Blood Metabolite Levels Research Articles

Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases

Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Influence of Loading Density and Gender on the Welfare and Meat Quality of Horses During Transport for Slaughter

The aim of this study was to determine the effects of loading density and gender on blood welfare indicators, carcass bruises and horsemeat quality. Data were collected from twelve transports of 89 slaughter horses originating from the same collection centre. The transportation of slaughter horses at high loading densities (>200 kg/m2), especially stallions, resulted in increased levels of lactate (p = 0.021), glucose (p < 0.0001), ceruloplasmin (p < 0.0001) and AOPP (p < 0.0001), but lower GSH levels (p < 0.0001). Compared to stallions and mares, geldings subjected to high loading density (>200 kg/m2) during transport had lower levels of the aforementioned blood metabolites. In addition, stallions exposed to a high load density (>200 kg/m2) had the highest frequency of severe (p = 0.0002), large (p < 0.0001) and circular (p = 0.0001) carcass bruises, which were predominantly located on the abdominal (p = 0.0056) and thoracic (p = 0.0004) wall. In contrast, a higher percentage (p < 0.0001) of undamaged carcasses was found in slaughter horses exposed to a low loading density (≤200 kg/m2) during transport. Stallions exposed to high loading densities (>200 kg/m2) during transport had the highest initial pH (p < 0.0001) and ultimate pH (p = 0.005) in terms of m. longissimus lumborum and redness (p = 0.017), but the lowest drip loss (p = 0.050) and lightness (p < 0.0001), which, consequently, led to the highest (p = 0.0045) proportion of DFD-like defects in the meat quality. In conclusion, the results of this study showed that high loading densities (>200 kg/m2), regardless of gender, negatively affect horse welfare during transport. In addition, stallions were more sensitive to poor pre-slaughter conditions and produced the lowest meat quality, while geldings were the most resistant. To determine the optimal transport density, further research is needed to determine the effects of different loading densities on the behaviour, physiology, carcass and meat quality of slaughter horses.

Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions.

Chemical screens across hundreds of cell lines have shown that the drug sensitivities of human cancers can vary by genotype or lineage. However, most drug discovery studies have relied on culture media that poorly reflect metabolite levels in human blood. Here, we perform drug screens in traditional and Human Plasma-Like Medium (HPLM). Sets of compounds that show conditional anticancer activity span different phases of global development and include non-oncology drugs. Comparisons of the synthetic and serum-derived components that comprise typical media trace sets of conditional phenotypes to nucleotide synthesis substrates. We also characterize a unique dual mechanism for brivudine, a compound approved for antiviral use. Brivudine selectively impairs cell growth in low folate conditions by targeting two enzymes involved in one-carbon metabolism. Cataloged gene essentiality data further suggest that conditional phenotypes for other compounds are linked to off-target effects. Our findings establish general strategies for identifying drug-nutrient interactions and mechanisms of action by exploiting conditional lethality in cancer cells.

Application of a deep-learning marker for morbidity and mortality prediction derived from retinal photographs: a cohort development and validation study

