endocrine-induced physical and psychosocial changes in stress responsiveness. The stress-sensitive cortical and limbic brain regions, which continue to develop during adolescence and young adulthood, may be vulnerable to such changes, yet have not yet been extensively investigated. To examine the activation state of the stress system in adolescence and to show its physiologic relevance, we employed Electrolytic Extracellular Tomography measurement cycles by bioimpedance (TomEEx, BioTekna Co, Venice). Analysis of changes in Basal Extracellular Conductance (BEC) and systemic hydroelectrolytic distribution (DECW + and DECW-) markers were obtained. The statistical analysis was performed using nonparametric tests. The highest possible precision (in statistics) was detected by a meta-analytic tool: Hedge's g correction for small samples bias. Stress system activity, BMI, and BEC, a biomarker of systemic inflammation, were significantly different in adolescents classified according to their depressive symptoms or self-preoccupation (p < 0.05). Importantly, BEC measures were predicted by stress activation system (p < 0.05). The results contribute to the understanding of the mediating processes in different stress activation-related states and inflammation during adolescence.
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10.
Chronic Systemic Inflammation Measured by Bioimpedance Technology Before and After Sleeve Gastrectomy: A Feasibility Study.
S, G, Cokkinos, D, Boschiero, D, Chrousos, GP, Albanopoulos, K
Advances in experimental medicine and biology. 2021;:169-177
Abstract
Stress induces obesity, while extreme obesity causes stress, anxiety, and even depression. Yet, knowledge on the underlying mechanism(s) has many gaps. To this end, we designed a feasibility study, focused on 18 bariatric patients recruited by the First Propaideutic Department of Surgery at the Hippokration University Hospital in Athens, Greece. The patients (aged 23-58 y, weight 101-185.4 kg before surgery) were weighted and evaluated by advanced bioimpedance technology 2-3 days before surgery at the Biomedical Research Foundation of the Academy of Athens. We employed Bioimpedance Electrolytic Extracellular Tomography (Tomeex), which characterizes (a) neurodegenerative responsiveness to stress, (b) sensory and autonomic tones by basal extracellular conductance (BEC), and (c) activity of limbic and cortical brain areas. The patients' mean body weight loss after 6 months was 48.8 ± 3.1Kg, while stress levels evaluated by appropriate questionnaires decreased (Spearman coefficient significance level p < 0.05). Anxiety and depressive symptoms decreased by 70%, accompanied by changes in measured sensory and autonomic tones (p = 0.003). Baseline blood markers, such as hsCRP and glucose, predicted lower abdominal inflammation (p = 0.034 and p = 0.058, respectively) 6 months postoperatively. In conclusion, chronic inflammation measures by bioimpedance are a useful non-invasive monitoring tool in bariatric surgery.