Unravelling the metabolic landscape of cutaneous melanoma: Insights from single-cell sequencing analysis and machine learning for prognostic assessment of lactate metabolism.

This manuscript presents a comprehensive investigation into the role of lactate metabolism-related genes as potential prognostic markers in skin cutaneous melanoma (SKCM). Bulk-transcriptome data from The Cancer Genome Atlas (TCGA) and GSE19234, GSE22153, and GSE65904 cohorts from GEO database were processed and harmonized to mitigate batch effects. Lactate metabolism scores were assigned to individual cells using the 'AUCell' package. Weighted Co-expression Network Analysis (WGCNA) was employed to identify gene modules correlated with lactate metabolism. Machine learning algorithms were applied to construct a prognostic model, and its performance was evaluated in multiple cohorts. Immune correlation, mutation analysis, and enrichment analysis were conducted to further characterize the prognostic model's biological implications. Finally, the function of key gene NDUFS7 was verified by cell experiments. Machine learning resulted in an optimal prognostic model, demonstrating significant prognostic value across various cohorts. In the different cohorts, the high-risk group showed a poor prognosis. Immune analysis indicated differences in immune cell infiltration and checkpoint gene expression between risk groups. Mutation analysis identified genes with high mutation loads in SKCM. Enrichment analysis unveiled enriched pathways and biological processes in high-risk SKCM patients. NDUFS7 was found to be a hub gene in the protein-protein interaction network. After the expression of NDUFS7 was reduced by siRNA knockdown, CCK-8, colony formation, transwell and wound healing tests showed that the activity, proliferation and migration of A375 and WM115 cell lines were significantly decreased. This study offers insights into the prognostic significance of lactate metabolism-related genes in SKCM.

Benefits and costs: Understanding the influence of heavy metal pollution on environmental adaptability in Strauchbufo raddei tadpoles through an energy budget perspective.

Understanding the impact of environmental pollution on organismal energy budgets is crucial for predicting adaptive responses and potential maladaptation to stressors. However, the regulatory mechanism governing the trade-off between energy intake and consumption remains largely unknown, particularly considering the diverse adaptations influenced by exposure history in realistic field conditions. In the present study, we conducted a simulated field reciprocal transplant experiment to compare the energy budget strategies of Strauchbufo raddei tadpoles exposed to heavy metal. The simulated heavy metal concentrations (0.29 mg/L Cu, 1.17 mg/L Zn, 0.47 mg/L Pb, 0.16 mg/L Cd) mirrored the actual environmental exposure concentrations observed in the field habitat. This allowed for a comparison between tadpoles with parental chronic exposure to heavy metal pollutants in their habitat and those without such exposure. Results revealed that under heavy metal exposure, tadpoles originating from unpolluted areas exhibited heightened vulnerability, characterized by reduced food intake, diminished nutrient absorption, increased metabolism cost, reduced energy reserves, and increased mortality rates. In contrast, tadpoles originating from areas with long-term heavy metal pollution demonstrated adaptive strategies, manifested through adjustments in liver and small intestine phenotypes, optimizing energy allocation, and reducing energy consumption to preserve energy, thus sustaining survival. However, tadpoles from polluted areas exhibited certain maladaptive such as growth inhibition, metabolic suppression, and immune compromise due to heavy metal exposure. In conclusion, while conserving energy consumption has proven to be an effective way to deal with long-term heavy metal stress, it poses a threat to individual survival and population development in the long run.

Despite plasticity, heatwaves are costly for a coral reef fish.