Biological ageing markers are useful to risk stratify morbidity and mortality more precisely than chronological age. In this study, we aimed to develop a novel deep-learning-based biological ageing marker (referred to as RetiPhenoAge hereafter) using retinal images and PhenoAge, a composite biomarker of phenotypic age. We used retinal photographs from the UK Biobank dataset to train a deep-learning algorithm to predict the composite score of PhenoAge. We used a deep convolutional neural network architecture with multiple layers to develop our deep-learning-based biological ageing marker, as RetiPhenoAge, with the aim of identifying patterns and features in the retina associated with variations of blood biomarkers related to renal, immune, liver functions, inflammation, and energy metabolism, and chronological age. We determined the performance of this biological ageing marker for the prediction of morbidity (cardiovascular disease and cancer events) and mortality (all-cause, cardiovascular disease, and cancer) in three independent cohorts (UK Biobank, the Singapore Epidemiology of Eye Diseases [SEED], and the Age-Related Eye Disease Study [AREDS] from the USA). We also compared the performance of RetiPhenoAge with two other known ageing biomarkers (hand grip strength and adjusted leukocyte telomere length) and one lifestyle factor (physical activity) for risk stratification of mortality and morbidity. We explored the underlying biology of RetiPhenoAge by assessing its associations with different systemic characteristics (eg, diabetes or hypertension) and blood metabolite levels. We also did a genome-wide association study to identify genetic variants associated with RetiPhenoAge, followed by expression quantitative trait loci mapping, a gene-based analysis, and a gene-set analysis. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and corresponding 95% CIs for the associations between RetiPhenoAge and the different morbidity and mortality outcomes. Retinal photographs for 34 061UK Biobank participants were used to train the model, and data for 9429participants from the SEED cohort and for 3986participants from the AREDS cohort were included in the study. RetiPhenoAge was associated with all-cause mortality (HR 1·92 [95% CI 1·42-2·61]), cardiovascular disease mortality (1·97 [1·02-3·82]), cancer mortality (2·07 [1·29-3·33]), and cardiovascular disease events (1·70[1·17-2·47]), independent of PhenoAge and other possible confounders. Similar findings were found in the two independent cohorts (HR 1·67 [1·21-2·31] for cardiovascular disease mortality in SEED and 2·07 [1·10-3·92] in AREDS). RetiPhenoAge had stronger associations with mortality and morbidity than did hand grip strength, telomere length, and physical activity. We identified two genetic variants that were significantly associated with RetiPhenoAge (single nucleotide polymorphisms rs3791224 and rs8001273), and were linked to expression quantitative trait locis in various tissues, including the heart, kidneys, and the brain. Our new deep-learning-derived biological ageing marker is a robust predictor of mortality and morbidity outcomes and could be used as a novel non-invasive method to measure ageing. Singapore National Medical Research Council and Agency for Science, Technology and Research, Singapore.

Blood based metabolic markers of glioma from pre-diagnosis to surgery

Gliomas are highly complex and metabolically active brain tumors associated with poor prognosis. Recent reports have found altered levels of blood metabolites during early tumor development, suggesting that tumor development could be detected several years before clinical manifestation. In this study, we performed metabolite analyses of blood samples collected from healthy controls and future glioma patients, up to eight years before glioma diagnosis, and on the day of glioma surgery. We discovered that metabolites related to early glioma development were associated with an increased energy turnover, as highlighted by elevated levels of TCA-related metabolites such as fumarate, malate, lactate and pyruvate in pre-diagnostic cases. We also found that metabolites related to glioma progression at surgery were primarily high levels of amino acids and metabolites of amino acid catabolism, with elevated levels of 11 amino acids and two branched-chain alpha-ketoacids, ketoleucine and ketoisoleucine. High amino acid turnover in glioma tumor tissue is currently utilized for PET imaging, diagnosis and delineation of tumor margins. By examining blood-based metabolic progression patterns towards disease onset, we demonstrate that this high amino acid turnover is also detectable in a simple blood sample. These findings provide additional insight of metabolic alterations during glioma development and progression.

Preliminary research on tailored fluid therapy in pigs: comparing customized ionic solutions with Hartmann’s solution

BackgroundFluid therapy in veterinary medicine is pivotal for treating various conditions in pigs; however, standard solutions, such as Hartmann’s solution, may not optimally align with pig physiology. This study explored the development and efficacy of a customized fluid therapy tailored to the ionic concentrations of pig blood, aiming to enhance treatment outcomes and safety in both healthy and diseased pigs.ResultsThe study involved two experiments: the first to assess the safety and stability of customized fluids in healthy pigs, and the second to evaluate the efficacy in pigs with clinical symptoms of dehydration. In healthy pigs, the administration of customized fluids showed no adverse effects, with slight alterations observed in pO2, hematocrit, and glucose levels in some groups. In symptomatic pigs, the customized fluid group did not show any improvement in clinical symptoms, with no significant changes in blood chemistry or metabolite levels compared to controls. The customized fluid group showed a mild increase in some values after administration, yet within normal physiological ranges. The study reported no significant improvements in clinical or dehydration status, attributing the observed variations in blood test results to the limited sample size and anaesthesia effects rather than fluid characteristics.ConclusionsCustomized fluid therapy, tailored to mimic the ionic concentrations of pig blood, appears to be a safe and potentially more effective alternative to conventional solutions such as Hartmann’s solution for treating pigs under various health conditions. Further research with larger sample sizes and controlled conditions is recommended to validate these findings and to explore the full potential of customized fluid therapy in veterinary practice.

