Phosphofurin acidic cluster sorting protein 2 (PACS2) plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy. Missense mutations, particularly E209K and E211K, are linked to developmental and epileptic encephalopathy-66 (DEE66), known as PACS2 syndrome. Individuals with this syndrome exhibit neurodevelopmental delay, seizures, facial dysmorphism, hypotonia, and delayed motor skills.Understanding the impact of these missense mutations on molecular processes is crucial. Studies suggest that E209K mutation decreases phosphorylation, increases the survival time of protein, and modifies protein-protein interaction, consequently leading to disruption of calcium flux and lower resistance to apoptosis induction. Unfortunately, to date, only a limited number of research groups have investigated the effects of mutations in the PACS2 gene. Current research on PACS2 syndrome is hampered by the lack of suitable models. While in vitro models using transfected cell lines offer insights, they cannot fully capture the disease's complexity.To address this, utilizing cells from individuals with PACS2 syndrome, specifically induced pluripotent stem cells (iPSCs), holds promise for understanding phenotypic diversity and developing personalized therapies. However, iPSC models may not fully capture tissue-specific effects of the E209K/E211K mutation. In vivo studies using animal models, particularly mice, could overcome these limitations.This review summarizes current knowledge about PACS2 structure and functions, explores the cellular consequences of E209K and E211K mutations, and highlights the potential of iPSC and mouse models in advancing our understanding of PACS2 syndrome.

• MeSH
• Induced Pluripotent Stem Cells metabolism   MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Mutation MeSH
• Vesicular Transport Proteins * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Gambling encompasses a wide variety of activities, and the structural characteristics of each form contribute to its potential risk. However, the literature does not fully agree on the risk levels of certain gambling forms. In this study, we classify less risky gambling forms (soft forms) based on public perceptions of their riskiness. We examine the link between gambling experience and problem gambling prevalence. A survey was conducted in a model region of the Czech Republic, a post-socialist country with high gambling availability, with N = 2,498 respondents. A typology of gambling forms (lotteries, betting, and casino games) was created based on perceived risk similarities. Lotteries are the most frequently played gambling form, with 86.3% reporting lifetime participation. Among those who exclusively engage in lottery-type forms, 15 percentage points more women than men participated in the last year, and the gap widens to 31 points over a lifetime. Forms of gambling perceived as more risky show a lower proportion of non-problem gamblers, both for recent and lifetime participation. Furthermore, individuals who gambled within the past month or year are at higher risk of developing gambling problems compared to those whose gambling experiences were less recent.

• MeSH
• Adult MeSH
• Gambling * psychology   classification   epidemiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Behavior, Addictive * psychology   epidemiology   classification   MeSH
• Prevalence MeSH
• Surveys and Questionnaires MeSH
• Risk-Taking * MeSH
• Risk Factors MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.