Climate change is intensifying extreme weather events, including marine heatwaves, which are prolonged periods of anomalously high sea surface temperature that pose a novel threat to aquatic animals. Tropical animals may be especially vulnerable to marine heatwaves because they are adapted to a narrow temperature range. If these animals cannot acclimate to marine heatwaves, the extreme heat could impair their behavior and fitness. Here, we investigated how marine heatwave conditions affected the performance and thermal tolerance of a tropical predatory fish, arceye hawkfish (Paracirrhites arcatus), across two seasons in Moorea, French Polynesia. We found that the fish's daily activities, including recovery from burst swimming and digestion, were more energetically costly in fish exposed to marine heatwave conditions across both seasons, while their aerobic capacity remained the same. Given their constrained energy budget, these rising costs associated with warming may impact how hawkfish prioritize activities. Additionally, hawkfish that were exposed to hotter temperatures exhibited cardiac plasticity by increasing their maximum heart rate but were still operating within a few degrees of their thermal limits. With more frequent and intense heatwaves, hawkfish, and other tropical fishes must rapidly acclimate, or they may suffer physiological consequences that alter their role in the ecosystem.

In silico and pharmacokinetic assessment of echinocystic acid effectiveness in Alzheimer's disease like pathology.

Aim: Alzheimer's disease causes dementia which impairs the cognitive domains. Methodology: The pharmacokinetic characteristics and biological activity of echinocystic acid are predicted in this work using in silico or computational approaches, including pkCSM, Swiss ADME, OSIRIS® property explorer, PASS online web resource and MOLINSPIRATION® software. Results & discussion: The compound has lipid metabolism regulating property as major role in decreasing the progression of Alzheimer's disease and it has no major side effects and ADR. The drug also has anti-inflammatory properties which can help in regulating the innate immunity that plays a major role in Alzheimer's disease. Conclusion: From the computational screening, we infer that, echinocystic acid can regulate memory loss, cognitive disability and also slow down the progression of Alzheimer's disease-like pathology.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by ß-amyloid (Aß) plaque deposition and neurofibrillary tangles of hyperphosphorylated tau. There is no treatment to completely cure AD and dementia but the progression of the disease can be slowed down and the major symptoms can be treated. Various online servers and web resources were employed in this study. The use of online and offline tools for the prediction and evaluation of the various drug properties and parameters have led to evidential conclusion of the study. The calculated binding affinities for all of the designed compounds range from -1.5 to -6.0 kcal/mol-1, while few receptors showed positive binding affinity indicating less binding with receptor. From the in silico study performed we infer that echinocystic acid can regulate memory loss, cognitive disability and slow down the progression of Alzheimer's disease like pathology.

Assessment of the disruption effects of tetrabromobisphenol A and its analogues on lipid metabolism using multiple in vitro models.

Tetrabromobisphenol A (TBBPA), a widely-used brominated flame retardant, has been revealed to exert endocrine disrupting effects and induce adipogenesis. Given the high structural similarities of TBBPA analogues and their increasing exposure risks, their effects on lipid metabolism are necessary to be explored. Herein, 9 representative TBBPA analogues were screened for their interference on 3T3-L1 preadipocyte adipogenesis, differentiation of C3H10T1/2 mesenchymal stem cells (MSCs) to brown adipocytes, and lipid accumulation of HepG2 cells. TBBPA bis(2-hydroxyethyl ether) (TBBPA-BHEE), TBBPA mono(2-hydroxyethyl ether) (TBBPA-MHEE), TBBPA bis(glycidyl ether) (TBBPA-BGE), and TBBPA mono(glycidyl ether) (TBBPA-MGE) were found to induce adipogenesis in 3T3-L1 preadipocytes to different extends, as evidenced by the upregulated intracellular lipid generation and expressions of adipogenesis-related biomarkers. TBBPA-BHEE exhibited a stronger obesogenic effect than did TBBPA. In contrast, the test chemicals had a weak impact on the differentiation process of C3H10T1/2 MSCs to brown adipocytes. As for hepatic lipid formation test, only TBBPA mono(allyl ether) (TBBPA-MAE) was found to significantly promote triglyceride (TG) accumulation in HepG2 cells, and the effective exposure concentration of the chemical under oleic acid (OA) co-exposure was lower than that without OA co-exposure. Collectively, TBBPA analogues may perturb lipid metabolism in multiple tissues, which varies with the test tissues. The findings highlight the potential health risks of this kind of emerging chemicals in inducing obesity, non-alcoholic fatty liver disease (NAFLD) and other lipid metabolism disorders, especially under the conditions in conjunction with high-fat diets.