ENDOTHELIAL DYSFUNCTION AND GASTROESOPHAGEAL REFLUX DISEASE: STUDY OF COMMON PATHOGENETIC MECHANISMS AND WAYS OF CORRECTION

The aim. To determine the role and place of endothelial dysfunction in the pathogenesis of comorbid gastroesophageal reflux disease (GERD) and obesity by studying the levels of nitric oxide (NO) metabolites in blood and urine. To evaluate the efficacy and benefits of the prescribed therapy, which included the additional inclusion of a peptide compound analogous to leu-enkephalin tyrosine-2-alanine-glycine-phenylalanine-leucyl-arginine diacetate (Dalargin).
 Materials and methods. Clinical manifestations were assessed using the GERD-HRQL questionnaire, levels of stable nitric oxide metabolites NO2 and total metabolites NO2 + NO3 were determined by spectrophotometric method, leptin levels were determined by enzyme-linked immunosorbent assay, pH-metry and motor function was studied by ultrasound. 130 patients were examined, including 70 patients with GERD with comorbid obesity of the first degree, 40 patients with GERD without concomitant pathology and 20 healthy individuals. The study was divided into 3 groups.
 Results. It was determined that the levels of stable metabolites NO2, NO2 + NO3 in blood and urine in the group of GERD with obesity are significantly lower than in the group of isolated GERD (p<0.001). A direct correlation between the level of nitric oxide metabolites in blood and urine and acidity in the stomach and oesophagus was established; an inverse relationship between NO metabolites and the degree of gastrointestinal motor and functional disorders, the severity of clinical manifestations, and the level of hormonal secretion by adipocytes. The supplemental inclusion of Dalargin improved the effectiveness and quality of pathogenetic therapy and achieved a more positive disease dynamics and is recommended for prescription in practice.
 Conclusions. Obesity is a predictor of a more severe course of GERD and more severe endothelial dysfunction. There is a correlation between the severity of endothelial dysfunction and the degree of functional, motor and secretory disorders of the stomach and oesophagus.

Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease.

Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

Interaction of blood calcium with milk yield, energy metabolites, subclinical mastitis, and reproductive performance in crossbred dairy cows.

Limited literature is available on the consequences of postpartum low blood calcium (Ca) concentration in crossbred cows. The research aimed to investigate the correlation between postpartum serum Ca levels and various parameters, including milk yield, serum energy metabolites, milk somatic cell count, and reproductive factors in crossbred cows. Following parturition, a total of 45 potential high-yielding F2 (HF × Sahiwal; Genotype: 75:25) dairy cows were enrolled . These cows were categorized based on plasma calcium concentrations into three groups: a low calcium group (Ca-L) with a calcium concentration of <5 mg/dL, a medium calcium group (Ca-M) with a calcium concentration ranging from 5 to 8.5 mg/dL, and a high calcium group (Ca-H) with a calcium concentration exceeding 8.5 mg/dL. The study parameters were measured over an 8-week period. The results indicated that overall milk yield and blood glucose were significantly higher in the Ca-H group compared to Ca-M and Ca-L (p < .01). Blood cholesterol was significantly higher in Ca-M (p < .01), while blood triglyceride was significantly lower in both Ca-M and Ca-H. Overall, blood cortisol did not show a significant change between these groups (p < .01); however, progesterone levels were higher (p < .01) in Ca-M and Ca-H cows. Furthermore, somatic cell count (SCC) significantly (p < .01) decreased in cows with Ca-H compared to Ca-L. Additionally, postpartum oestrous interval and interestrus interval decreased significantly (p < .01) in Ca-M and Ca-H compared to Ca-L. These findings suggest that cows with blood calcium levels exceeding 8.5 mg/dL exhibited significantly higher milk yield, blood metabolite levels, a lower likelihood of subclinical mastitis, and earlier reproductive activity after calving.