• MeSH
• Diet, High-Fat * MeSH
• Insulin Resistance MeSH
• Liver drug effects   metabolism   pathology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• Obesity * chemically induced   MeSH
• Pregnane X Receptor * metabolism   genetics   MeSH
• Fungicides, Industrial * toxicity   MeSH
• Triazoles * toxicity   MeSH
• Triglycerides blood   metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Fatty Liver * chemically induced   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The distribution of time across physical activity, sedentary behaviors, and sleep appears to be essential for the management of obesity. However, the impact of reallocating time among these behaviors, collectively known as 24-h movement behaviors, remains underexplored. OBJECTIVE: This study examines the theoretical effects of reallocating time between 24-h movement behaviors on obesity indicators across different age groups. METHODS: We performed a pooled data meta-analysis of 9818 participants from 11 observational and experimental studies. To estimate the time spent in movement behaviors, we reprocessed and harmonized individual-level raw accelerometer-derived data. Isotemporal substitution models estimated theoretical changes in body mass index (BMI) and waist circumference (WC) associated with time reallocation between movement behaviors. We performed the analysis separately for children, adolescents, adults, and older adults. RESULTS: Even minor reallocations of 10 min led to significant changes in obesity indicators, with pronounced effects observed when 30 min were reallocated. The most substantial adverse effects on BMI and WC occurred when moderate-to-vigorous physical activity (MVPA) was reallocated to other movement behaviors. For 30-min reallocations, the largest increase in BMI (or BMI z-score for children) occurred when MVPA was reallocated to light-intensity physical activity (LPA) in children (0.26 units, 95% confidence interval [CI] 0.15, 0.37) and to sedentary behavior (SB) in adults (0.72 kg/m2, 95% CI 0.47, 0.96) and older adults (0.73 kg/m2, 95% CI 0.59, 0.87). The largest increase in WC was observed when MVPA was substituted with LPA in adults (2.66 cm, 95% CI 1.42, 3.90) and with SB in older adults (2.43 cm, 95% CI 2.07, 2.79). Conversely, the highest magnitude of the decrease in obesity indicators was observed when SB was substituted with MVPA. Specifically, substituting 30 min of SB with MVPA was associated with a decrease in BMI z-score by - 0.15 units (95% CI - 0.21, - 0.10) in children and lower BMI by - 0.56 kg/m2 (95% CI - 0.74, - 0.39) in adults and by - 0.52 kg/m2 (95% CI - 0.61, - 0.43) in older adults. Reallocating time away from sleep and LPA showed several significant changes but lacked a consistent pattern. While the predicted changes in obesity indicators were generally consistent across age groups, inconsistent findings were observed in adolescents, particularly for reallocations between MVPA and other behaviors. CONCLUSIONS: This investigation emphasizes the crucial role of MVPA in mitigating obesity risk across the lifespan, and the benefit of substituting SB with low-intensity movement behaviors. The distinct patterns observed in adolescents suggest a need for age-specific lifestyle interventions to effectively address obesity. Emphasizing manageable shifts, such as 10-min reallocations, could have significant public health implications, promoting sustainable lifestyle changes that accommodate individuals with diverse needs, including those with severe obesity.

• MeSH
• Accelerometry MeSH
• Time Factors MeSH
• Exercise * MeSH
• Child MeSH
• Adult MeSH
• Body Mass Index MeSH
• Obesity Management * methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Obesity * MeSH
• Waist Circumference MeSH
• Sedentary Behavior * MeSH
• Aged MeSH
• Sleep MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.

• MeSH
• Azoxymethane toxicity   MeSH
• Chronic Disease MeSH
• Indoles pharmacology   therapeutic use   MeSH
• Colitis drug therapy   chemically induced   metabolism   pathology   MeSH
• Colorectal Neoplasms * drug therapy   metabolism   pathology   MeSH
• Disease Models, Animal * MeSH
• Molecular Mimicry MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• Colitis-Associated Neoplasms pathology   drug therapy   metabolism   MeSH
• Dextran Sulfate toxicity   MeSH
• Inflammation drug therapy   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

AIM: This study aimed to identify sleep profiles in a representative sample of Slovak adolescents and investigate their associations with adiposity indicators and cardiorespiratory fitness. METHODS: Data from the 2022 Health Behaviour in School-aged Children (HBSC) study conducted in Slovakia were analysed. Survey questions on sleep duration and problems from the entire HBSC sample (n = 8906) were used to identify sleep profiles. Associations with adiposity indicators and cardiorespiratory fitness were investigated in a subsample of 924 adolescents (average age 13.3 ± 1.48; 56.2% boys) who completed the HBSC survey, bioimpedance analysis, and 20-metre shuttle run test. RESULTS: Three sleep profiles were identified-optimal sleepers, optimal sleepers with sporadic sleep problems and poor sleepers. Crude models showed that poor sleepers had significantly higher body fat percentage and fat mass index, along with lower cardiorespiratory fitness, compared to optimal sleepers. After adjustment, only the association between sleep profiles and cardiorespiratory fitness remained significant. CONCLUSION: The observed associations between sleep profiles and cardiorespiratory fitness may help better target future intervention resources towards adolescents with low cardiorespiratory fitness levels.

• MeSH
• Adiposity * MeSH
• Child MeSH
• Cardiorespiratory Fitness * physiology   MeSH
• Humans MeSH
• Adolescent MeSH
• Cross-Sectional Studies MeSH
• Sleep * physiology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Slovakia MeSH

Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance, and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥ 30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5%-10% SPC, which reduced permeability even compared to control with "healthy" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behavior of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.