Label-free fluorescence lifetime imaging for the assessment of cell viability in living tumor fragments.

Significance: To enable non-destructive longitudinal assessment of drug agents in intact tumor tissue without the use of disruptive probes, we have designed a label-free method to quantify the health of individual tumor cells in excised tumor tissue using multiphoton fluorescence lifetime imaging microscopy (MP-FLIM). Aim: Using murine tumor fragments which preserve the native tumor microenvironment, we seek to demonstrate signals generated by the intrinsically fluorescent metabolic co-factors nicotinamide adenine dinucleotide phosphate [NAD(P)H] and flavin adenine dinucleotide (FAD) correlate with irreversible cascades leading to cell death. Approach: We use MP-FLIM of NAD(P)H and FAD on tissues and confirm viability using standard apoptosis and live/dead (Caspase 3/7 and propidium iodide, respectively) assays. Results: Through a statistical approach, reproducible shifts in FLIM data, determined through phasor analysis, are shown to correlate with loss of cell viability. With this, we demonstrate that cell death achieved through either apoptosis/necrosis or necroptosis can be discriminated. In addition, specific responses to common chemotherapeutic treatment inducing cell death were detected. Conclusions: These data demonstrate that MP-FLIM can detect and quantify cell viability without the use of potentially toxic dyes, thus enabling longitudinal multi-day studies assessing the effects of therapeutic agents on tumor fragments.

Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. HIGHLIGHTS: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.

Mechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition.

The tumour suppressor p16/CDKN2A and the metabolic gene, methyl-thio-adenosine phosphorylase (MTAP), are frequently co-deleted in some of the most aggressive and currently untreatable cancers. Cells with MTAP deletion are vulnerable to inhibition of the metabolic enzyme, methionine-adenosyl transferase 2A (MAT2A), and the protein arginine methyl transferase (PRMT5). This synthetic lethality has paved the way for the rapid development of drugs targeting the MAT2A/PRMT5 axis. MAT2A and its liver- and pancreas-specific isoform, MAT1A, generate the universal methyl donor S-adenosylmethionine (SAM) from ATP and methionine. Given the pleiotropic role SAM plays in methylation of diverse substrates, characterising the extent of SAM depletion and downstream perturbations following MAT2A/MAT1A inhibition (MATi) is critical for safety assessment. We have assessed in vivo target engagement and the resultant systemic phenotype using multi-omic tools to characterise response to a MAT2A inhibitor (AZ'9567). We observed significant SAM depletion and extensive methionine accumulation in the plasma, liver, brain and heart of treated rats, providing the first assessment of both global SAM depletion and evidence of hepatic MAT1A target engagement. An integrative analysis of multi-omic data from liver tissue identified broad perturbations in pathways covering one-carbon metabolism, trans-sulfuration and lipid metabolism. We infer that these pathway-wide perturbations represent adaptive responses to SAM depletion and confer a risk of oxidative stress, hepatic steatosis and an associated disturbance in plasma and cellular lipid homeostasis. The alterations also explain the dramatic increase in plasma and tissue methionine, which could be used as a safety and PD biomarker going forward to the clinic.

Probiotic and high-fat diet: effects on pain assessment, body composition, and cytokines in male and female adolescent and adult rats.