Mitigation of extreme winter stress in European seabass, Dicentrarchus labrax through dietary supplementation

Climate change is driving the dangerous confluence of extreme weather events. Among others, aquatic ecosystems are the most affected one. This study sheds light on how dietary supplements affect the physiological responses of European seabass during extreme winter exposure. Fish were provided with three dietary supplements: vitamins C and E (diet-1), propolis (diet-2), and phycocyanin (diet-3) for 45 days. They were then exposed to a simulated extreme winter cold (7 °C) for 20 days. The results showed that dietary supplements do not have a significant impact on weight, growth rate, and protein efficiency ratio before cold exposure. Levels of Na + and Cl − in the fish remained stable across all diets during both control (20 °C) and 7 °C exposure. However, on the 20th day of cold exposure, fish fed diet-3 exhibited notably higher levels of K+ compared to the other two diets, whereas blood glucose was significantly lower in fish fed diet-1. On day 20, significantly higher GPT activities were observed in fish fed diet-1. No significant effects of dietary supplementation were observed in fish serum cholesterol and protein levels. Before cold stress, fish fed the control diet exhibited significantly lower triglyceride levels (p < 0.05). However, during cold exposure, triglyceride levels increased in fish fed diet-1 and the control diet. On day 20, fish fed diet-3 exhibited a comparatively higher lactate content. Conversely, cortisol levels were significantly lower (p < 0.05) in fish fed diets 2 and 3 on the same day. No dietary effects were observed on fish muscle HSP70 gene expression. On days 10 and 20, SREBP1 was significantly upregulated in fish fed all diets. On day 20 of cold exposure, FADS2 and GLUT2 genes were downregulated in the fish fed control diet compared to those fed diets 2 and 3. Before cold stress, fish on the control diet showed higher TNF-1α expression in the spleen. SREBP1 showed a significant upregulation on day 10 in fish fed diet-2. FADS2 gene expression remained unchanged during cold stress. GLUT2 expression showed no noticeable effects throughout the study. Overall, during extreme cold exposure, we observed decreased levels of blood cortisol, transaminase, dehydrogenase, and metabolites, along with a comparatively higher upregulation of growth, metabolic, and immune genes in fish fed diets supplemented with propolis, phycocyanin, and vitamins C&E. These results suggest that dietary supplements can help European seabass cope better with extreme cold, at least for short periods of up to 20 days.

Mechanistic insights into inositol-mediated rumen function promotion and metabolic alteration using in vitro and in vivo models.

Inositol is a bioactive factor that is widely found in nature; however, there are few studies on its use in ruminant nutrition. This study investigated the effects of different inositol doses and fermentation times on rumen fermentation and microbial diversity, as well as the levels of rumen and blood metabolites in sheep. Rumen fermentation parameters, microbial diversity, and metabolites after different inositol doses were determined in vitro. According to the in vitro results, six small-tailed Han sheep fitted with permanent rumen fistulas were used in a 3 × 3 Latin square feeding experiment where inositol was injected into the rumen twice a day and rumen fluid and blood samples were collected. The in vitro results showed that inositol could increase in vitro dry matter digestibility, in vitro crude protein digestibility, NH3-N, acetic acid, propionic acid, and rumen microbial diversity and affect rumen metabolic pathways (p < 0.05). The feeding experiment results showed that inositol increased the blood concentration of high-density lipoprotein and IgG, IgM, and IL-4 levels. The rumen microbial composition was significantly affected (p < 0.05). Differential metabolites in the rumen were mainly involved in ABC transporters, biotin metabolism, and phenylalanine metabolism, whereas those in the blood were mainly involved in arginine biosynthesis and glutathione and tyrosine metabolism. In conclusion, inositol improves rumen function, affects rumen microorganisms and rumen and blood metabolites and may reduce inflammation, improving animal health.