• MeSH
• Models, Biological MeSH
• Ceramides * metabolism   MeSH
• Phosphorylcholine analogs & derivatives   MeSH
• Skin * metabolism   MeSH
• Fatty Acids, Nonesterified metabolism   MeSH
• Humans MeSH
• Lysophospholipids metabolism   MeSH
• Permeability drug effects   MeSH
• Sphingosine analogs & derivatives   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.

• MeSH
• Immunotherapy * methods   MeSH
• Papillomavirus Infections immunology   virology   MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Mutation * MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Tumor Microenvironment * immunology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Exome Sequencing MeSH
• Tumor Escape genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Over the past two decades, the global incidence of gout has markedly increased, affecting people worldwide. Considering the side effects of xanthine oxidase (XO) inhibitor drugs (e.g. allopurinol and febuxostat) used in the treatment of hyperuricemia and gout, the potential application of phytochemicals has been widely studied. In addition, XO also takes part in the elimination of certain drugs, including 6-mercaptopurine. In the current explorative study, we aimed to examine the potential effects of tea catechins, resveratrol, silymarin flavonolignans and some of their conjugated metabolites on XO-catalyzed xanthine and 6-mercaptopurine oxidation, applying in vitro assays and modeling studies. RESULTS: Catechins, resveratrol and resveratrol conjugates exerted no or only weak inhibitory effects on XO. Silybin A, silybin B and isosilybin A were weak, silychristin was a moderate, while 2,3-dehydrosilychristin was a potent inhibitor of the enzyme. Sulfate metabolites of silybin A, silybin B and isosilybin A were considerably stronger inhibitors compared to the parent flavonolignans, and the sulfation of 2,3-dehydrosilychristin slightly increased its inhibitory potency. Silychristin was the sole flavonolignan tested, where sulfate conjugation decreased its inhibitory effect. CONCLUSION: 2,3-Dehydrosilychristin seems to be a promising candidate for examining its in vivo antihyperuricemic effects, because both the parent compound and its sulfate conjugate are highly potent inhibitors of XO. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

• MeSH
• Enzyme Inhibitors * chemistry   pharmacology   MeSH
• Catalysis MeSH
• Catechin * chemistry   analogs & derivatives   pharmacology   MeSH
• Humans MeSH
• Mercaptopurine * chemistry   pharmacology   metabolism   MeSH
• Oxidation-Reduction * MeSH
• Resveratrol * chemistry   pharmacology   MeSH
• Silymarin * pharmacology   chemistry   MeSH
• Xanthine chemistry   metabolism   pharmacology   MeSH
• Xanthine Oxidase * antagonists & inhibitors   metabolism   chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for chronic kidney disease (CKD) evaluation and management bring important updates, particularly for European laboratories. These guidelines emphasize the need for harmonization in CKD testing, promoting the use of regional equations. In Europe, the European Kidney Function Consortium (EKFC) equation is particularly suited for European populations, particularly compared to the CKD-EPI 2021 race-free equation. A significant focus is placed on the combined use of creatinine and cystatin C to estimate glomerular filtration rate (eGFRcr-cys), improving diagnostic accuracy. In situations where eGFR may be inaccurate or clinically insufficient, the guidelines encourage the use of measured GFR (mGFR) through exogenous markers like iohexol. These guidelines emphasize the need to standardize creatinine and cystatin C measurements, ensure traceability to international reference materials, and adopt harmonized reporting practices. The recommendations also highlight the importance of incorporating risk prediction models, such as the Kidney Failure Risk Equation (KFRE), into routine clinical practice to better tailor patient care. This article provides a European perspective on how these KDIGO updates should be implemented in clinical laboratories to enhance CKD diagnosis and management, ensuring consistency across the continent.

• MeSH
• Renal Insufficiency, Chronic * diagnosis   therapy   MeSH
• Cystatin C blood   MeSH
• Glomerular Filtration Rate * MeSH
• Laboratories, Clinical MeSH
• Creatinine blood   MeSH
• Humans MeSH
• Practice Guidelines as Topic * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• Europe MeSH