Obesity in adolescence is increasing in frequency and is associated with elevated proinflammatory cytokines and chronic pain in a sex-dependent manner. Dietary probiotics may mitigate these detrimental effects of obesity. Using a Long-Evans adolescent and adult rat model of overweight (high fat diet - 45% kcal from fat from weaning; HFD), we determined the effect of a single strain dietary probiotic (L. plantarum 299v [Lp299v] from weaning) on the theoretically increased neuropathic injury-induced pain phenotype and inflammatory cytokines. We found that although HFD increased fat mass, it did not markedly affect pain phenotype, particularly in adolescence, but there were subtle differences in pain in adult male vs. female rats. The combination of HFD and Lp299v augmented the increase in leptin in adolescent females. There were many non-interacting, main effects of age, diet and probiotic on an array of cytokines and adipokines with adults being higher than adolescents, HFD higher than the control diet, and a decrease with probiotic compared to placebo. Of particular interest were the probiotic-induced increases in IL12p70 in female adolescents on a HFD. We conclude that a more striking pain phenotype could require a higher and longer duration caloric diet or different etiology of pain. A major strength of our study was that a single strain probiotic had a wide range of inhibiting effects on most pro-inflammatory cytokines. The positive effect of probiotic on leptin in female adolescent rats is intriguing and worthy of exploration.

Lipidomic Assessment of the Inhibitory Effect of Standardized Water Extract of Hydrangea serrata (Thunb.) Ser. Leaves during Adipogenesis.

Obesity is primarily exacerbated by excessive lipid accumulation during adipogenesis, with triacylglycerol (TG) as a major lipid marker. However, as the association between numerous lipid markers and various health conditions has recently been revealed, investigating the lipid metabolism in detail has become necessary. This study investigates the lipid metabolic effects of Hydrangea serrata (Thunb.) Ser. hot water leaf extract (WHS) on adipogenesis using LC-MS-based lipidomics analysis of undifferentiated, differentiated, and WHS-treated differentiated 3T3-L1 cells. WHS treatment effectively suppressed the elevation of glycerolipids, including TG and DG, and prevented a molecular shift in fatty acyl composition towards long-chain unsaturated fatty acids. This shift also impacted glycerophospholipid metabolism. Additionally, WHS stabilized significant lipid markers such as the PC/PE and LPC/PE ratios, SM, and Cer, which are associated with obesity and related comorbidities. This study suggests that WHS could reduce obesity-related risk factors by regulating lipid markers during adipogenesis. This study is the first to assess the underlying lipidomic mechanisms of the adipogenesis-inhibitory effect of WHS, highlighting its potential in developing natural products for treating obesity and related conditions. Our study provides a new strategy for the development of natural products for the treatment of obesity and related diseases.

Risk assessment model based on nucleotide metabolism-related genes highlights SLC27A2 as a potential therapeutic target in breast cancer.

PURPOSE: Breast cancer (BC) is the most prevalent malignant tumor worldwide among women, with the highest incidence rate. The mechanisms underlying nucleotide metabolism on biological functions in BC remain incompletely elucidated. MATERIALS AND METHODS: We harnessed differentially expressed nucleotide metabolism-related genes from The Cancer Genome Atlas-BRCA, constructing a prognostic risk model through univariate Cox regression and LASSO regression analyses. A validation set and the GSE7390 dataset were used to validate the risk model. Clinical relevance, survival and prognosis, immune infiltration, functional enrichment, and drug sensitivity analyses were conducted. RESULTS: Our findings identified four signature genes (DCTPP1, IFNG, SLC27A2, and MYH3) as nucleotide metabolism-related prognostic genes. Subsequently, patients were stratified into high- and low-risk groups, revealing the risk model's independence as a prognostic factor. Nomogram calibration underscored superior prediction accuracy. Gene Set Variation Analysis (GSVA) uncovered activated pathways in low-risk cohorts and mobilized pathways in high-risk cohorts. Distinctions in immune cells were noted between risk cohorts. Subsequent experiments validated that reducing SLC27A2 expression in BC cell lines or using the SLC27A2 inhibitor, Lipofermata, effectively inhibited tumor growth. CONCLUSIONS: We pinpointed four nucleotide metabolism-related prognostic genes, demonstrating promising accuracy as a risk prediction tool for patients with BC. SLC27A2 appears to be a potential therapeutic target for BC among these genes.