Modeling blood metabolite homeostatic levels reduces sample heterogeneity across cohorts

Blood metabolite levels are affected by numerous factors, including preanalytical factors such as collection methods and geographical sites. These perturbations have caused deleterious consequences for many metabolomics studies and represent a major challenge in the metabolomics field. It is important to understand these factors and develop models to reduce their perturbations. However, to date, the lack of suitable mathematical models for blood metabolite levels under homeostasis has hindered progress. In this study, we develop quantitative models of blood metabolite levels in healthy adults based on multisite sample cohorts that mimic the current challenge. Five cohorts of samples obtained across four geographically distinct sites were investigated, focusing on approximately 50 metabolites that were quantified using 1H NMR spectroscopy. More than one-third of the variation in these metabolite profiles is due to cross-cohort variation. A dramatic reduction in the variation of metabolite levels (90%), especially their site-to-site variation (95%), was achieved by modeling each metabolite using demographic and clinical factors and especially other metabolites, as observed in the top principal components. The results also reveal that several metabolites contribute disproportionately to such variation, which could be explained by their association with biological pathways including biosynthesis and degradation. The study demonstrates an intriguing network effect of metabolites that can be utilized to better define homeostatic metabolite levels, which may have implications for improved health monitoring. As an example of the potential utility of the approach, we show that modeling gender-related metabolic differences retains the interesting variance while reducing unwanted (site-related) variance.

Exploring the causal role of multiple metabolites on ovarian cancer: a two sample Mendelian randomization study

BackgroundThe mechanisms and risk factors underlying ovarian cancer (OC) remain under investigation, making the identification of new prognostic biomarkers and improved predictive factors critically important. Recently, circulating metabolites have shown potential in predicting survival outcomes and may be associated with the pathogenesis of OC. However, research into their genetic determinants is limited, and there are some inadequacies in understanding the distinct subtypes of OC. In this context, we conducted a Mendelian randomization study aiming to provide evidence for the relationship between genetically determined metabolites (GDMs) and the risk of OC and its subtypes.MethodsIn this study, we consolidated genetic statistical data of GDMs with OC and its subtypes through a genome-wide association study (GWAS) and conducted a two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method served as the primary approach, with MR-Egger and weighted median methods employed for cross-validation to determine whether a causal relationship exists between the metabolites and OC risk. Moreover, a range of sensitivity analyses were conducted to validate the robustness of the results. MR-Egger intercept, and Cochran’s Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. False discovery rate (FDR) correction was applied to validate the findings. We also conducted a reverse MR analysis to validate whether the observed blood metabolite levels were influenced by OC risk. Additionally, metabolic pathway analysis was carried out using the MetaboAnalyst 5.0 software.ResultsIn MR analysis, we discovered 18 suggestive causal associations involving 14 known metabolites, 8 metabolites as potential risk factors, and 6 as potential cancer risk reducers. In addition, three significant pathways, "caffeine metabolism," "arginine biosynthesis," and "citrate cycle (TCA cycle)" were associated with the development of mucinous ovarian cancer (MOC). The pathways "caffeine metabolism" and "alpha-linolenic acid metabolism" were associated with the onset of endometrioid ovarian cancer (OCED).ConclusionsOur MR analysis revealed both protective and risk-associated metabolites, providing insights into the potential causal relationships between GDMs and the metabolic pathways related to OC and its subtypes. The metabolites that drive OC could be potential candidates for biomarkers.

Sodium fluoride preserves blood metabolite integrity for biomarker discovery in large-scale, multi-site metabolomics investigations.

