Metabolites最新文献

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) "phenoconversion" factors, like drug-drug interactions and comorbidities. To address these limitations, a more phenotypic approach would be desirable, for which pharmacometabolomics (PMx) could be useful by studying and elucidating drug metabolism in patient samples, such as blood and urine. Methods: This study explored the potential of PMx to analyze real-world drug metabolite profiles of the extensively studied drug cyclosporine (CsA) using 24-h urine samples from 732 kidney and 350 liver transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT identifier NCT03272841). Detected metabolites were matched with existing information on CsA metabolism gathered through a comprehensive literature review, aiming to confirm previously reported metabolites and identify potentially unreported ones. Results: Our analyses confirmed the urinary presence of CsA and six known metabolites. Additionally, we detected three known metabolites not previously reported in urine and identified one unreported metabolite, potentially suggesting the involvement of glutathione conjugation. Lastly, the observed metabolic patterns showed no notable differences between kidney and liver transplant recipients. Conclusions: Our findings demonstrate the potential of PMx to enhance the understanding of drug metabolism, even for well-studied compounds such as CsA. Moreover, this study highlights the value of PMx in real-world drug metabolism research and its potential to complement PGx in advancing personalized medicine.

This study aimed to evaluate the efficacy of a novel "In & Out" strategy, combining topical and oral melatonin supplementation, in managing skin aging compared to topical treatment alone. A randomized, prospective study was conducted on 39 healthy females aged 55-69 years. Participants were divided into two groups: one received both the topical formula and oral melatonin supplementation (Group A), while the other received a topical melatonin-based formula (Group B). Clinical evaluations included lipidomic analysis, skin moisturization, and wrinkle depth analysis at baseline and after 84 days. The addition of oral melatonin supplementation to the topical regimen led to improvements in the skin's lipid profile and moisturization levels. These findings suggest that combining topical and oral melatonin may provide a more comprehensive approach to managing skin aging by addressing both local and systemic factors. Background/Objectives: With age, the endogenous antioxidant capacity of the skin decreases, including melatonin (Mel) synthesis. Skin aging is also associated with alterations in epidermal lipids, particularly a reduction in triglycerides and ceramides, which are essential for maintaining skin structure and hydration. The administration of exogenous melatonin could, therefore, be an effective anti-aging strategy. While some data suggest that melatonin may positively influence the lipid profile, specific data on its effects on skin aging are lacking. This study aimed to evaluate the anti-aging effects of an "In & Out" regimen consisting of a Mel-based cream and dietary supplement in comparison with topical treatment alone, focusing on clinical and lipidomic changes involved in skin homeostasis. Results: A statistically significant variation was observed in both groups compared to baseline (T0) in terms of moisturization (+23.6% in Group A, +18.3% in Group B) and wrinkle depth (-18.5% in Group A, -9.4% in Group B, p < 0.05). Both groups showed improvements in the lipid content of the skin, which typically decreases with age. The "In & Out" strategy resulted in a statistically significant increase in triacylglycerols and ceramides, key lipids that exhibit water-holding properties. Conclusions: The "In & Out" melatonin-based regimen demonstrated greater efficacy in clinical improvement and positive lipid profile modifications compared to topical treatment alone, highlighting its potential as a comprehensive anti-aging strategy.

Periodontitis, a chronic multifactorial inflammatory condition of the periodontium, is originated by a dysbiotic oral microbiota and is negatively correlated with several systemic diseases. The low-chronic burden of gingival inflammation not only exacerbates periodontitis but also predisposes individuals to a spectrum of age-related conditions, including cardiovascular diseases, neurodegenerative disorders, and metabolic dysfunction, especially related to ageing. In this regard, over the local periodontal treatment, lifestyle modifications and adjunctive therapies may offer synergistic benefits in ameliorating both oral and systemic health in ageing populations. Elucidating the intricate connections between periodontitis and senescence is important for understanding oral health's systemic implications for ageing and age-related diseases. Effective management strategies targeting the oral microbiota and senescent pathways may offer novel avenues for promoting healthy ageing and preventing age-related morbidities. This review will analyze the current literature about the intricate interplay between periodontitis, oral dysbiosis, and the processes of senescence, shedding light on their collective impact on the modulation and accelerated ageing and age-related diseases. Lastly, therapeutic strategies targeting periodontitis and oral dysbiosis to mitigate senescence and its associated morbidities will be discussed.

Background: There is a high rate of depressive symptoms such as irritability, anhedonia, fatigue, and hypersomnia in patients with type 2 diabetes mellitus (T2DM). However, the causes and underlying mechanisms of the comorbidity of depression and diabetes remain unknown.