Energy expenditure during nutritional rehabilitation: a scoping review to investigate hypermetabolism in individuals with anorexia nervosa.

BACKGROUND: Weight gain and nutritional rehabilitation are essential first steps to achieve medical stabilization in anorexia nervosa, and frequent resistance to weight gain requires patients to consume high kilocalorie loads. Adaptive hypometabolism is common when patients begin treatment, and rebound hypermetabolism is suspected to be a significant barrier to weight gain. The aim of this review was to summarize existing data describing metabolic changes in anorexia nervosa during weight restoration. The reported findings challenge current hypotheses of weight gain resistance and highlight key areas for future research. METHODS: Using scoping review guidelines, three databases were searched for studies investigating metabolic changes in anorexia nervosa before and after renourishment. Two reviewers systematically screened the titles and abstracts of 447 articles, and full-text versions of 106 studies were assessed for eligibility. A total of 36 studies were included for review. Data regarding the study description, sample population (including age, weight, BMI, duration of treatment, and caloric intake), and metabolic variable descriptions were extracted. RESULTS: Female patients with anorexia nervosa from studies across 13 countries were included. Across the studies, average BMI increased from 13.7 kg/m2 at admission to 17.57 kg/m2. Patients presented to treatment with clinically reduced energy expenditure levels. After varying levels of nutritional rehabilitation and weight restoration, measured energy expenditure increased significantly in 76% of the studies. Energy expenditure values at the second timepoint increased to the standard range for normal weight female teenagers and adults. Despite these increases, the studies do not indicate the presence of a hypermetabolic state during renourishment. Additionally, all studies including both measured and predicted energy expenditure reported that predicted energy expenditure overestimated measured values. CONCLUSION: This study provides a detailed evaluation of the literature investigating energy expenditure and metabolic rate in patients with anorexia nervosa before and following a period of renourishment. The findings from this review identify important gaps in the current beliefs of energy expenditure in anorexia nervosa and highlight a need for further exploration of metabolic alterations during weight restoration.

Nutritional rehabilitation and weight restoration are two primary goals of anorexia nervosa treatment that pose significant physiological and psychological challenges for patients. Patients often require high caloric loads to continue an adequate weight gain trajectory, but the underlying cause of weight gain resistance remains unknown. We completed a scoping review of research into energy expenditure and metabolic rate during treatment. Our search identified 447 relevant articles from academic databases, and 106 were deemed eligible after screening. We extracted data, including sample characteristics, kilocalorie intake, energy expenditure, and treatment information, from 36 studies. When individuals arrived for treatment, their energy expenditure was lower than that of individuals without an eating disorder due to the prolonged state of nutrient deprivation. After varying amounts of time and kilocalorie intake, most studies reported significant increases in energy expenditure. However, energy expenditure after a period of renourishment did not indicate an overactive metabolism (i.e., "hypermetabolism"). Funders should consider supporting exploration of additional factors that may be functioning as barriers to weight gain during treatment, in pursuit of making treatment more efficient and long-lasting. Additionally, future research describing metabolism in anorexia nervosa should provide more consistent methodologies, robust statical testing, and comprehensive reporting of dietary intake.

A Dose-Response Study to Examine Paraxanthine's Impact on Energy Expenditure, Hunger, Appetite, and Lipolysis.