Background: Metabolite profiling of blood by nuclear magnetic resonance (NMR) is invaluable to clinical biomarker discovery. To ensure robustness, biomarkers require validation in large cohorts and across multiple centres. However, collection procedures are known to impact on the stability of biofluids that may, in turn, degrade biomarker signals. We trialled three blood collection tubes with the aim of solving technical challenges due to preanalytical variation in blood metabolite levels that are common in cohort studies. Methods: We first investigated global NMR-based metabolite variability between biobanks, including the large-scale UK Biobank and TwinsUK biobank of the general UK population, and more targeted biobanks derived from multicentre clinical trials relating to inflammatory bowel disease. We then compared the blood metabolome of 12 healthy adult volunteers when collected into either sodium fluoride/potassium oxalate, lithium heparin, or serum blood tubes using different pre-processing parameters. Results: Preanalytical variation in the method of blood collection strongly influences metabolite composition within and between biobanks. This variability can largely be attributed to glucose and lactate. In the healthy control cohort, the fluoride oxalate collection tube prevented fluctuation in glucose and lactate levels for 24 hours at either 4 °C or room temperature (20 °C). Conclusions: Blood collection into a fluoride oxalate collection tube appears to preserve the blood metabolome with delayed processing up to 24 hours at 4 °C. This method may be considered as an alternative when rapid processing is not feasible.

Altered markers of mitochondrial function in adults with autism spectrum disorder.

Previous research suggests potential mitochondrial dysfunction and changes in fatty acid metabolism in a subgroup of individuals with autism spectrum disorder (ASD), indicated by higher lactate, pyruvate levels, and mitochondrial disorder prevalence. This study aimed to further investigate potential mitochondrial dysfunction in ASD by assessing blood metabolite levels linked to mitochondrial metabolism. Blood levels of creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, pyruvate, free and total carnitine, as well as acylcarnitines were obtained in 73 adults with ASD (47 males, 26 females) and compared with those of 71 neurotypical controls (NTC) (44 males, 27 females). Correlations between blood parameters and psychometric ASD symptom scores were also explored. Lower CK (pcorr = 0.045) levels were found exclusively in males with ASD compared to NTC, with no such variation in females. ALT and AST levels did not differ significantly between both groups. After correction for antipsychotic and antidepressant medication, CK remained significant. ASD participants had lower serum lactate levels (pcorr = 0.036) compared to NTC, but pyruvate and carnitine concentrations showed no significant difference. ASD subjects had significantly increased levels of certain acylcarnitines, with a decrease in tetradecadienoyl-carnitine (C14:2), and certain acylcarnitines correlated significantly with autistic symptom scores. We found reduced serum lactate levels in ASD, in contrast to previous studies suggesting elevated lactate or pyruvate. This difference may reflect the focus of our study on high-functioning adults with ASD, who are likely to have fewer secondary genetic conditions associated with mitochondrial dysfunction. Our findings of significantly altered acylcarnitine levels in ASD support the hypothesis of altered fatty acid metabolism in a subset of ASD patients.

Circulating biomarkers of mortality prediction in patients undergoing liver transplantation due to hepatocellular carcinoma

There are different macromorphological factors obtained prior to liver transplantation (LT) to predict the prognosis of hepatocellular carcinoma (HCC) patients undergoing LT. The use of blood biomarkers could help improve the prognosis prediction of these patients. Blood levels of alpha-fetoprotein (AFP) are the first and most studied prognostic blood biomarkers of HCC patients undergoing LT. This review is to summarize the evidence of prognostic blood biomarkers for HCC patients undergoing LT. A higher mortality rate has been found with high blood levels of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), C-reactive protein (CRP), albumin-bilirubin (ALBI) score, des-gamma-carboxy prothrombin (DCP), lactate dehydrogenase (LDH), gamma glutamyl transpeptidase (GGT), fibrinogen, vascular endothelial growth factor (VEGF), homocysteine, Golgi protein 73 (GP73), substance P, soluble CD40 ligand (sCD40L), caspase-cleaved cytokeratin (CCCK)-18, caspase-3, malondialdehyde and oxidized guanine species (OGS). A higher mortality rate has been found with low blood levels of lymphocyte-to-monocyte ratio (LMR), PD-L1, Galectin-9, total antioxidant capacity (TAC) and melatonin. Moreover, some studies with small sample sizes associate blood levels of metabolites and microRNAs (MIRs) with the prognosis of HCC patients undergoing LT. More research is warranted to determine the possible utility of these biomarkers to predict the prognosis of HCC.