Methods: For the first time, we identified Decidual protein induced by progesterone 1 (Depp1), also known as DEPP autophagy regulator 1, as a hub gene in both depression and T2DM models. Depp1 levels were increased in the mPFC but not in other brain regions, such as the hippocampus or nucleus accumbens, according to Western blot and PCR assays.

Results: Glucose dysregulation and synaptic loss occur in both depression and T2DM. The typical hyperglycemia in T2DM was observed in two models of depression, namely, chronic social defeat stress (CSDS) and chronic restraint stress (CRS). Hyperglycemia, which occurred in T2DM, was observed, and metabolomics data clearly showed the perturbation of glucose levels and glucose metabolism in the medial prefrontal cortex (mPFC). Decreased protein levels of BDNF and PSD95 suggested significant synaptic loss in depressed and diabetic mice.

Conclusion: These findings suggest that the comorbidity of depression and diabetes is involved in the dysfunction of Depp1 in the mPFC.

Background/Objectives: This study investigated the effects of maternal metabolic syndrome during pregnancy on hepatic fatty acid metabolism and betacellulin expression in rat offspring. A rat model of maternal metabolic syndrome was created with a high-fructose diet (15% fructose in drinking water for six months). Methods: The females with metabolic syndrome were divided into the CON group, the HF group, which received fructose in drinking water, and the HF-DHA group, which received fructose in water and increased amounts of DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) in the diet (2.5% fish oil in the diet). The male and female offspring were killed at birth and their liver tissue was analyzed for the fatty acid profile and expression of Δ-9-desaturase and betacellulin. Results: When the rat offspring were exposed in utero to maternal fatty acids altered by the high-fructose diet, this resulted in a similarly altered fatty acid profile in the liver, with the most significant changes being Δ-9 desaturation and a dramatic increase in monounsaturated fatty acids. The offspring also showed an overexpression of hepatic betacellulin. Supplementation with DHA and EPA increased the DHA content and normalized the fatty acid composition of oleic acid, saturated fatty acids, linoleic acid and n3-docosapentaenoic acid in the offspring of mothers on a high-fructose diet. In addition, the DHA/EPA supplementation of fructose-fed mothers normalized hepatic Δ-9-desaturase and betacellulin overexpression in the offspring, suggesting that DHA/EPA supplementation affects not only the fatty acid content but also the liver function. Conclusions: The changes observed in this study suggest that DHA/EPA supplementation may modulate the effects of maternal programming on disorders of the lipid metabolism in the offspring.

Background: Due to scientific advancements in high-throughput data production technologies, omics studies, such as genomics and metabolomics, often give rise to numerous measurements per sample/subject containing several noisy variables that potentially cloud the true signals relevant to the desired study outcome(s). Therefore, correcting for multiple testing is critical while performing any statistical test of significance to minimize the chances of false or missed discoveries. Such correction practice is commonplace in genome-wide association studies (GWAS) but is also becoming increasingly relevant to metabolome-wide association studies (MWAS). However, many existing procedures may be too conservative or too lenient, only assume a linear association between the features, or have not been evaluated on metabolomics data.

Methods: One such multiple testing correction strategy is to estimate the number of statistically independent tests, called the effective number of tests, based on the eigen-analysis of the correlation matrix between the features. This effective number is then used for a subsequent single-step adjustment to obtain the pointwise significance level. We propose a modification to the p-value adjustment based on a more general measure of association between two predictors, the distance correlation, with a specific focus on MWAS.

Results: We assessed common GWAS p-value adjustment procedures and one tailored for MWAS, which rely on eigen-analysis of the Pearson's correlation matrix. Our study, including varying sample size-to-feature ratios, response types, and metabolite groupings, highlights the superior performance of the distance correlation.

Conclusion: We propose the distance-correlation-based p-value adjustment (DisCo P-ad) as a novel modification that can enhance existing eigen-analysis-based multiple testing correction procedures by increasing power or reducing false positives. While our focus is on metabolomics, DisCo P-ad can also readily be applied to other high-dimensional omics studies.

Background: Quantifying urinary catecholamines and metanephrines is essential for the clinical screening and diagnosis of neuroendocrine tumours. HPLC with electrochemical detection (HPLC-ECD) is commonly used for this type of analysis but requires extensive sample cleanup. Simple and rapid dilute-and-shoot LC-multiple-reaction monitoring (MRM)-MS assays have been developed for quantitating these analytes in urine but have not yet been validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Methods: A simple dilute-and-shoot sample preparation without derivatization was used. C18 RP-UPLC-MRM-MS and positive-ion ESI were used, usually with two transitions per analyte being monitored. Certified deuterated internal standards were used for each analyte. Results: This assay was validated according to the CLSI C62-A guidelines, including accuracy/trueness, imprecision, sensitivity, specificity, carryover, stability, and linearity. The final MRM-MS method was compared to the established HPLC-ECD clinical chemistry reference method. The run time was reduced from 25 min to 5 min. Conclusions: A simple, robust, rapid, and cost-effective LC-MRM-MS assay for measuring urinary catecholamines and metanephrines was developed and validated according to the CLSI guidelines. This validated method requires minimal sample manipulation before analysis and provides sensitivity, specificity, and improved precision. The implementation of this assay in clinical laboratories will facilitate early and accurate diagnosis.