This study investigated if paraxanthine (PX) impacts energy expenditure, lipolysis and perceptual responses. In a randomized, double-blind, placebo-controlled, crossover fashion, 21 adults (13 M, 8 F; 26.0 ± 6.4 years, 174.9 ± 11.5 cm, 81.0 ± 15.7 kg body mass, 26.3 ± 3.4 kg/m2) consumed a placebo (PLA), 100 mg (PX100), 200 mg (PX200), and 300 mg of PX (PX300, enfinity®, Ingenious Ingredients, L.P. Lewisville, TX, USA). Venous blood was collected 0, 30, 60, 90, 120 and 180 min (min) after ingestion and analyzed for glycerol and free fatty acids. Resting hemodynamics, metabolic rate and perceptual indicators of hunger, appetite and anxiety were evaluated. Mixed factorial analysis of variance were used to evaluate changes time within and between groups. Heart rate decreased in PX100 compared to PLA 60 (p = .022) and 180 min (p = .001). Blood pressure did not change. Hunger ratings in PLA increased 30 (p = .05), 60 (p = .04), 90 (p = .02), and 180 min (p = .05) after ingestion when compared to PX200. PX200 increased energy expenditure (all p < .05) when compared to PLA. Rates of fat oxidation tended to increase 90 (p = .056) and 120 min (p = .066) in PX200 compared to PLA. Free fatty acids increased in PX300 compared to PLA (p = .002). Glycerol did not change. Ingestion of PX200 augmented energy expenditure and hunger ratings when compared to PLA without impacting hemodynamics or lipolysis.

Physiological Measurements and Transcriptomics Reveal the Fitness Costs of Monochamus saltuarius to Bursaphelenchus xylophilus.

The pine wood nematode (PWN) uses several Monochamus species as vehicles, through a temporary hitchhiking process known as phoresy, enabling it to access new host plant resources. Monochamus saltuarius acts as a new and major vector of the PWN in Northeastern China, showing lower PWN carrying capacity and a shorter transmission cycle compared to established vectors. The apparently altered symbiotic relationship offers an interesting area for researching the costs and adaptions involved in nematode-beetle, a specialized phoresy. We analyzed the response and fitness costs of M. saltuarius through physiological measurements and transcriptomics. The PWN exerted adverse repercussions on the growth and development of M. saltuarius. The PWN accelerated larval development into pupae, while beetle adults carrying the PWN exhibited an elevated abnormality rate and mortality, and reduced starvation resistance. During the pupal stage, the expression of growth-related genes, including ecdysone-inducible genes (E74EA), cuticle proteins, and chitin genes (CHTs), markedly increased. Meanwhile, the induced immune response, mainly by the IMD and Toll signaling pathways, could be a contributing factor to adult abnormality and mortality. Adult gonads and trachea exhibited enrichment in pathways related to fatty acid elongation, biosynthesis, and metabolism. FASN, ELOVL, and SCD possibly contributed to resistance against PWN. Our research indicated that phoretic interactions between vector beetles and PWN vary throughout the vector's lifespan, particularly before and after entry into the trachea. This study highlighted the fitness costs of immunity and metabolism on the vector beetle, indicating the adaptation mechanisms and evolutionary trade-offs to PWN.

Nutrition Assessment and Management in Celiac Disease.

Celiac disease (CeD) is the most common immune condition affecting the gastrointestinal tract; it is triggered by gluten and the only available treatment is a strict gluten-free diet (GFD). Therefore, for patients with CeD, adopting a GFD is not a lifestyle choice. The major problem is that a GFD is restrictive and, like all restrictive diets, it has the potential for adverse nutritional outcomes, especially if adopted for a long term. It is well known that GFD can be nutritionally inadequate and is frequently associated with vitamin and mineral deficiencies; it is also associated with excessive sugar and fat intake, particularly when gluten-free substitutes are consumed. Consequently, people with CeD are affected by higher rates of overweight and obesity and metabolic complications, such as fatty liver and cardiovascular disease. Therefore, assessment of nutritional status and diet quality at diagnosis and while on a long-term GFD is key in the management of CeD. This narrative review addresses nutritional considerations in CeD and management of common challenges associated with a GFD.

Simultaneous assessment of absorption and pharmacokinetic characteristics of four active flavonoids from Chimonanthus nitens Leaf Granules using LC-MS determination: in vivo and in vitro.