Comparative transcriptome and metabolome analyses of wild and mutant Oujiang color common carp through editing SCARB1 gene by CRISPR/Cas technology

SCARB1 is an important gene for carotenoid functioning and maintaining body color. In this study, we examined wild red (SCARB1+/+), mutant red (SCARB1−/+), and mutant white (SCARB1−/−) fish to investigate changes in gene expression and metabolic processes using skin transcriptomics and blood metabolomics in Oujiang color common carp, Cyprinus carpio var. color. According to our findings, 85 and 30 genes for lipid transport and metabolism and 12 and 4 genes for retinol metabolism were significantly differentially expressed (DE) respectively between the comparison of pairs SCARB1−/− vs SCARB1+/+ and SCARB1−/− vs SCARB1−/+. Besides, 6 metabolites for lipid transport and metabolism and 1 metabolite for retinol metabolism were significantly DE in SCARB1−/− vs SCARB1+/+ pair comparison. Analysis of data from multiple omics systems revealed significant changes in metabolic pathways, including statin, lipid, and carotenoid pathways. Notably, downregulation in gene expression and blood metabolite levels was observed in the glycerophospholipid and retinol metabolic pathways in SCARB1−/− fish as a result of the SCARB1 gene knock out. Down-regulated genes such as dgkA, CYP27C1, and the l-serine, and 4-Oxoretinol metabolites of the glycerophospholipid and retinol metabolic pathway are likely to regulate the pigmentation mechanism and carotenoid production in the skin cells of SCARB1−/− fish. Our investigation into the effects of SCARB1 gene knock out has yielded valuable insights into carotenoid functioning and integrated networks. This information contributes to further research on the molecular mechanisms underlying carotenoid functioning and its correlation with genes related to the SCARB1 gene.

A grape seed and bilberry extract reduces blood pressure in individuals at risk of developing type 2 diabetes: the PRECISE study, a double-blind placebo-controlled cross-over intervention study.

Type 2 Diabetes Mellitus (T2DM) is a major risk factor for the development of cardiometabolic diseases. T2DM prevention is largely based on weight-loss and whole diet changes, but intervention with dietary plant bioactives may also improve metabolic health. To assess whether supplementation with bilberry and grape seed extract for 12 weeks improves cardiometabolic outcomes in individuals at risk of developing T2DM, and to determine whether individual treatment response is associated with differences in gut microbiota composition and levels of phenolic metabolites in blood and feces. In the randomized, double-blind, placebo-controlled, cross-over PRECISE intervention study, 14 participants, aged ≥45 years, with a BMI >28 kg/m2, and having an increased risk of T2DM, received a supplement containing 250 mg of bilberry plus 300 mg of grape seed extract, or 550 mg of a control extract, per day, for 12 weeks each. Blood samples were obtained for the assessment of HbA1c, fasting glucose, oral glucose tolerance tests, insulin, glucagon levels, total, LDL and HDL cholesterol, and phenolic acids. We also assessed advanced glycation end products in the skin, ambulatory 24 hours blood pressure, 7-day dietary intake by weighed food diaries, fecal levels of phenolic metabolites using LC-MS/MS and gut microbiota composition using 16S rRNA gene sequencing analysis. The combined bilberry and grape seed extract did not affect glucose and cholesterol outcomes, but it decreased systolic and diastolic ambulatory blood pressure by 4.7 (p < 0.001) and 2.3 (p = 0.0009) mmHg, respectively. Eight out of fourteen participants were identified as blood pressure 'responders'. These responders had higher levels of phenylpropionic and phenyllactic acids in their fecal samples, and a higher proportional abundance of Fusicatenibacter-related bacteria (p < 0.01) in their baseline stool samples. Long-term supplementation with bilberry and grape seed extract can improve systolic and diastolic blood pressure in individuals at risk of T2DM. Individual responsiveness was correlated with the presence of certain fecal bacterial strains, and an ability to metabolize (epi)catechin into smaller phenolic metabolites.Clinical trial registry number: Research Registry (number 4084).