Background: Polyunsaturated fatty acids in particular omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients and components of the plasma membrane. They are involved in various processes, including synaptic development, functionality, integrity, and plasticity, and are therefore thought to have general neuroprotective properties. Considerable research evidence further supports the beneficial effects of omega-3 fatty acids, specifically on mitochondria, through their antioxidant and anti-apoptotic properties, making them an attractive addition in treatment options for neurodegenerative disorders in which mitochondrial alterations are commonly observed. However, precise information on the underlying protective mechanisms is still lacking. Methods: We utilized the most common neuronal cell line (SH-SY5Y) and induced mitochondrial oxidative stress through the addition of rotenone. To study the potential protective effect of DHA, the cells were additionally pre-treated with DHA prior to rotenone administration. By combining SILAC labeling, mitochondria enrichment, and subsequent proteomic analyses, we aimed to determine the capacity of DHA to alleviate mitochondrial oxidative stress in vitro and further shed light on the molecular mechanisms contributing to the proposed neuroprotective effect. Results: We confirmed a reduced cell viability and an increased abundance of reactive oxygen species upon rotenone treatment, DHA pre-treatment was shown to decrease said species. Additionally proteomic analysis revealed an increased expression of mitochondrial proteins in DHA pre-treated cells. Conclusions: With our study, we were able to define a potential compensatory mechanism by which the inhibition of complex I is overcome by an increased activity of the fatty acid beta oxidation in response to DHA.

Background/objectives: Early postmortem mitochondrial function and apoptotic activation affect meat quality development. Nicotinamide riboside (NR) supplementation to pigs prior to harvest can improve pork color stability, but its mechanism remains unclear. This study aimed to evaluate the impact of NR supplementation on early postmortem mitochondrial functionality and apoptosis.

Methods: Sixteen pigs (N = 16) were individually fed a control or NR-supplemented diet (30 mg·kg body weight^-1·d^-1) for 10 days prior to harvest. Longissimus dorsi muscle samples were collected at 45 min and 24 h postmortem and analyzed for mitochondrial functionality using high-resolution respirometry and apoptotic protein abundance (apoptosis regulator Bcl-2-associated X (BAX), apoptotic inducing factor (AIF), and caspase 3 (CASP3)) via immunoblotting.

Results: NR-supplemented muscle exhibited lower proton leak-associated respiration at 45 min postmortem (p < 0.05), followed by a slower accumulation of mitochondrial outer membrane permeabilization (MOMP; p < 0.05) and a slower loss of mitochondrial integral function (p < 0.05) from 45 min to 24 h postmortem. NR supplementation decreased BAX abundance at 45 min postmortem but increased mature AIF abundance (62 kDa) at 24 h postmortem (p < 0.05). The abundance of CASP3 fragments (~29 kDa) decreased from 45 min to 24 h postmortem, independent of treatment (p < 0.05).

Conclusions: NR supplementation demonstrated the potential to protect mitochondrial integral function and alleviate apoptotic activation in early postmortem porcine skeletal muscle, which might contribute to a higher meat color stability in NR-supplemented pork during retail display.

Background: Pregnancy induces significant physiological and metabolic changes in the mother to support fetal growth and prepare for childbirth. These adaptations impact various systems, including immune tolerance, metabolism, and endocrine function. While metabolomics has been utilized to study pregnancy-related metabolic changes, comprehensive comparisons between pregnant and non-pregnant states, particularly using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS), remain limited.

Methods: This study aimed to explore the dynamic, longitudinal metabolic shifts during pregnancy by profiling plasma samples from 65 pregnant women across three time points (6-14 weeks, 14-22 weeks, and >24 weeks) and 42 postpartum women. Lipidomics was prioritized, and a solvent mixture was employed to enhance lipid extraction, using UHPLC-QTOF-ESI⁺-MS.

Results: A total of 290 metabolites were identified and analyzed. Our results revealed significant metabolic differences between pregnant and postpartum women, with lipid molecules such as estrogen derivatives, fatty acids, and ceramides showing strong potential as biomarkers. Further biomarker analysis highlighted distinct metabolic signatures between early and late pregnancy stages, particularly in lipid metabolism (with AUC values > 0.8).

Conclusions: These findings contribute to a deeper understanding of pregnancy-related metabolic changes and may offer insights into maternal and neonatal health outcomes.