A sensitive UPLC-HRMS method was developed and validated for simultaneous quantification of four active flavonoids from Chimonanthus nitens Leaf Granules (CNLG) in biological matrix. The method was utilized in pharmacokinetic study of the four flavonoids in rats as well as other evaluation assays in vitro. It was revealed that rutin, nicotiflorin, and astragalin had poor oral bioavailability in rats possibly due to low intestinal permeability and metabolism in intestinal flora. Kaempferol underwent rapid glucuronidation and sulphation in rat plasma with medium permeability coefficient. The results provided valuable data for future research and development of CNLG flavonoids.

Quantitative assessment and monitoring of microplastics and nanoplastics distributions and lipid metabolism in live zebrafish using hyperspectral stimulated Raman scattering microscopy.

Microplastics (MP) and nanoplastics (NP) pollutions pose a rising environmental threat to humans and other living species, given their escalating presence in essential resources that living subjects ingest and/or inhale. Herein, to elucidate the potential health implications of MP/NP, we report for the first time by using label-free hyperspectral stimulated Raman scattering (SRS) imaging technique developed to quantitatively monitor the bioaccumulation and metabolic toxicity of MP/NP within live zebrafish larvae during their early developmental stages. Zebrafish embryos are exposed to environmentally related concentrations (3-60 µg/ml) of polystyrene (PS) beads with two typical sizes (2 µm and 50 nm). Zebrafish are administered isotope-tagged fatty acids through microinjection and dietary intake for in vivo tracking of lipid metabolism dynamics. In vivo 3D quantitative vibrational imaging of PS beads and intrinsic biomolecules across key zebrafish organs reveals that gut and liver are the primary target organs of MP/NP, while only 50 nm PS beads readily aggregate and adhere to the brain and blood vessels. The 50 nm PS beads are also found to induce more pronounced hepatic inflammatory response compared to 2 µm counterparts, characterized by increased biogenesis of lipid droplets and upregulation of arachidonic acid detected in zebrafish liver. Furthermore, Raman-tagged SRS imaging of fatty acids uncovers that MP/NP exposure significantly reduces yolk lipid utilization and promotes dietary lipid storage in zebrafish, possibly associated with developmental delays and more pronounced food dilution effects in zebrafish larvae exposed to 2 µm PS beads. The hyperspectral SRS imaging in this work shows that MP/NP exposure perturbs the development and lipid metabolism in zebrafish larvae, furthering the understanding of MP/NP ingestions and consequent toxicity in different organs in living species.

Assessment of regional and total skeletal metabolism using 18F-NaF PET/CT in patients with chronic kidney disease.

OBJECTIVE: The study aims to assess regional and total bone metabolic activity in patients with chronic kidney disease using Na[18F]F PET and correlation between semi-quantitative indices and blood parameters. METHODS: Seventy-two subjects (mean age 61.8 ± 13.8 years) were included. Of these 24/72 patients had end-stage renal disease (ESRD) (GFR < 15 mL/min/1.73 m2), 38/72 had chronic kidney disease (CKD) (GFR between 60 and 15 mL/min/1.73 m2), and 10/72 were controls with normal renal function. All subjects underwent Na[18F]F PET-CT with a dose activity of 0.06 mCi/Kg. Regional and total skeletal metabolism were assessed with mean SUVs in a skeletal volume of interest (VOI), bone to soft tissue index (B/S), global SUV mean (GSUV mean) of the whole bone, and uptake in the femoral neck. RESULTS: Statistically significant differences were observed in a number of 18F-NaF metrics like femoral neck metabolism in CKD and ERSD groups in comparison to control in right (P = 0.003) and left femur (P = 0.006), bone to soft tissue index in the femur (P = 0.016) and GSUV5 (P = 0.006). There is also a significant difference in SUV mean in lumbar vertebrae (L1-L4) among CKD, ESRD, and controls. There was a moderate correlation between 18F-NaF PET scan uptake and blood parameters such as ALP and PTH. Na[18F]F uptake parameters were significantly different in low versus high bone turnover state. CONCLUSIONS: The assessment of total skeleton and regional metabolism and bone turnover in CKD patients is feasible with Na[18F]F PET. Na[18F]F can help to detect early changes in bone metabolism and assess the progression of bone disease in this complex condition. Quantification with Na[18F]F PET might provide better assessment of the bone turnover. The difference in Na[18F]F uptake in CKD compared to controls is likely related to a change in bone turnover which, however, requires further validation.