Evolution of circulating metabolites through lifespan according to gender and APOE

AbstractBackgroundThere is increasing interest in blood‐based metabolic biomarkers for Alzheimer’s disease (AD). Studies show consistently that at branched chain amino acids (BCAAs) and a large scale of lipids are changed in patients with AD. Little is known of how these metabolites associate to age, genes and apolipoprotein E (APOE). This study aims to study these metabolites over the lifespan and determine the influence of age, sex and APOE.MethodWe conducted this study in UK Biobank, a large prospective cohort of 459,227 subjects with extensive genotypic and phenotypic data. Using the Nightingale nuclear magnetic resonance technology, 249 metabolites (165 directly measured metabolites and 84 derived measures) have been determined in the blood of 118,071 participants. We used mixed‐effect models to study the effect of age, sex and APOE on metabolite levels and adjust for lifestyle factors and medication.ResultsAPOE*4 is the major determinant of total of 216 metabolic of the Nightingale platform using a FDR &lt; 0.05. We find that 41 were also associated to dementia in the population 60+ years old. Also, APOE*2 is associated with 226 metabolites (FDR&lt;0.05) including 41 dementia associated metabolites. Concerning gender differences, significant differences were found for the metabolites at the FDR 0.05. Overall, we find a significant interaction between age^2 and APOE*4 for valine and BCAA. When stratifying for gender, for most of the metabolites concentrations in blood remain stable over age in men. For amino acids, we observed a decreased concentration level with age in me. For females, we find that the metabolite levels increase over age, reaching a plateau around 55 years old.ConclusionThis study shows that AD associated metabolite levels in blood are determined by sex and APOE. In women, the levels of metabolites in women are also associated to age up until menopause.

12-week combined strength and endurance exercise attenuates CD8+ T-cell differentiation and affects the kynurenine pathway in the elderly: a randomized controlled trial

BackgroundAge-related accumulation of highly differentiated CD8+ effector memory re-expressing CD45RA (EMRA) T-cells and disruption of the kynurenine (KYN) pathway are associated with chronic inflammation and the development of insulin resistance.In this study the aim was to investigate the effects of 12-week combined strength and endurance exercise on CD8+ T-cell differentiation and KYN pathway metabolites. Ninety-six elderly subjects (f/m, aged 50—70) were randomized to a control (CON) or exercise (EX) group. The EX group completed combined strength and endurance training twice weekly for one hour each time at an intensity of 60% of the one-repetition maximum for strength exercises and a perceived exertion of 15/20 for endurance exercises. The EX group was also randomly subdivided into two groups with or without a concomitant balanced diet intervention in order to examine additional effects besides exercise alone. Before and after the intervention phase, the proportions of CD8+ T-cell subsets and levels of KYN pathway metabolites in peripheral blood were determined.ResultsThe CD8+ EMRA T-cell subsets increased in the CON group but remained almost unchanged in the EX group (p = .02). Plasma levels of kynurenic acid (KA) increased in the EX group and decreased in the CON group (p = .03). Concomitant nutritional intervention resulted in lower levels of quinolinic acid (QA) compared with exercise alone (p = .03). Overall, there was a slight increase in the QA/KA ratio in the CON group, whereas it decreased in the EX group (p > .05).ConclusionsCombined strength and endurance training seems to be a suitable approach to attenuate CD8+ T-cell differentiation in the elderly and to redirect the KYN pathway towards KA. The clinical relevance of these effects needs further investigation.