How Much Energy Do E'Athletes Use during Gameplay? Quantifying Energy Expenditure and Heart Rate Variability Within E'Athletes.

BACKGROUND: Research into esports suggests that e'athletes experience physiological stressors and demands during competition and training. The physiological demands of esports are poorly understood and need to be investigated further to inform future training guidelines, optimise performance outcomes, and manage e'athlete wellbeing. This research aimed to quantify the metabolic rate of esports gameplay and compare this outcome with heart rate variability within expert e'athletes. RESULTS: Thirteen healthy male participants ranked within the top 10% of their respective esports title participated in the study (age = 20.7 ± 2.69 years; BMI = 24.6 ± 5.89 kg·m- 2). Expired gas analysis indirect calorimetry measured gas exchange during rest and gaming. Compared to resting conditions, competitive esports gameplay significantly increased median energy expenditure (1.28 (IQR 1.16-1.49) kcal·min- 1 vs. 1.45 (IQR 1.20-1.77) kcal·min- 1, p = .02), oxygen consumption (0.27 (IQR 0.24-0.30) L·min- 1 vs. 0.29 (IQR 0.24-0.35) L·min- 1, p = .02) and carbon dioxide production (0.20 (IQR 0.19-0.27) L·min- 1vs. 0.27 (IQR 0.24-0.33) L·min- 1, p = .01). Competitive gameplay also resulted in a significant increase in heart rate (84.5 (IQR 74.1-96.1) bpm vs. 87.1 (IQR 80.3-104) bpm, p = .01) and decrease in R-R interval's (710 (IQR 624-810) ms vs. 689 (IQR 579-747) ms, p = .02) when compared to rest. However, there were no significant differences in time or frequency measures of heart rate variability. CONCLUSIONS: The data reveal increased physiological responses to metabolic rate, energy expenditure and cardiovascular function to esports game play within expert e'athletes. Further physiological research into the physical demands on e'athletes, the influence of different training programs to esport performance, and the added multivariate determinants to elite level esport performance are warranted.

Molecular Assessment of Proadipogenic Effects for Common-Use Contraceptives and Their Mixtures.

Hormonal contraceptives are widely prescribed due to their effectiveness and convenience and have become an integral part of family planning strategies worldwide. In the United States, approximately 65% of reproductive-aged women are estimated to be using contraceptive options, with approximately 33% using one or a combination of hormonal contraceptives. While these methods have undeniably contributed to improved reproductive health, recent studies have raised concerns regarding their potential effect on metabolic health. Despite widespread anecdotal reports, epidemiological research has been mixed as to whether hormonal contraceptives contribute to metabolic health effects. As such, the goals of this study were to assess the adipogenic activity of common hormonal contraceptive chemicals and their mixtures. Five different models of adipogenesis were used to provide a rigorous assessment of metabolism-disrupting effects. Interestingly, every individual contraceptive (both estrogens and progestins) and each mixture promoted significant adipogenesis (eg, triglyceride accumulation and/or preadipocyte proliferation). These effects appeared to be mediated in part through estrogen receptor signaling, particularly for the contraceptive mixtures, as cotreatment with fulvestrant acted to inhibit contraceptive-mediated proadipogenic effects on triglyceride accumulation. In conclusion, this research provides valuable insights into the complex interactions between hormonal contraceptives and adipocyte development. The results suggest that both progestins and estrogens within these contraceptives can influence adipogenesis, and the specific effects may vary based on the receptor disruption profiles. Further research is warranted to establish translation of these findings to in vivo models and to further assess causal mechanisms underlying these effects.